Bipolar Disorder and the Frontal Lobes

Results of a MEDLINE Search by Ivan Goldberg, M.D.

1: Neuropsychopharmacology. 2003 Apr;28(4):711-9.

Pronounced cognitive deficits following an intravenous L-tryptophan challenge in
first-degree relatives of bipolar patients compared to healthy controls.

Sobczak S, Honig A, Schmitt JA, Riedel WJ.

Brain and Behavior Institute, Department of Psychiatry and Neuropsychology,
Universiteit Maastricht, The Netherlands.

Cognitive impairment has repeatedly been described in bipolar disorders (BD).
Serotonin (5-hydroxytryptophan; 5-HT) is possibly involved in these cognitive
processes, more particularly in executive functions, learning, memory, and
attention. The aim of this study was to investigate serotonergic vulnerability
and its relation to cognitive functioning in healthy first-degree relatives of
BD patients. We investigated the effects of an intravenous (i.v.) tryptophan
(Trp) challenge and placebo on cognitive performance in 30 healthy first-degree
relatives of bipolar patients (FH) and 15 matched controls in a double-blind
crossover design. A distinction was made between relatives of type I BD patients
(FH I) and type II BD patients (FH II). Performances on planning, memory,
attention, and psychomotor tasks were assessed 3 h after Trp infusion. After
Trp, planning and attention were impaired in FH subjects but not in controls.
Independent of Trp, FH subjects showed cognitive deficits on memory, focused and
divided attention, and psychomotor performance. FH I subjects showed more
pronounced cognitive impairments then FH II and controls. In all groups, Trp
impaired memory and psychomotor performance significantly. In conclusions,
cognitive deficits in FH following Trp may reflect a central 5-HT vulnerability
in frontal brain areas. Independent of Trp, cognitive deficits in FH provide
evidence for a trait marker for BD.

PMID: 12655316 [PubMed – indexed for MEDLINE]


2: Bipolar Disord. 2002 Dec;4(6):357-65.

Frontal lobe differences in bipolar disorder as determined by proton MR

Cecil KM, DelBello MP, Morey R, Strakowski SM.

Imaging Research Center, Department of Radiology, Children’s Hospital Medical
Center, Cincinnati, OH 45229, USA.

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.

PMID: 12519095 [PubMed – indexed for MEDLINE]


3: Cortex. 2002 Dec;38(5):743-52.

Persistent cognitive deficits associated with lithium intoxication: a
neuropsychological case description.

Bartha L, Marksteiner J, Bauer G, Benke T.

University Clinic of Neurology, Innsbruck, Austria.

We present the case of a 51-year-old patient with an acute lithium intoxication
associated with several cognitive deficits. During the acute phase of
intoxication the patient displayed general psychomotor slowing, dysarthric
speech, mood changes, and incoherent discourse. Neuropsychological assessment
revealed ideomotor apraxia, profound deficits of visuospatial processing, an
impairment of memory and of frontal-executive functions. Other cognitive
abilities, such as orientation, spontaneous speech, comprehension, naming,
reading, writing, and working memory remained intact. An electroencephalogram
revealed diffuse slowing with rhythmic trains, whereas MRI showed no cerebral
abnormality. Follow-up examinations at 4 and 14 weeks with lithium levels in the
normal range showed substantial recovery of memory abilities and executive
functions, whereas praxis and visuoperceptual functions remained impaired,
despite the fact that lithium was immediately withdrawn after the intoxication
became manifest. We conclude that lithium intoxication may be associated with
variable behavioural and cognitive impairments, some of them potentially
persistent. Different from other case studies our findings suggest that lithium
intoxication may cause a combined, multifocal functional impairment of
subcortical and cortical neural mechanisms in both hemispheres.

PMID: 12507043 [PubMed – indexed for MEDLINE]


4: Am J Psychiatry. 2003 Jan;160(1):76-82.

Response of cortical metabolic deficits to serotonergic challenge in familial
mood disorders.

Kegeles LS, Malone KM, Slifstein M, Ellis SP, Xanthopoulos E, Keilp JG, Campbell
C, Oquendo M, Van Heertum RL, Mann JJ.

Department of Psychiatry, Columbia University, New York, NY, USA.

OBJECTIVE: In subjects with mood disorders, positron emission tomography (PET)
with [(18)F]fluorodeoxyglucose has shown prefrontal cortical metabolism
deficits, including in a subgenual region in subjects with familial illness. The
authors applied a dl-fenfluramine challenge method to study metabolic response
in this region to serotonergic challenge in familial major depression. METHOD:
The study group consisted of 19 depressed subjects with major depressive
disorder or bipolar disorder, all of whom had at least one first-degree relative
with history of major depression, and 10 healthy volunteers with similar age and
gender distributions. PET images were acquired under placebo and challenge
conditions, and volumetric MRI scans were also obtained. Group comparisons of
metabolic and volumetric data were performed. Ratings of acute mood change
during serotonergic challenge were compared with the imaging data. RESULTS:
Within Brodmann’s area 32, a glucose metabolism deficit in the depressed
subjects on placebo day was observed by voxel-level analysis, but no volumetric
deficit was found in the subgenual regions examined. Under challenge, both
groups suppressed metabolism similarly. Within the patient group, the
correlation between acute mood improvement during challenge and greater
metabolic suppression approached significance. CONCLUSIONS: In familial mood
disorders, a ventromedial prefrontal cortical deficit in baseline metabolism is
not due to altered structural volume, and the response to serotonergic challenge
appears predictive of acute mood response. The potential to predict treatment
response can be tested by a combined challenge and treatment study.

