pre-supplementary motor area research




(Updated 2/23/05)

Nachev P, Rees G, Parton A, Kennard C, Husain M
Volition and conflict in human medial frontal cortex.
Curr Biol. 2005 Jan 26;15(2):122-8.
Controversy surrounds the role of human medial frontal cortex in controlling actions . Although damage to this area leads to severe difficulties in spontaneously initiating actions , the precise mechanisms underlying such "volitional" deficits remain to be established. Previous studies have implicated the medial frontal cortex in conflict monitoring and the control of voluntary action , suggesting that these key processes are functionally related or share neural substrates. Here, we combine a novel behavioral paradigm with functional imaging of the oculomotor system to reveal, for the first time, a functional subdivision of the pre-supplementary motor area (pre-SMA) into anatomically distinct areas that respond exclusively to either volition or conflict. We also demonstrate that activity in the supplementary eye field (SEF) distinguishes between success and failure in changing voluntary action plans during conflict, suggesting a role for the SEF in implementing the resolution of conflicting actions. We propose a functional architecture of human medial frontal cortex that incorporates the generation of action plans and the resolution of conflict. [Abstract]

Rushworth MF, Walton ME, Kennerley SW, Bannerman DM.
Action sets and decisions in the medial frontal cortex.
Trends Cogn Sci. 2004 Sep;8(9):410-417.
Activations in human dorsomedial frontal and cingulate cortices are often present in neuroimaging studies of decision making and action selection. Interpretations have emphasized executive control, movement sequencing, error detection and conflict monitoring. Recently, however, experimental approaches, using lesions, inactivation, and cell recording, have suggested that these are just components of the areas' functions. Here we review these results and integrate them with those from neuroimaging. A medial superior frontal gyrus (SFG) region centred on the pre-supplementary motor area (pre-SMA) is involved in the selection of action sets whereas the anterior cingulate cortex (ACC) has a fundamental role in relating actions to their consequences, both positive reinforcement outcomes and errors, and in guiding decisions about which actions are worth making. [Abstract]

Nakahara H, Doya K, Hikosaka O
Parallel cortico-basal ganglia mechanisms for acquisition and execution of visuomotor sequences - a computational approach.
J Cogn Neurosci. 2001 Jul 1;13(5):626-47.
Experimental studies have suggested that many brain areas, including the basal ganglia (BG), contribute to procedural learning. Focusing on the basal ganglia-thalamocortical (BG-TC) system, we propose a computational model to explain how different brain areas work together in procedural learning. The BG-TC system is composed of multiple separate loop circuits. According to our model, two separate BG-TC loops learn a visuomotor sequence concurrently but using different coordinates, one visual, and the other motor. The visual loop includes the dorsolateral prefrontal (DLPF) cortex and the anterior part of the BG, while the motor loop includes the supplementary motor area (SMA) and the posterior BG. The concurrent learning in these loops is based on reinforcement signals carried by dopaminergic (DA) neurons that project divergently to the anterior ("visual") and posterior ("motor") parts of the striatum. It is expected, however, that the visual loop learns a sequence faster than the motor loop due to their different coordinates. The difference in learning speed may lead to inconsistent outputs from the visual and motor loops, and this problem is solved by a mechanism called a "coordinator," which adjusts the contribution of the visual and motor loops to a final motor output. The coordinator is assumed to be in the presupplementary motor area (pre-SMA). We hypothesize that the visual and motor loops, with the help of the coordinator, achieve both the quick acquisition of novel sequences and the robust execution of well-learned sequences. A computational model based on the hypothesis is examined in a series of computer simulations, referring to the results of the 2 x 5 task experiments that have been used on both monkeys and humans. We found that the dual mechanism with the coordinator was superior to the single (visual or motor) mechanism. The model replicated the following essential features of the experimental results: (1) the time course of learning, (2) the effect of opposite hand use, (3) the effect of sequence reversal, and (4) the effects of localized brain inactivations. Our model may account for a common feature of procedural learning: A spatial sequence of discrete actions (subserved by the visual loop) is gradually replaced by a robust motor skill (subserved by the motor loop). [Abstract]

Akkal D, Bioulac B, Audin J, Burbaud P
Comparison of neuronal activity in the rostral supplementary and cingulate motor areas during a task with cognitive and motor demands.
Eur J Neurosci. 2002 Mar;15(5):887-904.
A number of cortical motor areas have been identified on the medial wall of the hemisphere in monkeys. However, their specific role in motor control remains unclear. In this study, we sought to describe and compare the functional properties of the presupplementary (pre-SMA) and rostral cingulate (CMAr) motor areas in two monkeys performing a visually instructed, delayed, sequential movement. We recorded 134 task-related neurons in the pre-SMA and 149 in the CMAr. The main difference between the two areas was the abundance of responses to targets (46%) in the pre-SMA, while CMAr activity was more related to reward (28%). Neuronal responses to targets were more phasic and higher in frequency in the pre-SMA than in the CMAr. During the delay, the percentage of neuronal responses was similar in the two areas. The discharge pattern was different depending upon whether the delay duration was fixed or variable but in most neurons was the same regardless of the sequence performed. Movement-related changes were common in the pre-SMA (75%) and in the CMAr (81%) but they occurred earlier in the former. Neurons activated exclusively during movement were more numerous in the CMAr. Finally, neuronal activity in the pre-SMA was more related to the sequential aspect of the task compared to the CMAr. Our results suggest that although the two areas share functional properties, they also participate in different aspects of motor behaviour. Their functional properties reflect their anatomical positions, which give them the potential to integrate external stimuli (pre-SMA) and internal states (CMAr) during motor planning. [Abstract]

Fassbender C, Murphy K, Foxe JJ, Wylie GR, Javitt DC, Robertson IH, Garavan H
A topography of executive functions and their interactions revealed by functional magnetic resonance imaging.
Brain Res Cogn Brain Res. 2004 Jul;20(2):132-43.
We used fMRI to study the brain processes involved in the executive control of behavior. The Sustained Attention to Response Task (SART), which allows unpredictable and predictable NOGO events to be contrasted, was imaged using a mixed (block and event-related) fMRI design to examine tonic and phasic processes involved in response inhibition, error detection, conflict monitoring and sustained attention. A network of regions, including right ventral prefrontal cortex (PFC), left dorsolateral PFC (DLPFC) and right inferior parietal cortex, was activated for successful unpredictable inhibitions, while rostral anterior cingulate was implicated in error processing and the pre-SMA in conflict monitoring. Furthermore, the pattern of correlations between left dorsolateral PFC, implicated in task-set maintenance, and the pre-SMA were indicative of a tight coupling between prefrontally mediated control and conflict levels monitored more posteriorly. The results reveal that the executive control of behavior can be separated into distinct functions performed by discrete cortical regions. [Abstract]

Garavan H, Ross TJ, Kaufman J, Stein EA
A midline dissociation between error-processing and response-conflict monitoring.
Neuroimage. 2003 Oct;20(2):1132-9.
Midline brain activation subsequent to errors has been proposed to reflect error detection and, alternatively, conflict-monitoring processes. Adjudicating between these alternatives is challenging as both predict high activation on error trials. In an effort to resolve these interpretations, subjects completed a GO/NOGO task in which errors of commission were frequent and response conflict was independently varied by manipulating response speeds. A mixed-block and event-related fMRI design identified task-related, tonic activation and event-related activations for correct and incorrect trials. The anterior cingulate was the only area with error-related activation that was not modulated by the conflict manipulation and hence is implicated in specific error-related processes. Conversely, activation in the pre-SMA was not specific to errors but was sensitive to the conflict manipulation. A significant region by conflict interaction for tonic activation supported a functional dissociation between these two midline areas. Finally, an intermediate, caudal cingulate area was implicated in both error processing and conflict monitoring. The results suggest that these two action-monitoring processes are distinct and dissociable and are localised along the midline. [Abstract]

Leuthold H, Jentzsch I
Spatiotemporal source localisation reveals involvement of medial premotor areas in movement reprogramming.
Exp Brain Res. 2002 May;144(2):178-88.
Response priming tasks reveal huge reaction time (RT) costs when invalidly prepared movements have to be reprogrammed after the imperative response signal. Yet, possible brain correlates of motor reprogramming have rarely been examined. The present experiments were designed to ascertain the brain correlates associated with motor reprogramming by combining the recording of event-related brain potentials (ERPs) with a spatiotemporal source-localisation approach. In two experiments either valid or invalid advance information about direction (experiment 1) and about direction and response hand (experiment 2) was provided. RTs showed considerable motor reprogramming costs in invalid trials. In both experiments reprogramming effects were reflected in ERP difference waveforms in terms of a centroparietally distributed negative and a frontal positive deviation. Source localisation of these ERP difference waveforms indicated brain activity in medial higher-order motor regions. Present findings accord with the assumption that the human pre-supplementary motor area plays an important role in motor reprogramming. [Abstract]

Petit L, Courtney SM, Ungerleider LG, Haxby JV
Sustained activity in the medial wall during working memory delays.
J Neurosci. 1998 Nov 15;18(22):9429-37.
We have taken advantage of the temporal resolution afforded by functional magnetic resonance imaging (fMRI) to investigate the role played by medial wall areas in humans during working memory tasks. We demarcated the medial motor areas activated during simple manual movement, namely the supplementary motor area (SMA) and the cingulate motor area (CMA), and those activated during visually guided saccadic eye movements, namely the supplementary eye field (SEF). We determined the location of sustained activity over working memory delays in the medial wall in relation to these functional landmarks during both spatial and face working memory tasks. We identified two distinct areas, namely the pre-SMA and the caudal part of the anterior cingulate cortex (caudal-AC), that showed similar sustained activity during both spatial and face working memory delays. These areas were distinct from and anterior to the SMA, CMA, and SEF. Both the pre-SMA and caudal-AC activation were identified by a contrast between sustained activity during working memory delays as compared with sustained activity during control delays in which subjects were waiting for a cue to make a simple manual motor response. Thus, the present findings suggest that sustained activity during working memory delays in both the pre-SMA and caudal-AC does not reflect simple motor preparation but rather a state of preparedness for selecting a motor response based on the information held on-line. [Abstract]

Hester R, Fassbender C, Garavan H
Individual differences in error processing: a review and reanalysis of three event-related fMRI studies using the GO/NOGO task.
Cereb Cortex. 2004 Sep;14(9):986-94.
Three previous studies using the GO/NOGO task were examined to characterize the pattern of functional activation seen during error-related processing. The large sample size (n = 44) also allowed investigation of the influence of individual differences in age, sex, self-reported absentmindedness and reaction speed on the level of activation. Errors were seen to activate a network of regions including the anterior cingulate cortex (ACC), pre-supplementary motor area (pre-SMA), bilateral insula, thalamus and right inferior parietal lobule. Split-half comparisons performed for each of the individual difference variables indicated greater ACC and pre-SMA activation for older subjects while slower responders showed greater activation in the parietal, lateral PFC, insula and ACC regions. Whereas males and females demonstrated equivalent levels of activation in both the ACC and insula, self-reported absentmindedness related to reduced activation in these regions. Our review of the current imaging literature on error-related activation indicates that, despite the use of a variety of other cognitive paradigms, the network of regions identified here is consistent with these previous studies, suggesting that these regions are critical to a 'general' error-related response. Furthermore, this response is, in part, influenced by individual differences in both demographic characteristics and behavioural performance. [Abstract]

Ikeda A, Yazawa S, Kunieda T, Ohara S, Terada K, Mikuni N, Nagamine T, Taki W, Kimura J, Shibasaki H
Cognitive motor control in human pre-supplementary motor area studied by subdural recording of discrimination/selection-related potentials.
Brain. 1999 May;122 ( Pt 5)915-31.
To clarify the functional role of human pre-supplementary motor area (pre-SMA) in 'cognitive' motor control as compared with other non-primary motor cortices (SMA-proper and lateral premotor areas) and prefrontal area, we recorded epicortical field potentials by using subdural electrodes in five epileptic patients during presurgical evaluation, whose pre-SMA, SMA-proper, prefrontal and lateral premotor areas were defined by electric cortical stimulation and recent anatomical orientations according to the bicommissural plane and callosal grid system. An S1-Go/NoGo choice and delayed reaction task (S1-choice paradigm) and a warned choice Go/NoGo reaction task (S2-choice paradigm) with inter-stimulus intervals of 2 s were employed. The results showed (i) transient potentials with onset and peak latencies of about 200 and 600 ms, respectively, after S1 in the S1-choice paradigm mainly at pre-SMA and to a lesser degree at the prefrontal and lateral premotor areas, but not in the S2-choice paradigm. At SMA-proper, a similar but much smaller potential was seen after S1 in both S1- and S2-choice paradigms and (ii) slow sustained potentials between S1 and S2 in both S1- and S2-choice paradigms in all of the non-primary motor areas investigated (pre-SMA, SMA-proper and lateral premotor areas) and prefrontal area. It is concluded that pre-SMA plays a more important role in cognitive motor control which involves sensory discrimination and decision making or motor selection for the action after stimuli, whereas SMA-proper is one of the main generators of Bereitschaftspotential preceding self-paced, voluntary movements. In the more general anticipation of and attention to the forthcoming stimuli, non-primary motor cortices including pre-SMA, SMA-proper and lateral premotor area, and the prefrontal area are commonly involved. [Abstract]

Kato C, Isoda H, Takehara Y, Matsuo K, Moriya T, Nakai T
Involvement of motor cortices in retrieval of kanji studied by functional MRI.
Neuroreport. 1999 Apr 26;10(6):1335-9.
Functional magnetic resonance imaging was successfully used to study the activation of the motor cortices during retrieval of Japanese ideogram, kanji. The subjects performed kanji completion tasks to generate a kanji in response to an element which is always written first. In most of the subjects, the contralateral premotor cortex, the presupplementary motor area (pre-SMA) and the bilateral intraparietal sulcus were activated during retrieval of kanji without actual writing nor intentional mental writing. Activation associated with actual writing was shown in the contralateral primary sensorimotor cortex and the SMA proper. These results suggested that retrieval of kanji would share the neural basis of motor representation with writing of kanji except for regions directly working for motor output. [Abstract]

Hoshi E, Tanji J
Differential roles of neuronal activity in the supplementary and presupplementary motor areas: from information retrieval to motor planning and execution.
J Neurophysiol. 2004 Dec;92(6):3482-99.
We explored functional differences between the supplementary and presupplementary motor areas (SMA and pre-SMA, respectively) systematically with respect to multiple behavioral factors, ranging from the retrieval and processing of associative visual signals to the planning and execution of target-reaching movement. We analyzed neuronal activity while monkeys performed a behavioral task in which two visual instruction cues were given successively with a delay: one cue instructed the location of the reach target, and the other instructed arm use (right or left). After a second delay, the monkey received a motor-set cue to be prepared to make the reaching movement as instructed. Finally, after a GO signal, it reached for the instructed target with the instructed arm. We found the following apparent differences in activity: 1) neuronal activity preceding the appearance of visual cues was more frequent in the pre-SMA; 2) a majority of pre-SMA neurons, but many fewer SMA neurons, responded to the first or second cue, reflecting what was shown or instructed; 3) in addition, pre-SMA neurons often reflected information combining the instructions in the first and second cues; 4) during the motor-set period, pre-SMA neurons preferentially reflected the location of the target, while SMA neurons mainly reflected which arm to use; and 5) when executing the movement, a majority of SMA neurons increased their activity and were largely selective for the use of either the ipsilateral or contralateral arm. In contrast, the activity of pre-SMA neurons tended to be suppressed. These findings point to the functional specialization of the two areas, with respect to receiving associative cues, information processing, motor behavior planning, and movement execution. [Abstract]

Fiehler K, Ullsperger M, von Cramon DY
Neural correlates of error detection and error correction: is there a common neuroanatomical substrate?
Eur J Neurosci. 2004 Jun;19(11):3081-7.
Successful behaviour requires error detection resulting in remedial actions, such as immediate error correction. The present event-related functional magnetic resonance imaging study in humans examined the neural correlates of error detection and error correction using a speeded modified flankers task. In order to investigate corrective behaviour, participants were randomly divided into two groups. The correction instructed group was asked to correct all encountered errors immediately. The correction not instructed group was unaware that corrective responses were recorded. The intention to correct errors significantly increased the correction rate. Brain activations correlating with error detection were isolated in the rostral cingulate zone and in the pre-supplementary motor area, supporting their important role in error processing. Error correction activated similar brain regions, suggesting a common neuroanatomical substrate. Additional activations were found in the parietal cortex, representing an interconnected cortical network, which processes somatosensory information of tactile stimuli. [Abstract]

Mostofsky SH, Schafer JG, Abrams MT, Goldberg MC, Flower AA, Boyce A, Courtney SM, Calhoun VD, Kraut MA, Denckla MB, Pekar JJ
fMRI evidence that the neural basis of response inhibition is task-dependent.
Brain Res Cogn Brain Res. 2003 Jul;17(2):419-30.
Event-related fMRI was used to investigate the hypothesis that neural activity involved in response inhibition depends upon the nature of the response being inhibited. Two different Go/No-go tasks were compared-one with a high working memory load and one with low. The 'simple' Go/No-go task with low working memory load required subjects to push a button in response to green spaceships but not red spaceships. A 'counting' Go/No-go task (high working memory load) required subjects to respond to green spaceships as well as to those red spaceships preceded by an even number of green spaceships. In both tasks, stimuli were presented every 1.5 s with a 5:1 ratio of green-to-red spaceships. fMRI group data for each task were analyzed using random effects models to determine signal change patterns associated with Go events and No-go events (corrected P< or =0.05). For both tasks, Go responses were associated with signal change in the left primary sensorimotor cortex, supplementary motor area (SMA) proper, and anterior cerebellum (right>left). For the simple task, No-go events were associated with activation in the pre-SMA; the working memory-loaded 'counting' task elicited additional No-go activation in the right dorsolateral prefrontal cortex. The findings suggest that neural contributions to response inhibition may be task dependent; the pre-SMA appears necessary for inhibition of unwanted movements, while the dorsolateral prefrontal cortex is recruited for tasks involving increased working memory load. [Abstract]

Isoda M
Context-dependent stimulation effects on saccade initiation in the presupplementary motor area of the monkey.
J Neurophysiol. 2005 Feb 9;
Although evidence suggests that the contribution of the presupplementary motor area (pre-SMA) to voluntary motor control is effector-nonselective, the question of how electrical stimulation of the pre-SMA affects eye movements remains unanswered. To address this issue, stimulus effects of the pre-SMA of monkeys on saccade initiation were investigated during performance of a visually guided saccade task with an instructed delay period. This report describes two major findings. First, when stimuli with currents of 80 microA or less were applied before the presentation of a GO signal, the reaction time (RT) of an upcoming saccade shortened, with comparable effects on ipsiversive and contraversive saccades. Second, stimuli that were delivered after the GO signal lengthened the RT, which resulted in greater effects on ipsiversive saccades. In addition, the stimulation yielded a mild impairment of saccade accuracy, particularly when the stimulation was delivered following the GO signal. By themselves, however, these stimuli did not directly elicit eye movements. Therefore, the stimulus effects appeared only in the context of the behavioral task and were dependent on the phase of the task. These findings provide additional support for the hypothesis that the involvement of the pre-SMA in motor control can be linked to either eye or arm motor system, dependent on behavioral context. [Abstract]

Curtis CE, D'Esposito M
Success and failure suppressing reflexive behavior.
J Cogn Neurosci. 2003 Apr 1;15(3):409-18.
The dynamic interplay between reflexive and controlled determinants of behavior is one of the most general organizing principles of brain function. A powerful analogue of this interplay is seen in the antisaccade task, which pits reflexive and willed saccadic mechanisms against one another. Event-related functional magnetic resonance imaging of the human brain showed greater prestimulus preparatory activity in the pre-supplementary motor area before voluntary antisaccades (saccades away from a target) compared with reflexive prosaccades (saccades to a target). Moreover, this preparatory activity was critically associated with reflex suppression; it predicted whether the reflex was later successfully inhibited in the trial. These dataillustrate a mechanism for top-down control over reflexive behavior. [Abstract]

Tsujimoto T, Ogawa M, Tsukada H, Kakiuchi T, Sasaki K
Activation of the ventral and mesial frontal cortex of the monkey by self-initiated movement tasks as revealed by positron emission tomography.
Neurosci Lett. 1998 Dec 18;258(2):117-20.
In order to investigate the neural mechanisms of movement initiation, we measured the regional cerebral blood flow (rCBF) of the monkey during self-initiated and visually-initiated hand movement tasks using positron emission tomography (PET). The orbitofrontal, cingulate, and anteromedial part of the dorsal premotor areas were preferentially activated by the self-initiated hand movement task (SELF). The pre-supplementary motor area and the cingulate motor area were also included in the active foci during the task. In the visually-initiated task (VISUAL), the V1, V2, V3, V3A, and V4 were activated, whereas the activity of the dorsolateral premotor and primary motor areas was not significantly different between the two tasks. These findings suggest that the orbitofrontal and mesial frontal cortices play an important role in the neural processes involved in self-initiation of movement and self-regulation of inner drives. [Abstract]

