Blumberg HP, Stern E, Martinez D, Ricketts S, de Asis J, White
T, Epstein J, McBride PA, Eidelberg D, Kocsis JH, Silbersweig DA.
Increased anterior cingulate and caudate activity in bipolar mania.
Biol Psychiatry 2000 Dec 1;48(11):1045-52
"BACKGROUND: Executive control
of cognition, emotion, and behavior are disrupted in the manic state of bipolar
disorder. Whereas frontal systems are implicated in such dysfunction, the localization
of functional brain abnormalities in the manic state is not well understood. METHODS:
We utilized a high-sensitivity H(2)(15)0 positron emission tomography technique
to investigate regions of increased brain activity in mania, compared to euthymia,
in bipolar disorder. RESULTS: The principal findings were manic state-related
increased activity in left dorsal anterior cingulate, and left head of caudate.
CONCLUSIONS: The findings suggest that the manic state of bipolar disorder may
be associated with heightened activity in a frontal cortical-subcortical neural
system that includes the anterior cingulate and caudate." [Abstract]
RT, Kimbrell TA, Ketter TA, Frye MA, Willis MW, Luckenbaugh DA, Post RM.
Principal components of the Beck Depression Inventory and regional cerebral
metabolism in unipolar and bipolar depression.
2002 Mar 1;51(5):387-99
"BACKGROUND: We determined clustering of depressive
symptoms in a combined group of unipolar and patients with bipolar disorder using
Principle Components Analysis of the Beck Depression Inventory. Then, comparing
unipolars and bipolars, these symptom clusters were examined for interrelationships,
and for relationships to regional cerebral metabolism for glucose measured by
positron emission tomography. METHODS: [18F]-fluoro-deoxyglucose positron emission
tomography scans and Beck Depression Inventory administered to 31 unipolars and
27 bipolars, all medication-free, mildly-to-severely depressed. BDI component
and total scores were correlated with global cerebral metabolism for glucose,
and voxel-by-voxel with cerebral metabolism for glucose corrected for multiple
comparisons. RESULTS: In both unipolars and bipolars, the psychomotor-anhedonia
symptom cluster correlated with lower absolute metabolism in right insula, claustrum,
anteroventral caudate/putamen, and temporal cortex, and with higher normalized
metabolism in anterior cingulate. In unipolars, the negative cognitions cluster
correlated with lower absolute metabolism bilaterally in frontal poles, and in
right dorsolateral frontal cortex and supracallosal cingulate. CONCLUSIONS: Psychomotor-anhedonia
symptoms in unipolar and bipolar depression appear to have common, largely right-sided
neural substrates, and these may be fundamental to the depressive syndrome in
bipolars. In unipolars, but not bipolars, negative cognitions are associated with
decreased frontal metabolism. Thus, different depressive symptom clusters may
have different neural substrates in unipolars, but clusters and their substrates
are convergent in bipolars." [Abstract]
CM, Breeze JL, Gruber SA, Babb SM, Frederick BB, Villafuerte RA, Stoll AL, Hennen
J, Yurgelun-Todd DA, Cohen BM, Renshaw PF.
and mood in bipolar disorder: a proton magnetic resonance spectroscopic imaging
study of the anterior cingulate cortex.
2000 Sep;2(3 Pt 2):207-16
"OBJECTIVES: Alterations in choline and myo-inositol
metabolism have been noted in bipolar disorder, and the therapeutic efficacy of
lithium in mania may be related to these effects. We wished to determine the relationship
between anterior cingulate cortex choline and myo-inositol levels, assessed using
proton magnetic resonance spectroscopic imaging (MRSI), and mood state in subjects
with bipolar disorder. METHODS: Serial assessments of anterior cingulate cortex
choline and myo-inositol metabolism were performed in nine subjects with bipolar
disorder, taking either lithium or valproate, and 14 controls. Each bipolar subject
was examined between one and four times (3.1 +/- 1.3). On the occasion of each
examination, standardized ratings of both depression and mania were recorded.