Publication Types:
Clinical Trial

PMID: 12505804 [PubMed – indexed for MEDLINE]


5: Proc Natl Acad Sci U S A. 2003 Jan 7;100(1):313-7. Epub 2002 Dec 20.

Up-regulation of neuronal calcium sensor-1 (NCS-1) in the prefrontal cortex of
schizophrenic and bipolar patients.

Koh PO, Undie AS, Kabbani N, Levenson R, Goldman-Rakic PS, Lidow MS.

Departments of Oral and Craniofacial Biological Sciences, University of
Maryland, Baltimore 21201, USA.

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.

PMID: 12496348 [PubMed – indexed for MEDLINE]


6: Neuropsychopharmacology. 2002 Nov;27(5):792-9.

Anatomical MRI study of subgenual prefrontal cortex in bipolar and unipolar

Brambilla P, Nicoletti MA, Harenski K, Sassi RB, Mallinger AG, Frank E, Kupfer
DJ, Keshavan MS, Soares JC.

Department of Psychiatry, Western Psychiatric Institute and Clinic, University
of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

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.

PMID: 12431853 [PubMed – indexed for MEDLINE]


7: Hum Psychopharmacol. 2002 Oct;17(7):321-7.

Chronic treatment with both lithium and sodium valproate may normalize
phosphoinositol cycle activity in bipolar patients.

Silverstone PH, Wu RH, O’Donnell T, Ulrich M, Asghar SJ, Hanstock CC.

Department of Psychiatry, University of Alberta, Edmonton, Alberta, Canada.

BACKGROUND: It has been proposed that lithium may be clinically effective due to
its actions on the phosphoinositol second messenger system (PI-cycle). Studies
have also suggested that untreated manic patients may have raised myo-inositol
and phosphomonoester (PME) concentrations and also that unmedicated euthymic
bipolar patients may have lowered PME concentrations. The objective of the
present study was to test the hypothesis that chronic treatment with either
lithium or sodium valproate in patients with bipolar mood disorder leads to a
normalization in the activity of the PI-cycle. METHODS: This study had two parts
each with different MRS methodology. The first part compared healthy controls (n
= 19) with euthymic bipolar patients who were taking either lithium (n = 16) or
sodium valproate (n = 11) using both (1)H-MRS and (31)P-MRS. In the second part
we examined a separate group of euthymic bipolar disorder patients taking sodium
valproate (n = 9) and compared these with age and sex-matched healthy controls
(n = 11) using (1)H-MRS. RESULTS: Both studies showed that there were no
differences in either myo-inositol or phosphomonoester (PME) concentrations
between controls and patients taking either medication. CONCLUSIONS: These
findings examine two key components of the PI-cycle in treated euthymic bipolar
(myo-inositol and PME concentrations). The results from this study are
consistent with the suggestion that chronic treatment with either lithium or
sodium valproate in bipolar patients may normalize PI-cycle functioning.
Copyright 2002 John Wiley & Sons, Ltd.

Publication Types:
Clinical Trial

PMID: 12415549 [PubMed – indexed for MEDLINE]


8: Semin Clin Neuropsychiatry. 2002 Oct;7(4):243-54.

Frontotemporal neural systems in bipolar disorder.

Blumberg HP, Charney DS, Krystal JH.

Department of Psychiatry, Yale University School of Medicine, New Haven, CT,

Relatively 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. Copyright 2002, Elsevier
Science (USA). All rights reserved.

Publication Types:
Review, Tutorial

PMID: 12382207 [PubMed – indexed for MEDLINE]


9: Schizophr Res. 2002 Nov 1;58(1):63-7.

An investigation of the Wnt-signalling pathway in the prefrontal cortex in
schizophrenia, bipolar disorder and major depressive disorder.

Beasley C, Cotter D, Everall I.

Department of Neuropathology, Institute of Psychiatry, DeCrespigny Park, London
SE5 8AF, UK.

The Wnt-signalling pathway has been implicated in a variety of processes
including cortical development and plasticity. We have previously demonstrated a
reduction in glycogen synthase kinase-3beta (GSK-3beta) levels in the prefrontal
cortex in schizophrenia and aimed to further elucidate the abnormalities of the
Wnt-signalling pathway in this and other psychiatric disorders. Immunoblotting
was performed to quantify the levels of three members of the Wnt-signalling
pathway, GSK-3beta, beta-catenin and dishevelled-2 (Dvl-2), in the prefrontal
cortex in schizophrenia, bipolar disorder and major depressive disorder and in
matched controls. We found no significant differences between the disease and
control groups for any of the proteins studied, and therefore, cannot confirm
our earlier findings of abnormalities of GSK-3beta in schizophrenia. Copyright
2002 Elsevier Science B.V.

PMID: 12363391 [PubMed – indexed for MEDLINE]


10: Child Adolesc Psychiatr Clin N Am. 2002 Jul;11(3):499-518.

Etiology and genetics of early-onset mood disorders.

Todd RD, Botteron KN.

Division of Child Psychiatry, Department of Psychiatry, Washington University
School of Medicine, 660 South Euclid Avenue, Box 8134, St. Louis, MO 63110, USA.

