Manji HK, Lenox RH.
Signaling: cellular insights
into the pathophysiology of bipolar disorder.
2000 Sep 15;48(6):518-30
"Clinical studies over the years have provided
evidence that monoamine signaling and hypothalamic-pituitary-adrenal axis disruption
are integral to the pathophysiology of bipolar disorder. A full understanding
of the pathophysiology from a molecular to a systems level must await the identification
of the susceptibility and protective genes driving the underlying neurobiology
of bipolar disorder. Furthermore, the complexity of the unique biology of this
affective disorder, which includes the predisposition to episodic and often progressive
mood disturbance, and the dynamic nature of compensatory processes in the brain,
coupled with limitations in experimental design, have hindered our progress to
date. Imaging studies in patient populations have provided evidence of a role
for anterior cingulate, amygdala, and prefrontal cortex in the pathophysiology
of bipolar disorder. More recent research strategies designed to uncover the molecular
mechanisms underlying our pharmacologic treatments and their interaction in the
regulation of signal transduction as well as more advanced brain imaging studies
remain promising approaches. This experimental strategy provides data derived
from the physiologic response of the system in affected individuals and addresses
the critical dynamic interaction with pharmacologic agents that effectively modify
the clinical expression of the pathophysiology." [Abstract]
MP, Freed WJ, Kleinman JE.
Neuropathology of bipolar disorder.
Biol Psychiatry 2000 Sep 15;48(6):486-504
"The literature on the neuropathology
of bipolar disorder (BD) is reviewed. Postmortem findings in the areas of pathomorphology,
signal transduction, neuropeptides, neurotransmitters, cell adhesion molecules,
and synaptic proteins are considered. Decreased glial numbers and density in both
BD and major depressive disorder (MDD) have been reported, whereas cortical neuron
counts were not different in BD (in Brodmann's areas [BAs] 9 and 24). In contrast,
MDD patients showed reductions in neuronal size and density (BA 9, BA 47). There
are a number of findings of alterations in neuropeptides and monoamines in BD
brains. Norepinephrine turnover was increased in several cortical regions and
thalamus, whereas the serotonin metabolite, 5-hydroxyindoleacetic acid, and the
serotonin transporter were reduced in the cortex. Several reports further implicated
both cyclic adenosine monophosphate and phosphatidylinositol (PI) cascade abnormalities.
G protein concentrations and activity increases were found in the occipital, prefrontal,
and temporal cortices in BD. In the PI signal cascade, alterations in PKC activity
were found in the prefrontal cortex. In the occipital cortex, PI hydrolysis was
decreased. Two isoforms of the neural cell adhesion molecules were increased in
the hippocampus of BD, whereas the synaptic protein marker, synaptophysin, was
not changed. The findings of glial reduction, excess signal activity, neuropeptide
abnormalities, and monoamine alterations suggest distinct imbalances in neurochemical
regulation. Possible alterations in pathways involving ascending projections from
the brain stem are considered. Larger numbers of BD brains are needed to further
refine the conceptual models that have been proposed, and to develop coherent
models of the pathophysiology of BD." [Abstract]
N, Erfurth A, Ohrmann P, Gossling M, Arolt V, Heindel W, Pfleiderer B.
mania is accompanied by elevated glutamate/glutamine levels within the left dorsolateral
Psychopharmacology (Berl). 2003 Apr 9
[Epub ahead of print].
"RATIONALE. The dorsolateral prefrontal cortex
(DLPFC) participates in the pathophysiology of mania. In particular, left-sided
structural and metabolic abnormalities have been described. OBJECTIVES. Clinical
symptoms may be due to hyperactivity of cortical glutamatergic neurons, resulting
in increased excitatory neurotransmitter flux and thus enhanced Glx levels. METHODS.
Glutamate/glutamine (Glx) levels were assessed by proton magnetic resonance spectroscopy
((1)H-MRS) in eight acute manic patients compared with age- and gender-matched
controls. RESULTS. Manic patients had significantly elevated Glx levels ( t-test;
t=-3.1, P=0.008) within the left DLPFC. CONCLUSIONS. Our results indicate that
the prefrontal cortical glutamatergic system is involved in the pathophysiology
of acute mania. This may have implications for the treatment of mania." [Abstract]
Grisaru N, Chudakov B, Yaroslavsky Y, Belmaker RH.
Transcranial magnetic stimulation in mania: a controlled study.
Am J Psychiatry 1998 Nov;155(11):1608-10
"OBJECTIVE: Left prefrontal
transcranial magnetic stimulation has been reported to have ECT-like effects in
depression; therefore, the authors planned a study of transcranial magnetic stimulation
in mania. METHOD: Sixteen patients completed a 14-day double-blind, controlled
trial of right versus left prefrontal transcranial magnetic stimulation at 20
Hz (2-second duration per train, 20 trains/day for 10 treatment days). Mania was
evaluated with the Mania Scale, the Brief Psychiatric Rating Scale, and the Clinical
Global Impression. RESULTS: Significantly more improvement was observed in patients
treated with right than with left prefrontal transcranial magnetic stimulation.
CONCLUSIONS: The therapeutic effect of transcranial magnetic stimulation in mania
may show laterality opposite to its effect in depression." [Abstract]
LR Jr, Schwartz JM, Phelps ME, Mazziotta JC, Guze BH, Selin CE, Gerner RH, Sumida
Reduction of prefrontal cortex glucose metabolism common to
three types of depression.
Arch Gen Psychiatry 1989 Mar;46(3):243-50
"Using positron emission tomography, we studied cerebral glucose metabolism
in drug-free, age- and sex-matched, right-handed patients with unipolar depression
(n = 10), bipolar depression (n = 10), obsessive-compulsive disorder (OCD) with
secondary depression (n = 10), OCD without major depression (n = 14), and normal
controls (n = 12). Depressed patients were matched for depression on the Hamilton
Depression Rating Scale, and subjects with OCD without depression and OCD with
depression had similar levels of OCD without depression and OCD with depression
had similar levels of OCD pathology. We also studied six non-sex-matched patients
with mania. Mean (+/- SD) glucose metabolic rates for the left dorsal anterolateral
prefrontal cortex, divided by the rate for the ipsilateral hemisphere as a whole
(ALPFC/hem), were similar in the primary depressions (unipolar depression = 1.05
+/- 0.05; bipolar depression = 1.04 +/- 0.05), and were significantly lower than
those in normal controls (1.12 +/- 0.06) or OCD without depression (1.15 +/- 0.05).
Results for the right hemisphere were similar. Values in subjects with OCD with
depression (1.10 +/- 0.05) were also significantly lower than in subjects with
OCD without depression, and values in subjects with bipolar depression were lower
than those in manic subjects (1.12 +/- 0.03) on this measure in the left hemisphere,
although results were not significant in the right hemisphere. There was a significant
correlation between the HAM-D score and the left ALPFC/hem. With medication for
depression (n = 12), the left ALPFC/hem increased significantly and the percentage
change in the Hamilton scale score correlated with the percentage change in the
left ALPFC/hem." [Abstract]
TA, Kimbrell TA, George MS, Dunn RT, Speer AM, Benson BE, Willis MW, Danielson
A, Frye MA, Herscovitch P, Post RM.