Houdé O, Zago L, Mellet E, Moutier S, Pineau A, Mazoyer B, Tzourio-Mazoyer N
Shifting from the perceptual brain to the logical brain: the neural impact of cognitive inhibition training.
J Cogn Neurosci. 2000 Sep;12(5):721-8.
What happens in the human brain when the mind has to inhibit a perceptual process in order to activate a logical reasoning process? Here, we use functional imaging to show the networks of brain areas involved in a deductive logic task performed twice by the same subjects, first with a perceptual bias and then with a logical response following bias-inhibition training. The main finding is a striking shift in the cortical anatomy of reasoning from the posterior part of the brain (the ventral and dorsal pathways) to a left-prefrontal network including the middle-frontal gyrus, Broca's area, the anterior insula, and the pre-SMA. This result indicates that such brain shifting is an essential element for human access to logical thinking. [Abstract]

Harada T, Saito DN, Kashikura K, Sato T, Yonekura Y, Honda M, Sadato N
Asymmetrical neural substrates of tactile discrimination in humans: a functional magnetic resonance imaging study.
J Neurosci. 2004 Aug 25;24(34):7524-30.
The left-hand advantage seen during tactile discrimination tasks suggests hemispheric-processing asymmetry, although its neural substrates are not well known. We used functional magnetic resonance imaging to evaluate the laterality of the neural substrates involved in tactile discrimination in 19 normal volunteers. Passive tactile discrimination tasks, along with appropriate control tasks, were performed with both the right and left hands to evaluate the effects of the hand used and hemispheric effects (i.e., laterality of the activation pattern). Regardless of the hand used, the right dorsolateral prefrontal cortex, posterior parietal cortex, pre-supplementary motor area, and rostral portion of the dorsal premotor cortex (PMdr) were activated asymmetrically during tactile discrimination. This confirms the previous finding of a right-sided asymmetry for tactile shape discrimination. Hand effects were found in the left caudal portion of PMd (PMdc) adjacent to the central sulcus, which showed prominent activation during right-handed but not left-handed discrimination tasks. This asymmetric activation in the left PMdc might be related to the asymmetric interhemispheric interaction during right-handed tactile discrimination. [Abstract]

Tsukamoto Y, Ohno K, Kashiwagi T, Tanabe H
[Releasing phenomenon of learned movements]
No To Shinkei. 1998 Oct;50(10):941-7.
Involuntary movements that resembled the shooting of a basketball and piano playing were observed after brain damage in a 13-year-old female and a 74-year-old female, respectively. The movements were characterized as involuntarily triggered movements that occurred in the presence and absence of exteroceptive stimuli, movements had been practiced repeatedly just before the occurrence of the brain damage, and that could be stopped on command. According to the MRI findings, the lesions extended into the pre-supplementary motor area (pre-SMA). The characteristics of the patients movements were different from previously reported involuntary movements such as compulsive manipulation of tools, utilization behavior, and imitation behavior. Hikosaka et al (1996) reported the role of the pre-SMA in learning new sequential procedures. We speculate that damage to the pre-SMA may be associated with the etiology of these movements. [Abstract]

MacDonald V, Halliday GM
Selective loss of pyramidal neurons in the pre-supplementary motor cortex in Parkinson's disease.
Mov Disord. 2002 Nov;17(6):1166-73.
The nonprimary motor cortices have not previously been studied in Parkinson's disease, despite the selective pattern of dysfunction observed in these regions. In particular, the pre-supplementary motor region is consistently underactive, with successful treatments correlating with increased excitatory drive to nonprimary motor regions. This finding could suggest a primary cortical abnormality in the pre-supplementary motor area (pre-SMA) in Parkinson's disease. We analysed and compared neuronal number in the pre-SMA and dorsolateral premotor cortical regions in 5 cases of Parkinson's disease and 5 controls. For each cortical region, the total neuronal number as well as the estimated numbers of subpopulations of interneurons and pyramidal neurons was quantified using previously published unbiased techniques. The results showed a significant loss of cortico-cortical projecting pyramidal neurons in the pre-SMA with no loss of other pyramidal neurons or interneurons either in this region or in the dorsolateral premotor region. These findings indicate a highly selective loss of pyramidal cells in the pre-SMA in Parkinson's disease, consistent with previous imaging findings in this disease. Our results implicate the degeneration of the premotor projection from the pre-SMA, along with dopaminergic basal ganglia dysfunction, in the pathogenesis of Parkinson's disease. [Abstract]

Sestini S, Scotto di Luzio A, Ammannati F, De Cristofaro MT, Passeri A, Martini S, Pupi A
Changes in regional cerebral blood flow caused by deep-brain stimulation of the subthalamic nucleus in Parkinson's disease.
J Nucl Med. 2002 Jun;43(6):725-32.
The aim of this study was to investigate the effect of deep-brain stimulation of the subthalamic nucleus (STN) on regional cerebral blood flow (rCBF) throughout the entire brain volume in patients with Parkinson's disease and to evaluate which of the brain areas showing an rCBF increase during STN stimulation related significantly to the improvement in motor function. METHODS: Ten consecutive Parkinson's disease patients (6 men, 4 women; mean age +/- SD, 59 +/- 8 y) with bilateral STN stimulators underwent 3 rCBF SPECT examinations at rest: the first preoperatively and the second and third postoperatively (follow-up, 4.8 +/- 1.4 mo) with STN stimulators on and off, respectively. The motor unified Parkinson's disease rating scale, the Hoehn and Yahr disability scale, and the Schwab and England activities-of-daily-living scale were used to evaluate the clinical state under each condition. Statistical parametric mapping was used to investigate rCBF during STN stimulation in comparison with rCBF preoperatively and with STN stimulators off. Also evaluated with statistical parametric mapping was the relationship between rCBF and individual motor scores used as covariates of interest. RESULTS: STN stimulation significantly changed rCBF in the right pre-supplementary motor area (pre-SMA), anterior cingulate cortex, and dorsolateral prefrontal cortex and in the medial Brodmann's area 8 (BA8) as defined in the atlas of Talairach and Tournoux (P < 0.05 corrected for multiple comparisons). The rCBF in these areas increased from the preoperative condition to the stimulators-on condition and decreased again after the stimulators were switched off. A significant correlation was detected between the improvement in motor scores and the rCBF increase only in the right pre-SMA and in the anterior cingulate motor area (P < 0.005, uncorrected). CONCLUSION: According to the topographic organization of the primate STN, our study shows that stimulation of the STN leads to rCBF increases in the motor (pre-SMA), associative, and limbic territories (anterior cingulate) in the frontal cortex. The significant correlation between motor improvement and rCBF increase in the pre-SMA and the anterior cingulate motor area reinforces the hypothesis that STN stimulation in parkinsonian patients can potentiate the cortical areas participating in higher-order aspects of motor control. [Abstract]

Cunnington R, Egan GF, O'Sullivan JD, Hughes AJ, Bradshaw JL, Colebatch JG
Motor imagery in Parkinson's disease: a PET study.
Mov Disord. 2001 Sep;16(5):849-57.
We used positron emission tomography (PET) with 15O-labelled water to record patterns of cerebral activation in six patients with Parkinson's disease (PD), studied when clinically "off" and after turning "on" as a result of dopaminergic stimulation. They were asked to imagine a finger opposition movement performed with their right hand, externally paced at a rate of 1 Hz. Trials alternating between motor imagery and rest were measured. A pilot study of three age-matched controls was also performed. We chose the task as a robust method of activating the supplementary motor area (SMA), defects of which have been reported in PD. The PD patients showed normal degrees of activation of the SMA (proper) when both "off" and "on." Significant activation with imagining movement also occurred in the ipsilateral inferior parietal cortex (both "off" and when "on") and ipsilateral premotor cortex (when "off" only). The patients showed significantly greater activation of the rostral anterior cingulate and significantly less activation of the left lingual gyrus and precuneus when performing the task "on" compared with their performance when "off." PD patients when imagining movement and "off" showed less activation of several sites including the right dorsolateral prefrontal cortex (DLPFC) when compared to the controls performing the same task. No significant differences from controls were present when the patients imagined when "on." Our results are consistent with other studies showing deficits of pre-SMA function in PD with preserved function of the SMA proper. In addition to the areas of reduced activation (anterior cingulate, DLPFC), there were also sites of activation (ipsilateral premotor and inferior parietal cortex) previously reported as locations of compensatory overactivity for PD patients performing similar tasks. Both failure of activation and compensatory changes are likely to contribute to the motor deficit in PD. [Abstract]

Nakamura T, Ghilardi MF, Mentis M, Dhawan V, Fukuda M, Hacking A, Moeller JR, Ghez C, Eidelberg D
Functional networks in motor sequence learning: abnormal topographies in Parkinson's disease.
Hum Brain Mapp. 2001 Jan;12(1):42-60.
We examined the neural circuitry underlying the explicit learning of motor sequences in normal subjects and patients with early stage Parkinson's disease (PD) using 15O-water (H2 15O) positron emission tomography (PET) and network analysis. All subjects were scanned while learning motor sequences in a task emphasizing explicit learning, and during a kinematically controlled motor execution reference task. Because different brain networks are thought to subserve target acquisition and retrieval during motor sequence learning, we used separate behavioral indices to quantify these aspects of learning during the PET experiments. In the normal cohort, network analysis of the PET data revealed a significant covariance pattern associated with acquisition performance. This topography was characterized by activations in the left dorsolateral prefrontal cortex (PFdl), rostral supplementary motor area (preSMA), anterior cingulate cortex, and in the left caudate/putamen. A second independent covariance pattern was associated with retrieval performance. This topography was characterized by bilateral activations in the premotor cortex (PMC), and in the right precuneus and posterior parietal cortex. The normal learning-related topographies failed to predict acquisition performance in PD patients and predicted retrieval performance less accurately in the controls. A separate network analysis was performed to identify discrete learning-related topographies in the PD cohort. In PD patients, acquisition performance was associated with a covariance pattern characterized by activations in the left PFdl, ventral prefrontal, and rostral premotor regions, but not in the striatum. Retrieval performance in PD patients was associated with a covariance pattern characterized by activations in the right PFdl, and bilaterally in the PMC, posterior parietal cortex, and precuneus. These results suggest that in early stage PD sequence learning networks are associated with additional cortical activation compensating for abnormalities in basal ganglia function. [Abstract]

Escola L, Michelet T, Macia F, Guehl D, Bioulac B, Burbaud P
Disruption of information processing in the supplementary motor area of the MPTP-treated monkey: a clue to the pathophysiology of akinesia?
Brain. 2003 Jan;126(Pt 1):95-114.
It has been suggested that the underactivity of mesial frontal structures induced by dopamine depletion could constitute one of the main substrates underlying akinesia in Parkinson's disease. Functional imaging and movement-related potential recordings indicate an implication of the frontal lobes in this pathological process, but the question has not yet been investigated at a cellular level using single unit recording. We therefore compared neuronal activity in both the presupplementary motor area (pre-SMA) and the supplementary motor area proper (SMAp) of the Macaca mulatta monkey during a delayed motor task, before and after MPTP treatment. In the pre-SMA, which receives strong inputs from the prefrontal cortex, the baseline firing frequency and the percentage of neurons responding to visual instruction cues decreased in lesioned monkeys. In the SMAp, which sends direct outputs to the primary motor cortex, not only was the response to visual cues impaired, but the percentage of SMAp neurons responding to intracortical microstimulation fell and the threshold of response rose. Neuronal activity after the Go signal diminished sharply in both structures in the symptomatic animal and the discharge pattern became more irregular; in the SMAp neuronal activity remained modified longer. Most of these changes could already be observed in the presymptomatic animal presenting no clinical signs of parkinsonism. These data would indicate that, at the moment when dopamine depletion has impaired the ability of cortical neurons to operate the focused selection of incoming information giving instructions for movement, pre-SMA and SMAp neurons are also in a state of severe hypoactivity. The conjunction of these phenomena could play a critical role in the genesis of akinesia. [Abstract]

Toma K, Honda M, Hanakawa T, Okada T, Fukuyama H, Ikeda A, Nishizawa S, Konishi J, Shibasaki H
Activities of the primary and supplementary motor areas increase in preparation and execution of voluntary muscle relaxation: an event-related fMRI study.
J Neurosci. 1999 May 1;19(9):3527-34.
Brain activity associated with voluntary muscle relaxation was examined by applying event-related functional magnetic resonance imaging (fMRI) technique, which enables us to observe change of fMRI signals associated with a single motor trial. The subject voluntarily relaxed or contracted the right upper limb muscles. Each motor mode had two conditions; one required joint movement, and the other did not. Five axial images covering the primary motor area (M1) and supplementary motor area (SMA) were obtained once every second, using an echoplanar 1.5 tesla MRI scanner. One session consisted of 60 dynamic scans (i.e., 60 sec). The subject performed a single motor trial (i.e., relaxation or contraction) during one session in his own time. Ten sessions were done for each task. During fMRI scanning, electromyogram (EMG) was monitored from the right forearm muscles to identify the motor onset. We calculated the correlation between the obtained fMRI signal and the expected hemodynamic response. The muscle relaxation showed transient signal increase time-locked to the EMG offset in the M1 contralateral to the movement and bilateral SMAs, where activation was observed also in the muscle contraction. Activated volume in both the rostral and caudal parts of SMA was significantly larger for the muscle relaxation than for the muscle contraction (p < 0.05). The results suggest that voluntary muscle relaxation occurs as a consequence of excitation of corticospinal projection neurons or intracortical inhibitory interneurons, or both, in the M1 and SMA, and both pre-SMA and SMA proper play an important role in motor inhibition. [Abstract]

Sakai ST, Stepniewska I, Qi HX, Kaas JH
Pallidal and cerebellar afferents to pre-supplementary motor area thalamocortical neurons in the owl monkey: a multiple labeling study.
J Comp Neurol. 2000 Feb 7;417(2):164-80.
In the present study, we determined where thalamic neurons projecting to the pre-supplementary motor area (pre-SMA) are located relative to pallidothalamic and cerebellothalamic inputs and nuclear boundaries. We employed a triple-labeling technique in the same owl monkey (Aotus trivirgatus). The cerebellothalamic projections were labeled with injections of wheat germ agglutinin conjugated to horseradish peroxidase, and the pallidothalamic projections were labeled with biotinylated dextran amine. The pre-SMA was identified by location and movement patterns evoked by intracortical microstimulation and injected with the retrograde tracer cholera toxin subunit B. Brain sections were processed sequentially using different chromogens to visualize all three tracers in the same section. Alternate sections were processed for Nissl cytoarchitecture or acetylcholinesterase chemoarchitecture for nuclear boundaries. The cerebellar nuclei primarily projected to posterior (VLp), medial (VLx), and dorsal (VLd) divisions of the ventral lateral nucleus; the pallidum largely projected to the anterior division (VLa) of the ventral lateral nucleus and the parvocellular part of the ventral anterior nucleus (VApc). However, we also found zones of overlapping projections, as well as interdigitating foci of pallidal and cerebellar label, particularly in border regions of the VLa and VApc. Thalamic neurons labeled by pre-SMA injections occupied a wide band and were especially concentrated in the VLx and VApc, cerebellar and pallidal territories, respectively. Labeled thalamocortical neurons overlapped cerebellar inputs in the VLd and VApc and overlapped pallidal inputs in the VLa and the ventral medial nucleus. The results demonstrate that inputs from both the cerebellum and globus pallidus are relayed to the pre-SMA. [Abstract]

Inase M, Tokuno H, Nambu A, Akazawa T, Takada M
Origin of thalamocortical projections to the presupplementary motor area (pre-SMA) in the macaque monkey.
Neurosci Res. 1996 Jul;25(3):217-27.
The presupplementary motor area (pre-SMA) is a recently defined cortical motor area that is located immediately rostral to the supplementary motor area (SMA) and is considered to play more complex roles in motor control than the SMA. In the present study, we examined the distribution of cells of origin of thalamocortical projections to the pre-SMA in the macaque monkey. Under the guidance of intracortical microstimulation mapping, the retrograde tracer biotinylated dextran amine was injected into the pre-SMA. Retrogradely labeled neurons were distributed primarily in the parvicellular division of the ventroanterior nucleus (VApc), oral division of the ventrolateral nucleus (VLo), area X, and mediodorsal nucleus (MD). Some labeled neurons were also observed in the medial and caudal divisions of the ventrolateral nucleus. The results indicate that the pre-SMA may receive not only basal ganglia inputs via the VApc, VLo, and MD, but also a cerebellar input via the X. [Abstract]

Wang Y, Shima K, Sawamura H, Tanji J
Spatial distribution of cingulate cells projecting to the primary, supplementary, and pre-supplementary motor areas: a retrograde multiple labeling study in the macaque monkey.
Neurosci Res. 2001 Jan;39(1):39-49.
We examined the location and spatial distribution of cingulate cortical cells projecting to the forelimb areas of the primary motor cortex (MI), supplementary motor area (SMA), and pre-supplementary motor area (pre-SMA) using a multiple retrograde labeling technique in the monkeys (Macaca fuscata). The forelimb areas of the MI, SMA and pre-SMA were physiologically identified, based on the findings of intracortical microstimulation (ICMS) and single cell recording. Three different tracers, diamidino yellow (DY), fast blue (FB), and wheat germ agglutinin conjugated to horseradish peroxidase (WGA-HRP), were injected into each of the three motor areas in the same monkey. Retrogradely labeled cells in the cingulate cortex were plotted with an automated plotting system. Cells projecting to the forelimb area of the MI were distributed in the two separate regions situated rostrocaudally in the dorsal and ventral banks of the cingulate sulcus, namely the rostral cingulate motor area (CMAr) and caudal cingulate motor area (CMAc). These two regions corresponded to the forelimb areas identified by the ICMS in the same animal. The distribution of projection cells to the SMA overlapped extensively with that of projection cells to the MI. Although the MI received relatively sparse inputs from the CMAr than from the CMAc, the SMA received inputs from the CMAr and its adjacent areas as much as from the CMAc. The projection cells to the pre-SMA were distributed in the anterior portion of the cingulate cortex, including the anterior part of the CMAr and in a small part of the cingulate gyrus. These findings indicate that the MI and SMA share a considerable common information from the cingulate cortex, including the CMAr and CMAc, whereas the pre-SMA receives a different set of information from the anterior part of the cingulate cortex. [Abstract]

Johansen-Berg H, Behrens TE, Robson MD, Drobnjak I, Rushworth MF, Brady JM, Smith SM, Higham DJ, Matthews PM.
Changes in connectivity profiles define functionally distinct regions in human medial frontal cortex.
Proc Natl Acad Sci U S A. 2004 Sep 7;101(36):13335-40. Epub 2004 Aug 30.
A fundamental issue in neuroscience is the relation between structure and function. However, gross landmarks do not correspond well to microstructural borders and cytoarchitecture cannot be visualized in a living brain used for functional studies. Here, we used diffusion-weighted and functional MRI to test structure-function relations directly. Distinct neocortical regions were defined as volumes having similar connectivity profiles and borders identified where connectivity changed. Without using prior information, we found an abrupt profile change where the border between supplementary motor area (SMA) and pre-SMA is expected. Consistent with this anatomical assignment, putative SMA and pre-SMA connected to motor and prefrontal regions, respectively. Excellent spatial correlations were found between volumes defined by using connectivity alone and volumes activated during tasks designed to involve SMA or pre-SMA selectively. This finding demonstrates a strong relationship between structure and function in medial frontal cortex and offers a strategy for testing such correspondences elsewhere in the brain. [Abstract]

Takada M, Nambu A, Hatanaka N, Tachibana Y, Miyachi S, Taira M, Inase M.
Organization of prefrontal outflow toward frontal motor-related areas in macaque monkeys.
Eur J Neurosci. 2004 Jun;19(12):3328-42.
Linkage between the prefrontal cortex and the primary motor cortex is mediated by nonprimary motor-related areas of the frontal lobe. In an attempt to analyse the organization of the prefrontal outflow from area 46 toward the frontal motor-related areas, we investigated the pattern of projections involving the higher-order motor-related areas, such as the presupplementary motor area (pre-SMA) and the rostral cingulate motor area (CMAr). Tracer injections were made into these motor-related areas (their forelimb representation) on the medial wall that had been identified electrophysiologically. The following data were obtained from a series of tract-tracing experiments in Japanese monkeys. (i) Only a few neurons in area 46 were retrogradely labelled from the pre-SMA and CMAr; (ii) terminal labelling from area 46 occurred sparsely in the pre-SMA and CMAr; (iii) a dual labelling technique revealed that the sites of overlap of anterograde labelling from area 46 and retrograde labelling from the pre-SMA and CMAr were evident in the rostral parts of the dorsal and ventral premotor cortices (PMdr and PMvr); (iv) and tracer injections into the PMdr produced neuronal cell labelling in area 46 and terminal labelling in the pre-SMA and CMAr. The present results indicate that a large portion of the prefrontal signals from area 46 is not directly conveyed to the pre-SMA and CMAr, but rather indirectly by way of the PMdr and PMvr. This suggests that area 46 exerts its major influence on the cortical motor system via these premotor areas. [Abstract]