RESULTS: In the left cingulate cortex, the bipolar subjects' depression ratings
correlated positively with MRSI measures of Cho/Cr-PCr. In the right cingulate
cortex, the Cho/Cr-PCr ratio was significantly higher in subjects with bipolar
disorder compared with control subjects. In addition, bipolar subjects not taking
antidepressants had a significantly higher right cingulate cortex Cho/Cr-PCr ratio
compared with patients taking antidepressants or controls. No clinical or drug-related
changes were observed for the Ino/Cr-PCr ratio. CONCLUSIONS: The results of this
study suggest that bipolar disorder is associated with alterations in the metabolism
of cytosolic, choline-containing compounds in the anterior cingulate cortex. As
this resonance arises primarily from phosphocholine and glycerophosphocholine,
both of which are metabolites of phosphatidylcholine, these results are consistent
with impaired intraneuronal signaling mechanisms." [Abstract]
P, Yue K, Thomas MA, Belin T, Mintz J, Venkatraman TN, Santoro E, Barnett S, McCracken
Proton magnetic resonance spectroscopy of bipolar disorder versus
intermittent explosive disorder in children and adolescents.
J Psychiatry. 2003 Aug;160(8):1442-52.
OBJECTIVE: The diagnosis of bipolar
disorder in juveniles is controversial. This study was designed to compare proton
magnetic resonance spectroscopy ((1)H MRS) in patients with bipolar disorder or
intermittent explosive disorder, two groups with symptomatic overlap but categorical
distinction. Children with intermittent explosive disorder designate patients
whose illness clinically resembles pediatric bipolar disorder but does not satisfy
DSM-IV criteria for mania. Based on the authors' previous report of higher levels
of (1)H MRS cingulate myo-inositol/creatine in youngsters with bipolar disorder
than in normal comparison subjects, they hypothesized that patients with bipolar
disorder would have higher cingulate myo-inositol/creatine-phosphocreatine measurements
than patients with intermittent explosive disorder and normal comparison subjects.
METHOD: Myo-inositol levels were measured with a 2x2x2 cm(3) voxel placed in the
anterior cingulate for acquisition of (1)H MRS in 10 patients with bipolar disorder,
10 patients with intermittent explosive disorder, and 13 normal comparison subjects.
N-Acetylaspartate, choline moieties, creatine-phosphocreatine, and glutamate-glutamine
metabolite levels were also measured. RESULTS: The patients with bipolar disorder
showed significantly higher anterior cingulate myo-inositol/creatine-phosphocreatine
and myo-inositol (mmol/liter) levels than the patients with intermittent explosive
disorder and the normal comparison subjects. No significant differences were found
across groups for myo-inositol or other metabolites in the occipital cortex. CONCLUSIONS:
These data provide evidence that differences in the concentration of myo-inositol
(mmol/liter) in the anterior cingulate cortex in (1)H MRS may differentiate these
two populations. Follow-up studies involving larger samples may conclusively estimate
the biological specificity between pediatric bipolar disorder and other disorders,
which overlap clinically. [Abstract]
P, Thomas MA, Yue K, Oshiro T, Belin T, Strober M, McCracken J.
anterior cingulate myo-inositol/creatine spectroscopy resonance with lithium treatment
in children with bipolar disorder.
"This project was designed to compare differences
in brain proton spectra between children and adolescents with bipolar disorder
(BPD) and gender and age-matched normal controls, and to measure changes in myo-inositol
levels following lithium therapy, utilizing in vivo proton magnetic resonance
spectroscopy (1H MRS). A single voxel (2x2x2 cm3) was placed in brain anterior
cingulate cortex for acquisition of the 1H spectra at baseline and after acute
(7 days) lithium administration in 11 children (mean age 11.4 years) diagnosed
with BPD, and in 11 normal controls. Acute lithium treatment was associated with
a significant reduction in the myo-inositol/creatine ratio. This decrement was
also significant in lithium-responders when analyzed separate from non-responders.