Effects of mood and subtype
on cerebral glucose metabolism in treatment-resistant bipolar disorder.
Biol Psychiatry 2001 Jan 15;49(2):97-109
"BACKGROUND: Functional brain
imaging studies in unipolar and secondary depression have generally found decreased
prefrontal cortical activity, but in bipolar disorders findings have been more
variable. METHODS: Forty-three medication-free, treatment-resistant, predominantly
rapid-cycling bipolar disorder patients and 43 age- and gender-matched healthy
control subjects had cerebral glucose metabolism assessed using positron emission
tomography and fluorine-18-deoxyglucose. RESULTS: Depressed bipolar disorder patients
compared to control subjects had decreased global, absolute prefrontal and anterior
paralimbic cortical, and increased normalized subcortical (ventral striatum, thalamus,
right amygdala) metabolism. Degree of depression correlated negatively with absolute
prefrontal and paralimbic cortical, and positively with normalized anterior paralimbic
subcortical metabolism. Increased normalized cerebello-posterior cortical metabolism
was seen in all patient subgroups compared to control subjects, independent of
mood state, disorder subtype, or cycle frequency. CONCLUSIONS: In bipolar depression,
we observed a pattern of prefrontal hypometabolism, consistent with observations
in primary unipolar and secondary depression, suggesting this is part of a common
neural substrate for depression independent of etiology. In contrast, the cerebello-posterior
cortical normalized hypermetabolism seen in all bipolar subgroups (including euthymic)
suggests a possible congenital or acquired trait abnormality. The degree to which
these findings in treatment-resistant, predominantly rapid-cycling patients pertain
to community samples remains to be established." [Abstract]
DA, Gruber SA, Kanayama G, Killgore WD, Baird AA, Young AD.
during affect discrimination in bipolar affective disorder.
Bipolar Disord 2000 Sep;2(3 Pt 2):237-48
"OBJECTIVE: It has been hypothesized
that disturbances in affect may represent distinct etiologic factors for bipolar
affective disorder. The neural mechanisms mediating affective processes and their
relationship to brain development and the pathophysiology of bipolar affective
disorder remain to be clarified. Recent advances in neuroimaging techniques have
made possible the non-invasive examination of specific brain regions during cortical
challenge paradigms. This study reports findings based on fMRI data acquired during
fearful and happy affect recognition paradigms in patients with bipolar affective
disorder and in healthy adult subjects. METHODS: Prior to the scan, subjects were
instructed to view the stimuli and to identify the type of facial expression presented.
Echo planar scanning was performed on a 1.5 Tesla scanner which had been retrofitted
with a whole body echo planar coil, using a head coil. RESULTS: The data indicate
that in adult subjects with bipolar affective disorder, there is a reduction in
dorsolateral prefrontal cortex activation and an increase in amygdalar activation
in response to fearful facial affect. In a healthy comparison group, signal intensity
changes were not found in these regions. In addition, although the patients with
bipolar affective disorder completed the task demands, they demonstrated an impaired
ability to correctly identify fearful facial affect but not the happy facial affect
displayed. CONCLUSION: These findings are consistent with the hypothesis that
in some patients with bipolar affective disorder, there may be a reduction of
frontal cortical function which may be associated with affective as well as attentional
processing deficits." [Abstract]
KM, DelBello MP, Morey R, Strakowski SM.
Frontal lobe differences
in bipolar disorder as determined by proton MR spectroscopy.
Disord. 2002 Dec;4(6):357-65.
"OBJECTIVES: Proton magnetic resonance spectroscopy
(MRS) provides insight into neurochemical processes. Imaging and postmortem studies
have implicated abnormalities of structure and function within the frontal lobe.
Patients with bipolar disorder having a manic or mixed episode were hypothesized
to demonstrate metabolic abnormalities within the frontal lobe. METHODS: Seventeen
patients with bipolar disorder type I (ages 16-35 years, mean 22 +/- 7.3 years)
hospitalized for a manic (n = 9) or mixed (n = 8) episode and 21 healthy subjects
(ages 16-35 years, mean 21.7 +/- 5.2 years) were evaluated with proton MRS. The
gray matter medially and white matter laterally within the frontal lobe were sampled.
Metabolite concentrations were calculated for each voxel, corrected for cerebral
spinal fluid (CSF) contributions to the voxel, and compared between study populations.
RESULTS: Patients demonstrated with multivariate analyses of variance (MANOVA)
a significant overall difference in gray matter metabolite concentrations compared
with healthy subjects. The largest effect sizes for group differences were found
with reductions of N-acetyl aspartate (NAA) and Choline (Cho) concentrations (f
= 0.41 and 0.37, respectively). A significant group difference with MANOVA in
white matter metabolite concentrations was also observed with the largest effect
size at f = 0.44 for elevation of the composite amino acid (AA) concentration.
CONCLUSIONS: A reduction of NAA within the gray matter of patients suggests neuronal
dysfunction. Altered phospholipid metabolism suggestive of a trend toward decreased
volume is implicated with a reduction of Cho concentrations. Within white matter,
composite concentrations of AAs were elevated in patients indicating altered neurotransmission."
S, Reynolds LM, Reynolds GP.
N-acetylaspartate and N-Acetylaspartylglutamate
deficits in superior temporal cortex in schizophrenia and bipolar disorder: a
Biol Psychiatry. 2003 Jun 15;53(12):1138-41.
N-acetylaspartylglutamate is found in neurons and its metabolite N-acetylaspartate,
which can be measured by magnetic resonance spectroscopy, is considered a marker
of neuronal integrity. Several magnetic resonance spectroscopy studies have found
evidence of N-acetylaspartate deficits in schizophrenia. METHODS: We employed
a high-pressure liquid chromatography method to determine N-acetylaspartate and
N-acetylaspartylglutamate in postmortem brain tissues taken from a well-defined
series of psychiatric cases. N-acetylaspartate and N-acetylaspartylglutamate concentrations
were measured in superior temporal and frontal cortices of patients with schizophrenia,
bipolar disorder, and depression and control subjects. RESULTS: N-acetylaspartate
was significantly decreased below controls in superior temporal cortex in schizophrenia
(p <.01) and bipolar disorder (p <.01), but no deficits were found in frontal
cortex. N-acetylaspartylglutamate was significantly decreased only in superior
temporal cortex in schizophrenia. CONCLUSIONS: The results are consistent with
evidence of superior temporal cortex abnormalities in schizophrenia. The finding
in bipolar disorder suggests that temporal cortex N-acetylaspartate deficits may
be a common feature of psychotic disorders." [Abstract]
Lopez-Larson MP, DelBello MP, Zimmerman ME, Schwiers
ML, Strakowski SM.