Most studies dealing with the familiality and genetics of mood disorders have
been limited to adults, but several studies suggest that there is continuity
between childhood- and adolescence-onset depression and mania and adult illness.
More direct estimates of the heritability of depressive symptoms or episodes in
children and adolescents indicate that the genetic contributions may be greater
than 50%. A number of functional and structural imaging studies have identified
particular circuitry as being involved in the generation of emotion and mood
disorders. Imaging studies of twins have suggested that regional brain volume
and characteristics of brain shape are heritable. A potentially important new
avenue of research will be the correlation of the genetics of brain structure or
function with the genetics of mood disorders. Preliminary studies of adolescent
and young adult twins suggest a significant correspondence between the genetic
contributions to some regional brain volumes and early-onset mood disorders.

Publication Types:
Review, Academic

PMID: 12222080 [PubMed – indexed for MEDLINE]


11: Biol Psychiatry. 2002 Jul 15;52(2):93-100.

Regional prefrontal gray and white matter abnormalities in bipolar disorder.

Lopez-Larson MP, DelBello MP, Zimmerman ME, Schwiers ML, Strakowski SM.

Bipolar and Psychotic Disorders Research Program, Department of Psychiatry,
University of Cincinnati College of Medicine, Cincinnati, Ohio 45267-0559, USA.

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.

PMID: 12114000 [PubMed – indexed for MEDLINE]


12: J Pers Soc Psychol. 2002 Apr;82(4):610-8.

Proneness to hypomania/mania symptoms or depression symptoms and asymmetrical
frontal cortical responses to an anger-evoking event.

Harmon-Jones E, Abramson LY, Sigelman J, Bohlig A, Hogan ME, Harmon-Jones C.

Department of Psychology, University of Wisconsin-Madison, 53706, USA.

The behavioral approach system (BAS) reflects the propensity to respond to
signals of reward, including stimuli associated with safety and goal-oriented
attack (e.g., anger). Hypomania/mania has been posited to involve increased BAS
activity. In contrast, depression has been posited to involve decreased BAS
activity. Building on past research, which suggests that increased left frontal
cortical activity is a neurophysiological index of BAS activity, the present
research tested the hypotheses that proneness toward hypomania/mania symptoms
would be related to increased relative left frontal activity and that proneness
toward depression symptoms would be related to decreased relative left frontal
activity in response to an anger-evoking event. Results from 67 individuals who
had completed a measure of proneness toward these affective symptoms and were
exposed to an anger-evoking event supported the hypotheses.

PMID: 11999927 [PubMed – indexed for MEDLINE]


13: Mol Psychiatry. 2002;7(4):392-404.

Molecular abnormalities in the major psychiatric illnesses: Classification and
Regression Tree (CRT) analysis of post-mortem prefrontal markers.

Knable MB, Barci BM, Bartko JJ, Webster MJ, Torrey EF.

Stanley Foundation Research Programs, Bethesda, MD 20814, USA.

Post-mortem specimens from the Stanley Foundation Neuropathology Consortium,
which contains matched samples from patients with schizophrenia, bipolar
disorder, non-psychotic depression and normal controls (n = 15 per group), have
been distributed to many research groups around the world. This paper provides a
summary of abnormal markers found in prefrontal cortical areas from this
collection between 1997 and 2001. With parametric analyses of variance of 102
separate data sets, 14 markers were abnormal in at least one disease. The
markers pertained to a variety of neural systems and processes including
neuronal plasticity, neurotransmission, signal transduction, inhibitory
interneuron function and glial cells. The data sets were also examined using the
non-parametric Classification and Regression Tree (CRT) technique for the four
diagnostic groups and in pair-wise combinations. In contrast to the results
obtained with analyses of variance, the CRT method identified a smaller set of
nine markers that contributed maximally to the diagnostic classifications. Three
of the nine markers observed with CRT overlapped with the ANOVA results. Six of
the nine markers observed with the CRT technique pertained to aspects of
glutamatergic, GABA-ergic, and dopaminergic neurotransmission.

PMID: 11986983 [PubMed – indexed for MEDLINE]


14: Neuroreport. 2002 Mar 25;13(4):501-5.

Decreased prefrontal CaMKII alpha mRNA in bipolar illness.

Xing G, Russell S, Hough C, O’Grady J, Zhang L, Yang S, Zhang LX, Post R.

Department of Psychiatry, Uniformed Services University of the Health Sciences,
4301 Jones Bridge Road, Bethesda, MD 20814, USA.

Ca2+/calmodulin-dependent 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.

PMID: 11930170 [PubMed – indexed for MEDLINE]


15: J Clin Psychiatry. 2002 Mar;63(3):249.

Switch to mania after slow rTMS of the right prefrontal cortex.

Ella R, Zwanzger P, Stampfer R, Preuss UW, Muller-Siecheneder F, Moller HJ,
Padberg F.

Publication Types:

PMID: 11926727 [PubMed – indexed for MEDLINE]


16: Br J Psychiatry. 2002 Apr;180:320-6.

Comment in:
Br J Psychiatry. 2002 Apr;180:293-5.

Case-control study of neurocognitive function in euthymic patients with bipolar
disorder: an association with mania.

Cavanagh JT, Van Beck M, Muir W, Blackwood DH.

Department of Psychological Medicine, University of Glasgow, UK.

