Brain Structural Effects of Psychopharmacological Treatment in Bipolar Disorder

Bipolar disorder is associated with subtle neuroanatomical deficits including lateral ventricular enlargement, grey matter deficits incorporating limbic system structures, and distributed white matter pathophysiology. Substantial heterogeneity has been identified by structural neuroimaging studies to date and differential psychotropic medication use is potentially a substantial contributor to this. This selective review of structural neuroimaging and diffusion tensor imaging studies considers evidence that lithium, mood stabilisers, antipsychotic medication and antidepressant medications are associated with neuroanatomical variation. Most studies are negative and suffer from methodological weaknesses in terms of directly assessing medication effects on neuroanatomy, since they commonly comprise posthoc assessments of medication associations with neuroimaging metrics in small heterogenous patient groups. However the studies which report positive findings tend to form a relatively consistent picture whereby lithium and antiepileptic mood stabiliser use is associated with increased regional grey matter volume, especially in limbic structures. These findings are further supported by the more methodologically robust studies which include large numbers of patients or repeated intra-individual scanning in longitudinal designs. Some similar findings of an apparently ameliorative effect of lithium on white matter microstructure are also emerging. There is less support for an effect of antipsychotic or antidepressant medication on brain structure in bipolar disorder, but these studies are further limited by methodological difficulties. In general the literature to date supports a normalising effect of lithium and mood stabilisers on brain structure in bipolar disorder, which is consistent with the neuroprotective characteristics of these medications identified by preclinical studies.     

Investigating endophenotype of endogeneous psychotic disorders]

Accumulated evidence from a number of previous structural MRI studies have revealed 1) the existence of abnormalities even at the brain structural level in subjects at an early stage of endogeneous psychotic illness, including schizophrenia and bipolar disorder, and 2) the existence of similar brain structural abnormalities to the patients even in individuals at high-risk of endogeneous psychotic illness. Recently, an increasing number of studies have investigated the associations between the functional polymorphism of candidate genes for susceptibility to schizophrenia and regional brain volume, a highly heritable trait marker, to uncover the linkage between the candidate genes and endophenotype of schizophrenia. Firstly, this review article overviewed recent literature examining the relationship between the candidate genes for susceptibility to schizophrenia and indices obtained from neuroimaging modalities. In contrast, a relatively limited number of previous studies examined associations between candidate genes for susceptibility to bipolar disorder and regional brain volume, although the high heritability of bipolar disorder has been reported as comparable to that of schizophrenia. Then, we discussed the possibility of endophenotyping of bipolar disorder and introduced our preliminary study. Finally, methodological considerations and future directions of endophenotyping of endogeneous psychosis were suggested.     

Psychosis and brain volume changes during the first five years of schizophrenia

The underlying mechanisms explaining brain volume changes in schizophrenia are not yet understood, but psychosis might be related to these changes. Forty-eight patients with first-episode schizophrenia underwent Magnetic Resonance Imaging brain scanning at inclusion and after five years. An association was found between longer duration of psychosis, larger gray matter volume decrease and larger ventricular volume increase. These findings strongly suggest that psychosis contributes to brain volume reductions found in schizophrenia.     

Brain volume changes after withdrawal of atypical antipsychotics in patients with first-episode schizophrenia

The influence of antipsychotic medication on brain morphology in schizophrenia may confound interpretation of brain changes over time. We aimed to assess the effect of discontinuation of atypical antipsychotic medication on change in brain volume in patients. Sixteen remitted, stable patients with first-episode schizophrenia, schizoaffective or schizophreniform disorder and 20 healthy controls were included. Two magnetic resonance imaging brain scans were obtained from all subjects with a 1-year interval. The patients either discontinued (n = 8) their atypical antipsychotic medication (olanzapine, risperidone, or quetiapine) or did not (n = 8) discontinue during the follow-up period. Intracranial volume and volumes of total brain, cerebral gray and white matter, cerebellum, third and lateral ventricle, nucleus caudatus, nucleus accumbens, and putamen were obtained. Multiple linear regression analyses were used to assess main effects for group (patient-control) and discontinuation (yes-no) for brain volume (change) while correcting for age, sex, and intracranial volume. Decrease in cerebral gray matter and caudate nucleus volume over time was significantly more pronounced in patients relative to controls. Our data suggest decreases in the nucleus accumbens and putamen volumes during the interval in patients who discontinued antipsychotic medication, whereas increases were found in patients who continued their antipsychotics. We confirmed earlier findings of excessive gray matter volume decrements in patients with schizophrenia compared with normal controls. We found evidence suggestive of decreasing volumes of the putamen and nucleus accumbens over time after discontinuation of medication. This might suggest that discontinuation reverses effects of atypical medication.     