Regional prefrontal gray and white matter abnormalities
in bipolar disorder.
Biol Psychiatry 2002 Jul 15;52(2):93-100
"BACKGROUND: Previous magnetic resonance imaging (MRI) studies indicate that
compared with healthy volunteers, patients with bipolar disorder have structural
and functional abnormalities in the prefrontal cortex. The aim of this study was
to investigate differences in prefrontal subregions between bipolar patients and
healthy subjects. METHODS: Bipolar patients hospitalized for a manic episode (n
= 17), and demographically matched healthy volunteers (n = 12) were recruited.
Contiguous 1-mm coronal T1-weighted MRI slices were obtained using a Picker 1.5
Tesla scanner. The gray and white matter volumes of five prefrontal subregions
of interest were measured: superior, middle, inferior, cingulate, and orbital.
RESULTS: Bipolar patients had smaller left prefrontal gray matter volumes, specifically
in the middle and superior subregions and smaller right prefrontal gray matter
volumes, specifically in the inferior and middle subregions. White matter differences
were not observed in any of the prefrontal subregions. CONCLUSIONS: The results
suggest that bipolar patients have subregion-specific gray matter volume reductions
in the prefrontal cortex as compared to healthy subjects. Further investigations
into the role of specific prefrontal subregions in bipolar disorder are warranted."
HP, Martin A, Kaufman J, Leung HC, Skudlarski P, Lacadie C, Fulbright RK, Gore
JC, Charney DS, Krystal JH, Peterson BS.
in adolescents with bipolar disorder: preliminary observations from functional
Am J Psychiatry. 2003 Jul;160(7):1345-7.
This study investigated whether the functional abnormalities in prefrontal systems
observed in adult bipolar disorder are manifested in adolescents with this illness.
METHOD: Ten adolescents with bipolar disorder and 10 healthy comparison subjects
participated in a color-naming Stroop task during event-related functional magnetic
resonance imaging. RESULTS: Signal increases in the left putamen and thalamus
were significantly greater in the bipolar disorder group than in the healthy group.
Age correlated positively with signal increases in the bilateral rostroventral
prefrontal cortex and the striatum in the healthy group but not in the bipolar
disorder group. In the bipolar disorder subjects, depressive symptoms correlated
positively with signal increases in the ventral striatum. CONCLUSIONS: These findings
suggest the presence of dysfunction in the subcortical portions of the frontostriatal
circuits in adolescents with bipolar disorder. The absence of the prefrontal abnormalities
that were observed previously in adults and the absence of the age-related increases
in prefrontal activity observed in normal comparison subjects suggest that a developmental
disturbance in prefrontal function may emerge in bipolar disorder over the course
of adolescence." [Abstract]
Xing G, Russell S, Hough C, O'Grady J, Zhang L, Yang S,
Zhang LX, Post R.
Decreased prefrontal CaMKII alpha mRNA in bipolar
Neuroreport 2002 Mar 25;13(4):501-5
protein kinase II (CaMKII) plays critical roles in neurotransmission, synaptic
plasticity, learning and memory. The aim of this study was to examine, by in situ
hybridization, prefrontal cortical expression of CaMKII alpha mRNA in postmortem
brains of unipolar, bipolar, schizophrenic, and control subjects. Compared to
controls, bipolar patients had significantly lower levels of CaMKII alpha mRNA
in laminae I-VI of Brodmann's area 9 and laminae I-III and VI of area 46. Unipolar
patients also exhibited significantly lower levels of CaMKII alpha mRNA in laminae
I-IV of area 9 than did controls. The significant decrease in CaMKII alpha mRNA
in bipolar patients could be associated with some of the affective and cognitive
alterations that have been linked to prefrontal cortical dysfunction in bipolar
disorder, although this requires further direct examination." [Abstract]
PO, Undie AS, Kabbani N, Levenson R, Goldman-Rakic PS, Lidow MS.
of neuronal calcium sensor-1 (NCS-1) in the prefrontal cortex of schizophrenic
and bipolar patients.
Proc Natl Acad Sci U S A. 2003 Jan
7;100(1):313-7. Epub 2002 Dec 20.
"The delineation of dopamine dysfunction
in the mentally ill has been a long-standing quest of biological psychiatry. The
present study focuses on a recently recognized group of dopamine receptor-interacting
proteins as possible novel sites of dysfunction in schizophrenic and bipolar patients.
We demonstrate that the dorsolateral prefrontal cortex in schizophrenia and bipolar
cases from the Stanley Foundation Neuropathology Consortium display significantly
elevated levels of the D2 dopamine receptor desensitization regulatory protein,
neuronal calcium sensor-1. These levels of neuronal calcium sensor-1 were not
influenced by age, gender, hemisphere, cause of death, postmortem period, alcohol
consumption, or antipsychotic and mood stabilizing medications. The present study
supports the hypothesis that schizophrenia and bipolar disorder may be associated
with abnormalities in dopamine receptor-interacting proteins." [Abstract]
L, Hurd YL.
Reduced neuropeptide Y mRNA expression in the prefrontal
cortex of subjects with bipolar disorder.
"In the present study, we compared neuropeptide Y
mRNA expression levels in the prefrontal cortex (Brodmann area 9 and 46) of subjects
diagnosed with major depression, bipolar disorder and schizophrenia with those
in normal controls without a psychiatric history. No correlation was found regarding
neuropeptide Y mRNA expression and postmortem interval, age, gender, hemisphere
side, suicide as cause of death, or the history of use of substances such as alcohol,
marihuana and cocaine/amphetamine. The only significant alteration found was related
to the clinical diagnosis; neuropeptide Y mRNA expression was reduced in the group
of bipolar subjects as compared to the controls. Overall, the present results
confirm an involvement of neuropeptide Y in affective disorders, and show for
the first time a specific association between NPY and bipolar disorder."
N, Orlovskaya D, Vikhreva O, Zimina I, Kolomeets N, Vostrikov V, Rachmanova V.
Electron microscopy of oligodendroglia in severe mental illness.
Brain Res Bull 2001 Jul 15;55(5):597-610
"Qualitative electron microscopy
was performed to verify whether brain pathology in schizophrenia and bipolar disorder
is associated with alterations of oligodendroglial cells and myelinated fibers.
Ultrastructural signs of apoptosis and necrosis of oligodendroglial cells were
found in the prefrontal area 10 and the caudate nucleus in both schizophrenia
and bipolar disorder." [Abstract]
G, Halaris A, Selemon LD.
Reductions in neuronal and glial density
characterize the dorsolateral prefrontal cortex in bipolar disorder.