BACKGROUND: Neurocognitive impairments in euthymic patients with bipolar
disorder may represent trait rather than state variables. AIMS: To test the
hypothesis that euthymic patients with bipolar disorder would exhibit impairment
in verbal learning and memory and executive function compared with healthy
controls matched for age, gender and premorbid IQ. METHOD: Twenty euthymic
patients with bipolar disorder were matched, on a case-by-case basis, to twenty
healthy community controls. Cases and controls were tested with a battery of
neuropsychological tests. RESULTS: Impairments were found in cases compared with
controls in tests of verbal learning and memory. Verbal learning and memory
correlated negatively with the number of manic episodes. CONCLUSIONS: Impaired
verbal learning and memory may be a trait variable in bipolar disease. There are
implications for adherence to medication and relapse and for the role of early
treatment interventions. Prospective designs and targeting first-episode groups
may help to differentiate trait v. disease process effects.

PMID: 11925354 [PubMed – indexed for MEDLINE]


17: Br J Psychiatry. 2002 Apr;180:313-9.

Comment in:
Br J Psychiatry. 2002 Apr;180:293-5.

Sustained attention deficit in bipolar disorder.

Clark L, Iversen SD, Goodwin GM.

University Department of Psychiatry, Warneford Hospital, Oxford.

BACKGROUND: Recovery in bipolar disorder is central to its definition but is
rarely complete. Previous work has suggested that neuropsychological impairment
persists during the euthymic state but has been confounded partly by mild
affective symptoms in remitted patients. AIMS: To characterise
neuropsychological functioning in the euthymic phase of bipolar disorder with an
emphasis on tasks of executive functioning. METHOD: Thirty euthymic patients
with bipolar disorder were compared with thirty healthy controls on
neuropsychological tasks differentially sensitive to damage within prefrontal
cortex. RESULTS: Bipolar I patients were impaired on tasks of attentional set
shifting, verbal memory and sustained attention. Only sustained attention
deficit survived controlling for mild affective symptoms. This deficit was
related to progression of illness, but was none the less present in a subgroup
of patients near illness onset. CONCLUSIONS: Sustained attention deficit may
represent a neuropsychological vulnerability marker for bipolar disorder,
providing a focus for further understanding of the phenotype and analysis of the
neuronal networks involved.

PMID: 11925353 [PubMed – indexed for MEDLINE]


18: Eur Neuropsychopharmacol. 2002 Apr;12(2):123-8.

Effects of acute tryptophan depletion on cognitive function in euthymic bipolar

Hughes JH, Gallagher P, Young AH.

Stanley Foundation Research Centre, Department of Psychiatry, University of
Newcastle-upon-Tyne, Leazes Wing, Royal Victoria Infirmary, Newcastle-upon-Tyne
NE1 4LP, UK.

Decreasing brain 5-HT levels by acute tryptophan depletion has been shown to
selectively impair cognition in healthy volunteers. In bipolar disorder, ATD
causes measurable neurophysiological effects without altering mood. The purpose
of this study was to examine the effects of ATD on neuropsychological
performance in 14 euthymic bipolar patients. Cognitive function was evaluated
4-6 h after ingestion of a control or depleting amino-acid drink. Plasma
tryptophan levels fell significantly following the depleting drink, however
there were no main effects on the ID/ED set-shift task, Paired Associates
Learning or Vigil. A trend towards a decrease in the proportion of perfect
solutions on the Tower of London task was observed when depleted. While ATD
reduces 5-HT levels in the brain, it does not appear to alter neuropsychological
performance on tests of sustained attention or associative learning. Effects on
specific ‘executive’ functions are less clear, and should be the focus for
future research.

Publication Types:
Clinical Trial
Controlled Clinical Trial

PMID: 11872328 [PubMed – indexed for MEDLINE]


19: Neuropsychologia. 2002;40(3):245-52.

Mania caused by a diencephalic lesion.

Benke T, Kurzthaler I, Schmidauer Ch, Moncayo R, Donnemiller E.

University Clinic of Neurology, Anichstr. 35, 6020, Innsbruck, Austria.

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

PMID: 11684157 [PubMed – indexed for MEDLINE]


20: Am J Psychiatry. 2001 Oct;158(10):1605-11.

A neuropsychological investigation of prefrontal cortex involvement in acute

Clark L, Iversen SD, Goodwin GM.

Department of Psychiatry, University of Oxford, UK.

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.

PMID: 11578991 [PubMed – indexed for MEDLINE]


21: J Affect Disord. 2001 Oct;66(2-3):111-21.

Differential frontal activation in schizophrenia and bipolar illness during
verbal fluency.

Curtis VA, Dixon TA, Morris RG, Bullmore ET, Brammer MJ, Williams SC, Sharma T,
Murray RM, McGuire PK.

Department of Psychological Medicine, Institute of Psychiatry, De Crespigny
Park, London SE5 8AF, UK.

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.

PMID: 11578663 [PubMed – indexed for MEDLINE]


22: Epilepsia. 2001 Aug;42(8):1036-42.

Manic episode in epilepsy and bipolar I disorder: a comparative analysis of 13

Kudo T, Ishida S, Kubota H, Yagi K.

National Epilepsy Center, Shizuoka Higashi Hospital, Shizuoka, Japan.