Barba C, Frot M, Guénot M, Mauguière F
Stereotactic recordings of median nerve somatosensory-evoked potentials in the human pre-supplementary motor area.
Eur J Neurosci. 2001 Jan;13(2):347-56.
Median nerve somatosensory-evoked potentials (SEPs) have been recorded using intracortical electrodes stereotactically implanted in the frontal lobe of eight epileptic patients in order to assess the waveforms, latencies and surface-to-depth distributions of somatosensory responses generated in the anterior subdivision of supplementary motor areas (SMAs), the so-called pre-SMA. Intracortical responses were analysed in two latency ranges: 0--50 ms and 50--150 ms after stimulus. In all patients, we recorded in the first 50 ms after stimulus two positive P14 and P20 potentials followed by a N30 negativity. In the hemisphere contralateral to stimulation, the P20--N30 potentials showed a clear amplitude decrease from the outer to the inner aspect of the frontal lobe with minimal amplitudes in the pre-SMA. In the hemisphere ipsilateral to stimulus, P20 and N30 amplitudes were decreasing from mesial to lateral frontal cortex. In the 50--150 ms latency range, contacts implanted in the pre-SMA recorded a negative potential in the 60--70 ms latency range which, in five patients, was followed by a positive response peaking 80--110 ms after stimulus. These potentials were not picked up by more superficial contacts. We conclude that no early SEP is generated in pre-SMA in the first 50 ms after stimulation, while some potentials peaking in the 60--100 ms after stimulus are likely to originate from this cortical area. The latency of the pre-SMA responses recorded in our patients supports the hypothesis that the pre-SMA does not receive short-latency somatosensory inputs via direct thalamocortical projections. More probably the pre-SMA receives somatosensory inputs mediated by a polysynaptic transcortical transmission through functionally secondary motor and somatosensory areas. [Abstract]

Liu J, Morel A, Wannier T, Rouiller EM
Origins of callosal projections to the supplementary motor area (SMA): a direct comparison between pre-SMA and SMA-proper in macaque monkeys.
J Comp Neurol. 2002 Jan 28;443(1):71-85.
The two subdivisions of the supplementary motor area (SMA), the pre-SMA (rostrally) and SMA-proper (caudally), exhibit distinct functional properties and clear differences with respect to their connectivity with the spinal cord, the thalamus, and other homolateral motor cortical areas. The goal of the present study was to establish in monkeys whether these subdivisions also differ with regard to their callosal connectivity. Two fluorescent retrograde tracers (Fast Blue and Diamidino Yellow) were injected in each animal, one in the pre-SMA and the second in the SMA-proper. Tracer injections in the pre-SMA or in SMA-proper resulted in significant numbers of labeled neurons in the opposite SMA, premotor cortex (PM), cingulate motor areas (CMA), and cingulate gyrus. Labeled neurons in M1 were rare, being observed only after injection in the SMA-proper. The two subdivisions of the SMA differed in the proportion of labeled neurons found across areas providing their callosal inputs. The SMA-proper receives about half of its callosal inputs from its counterpart in the other hemisphere (42-65% across monkeys). A comparable proportion of neurons was found in the pre-SMA after injection in the opposite pre-SMA (32-47%). The pre-SMA receives more callosal inputs from the rostral halves of the dorsal PM, the ventral PM, and the CMA than from their caudal halves. In addition, the pre-SMA, but not the SMA-proper, receives callosal inputs from the prefrontal cortex. The SMA-proper receives more callosal inputs from the caudal halves of the dorsal PM and ventral PM than from their rostral halves. The two subdivisions of the SMA receive callosal inputs from the same cortical areas (except the prefrontal cortex and M1), but they differ with respect to the quantitative contribution of each area of origin. In conclusion, quantitative data now support the notion that pre-SMA receives more transcallosal inputs than the SMA-proper. [Abstract]

Lehéricy S, Ducros M, Krainik A, Francois C, Van de Moortele PF, Ugurbil K, Kim DS
3-D diffusion tensor axonal tracking shows distinct SMA and pre-SMA projections to the human striatum.
Cereb Cortex. 2004 Dec;14(12):1302-9.
Studies in non-human primates have shown that medial premotor projections to the striatum are characterized as a set of distinct circuits conveying different type of information. This study assesses the anatomical projections from the supplementary motor area (SMA), pre-SMA and motor cortex (MC) to the human striatum using diffusion tensor imaging (DTI) axonal tracking. Eight right-handed volunteers were studied at 1.5 T using DTI axonal tracking. A connectivity matrix was computed, which tested for connections between cortical areas (MC, SMA and pre-SMA) and subcortical areas (posterior, middle and anterior putamen and the head of the caudate nucleus) in each hemisphere. Pre-SMA projections to the striatum were located rostral to SMA projections to the striatum. The SMA and the MC were similarly connected to the posterior and middle putamen and not to the anterior striatum. These data show that the MC and SMA have connections with similar parts of the sensorimotor compartment of the human striatum, whereas the pre-SMA sends connections to more rostral parts of the striatum, including the associative compartment. [Abstract]

Tanné-Gariépy J, Boussaoud D, Rouiller EM
Projections of the claustrum to the primary motor, premotor, and prefrontal cortices in the macaque monkey.
J Comp Neurol. 2002 Dec 9;454(2):140-57.
The claustrum is interconnected with the frontal lobe, including the motor cortex, prefrontal cortex, and cingulate cortex. The goal of the present study was to assess whether the claustral projections to distinct areas within the frontal cortex arise from separate regions within the claustrum. Multiple injections of tracers were performed in 15 macaque monkeys, aimed toward primary motor area (M1), pre-supplementary motor area (pre-SMA), SMA-proper, rostral (PMd-r) and caudal (PMd-c) parts of the dorsal premotor cortex (PM), rostral (PMv-r) and caudal (PMv-c) parts of the ventral PM, and superior and inferior parts of area 46. The distribution of retrogradely labeled neurons showed no clear segregation along the rostrocaudal axis of the claustrum; they were usually located along the entire anteroposterior extent of the claustrum. For all motor cortical areas, there was a general trend of the labeled neurons to occupy the dorsal and intermediate parts of the claustrum along the dorsoventral axis. The same territories were labeled after injection in area 46, but in addition numerous labeled neurons were found in the most ventral part of the claustrum. At higher resolution, however, there was clear evidence that the territories projecting to pre-SMA and SMA-proper formed separate, interdigitating, clusters along the dorsoventral axis. A comparable local segregation was observed for the two subdivisions of area 46, whereas there was more local overlap among the subareas of PM. The projections from the claustrum to the multiple subareas of the motor cortex and to area 46 arise from largely overlapping territories, with, however, some degree of local segregation. [Abstract]

Luppino G, Calzavara R, Rozzi S, Matelli M
Projections from the superior temporal sulcus to the agranular frontal cortex in the macaque.
Eur J Neurosci. 2001 Sep;14(6):1035-40.
The aim of this study was to investigate the organization of the projections from the superior temporal sulcus (STS) to the various areas forming the agranular frontal cortex. Injections of retrograde neuronal tracers were made in the various agranular areas, in nine macaque monkeys. The results showed that two rostral premotor areas, F6 (pre-SMA) and F7, and the ventrorostral part of area F2 (F2vr) are targets of projections from the upper bank of the STS (uSTS). F6 and the dorsorostral part of F7 (supplementary eye field, SEF) are targets of projections from the rostral part of the uSTS, corresponding to the so-called 'superior temporal polysensory area' (STP). In contrast, the ventral part of area F7 (not including the SEF) and F2vr are targets of afferents from the caudal part of the uSTS. Ventral F7 is the target of weak afferents from the caudalmost and dorsalmost part of the uSTS (area 7a), whilst F2vr is the target of projections from a relatively more rostral and ventral sector of the uSTS, close to the fundus of the sulcus. This sector should correspond to area MST. In conclusion, F6 and SEF receive high order information from STP, whereas ventral F7 and F2vr receive information from areas of the dorsal visual stream. [Abstract]

Inase M, Tokuno H, Nambu A, Akazawa T, Takada M
Corticostriatal and corticosubthalamic input zones from the presupplementary motor area in the macaque monkey: comparison with the input zones from the supplementary motor area.
Brain Res. 1999 Jul 3;833(2):191-201.
The presupplementary motor area (pre-SMA) is a cortical motor-related area which lies in the medial wall of the frontal lobe, immediately anterior to the supplementary motor area (SMA). This area has been considered to participate in the control of complex forelimb movements in a way different from the SMA. In an attempt to analyze the patterns of projections from the pre-SMA to the basal ganglia, we examined the distributions of pre-SMA inputs in the striatum and the subthalamic nucleus and compared them with the SMA input distributions. To detect morphologically the terminal fields from the pre-SMA and the forelimb region of the SMA, anterograde tracers were injected into such areas that had been identified electrophysiologically in the macaque monkey. Corticostriatal inputs from the pre-SMA were distributed mainly in the striatal cell bridges connecting the rostral aspects of the caudate nucleus and the putamen, as well as in their neighboring striatal portions. These input zones were located, with no substantial overlap, rostral to corticostriatal input zones from the SMA forelimb region. Corticosubthalamic input zones from the pre-SMA were almost localized in the medial aspect of the nucleus, where corticosubthalamic inputs from the SMA forelimb region were also distributed predominantly. However, the major terminal fields from the pre-SMA were centered ventrally to those from the SMA. The present results indicate that the corticostriatal and corticosubthalamic input zones from the pre-SMA appear to be segregated from the SMA-derived input zones. This implies the possibility of parallel processing of motor information from the pre-SMA and SMA in the cortico-basal ganglia circuit. [Abstract]

Nakano K, Kayahara T, Tsutsumi T, Ushiro H
Neural circuits and functional organization of the striatum.
J Neurol. 2000 Sep;247 Suppl 5V1-15.
The basal ganglia and motor thalamic nuclei are functionally and anatomically divided into the sensorimotor, supplementary motor, premotor, associative and limbic territories. There exist both primary segregated basal ganglia-thalamocortical loops and convergence of functionally related information from different cortical areas onto these cortical basal ganglia-thalamocortical loops. The basal ganglia-thalamocortical loop arising from the sensorimotor area, supplementary motor area (SMA), premotor area and cingulate motor area provides distinct segregated subloops through the functionally distinct striatal, pallidal and thalamic regions with partial overlap. The subthalamic nucleus (STN) is also topographically organized. The ventrolateral part of the caudal 2/3 levels of the medial pallidal segment (GPi) projects to the primary motor area via the oral part of the ventral lateral thalamic nucleus (VLo) (Voa, Vop by Hassler's nomenclature). The thalamic relay nuclei of the GPi projection to SMA are identified in the transitional zone of the VApc (parvicellular part of the anterior ventral nucleus)-VLo and in the rostromedial part of the VLo. The thalamic nuclei relaying the cingulate subloop are not yet clearly defined. The supplementary motor subloop appears to be divided into the pre-SMA and SMA proper subloops. The premotor area is also divided into the dorsal premotor area subloop and the ventral premotor area subloop. It is suggested that the limbic loop consists of a number of subloops in the monkey as indicated by Haber et al. and in rats. We review here the microcircuitry of the striatum, as well as the convergence and integration between the functionally segregated loops. Finally, we discuss the functional implications of striatal connections. [Abstract]

Acuna BD, Eliassen JC, Donoghue JP, Sanes JN
Frontal and parietal lobe activation during transitive inference in humans.
Cereb Cortex. 2002 Dec;12(12):1312-21.
Cortical areas engaged in knowledge manipulation during reasoning were identified with functional magnetic resonance imaging (MRI) while participants performed transitive inference (TI) on an ordered list of 11 items (e.g. if A < B and B < C, then A < C). Initially, participants learned a list of arbitrarily ordered visual shapes. Learning occurred by exposure to pairs of list items that were adjacent in the sequence. Subsequently, functional MR images were acquired as participants performed TI on non-adjacent sequence items. Control tasks consisted of height comparisons (HT) and passive viewing (VIS). Comparison of the TI task with the HT task identified activation resulting from TI, termed 'reasoning', while controlling for rule application, decision processes, perception, and movement, collectively termed 'support processes'. The HT-VIS comparison revealed activation related to support processes. The TI reasoning network included bilateral prefrontal cortex (PFC), pre-supplementary motor area (preSMA), premotor area (PMA), insula, precuneus, and lateral posterior parietal cortex. By contrast, cortical regions activated by support processes included the bilateral supplementary motor area (SMA), primary motor cortex (M1), somatic sensory cortices, and right PMA. These results emphasize the role of a prefrontal-parietal network in manipulating information to form new knowledge based on familiar facts. The findings also demonstrate PFC activation beyond short-term memory to include mental operations associated with reasoning. [Abstract]

Hanakawa T, Honda M, Sawamoto N, Okada T, Yonekura Y, Fukuyama H, Shibasaki H
The role of rostral Brodmann area 6 in mental-operation tasks: an integrative neuroimaging approach.
Cereb Cortex. 2002 Nov;12(11):1157-70.
Recent evidence indicates that classical 'motor' areas may also have cognitive functions. We performed three neuroimaging experiments to investigate the functional neuroanatomy underlying three types of nonmotor mental-operation tasks: numerical, verbal, and spatial. (i) Positron emission tomography showed that parts of the posterior frontal cortex, which are consistent with the pre-supplementary motor area (pre-SMA) and the rostral part of the dorsolateral premotor cortex (PMdr), were active during all three tasks. We also observed activity in the posterior parietal cortex and cerebellar hemispheres during all three tasks. Electrophysiological monitoring confirmed that there were no skeletomotor, oculomotor or articulatory movements during task performance. (ii) Functional magnetic resonance imaging (fMRI) showed that PMdr activity during the mental-operation tasks was localized in the depths of the superior precentral sulcus, which substantially overlapped the region active during complex finger movements and was located dorsomedial to the presumptive frontal eye fields. (iii) Single-trial fMRI showed a transient increase in activity time-locked to the performance of mental operations in the pre-SMA and PMdr. The results of the present study suggest that the PMdr is important in the rule-based association of symbolic cues and responses in both motor and nonmotor behaviors. [Abstract]

Bunge SA, Kahn I, Wallis JD, Miller EK, Wagner AD
Neural circuits subserving the retrieval and maintenance of abstract rules.
J Neurophysiol. 2003 Nov;90(5):3419-28.
Behavior is often governed by abstract rules or instructions for behavior that can be abstracted from one context and applied to another. Prefrontal cortex (PFC) is thought to be important for representing rules, although the contributions of ventrolateral (VLPFC) and dorsolateral (DLPFC) regions remain under-specified. In the present study, event-related fMRI was used to examine abstract rule representation in humans. Prior to scanning, subjects learned to associate unfamiliar shapes and nonwords with particular rules. During each fMRI trial, presentation of one of these cues was followed by a delay and then by sample and probe stimuli. Match and non-match rules required subjects to indicate whether or not the sample and probe matched; go rules required subjects to make a response that was not contingent on the sample/probe relation. Left VLPFC, parietal cortex, and pre-SMA exhibited sensitivity to rule type during the cue and delay periods. Delay-period activation in these regions, but not DLPFC, was greater when subjects had to maintain response contingencies (match, non-match) relative to when the cue signaled a specific response (go). In contrast, left middle temporal cortex exhibited rule sensitivity during the cue but not delay period. These results support the hypothesis that VLPFC interacts with temporal cortex to retrieve semantic information associated with a cue and with parietal cortex to retrieve and maintain relevant response contingencies across delays. Future investigations of cross-regional interactions will enable full assessment of this account. Collectively, these results demonstrate that multiple, neurally separable processes are recruited during abstract rule representation. [Abstract]

Crosson B, Sadek JR, Maron L, Gökçay D, Mohr CM, Auerbach EJ, Freeman AJ, Leonard CM, Briggs RW
Relative shift in activity from medial to lateral frontal cortex during internally versus externally guided word generation.
J Cogn Neurosci. 2001 Feb 15;13(2):272-83.
Goldberg (1985) hypothesized that as language output changes from internally to externally guided production, activity shifts from supplementary motor area (SMA) to lateral premotor areas, including Broca's area. To test this hypothesis, 15 right-handed native English speakers performed three word generation tasks varying in the amount of internal guidance and a repetition task during functional magnetic resonance imaging (fMRI). Volumes of significant activity for each task versus a resting state were derived using voxel-by-voxel repeated-measures t tests (p <.001) across subjects. Changes in the size of activity volumes for left medial frontal regions (SMA and pre-SMA/BA 32) versus left lateral frontal regions (Broca's area, inferior frontal sulcus) were assessed as internal guidance of word generation decreased and external guidance increased. Comparing SMA to Broca's area, Goldberg's hypothesis was not verified. However, pre-SMA/BA 32 activity volumes decreased significantly and inferior frontal sulcus activity volumes increased significantly as word generation tasks moved from internally to externally guided. [Abstract]

Crosson B, Benefield H, Cato MA, Sadek JR, Moore AB, Wierenga CE, Gopinath K, Soltysik D, Bauer RM, Auerbach EJ, Gökçay D, Leonard CM, Briggs RW
Left and right basal ganglia and frontal activity during language generation: contributions to lexical, semantic, and phonological processes.
J Int Neuropsychol Soc. 2003 Nov;9(7):1061-77.
fMRI was used to determine the frontal, basal ganglia, and thalamic structures engaged by three facets of language generation: lexical status of generated items, the use of semantic vs. phonological information during language generation, and rate of generation. During fMRI, 21 neurologically normal subjects performed four tasks: generation of nonsense syllables given beginning and ending consonant blends, generation of words given a rhyming word, generation of words given a semantic category at a fast rate (matched to the rate of nonsense syllable generation), and generation of words given a semantic category at a slow rate (matched to the rate of generating of rhyming words). Components of a left pre-SMA-dorsal caudate nucleus-ventral anterior thalamic loop were active during word generation from rhyming or category cues but not during nonsense syllable generation. Findings indicate that this loop is involved in retrieving words from pre-existing lexical stores. Relatively diffuse activity in the right basal ganglia (caudate nucleus and putamen) also was found during word-generation tasks but not during nonsense syllable generation. Given the relative absence of right frontal activity during the word generation tasks, we suggest that the right basal ganglia activity serves to suppress right frontal activity, preventing right frontal structures from interfering with language production. Current findings establish roles for the left and the right basal ganglia in word generation. Hypotheses are discussed for future research to help refine our understanding of basal ganglia functions in language generation. [Abstract]

Jäncke L, Specht K, Shah JN, Hugdahl K
Focused attention in a simple dichotic listening task: an fMRI experiment.
Brain Res Cogn Brain Res. 2003 Apr;16(2):257-66.
Whole-head functional magnetic resonance imaging (fMRI) was used in nine neurologically intact subjects to measure the hemodynamic responses in the context of dichotic listening (DL). In order to eliminate the influence of verbal information processing, tones of different frequencies were used as stimuli. Three different dichotic listening tasks were used: the subjects were instructed to either concentrate on the stimuli presented in both ears (DIV), or only in the left (FL) or right (FR) ear and to monitor the auditory input for a specific target tone. When the target tone was detected, the subjects were required to indicate this by pressing a response button. Compared to the resting state, all dichotic listening tasks evoked strong hemodynamic responses within a distributed network comprising of temporal, parietal, and frontal brain areas. Thus, it is clear that dichotic listening makes use of various cognitive functions located within the dorsal and ventral stream of auditory information processing (i.e., the 'what' and 'where' streams). Comparing the three different dichotic listening conditions with each other only revealed a significant difference in the pre-SMA and within the left planum temporale area. The pre-SMA was generally more strongly activated during the DIV condition than during the FR and FL conditions. Within the planum temporale, the strongest activation was found during the FR condition and the weakest during the DIV condition. These findings were taken as evidence that even a simple dichotic listening task such as the one used here, makes use of a distributed neural network comprising of the dorsal and ventral stream of auditory information processing. In addition, these results support the previously made assumption that planum temporale activation is modulated by attentional strategies. Finally, the present findings uncovered that the pre-SMA, which is mostly thought to be involved in higher-order motor control processes, is also involved in cognitive processes operative during dichotic listening. [Abstract]