Biol Psychiatry 2001 May 1;49(9):741-52
"BACKGROUND: Bipolar disorder
(BPD) is a mental illness in which depression and mania typically alternate, and
both phases can present with psychotic features. The symptomatology of BPD, therefore,
resembles major depressive disorder (MDD) and schizophrenia (SCHZ), posing diagnostic
dilemmas. Distinct alterations in cellular architecture of the dorsolateral prefrontal
cortex distinguish SCHZ and MDD, whereas the cellular neuropathology of BPD has
not been studied. METHODS: Dorsolateral prefrontal area 9 was analyzed using a
three-dimensional morphometric method in postmortem brains from 10 BPD patients
and 11 matched nonpsychiatric control subjects. RESULTS: Area 9 in BPD was characterized
by reduced neuronal density in layer III (16%-22%) and reduced pyramidal cell
density in layers III and V (17%-30%). A 19% reduction in glial density was found
in sublayer IIIc coupled with enlargement and changes in shape of glial nuclei
spanning multiple layers. CONCLUSIONS: The morphologic signature of BPD, i.e.,
decreased neuronal and glial density in association with glial hypertrophy, is
distinct from previously described elevations in neuronal density in SCHZ, instead
resembling the reductions in cell density found in MDD. Thus, the neuropathologic
distinctions between BPD and SCHZ are indicative of separate mental illnesses,
each with a unique morphologic disturbance of specific neural circuits."
FM, Vincent SL, Todtenkopf M.
The density of pyramidal and nonpyramidal
neurons in anterior cingulate cortex of schizophrenic and bipolar subjects.
Biol Psychiatry 2001 Sep 15;50(6):395-406
"BACKGROUND: A recent study
reported a decreased density of nonpyramidal neurons (NPs) in layer II of the
anterior cingulate (ACCx) and prefrontal (PFCx) cortices of schizophrenic brain
that was most pronounced in schizoaffective subjects. Our study assessed whether
a decrease of NPs in ACCx may show a stronger covariation with affective disorder.
A cohort consisting of 12 normal control (CONs), 11 schizophrenic, and 10 bipolar
subjects matched for age and postmortem interval (PMI) has been analyzed. METHODS:
A two-dimensional technique was employed for counting cells in a large x,y sampling
column that extended across layers I through VI of ACCx. RESULTS: There was a
27% reduction in the density of NPs in layer II of the bipolar group, whereas
in the schizophrenic group, this density was 16.2% lower. There were no differences
in NPs in layers III through VI of either the schizophrenic or bipolar group.
Both groups also showed modest decreases of PNs in the deeper laminae; however,
these differences were only significant in layer IV of the schizophrenic subjects.
The density of glial cells was similar across the control, schizophrenic, and
bipolar groups. An Abercrombie correction for cell size did not alter the nature
of the results. Subjects both with and without neuroleptic exposure showed a lower
density of NPs in layer II of bipolar subjects or PNS in deeper laminae of schizophrenic
subjects. CONCLUSIONS: Overall, the findings reported here suggest that local
circuit cells in layer II of ACCx may be decreased in bipolar disorder, whereas
projection neurons in deeper laminae are decreased in schizophrenia." [Abstract]
A, Auta J, Davis JM, Di-Giorgi-Gerevini V, Dwivedi Y, Grayson DR, Impagnatiello
F, Pandey G, Pesold C, Sharma R, Uzunov D, Costa E, DiGiorgi Gerevini V.
in reelin and glutamic acid decarboxylase67 (GAD67) expression in schizophrenia
and bipolar disorder: a postmortem brain study.
Psychiatry 2000 Nov;57(11):1061-9
"BACKGROUND: Reelin (RELN) is a glycoprotein
secreted preferentially by cortical gamma-aminobutyric acid-ergic (GABAergic)
interneurons (layers I and II) that binds to integrin receptors located on dendritic
spines of pyramidal neurons or on GABAergic interneurons of layers III through
V expressing the disabled-1 gene product (DAB1), a cytosolic adaptor protein that
mediates RELN action. To replicate earlier findings that RELN and glutamic acid
decarboxylase (GAD)(67), but not DAB1 expression, are down-regulated in schizophrenic
brains, and to verify whether other psychiatric disorders express similar deficits,
we analyzed, blind, an entirely new cohort of 60 postmortem brains, including
equal numbers of patients matched for schizophrenia, unipolar depression, and
bipolar disorder with nonpsychiatric subjects. METHODS: Reelin, GAD(65), GAD(67),
DAB1, and neuron-specific-enolase messenger RNAs (mRNAs) and respective proteins
were measured with quantitative reverse transcriptase-polymerase chain reaction
(RT-PCR) or Western blot analyses. Reelin-positive neurons were identified by
immunohistochemistry using a monoclonal antibody. RESULTS: Prefrontal cortex and
cerebellar expression of RELN mRNA, GAD(67) protein and mRNA, and prefrontal cortex
RELN-positive cells was significantly decreased by 30% to 50% in patients with
schizophrenia or bipolar disorder with psychosis, but not in those with unipolar
depression without psychosis when compared with nonpsychiatric subjects. Group
differences were absent for DAB1,GAD(65) and neuron-specific-enolase expression
implying that RELN and GAD(67) down-regulations were unrelated to neuronal damage.
Reelin and GAD(67) were also unrelated to postmortem intervals, dose, duration,
or presence of antipsychotic medication. CONCLUSIONS: The selective down-regulation
of RELN and GAD(67) in prefrontal cortex of patients with schizophrenia and bipolar
disorder who have psychosis is consistent with the hypothesis that these parameters
are vulnerability factors in psychosis; this plus the loss of the correlation
between these 2 parameters that exists in nonpsychotic subjects support the hypothesis
that these changes may be liability factors underlying psychosis." [Abstract]
T, Kurzthaler I, Schmidauer Ch, Moncayo R, Donnemiller E.
caused by a diencephalic lesion.
"We describe the case of a young male patient, SN, who suffered a MR-documented
ischaemic lesion of both dorsomedial thalami and presented with a transient maniform
syndrome. SN's neuropsychological, structural and functional imaging findings
are compared with similar reported cases and are discussed in the framework of
fronto-subcortical circuits and their proposed behavioural disorders. SN's mania
was characterized by restlessness, mood elevation, a tendency for pleasurable
activities, inflated self-esteem and loss of disease awareness. Other symptoms
were sexual disinhibition, tactlessness, abnormal discourse, and reduced need
for food and sleep. His neuropsychological assessment revealed an anterograde
amnesia, and an impairment of frontal-executive functions. A SPECT-study showed
diaschisis-related areas of hypoperfusion in both prefrontal regions which were
interpreted as equivalents of SN's frontal-dysexecutive syndrome. In addition,
there was a perfusion deficit in the right orbitofrontal cortex, which was taken
as the imaging correlate of SN's secondary mania and personality disorder. These
findings suggest that SN's mania and his other symptoms result from the twofold
disruption of fronto-subcortical connections, namely of the right orbitofrontal
loop which is concerned with mood regulation and socially appropriate behaviour,
and of the dorsolateral prefrontal loop which mediates executive cognitive functions."
Pang A, Lewis SW.
Bipolar affective disorder
minus left prefrontal cortex equals schizophrenia.