Dysregulation of the neural cell adhesion molecule and neuropsychiatric disorders

Cell adhesion molecule proteins play a diverse role in neural development, signal transduction, structural linkages to extracellular and intracellular proteins, synaptic stabilization, neurogenesis, and learning. Three basic mRNA isoforms and potent posttranslational modifications differentially regulate these neurobiological properties of the neural cell adhesion molecule (N-CAM). Abnormal concentrations of N-CAM 105-115 kDa (cN-CAM), N-CAM variable alternative spliced exon (VASE), and N-CAM secreted exon (SEC) are related to schizophrenia and bipolar neuropsychiatric disorders. These N-CAM isoforms provide potential mechanisms for expression of multiple neurobiological alterations between controls and individuals with schizophrenia or bipolar illness. Multiple processes can trigger the dysregulation of N-CAM isoforms. Differences in neuropil volume, neuronal diameter, gray matter thickness, and ventricular size can be related to N-CAM neurobiological properties in neuropsychiatric disorders. Potential test of the N-CAM dysregulation hypothesis of neuropsychiatric disorder is whether ongoing dysregulation of N-CAM would cause cognitive impairments, increased lateral ventricle volume, and decreased hippocampal volume observed in schizophrenia and to a lesser extent in bipolar disorder. An indirect test of this theory conducted in animal experiments lend support to this N-CAM hypothesis. N-CAM dysregulation is consistent with a synaptic abnormality that could underlie the disconnection between brain regions consistent with neuroimaging reports. Synapse stability and plasticity may be part of the molecular neuropathology of these disorders.     

Illness duration and total brain gray matter in bipolar disorder: Evidence for neurodegeneration?

Previous studies have suggested that bipolar disorder (BD) is associated with alterations in neuronal plasticity, but the effects of the progression of illness on brain anatomy have been poorly investigated. We studied the correlation between length of illness, age, age at onset, and the number of previous episodes and total brain, total gray, and total white matter volumes in BD, unipolar (UP) and healthy control (HC) subjects. Thirty-six BD, 31 UP and 55 HCs underwent a 1.5 T brain magnetic resonance imaging scan, and gray and white matter volumes were manually traced blinded to the subjects' diagnosis. Partial correlation analysis showed that length of illness was inversely correlated with total gray matter volume after adjusting for total intracranial volume in BD (r(p)=-0.51; p=0.003) but not in UP subjects (r(p)=-0.23; p=0.21). Age at illness onset and the number of previous episodes were not significantly correlated with gray matter volumes in BD or UP subjects. No significant correlation with total white matter volume was observed. These results suggest that the progression of illness may be associated with abnormal cellular plasticity. Prospective longitudinal studies are necessary to elucidate the long-term effects of illness progression on brain structure in major mood disorders.     

Gray and white matter changes and their relation to illness trajectory in first episode psychosis

Previous works have studied structural brain characteristics in first-episode psychosis (FEP), but few have focused on the relation between brain differences and illness trajectories. The aim of this study is to analyze gray and white matter changes in FEP patients and their relation with one-year clinical outcomes. A sample of 41 FEP patients and 41 healthy controls (HC), matched by age and educational level was scanned with a 3 T MRI during the first month of illness onset. One year later, patients were assigned to two illness trajectories (schizophrenia and non-schizophrenia). Voxel-based morphometry (VBM) was used for gray matter and Tract-based spatial statistics (TBSS) was used for white matter data analysis. VBM revealed significant and widespread bilateral gray matter density differences between FEP and HC groups in areas that included the right insular Cortex, the inferior frontal gyrus and orbito-frontal cortices, and segments of the occipital cortex. TBSS showed a significant lower fractional anisotropy (FA) in 8 clusters that included segments of the anterior thalamic radiation, the left body and forceps minor of corpus callosum, the right anterior segment of the inferior fronto-occipital fasciculus and the anterior segments of the cingulum. The sub-groups comparison revealed significant lower FA in the schizophrenia sub-group in two clusters: the anterior thalamic radiation and the anterior segment of left cingulum. These findings are coherent with previous morphology studies. The results suggest that gray and white matter abnormalities are present at early stages of the disease, and white matter differences may distinguish different illness prognosis.     