Buckner RL, Raichle ME, Miezin FM, Petersen SE
Functional anatomic studies of memory retrieval for auditory words and visual pictures.
J Neurosci. 1996 Oct 1;16(19):6219-35.
Functional neuroimaging with positron emission tomography was used to study brain areas activated during memory retrieval. Subjects (n = 15) recalled items from a recent study episode (episodic memory) during two paired-associate recall tasks. The tasks differed in that PICTURE RECALL required pictorial retrieval, whereas AUDITORY WORD RECALL required word retrieval. Word REPETITION and REST served as two reference tasks. Comparing recall with repetition revealed the following observations. (1) Right anterior prefrontal activation (similar to that seen in several previous experiments), in addition to bilateral frontal-opercular and anterior cingulate activations. (2) An anterior subdivision of medial frontal cortex [pre-supplementary motor area (SMA)] was activated, which could be dissociated from a more posterior area (SMA proper). (3) Parietal areas were activated, including a posterior medial area near precuneus, that could be dissociated from an anterior parietal area that was deactivated. (4) Multiple medial and lateral cerebellar areas were activated. Comparing recall with rest revealed similar activations, except right prefrontal activation was minimal and activations related to motor and auditory demands became apparent (e.g., bilateral motor and temporal cortex). Directly comparing picture recall with auditory word recall revealed few notable activations. Taken together, these findings suggest a pathway that is commonly used during the episodic retrieval of picture and word stimuli under these conditions. Many areas in this pathway overlap with areas previously activated by a different set of retrieval tasks using stem-cued recall, demonstrating their generality. Examination of activations within individual subjects in relation to structural magnetic resonance images provided an-atomic information about the location of these activations. Such data, when combined with the dissociations between functional areas, provide an increasingly detailed picture of the brain pathways involved in episodic retrieval tasks. [Abstract]

Kraut MA, Kremen S, Moo LR, Segal JB, Calhoun V, Hart J
Object activation in semantic memory from visual multimodal feature input.
J Cogn Neurosci. 2002 Jan 1;14(1):37-47.
The human brain's representation of objects has been proposed to exist as a network of coactivated neural regions present in multiple cognitive systems. However, it is not known if there is a region specific to the process of activating an integrated object representation in semantic memory from multimodal feature stimuli (e.g., picture-word). A previous study using word-word feature pairs as stimulus input showed that the left thalamus is integrally involved in object activation (Kraut, Kremen, Segal, et al., this issue). In the present study, participants were presented picture-word pairs that are features of objects, with the task being to decide if together they "activated" an object not explicitly presented (e.g., picture of a candle and the word "icing" activate the internal representation of a "cake"). For picture-word pairs that combine to elicit an object, signal change was detected in the ventral temporo-occipital regions, pre-SMA, left primary somatomotor cortex, both caudate nuclei, and the dorsal thalami bilaterally. These findings suggest that the left thalamus is engaged for either picture or word stimuli, but the right thalamus appears to be involved when picture stimuli are also presented with words in semantic object activation tasks. The somatomotor signal changes are likely secondary to activation of the semantic object representations from multimodal visual stimuli. [Abstract]

Pollmann S, von Cramon DY
Object working memory and visuospatial processing: functional neuroanatomy analyzed by event-related fMRI.
Exp Brain Res. 2000 Jul;133(1):12-22.
We report an event-related functional magnetic-resonance-imaging (fMRI) experiment that investigates the relationship of transient visual object memory, visuospatial orienting, and object recognition. Delayed object matching and visuospatial orienting involved a highly overlapping network of brain areas. Common areas were the frontal eye fields (FEF), the pre-supplementary motor area (pre-SMA)/SMA complex, the precentral gyri, and the horizontal and descending branches of the intraparietal sulcus (IPS). Selective delay activation was observed anterior to the FEF and in the ascending part of the IPS. Right dorsolateral prefrontal cortex was involved in goal-directed visual search, but showed no delay activity. [Abstract]

Linden DE, Bittner RA, Muckli L, Waltz JA, Kriegeskorte N, Goebel R, Singer W, Munk MH
Cortical capacity constraints for visual working memory: dissociation of fMRI load effects in a fronto-parietal network.
Neuroimage. 2003 Nov;20(3):1518-30.
Working memory (WM) capacity limitations and their neurophysiological correlates are of special relevance for the understanding of higher cognitive functions. Evidence from behavioral studies suggests that restricted attentional resources contribute to these capacity limitations. In an event-related functional magnetic resonance imaging (fMRI) study, we probed the capacity of the human visual WM system for up to four complex nonnatural objects using a delayed discrimination task. A number of prefrontal and parietal areas bilaterally showed increased blood oxygen level-dependent activity, relative to baseline, throughout the task when more than one object had to be held in memory. Monotonic increases in response to memory load were observed bilaterally in the dorsolateral prefrontal cortex (DLPFC) and the presupplementary motor area (pre-SMA). Conversely, activity in the frontal eye fields (FEFs) and in areas along the intraparietal sulcus (IPS) peaked when subjects had to maintain only two or three objects and decreased in the highest load condition. This dissociation of memory load effects on cortical activity suggests that the cognitive operations subserved by the IPS and FEF, which are most likely related to attention, fail to support visual WM when the capacity limit is approached. The correlation of brain activity with performance implies that only the operations performed by the DLPFC and pre-SMA, which support an integrated representation of visual information, helped subjects to maintain a reasonable level of performance in the highest load condition. These results indicate that at least two distinct cortical subsystems are recruited for visual WM, and that their interplay changes when the capacity limit is reached. [Abstract]

Hermsdörfer J, Goldenberg G, Wachsmuth C, Conrad B, Ceballos-Baumann AO, Bartenstein P, Schwaiger M, Boecker H
Cortical correlates of gesture processing: clues to the cerebral mechanisms underlying apraxia during the imitation of meaningless gestures.
Neuroimage. 2001 Jul;14(1 Pt 1):149-61.
The clinical test of imitation of meaningless gestures is highly sensitive in revealing limb apraxia after dominant left brain damage. To relate lesion locations in apraxic patients to functional brain activation and to reveal the neuronal network subserving gesture representation, repeated H2(15O)-PET measurements were made in seven healthy subjects during a gesture discrimination task. Observing paired images of either meaningless hand or meaningless finger gestures, subjects had to indicate whether they were identical or different. As a control condition subjects simply had to indicate whether two portrayed persons were identical or not. Brain activity during the discrimination of hand gestures was strongly lateralized to the left hemisphere, a prominent peak activation being localized within the inferior parietal cortex (BA40). The discrimination of finger gestures induced a more symmetrical activation and rCBF peaks in the right intraparietal sulcus and in medial visual association areas (BA18/19). Two additional foci of prominent rCBF increase were found. One focus was located at the left lateral occipitotemporal junction (BA 19/37) and was related to both tasks; the other in the pre-SMA was particularly related to hand gestures. The pattern of task-dependent activation corresponds closely to the predictions made from the clinical findings, and underlines the left brain dominance for meaningless hand gestures and the critical involvement of the parietal cortex. The lateral visual association areas appear to support first stages of gesture representation, and the parietal cortex is part of the dorsal action stream. Finger gestures may require in addition precise visual analysis and spatial attention enabled by occipital and right intraparietal activity. Pre-SMA activity during the perception of hand gestures may reflect engagement of a network that is intimately related to gesture execution. [Abstract]

Lau HC, Rogers RD, Ramnani N, Passingham RE
Willed action and attention to the selection of action.
Neuroimage. 2004 Apr;21(4):1407-15.
Actions are said to be 'willed' if we consciously pay attention to their selection. It has been suggested that they are associated with activations in the dorsal prefrontal cortex (area 46). However, because previous experiments typically used a 'free selection' paradigm to examine this hypothesis, it is unclear whether the results reflected the attention to the selection of action or the freedom of choice allowed by the tasks. In this experiment, we minimized the difference of working memory demand across task conditions by using novel stimuli in each trial. We found that activation in the dorsal prefrontal cortex on a free selection task was not significantly different from that induced by another task that required attention to the selection of action, although the responses were externally specified. This suggests that the dorsal prefrontal cortex is in fact associated with attention to the selection of action, but does not play a unique role in the generation of internally initiated actions. However, the presupplementary motor area (pre-SMA) may subserve this function as activity in this region was found to be tightly associated with the free selection of responses. [Abstract]

Schubotz RI, von Cramon DY
Functional organization of the lateral premotor cortex: fMRI reveals different regions activated by anticipation of object properties, location and speed.
Brain Res Cogn Brain Res. 2001 Mar;11(1):97-112.
Previous studies have provided evidence that the lateral premotor cortex (PMC) is involved in representations triggered by attended sensory events. However, while the functional specificity of subregions of this large cortical structure has been intensively investigated in the monkey, little is known about functional differences within human lateral premotor areas. In the present study, functional magnetic resonance imaging was used to investigate if attending to object-specific (O), spatial (S), or temporal (T) properties of the same sensory event, i.e. moving objects, involves different premotor areas. We found a frontoparietal 'prehension network' comprising the pre-supplementary motor area (preSMA), the ventral PMC, and the left anterior intraparietal sulcus (aIPS) to be activated independently of the attended stimulus property, but most intensively during object-related attention. Moreover, several areas were exclusively activated according to the attended stimulus property. Particularly, different PMC regions responded to the Object (O) task (left superior ventrolateral PMC), the Spatial (S) task (dorsolateral PMC), and the Timing (T) task (frontal opercular cortex (FOP)). These results indicate that the representation of different stimulus dimensions engage distinct premotor areas and, therefore, that there is a functional specificity of lateral premotor subregions. [Abstract]

Eagleman DM
Neuroscience. The where and when of intention.
Science. 2004 Feb 20;303(5661):1144-6. [Abstract] [PDF]

Lau HC, Rogers RD, Haggard P, Passingham RE.
Attention to intention.
Science. 2004 Feb 20;303(5661):1208-10.
"Intention is central to the concept of voluntary action. Using functional magnetic resonance imaging, we compared conditions in which participants made self-paced actions and attended either to their intention to move or to the actual movement. When they attended to their intention rather than their movement, there was an enhancement of activity in the pre-supplementary motor area (pre-SMA). We also found activations in the right dorsal prefrontal cortex and left intraparietal cortex. Prefrontal activity, but not parietal activity, was more strongly coupled with activity in the pre-SMA. We conclude that activity in the pre-SMA reflects the representation of intention." [Abstract]

Amador N, Fried I
Single-neuron activity in the human supplementary motor area underlying preparation for action.
J Neurosurg. 2004 Feb;100(2):250-9.
OBJECT: The supplementary motor area (SMA) is considered critical in the planning, initiation, and execution of motor acts. Despite decades of research, including electrical stimulation mapping in patients undergoing neurosurgery, the contribution of this region to the generation of motor behavior has remained enigmatic. This is a study of single-neuron responses at various stages of a motor task during depth electrode recording in the SMA, pre-SMA, and medial temporal lobe of humans, with the goal of elucidating the disparate roles of neurons in these regions during movements. METHODS: The patients were undergoing evaluation for epilepsy surgery requiring implantation of intracranial depth electrodes. Single-unit recordings were made during both the execution and mental imagery of finger apposition sequences. Only medial frontal neurons responded selectively to specific features of the motor plan, such as which hand performed the motor activity or the complexity of the sequence. Neuron activity progressively increased before the patient was given a "go" cue for the execution of movements; this activity peaked earlier in the pre-SMA than in the SMA proper. We observed similar patterns of activation during motor imagery and actual movement, but only neurons in the SMA differentiated between imagined and real movements. CONCLUSIONS: These results provide support at the single-neuron level for the role of the medial frontal cortex in the temporal organization and planning of movements in humans. [Abstract]

Shima K, Tanji J
Neuronal activity in the supplementary and presupplementary motor areas for temporal organization of multiple movements.
J Neurophysiol. 2000 Oct;84(4):2148-60.
To study how neurons in the medial motor areas participate in performing sequential multiple movements that are individually separated in time, we analyzed neuronal activity in the supplementary (SMA) and presupplementary (pre-SMA) motor areas. Monkeys were trained to perform three different movements separated by waiting times, in four or six different orders. Initially each series of movements was learned during five trials guided by visual signals that indicated the correct movements. The monkeys subsequently executed the three movements in the memorized order without the visual signals. Three types of neuronal activity were of particular interest; these appeared to be crucially involved in sequencing the multiple motor tasks in different orders. First, we found activity changes that were selective for a particular sequence of the three movements that the monkeys were prepared to perform. The sequence-selective activity ceased when the monkeys initiated the first movement. Second, we found interval-selective activity that appeared in the interval between one particular movement and the next. Third, we found neuronal activity representing the rank order of three movements arranged chronologically; that is, the activity differed selectively in the process of preparing the first, second, or third movements in individual trials. The interval-selective activity was more prevalent in the SMA, whereas the rank-order selective activity was more frequently recorded in the pre-SMA. These results suggest how neurons in the SMA and pre-SMA are involved in sequencing multiple movements over time. [Abstract]

Shima K, Mushiake H, Saito N, Tanji J.
Role for cells in the presupplementary motor area in updating motor plans.
Proc Natl Acad Sci U S A. 1996 Aug 6;93(16):8694-8.
Two motor areas are known to exist in the medial frontal lobe of the cerebral cortex of primates, the supplementary motor area (SMA) and the presupplementary motor area (pre-SMA). We report here on an aspect of cellular activity that characterizes the pre-SMA. Monkeys were trained to perform three different movements sequentially in a temporal order. The correct order was planned on the basis of visual information before its execution. A group of pre-SMA cells (n = 64, 25%) were active during a process when monkeys were required to discard a current motor plan and develop a plan appropriate for the next orderly movements. Such activity was not common in the SMA and not found in the primary motor cortex. Our data suggest a role of pre-SMA cells in updating motor plans for subsequent temporally ordered movements. [Abstract/ Full Text PDF]

Picard N, Strick PL
Imaging the premotor areas.
Curr Opin Neurobiol. 2001 Dec;11(6):663-72.
Recent imaging studies of motor function provide new insights into the organization of the premotor areas of the frontal lobe. The pre-supplementary motor area and the rostral portion of the dorsal premotor cortex, the 'pre-PMd', are, in many respects, more like prefrontal areas than motor areas. Recent data also suggest the existence of separate functional divisions in the rostral cingulate zone. [Abstract]

Ohara S, Mima T, Baba K, Ikeda A, Kunieda T, Matsumoto R, Yamamoto J, Matsuhashi M, Nagamine T, Hirasawa K, Hori T, Mihara T, Hashimoto N, Salenius S, Shibasaki H
Increased synchronization of cortical oscillatory activities between human supplementary motor and primary sensorimotor areas during voluntary movements.
J Neurosci. 2001 Dec 1;21(23):9377-86.
In human, both primary and nonprimary motor areas are involved in the control of voluntary movements. However, the dynamics of functional coupling among different motor areas has not been fully clarified yet. Because it has been proposed that the functional coupling among cortical areas might be achieved by the synchronization of oscillatory activity, we investigated the electrocorticographic coherence between the supplementary motor and primary sensorimotor areas (SMA and S1-M1) by means of event-related partial coherence analysis in 11 intractable epilepsy patients. We found premovement increase of coherence between the SMA proper and S1-M1 at the frequency of 0-33 Hz and between the pre-SMA and S1-M1 at 0-18 Hz. Coherence between the SMA proper and M1 started to increase 0.9 sec before the movement onset and peaked 0.3 sec after the movement. There was no systematic difference within the SMA (SMA proper vs pre-SMA) or within the S1-M1, in terms of the time course as well as the peak value of coherence. The phase spectra revealed near-zero phase difference in 57% (20 of 35) of region pairs analyzed, and the remaining pairs showed inconsistent results. This increase of synchronization between multiple motor areas in the preparation and execution of voluntary movements may reflect the multiregional functional interactions in human motor behavior. [Abstract]

Lee KM, Chang KH, Roh JK
Subregions within the supplementary motor area activated at different stages of movement preparation and execution.
Neuroimage. 1999 Jan;9(1):117-23.
Previous studies have provided evidence that the primary motor area (M1) is involved in actual execution of a motor program, while the premotor area (PreMA) and the supplementary motor area (SMA) play a role in its preparation. We have used the high temporospatial resolution of functional magnetic resonance imaging (fMRI) to study the relationship between stages of a motor program and activation of these motor-related cortical areas. Seven normal volunteers performed a delayed-motor task in which the preparation of finger movements was dissociated in time from movement execution, while event-related fMRI was obtained. The M1 and PreMA showed expected activation associated with execution and preparation stages, respectively. Within SMA, subregions with different temporal profiles of activation were identified: The anterior part became activated early in the preparation period, whereas the posterior part only with movement execution. This supports the notion that the classic SMA consists of the pre-SMA and SMA proper each with different functions. [Abstract]

Kennerley SW, Sakai K, Rushworth MF
Organization of action sequences and the role of the pre-SMA.
J Neurophysiol. 2004 Feb;91(2):978-93.
To understand the contribution of the human presupplementary motor area (pre-SMA) in sequential motor behavior, we performed a series of finger key-press experiments. Experiment 1 revealed that each subject had a spontaneous tendency to organize or "chunk" a long sequence into shorter components. We hypothesized that the pre-SMA might have a special role in initiating each chunk but not at other points during the sequence. Experiment 2 therefore examined the effect of 0.5-s, 10-Hz repetitive transcranial magnetic stimulation (rTMS) directed over the pre-SMA. As hypothesized, performance was disrupted when rTMS was delivered over the pre-SMA at the beginning of the second chunk but not when it was delivered in the middle of a chunk. Contrary to the hypothesis, TMS did not disrupt sequence initiation. Experiments 3 and 4 examined whether the very first movement of a sequence could be disrupted under any circumstances. Pre-SMA TMS did disrupt the initiation of sequences but only when subjects had to switch between sequences and when the first movement of each sequence was not covertly instructed by a learned visuomotor association. In conjunction, the results suggest that for overlearned sequences the pre-SMA is primarily concerned with the initiation of a sequence or sequence chunk and the role of the pre-SMA in sequence initiation is only discerned when subjects must retrieve the sequence from memory as a superordinate set of movements without the aid of a visuomotor association. Control experiments revealed such effects were not present when rTMS was applied over the left dorsal premotor cortex. [Abstract]

Sakai K, Hikosaka O, Miyauchi S, Sasaki Y, Fujimaki N, Pütz B
Presupplementary motor area activation during sequence learning reflects visuo-motor association.
J Neurosci. 1999 May 15;19(10):RC1.
In preceding studies (Hikosaka et al., 1996; Sakai et al., 1998) we have shown that the presupplementary motor area (pre-SMA), an anterior part of the medial premotor cortex, is active during visuo-motor sequence learning. However, the paradigm required the subjects first to acquire correct visuo-motor association and then to acquire correct sequence, and it was still unknown which of the two processes the pre-SMA is involved in. To further characterize the role of pre-SMA, we have conducted another series of functional magnetic resonance imaging experiments using three learning paradigms. The three were the same in that they involved a visuo-motor association component, but they differed in terms of the involvement of sequential components; one involved no sequence learning, whereas the other two involved learning of motor sequence or perceptual sequence. Comparison of the learning conditions with the any-order button press condition revealed pre-SMA activation in all three paradigms. The pre-SMA activation remained unchanged during learning of visuo-motor associations but decreased during learning of sequences, suggesting that the pre-SMA is related to visuo-motor association rather than sequence. The decrease of pre-SMA activation in the sequential paradigms may reflect the process by which individual visuo-motor associations were replaced by the formation of sequential procedural memory, which occurs outside the pre-SMA. Thus activation of the pre-SMA was related to the extent to which the task performance depended on conscious visuo-motor associations. [Abstract]

Nakamura K, Sakai K, Hikosaka O
Effects of local inactivation of monkey medial frontal cortex in learning of sequential procedures.
J Neurophysiol. 1999 Aug;82(2):1063-8.
To examine the role of the medial frontal cortex, supplementary motor area (SMA), and pre-SMA in the acquisition and control of sequential movements, we locally injected muscimol into 43 sites in the medial frontal cortex while monkeys (n = 2) performed a sequential button-press task. In this task, the monkey had to press two of 16 (4 x 4 matrix) buttons illuminated simultaneously in a predetermined order. A total of five pairs were presented in a fixed order for completion of a trial. To clarify the differential contribution of the medial frontal cortex for new acquisition and control of sequential movements, we used novel and learned sequences (that had been learned after extensive practice). We found that the number of errors increased for novel sequences, but not for learned sequences, after pre-SMA inactivations. A similar, but insignificant, trend was observed after SMA injections. The reaction time of button presses for both novel and learned sequences was prolonged by inactivations of both SMA and pre-SMA, with a trend for the effect to be larger for SMA inactivations. These findings suggest that the medial frontal cortex, especially pre-SMA, is related to the acquisition, rather than the storage or execution, of the correct order of button presses. [Abstract]