Psychiatry 1996 May;168(5):647-50
"BACKGROUND. An investigation of the
relationship between bipolar affective disorder and schizophrenia, following a
severe head injury and removal of the left prefrontal cortex. METHOD. A single
case report. RESULTS. An individual with past history of bipolar affective disorder
suffered traumatic damages to the left prefrontal cortex with a second lesion
in the left temporal lobe. The patient developed typical schizophrenia nine months
later. The relevance of his brain lesions in determining the schizophrenic symptoms
is discussed. CONCLUSION. We propose that the specific pattern of brain injury
in this patient was sufficient to change the phenotype from bipolar affective
disorder to schizophrenia." [Abstract]
Blumberg HP, Leung HC, Skudlarski P, Lacadie CM,
Fredericks CA, Harris BC, Charney DS, Gore JC, Krystal JH, Peterson BS.
functional magnetic resonance imaging study of bipolar disorder: state- and trait-related
dysfunction in ventral prefrontal cortices.
Arch Gen Psychiatry.
"BACKGROUND: Abnormalities in prefrontal and anterior
cingulate cortices are implicated in disturbances of attention, cognition, and
impulse regulation in bipolar disorder. Acute episodes have been associated with
dysfunction in these brain regions, and more enduring trait-related dysfunction
has been implicated by volumetric and cellular abnormalities in these regions.
The relative contributions of prefrontal regions to state and trait disturbances
in bipolar disorder, however, have not been defined. We sought to characterize
state- and trait-related functional impairment in frontal systems in bipolar disorder.
METHODS: Thirty-six individuals with bipolar disorder I (11 with elevated, 10
with depressed, and 15 with euthymic mood states) and 20 healthy control subjects
matched for handedness and sex participated in an event-related functional magnetic
resonance imaging study of the color-word Stroop to determine mean percentage
of regional task-related signal change. RESULTS: Signal increased during the Stroop
task similarly across diagnostic groups in a distribution that included dorsal
anterior cingulate and prefrontal cortices, consistent with previously reported
activations in this task. Signal changes associated with specific mood states
in bipolar disorder were detected in ventral prefrontal cortex, with a blunted
increase in signal on the right side in the elevated mood group (P =.005) and
an exaggerated increase in signal on the left side in the depressed group (P =.02)
compared with the euthymic group. Patients (vs healthy controls) demonstrated
blunted activation in a spatially distinct, rostral region of left ventral prefrontal
cortex that was independent of mood state (P<.005). CONCLUSIONS: Bipolar disorder
is associated with a trait abnormality in left ventral prefrontal cortex. Additional
ventral prefrontal abnormalities may be associated with specific acute mood states.
The hemispheric laterality of the abnormality and the directions of signal change
may relate to the valence of the mood episode." [Abstract]
JS, Fletcher PC, Rogers RD, Ho LW, Aigbirhio FI, Paykel ES, Robbins TW, Sahakian
Decision-making in mania: a PET study.
Brain 2001 Dec;124(Pt 12):2550-63
"Poor decision-making is often observed
clinically in the manic syndrome. In normal volunteers, decision-making has been
associated with activation in the ventral prefrontal cortex and the anterior cingulate
gyrus. The aim of this study was to evaluate task-related activation in bipolar
manic patients in these regions of the prefrontal cortex using PET. Six subjects
with mania, 10 controls and six subjects with unipolar depression (an affective
patient control group) were scanned using the bolus H(2)(15)O method while they
were performing a decision-making task. Activations associated with the decision-making
task were observed at two levels of difficulty. Task-related activation was increased
in the manic patients compared with the control patients in the left dorsal anterior
cingulate [Brodmann area (BA) 32] but decreased in the right frontal polar region
(BA 10). In addition, controls showed greater task-related activation in the inferior
frontal gyrus (BA 47) than manic patients. A positive correlation (r(s) = 0.88)
between task-related activation in the anterior cingulate and increasing severity
of manic symptoms was found. Depressed patients did not show significant task-related
differences in activation compared with control subjects in the regions of interest.
In conclusion, these patterns of activation point to abnormal task-related responses
in specific frontal regions in manic patients. Moreover, they are consistent with
neuropsychological observations in patients with lesions in the ventromedial prefrontal
cortex, who show similar difficulties with decision-making and provide early evidence
for context-specific neural correlates of mania." [Abstract]
Clark L, Iversen SD, Goodwin GM.
investigation of prefrontal cortex involvement in acute mania.
Am J Psychiatry 2001 Oct;158(10):1605-11
"OBJECTIVE: Mania has received
little attention from a contemporary neuropsychological perspective despite its
clear resemblance to the disinhibition syndrome sometimes seen after frontal brain
injury, particularly injury to the inferior aspect of the prefrontal cortex. The
purpose of this investigation was to describe the neuropsychological profile of
severe acute mania by using a range of tasks selected primarily for the detection
of localized neural disruption within the prefrontal cortex. METHOD: Fifteen acutely
manic inpatients were compared with 30 nonpsychiatric subjects on tasks from the
Cambridge Automated Neuropsychological Test Battery (Tower of London, spatial
working memory, intradimensional-extradimensional attentional shift, and rapid
visual information processing tasks) and on the Iowa Gambling Task, Stroop Color
and Word Test, a verbal fluency task, and the California Verbal Learning Test.
RESULTS: Discriminant function analysis identified deficits in sustained attention
(on the rapid visual information processing task) and verbal learning (on the
California Verbal Learning Test) as the best indicators of manic performance,
rather than deficits on any of the tests of executive functioning. The model correctly
classified 91% of subjects overall and 87% of manic subjects. Manic patients did
not resemble patients with ventromedial prefrontal cortex damage in their performance
on the Iowa Gambling Task. CONCLUSIONS: Acute mania is characterized by core deficits
in verbal memory and sustained attention against a background of milder impairments
in functions that are traditional measures of prefrontal cortex integrity (attentional
set shifting, planning, working memory). The data do not implicate ventral prefrontal
cortex disruption as a locus of pathology in acute mania. Verbal memory and sustained
attention deficits may relate differentially to the state and trait characteristics
of bipolar disorder." [Abstract]
HP, Stern E, Ricketts S, Martinez D, de Asis J, White T, Epstein J, Isenberg N,
McBride PA, Kemperman I, Emmerich S, Dhawan V, Eidelberg D, Kocsis JH, Silbersweig
Rostral and orbital prefrontal cortex dysfunction in the manic
state of bipolar disorder.
Am J Psychiatry 1999 Dec;156(12):1986-8
"OBJECTIVE: This study investigated prefrontal cortex function in the manic
state of bipolar disorder. METHOD: High-sensitivity [15O]H2O positron emission
tomography and a word generation activation paradigm were used to study regional
cerebral blood flow in five manic and six euthymic individuals with bipolar disorder
and in five healthy individuals. RESULTS: Decreased right rostral and orbital
prefrontal cortex activation during word generation and decreased orbitofrontal
activity during rest were associated with mania. CONCLUSIONS: The data support
the presence of rostral and orbital prefrontal dysfunction in primary mania. These
findings, when seen in the context of the human brain lesion and the behavioral
neuroanatomic literatures, may help to explain some of the neurobehavioral abnormalities
characteristic of the manic state." [Abstract]
Prefrontal cortical-amygdalar metabolism in major depression.