Compared to normal controls, BPD subjects showed a trend towards a higher myo-inositol/creatine
during the manic phase. These preliminary data provide evidence that a significant
reduction in anterior cingulate myo-inositol magnetic resonance may occur after
lithium treatment, especially among responders. Follow-up studies involving a
larger sample may allow us to confirm whether changes in myo-inositol associated
with acute lithium therapy persist in long-term clinical response of patients
with and without lithium compliance." [Abstract]
Thomas AJ, Davis S, Ferrier IN, Kalaria RN, O'Brien
Elevation of cell adhesion molecule immunoreactivity
in the anterior cingulate cortex in bipolar disorder.
Psychiatry. 2004 Mar 15;55(6):652-5.
BACKGROUND: Neuroimaging reports of increases
in signal hyperintensities in white and deep gray matter and other work indicate
that there might be an inflammatory response in affective disorders. METHODS:
The microvascular immunoreactivity of intercellular adhesion molecule-1 and vascular
cell adhesion molecule-1 was measured with image analysis in postmortem tissue
from the anterior cingulate cortex (ACC) and dorsolateral prefrontal cortex (DLPFC)
from 15 unipolar and 15 bipolar subjects and compared with each other and with
15 subjects with schizophrenia and 15 control subjects. RESULTS: Intercellular
adhesion molecule-1 immunoreactivity in gray and white matter of the ACC in bipolar
subjects was increased compared with control subjects (gray: p =.001; white: p
<.001) and schizophrenic subjects (gray: p =.016; white: p =.025) and modestly
increased in white matter compared with unipolar subjects (p =.049). No such differences
were found in the DLPFC. CONCLUSIONS: These findings are consistent with the presence
of an inflammatory response in the ACC in bipolar disorder. [Abstract]
TU, Walsh JP, Benes FM
Density of glutamic acid decarboxylase
67 messenger RNA-containing neurons that express the N-methyl-D-aspartate receptor
subunit NR2A in the anterior cingulate cortex in schizophrenia and bipolar disorder.
Gen Psychiatry. 2004 Jul;61(7):649-57.
BACKGROUND: Disturbances of gamma-aminobutyric
acid interneurons in the cerebral cortex contribute to the pathophysiology of
schizophrenia and bipolar disorder. The activity of these neurons is, in turn,
modulated by glutamatergic inputs furnished by pyramidal neurons. OBJECTIVE: To
test the hypothesis that glutamatergic inputs onto gamma-aminobutyric acid interneurons
via the N-methyl-d-aspartate (NMDA) receptor are altered in the anterior cingulate
cortex in schizophrenia and bipolar disorder. DESIGN: A double in situ hybridization
technique was used to simultaneously label the messenger RNA (mRNA) for the NMDA
NR(2A) subunit with (35)sulfur and the mRNA for the 67-kDa isoform of the gamma-aminobutyric
acid synthesizing enzyme glutamic acid decarboxylase (GAD(67)) with digoxigenin.
SETTING: Postmortem human brain studies. PARTICIPANTS: We studied 17 subjects
with schizophrenia, 17 subjects with bipolar disorder, and 17 normal control subjects.
RESULTS: The density of all GAD(67) mRNA-containing neurons was decreased by 53%
and 28%, in layers 2 and 5, respectively, in subjects with schizophrenia, whereas
in subjects with bipolar disorder there was a 35% reduction in layer 2 only. For
GAD(67) mRNA-containing neurons that co-expressed NR(2A)mRNA, their numerical
density was decreased by 73% and 52%, in layers 2 and 5, respectively, in subjects
with schizophrenia and by 60% in layer 2 in those with bipolar disorder. In the
schizophrenia group, the density of the GAD(67)mRNA-containing neurons that did
not co-express NR(2A)mRNA was also decreased by 42% in layer 2. In both disease
groups, the expression level of NR(2A)mRNA in GAD(67) mRNA-containing cells was
unaltered. CONCLUSIONS: The density of gamma-aminobutyric acid interneurons that
express the NMDA NR(2A)subunit appears to be decreased in schizophrenia and bipolar
disorder. Future studies will address whether subpopulations of these neurons
may be differentially affected in the 2 conditions. [Abstract]
SL, Harrison PJ.