Shima K, Tanji J
Both supplementary and presupplementary motor areas are crucial for the temporal organization of multiple movements.
J Neurophysiol. 1998 Dec;80(6):3247-60.
Both supplementary and presupplementary motor areas are crucial for the temporal organization of multiple movements. J. Neurophysiol. 80: 3247-3260, 1998. To study the involvement of the supplementary (SMA) and presupplementary (pre-SMA) motor areas in performing sequential multiple movements that are individually separated in time, we injected muscimol, a gamma-aminobutyric acid agonist, bilaterally into the part of each area that represents the forelimb. Two monkeys were trained to perform three different movements, separated by a waiting time, in four or six different orders. First, each series of movements was learned during five trials guided by visual signals that indicated the correct movements. The monkeys subsequently executed the three movements in the memorized order, without the visual signals. After the injection of muscimol (3 microliter, 5 micrograms/microliters in 10 min) into either the SMA or pre-SMA bilaterally, the animals started making errors in performing the sequence of movements correctly from memory. However, when guided with a visual signal, they could select and perform the three movements correctly. The impaired memory-based sequencing of movements worsened progressively with time until the animals could not perform the task. Yet they still could associate the visual signals with the different movements at that stage. In control experiments on two separate monkeys, we found that injections of the same amount of muscimol into either the SMA or pre-SMA did not cause problems with nonsequential reaching movement regardless of whether it was visually triggered or self-initiated. These results support the view that both the SMA and pre-SMA are crucially involved in sequencing multiple movements over time. [Abstract]

Jäncke L, Shah NJ, Peters M
Cortical activations in primary and secondary motor areas for complex bimanual movements in professional pianists.
Brain Res Cogn Brain Res. 2000 Sep;10(1-2):177-83.
Hemodynamic responses were measured applying functional magnetic resonance imaging in two professional piano players and two carefully matched non-musician control subjects during the performance of self-paced bimanual and unimanual tapping tasks. The bimanual tasks were chosen because they resemble typical movements pianists have to generate during piano exercises. The results showed that the primary and secondary motor areas (M1, SMA, pre-SMA, and CMA) were considerably activated to a much lesser degree in professional pianists than in non-musicians. This difference was strongest for the pre-SMA and CMA, where professional pianists showed very little activation. The results suggest that the long lasting extensive hand skill training of the pianists leads to greater efficiency which is reflected in a smaller number of active neurons needed to perform given finger movements. This in turn enlarges the possible control capacity for a wide range of movements because more movements, or more 'degrees of freedom', are controllable. [Abstract]

Sakai K, Hikosaka O, Miyauchi S, Takino R, Sasaki Y, Pütz B
Transition of brain activation from frontal to parietal areas in visuomotor sequence learning.
J Neurosci. 1998 Mar 1;18(5):1827-40.
We studied the neural correlates of visuomotor sequence learning using functional magnetic resonance imaging (fMRI). In the test condition, subjects learned, by trial and error, the correct order of pressing two buttons consecutively for 10 pairs of buttons (2 x 10 task); in the control condition, they pressed buttons in any order. Comparison between the test condition and the control condition revealed four brain areas specifically related to learning: the dorsolateral prefrontal cortex (DLPFC), the presupplementary motor area (pre-SMA), the precuneus, and the intraparietal sulcus (IPS). We found that the time course of activation during learning was different between these areas. To normalize the individual differences in the speed of learning, we classified the performance of each subject into three learning stages: early, intermediate, and advanced stages. Both the relative increase of signal intensity and the number of activated pixels within the four areas showed significant changes across the learning stages, with different time courses. The two frontal areas, DLPFC and pre-SMA, were activated in the earlier stages of learning, whereas the two parietal areas, precuneus and IPS, were activated in the later stages. Specifically, DLPFC, pre-SMA, precuneus, and IPS were most highly activated in the early stage, in both the early and intermediate stages, in the intermediate stage, and in both the intermediate and advanced stages, respectively. The results suggest that the acquisition of visuomotor sequences requires frontal activation, whereas the retrieval of visuomotor sequences requires parietal activation, which might reflect the transition from the declarative stage to the procedural stage. [Abstract]

Kawashima R, Inoue K, Sugiura M, Okada K, Ogawa A, Fukuda H
A positron emission tomography study of self-paced finger movements at different frequencies.
Neuroscience. 1999;92(1):107-12.
Regional cerebral blood flow was measured in six right-handed volunteers using positron emission tomography during tasks involving repetitive self-paced finger tapping at five different frequencies. The contralateral primary sensorimotor cortex, the pre-supplementary motor area and the cingulate motor area showed significant activation during self-paced finger tapping tasks, compared with the resting state. A positive correlation between the regional cerebral blood flow and the movement frequency was found only in the primary sensorimotor cortex. In the pre-supplementary motor area and the cingulate motor area, however, activity increased when the subject employed movement frequencies faster or slower than his own pace. The same tendency was noted with respect to the relative variability of the inter-tapping interval. The results therefore indicate that the activity of the pre-supplementary motor area and the cingulate motor area may well be related to the increased difficulty in motor control rather than to the execution of the movement itself. [Abstract]

Rushworth MF, Hadland KA, Paus T, Sipila PK
Role of the human medial frontal cortex in task switching: a combined fMRI and TMS study.
J Neurophysiol. 2002 May;87(5):2577-92.
We used event-related functional magnetic resonance imaging (fMRI) to measure brain activity when subjects were performing identical tasks in the context of either a task-set switch or a continuation of earlier performance. The context, i.e., switching or staying with the current task, influenced medial frontal cortical activation; the medial frontal cortex is transiently activated at the time that subjects switch from one way of performing a task to another. Two types of task-set-switching paradigms were investigated. In the response-switching (RS) paradigm, subjects switched between different rules for response selection and had to choose between competing responses. In the visual-switching (VS) paradigm, subjects switched between different rules for stimulus selection and had to choose between competing visual stimuli. The type of conflict, sensory (VS) or motor (RS), involved in switching was critical in determining medial frontal activation. Switching in the RS paradigm was associated with clear blood-oxygenation-level-dependent signal increases ("activations") in three medial frontal areas: the rostral cingulate zone, the caudal cingulate zone, and the presupplementary motor area (pre-SMA). Switching in the VS task was associated with definite activation in just one medial frontal area, a region on the border between the pre-SMA and the SMA. Subsequent to the fMRI session, we used MRI-guided frameless stereotaxic procedures and repetitive transcranial magnetic stimulation (rTMS) to test the importance of the medial frontal activations for task switching. Applying rTMS over the pre-SMA disrupted subsequent RS performance but only when it was applied in the context of a switch. This result shows, first, that the pre-SMA is essential for task switching and second that its essential role is transient and limited to just the time of behavioral switching. The results are consistent with a role for the pre-SMA in selecting between response sets at a superordinate level rather than in selecting individual responses. The effect of the rTMS was not simply due to the tactile and auditory artifacts associated with each pulse; rTMS over several control regions did not selectively disrupt switching. Applying rTMS over the SMA/pre-SMA area activated in the VS paradigm did not disrupt switching. This result, first, confirms the limited importance of the medial frontal cortex for sensory attentional switching. Second, the VS rTMS results suggest that just because an area is activated in two paradigms does not mean that it plays the same essential role in both cases. [Abstract]

Shima K, Mushiake H, Saito N, Tanji J
Role for cells in the presupplementary motor area in updating motor plans.
Proc Natl Acad Sci U S A. 1996 Aug 6;93(16):8694-8.
Two motor areas are known to exist in the medial frontal lobe of the cerebral cortex of primates, the supplementary motor area (SMA) and the presupplementary motor area (pre-SMA). We report here on an aspect of cellular activity that characterizes the pre-SMA. Monkeys were trained to perform three different movements sequentially in a temporal order. The correct order was planned on the basis of visual information before its execution. A group of pre-SMA cells (n = 64, 25%) were active during a process when monkeys were required to discard a current motor plan and develop a plan appropriate for the next orderly movements. Such activity was not common in the SMA and not found in the primary motor cortex. Our data suggest a role of pre-SMA cells in updating motor plans for subsequent temporally ordered movements. [Abstract]

Jäncke L, Himmelbach M, Shah NJ, Zilles K
The effect of switching between sequential and repetitive movements on cortical activation.
Neuroimage. 2000 Nov;12(5):528-37.
We used whole-head functional magnetic resonance imaging (fMRI) to investigate the effect of switching between different sequential and repetitive movements in the context of conditional and fixed tasks. Four different movement tasks were applied: (1) unpredictable switching between two movement sequences comprising six submovements each according to visual cues (SEQ-VC); (2) unpredictable switching between repetitive movement of one finger according to visual cues (REP-VC); (3) performance of the same sequential movements used for SEQ-VC but in a fixed mode triggered by a visual stimulus (SEQ-FIX); (4) performance of the repetitive movements used for REP-FIX but in a fixed mode by a visual stimulus (REP-FIX). The statistical group analysis of the hemodynamic responses revealed the following results: (1) the SEQ-VC compared to the SEQ-FIX condition (switching between movement sequences) engendered stronger activations in the left rostral supplementary motor area (pre-SMA), bilaterally in the posterior parietal lobule, the left ventral premotor area, and the visual cortices; (2) the REP-VC compared to the REP-FIX condition (switching between repetitive movements) only revealed stronger activation in extra-striate areas. We hypothesize that during switching of movement sequences higher motor control aspects are involved including movement selection, updating of motor plans, as well as recalling and restoring motor plans. The repetitive movements are too simple in order to evoke additional activations in the medial and lateral premotor areas, as well as in parietal areas. [Abstract]

Matsuzaka Y, Tanji J
Changing directions of forthcoming arm movements: neuronal activity in the presupplementary and supplementary motor area of monkey cerebral cortex.
J Neurophysiol. 1996 Oct;76(4):2327-42.
1. To understand roles played by two cortical motor areas, the presupplementary motor area (pre-SMA) and supplementary motor area (SMA), in changing planned movements voluntarily, cellular activity was examined in two monkeys (Macaca fuscata) trained to perform an arm-reaching task in which they were asked to press one of two target buttons (right or left) in three different task modes. 2. In the first mode (visual), monkeys were visually instructed to result and press either a right or left key in response to a forth coming trigger signal. In the second mode (stay), monkeys were required to wait for the trigger signal and press the same target key as pressed in preceding trials. In the third mode (shift), a 50 Hz auditory cue instructed the monkey to shift the target of the future reach from the previous target to the previous nontarget. 3. While the monkeys were performing this task, we recorded 399 task-related cellular activities from the SMA and the pre-SMA. Among them, we found a group of neurons that exhibited activity changes related specifically to shift trials (shift-related cells). The following properties characterized these 112 neurons. First, they exhibited activity changes after the onset of the 50-Hz auditory cue and before the movement execution when the monkeys were required to change the direction of forthcoming movement. Second, they were not active when the monkeys pressed the same key without changing the direction of the movements. Third, they were not active when the monkeys received the 50-Hz auditory cue but failed to change the direction of the movements by mistake. These observations indicate that the activity of shift-related cells is related to the redirection of the forthcoming movements, but not to the auditory instruction itself or to the location of the target key or the direction of the forthcoming movements. 4. Although infrequently, monkeys made errors in the stay trials and changed directions of the reach voluntarily. In that case, a considerably high proportion of shift-related neurons (12 of 19) exhibited significant activity changes long before initiation of the reach movement. These long-lasting activities were not observed during the preparatory period in correct stay trials, but resembled the shift-related activity observed when the target shift was made toward the same direction. Thus these activity changes were considered to be also related to the process of changing the intended movements voluntarily. 5. We found another population of neurons that showed activity modulation when the target shift was induced by the visual instruction in visual trials (visually guided shift-related neurons). These neurons were active when the light-emitting diode (LED) guided the forthcoming reach to the previous nontarget but not to the previous target. Therefore their activity was not a simple visual response to the LED per se. A majority of them also showed shift-related activity in shift trials (19 of 22 in monkey 2). 6. Neurons exhibiting the shift-related activity were distributed differentially among the two areas. In the pre-SMA, 31% of the neurons recorded showed the shift-related activity, whereas in the SMA, only 7% showed such an activity. These results suggest that pre-SMA and SMA play differential roles in updating the motor plans in accordance with current requirements. [Abstract]

Nakamura K, Sakai K, Hikosaka O
Neuronal activity in medial frontal cortex during learning of sequential procedures.
J Neurophysiol. 1998 Nov;80(5):2671-87.
To study the role of medial frontal cortex in learning and memory of sequential procedures, we examined neuronal activity of the presupplementary motor area (pre-SMA) and supplementary motor area (SMA) while monkeys (n = 2) performed a sequential button press task, "2 x 5 task." In this paradigm, 2 of 16 (4 x 4 matrix) light-emitting diode buttons (called "set") were illuminated simultaneously and the monkey had to press them in a predetermined order. A total of five sets (called "hyperset") was presented in a fixed order for completion of a trial. We examined the neuronal activity of each cell using two kinds of hypersets: new hypersets that the monkey experienced for the first time for which he had to find the correct orders of button presses by trial-and-error and learned hypersets that the monkey had learned with extensive practice (n = 16 and 10 for each monkey). To investigate whether cells in medial frontal cortex are involved in the acquisition of new sequences or execution of well-learned procedures, we examined three to five new hypersets and three to five learned hypersets for each cell. Among 345 task-related cells, we found 78 cells that were more active during performance of new hypersets than learned hypersets (new-preferring cells) and 18 cells that were more active for learned hypersets (learned-preferring cells). Among new-preferring cells, 33 cells showed a learning-dependent decrease of cell activity: their activity was highest at the beginning of learning and decreased as the animal acquired the correct response for each set with increasing reliability. In contrast, 11 learned-preferring cells showed a learning-dependent increase of neuronal activity. We found a difference in the anatomic distribution of new-preferring cells. The proportion of new-preferring cells was greater in the rostral part of the medial frontal cortex, corresponding to the pre-SMA, than the posterior part, the SMA. There was some trend that learned-preferring cells were more abundant in the SMA. These results suggest that the pre-SMA, rather than SMA, is more involved in the acquisition of new sequential procedures. [Abstract]

Clower WT, Alexander GE

Movement sequence-related activity reflecting numerical order of components in supplementary and presupplementary motor areas.
J Neurophysiol. 1998 Sep;80(3):1562-6.
The supplementary motor area (SMA) and presupplementary motor areas (pre-SMA) have been implicated in movement sequencing, and neurons in SMA have been shown to encode what might be termed the relational order among sequence components (e.g., movement X followed by movement Y). To determine whether other aspects of movement sequencing might also be encoded by SMA or pre-SMA neurons, we analyzed task-related activity recorded from both areas in conjunction with a sequencing task that dissociated the numerical order of components (e.g., movement X as the 2nd component, irrespective of which movements precede or follow X). Sequences were constructed from eight component movements, each characterized by three spatial variables (origin, direction, and endpoint). Task-related activity recorded from 56 SMA and 63 pre-SMA neurons was categorized according to both the epoch (delay, reaction time, and movement time) and the spatial variable or component movement with which it was associated. All but one instance of task-related activity was selective for one of the spatial variables (SV-selective) rather than for any of the component movements themselves. Of 110 instances of SV-selective activity in SMA, 43 (39%) showed significant effects of numerical order. The corresponding incidence in pre-SMA, 82 (71%) of 116, was substantially higher (P < 0.00001). No effects of numerical order were evident among the hand paths, movement times, or electromyographic activity associated with task performance. We concluded that neurons in SMA and pre-SMA may encode the numerical order of components, at least for sequences that are distinguished mainly by that aspect of component ordering. [Abstract]

Isoda M, Tanji J
Participation of the primate presupplementary motor area in sequencing multiple saccades.
J Neurophysiol. 2004 Jul;92(1):653-9.
The aim of this study was to investigate whether, and how, the presupplementary motor area (pre-SMA) is involved in the organization of oculomotor sequence. We trained two monkeys to perform three center-out saccades in six different orders. Each sequence consisted of a block of eight trials, initially with visual instruction (4 trials) and then from memory (4 trials). During memory-guided performance of sequential saccades, approximately 75% of task-related neuronal activity was selective for, or influenced by, the numerical position of saccades within each sequence (rank order). Neurons tuned for the direction of saccades were in the minority. We also found that 22% of sampled neurons increased their activity preferentially at a transitional period when monkeys were in the process of renewal of required saccade sequences. These data indicate that the pre-SMA is involved in the organization of oculomotor sequence, particularly in representing rank-order information and in updating sequence information. Together with previous reports on the participation of the pre-SMA in sequencing of multiple arm movements, we propose here that this area may contribute to cognitive aspects of sequential behavioral control, in an effector-independent manner. [Abstract]

Kawashima R, Tanji J, Okada K, Sugiura M, Sato K, Kinomura S, Inoue K, Ogawa A, Fukuda H
Oculomotor sequence learning: a positron emission tomography study.
Exp Brain Res. 1998 Sep;122(1):1-8.
The purpose of this study was to identify the brain regions activated in relation to oculomotor sequence learning. Nine healthy subjects participated in the study, which consisted of three positron emission tomography scans. In the initial learning task, subjects were instructed to track a sequence of seven successive positions of visual targets and to memorize the order of the targets as well as their spatial locations. In the saccade task, subjects were instructed to track visual targets presented at random locations. In the control task, subjects were instructed to gaze at a fixation point. Fields showing significant regional cerebral blood flow change were determined from task-minus-control subtraction images. We determined that fields in the pre-supplementary motor area (pre-SMA), the intraparietal cortex, and the prefrontal cortex were activated not only in the learning-minus-control images but also in the learning-minus-saccade images. Although prefrontal and parietal activations were bilateral, pre-SMA activation was confined to the left hemisphere. The results indicate that these fields function as a part of the neural network involved in the learning of sequential saccadic eye movements. [Abstract]

Fujii N, Mushiake H, Tanji J
Distribution of eye- and arm-movement-related neuronal activity in the SEF and in the SMA and Pre-SMA of monkeys.
J Neurophysiol. 2002 Apr;87(4):2158-66.
We analyzed neuronal activity in the supplementary eye field (SEF), supplementary motor area (SMA), and presupplementary motor area (pre-SMA) during the performance of three motor tasks: capturing a visual target with a saccade, reaching one arm to a target while gazing at a visual fixation point, or capturing a target with a saccade and arm-reach together. Our data demonstrated that each area was involved in controlling the arm and eye movements in a different manner. Saccade-related neurons were found mainly in the SEF. In contrast, arm-movement-related neurons were found primarily in the SMA and pre-SMA. In addition, we found that the activity of both arm-movement- and saccade-related neurons differed depending on the presence or absence of an accompanying saccade or arm movement. Such context dependency was found in all three areas. We also discovered that activity preceding eye or arm movement alone, and eye and arm movement combined, appeared more often in the pre-SMA and SEF, suggesting their involvement in effector-independent aspects of motor behavior. Subsequent analysis revealed that the laterality of arm representation differed in the three areas: it was predominantly contralateral in the SMA but largely bilateral in the pre-SMA and SEF. [Abstract]

Coull JT.
fMRI studies of temporal attention: allocating attention within, or towards, time.
Brain Res Cogn Brain Res. 2004 Oct;21(2):216-26.
Attention is distributed in time as well as space. Moreover, attention can be actively directed both within, and towards, time. This review article summarises behavioural and neuroanatomical correlates of temporal aspects of attention. Orienting attention to particular moments in time, or selectively attending to temporal rather than non-temporal stimulus features, improves behavioural measures of performance. These effects are accompanied by specific increases in activity of functionally specialised, and anatomically discrete, brain regions. Left parietal cortex is associated with orienting attention to specific moments in time. Pre-supplementary motor area (SMA) is associated with selectively attending to, and estimating, time. Frontal operculum is associated with all of these processes as well as being activated when attentional resources are limited by time itself. The frontal operculum therefore plays a pivotal role in the multi-faceted interaction between time and attention. [Abstract]

Coull JT, Vidal F, Nazarian B, Macar F
Functional anatomy of the attentional modulation of time estimation.
Science. 2004 Mar 5;303(5663):1506-8.
Attention modulates our subjective perception of time. The less we attend to an event's duration, the shorter it seems to last. Attention to time or color stimulus attributes was modulated parametrically in an event-related functional magnetic resonance imaging study. Linear increases in task performance were accompanied by corresponding increases in brain activity. Increasing attention to time selectively increased activity in a corticostriatal network, including pre-supplementary motor area and right frontal operculum. Increasing attention to color selectively increased activity in area V4. By identifying areas whose activity was specifically modulated by attention to time, we have defined the core neuroanatomical substrates of timing behavior. [Abstract]

Pastor MA, Day BL, Macaluso E, Friston KJ, Frackowiak RS
The functional neuroanatomy of temporal discrimination.
J Neurosci. 2004 Mar 10;24(10):2585-91.
Two identical stimuli, such as a pair of electrical shocks to the skin, are readily perceived as two separate events in time provided the interval between them is sufficiently long. However, as they are presented progressively closer together, there comes a point when the two separate stimuli are perceived as a single stimulus. Damage to posterior parietal cortex, peri-supplementary motor area (peri-SMA), and basal ganglia can disturb this form of temporal discrimination. Our aim was to establish, in healthy subjects, the brain areas that are involved in this process. During functional magnetic resonance imaging scanning, paired electrical pulses, separated by variable inter-stimulus intervals (5-110 msec), were delivered to different sites on one forearm (8-64 mm from the midline). Subjects were required to simply detect the stimulus (control task) or to identify a stimulus property. For temporal discrimination (TD), subjects reported whether they felt one or two stimuli. For spatial discrimination, they reported whether the stimuli were located on the right or left side of the forearm. Subjects reported their choice by pressing a button with the opposite hand. Our results showed that discrimination, as opposed to simply detection, activated several brain areas. Most were common to both discrimination tasks. These included regions of prefrontal cortex, right postcentral gyrus and inferior parietal lobule, basal ganglia, and cerebellum. However, activation of pre-SMA and anterior cingulate was found to be specific to the TD task. This suggests that these two frontal regions may play a role in the temporal processing of somatosensory events. [Abstract]