Ann N Y Acad Sci 1999 Jun 29;877:614-37
"Functional neuroimaging studies
of the anatomical correlates of familial major depressive disorder (MDD) and bipolar
disorder (BD) have identified abnormalities of resting blood flow (BF) and glucose
metabolism in depression in the amygdala and the orbital and medial prefrontal
cortical (PFC) areas that are extensively connected with the amygdala. The amygdala
metabolism in MDD and BD is positively correlated with both depression severity
and "stressed" plasma cortisol concentrations measured during scanning.
During antidepressant drug treatment, the mean amygdala metabolism decreases in
treatment responders, and the persistence of elevated amygdala metabolism during
remission is associated with a high risk for the development of depressive relapse.
The orbital C metabolism is also abnormally elevated during depression, but is
negatively correlated with both depression severity and amygdala metabolism, suggesting
that this structure may be activated as a compensatory mechanism to modulate amygdala
activity or amygdala-driven emotional responses. The posterior orbital C and anterior
cingulate C ventral to the genu of the corpus callosum (subgenual PFC) have more
recently been shown in morphometric MRI and/or post mortem histopathological studies
to have reduced grey matter volume and reduced glial cell numbers (with no equivalent
loss of neurons) in familial MDD and BD. These data suggest a neural model in
which dysfunction of limbic PFC structures impairs the modulation of the amygdala,
leading to abnormal processing of emotional stimuli. Antidepressant drugs may
compensate for this dysfunction by inhibiting pathological limbic activity."
HP, Charney DS, Krystal JH.
Frontotemporal neural systems in bipolar
Semin Clin Neuropsychiatry. 2002 Oct;7(4):243-54.
less research has been performed in the delineation of the neural system abnormalities
underlying bipolar disorder (BD) than in their correlates in unipolar depression.
However, neuroimaging research has recently provided in vivo evidence to support
the involvement of regional brain abnormalities in BD implicated by the localization
of lesions associated with secondary mood symptoms. This article reviews (1) neural
systems implicated in BD by brain lesions associated with secondary mood changes
and impaired neuropsychologic paradigm performance; (2) structural and functional
neuroimaging evidence to support the involvement of these neural systems in BD;
and (3) potential functional neuroanatomic models of BD symptoms. Because depression
is covered in detail elsewhere in this issue, this article focuses primarily on
abnormalities associated with the manic state, as well as ones associated with
euthymia, and may thus represent trait abnormalities in BD. We suggest that ventral
and medial prefrontal and amygdalar abnormalities may play important roles in
a subset of BD symptoms and are potential targets for treatments." [Abstract]
VA, Dixon TA, Morris RG, Bullmore ET, Brammer MJ, Williams SC, Sharma T, Murray
RM, McGuire PK.
Differential frontal activation in schizophrenia
and bipolar illness during verbal fluency.
J Affect Disord
"INTRODUCTION: The precise nature of frontal
lobe dysfunction in schizophrenia remains unclear. We have previously demonstrated,
using fMRI, a task-specific attenuation of frontal activation in schizophrenic
patients. By using an identical methodology in matched bipolar subjects, we sought
to determine whether this finding is specific to schizophrenia or a correlate
of psychosis in general. METHOD: Five dextral male bipolar patients and matching
groups of schizophrenic subjects and controls were studied using fMRI. Echoplanar
images were acquired while subjects performed two paced tasks: covert verbal fluency
and a semantic decision task. Generic brain activation maps were constructed from
individual images by sinusoidal regression analysis. Between-group differences
in the mean power of experimental response were identified on a voxel-wise basis
by an analysis of variance (ANOVA). RESULTS: The bipolar patients showed extensive
prefrontal activation during verbal fluency which was significantly greater than
in controls. There was no difference in the prefrontal BOLD response during the
semantic decision task. CONCLUSIONS: These data indicate that bipolar patients
show a strikingly different pattern of frontal responses compared to those with
schizophrenia and provide further evidence that abnormal frontal activation in
psychotic disorders is more apparent during verbal fluency than semantic decision."
G, Masana MI, Manji HK.
Lithium regulates PKC-mediated intracellular
cross-talk and gene expression in the CNS in vivo.
Disord 2000 Sep;2(3 Pt 2):217-36
"It has become increasingly appreciated
that the long-term treatment of complex neuropsychiatric disorders like bipolar
disorder (BD) involves the strategic regulation of signaling pathways and gene
expression in critical neuronal circuits. Accumulating evidence from our laboratories
and others has identified the family of protein kinase C (PKC) isozymes as a shared
target in the brain for the long-term action of both lithium and valproate (VPA)
in the treatment of BD. In rats chronically treated with lithium at therapeutic
levels, there is a reduction in the levels of frontal cortical and hippocampal
membrane-associated PKC alpha and PKC epsilon. Using in vivO microdialysis, we
have investigated the effects of chronic lithium on the intracellular cross-talk
between PKC and the cyclic AMP (cAMP) generating system in vivo. We have found
that activation of PKC produces an increase in dialysate cAMP levels in both prefrontal
cortex and hippocampus, effects which are attenuated by chronic lithium administration.
Lithium also regulates the activity of another major signaling pathway the c-Jun
N-terminal kinase pathway--in a PKC-dependent manner. Both Li and VPA, at therapeutically
relevant concentrations, increase the DNA binding of activator protein 1 (AP-1)
family of transcription factors in cultured cells in vitro, and in rat brain ex
vivo. Furthermore, both agents increase the expression of an AP-1 driven reporter
gene, as well as the expression of several endogenous genes known to be regulated
by AP-1. Together, these results suggest that the PKC signaling pathway and PKC-mediated
gene expression may be important mediators of lithium's long-term therapeutic
effects in a disorder as complex as BD." [Abstract]
LT, Li PP, Kish SJ, Siu KP, Kamble A, Hornykiewicz O, Warsh JJ.
cortex Gs alpha protein levels and forskolin-stimulated cyclic AMP formation are
increased in bipolar affective disorder.