PURPOSE: To determine whether the manic episode of patients with epilepsy has
different characteristics from manic episode of patients with bipolar disorder.
METHODS: Interictal manic episodes in patients with epilepsy (epilepsy group)
were compared with mood disorders in patients with bipolar I disorder (bipolar
group), as defined by the DSM-IV. There were 13 patients (five women and eight
men) in each group. RESULTS: Five epilepsy patients had relatives with epilepsy
and/or convulsions, and four bipolar patients had relatives with mood disorders.
In the epilepsy group, two had substance-related or organic factors associated
with the episodes besides epilepsy, and two exhibited a postictal manic state
that had the same symptoms as those of their interictal manic episodes. Ten
patients of the epilepsy group had dependent-childish behavior. The epilepsy
group had fewer severe mood episodes than the bipolar group. Ten epilepsy
patients had fluctuating mood disturbances, and eight had rapid cycling of mood
episodes. The epileptogenic zone was in the frontal and/or temporal lobes of
eight patients and in multiple lobes of two others; it could not be localized in
the three remaining patients. CONCLUSIONS: The clinical features of the
interictal manic episodes in the epilepsy group were different from those in the
bipolar group. The manic episodes of the epilepsy group appeared heterogeneous
in their causal factors. An epileptogenic zone in the frontal and temporal lobes
seems to play an important role in the mood episodes of the majority of patients
with epilepsy.

PMID: 11554891 [PubMed – indexed for MEDLINE]


23: Rev Esp Med Nucl. 2001 Aug;20(5):386-90.

[Functional neuroimaging in patients with rapid cycling bipolar depression] [Article in Spanish]

Benabarre A, Vieta E, Martin F, Lomena F.

Institut Clinic de Psiquiatria i Psicologia, Hospital Clinic, Universitat de
Barcelona, Stanley Foundation Barcelona Center.

Bipolar patients with a rapid cycling clinical course constitute an interesting
sub-group for studies focused on the pathophysiology of the disorder, since
several switches can be studied by the investigators in a short period of time.
At present, functional neuroimaging techniques, as SPECT and PET, may be used
for the neurobiological study of affective disorders. Few longitudinal
functional neuroimaging studies assessing the different phases of bipolar
disorder have been carried out. However, the published data suggest an
asymmetrical temporal lobe dysfunction in depressive and manic phases of bipolar
depression. Further studies with larger samples of patients are needed in order
to improve our knowledge of the pathophysiology of bipolar disorder.

Publication Types:
Review, Tutorial

PMID: 11470074 [PubMed – indexed for MEDLINE]


24: Bipolar Disord. 2001 Jun;3(3):106-50; discussion 151-3.

The neuropsychology and neuroanatomy of bipolar affective disorder: a critical

Bearden CE, Hoffman KM, Cannon TD.

Department of Psychiatry, University of Pennsylvania, Philadelphia, USA.

Bearden CE, Hoffman KM, Cannon TD. The neuropsychology and neuroanatomy of
bipolar affective disorder: a critical review. Bipolar Disord 2001: 3: 106 150.
C Munksgaard, 2001 OBJECTIVES: To present a comprehensive review of the existing
neuropsychological and neuroimaging literature on bipolar affective disorder.
This review critically evaluates two common conceptions regarding the
neuropsychology of bipolar disorder: 1) that, in contrast to schizophrenia,
bipolar affective disorder is not associated with general cognitive impairment
independent of illness episodes, and 2) relative right hemisphere (RH)
dysfunction is implicated in bipolar illness patients, supported by reports of
relatively greater impairment in visuospatial functioning, lateralization
abnormalities, and mania secondary to RH lesions. METHODS: The major
computerized databases (Medline and PSYCInfo) were consulted in order to conduct
a comprehensive, integrated review of the literature on the neuropsychology and
neuroanatomy of bipolar disorder. Articles meeting specified criteria were
included in this review. RESULTS: In a critical evaluation of the above notions,
this paper determines that: 1) while there is little evidence for selective RH
dysfunction, significant cognitive impairment may be present in bipolar illness,
particularly in a subgroup of chronic, elderly or multiple-episode patients,
suggesting a possible toxic disease process, and 2) the underlying functional
correlate of these cognitive deficits may be white matter lesions (‘signal
hyperintensities’) in the frontal lobes and basal ganglia, regions critical for
executive function, attention, speeded information processing, learning and
memory, and affect regulation. While this hypothesized neural correlate of
cognitive impairment in bipolar disorder is speculative, preliminary functional
neuroimaging evidence supports the notion of frontal and subcortical
hypometabolism in bipolar illness. CONCLUSIONS: The etiology of the structural
brain abnormalities commonly seen in bipolar illness, and their corresponding
functional deficits, remains unknown. It is possible that neurodevelopmental
anomalies may play a role, and it remains to be determined whether there is also
some pathophysiological progression that occurs with repeated illness episodes.
More research is needed on first-episode patients, relatives of bipolar
probands, and within prospective longitudinal paradigms in order to isolate
disease-specific impairments and genetic markers of neurocognitive function in
bipolar disorder.

Publication Types:
Review, Tutorial

PMID: 11465675 [PubMed – indexed for MEDLINE]


25: Psychol Med. 2001 Jul;31(5):915-22.

Different trait markers for schizophrenia and bipolar disorder: a neurocognitive

Keri S, Kelemen O, Benedek G, Janka Z.

Department of Psychiatry, University of Szeged, Hungary.