Akkal D, Escola L, Bioulac B, Burbaud P
Time predictability modulates pre-supplementary motor area neuronal activity.
Neuroreport. 2004 Jun 7;15(8):1283-6.
Two monkeys were trained in a delayed sequential motor task in which the time interval between events and the delay duration were either fixed or variable. Single-unit neuronal activity was recorded in the pre-supplementary motor area (pre-SMA). During the delay, we observed a gradual increase in activity (build-up pattern) in the fixed but not in the variable condition. In the former but not in the latter, the monkey had the opportunity to estimate time duration. Consequently, the build-up pattern observed in the pre-SMA might represent the neuronal substrate of a time accumulator system proposed by previous authors on the basis of functional imaging data. Such a system could play a critical role in the working memory of temporal information. [Abstract]

Schubotz RI, von Cramon DY
Interval and ordinal properties of sequences are associated with distinct premotor areas.
Cereb Cortex. 2001 Mar;11(3):210-22.
Lesion and imaging studies have suggested that the premotor cortex (PMC) is a crucial component in the neural network underlying the processing of sequential information. However, whether different aspects of sequential information like interval and ordinal properties are supported by different anatomical regions, and whether the representation of sequential information within the PMC is necessarily related to motor requirements, remain open questions. Brain activations were investigated during a sequence encoding paradigm in 12 healthy subjects using functional magnetic resonance imaging. Subjects had to attend either to the interval or to the ordinal information of a sequence of visually presented stimuli and had to encode the relevant information either before motor reproduction or before perceptual monitoring. Although interval and ordinal information led to activations within the same neural network, direct comparisons revealed significant differences. The pre-supplementary motor area (preSMA), the lateral PMC, the frontal opercular cortex as well as basal ganglia and the left lateral cerebellar cortex (CE) were activated significantly more strongly by interval information, whereas the SMA, the frontal eye field, the primary motor cortex (MI), the primary somatosensory cortex, the cuneus as well as the medial CE and the thalamus were activated more strongly by ordinal information. In addition, serial encoding before reproduction led to higher activations than serial encoding before monitoring in the preSMA, SMA, MI and medial CE. Our findings suggest overlapping but different kinds of sequential representation, depending on both the ordinal and interval aspects as well as motor requirements. [Abstract]

Lewis PA, Miall RC
Brain activation patterns during measurement of sub- and supra-second intervals.
Neuropsychologia. 2003;41(12):1583-92.
The possibility that different neural systems are used to measure temporal durations at the sub-second and several second ranges has been supported by pharmacological manipulation, psychophysics, and neural network modelling. Here, we add to this literature by using fMRI to isolate differences between the brain networks which measure 0.6 and 3s in a temporal discrimination task with visual discrimination for control. We observe activity in bilateral insula and dorsolateral prefrontal cortex, and in right hemispheric pre-supplementary motor area, frontal pole, and inferior parietal cortex during measurement of both intervals, suggesting that these regions constitute a system used in temporal discrimination at both ranges. The frontal operculum, left cerebellar hemisphere and middle and superior temporal gyri, all show significantly greater activity during measurement of the shorter interval, supporting the hypotheses that the motor system is preferentially involved in the measurement of sub-second intervals, and that auditory imagery is preferentially used during measurement of the same. Only a few voxels, falling in the left posterior cingulate and inferior parietal lobe, are more active in the 3s condition. Overall, this study shows that although many brain regions are used for the measurement of both sub- and supra-second temporal durations, there are also differences in activation patterns, suggesting that distinct components are used for the two durations. [Abstract]

Deiber MP, Honda M, Ibañez V, Sadato N, Hallett M
Mesial motor areas in self-initiated versus externally triggered movements examined with fMRI: effect of movement type and rate.
J Neurophysiol. 1999 Jun;81(6):3065-77.
The human frontomesial cortex reportedly contains at least four cortical areas that are involved in motor control: the anterior supplementary motor area (pre-SMA), the posterior SMA (SMA proper, or SMA), and, in the anterior cingulate cortex, the rostral cingulate zone (RCZ) and the caudal cingulate zone (CCZ). We used functional magnetic resonance imaging (fMRI) to examine the role of each of these mesial motor areas in self-initiated and visually triggered movements. Healthy subjects performed self-initiated movements of the right fingers (self-initiated task, SI). Each movement elicited a visual signal that was recorded. The recorded sequence of visual signals was played back, and the subjects moved the right fingers in response to each signal (visually triggered task, VT). There were two types of movements: repetitive (FIXED) or sequential (SEQUENCE), performed at two different rates: SLOW or FAST. The four regions of interest (pre-SMA, SMA, RCZ, CCZ) were traced on a high-resolution MRI of each subject's brain. Descriptive analysis, consisting of individual assessment of significant activation, revealed a bilateral activation in the four mesial structures for all movement conditions, but SI movements were more efficient than VT movements. The more complex and more rapid the movements, the smaller the difference in activation efficiency between the SI and the VT tasks, which indicated an additional processing role of the mesial motor areas involving both the type and rate of movements. Quantitative analysis was performed on the spatial extent of the area activated and the percentage of change in signal amplitude. In the pre-SMA, activation was more extensive for SI than for VT movements, and for fast than for slow movements; the extent of activation was larger in the ipsilateral pre-SMA. In the SMA, the difference was not significant in the extent and magnitude of activation between SI and VT movements, but activation was more extensive for sequential than for fixed movements. In the RCZ and CCZ, both the extent and magnitude of activation were larger for SI than for VT movements. In the CCZ, both indices of activation were also larger for sequential than for fixed movements, and for fast than for slow movements. These data suggest functional specificities of the frontomesial motor areas with respect not only to the mode of movement initiation (self-initiated or externally triggered) but also to the movement type and rate. [Abstract]

Lewis PA, Wing AM, Pope PA, Praamstra P, Miall RC
Brain activity correlates differentially with increasing temporal complexity of rhythms during initialisation, synchronisation, and continuation phases of paced finger tapping.
Neuropsychologia. 2004;42(10):1301-12.
Activity in parts of the human motor system has been shown to correlate with the complexity of performed motor sequences in terms of the number of limbs moved, number of movements, and number of trajectories. Here, we searched for activity correlating with temporal complexity, in terms of the number of different intervals produced in the sequence, using an overlearned tapping task. Our task was divided into three phases: movement selection and initiation (initiate), synchronisation of finger tapping with an external auditory cue (synchronise), and continued tapping in absence of the auditory pacer (continue). Comparisons between synchronisation and continuation showed a pattern in keeping with prior neuroimaging studies of paced finger tapping. Thus, activation of bilateral SMA and basal ganglia was greater in continuation tapping than in synchronisation tapping. Parametric analysis revealed activity correlating with temporal complexity during initiate in bilateral supplementary and pre-supplementary motor cortex (SMA and preSMA), rostral dorsal premotor cortex (PMC), basal ganglia, and dorsolateral prefrontal cortex (DLPFC), among other areas. During synchronise, correlated activity was observed in bilateral SMA, more caudal dorsal and ventral PMC, right DLPFC and right primary motor cortex. No correlated activity was observed during continue at P<0.01 (corrected, cluster level), though left angular gyrus was active at P<0.05. We suggest that the preSMA and rostral dorsal PMC activities during initiate may be associated with selection of timing parameters, while activation in centromedial prefrontal cortex during both initiate and synchronise may be associated with temporal error monitoring or correction. The absence of activity significantly correlated with temporal complexity during continue suggests that, once an overlearned timed movement sequence has been selected and initiated, there is no further adjustment of the timing control processes related to its continued production in absence of external cues. [Abstract]

Boecker H, Dagher A, Ceballos-Baumann AO, Passingham RE, Samuel M, Friston KJ, Poline J, Dettmers C, Conrad B, Brooks DJ
Role of the human rostral supplementary motor area and the basal ganglia in motor sequence control: investigations with H2 15O PET.
J Neurophysiol. 1998 Feb;79(2):1070-80.
The aim of this study was to investigate the functional anatomy of distributed cortical and subcortical motor areas in the human brain that participate in the central control of overlearned complex sequential unimanual finger movements. On the basis of previous research in nonhuman primates, a principal involvement of basal ganglia medial premotor loops [corrected] was predicted for central control of finger sequences performed automatically. In pertinent areas, a correlation of activation levels with the complexity of a motor sequence was hypothesized. H2 15O positron emission tomography (PET) was used in a group of seven healthy male volunteers [mean age 32.0 +/- 10.4 yr] to determine brain regions where levels of regional cerebral blood flow (rCBF) correlated with graded complexity levels of five different key-press sequences. All sequences were overlearned before PET and involved key-presses of fingers II-V of the right hand. Movements of individual fingers were kept constant throughout all five conditions by external pacing at 1-Hz intervals. Positive correlations of rCBF with increasing sequence complexity were identified in the contralateral rostral supplementary motor area (pre-SMA) and the associated pallido-thalamic loop, as well as in right parietal area 7 and ipsilateral primary motor cortex (M1). In contrast, while rCBF in contralateral M1 and [corrected] extensive parts of caudal SMA was increased compared with rest during task performance, significant correlated increases of rCBF with sequence complexity were not observed. Inverse correlations of rCBF with increasing sequence complexity were identified in mesial prefrontal-, medial temporal-, and anterior cingulate areas. The findings provide further evidence in humans supporting the notion of a segregation of SMA into functionally distinct subcomponents: although pre-SMA was differentially activated depending on the complexity of a sequence of learned finger movements, such modulation was not detectable in caudal SMA (except the most antero-superior part), implicating a motor executive role. Our observations of complexity-correlated rCBF increases in anterior globus pallidus suggest a specific role for the basal ganglia in the process of sequence facilitation and control. They may act to filter and focus input from motor cortical areas as patterns of action become increasingly complex. [Abstract]

Kunieda T, Ikeda A, Ohara S, Yazawa S, Nagamine T, Taki W, Hashimoto N, Shibasaki H
Different activation of presupplementary motor area, supplementary motor area proper, and primary sensorimotor area, depending on the movement repetition rate in humans.
Exp Brain Res. 2000 Nov;135(2):163-72.
In order to clarify the functional role of the supplementary motor area (SMA) and its rostral part (pre-SMA) in relation to the rate of repetitive finger movements, we recorded movement-related cortical potentials (MRCPs) directly from the surface of the mesial frontal lobe by using subdural electrode grids implanted in four patients with intractable partial epilepsy. Two subregions in the SMA were identified based on the anatomical location and the different response to cortical stimulation. In three of the four subjects, we also recorded MRCPs from the surface of the lateral convexity covering the primary sensorimotor areas (SI-MI), which were defined by cortical stimulation and SEP recording. The subjects extended the middle finger or opposed the thumb against other fingers of the same hand at a self-paced rate of 0.2 Hz (slow) and 2 Hz (rapid), each in separate sessions. As a result, pre-and postmovement potentials were clearly seen at the SI-MI in both slow- and rapid-rate movements. By contrast, in the SMA, especially in the pre-SMA, premovement potentials were not seen and postmovement potentials were seldom seen in the rapid rate movement. In the slow-rate condition, pre- and postmovement potentials were clearly seen in both the pre-SMA and the SMA proper. In conclusion, the SMA, especially the pre-SMA, is less activated electrophysiologically in the rapid-rate movements, while the SI-MI remains active regardless of the movement rate. [Abstract]

Rivkin MJ, Vajapeyam S, Hutton C, Weiler ML, Hall EK, Wolraich DA, Yoo SS, Mulkern RV, Forbes PW, Wolff PH, Waber DP
A functional magnetic resonance imaging study of paced finger tapping in children.
Pediatr Neurol. 2003 Feb;28(2):89-95.
Fourteen typically developing children from 7.9-11.3 years in age were studied with functional magnetic resonance imaging to identify the cerebral loci involved in performance of paced finger tapping by children. Each child performed two bimanual alternating paced finger-tapping tasks. In the first, paced finger tapping was conducted to external 3-Hz pacing provided by a metronome. In the second, the metronome was turned off and finger tapping continued while each child tried to maintain the 3-Hz rhythm by self pacing. Individual and group data were analyzed with statistical parametric mapping techniques that resulted in activation maps for the two tasks. Metronome tapping produced activation of the posterior regions of both superior temporal gyri, both primary sensorimotor cortices, anterodorsomedial cerebellum and supplementary motor area. Self-tapping resulted in recruitment of pre-supplementary motor area and cerebellum in addition to bilateral supplementary motor area and primary sensorimotor cortical activation. Bimanual alternating paced finger tapping performed by children activates a neural network involving primary motor cortex, supplementary motor area, and cerebellum. Posterior superior temporal gyrus may be important for encoding auditory information, and presupplementary motor area and midline cerebellum play an important role in self-paced finger tapping. [Abstract]

Ullén F, Forssberg H, Ehrsson HH
Neural networks for the coordination of the hands in time.
J Neurophysiol. 2003 Feb;89(2):1126-35.
Without practice, bimanual movements can typically be performed either in phase or in antiphase. Complex temporal coordination, e.g., during movements at different frequencies with a noninteger ratio (polyrhythms), requires training. Here, we investigate the organization of the neural control systems for in-phase, antiphase, and polyrhythmic coordination using functional magnetic resonance imaging (fMRI). Brisk rhythmic tapping with the index fingers was used as a model behavior. We demonstrate different patterns of brain activity during in-phase and antiphase coordination. In-phase coordination was characterized by activation of the right anterior cerebellum and cingulate motor area (CMA). Antiphase coordination was accompanied by extensive fronto-parieto-temporal activations, including the supplementary motor area (SMA), the preSMA, and the bilateral inferior parietal gyri, premotor cortex, and superior temporal gyri. When contrasting polyrhythmic tapping with in-phase tapping, activity was seen in the same set of brain regions, and in the posterior cerebellum and the CMA. Antiphase and polyrhythmic coordination may thus to a large extent use common neural control circuitry. In a separate experiment, we analyzed the neural control of the rhythmic structure and the serial order of finger movements during polyrhythmic tapping. Polyrhythmic tapping was compared with an isochronous coordination pattern that retained the same serial order of finger movements as the polyrhythm. This experiment showed that the preSMA and the bilateral superior temporal gyri may be crucial for the rhythmic control of polyrhythmic tapping, while the cerebellum, the CMA, and the premotor cortices presumably are more involved in the ordinal control of the sequence of finger movements. [Abstract]

Kurata K, Tsuji T, Naraki S, Seino M, Abe Y
Activation of the dorsal premotor cortex and pre-supplementary motor area of humans during an auditory conditional motor task.
J Neurophysiol. 2000 Sep;84(3):1667-72.
Using functional magnetic resonance imaging (fMRI), we measured regional blood flow to examine which motor areas of the human cerebral cortex are preferentially involved in an auditory conditional motor behavior. As a conditional motor task, randomly selected 330 or 660 Hz tones were presented to the subjects every 1. 0 s. The low and high tones indicated that the subjects should initiate three successive opposition movements by tapping together the right thumb and index finger or the right thumb and little finger, respectively. As a control task, the same subjects were asked to alternate the two opposition movements, in response to randomly selected tones that were presented at the same frequencies. Between the two tasks, MRI images were also scanned in the resting state while the tones were presented in the same way. Comparing the images during each of the two tasks with images during the resting state, it was observed that several frontal motor areas, including the primary motor cortex, dorsal premotor cortex (PMd), supplementary motor area (SMA), and pre-SMA, were activated. However, preferential activation during the conditional motor task was observed only in the PMd and pre-SMA of the subjects' left (contralateral) frontal cortex. The PMd has been thought to play an important role in transforming conditional as well as spatial visual cues into corresponding motor responses, but our results suggest that the PMd along with the pre-SMA are the sites where more general and extensive sensorimotor integration takes place. [Abstract]

Rektor I
Scalp-recorded Bereitschaftspotential is the result of the activity of cortical and subcortical generators--a hypothesis.
Clin Neurophysiol. 2002 Dec;113(12):1998-2005.
OBJECTIVE: The source of scalp-recorded Bereitschaftspotential (BP) remains a subject of ongoing discussion. This paper presents arguments in favour of the hypothesis that explains scalp-recorded BP as the result of the activity of both cortical and subcortical BP generators. METHODS: Intracranial recordings of BP were performed, mostly with depth electrodes in epilepsy surgery candidates. In some patients undergoing intracranial exploration, an electrode may have had contacts in the subcortical structures. RESULTS: BP is generated in several cortical and subcortical structures that are known to be directly or indirectly linked with motor control. Cortical sources of BP were displayed contralaterally to the movement in the primary motor cortex and somatosensory cortex, and bilaterally in the supplementary motor area (SMA), in the preSMA, and in the cingulate. A few other generators may be revealed in structures that have not yet been sufficiently explored. Subcortical generators of BP were found in the putamen, pallidum, caudate, and in the thalamus. In earlier recordings, BP was described rostrally to the thalamic region and in the brainstem, i.e. in the pes peripedunculi, nucleus peripeduncularis, pulvinar, and medial geniculate. CONCLUSIONS: Our observations do not explain the generation of scalp-recorded BP by the contribution of either cortical or subcortical sources alone. Intracranial cortical recordings contradict a wide distribution of scalp-recorded BP. Widely synchronised cerebral electromagnetic activity can be recorded on the scalp. We presume that in the case of BP, the weak deep dipoles might reach the scalp, as they are produced by a relatively huge mass of subcortical neuronal tissue. We strongly suspect that scalp-recorded BP represents a summation of potentials that are generated simultaneously in several cortical as well as in several subcortical structures. [Abstract]

Derrfuss J, Brass M, von Cramon DY
Cognitive control in the posterior frontolateral cortex: evidence from common activations in task coordination, interference control, and working memory.
Neuroimage. 2004 Oct;23(2):604-12.
Cognitive control has often been associated with activations of middorsolateral prefrontal cortex. However, recent evidence highlights the importance of a more posterior frontolateral region around the junction of the inferior frontal sulcus and the inferior precentral sulcus (the inferior frontal junction area, IFJ). In the present experiment, we investigated the involvement of the IFJ in a task-switching paradigm, a manual Stroop task, and a verbal n-back task in a within-session within-group design. After computing contrasts for the individual tasks, the resulting z maps were overlaid to identify areas commonly activated by these tasks. Common activations were found in the IFJ, in the pre-SMA extending into mesial BA 8, in the middle frontal gyrus bordering the inferior frontal sulcus, in the anterior insula, and in parietal and thalamic regions. These results indicate the existence of a network of prefrontal, parietal, and subcortical regions mediating cognitive control in task coordination, interference control, and working memory. In particular, the results provide evidence for the assumption that, in the frontolateral cortex, not only the middorsolateral region but also the IFJ plays an important role in cognitive control. [Abstract]

Ikeda A, Yazawa S, Kunieda T, Ohara S, Terada K, Mikuni N, Nagamine T, Taki W, Kimura J, Shibasaki H.
Cognitive motor control in human pre-supplementary motor area studied by subdural recording of discrimination/selection-related potentials.
Brain. 1999 May;122 ( Pt 5):915-31.
To clarify the functional role of human pre-supplementary motor area (pre-SMA) in 'cognitive' motor control as compared with other non-primary motor cortices (SMA-proper and lateral premotor areas) and prefrontal area, we recorded epicortical field potentials by using subdural electrodes in five epileptic patients during presurgical evaluation, whose pre-SMA, SMA-proper, prefrontal and lateral premotor areas were defined by electric cortical stimulation and recent anatomical orientations according to the bicommissural plane and callosal grid system. An S1-Go/NoGo choice and delayed reaction task (S1-choice paradigm) and a warned choice Go/NoGo reaction task (S2-choice paradigm) with inter-stimulus intervals of 2 s were employed. The results showed (i) transient potentials with onset and peak latencies of about 200 and 600 ms, respectively, after S1 in the S1-choice paradigm mainly at pre-SMA and to a lesser degree at the prefrontal and lateral premotor areas, but not in the S2-choice paradigm. At SMA-proper, a similar but much smaller potential was seen after S1 in both S1- and S2-choice paradigms and (ii) slow sustained potentials between S1 and S2 in both S1- and S2-choice paradigms in all of the non-primary motor areas investigated (pre-SMA, SMA-proper and lateral premotor areas) and prefrontal area. It is concluded that pre-SMA plays a more important role in cognitive motor control which involves sensory discrimination and decision making or motor selection for the action after stimuli, whereas SMA-proper is one of the main generators of Bereitschaftspotential preceding self-paced, voluntary movements. In the more general anticipation of and attention to the forthcoming stimuli, non-primary motor cortices including pre-SMA, SMA-proper and lateral premotor area, and the prefrontal area are commonly involved. [Full Text]