Synaptic pathology in the anterior cingulate cortex
in schizophrenia and mood disorders. A review and a Western blot study of synaptophysin,
GAP-43 and the complexins.
Brain Res Bull 2001 Jul 15;55(5):569-78
"There are several reports of ultrastructural and protein changes affecting
synapses in the anterior cingulate cortex in schizophrenia. Altered cytoarchitecture
has also been described in this region in schizophrenia as well as in mood disorders.
In this paper we review the literature and present a new study investigating synaptic
abnormalities in the anterior cingulate cortex (area 24) in the Stanley Foundation
brain series. We used Western blotting to assess four synaptic proteins: synaptophysin,
growth-associated protein-43 (GAP-43), complexin I and complexin II, which inform
about somewhat different aspects of the synaptic circuitry. Synaptophysin, complexin
II and GAP-43 were reduced in bipolar disorder. The decreases correlated with
the duration of illness and tended to be greater in subjects without a family
history. Complexin II was also reduced in major depression. Complexin I and the
housekeeping protein beta-actin did not differ between groups. None of the proteins
changed significantly in schizophrenia. The results indicate the presence of a
synaptic pathology in the anterior cingulate cortex in mood disorders, especially
bipolar disorder. The abnormalities may contribute to the dysfunction of cingulate
neural circuits. The loss of synaptophysin is suggestive of decreased synaptic
density whilst the decrease in GAP-43 may denote impaired synaptic plasticity
and the reduction of complexin II but not complexin I implies that the alterations
particularly affect excitatory connections. The reductions may be progressive."
Z, Andrew K, Filomena M, Xu-Feng H.
Investigation of m1/m4 muscarinic
receptors in the anterior cingulate cortex in schizophrenia, bipolar disorder,
and major depression disorder.
Abnormal cholinergic neurotransmission has been suggested
to occur in psychiatric illness. Therefore, this study investigated cholinergic
muscarinic receptors in the anterior cingulate cortex (ACC) of schizophrenia,
bipolar disorder and major depression disorder (n=15 per group). We used quantitative
autoradiography to measure [(3)H]pirenzepine binding to M1 and M4 receptors. Brain
tissue was obtained from the Stanley Foundation Neuropathology Consortium. [(3)H]pirenzepine
binding was higher in superficial laminae (I-II) than in deep laminae (III-VI)
of the ACC. There was a significant 24% reduction in the density of [(3)H]pirenzepine
in the deep laminae and a significant 19% reduction in the upper laminae of the
ACC in the schizophrenia group compared to the control group. There were no differences
in [(3)H]pirenzepine binding in any laminae of the ACC in the bipolar or major
depression groups compared with the control group, except for a trend towards
decreased [(3)H]pirenzepine binding in subjects with major depression relative
to control subjects. We also detected a significant effect of suicide on [(3)H]pirenzepine
binding in the ACC in subjects who died as a result of suicide relative to those
who did not, which was more evident in patients with schizophrenia. A significant
effect of the onset of the disease was also observed that was more evident in
patients with bipolar disorder. The study provides evidence of decreased muscarinic
receptor density in the ACC in schizophrenia but no evidence for significant changes
in these receptors in the bipolar and major depression groups. The changes observed
in schizophrenia may contribute to dysfunctional ACC neural circuits. [Abstract]
ES, Yildiz A, C Soares J
[Magnetic Resonance Spectroscopy
(MRS) Applications in Bipolar Disorder]
Derg. 2004 Summer;15(2):138-47.
OBJECTIVE: Magnetic resonance spectroscopy
(MRS) is a noninvasive in vivo imaging technique that can directly assess the
living biochemistry in localized brain regions without involving ionizing radiation.