BACKGROUND: The aim of this study was to assess visual information processing
and cognitive functions in unaffected siblings of patients with schizophrenia,
bipolar disorder and control subjects with a negative family history. METHODS:
The siblings of patients with schizophrenia (N = 25), bipolar disorder (N = 20)
and the controls subjects (N = 20) were matched for age, education, IQ, and
psychosocial functioning, as indexed by the Global Assessment of Functioning
scale. Visual information processing was measured using two visual backward
masking (VBM) tests (target location and target identification). The evaluation
of higher cognitive functions included spatial and verbal working memory,
Wisconsin Card Sorting Test, letter fluency, short/long delay verbal recall and
recognition. RESULTS: The relatives of schizophrenia patients were impaired in
the VBM procedure, more pronouncedly at short interstimulus intervals (14, 28,
42 ms) and in the target location task. Marked dysfunctions were also found in
the spatial working memory task and in the long delay verbal recall test. In
contrast, the siblings of patients with bipolar disorder exhibited spared
performances with the exception of a deficit in the long delay recall task.
CONCLUSIONS: Dysfunctions of sensory-perceptual analysis (VBM) and working
memory for spatial information distinguished the siblings of schizophrenia
patients from the siblings of individuals with bipolar disorder. Verbal recall
deficit was present in both groups, suggesting a common impairment of the
fronto-hippocampal system.

PMID: 11459389 [PubMed – indexed for MEDLINE]


26: Psychiatry Res. 2001 May 30;106(3):181-91.

31P Nuclear magnetic resonance spectroscopy findings in bipolar illness: a

Yildiz A, Sachs GS, Dorer DJ, Renshaw PF.

Dokuz Eylul Medical School, Department of Psychiatry, Izmir, Turkey.

Published literature comparing 31P MR brain spectra of bipolar patients to
healthy controls was evaluated, focusing on phosphomonoester
(PME)/phosphodiester (PDE) resonance areas because these metabolites are related
to membrane phospholipids and membrane defects in bipolar disorder have been
suggested. Studies comparing PME and/or PDE values of bipolar subjects to values
observed in healthy controls were reviewed. Data from the studies meeting our
inclusion criteria (8 reports involving 139 bipolar and 189 comparison subjects)
were grouped according to the mood state of the subjects. Meta-analyses of data
were performed to compare PME and PDE levels of euthymic bipolar patients to
healthy controls, as well as comparing PME levels during euthymia in bipolar
subjects to values observed during manic and depressed states. The PME values of
euthymic bipolar patients were found to be significantly lower than PME values
of healthy controls. Depressed bipolar patients had significantly higher PME
values in comparison to euthymic bipolar patients. No significant difference
could be detected between the PDE values of bipolars and controls. This
meta-analysis found support for trait- and possibly state-dependent
abnormalities of membrane phospholipid metabolism, which may reflect a
dysregulation in brain-signal transduction systems of relevance in bipolar

Publication Types:

PMID: 11382540 [PubMed – indexed for MEDLINE]


27: Neuropsychopharmacology. 2001 Jul;25(1):91-7.

Neuropeptide Y Y(1) and Y(2) receptor mRNA expression in the prefrontal cortex
of psychiatric subjects. Relationship of Y(2) subtype to suicidal behavior.

Caberlotto L, Hurd YL.

Karolinska Institute, Department of Clinical Neuroscience, Psychiatry Section,
Karolinska Hospital, Stockholm, Sweden.

It has been hypothesized that the neuropeptide Y (NPY) system is involved in the
pathogenesis of mood disorder. In this study, Y(1) and Y(2) receptor mRNA
expression levels were analyzed in the dorsolateral prefrontal cortex of
subjects affected with major depression, bipolar disorder, or schizophrenia and
compared to normal controls. No significant alterations in Y(1) or Y(2) mRNA
expression levels were observed between the groups. However, the Y(2) mRNA
expression was elevated in layer IV in subjects with suicide as a cause of
death. For the Y(1) mRNA expression, there was a negative correlation with
increasing subject age in the prefrontal cortex. Analysis of covariance revealed
a significant elevation of the Y(1) mRNA expression levels in individuals with a
current history of marijuana use but no other drug. In summary, the current
results suggest distinct alterations of the prefrontal Y(1) and Y(2) neuronal
populations in aging and suicide.

PMID: 11377922 [PubMed – indexed for MEDLINE]


28: J Affect Disord. 2001 Jul;65(2):197-215.

Evolutionary recasting: ADHD, mania and its variants.

Brody JF.

This paper reviews clinical observations and evolutionary theory in relation to
attention deficit hyperactivity disorder (ADHD) on the one hand and mania and
its variants on the other. Both groups of disorders resemble each other in
regard to high levels of motor activity, perhaps occurring together more often
than not, and are confounded in most existing research. Making distinctions
requires isolating the contribution of activity level from other characteristics
such as those of flawed executive functions for ADHD or grandiosity and lapses
in reciprocity for mania. High activity level is an asset throughout nature
except in extreme intensities or when it amplifies the characteristics of
psychopathology. Fitness, social displays, and behavioral adaptations for
survival are clues to some aspects of hypomania and ADHD. While hypomania can be
a competitive advantage in certain niches, it appears there can be few
opportunities for ADHD to do so. Indeed, the impulsiveness seen in ADHD is
probably the outcome of flaws in executive functions rather than being the cause
of them. Neither lapses in executive functions nor in reciprocity are apt to be
domain general but may interact sharply with each person’s repertoire of
psychological adaptations. The author submits that a theoretical orientation as
outlined here would not only help in better understanding the disorders under
consideration, but could be useful in providing new directions to treatment

Publication Types:
Review, Tutorial

PMID: 11356245 [PubMed – indexed for MEDLINE]


29: Bipolar Disord. 2001 Apr;3(2):88-94.

