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 examin