This review provides a brief description of spectroscopy, followed by a literature
review of the key spectroscopy findings in bipolar disorder. METHOD: We conducted
a Medline literature review for the period 1966-2003, and included all the controlled
studies using MRS in bipolar disorder, as well as other relevant papers with important
findings. RESULTS: Studies showed an increase in choline (Cho) levels in basal
ganglia and cingulate, and a decrease in dorsolateral prefrontal cortical (DLPFC)
and hippocampal N-acetyl aspartate (NAA) levels. Frontal lobe phosphomonoester
(PME) levels were decreased in the euthymic state and were higher in the manic
and depressive states. Myoinositol (mI) was reduced by lithium treatment and this
decrease was positively correlated with treatment response. CONCLUSION: The findings
from MRS studies of bipolar disorder demonstrate alterations in the neurochemistry
of key brain regions participating in the fronto-limbic-subcortical circuits implicated
in the pathophysiology of the disorder. These findings suggest abnormalities of
the membrane phospholipid metabolism, cellular energy metabolism and myelin formation
/maintenance in the DLPFC, cingulate, hippocampus and basal ganglia in bipolar
disorder. Further studies are needed to distinguish between the changes that are
due to the pathophysiology of bipolar disorder and those due to the effects of
Rubinsztein JS, Fletcher PC, Rogers RD, Ho LW,
Aigbirhio FI, Paykel ES, Robbins TW, Sahakian BJ.
in mania: a PET study.
Brain 2001 Dec;124(Pt 12):2550-63or
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." [Abstract]
S, Seminowicz D, Goldapple K, Kennedy SH, Mayberg HS.
State and trait
influences on mood regulation in bipolar disorder: blood flow differences with
an acute mood challenge.
Biol Psychiatry. 2003 Dec 1;54(11):1274-83.
Even in remission, patients with bipolar disorder (BD) remain sensitive to external
stressors that can trigger new episodes. Imitating such stressors by the controlled
transient exposure to an emotional stimulus may help to identify brain regions
modulating this sensitivity. METHODS: Transient sadness was induced in 9 euthymic
and in 11 depressed subjects with BD. Regional blood flow (rCBF) changes were
measured using (15)O-water positron emission tomography. RESULTS: Common changes
in both groups were increased rCBF in anterior insula and cerebellum and decreased
rCBF in dorsal-ventral-medial frontal cortex, posterior cingulate, inferior parietal,
and temporal cortices. Decreases in dorsal ventral medial frontal cortices occurred
in both groups, but subjects in remission showed a greater magnitude of change.
Unique to remitted subjects with BD were rCBF increases in dorsal anterior cingulate
and in premotor cortex. Lateral prefrontal rCBF decreases were unique to depressed
subjects with BD. At baseline, remitted subjects showed a unique increase in dorsal
anterior cingulate and orbitofrontal cortex. CONCLUSIONS: Common rCBF changes
in remitted and depressed subjects identifies potential sites of disease vulnerability.
Unique cingulate and orbitofrontal changes both at baseline and with induced sadness
seen in the absence of prefrontal rCBF decreases may identify regional interactions
important to the euthymic state in this population. [Abstract]
CJ, Frackowiak RS, Dolan RJ.
Changes in regional cerebral blood
flow on recovery from depression.
Psychol Med 1995 Mar;25(2):247-61
"We have previously described focal abnormalities of regional cerebral blood
flow (rCBF) in the left dorsolateral prefrontal cortex (DLPFC), anterior cingulate
cortex and angular gyrus in 40 patients with major depression. We now report on
the patterns of change in rCBF in a subgroup of 25 of the same patients who were
rescanned following clinical remission of depression. Fifteen patients were scanned
when optimally matched for drug treatment (4) or drug free on both occasions (11).