Neuropsychological frontal lobe tests indicate that bipolar depressed patients
are more impaired than unipolar.

Borkowska A, Rybakowski JK.

Department of Psychiatry, University School of Medical Science, Bydgoszcz,

OBJECTIVES: The aim of this study was to compare the neuropsychological
performance of patients with bipolar or unipolar mood disorders during acute
episodes of depression using intelligence and frontal lobe tests. METHODS:
Fifteen patients with bipolar depression (BP) and 30 with unipolar depression
(UP) were studied. For the neuropsychological assessment, the following tests:
the Wechsler Adult Intelligence Scale-Revised (WAIS-R), the Trail Making Test
(TMT), the Stroop test, the verbal fluency test and the Wisconsin Card Sorting
Test (WCST) were used. RESULTS: The mean intensity of depression and mean
duration of illness were similar in both groups. Patients in the BP group
achieved significantly lower levels of performance in the non-verbal part of
WAIS-R, in both parts of the Stroop test, in the verbal fluency test and also
showed a tendency to achieve poorer results in TMT-B than those in the UP group.
Bipolar depressed patients also produced significantly poorer results with the
WCST as they made twice as many perseverative errors and only completed half of
the correct categories compared with the UP patients. The results of the TMT-A
tests, which measure psychomotor slowness, were similar in BP and UP patients.
No differences between the results of male and female patients were noted in
either group. Deterioration of the results associated with duration of the
illness was only observed in the UP patients. CONCLUSIONS: A higher degree of
cognitive dysfunction connected with frontal lobe activity during an acute
depressive episode was found in bipolar compared with unipolar depressed
patients. These results may corroborate other findings pointing to pathogenic
distinctions between bipolar and unipolar affective illness and to some
similarities between bipolar illness and schizophrenia.

PMID: 11333068 [PubMed – indexed for MEDLINE]


30: Biol Psychiatry. 2001 May 1;49(9):741-52.

Comment in:
Biol Psychiatry. 2002 May 15;51(10):838-40; discussion, 842-6.

Reductions in neuronal and glial density characterize the dorsolateral prefrontal
cortex in bipolar disorder.

Rajkowska G, Halaris A, Selemon LD.

Laboratory of Quantitative Neuroanatomy, Department of Psychiatry and Human
Behavior, University of Mississippi Medical Center, Jackson 39216, USA.

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.

PMID: 11331082 [PubMed – indexed for MEDLINE]


31: Eur Arch Psychiatry Clin Neurosci. 2001;251(1):29-31.

Sleep and sleep-wake cycle in an 81-year-old patient with de novo ultra-rapid
cycling bipolar disorder.

Schreiner R, Mirisch S, Vesely Z, Wiegand MH.

Department of Neurology and Clinical Neurophysiology, Stadtisches Krankenhaus
Munchen-Bogenhausen, Englschalkinger Strasse 77, 81925 Munich, Germany.

This is a case report of an 81-year-old man who developed de novo bipolar
disorder with ultrarapid cycling at the age of 80. Mood was self-rated daily
over a period of ten weeks; in addition, polysomnographic and motor activity
recordings were performed during a drug-free baseline period. Both depressive
and hypomanic episodes had an average duration of about 30 hours; the affective
cycle was thus independent from the sleep-wake cycle. When mood shifts occurred
during nighttime, sleep was different in nights following depression than in
nights following hypomania. Positron emission tomography revealed a moderate
bilateral frontal hypermetabolism in the hypomanic phase and yielded normal
findings for the depressive stage. In contrast to what is usually expected in
ultra-rapid cycling bipolar disorder, this case demonstrates an unusual
sleep-unrelated cycle duration in the oldest reported patient so far.

PMID: 11315515 [PubMed – indexed for MEDLINE]


32: Bipolar Disord. 2000 Sep;2(3 Pt 1):148-64.

Neuroimaging in bipolar disorder.

Strakowski SM, DelBello MP, Adler C, Cecil DM, Sax KW.

Bipolar and Psychotic Disorders Research Program, Department of Psychiatry,
University of Cincinnati College of Medicine, OH 45267-0559, USA.

OBJECTIVE: The authors reviewed neuroimaging studies of bipolar disorder in
order to evaluate how this literature contributes to the current understanding
of the neurophysiology of the illness. METHOD: Papers were reviewed as
identified, using the NIMH PubMed literature search systems that reported
results of neuroimaging studies involving a minimum of five bipolar disorder
patients compared with healthy comparison subjects. RESULTS: Structural
neuroimaging studies report mixed results for lateral and third
ventriculomegaly. Recent studies suggest subcortical structural abnormalities in
the striatum and amygdala, as well as the prefrontal cortex. Proton
spectroscopic studies suggest that abnormalities in choline metabolism exist in
bipolar disorder, particularly in the basal ganglia. Additionally, phosphorous
MRS suggests that there may be abnormalities in frontal phospholipid metabolism
in bipolar disorder. Functional studies have identified affective state-related
changes in cerebral glucose metabolism and blood flow, particularly in the
prefrontal cortex during depression, but no clear abnormalities specific to
bipolar disorder have been consistently observed. CONCLUSIONS: The current
literature examining the neurophysiology of bipolar disorder using neuroimaging
is limited. Nonetheless, abnormalities in specific frontal-subcortical brain
circuits seem likely. Additional targeted studies are needed to capitalize on
this burgeoning technology to advance our understanding of the neurophysiology
of bipolar disorder.