Yamamoto J, Ikeda A, Satow T, Matsuhashi M, Baba K, Yamane F, Miyamoto S, Mihara T, Hori T, Taki W, Hashimoto N, Shibasaki H
Human eye fields in the frontal lobe as studied by epicortical recording of movement-related cortical potentials.
Brain. 2004 Apr;127(Pt 4):873-87.
We studied the generator location of premovement subcomponents of movement-related cortical potentials (MRCPs) [Bereitschaftspotential (BP), negative slope (NS') and motor potential (MP)] associated with voluntary, self-paced horizontal saccade in the human frontal lobe. Self-paced horizontal saccade, wrist (or middle finger) extension and foot dorsiflexion were employed in 10 patients (lateral surface of the frontal lobe in seven and mesial in three) as part of the presurgical evaluation, and data of five patients (lateral in four and mesial in three) were used in the final analysis. On the lateral frontal lobe, the maximum BP, NS' or MP with horizontal saccade was seen at or 1-2 cm rostral to the hand, arm or face area of the primary motor cortex (MI) in all four subjects investigated. This area exactly corresponded to the frontal eye field (FEF) identified by electrical stimulation. The amplitude of MRCPs with saccade was smaller than that with hand movements. On the mesial surface, within the supplementary motor area (SMA) proper, BP and/or NS' for horizontal saccade was located 1-2 cm rostral to that for hand and foot movements. BP and/or NS' delineated the supplementary eye field (SEF) at the rostral part of the SMA proper, and SEF partly overlapped with the hand and foot areas of the SMA proper. At the area just rostral to the vertical anterior commissure line and/or the pre-SMA defined by electrical stimulation, BP and/or NS' was seen invariably, regardless of the sites of movements, and in contrast with the SMA proper, there was no somatotopic representation. No clear MPs were elicited by eye movements on the mesial surface. In one of the two subjects whose MRCPs with horizontal saccade were recorded simultaneously from the lateral and mesial surfaces of the frontal lobe, BP from the SEF and pre-SMA preceded that from the FEF. It is concluded that MRCPs with horizontal saccade are useful for defining the FEF, SEF and pre-SMA, and that the SEF and pre-SMA become active in preparation for horizontal saccade earlier than the FEF. [Abstract]

Laureys S, Peigneux P, Phillips C, Fuchs S, Degueldre C, Aerts J, Del Fiore G, Petiau C, Luxen A, van der Linden M, Cleeremans A, Smith C, Maquet P
Experience-dependent changes in cerebral functional connectivity during human rapid eye movement sleep.
Neuroscience. 2001;105(3):521-5.
One function of sleep is hypothesized to be the reprocessing and consolidation of memory traces (Smith, 1995; Gais et al., 2000; McGaugh, 2000; Stickgold et al., 2000). At the cellular level, neuronal reactivations during post-training sleep in animals have been observed in hippocampal (Wilson and McNaughton, 1994) and cortical (Amzica et al., 1997) neuronal populations. At the systems level, using positron emission tomography, we have recently shown that some brain areas reactivated during rapid-eye-movement sleep in human subjects previously trained on an implicit learning task (a serial reaction time task) (Maquet et al., 2000). These cortical reactivations, located in the left premotor area and bilateral cuneus, were thought to reflect the reprocessing--possibly the consolidation--of memory traces during post-training rapid-eye-movement sleep. Here, the experience-dependent functional connectivity of these brain regions is examined. It is shown that the left premotor cortex is functionally more correlated with the left posterior parietal cortex and bilateral pre-supplementary motor area during rapid-eye-movement sleep of subjects previously trained to the reaction time task compared to rapid-eye-movement sleep of untrained subjects. The increase in functional connectivity during post-training rapid-eye-movement sleep suggests that the brain areas reactivated during post-training rapid-eye-movement sleep participate in the optimization of the network that subtends subject's visuo-motor response. The optimization of this visuo-motor network during sleep could explain the gain in performance observed during the following day. [Abstract]

Malouin F, Richards CL, Jackson PL, Dumas F, Doyon J
Brain activations during motor imagery of locomotor-related tasks: a PET study.
Hum Brain Mapp. 2003 May;19(1):47-62.
Positron emission tomography (PET) was used to study the involvement of supraspinal structures in human locomotion. Six right-handed adults were scanned in four conditions while imagining locomotor-related tasks in the first person perspective: Standing (S), Initiating gait (IG), Walking (W) and Walking with obstacles (WO). When these conditions were compared to a rest (control) condition to identify the neural structures involved in the imagination of locomotor-related tasks, the results revealed a common pattern of activations, which included the dorsal premotor cortex and precuneus bilaterally, the left dorsolateral prefrontal cortex, the left inferior parietal lobule, and the right posterior cingulate cortex. Additional areas involving the pre-supplementary motor area (pre-SMA), the precentral gyrus, were activated during conditions that required the imagery of locomotor movements. Further subtractions between the different locomotor conditions were then carried out to determine the cerebral regions associated with the simulation of increasingly complex locomotor functions. These analyses revealed increases in rCBF activity in the left cuneus and left caudate when the W condition was compared to the IG condition, suggesting that the basal ganglia plays a role in locomotor movements that are automatic in nature. Finally, subtraction of the W from the WO condition yielded increases in activity in the precuneus bilaterally, the left SMA, the right parietal inferior cortex and the left parahippocampal gyrus. Altogether, the present findings suggest that higher brain centers become progressively engaged when demands of locomotor tasks require increasing cognitive and sensory information processing. [Abstract]

Mecklinger A, Bosch V, Gruenewald C, Bentin S, von Cramon DY
What have Klingon letters and faces in common? An fMRI study on content-specific working memory systems.
Hum Brain Mapp. 2000 Nov;11(3):146-61.
Neuroimaging studies show that prefrontal, premotor, and parietal cortical regions are part of a working memory network that supports the active retention of information. In two experiments we used fMRI to examine whether prefrontal and posterior cortical areas are organized in a content-specific way for object and spatial working memory. Subjects performed a delayed matching-to-sample task modified to allow the examination of content-specific retention processes, independent of perceptual and decision-related processes. In Experiment 1, either unfamiliar geometrical objects (Klingon letters from an artificial alphabet unknown to the participants) or their spatial locations had to be memorized, whereas in Experiment 2, either unfamiliar faces or biological objects (butterflies) were actively memorized. All tasks activated a similar cortical network including posterior parietal (banks of the intraparietal sulcus), premotor (banks of the inferior precentral sulcus) and prefrontal regions (banks of the inferior frontal sulcus), and the presupplementary motor area (pre-SMA). For geometrical objects and faces for which strategic semantic processing can be assumed, this activation was larger in the left than in the right hemisphere, whereas a bilateral or right dominant distribution was obtained for butterflies and spatial locations. The present results do not support the process-specific or content-specific view of the role of the prefrontal cortex in working memory task. Rather, they suggest that the inferior prefrontal cortex houses nonmemonic strategic processing systems required for response selection and task management that can flexibly be used across a variety of tasks and informational domains. [Abstract]

Mellet E, Briscogne S, Tzourio-Mazoyer N, Ghaëm O, Petit L, Zago L, Etard O, Berthoz A, Mazoyer B, Denis M
Neural correlates of topographic mental exploration: the impact of route versus survey perspective learning.
Neuroimage. 2000 Nov;12(5):588-600.
There are two major sources of information to build a topographic representation of an environment, namely actual navigation within the environment (route perspective) and map learning (survey perspective). The aim of the present work was to use positron emission tomography (PET) to compare the neural substrate of the topographic representation built from these two modes. One group of subjects performed a mental exploration task in an environment learned from actual navigation (mental navigation task). Another group of subjects performed exploration in the same environment learned from a map (mental map task). A right hippocampal activation common to both mental navigation and mental map tasks was evidenced and may correspond the neural substrate of a "dual-perspective" representation. The parahippocampal gyrus was additionally activated bilaterally during mental navigation only. These results suggest that the right hippocampus involvement would be sufficient when the representation incorporates essentially survey information while the bilateral parahippocampal gyrus would be involved when the environment incorporates route information and includes "object" landmarks. The activation of a parietofrontal network composed of the intraparietal sulcus, the superior frontal sulcus, the middle frontal gyrus, and the pre-SMA was observed in common for both mental navigation and mental map and is likely to reflect the spatial mental imagery components of the tasks. [Abstract]

Krakauer JW, Ghilardi MF, Mentis M, Barnes A, Veytsman M, Eidelberg D, Ghez C
Differential cortical and subcortical activations in learning rotations and gains for reaching: a PET study.
J Neurophysiol. 2004 Feb;91(2):924-33.
Previous studies suggest that horizontal reaching movements are planned vectorially with independent specification of direction and extent. The transformation from visual to hand-centered coordinates requires the learning of a task-specific reference frame and scaling factor. We studied learning of a novel reference frame by imposing a screen-cursor rotation and learning of a scaling factor by imposing a novel gain. Previous work demonstrates that rotation and gain learning have different time courses and patterns of generalization. Here we used PET to identify and compare brain areas activated during rotation and gain learning, with a baseline motor-execution task as the subtracted control. Previous work has shown that the time courses of rotation and gain adaptation have a short rapid phase followed by a longer slow phase. We therefore also sought to compare activations associated with the rapid and slower phases of adaptation. We isolated the rapid phase by alternating opposite values of the rotation or gain every 16 movements. The rapid phase of rotation adaptation activated the preSMA. More complete adaptation to the rotation activated right ventral premotor cortex, right posterior parietal cortex, and the left lateral cerebellum. The rapid phase of gain learning only activated subcortical structures: bilateral putamen and left cerebellum. More complete gain learning failed to show any significant activation. We conclude that the time course of rotation adaptation is paralleled by a frontoparietal shift in activated cortical regions. In contrast, early gain adaptation involves only subcortical structures, which we suggest reflects a more automatic process of contextual recalibration of a scaling factor. [Abstract]

Johnston S, Leek EC, Atherton C, Thacker N, Jackson A
Functional contribution of medial premotor cortex to visuo-spatial transformation in humans.
Neurosci Lett. 2004 Jan 30;355(3):209-12.
This paper examines the functional contribution of medial premotor cortex, the supplementary motor area (SMA), to visuo-spatial transformation. Previous studies have found evidence of activation in SMA using 'mental rotation' tasks in which subjects make mirror-image judgements about simultaneously presented depth rotated novel forms. This manipulation induces potential confounds in the cognitive demands of the task in addition to spatial normalization processes. We clarify the role of SMA in visuo-spatial normalization using functional magnetic resonance imaging with a sequential mirror-image judgement task involving 2D image-plane rotated forms. The results show preferential activation of pre-SMA, as well as the ventrolateral prefrontal and parietal cortex during the visuo-spatial transformation of mirror-image stimuli. [Abstract]

Hamzei F, Dettmers C, Rijntjes M, Glauche V, Kiebel S, Weber B, Weiller C
Visuomotor control within a distributed parieto-frontal network.
Exp Brain Res. 2002 Oct;146(3):273-81.
The aim of this functional magnetic resonance imaging study was to investigate differences in visuomotor control with increasing task complexity. Twelve right-handed volunteers were asked to perform their signature under different degrees of visual control: internally generated movement with closed eyes, signing with open eyes, tracking the line of the projected signature forwards, and tracking the line of the projected signature backwards. There was a gradual onset and disappearance of activation within a distributed network. Parietal, lateral and medial frontal brain areas were activated during all conditions, confirming the involvement of a parieto-frontal system. The weight of activation shifted with increasing task complexity. Internally generated movements activated predominantly the inferior parietal lobule and the ventral premotor cortex, as well as the rostral cingulate area, pre-supplementary motor area (pre-SMA) and SMA proper. Opening the eyes reduced SMA and cingulate activation and activated increasingly the occipito-parietal areas with higher task complexity. Visually guided movements produced an activation predominantly in the superior parietal lobule and dorsal premotor cortex. This study bridges human activation studies with the results of neurophysiological studies with monkeys. It confirms a gradual transition of visuomotor control with increasing task complexity within a distributed parieto-frontal network. [Abstract]


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Recent Pre-supplementary Motor Area Research

1) Aizawa E, Sato Y, Kochiyama T, Saito N, Izumiyama M, Morishita J, Kanazawa M, Shima K, Mushiake H, Hongo M, Fukudo S
Altered Cognitive Function of Prefrontal Cortex during Error Feedback in Patients with Irritable Bowel Syndrome, Based on fMRI and Dynamic Causal Modeling.
Gastroenterology. 2012 Jul 26;
AIM: Patients with irritable bowel syndrome (IBS) have increased activity in the insula and reduced activation of the dorsolateral prefrontal cortex (DLPFC) in response to visceral stimulation. We investigated whether they have latent impairments in cognitive flexibility because of dysfunction in the DLPFC and insula and altered connectivity between brain regions. METHODS: We analyzed data from 30 individuals with IBS (15 men, 21.7 ± 3.0 years old) diagnosed based on Rome III criteria, along with 30 individuals matched for age, sex, and education level (controls). Event-related functional magnetic resonance imaging of the brain was performed to evaluate cognitive flexibility and assessed by the Wisconsin Card Sorting Test, in which subjects are allowed to change choice criteria, defined as set-shifting in response to error feedback. Brain images were analyzed with statistical parametric mapping 5 and 8 software and dynamic causal modeling (DCM). RESULTS: Subjects with IBS had significantly more Nelson perseverative errors (P < .05) and set-maintenance difficulties ( P < .05) than controls. They also showed significantly decreased activity of the right DLPFC (BA9, P < .001) and right hippocampus ( P < .001), and significantly increased activity of the left posterior insula (P < .001) at error feedback during set-shifting. DCM analysis during set-shifting revealed significantly less connectivity from the DLPFC to pre-supplementary motor area (pre-SMA) in subjects with IBS, compared with controls ( P = .012). CONCLUSION: Individuals with IBS have latent impairments in cognitive flexibility due to altered activity of the DLPFC, insula, and hippocampus, and impaired connectivity between the DLPFC and pre-SMA. [PubMed Citation] [Order full text from Infotrieve]

2) Adank P
Design Choices in Imaging Speech Comprehension: An Activation Likelihood Estimation (ALE) Meta-Analysis.
Neuroimage. 2012 Jul 23;
The localisation of spoken language comprehension is debated extensively: is processing located anterior or posterior on the left temporal lobe, and is it left- or bilaterally organised? An Activation Likelihood Estimation (ALE) analysis was conducted on functional MRI and PET studies investigating speech comprehension to identify the neural network involved in comprehension processing. Furthermore, the analysis aimed to establish the effect of four design choices (scanning paradigm, non-speech baseline, the presence of a task, and the type of stimulus material) on this comprehension network. The analysis included 57 experiments contrasting intelligible with less intelligible or unintelligible stimuli. A large comprehension network was found across bilateral Superior Temporal Sulcus (STS), Middle Temporal Gyrus (MTG) and Superior Temporal (STS) bilaterally, in left Inferior Frontal Gyrus (IFG), left Precentral Gyrus, and Supplementary Motor Area (SMA) and pre-SMA. The core network for post-lexical processing was restricted to the temporal lobes bilaterally with the highest ALE values located anterior to Heschl's Gyrus. Activations in the ALE comprehension network outside the temporal lobes (left IFG, SMA/pre-SMA, and Precentral Gyrus) were driven by the use of sentences instead of words, the scanning paradigm, or the type of non-speech baseline. [PubMed Citation] [Order full text from Infotrieve]

3) Hayes SJ, Elliott D, Andrew M, Roberts JW, Bennett SJ
Dissociable contributions of motor-execution and action-observation to intramanual transfer.
Exp Brain Res. 2012 Jul 22;
We examined the hypothesis that different processes and representations are associated with the learning of a movement sequence through motor-execution and action-observation. Following a pre-test in which participants attempted to achieve an absolute, and relative, time goal in a sequential goal-directed aiming movement, participants received either physical or observational practice with feedback. Post-test performance indicated that motor-execution and action-observation participants learned equally well. Participants then transferred to conditions where the gain between the limb movements and their visual consequences were manipulated. Under both bigger and smaller transfer conditions, motor-execution and action-observation participants exhibited similar intramanual transfer of absolute timing. However, participants in the action-observation group exhibited superior transfer of relative timing than the motor-execution group. These findings suggest that learning via action-observation is underpinned by a visual-spatial representation, while learning via motor-execution depends more on specific force-time planning (feed forward) and afferent processing associated with sensorimotor feedback. These behavioural effects are discussed with reference to neural processes associated with striatum, cerebellum and motor cortical regions (pre-motor cortex; SMA; pre-SMA). [PubMed Citation] [Order full text from Infotrieve]

4) Bastin J, Lebranchu P, Jerbi K, Kahane P, Orban G, Lachaux JP, Berthoz A
Direct recordings in human cortex reveal the dynamics of gamma-band [50-150Hz] activity during pursuit eye movement control.
Neuroimage. 2012 Jul 20;63(1):339-347.
The time course of neural activity in human brain regions involved in mediating pursuit eye movements is unclear. To address this question, we recorded intracerebral electroencephalography activity in eight epileptic patients while they performed a pursuit task that dissociates reactive, predictive and inhibited pursuits. A sustained gamma band (50-150Hz) activity corresponding to pursuit maintenance was observed in the pursuit (and not saccade) area of the frontal eye field (FEF), in the ventral intraparietal sulcus (VIPS) and in occipital areas. The latency of gamma increase was found to precede target onset in FEF and VIPS, suggesting that those areas could also be involved during pursuit preparation/initiation. During pursuit inhibition, a sustained gamma band response was observed within prefrontal areas (pre-supplementary-motor-area, dorso-lateral prefrontal and frontopolar cortex). This study describes for the first time the dynamics of the neural activity in four areas of the pursuit system, not previously available in humans. These findings provide novel timing constraints to current models of the human pursuit system and establish the relevance of direct recordings to precisely relate eye movement behavior with neural activity in humans. [PubMed Citation] [Order full text from Infotrieve]

5) Mattia M, Spadacenta S, Pavone L, Quarato P, Esposito V, Sparano A, Sebastiano F, Di Gennaro G, Morace R, Cantore G, Mirabella G
Stop-event-related potentials from intracranial electrodes reveal a key role of premotor and motor cortices in stopping ongoing movements.
Front Neuroeng. 2012;5:12.
In humans, the ability to withhold manual motor responses seems to rely on a right-lateralized frontal-basal ganglia-thalamic network, including the pre-supplementary motor area and the inferior frontal gyrus (IFG). These areas should drive subthalamic nuclei to implement movement inhibition via the hyperdirect pathway. The output of this network is expected to influence those cortical areas underlying limb movement preparation and initiation, i.e., premotor (PMA) and primary motor (M1) cortices. Electroencephalographic (EEG) studies have shown an enhancement of the N200/P300 complex in the event-related potentials (ERPs) when a planned reaching movement is successfully stopped after the presentation of an infrequent stop-signal. PMA and M1 have been suggested as possible neural sources of this ERP complex but, due to the limited spatial resolution of scalp EEG, it is not yet clear which cortical areas contribute to its generation. To elucidate the role of motor cortices, we recorded epicortical ERPs from the lateral surface of the fronto-temporal lobes of five pharmacoresistant epileptic patients performing a reaching version of the countermanding task while undergoing presurgical monitoring. We consistently found a stereotyped ERP complex on a single-trial level when a movement was successfully cancelled. These ERPs were selectively expressed in M1, PMA, and Brodmann's area (BA) 9 and their onsets preceded the end of the stop process, suggesting a causal involvement in this executive function. Such ERPs also occurred in unsuccessful-stop (US) trials, that is, when subjects moved despite the occurrence of a stop-signal, mostly when they had long reaction times (RTs). These findings support the hypothesis that motor cortices are the final target of the inhibitory command elaborated by the frontal-basal ganglia-thalamic network. [PubMed Citation] [Order full text from Infotrieve]

6) de Manzano O, Ullén F
Activation and connectivity patterns of the presupplementary and dorsal premotor areas during free improvisation of melodies and rhythms.
Neuroimage. 2012 Jun 23;63(1):272-280.
Free, i.e. non-externally cued generation of movement sequences is fundamental to human behavior. We have earlier hypothesized that the dorsal premotor cortex (PMD), which has been consistently implicated in cognitive aspects of planning and selection of spatial motor sequences may be particularly important for the free generation of spatial movement sequences, whereas the pre-supplementary motor area (pre-SMA), which shows increased activation during perception, learning and reproduction of temporal sequences, may contribute more to the generation of temporal structures. Here we test this hypothesis using fMRI and musical improvisation in professional pianists as a model behavior. We employed a 2×2 factorial design with the factors Melody (Specified/Improvised) and Rhythm (Specified/Improvised). The main effect analyses partly confirmed our hypothesis: there was a main effect of Melody in the PMD; the pre-SMA was present in the main effect of Rhythm, as predicted, as well as in the main effect of Melody. A psychophysiological interaction analysis of functional connectivity demonstrated that the correlation in activity between the pre-SMA and cerebellum was higher during rhythmic improvisation than during the other conditions. In summary, there were only subtle differences in activity level between the pre-SMA and PMD during improvisation, regardless of condition. Consequently, the free generation of rhythmic and melodic structures, appears to be largely integrated processes but the functional connectivity between premotor areas and other regions may change during free generation in response to sequence-specific spatiotemporal demands. [PubMed Citation] [Order full text from Infotrieve]