The other 10 patients were fully recovered but could not be matched for drug status
for clinical and ethical reasons. In a paired comparison of the same patients
when ill and following recovery it was evident that remission was associated with
a significant increase in rCBF in the left DLPFC and medial prefrontal cortex
including anterior cingulate. Increases in rCBF in the angular gyrus were not
seen when the comparison of depressed and recovered scans was matched for medication.
The previously described relationship between clinical symptoms and brain perfusion
in the depressed state was no longer present in the recovered state; this supports
the hypothesis of state relatedness. Thus, recovery from depression is associated
with increases in rCBF in the same areas in which focal decreases in rCBF are
described in the depressed state in comparison with normal controls." [Abstract]
[This study was not bipolar disorder specific, but it included "bipolar disorder"
as a search term.]
Osuch EA, Ketter TA, Kimbrell TA,
George MS, Benson BE, Willis MW, Herscovitch P, Post RM.
cerebral metabolism associated with anxiety symptoms in affective disorder patients.
Biol Psychiatry 2000 Nov 15;48(10):1020-3
"BACKGROUND: We studied the
relationship between regional cerebral metabolism and the severity of anxiety
in mood disorder patients, controlling for depression severity. METHODS: Fifty-two
medication-free patients with unipolar or bipolar illness underwent positron emission
tomography with [(18)F]-fluorodeoxyglucose. Hamilton Depression Rating Scale and
Spielberger Anxiety-State Scale scores were obtained for the week of the scan.
Analyses were performed on globally normalized images and were corrected for multiple
comparisons. RESULTS: After covarying for depression scores, age, and gender,
Spielberger Anxiety-State Scale scores correlated directly with regional cerebral
metabolism in the right parahippocampal and left anterior cingulate regions, and
inversely with metabolism in the cerebellum, left fusiform, left superior temporal,
left angular gyrus, and left insula. In contrast, covarying for anxiety scores,
age, and gender, Hamilton Depression Rating Scale scores correlated directly with
regional cerebral metabolism in the bilateral medial frontal, right anterior cingulate,
and right dorsolateral prefrontal cortices. CONCLUSIONS: Comorbid anxiety symptoms
are associated with specific cerebral metabolic correlates that partially overlap
with those in the primary anxiety disorders and differ from those associated with
depression severity." [Abstract]
K, Adleman NE, Dienes K, Simeonova DI, Menon V, Reiss A
prefrontal-subcortical activation in familial pediatric bipolar disorder: a functional
magnetic resonance imaging investigation.
Psychiatry. 2004 Aug;61(8):781-92.
BACKGROUND: The neurobiological features
of pediatric bipolar disorder (BD) are largely unknown. Children and adolescents
with BD may be important to study with functional neuroimaging techniques because
of their unique status of early-onset BD and high familial loading for the disorder.
Neuroimaging studies of adults with BD have implicated the dorsolateral prefrontal
cortex (DLPFC) and anterior cingulate cortex (ACC) in the development of this
disorder. OBJECTIVES: To study children and adolescents with BD via functional
magnetic resonance imaging using cognitive and affective tasks and to examine
possible abnormalities in the DLPFC and ACC, as well as selected subcortical areas,
in pediatric familial BD. DESIGN: We evaluated 12 male subjects aged 9 to 18 years
with BD who had at least 1 parent with BD as well as 10 age- and IQ-matched healthy
male controls. Stimulants were discontinued for at least 24 hours; other medications
were continued. Subjects underwent functional magnetic resonance imaging at 3
T while performing a 2-back visuospatial working memory task and an affective
task involving the visualization of positively, neutrally, or negatively valenced
pictures. SETTING: An academic referral setting, drawing from the Bay Area of
San Francisco, Calif. RESULTS: Compared with controls, for the visuospatial working
memory task, subjects with BD had greater activation in several areas including
the bilateral ACC, left putamen, left thalamus, left DLPFC, and right inferior
frontal gyrus. Controls had greater activation in the cerebellar vermis. In viewing
negatively valenced pictures, subjects with BD had greater activation in the bilateral
DLPFC, inferior frontal gyrus, and right insula. Controls had greater activation
in the right posterior cingulate gyrus. For positively valenced pictures, subjects
with BD had greater activation in the bilateral caudate and thalamus, left middle/superior
frontal gyrus, and left ACC, whereas controls had no areas of greater activation.