Publication Types:
Review, Tutorial

PMID: 11256682 [PubMed – indexed for MEDLINE]


33: Bipolar Disord. 2000 Sep;2(3 Pt 2):237-48.

fMRI during affect discrimination in bipolar affective disorder.

Yurgelun-Todd DA, Gruber SA, Kanayama G, Killgore WD, Baird AA, Young AD.

Cognitive Neuroimaging Laboratory, Brain Imaging Center, McLean Hospital,
Harvard Medical School, Belmont, MA 02478, USA.

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.

PMID: 11249801 [PubMed – indexed for MEDLINE]


34: Neurology. 2000 Mar 28;54(6):1389-90.

Hypomania from the left frontal AVM resection.

Benjamin S, Kirsch D, Visscher T, Ozbayrak KR, Weaver JP.

Department of Psychiatry, University of Massachusetts Medical School, Worcester
01655, USA.

PMID: 10746620 [PubMed – indexed for MEDLINE]


35: Biol Psychiatry. 2000 Mar 15;47(6):475-81.

Decreased dorsolateral prefrontal N-acetyl aspartate in bipolar disorder.

Winsberg ME, Sachs N, Tate DL, Adalsteinsson E, Spielman D, Ketter TA.

Department of Psychiatry and Behavioral Sciences, Stanford University School of
Medicine, Stanford, California, USA.

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.

PMID: 10715353 [PubMed – indexed for MEDLINE]


36: Psychol Med. 1999 Nov;29(6):1307-21.

Emotional bias and inhibitory control processes in mania and depression.

Murphy FC, Sahakian BJ, Rubinsztein JS, Michael A, Rogers RD, Robbins TW, Paykel

Department of Psychiatry, University of Cambridge.

BACKGROUND: Despite markedly different clinical presentations, few studies have
reported differences in neuropsychological functioning between mania and
depression. The disinhibited behaviour characteristic of mania and evidence that
subgenual prefrontal cortex is differentially activated in mania and depression
both suggest that dissociable deficits will emerge on tasks that require
inhibitory control and are subserved by ventromedial prefrontal cortex. METHODS:
Manic patients and controls undertook computerized neuropsychological tests of
memory and planning ability. In addition, manic and depressed patients were
directly compared with controls on a novel affective shifting task that requires
inhibitory control over different components of cognitive and emotional
processing. RESULTS: Manic patients were impaired on tests of memory and
planning. Importantly, affective shifting performance of manic patients differed
from that of depressed patients. Manic patients were impaired in their ability
to inhibit behavioural responses and focus attention, but depressed patients
were impaired in their ability to shift the focus of attention. Depressed
patients exhibited an affective bias for negative stimuli, and we believe this
to be the first demonstration of an affective bias for positive stimuli in manic
patients. CONCLUSIONS: Observed impairments on tests of memory and planning
suggest a global pathology for mania consistent with previous profiles for this
disorder and similar to established profiles for depression. The results on the
affective shifting task demonstrate the presence of mood-congruent bias and
dissociable components of inhibitory control in mania and depression. Against a
background of memory and planning impairments in the two groups, these findings
are consistent with a role for the ventromedial prefrontal cortex in mediating
mood-cognition relationships.

PMID: 10616937 [PubMed – indexed for MEDLINE]


37: Psychother Psychosom. 2000;69(1):2-18.

Cognitive dysfunctions in bipolar disorder: evidence of neuropsychological

Martinez-Aran A, Vieta E, Colom F, Reinares M, Benabarre A, Gasto C, Salamero M.

Bipolar Disorders Program, Department of Psychiatry, Hospital Clinic, University
of Barcelona, Spain.

Although cognitive dysfunctions in psychosis have classically been associated
with schizophrenia, there is clinical evidence that some bipolar patients show
cognitive disturbances either during acute phases or in remission periods. The
authors critically review the data on cognitive impairment in bipolar disorder.
The main computerized databases (Medline, Psychological Abstracts, Current
Contents) have been consulted crossing the terms ‘cognitive deficits’,
‘neuropsychology’, ‘intellectual impairment’, ‘mania’, ‘depression’ and ‘bipolar
disorder’. Changes in the fluency of thought and speech, learning and memory
impairment, and disturbances in associational patterns and attentional processes
are as fundamental to depression and mania as are changes in mood and behavior.
Moreover, a significant number of bipolar patients show persistent cognitive
deficits during remission from affective symptoms. However, there are several
methodological pitfalls in most studies such as unclear remission criteria,
diagnostic heterogeneity, small sample sizes, absence of longitudinal
assessment, practice effect and poor control of the influence of pharmacological
treatment. Most studies point at the presence of diffuse cognitive dysfunction
during the acute phases of bipolar illness. Most of these deficits seem to remit
during periods of euthymia, but some of them may persist in approximately one
third of bipolar patients. Methodological limitations warrant further research
in order to clear up the relationship between neuropsychological functioning and
clinical, demographic and treatment variables in bipolar disorder. Copyright
2000 S. Karger AG, Basel.

Publication Types:
Review, Tutorial

PMID: 10601830 [PubMed – indexed for MEDLINE]


38: Am J Psychiatry. 1999 Dec;156(12):1986-8.

Rostral and orbital prefrontal cortex dysfunction in the manic state of bipolar

Blumberg 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 DA.

Department of Psychiatry, New York Hospital-Cornell Medical Center, New York,

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.

PMID: 10588416 [PubMed – indexed for MEDLINE]