7) Coxon JP, Van Impe A, Wenderoth N, Swinnen SP
Aging and inhibitory control of action: cortico-subthalamic connection strength predicts stopping performance.
J Neurosci. 2012 Jun 13;32(24):8401-12.
Diffusion weighted imaging (DWI) studies in humans have shown that seniors exhibit reduced white matter integrity compared with young adults, with the most pronounced change occurring in frontal white matter. It is generally assumed that this structural deterioration underlies inhibitory control deficits in old age, but specific evidence from a structural neuroscience perspective is lacking. Cognitive action control is thought to rely on an interconnected network consisting of right inferior frontal cortex (r-IFC), pre-supplementary motor area (preSMA), and the subthalamic nucleus (STN). Here we performed probabilistic DWI tractography to delineate this cognitive control network and had the same individuals (20 young, 20 older adults) perform a task probing both response inhibition and action reprogramming. We hypothesized that structural integrity (fractional anisotropy) and connection strength within this network would be predictive of individual and age-related differences in task performance. We show that the integrity of r-IFC white matter is an age-independent predictor of stop-signal reaction time (SSRT). We further provide evidence that the integrity of white matter projecting to STN predicts both outright stopping (SSRT) and transient braking of response initiation to buy time for action reprogramming (stopping interference effects). These associations remain even after controlling for Go task performance, demonstrating specificity to the Stop component of this task. Finally, a multiple regression analysis reveals bilateral preSMA-STN tract strength as a significant predictor of SSRT in older adults. Our data link age-related decline in inhibitory control with structural decline of STN projections. [PubMed Citation] [Order full text from Infotrieve]

8) Mohseni HR, Smith PP, Parsons CE, Young KS, Hyam JA, Stein A, Stein JF, Green AL, Aziz TZ, Kringelbach ML
MEG can map short and long-term changes in brain activity following deep brain stimulation for chronic pain.
PLoS One. 2012;7(6):e37993.
Deep brain stimulation (DBS) has been shown to be clinically effective for some forms of treatment-resistant chronic pain, but the precise mechanisms of action are not well understood. Here, we present an analysis of magnetoencephalography (MEG) data from a patient with whole-body chronic pain, in order to investigate changes in neural activity induced by DBS for pain relief over both short- and long-term. This patient is one of the few cases treated using DBS of the anterior cingulate cortex (ACC). We demonstrate that a novel method, null-beamforming, can be used to localise accurately brain activity despite the artefacts caused by the presence of DBS electrodes and stimulus pulses. The accuracy of our source localisation was verified by correlating the predicted DBS electrode positions with their actual positions. Using this beamforming method, we examined changes in whole-brain activity comparing pain relief achieved with deep brain stimulation (DBS ON) and compared with pain experienced with no stimulation (DBS OFF). We found significant changes in activity in pain-related regions including the pre-supplementary motor area, brainstem (periaqueductal gray) and dissociable parts of caudal and rostral ACC. In particular, when the patient reported experiencing pain, there was increased activity in different regions of ACC compared to when he experienced pain relief. We were also able to demonstrate long-term functional brain changes as a result of continuous DBS over one year, leading to specific changes in the activity in dissociable regions of caudal and rostral ACC. These results broaden our understanding of the underlying mechanisms of DBS in the human brain. [PubMed Citation] [Order full text from Infotrieve]

9) Wendelken C, Munakata Y, Baym C, Souza M, Bunge SA
Flexible rule use: common neural substrates in children and adults.
Dev Cogn Neurosci. 2012 Jul;2(3):329-39.
Flexible rule-guided behavior develops gradually, and requires the ability to remember the rules, switch between them as needed, and implement them in the face of competing information. Our goals for this study were twofold: first, to assess whether these components of rule-guided behavior are separable at the neural level, and second, to identify age-related differences in one or more component that could support the emergence of increasingly accurate and flexible rule use over development. We collected event-related fMRI data while 36 children aged 8-13 and adults aged 20-27 performed a task that manipulated rule representation, rule switching, and stimulus incongruency. Several regions - left dorsolateral prefrontal cortex (DLPFC), left posterior parietal cortex, and pre-supplementary motor area - were engaged by both the rule representation and the rule-switching manipulations. These regions were engaged similarly across age groups, though contrasting timecourses of activation in left DLPFC suggest that children updated task rules more slowly than did adults. These findings support the idea that common networks can contribute to a variety of executive functions, and that some developmental changes take the form of changes in temporal dynamics rather than qualitative changes in the network of brain regions engaged. [PubMed Citation] [Order full text from Infotrieve]

10) Rochas V, Gelmini L, Krolak-Salmon P, Poulet E, Saoud M, Brunelin J, Bediou B
Disrupting Pre-SMA Activity Impairs Facial Happiness Recognition: An Event-Related TMS Study.
Cereb Cortex. 2012 Jun 1;
It has been suggested that the left pre-supplementary motor area (pre-SMA) could be implicated in facial emotion expression and recognition, especially for laughter/happiness. To test this hypothesis, in a single-blind, randomized crossover study, we investigated the impact of transcranial magnetic stimulation (TMS) on performances of 18 healthy participants during a facial emotion recognition task. Using a neuronavigation system based on T1-weighted magnetic resonance imaging of each participant, TMS (5 pulses, 10 Hz) was delivered over the pre-SMA or the vertex (control condition) in an event-related fashion after the presentation of happy, fear, and angry faces. Compared with performances during vertex stimulation, we observed that TMS applied over the left pre-SMA specifically disrupted facial happiness recognition (FHR). No difference was observed between the 2 conditions neither for fear and anger recognition nor for reaction times (RT). Thus, interfering with pre-SMA activity with event-related TMS after stimulus presentation produced a selective impairment in the recognition of happy faces. These findings provide new insights into the functional implication of the pre-SMA in FHR, which may rely on the mirror properties of pre-SMA neurons. [PubMed Citation] [Order full text from Infotrieve]

11) Vollmann H, Conde V, Sewerin S, Taubert M, Sehm B, Witte OW, Villringer A, Ragert P
Anodal transcranial direct current stimulation (tDCS) over supplementary motor area (SMA) but not pre-SMA promotes short-term visuomotor learning.
Brain Stimul. 2012 May 7;
BACKGROUND: Non-invasive brain stimulation such as transcranial direct current stimulation (tDCS) has been shown to modulate cortical excitability and thereby influencing motor behaviour and learning. HYPOTHESIS: While there is increasing knowledge about the importance of the primary motor cortex (M1) in short- and long-term motor skill learning, little is known about the role of secondary motor areas such as the supplementary and pre-supplementary motor area (SMA/pre-SMA) especially in short-term motor performance. Since SMA but not pre-SMA is directly connected to M1, we hypothesize that anodal tDCS over SMA but not pre-SMA will facilitate visuomotor learning. METHODS: We applied anodal tDCS (tDCS(anodal)) over left SMA, pre-SMA or M1 (n=12 in each group) while subjects performed a visuomotor pinch force task (VPFT) with their right hand and compared VPFT performance relative to sham (tDCS(sham)). RESULTS: For the first time, we could show that apart from tDCS(anodal) over left M1 also SMA but not pre-SMA stimulation promotes short-term improvements in visuomotor learning relative to tDCS(sham). CONCLUSIONS: Our findings provide novel evidence about the role of SMA in short-term visuomotor performance. This knowledge might be beneficial in developing hypothesis-driven clinical studies in neurorehabilitation. [PubMed Citation] [Order full text from Infotrieve]

12) Adleman NE, Fromm SJ, Razdan V, Kayser R, Dickstein DP, Brotman MA, Pine DS, Leibenluft E
Cross-sectional and longitudinal abnormalities in brain structure in children with severe mood dysregulation or bipolar disorder.
J Child Psychol Psychiatry. 2012 Jun 1;
Background:? There is debate as to whether chronic irritability (operationalized as severe mood dysregulation, SMD) is a developmental form of bipolar disorder (BD). Although structural brain abnormalities in BD have been demonstrated, no study compares neuroanatomy among SMD, BD, and healthy volunteers (HV) either cross-sectionally or over time. Furthermore, the developmental trajectories of structural abnormalities in BD or SMD are unknown. This study provides such data in BD, SMD, and HV. Methods:? An optimized, modulated voxel-based morphometry (VBM) analysis was conducted on structural MRI scans from 201 children (78 SMD, 55 BD, and 68 HV). In addition, 92 children (31 SMD, 34 BD, and 27 HV) were rescanned after 2?years (mean interval 1.99?±?0.94?years), to compare time-related changes among the three groups. Results:? Cross-sectionally, the groups differed in gray matter (GM) volume in presupplementary motor area (pre-SMA), dorsolateral prefrontal cortex (DLPFC), insula, and globus pallidus. The cortical differences were driven mainly by increased GM volume in HV compared with BD and SMD. In globus pallidus, there was increased GM in BD compared with HV and SMD. Longitudinally, group-by-time interactions were evident in two clusters in the superior/inferior parietal lobule (R SPL/IPL) and in the precuneus. In both clusters, the interactions were driven by an abnormal increase in volume in BD. Conclusions:? Cross-sectionally, both BD and SMD are associated with structural abnormalities in frontal cortex, insula, and basal ganglia. Although some of these deficits overlap (insula and DLPFC), others differentiate SMD and BD (pre-SMA and globus pallidus). Abnormal developmental trajectories in lateral parietal cortex and precuneus are present in, and unique to, BD. Because of the high proportion of co-occurring ADHD in the SMD subjects, we could not separate effects of ADHD from those of SMD, and future research including a nonirritable ADHD group must address this issue. [PubMed Citation] [Order full text from Infotrieve]

13) Adank P
The neural bases of difficult speech comprehension and speech production: Two Activation Likelihood Estimation (ALE) meta-analyses.
Brain Lang. 2012 Jul;122(1):42-54.
The role of speech production mechanisms in difficult speech comprehension is the subject of on-going debate in speech science. Two Activation Likelihood Estimation (ALE) analyses were conducted on neuroimaging studies investigating difficult speech comprehension or speech production. Meta-analysis 1 included 10 studies contrasting comprehension of less intelligible/distorted speech with more intelligible speech. Meta-analysis 2 (21 studies) identified areas associated with speech production. The results indicate that difficult comprehension involves increased reliance of cortical regions in which comprehension and production overlapped (bilateral anterior Superior Temporal Sulcus (STS) and anterior Supplementary Motor Area (pre-SMA)) and in an area associated with intelligibility processing (left posterior MTG), and second involves increased reliance on cortical areas associated with general executive processes (bilateral anterior insulae). Comprehension of distorted speech may be supported by a hybrid neural mechanism combining increased involvement of areas associated with general executive processing and areas shared between comprehension and production. [PubMed Citation] [Order full text from Infotrieve]

14) Özyurt J, Rietze M, Thiel CM
Prefrontal neural activity when feedback is not relevant to adjust performance.
PLoS One. 2012;7(5):e36509.
It has been shown that the rostral cingulate zone (RCZ) in humans uses both positive and negative feedback to evaluate performance and to flexibly adjust behaviour. Less is known on how the feedback types are processed by the RCZ and other prefrontal brain areas, when feedback can only be used to evaluate performance, but cannot be used to adjust behaviour. The present fMRI study aimed at investigating feedback that can only be used to evaluate performance in a word-learning paradigm. One group of volunteers (N = 17) received informative, performance-dependent positive or negative feedback after each trial. Since new words had to be learnt in each trial, the feedback could not be used for task-specific adaptations. The other group (N = 17) always received non-informative feedback, providing neither information about performance nor about possible task-specific adaptations. Effects of the informational value of feedback were assessed between-subjects, comparing trials with positive and negative informative feedback to non-informative feedback. Effects of feedback valence were assessed by comparing neural activity to positive and negative feedback within the informative-feedback group. Our results show that several prefrontal regions, including the pre-SMA, the inferior frontal cortex and the insula were sensitive to both, the informational value and the valence aspect of the feedback with stronger activations to informative as compared to non-informative feedback and to informative negative compared to informative positive feedback. The only exception was RCZ which was sensitive to the informational value of the feedback, but not to feedback valence. The findings indicate that outcome information per se is sufficient to activate prefrontal brain regions, with the RCZ being the only prefrontal brain region which is equally sensitive to positive and negative feedback. [PubMed Citation] [Order full text from Infotrieve]

15) Kaas AL, van Mier H, Visser M, Goebel R
The neural substrate for working memory of tactile surface texture.
Hum Brain Mapp. 2012 Jan 16;
Fine surface texture is best discriminated by touch, in contrast to macro geometric features like shape. We used functional magnetic resonance imaging and a delayed match-to-sample task to investigate the neural substrate for working memory of tactile surface texture. Blindfolded right-handed males encoded the texture or location of up to four sandpaper stimuli using the dominant or non-dominant hand. They maintained the information for 10-12 s and then answered whether a probe stimulus matched the memory array. Analyses of variance with the factors Hand, Task, and Load were performed on the estimated percent signal change for the encoding and delay phase. During encoding, contralateral effects of Hand were found in sensorimotor regions, whereas Load effects were observed in bilateral postcentral sulcus (BA2), secondary somatosensory cortex (S2), pre-SMA, dorsolateral prefrontal cortex (dlPFC), and superior parietal lobule (SPL). During encoding and delay, Task effects (texture > location) were found in central sulcus, S2, pre-SMA, dlPFC, and SPL. The Task and Load effects found in hand- and modality-specific regions BA2 and S2 indicate involvement of these regions in the tactile encoding and maintenance of fine surface textures. Similar effects in hand- and modality-unspecific areas dlPFC, pre-SMA and SPL suggest that these regions contribute to the cognitive monitoring required to encode and maintain multiple items. Our findings stress both the particular importance of S2 for the encoding and maintenance of tactile surface texture, as well as the supramodal nature of parieto-frontal networks involved in cognitive control. Hum Brain Mapp, 2012. © 2012 Wiley Periodicals, Inc. [PubMed Citation] [Order full text from Infotrieve]

16) Rosenberg-Katz K, Jamshy S, Singer N, Podlipsky I, Kipervasser S, Andelman F, Neufeld MY, Intrator N, Fried I, Hendler T
Enhanced functional synchronization of medial and lateral PFC underlies internally-guided action planning.
Front Hum Neurosci. 2012;6:79.
Actions are often internally guided, reflecting our covert will and intentions. The dorsomedial prefrontal cortex, including the pre-Supplementary Motor Area (pre-SMA), has been implicated in the internally generated aspects of action planning, such as choice and intention. Yet, the mechanism by which this area interacts with other cognitive brain regions such as the dorsolateral prefrontal cortex, a central node in decision-making, is still unclear. To shed light on this mechanism, brain activity was measured via fMRI and intracranial EEG in two studies during the performance of visually cued repeated finger tapping in which the choice of finger was guided by either a presented number (external) or self-choice (internal). A functional-MRI (fMRI) study in 15 healthy participants demonstrated that the pre-SMA, compared to the SMA proper, was more active and also more functionally correlated with the dorsolateral prefrontal cortex during internally compared to externally guided action planning (p < 0.05, random effect). In a similar manner, an intracranial-EEG study in five epilepsy patients showed greater inter-regional gamma-related connectivity between electrodes situated in medial and lateral aspects of the prefrontal cortex for internally compared to externally guided actions. Although this finding was observed for groups of electrodes situated both in the pre-SMA and SMA-proper, increased intra-cluster gamma-related connectivity was only observed for the pre-SMA (sign-test, p < 0.0001). Overall our findings provide multi-scale indications for the involvement of the dorsomedial prefrontal cortex, and especially the pre-SMA, in generating internally guided motor planning. Our intracranial-EEG results further point to enhanced functional connectivity between decision-making- and motor planning aspects of the PFC, as a possible neural mechanism for internally generated action planning. [PubMed Citation] [Order full text from Infotrieve]

17) Cai W, George JS, Verbruggen F, Chambers CD, Aron AR
The role of the right presupplementary motor area in stopping action: two studies with event-related transcranial magnetic stimulation.
J Neurophysiol. 2012 Jul;108(2):380-9.
Rapidly stopping action engages a network in the brain including the right presupplementary motor area (preSMA), the right inferior frontal gyrus, and the basal ganglia. Yet the functional role of these different regions within the overall network still remains unclear. Here we focused on the role of the right preSMA in behavioral stopping. We hypothesized that the underlying neurocognitive function of this region is one or more of setting up a stopping rule in advance, modulating response tendencies (e.g., slowing down in anticipation of stopping), and implementing stopping when the stop signal occurs. We performed two experiments with magnetic resonance imaging (MRI)-guided, event-related, transcranial magnetic stimulation(TMS), during the performance of variants of the stop signal task. In experiment 1 we show that stimulation of the right preSMA versus vertex (control site) slowed the implementation of stopping (measured via stop signal reaction time) but had no influence on modulation of response tendencies. In experiment 2, we showed that stimulation of the right preSMA slowed implementation of stopping in a mechanistically selective form of stopping but had no influence on setting up stopping rules. The results go beyond the replication of prior findings by showing that TMS of the right preSMA impairs stopping behavior (including a behaviorally selective form of stopping) through a specific disruption of the implementation of stopping. Future studies are required to establish whether this was due to stimulation of the right preSMA itself or because of remote effects on the wider stopping network. [PubMed Citation] [Order full text from Infotrieve]

18) Juan CH, Muggleton NG
Brain stimulation and inhibitory control.
Brain Stimul. 2012 Apr;5(2):63-9.
Inhibitory control mechanisms are important in a range of behaviours to prevent execution of motor acts which, having been planned, are no longer necessary or appropriate. Examples of this can be seen in a range of sports, such as cricket and baseball, where the choice between execution and inhibition of a bat swing must be made in a very brief time window. Deficits in inhibitory control have been associated with problems in behavioural regulation in impulsive violence as well as a range of clinical disorders. The roles of various areas, including the frontal eye fields (FEF), the pre-supplementary motor area (pre-SMA) and the inferior frontal gyrus, in inhibitory control have been investigated using an inhibitory control task and both transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS). Typically effects on response inhibition but no effects on response generation have been seen. The contributions of these areas to performance seem to differ with, for example, pre-SMA being involved when the task is relatively novel whereas this is not the case for FEF. The findings from brain stimulation studies offer both insight into which areas are necessary for effective inhibitory control and recent extension of findings for the role of the inferior frontal gyrus illustrate how the specific functions by which these areas contribute may be further clarified. Future work, including making use of the temporal specificity of TMS and combination of TMS/tDCS with other neuroimaging techniques, may further clarify the nature and functions played by the network of areas involved in inhibitory control. [PubMed Citation] [Order full text from Infotrieve]

19) Ferri F, Frassinetti F, Ardizzi M, Costantini M, Gallese V
A sensorimotor network for the bodily self.
J Cogn Neurosci. 2012 Jul;24(7):1584-95.
Neuroscientists and philosophers, among others, have long questioned the contribution of bodily experience to the constitution of self-consciousness. Contemporary research answers this question by focusing on the notions of sense of agency and/or sense of ownership. Recently, however, it has been proposed that the bodily self might also be rooted in bodily motor experience, that is, in the experience of oneself as instantiating a bodily structure that enables a specific range of actions. In the current fMRI study, we tested this hypothesis by making participants undergo a hand laterality judgment task, which is known to be solved by simulating a motor rotation of one's own hand. The stimulus to be judged was either the participant's own hand or the hand of a stranger. We used this task to investigate whether mental rotation of pictures depicting one's own hands leads to a different activation of the sensorimotor areas as compared with the mental rotation of pictures depicting another's hand. We revealed a neural network for the general representation of the bodily self encompassing the SMA and pre-SMA, the anterior insula, and the occipital cortex, bilaterally. Crucially, the representation of one's own dominant hand turned out to be primarily confined to the left premotor cortex. Our data seem to support the existence of a sense of bodily self encased within the sensorimotor system. We propose that such a sensorimotor representation of the bodily self might help us to differentiate our own body from that of others. [PubMed Citation] [Order full text from Infotrieve]

20) Wai YY, Wang JJ, Weng YH, Lin WY, Ma HK, Ng SH, Wan YL, Wang CH
Cortical involvement in a gait-related imagery task: comparison between Parkinson's disease and normal aging.
Parkinsonism Relat Disord. 2012 Jun;18(5):537-42.
[PubMed Citation] [Order full text from Infotrieve]