CONCLUSIONS: Children and adolescents with BD may have underlying abnormalities
in the regulation of prefrontal-subcortical circuits. Further functional magnetic
resonance imaging studies of attention and mood with greater sample sizes are
G, Landau S, Beasley C, Everall IP, Cotter D.
of cytoarchitecture in the anterior cingulate cortex in major depressive disorder,
bipolar disorder, and schizophrenia: evidence for decreased neuronal somal size
and increased neuronal density.
Biol Psychiatry. 2003 Jun
"BACKGROUND: Abnormalities of cortical neuronal organization
and reductions in neuronal somal size have been reported in schizophrenia. The
purpose of this investigation was to assess patterns of neuronal and glial distribution
in the anterior cingulate cortex (ACC) in major depressive disorder (MDD), schizophrenia,
bipolar disorder (BPD), and normal control subjects (15 subjects per group). METHODS:
Estimates for neuronal somal and glial nuclear size and density were obtained.
We employed two-dimensional morphometric analysis to examine the location of neurons
and glia in a 1000-microm-wide strip of cortex. RESULTS: A decreased clustering
of neurons was seen in BPD (p =.001). No other group differences were observed
in the clustering of neurons, glia, or of neurons about glia. Neuronal somal size
was reduced in layer 5 in schizophrenia (18%, p =.001), BPD (16%, p <.001),
and MDD (9%, p =.01). Neuronal density was increased in layer 6 in BPD (63%, p
=.004) and schizophrenia (61%, p =.006) and in layer 5 in MDD (24%, p =.018) and
schizophrenia (33%, p =.003). CONCLUSIONS: The results of this study indicate
that reduced neuronal somal size and increased neuronal density in cortical layers
5 and 6 of the ACC may be key features of schizophrenia, MDD, and BPD." [Abstract]
Cotter D, Mackay D, Landau S, Kerwin R, Everall I.
Reduced glial cell density and neuronal size in the anterior cingulate
cortex in major depressive disorder.
Arch Gen Psychiatry
"BACKGROUND: Glial cells are more numerous than
neurons in the cortex and are crucial to neuronal function. There is evidence
for reduced neuronal size in schizophrenia, with suggestive evidence for reduced
glial cell density in mood disorders. In this investigation, we have simultaneously
assessed glial cell density and neuronal density and size in the anterior cingulate
cortex in schizophrenia, major depressive disorder, and bipolar disorder. METHODS:
We examined tissue from area 24b of the supracallosal anterior cingulate cortex
in 60 postmortem brain specimens from 4 groups of 15 subjects, as follows: major
depressive disorder, schizophrenia, bipolar disorder, and normal controls. Glial
cell density and neuronal size and density were examined in all subjects using
the nucleator and the optical disector. RESULTS: Glial cell density (22%) (P =.004)
and neuronal size (23%) (P =.01) were reduced in layer 6 in major depressive disorder
compared with controls. There was some evidence for reduced glial density in layer
6 (20%) (P =.02) in schizophrenia compared with controls, before adjusting for
multiple layerwise comparisons, but there were no significant changes in neuronal
size. There was no evidence for differences in glial density or neuronal size
in bipolar disorder compared with controls. Neuronal density was similar in all
groups to that found in controls. CONCLUSION: These findings suggest that there
is reduced frontal cortical glial cell density and neuronal size in major depressive
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]
RA, Parsey RV, Oquendo MA, Mann JJ
gray matter volume differences in patients with bipolar disorder as assessed by
optimized voxel-based morphometry.