Childhood abuse and white matter integrity in bipolar disorder patients and healthy controls

Childhood trauma has a negative impact on the developing brain and increases the risk for almost all psychiatric disorders including bipolar disorder. White matter abnormalities may play a role in the persistently increased risk for bipolar disorder following childhood trauma.We therefore examined the influence of childhood abuse and neglect on white matter integrity using diffusion tensor imaging (DTI), quantified as fractional anisotropy (FA), in patients with bipolar I disorder (N = 251) and healthy controls (N = 163). Bipolar patients experienced more childhood abuse (30.6% vs 8.0%; p< 0.001) and childhood neglect (36.3% vs 22.7%; p = 0.003) than controls. Childhood abuse had different effects on whole brain FA in patients with bipolar disorder compared to healthy individuals (F[1,410] = 3.060; p = 0.006). Specifically, whereas patients with bipolar disorder with childhood abuse had lower FA in widespread regions of the brain relative to patients without childhood abuse (t[249] = 2.28; p = 0.024), no differences were found between healthy individuals with and without abuse (t[161]=?0.18; p = 0.986). Differences in mean FA significantly mediated the association between childhood abuse and bipolar disorder. In contrast, childhood neglect was not significantly associated with FA in patients with bipolar disorder nor in healthy controls.Together, these results show that childhood abuse but not neglect is associated with lower integrity of white matter microstructure across the brain in patients with bipolar I disorder but not in healthy individuals. Therefore, white matter integrity might be involved the relationship between childhood abuse and bipolar disorder, even though the directionality cannot be proven due to the cross-sectional design of our study.     

Clinical and neuropsychological correlates of white matter abnormalities in recent onset schizophrenia.

The objective of this study was to investigate the clinical and neuropsychological correlates of white matter abnormalities in patients with schizophrenia studied early in the course of illness. A total of 33 (21 male/12 female) patients with recent onset schizophrenia and 30 (18 male/12 female) healthy volunteers completed structural and diffusion tensor imaging exams. Patients also received clinical and neuropsychological assessments. Fractional anisotropy (FA) maps were compared between groups in the white matter using a voxelwise analysis following intersubject registration to Talairach space and correlated with functional indices. Compared to healthy volunteers, patients demonstrated significantly (p<0.001, cluster size >or=100) lower FA within temporal lobe white matter regions corresponding approximately to the right and left uncinate fasciculus, left inferior fronto-occipital fasciculus, and left superior longitudinal fasciculus. There were no areas of significantly higher FA in patients compared to healthy volunteers. Lower FA in the bilateral uncinate fasciculus correlated significantly with greater severity of negative symptoms (alogia and affective flattening), and worse verbal learning/memory functioning. In addition, higher FA in the inferior fronto-occipital fasciculus correlated significantly with greater severity of delusions and hallucinations. White matter abnormalities are evident in patients with schizophrenia early in the course of illness, appearing most robust in left temporal regions. These abnormalities have clinical and neuropsychological correlates, which may be useful in further characterizing structure-function relations in schizophrenia and constraining neurobiological models of the disorder.     

Oligodendroglial abnormalities in schizophrenia, mood disorders and substance abuse. Comorbidity, shared traits, or molecular phenocopies?