J Neurochem 1993
"Experimental animal and peripheral blood cell studies
point to guanine nucleotide regulatory (G) protein disturbances in bipolar affective
disorder. We have previously reported elevated prefrontal cortex Gs alpha protein
in bipolar affective disorder and have now extended these preliminary observations
in a larger number of subjects, assessing the brain regional specificity of these
changes in greater detail, determining the functional biochemical correlates of
such changes, and evaluating their diagnostic specificity. Membrane G protein
(Gs alpha, Gi alpha, Go alpha, and G beta) immunoreactivities were estimated by
western blotting in postmortem brain regions obtained from 10 patients with a
DSMIII-R diagnosis of bipolar affective disorder and 10 nonpsychiatric controls
matched on the basis of age, postmortem delay, and brain pH. To examine whether
there were functional correlates to the observed elevated Gs alpha levels, basal
and GTP gamma S- and forskolin-stimulated cyclic AMP production was determined
in the same brain regions. Compared with controls, Gs alpha (52-kDa species) immunoreactivity
was significantly (p < 0.05) elevated in prefrontal (+36%), temporal (+65%),
and occipital (+96%) cortex but not in hippocampus (+28%), thalamus (-23%), or
cerebellum (+21%). In contrast, no significant differences were found in the other
G protein subunits (Gi alpha, Go alpha, G beta) measured in these regions. Forskolin-stimulated
cyclic AMP production was significantly increased in temporal (+31%) and occipital
(+96%) cortex but not in other regions. No significant differences were apparent
in basal or GTP gamma S-stimulated cyclic AMP production." [Abstract]
CL, Zhang ZJ, Patten I, Reynolds GP.
Selective deficits in prefrontal
cortical GABAergic neurons in schizophrenia defined by the presence of calcium-binding
Biol Psychiatry 2002 Oct 1;52(7):708-15
Postmortem studies have provided evidence for abnormalities of the gamma-aminobutyric
acid (GABA)-ergic system in schizophrenia, including deficits of GABA-containing
interneurons. The calcium-binding proteins parvalbumin, calbindin, and calretinin
can be used as markers for specific subpopulations of cortical GABAergic interneurons.METHODS:
Following our previous observation of a reduction in the density of parvalbumin-
but not calretinin-immunoreactive cells in the prefrontal cortex (Brodmann area
10) in schizophrenia, we have quantified the laminar density of neurons immunoreactive
for the calcium-binding proteins parvalbumin, calbindin, and calretinin in a further
prefrontal cortical region (Brodmann area 9) in patients with schizophrenia, bipolar
disorder, major depression, and in matched control subjects (each group n = 15).RESULTS:
Initial statistical analysis revealed reductions in the total cortical density
of parvalbumin- and calbindin- but not calretinin-immunoreactive neurons in schizophrenia
relative to control subjects. Further analysis comparing individual laminar densities
between groups indicated that, following correction for multiple comparisons,
only a reduction in calbindin-immunoreactive neurons in cortical layer II in the
schizophrenic group attained statistical significance.CONCLUSIONS: These findings
suggest that deficits of specific GABAergic neurons, defined by the presence of
calcium-binding proteins, are present in schizophrenia. Trends toward similar
reductions are observed in bipolar disorder." [Abstract]
Elizabeth A. Thomas, Brian Dean, Geoffrey Pavey, and J.
Increased CNS levels of apolipoprotein D in schizophrenic
and bipolar subjects: Implications for the pathophysiology of psychiatric disorders
PNAS 98: 4066-4071, March 2001.
of the atypical antipsychotic drug, clozapine, to rodents has been shown to increase
the concentration of apolipoprotein D (apoD) in several area of the brain, suggesting
that apoD could be involved in the therapeutic effects of antipsychotic drugs
and/or the pathology of psychotic illnesses. Here, we measured a significant decrease
in the concentration of apoD in serum samples from schizophrenic patients. In
contrast, apoD levels were significantly increased (92-287%) in dorsolateral prefrontal
cortex (Brodmann's area 9) of schizophrenic and bipolar subjects. Elevated levels
of apoD expression were also observed in the caudate of schizophrenic and bipolar
subjects (68-89%). No differences in apoD immunoreactivity were detected in occipital
cortex (Brodmann's area 18) in either group, or in the hippocampus, substantia
nigra, or cerebellum of the schizophrenic group. The low serum concentrations
of apoD observed in these patients supports recent hypotheses involving systemic
insufficiencies in lipid metabolism/signaling in schizophrenia. Elevation of apoD
expression selectively within central nervous system regions implicated in the
pathology of these neuropsychiatric disorders suggests a focal compensatory response
that neuroleptic drug regimens may augment." [Full
studies in mood disorders indicate altered numbers of neurons and glial cells.
Biol Psychiatry 2000 Oct 15;48(8):766-77
"The influence of stress and
glucocorticoids on neuronal pathology has been demonstrated in animal and clinical
studies. It has been proposed that stress-induced changes in the hippocampus may
be central to the development of depression in genetically vulnerable individuals.
New evidence implicates the prefrontal cortex (PFC) in addition to the hippocampus
as a site of neuropathology in depression. The PFC may be involved in stress-mediated
neurotoxicity because stress alters PFC functions and glucocorticoid receptors,
the PFC is directly interconnected with the hippocampus, and metabolic alterations
are present in the PFC in depressed patients. Postmortem studies in major depression
and bipolar disorder provide the first evidence for specific neuronal and glial
histopathology in mood disorders. Three patterns of morphometric cellular changes
are noted: cell loss (subgenual PFC), cell atrophy (dorsolateral PFC and orbitofrontal
cortex), and increased numbers of cells (hypothalamus, dorsal raphe nucleus).
The relevance of cellular changes in mood disorders to stress and prolonged PFC
development and a role of neurotrophic/neuroprotective factors are suggested,
and a link between cellular changes and the action of therapeutic drugs is discussed.
The precise anatomic localization of dysfunctional neurons and glia in mood disorders
may reveal cortical targets for novel antidepressants and mood stabilizers."
ME, Sachs N, Tate DL, Adalsteinsson E, Spielman D, Ketter TA.
dorsolateral prefrontal N-acetyl aspartate in bipolar disorder.
Biol Psychiatry 2000 Mar 15;47(6):475-81
"BACKGROUND: N-acetyl aspartate
(NAA) is an amino acid present in high concentrations in neurons and is thus a
putative neuronal marker. In vivo proton magnetic resonance spectroscopy ((1)H
MRS) studies have shown lower NAA concentrations in patients with various neurodegenerative
disorders, suggesting decreased neuronal number, size, or function. Dorsolateral
prefrontal (DLPF) NAA has not been extensively assessed in bipolar disorder patients,
but it could be decreased in view of consistent reports of decreased DLPF cerebral
blood flow and metabolism in mood disorders. We measured DLPF NAA in patients
with bipolar disorder and healthy control subjects using in vivo (1)H MRS. METHODS:
We obtained ratios of NAA, choline, and myoinositol (mI) to creatine-phosphocreatine
(Cr-PCr) in bilateral DLPF 8-mL voxels of 20 bipolar patients (10 Bipolar I, 10
Bipolar II) and 20 age- and gender-matched healthy control subjects using (1)H
MRS. RESULTS: DLPF NAA/Cr-PCr ratios were lower on the right hemisphere (p<.03)
and the left hemisphere (p<.003) in bipolar disorder patients compared with
healthy control subjects. CONCLUSIONS: These preliminary data suggest that bipolar
disorder patients have decreased DLPF NAA/Cr-PCr. This finding could represent
decreased neuronal density or neuronal dysfunction in the DLPF region." [Abstract]
K, Adleman N, Dienes K, Barnea-Goraly N, Reiss A, Ketter T.