2004 Jun 15;55(12):1154-62.
BACKGROUND: Structural magnetic resonance imaging
(MRI) studies of regions of interest in brain have been inconsistent in demonstrating
volumetric differences in subjects with bipolar disorder (BD). Voxel-based morphometry
(VBM) provides an unbiased survey of the brain, can identify novel brain areas,
and validates previously hypothesized regions. We conducted both optimized VBM,
comparing MRI gray matter volume, and traditional VBM, comparing MRI gray matter
density, in 11 BD subjects and 31 healthy volunteers. To our knowledge, these
are the first VBM analyses of BD. METHODS: Segmented MRI gray matter images were
normalized into standardized stereotactic space, modulated to allow volumetric
analysis (optimized only), smoothed, and compared at the voxel level with statistical
parametric mapping. RESULTS: Optimized VBM showed that BD subjects had smaller
volume in left ventromedial temporal cortex and bilateral cingulate cortex and
larger volume in left insular/frontoparietal operculum cortex and left ventral
occipitotemporal cortex. Traditional VBM showed that BD subjects had less gray
matter density in left ventromedial temporal cortex and greater gray matter density
in left insular/frontoparietal operculum cortex and bilateral thalamic cortex.
Exploratory analyses suggest that these abnormalities might differ according to
gender. CONCLUSIONS: Bipolar disorder is associated with volumetric and gray matter
density changes that involve brain regions hypothesized to influence mood. [Abstract]
IK, Kim MJ, Stoll AL, Demopulos CM, Parow AM, Dager SR, Friedman SD, Dunner DL,
Frontal lobe gray matter density decreases
in bipolar I disorder.
Biol Psychiatry. 2004 Mar
BACKGROUND: This study was conducted to explore differences
in gray and white matter density between bipolar and healthy comparison groups
using voxel-based morphometry (VBM). METHODS: Brain magnetic resonance imaging
was performed for 39 subjects with bipolar I disorder and 43 comparison subjects.
Images were registered into a proportional stereotaxic space and segmented into
gray matter, white mater, and cerebrospinal fluid. Statistical parametric mapping
was used to calculate differences in gray and white matter density between groups.
RESULTS: Bipolar subjects had decreased gray matter density in left anterior cingulate
gyrus (Brodmann's area [BA] 32, 7.3% decrease), an adjacent left medial frontal
gyrus (BA 10, 6.9% decrease), right inferior frontal gyrus (BA 47, 9.2% decrease),
and right precentral gyrus (BA 44, 6.2% decrease), relative to comparison subjects.
CONCLUSIONS: The observation of a gray matter density decrease in the left anterior
cingulate, which processes emotions, in bipolar subjects is consistent with prior
reports that used region-of-interest analytic methods. Decreased gray matter density
in the right inferior frontal gyrus, which processes nonverbal and intrinsic functions,
supports nondominant hemisphere dysfunction as a component of bipolar disorder.
M, Kowatch RA, DelBello MP, Mills NP, Holland SK
morphometry in adolescents with bipolar disorder: first results.
Res. 2004 May 30;131(1):57-69.
Bipolar disorder is an increasingly recognized
cause of significant morbidity in the pediatric age group. However, there is still
a large degree of uncertainty regarding the underlying neurobiological deficits.
In this preliminary study, we performed automated volumetric studies and whole-brain
voxel-based morphometry (VBM) on gray matter. Imaging data from 10 adolescents
with bipolar disorder were compared with data from 52 age- and gender-matched
healthy controls. Previously defined brain parcellations and optimized VBM protocols
were used, based on custom-made pediatric reference data. An additional, exploratory
whole-brain comparison was also implemented. The volumetric region-of-interest
study revealed significantly greater gray matter volume in central gray matter
structures bilaterally (including the basal ganglia and the thalamus) and the
left temporal lobe in the bipolar group. VBM confirmed bilaterally larger basal
ganglia. Localized gray matter deficits in bipolar subjects were found in the
medial temporal lobe, orbito-frontal cortex, and the anterior cingulate, confirming
and extending earlier studies. [Abstract]