The evidence implicating oligodendroglia in major mental disorders has grown significantly in the past few years. Microarray analysis revealed altered expression of oligodendroglia-related genes in multiple brain regions from several, clinically diverse groups of subjects with schizophrenia (SZ) as well as subjects with bipolar disorder (BD) and major depressive disorders (MDD), alcoholics and cocaine users. In line with gene expression findings, evidence for ultrastructural changes in white matter and altered oligodendroglia in these disorders were reported in neuroimaging and neuropathological studies. Changes in oligodendroglia-related genes reported in SZ, BD and MDD appear to display considerable similarities (particularly decreased expression of MAG, ERBB, TF, PLP1, MOG, MOBP, MOG), while changes in cocaine abuse and alcoholism are more diverse. Common oligodendroglial abnormalities might indicate aetiological or pathophysiological overlaps between different disorders. The possible mechanisms of oligodendroglial abnormalities may involve functional variations in oligodendroglia-related genes, epigenetic regulation of chromatin, DA system hyperactivity and other mechanisms.     

The ZNF804A Gene: Characterization of a Novel Neural Risk Mechanism for the Major Psychoses

Schizophrenia and bipolar disorder share genetic risk, brain vulnerability, and clinical symptoms. The ZNF804A risk variant, rs1344706, confers susceptibility for both disorders. This study aimed to identify neural mechanisms common to both schizophrenia and bipolar disorder through this variant''s potential effects on cortical thickness, white matter tract integrity, and cognitive function. Imaging, genetics, and cognitive measures were ascertained in 62 healthy adults aged between 18 and 59 years. High-resolution multimodal MRI/DTI imaging was used to measure cortical thickness and major frontotemporal and interhemispheric white matter tracts. The general linear model was used to examine the influence of the ZNF804A rs1344706 risk variant on cortical thickness, white matter tract integrity, and cognitive measures. Individuals homozygous for the risk variant (‘A'' allele) demonstrated reduced cortical gray matter thickness in the superior temporal gyrus, and in the anterior and posterior cingulate cortices compared with C-allele carriers. No effect of the risk variant on microstructural integrity of white matter tracts was found. Reduced attention control was found in risk allele homozygotes, aligning with findings in the anterior cingulate cortex. Our data provide a novel, genetically based neural risk mechanism for the major psychoses by effects of the ZNF804A risk variant on neural structures and cognitive function susceptible in both disorders. Our findings link genetic, imaging, and cognitive susceptibility relevant to both schizophrenia and bipolar disorder.     

Dermatoglyphics in relation to brain volumes in twins concordant and discordant for bipolar disorder

Palmar and finger dermatoglyphics are formed between the 10th and the 17th weeks of gestation and their morphology can be influenced by genetic or environmental factors, interfering with normal intrauterine development. As both the skin and the brain develop from the same embryonal ectoderm, dermatoglyphic alterations may be informative for early abnormal neurodevelopmental processes in the brain. We investigated whether dermatoglyphic alterations are related to structural brain abnormalities in bipolar disorder and to what extent they are of a genetic and of an environmental origin. Dermatoglyphics and volumetric data from structural MRI were obtained in 53 twin pairs concordant or discordant for bipolar disorder and 51 healthy matched control twin pairs. Structural equation modeling was used. Bipolar disorder was significantly positively associated with palmar a–b ridge count (ABRC), indicating higher ABRC in bipolar patients (rph=.17 (CI .04–.30)). Common genes appear to be involved because the genetic correlation with ABRC was significant (rph-A=.21 (CI .05-.36). Irrespective of disease, ABRC showed a genetically mediated association with brain volume, indicated by a significant genetic correlation rph-A of respectively −.36 (CI −.52 to −.22) for total brain, −.34 (CI −.51 to −.16) total cortical volume, −.27 (CI −.43 to −.08) cortical gray matter and −.23 (CI −.41 to −.04) cortical white matter. In conclusion, a genetically determined abnormal development of the foetal ectoderm between the 10th and 15th week of gestation appears related to smaller brain volumes in (subjects at risk for) bipolar disorder.     