N-acetylaspartate in children with familial bipolar disorder.
Psychiatry. 2003 Jun 1;53(11):1059-65.
"BACKGROUND: Relatively low levels
of brain N-acetylaspartate, as measured by magnetic resonance spectroscopy, may
indicate decreased neuronal density or viability. Dorsolateral prefrontal levels
of N-acetylaspartate have been reported to be decreased in adults with bipolar
disorder. We used proton magnetic resonance spectroscopy to investigate dorsolateral
prefrontal N-acetylaspartate levels in children with familial bipolar disorder.
METHODS: Subjects were 15 children and adolescents with bipolar disorder, who
each had at least one parent with bipolar disorder, and 11 healthy controls. Mean
age was 12.6 years for subjects and controls. Subjects were allowed to continue
current medications. Proton magnetic resonance spectroscopy at 3-Tesla was used
to study 8 cm(3) voxels placed in left and right dorsolateral prefrontal cortex.
RESULTS: Bipolar subjects had lower N-acetylaspartate/Creatine ratios only in
the right dorsolateral prefrontal cortex (p <.02). No differences in myoinositol
or choline levels were found. CONCLUSIONS: Children and adolescents with bipolar
disorder may have decreased dorsolateral prefrontal N-acetylaspartate, similar
to adults with BD, indicating a common neuropathophysiology. Longitudinal studies
of at-risk children before the onset and during the early course of bipolar disorder
are needed to determine the role of prefrontal N-acetylaspartate as a possible
risk marker and/or indication of early bipolar illness progression." [Abstract]
Dost Öngür, Wayne C. Drevets, and Joseph
Glial reduction in the subgenual prefrontal cortex in
PNAS 95: 13290-13295, 1998.
disorders are among the most common neuropsychiatric illnesses, yet little is
known about their neurobiology. Recent neuroimaging studies have found that the
volume of the subgenual part of Brodmann's area 24 (sg24) is reduced in familial
forms of major depressive disorder (MDD) and bipolar disorder (BD). In this histological
study, we used unbiased stereological techniques to examine the cellular composition
of area sg24 in two different sets of brains. There was no change in the number
or size of neurons in area sg24 in mood disorders. In contrast, the numbers of
glia were reduced markedly in both MDD and BD. The reduction in glial number was
most prominent in subgroups of subjects with familial MDD (24%, P = 0.01) or BD
(41%, P = 0.01). The glial reduction in subjects without a clear family history
was lower in magnitude and not statistically significant. Consistent with neuroimaging
findings, cortical volume was reduced in area sg24 in subjects with familial mood
disorders. Schizophrenic brains studied as psychiatric controls had normal neuronal
and glial numbers and cortical volume. Glial and neuronal numbers also were counted
in area 3b of the somatosensory cortex in the same group of brains and were normal
in all psychiatric groups. Glia affect several processes, including regulation
of extracellular potassium, glucose storage and metabolism, and glutamate uptake,
all of which are crucial for normal neuronal activity. We thus have identified
a biological marker associated with familial mood disorders that may provide important
clues regarding the pathogenesis of these common psychiatric conditions."
WC, Ongur D, Price JL.
Neuroimaging abnormalities in the subgenual
prefrontal cortex: implications for the pathophysiology of familial mood disorders.
Mol Psychiatry 1998 May;3(3):220-6, 190-1
"The prefrontal cortex (PFC)
ventral to the genu of the corpus callosum has been implicated in the modulation
of visceral responses to stressful and emotionally provocative stimuli, based
upon analysis of lesion effects involving this area in humans and experimental
animals. In a recent magnetic resonance imaging (MRI) study of familial mood disorders,
we demonstrated that the mean grey matter volume of this cortex is abnormally
reduced in subjects with major depressive disorder (MDD) and bipolar disorder,
irrespective of their treatment status or current mood state. Moreover, in preliminary
histopathological assessments of subgenual PFC tissue taken post mortem from subjects
with MDD and bipolar disorder we obtained results suggesting that this decrement
in grey matter volume is associated with a reduction in glia without an equivalent
loss of neurons. The potential functional significance of these neuroimaging and
microscopic abnormalities is discussed with respect to evidence that subgenual
PFC dysfunction may disturb stress-related autonomic and neuroendocrine responses
and reward-related mesolimbic dopamine function. These data may thus hold important
implications for the development of neural models of mood disorders that can account
for the abnormal hedonic, motivational, neuroendocrine, and autonomic manifestations
evident in these idiopathic conditions." [Abstract]
P, Nicoletti MA, Harenski K, Sassi RB, Mallinger AG, Frank E, Kupfer DJ, Keshavan
MS, Soares JC.
Anatomical MRI study of subgenual prefrontal cortex
in bipolar and unipolar subjects.
"This study attempted to replicate previous findings
of decreased gray matter content in the subgenual prefrontal cortex (SGPFC) in
mood disorder patients. Eighteen DSM-IV unipolar patients, 27 DSM-IV bipolar patients,
and 38 healthy controls were studied. A 1.5T GE Signa Imaging System with Signa
5.4.3 software was used. The semi-automated software MedX (Sensor Systems, Sterling,
VA) was utilized for the anatomical measures of SGPFC volumes. There were no significant
differences in SGPFC volumes in familial and non-familial unipolar and bipolar
patients compared with healthy controls, nor between drug-free and lithium-treated
bipolar patients (ANOVA, p >.05). In vivo abnormalities in the volumes of SGPFC
were not identified in mildly depressed or euthymic unipolar or bipolar mood disorder
outpatients, either familial or non-familial." [Abstract]
Gooding DC, Tallent KA.
The association between
antisaccade task and working memory task performance in schizophrenia and bipolar
J Nerv Ment Dis 2001 Jan;189(1):8-16
date, the research literature has yielded conflicting reports regarding the specificity
of antisaccade deficits to schizophrenia. We sought to examine antisaccade and
working memory task performance in schizophrenia patients and bipolar patients,
as well as to examine the relationship between the two tasks in both patient populations.
Thirty-four schizophrenia patients, 20 bipolar patients, and 30 nonpatient controls
were administered saccadic inhibition (antisaccade), working memory, and sensorimotor
tasks. Compared with the controls, the schizophrenia patients displayed both antisaccade
deficits and working memory deficits. In contrast, the bipolar patients produced
significantly more errors on the antisaccade task than the controls, though the
bipolar group performed similarly to the control group on the working memory task.
Mediational analyses demonstrated that working memory partially mediates the relationship
between patients' diagnostic group status and antisaccade task performance; working
memory performance contributed uniquely to the prediction of antisaccade task
performance in the two patient groups. Antisaccade deficits do not appear specific
to schizophrenia. The results suggest that in schizophrenia, working memory and
antisaccade tasks are tapping similar cognitive processes, whereas in bipolar
patients the processes underlying antisaccade and working memory performance are