Cortical thickness,cortical surface area and subcortical volumes in schizophrenia and bipolar disorder patients with cannabis use

Cannabis is associated with increased risk for severe mental illness and is commonly used among individuals with schizophrenia or bipolar disorder.In this study we investigated associations between cannabis use and brain structures among patients with schizophrenia or bipolar disorders. Magnetic resonance imaging scans were obtained for 77 schizophrenia and 55 bipolar patients with a history of cannabis use (defined as lifetime use >10 times during one month or abuse/dependence), and 97 schizophrenia, 85 bipolar disorder patients and 277 healthy controls without any previous cannabis use. Cortical thickness, cortical surface area and subcortical volumes were compared between groups. Both hypothesis-driven region-of-interest analyses from 11 preselected brain regions in each hemisphere and exploratory point-by-point analyses were performed. We tested for diagnostic interactions and controlled for potential confounders.After controlling for confounders such as tobacco use and alcohol use disorders we found reduced cortical thickness in the caudal middle frontal gyrus compared to non-user patients and healthy controls. The findings were not significant when patients with co-morbid alcohol and illicit drug use were excluded from the analyses, but onset of cannabis use before illness onset was associated with cortical thinning in the caudal middle frontal gyrus.To conclude, we found no structural brain changes associated with cannabis use among patients with severe mental illness, but the findings indicate excess cortical thinning among those who use cannabis before illness onset. The present findings support the understanding that cannabis use is associated with limited brain effects in schizophrenia as well as bipolar disorder.     

Disturbed grey matter coupling in schizophrenia

In schizophrenia, grey matter deficits have been shown for many regions throughout the brain. These regions do not operate in isolation. Rather, they form a structural network of interconnected grey matter regions. To examine the mutual dependence of brain regions, this study investigated interregional coupling in lobar and regional grey matter volumes obtained from 146 schizophrenia patients and 122 healthy comparison subjects. Compared to healthy controls, schizophrenia patients showed both decreased (e.g. between left frontal and bilateral subcortical, p≤0.005) and increased (e.g. between left temporal and bilateral subcortical, p≤0.001) coupling between lobar grey matter volumes. On a regional scale, decreased coupling was most pronounced between fronto-parietal cortical regions and subcortical structures, and between frontal and occipital regions. In addition, an increased association was found among frontal and limbic regions, and for temporo-occipital connexions. Consistent with dysconnectivity theories of schizophrenia, impaired grey matter coupling may be reflective of reduced integrity of the brain's network. Furthermore, as cross-sectional volumetric coupling is indicative of maturational coupling, aberrant grey matter coupling may be a marker of neurodevelopmental abnormalities in schizophrenia.     

Schizophrenia and bipolar disorder: similarities in pathogenic mechanisms but differences in neurodevelopment

Over the past 100 years, the Kraepelinian classification of psychoses has dominated our approach to schizophrenia and bipolar disorder. However, controversy as to the nature of the illnesses--whether they can be viewed as completely distinct, essentially the same, or occupying different points along a psychosis spectrum--has intensified in recent years. This paper reviews the evidence for these differing opinions, examining both the commonalities between the two diseases and the distinctions. A genetic propensity towards psychotic disorders is widely acknowledged; more recent studies suggest a considerable overlap in genetic susceptibility to schizophrenia and bipolar disorder. The influence of early environmental effects, such as obstetric complications, on schizophrenia is also established but little such evidence exists for bipolar disorder. Structural abnormalities of the brain of developmental origin as well as neuropsychological deficits have been clearly identified in schizophrenia but less evidence has been found in bipolar disorder. The most plausible explanation is that one or more susceptible genes are shared between schizophrenia and bipolar illness, and can be thought of as predisposing individuals to psychosis, perhaps by producing a dysregulation of the dopaminergic response to stress. Other genes and environmental factors are likely to have more specific effects and contribute to producing the patterns that psychiatrists recognize as 'classical' schizophrenia and mania. In particular, genes involved in early cortical development and early neurodevelopmental insults causing developmental impairment may put individuals on a trajectory towards schizophrenia rather than bipolar illness.     

MRI analysis of the cerebellum in bipolar disorder: a pilot study.

Since qualitative CT studies have suggested decreased cerebellar size in patients with bipolar disorder, we performed a quantitative analysis of the cerebellum in patients with bipolar disorder to determine whether high-resolution, thin slice magnetic resonance imaging (MRI) morphometry would reveal similar results. Bipolar patients hospitalized for a first manic episode (n = 16), bipolar patients with prior manic episodes hospitalized for a manic episode (n = 14), and normal volunteers (n = 15) matched for age, sex, race, and education were recruited and anatomic brain scans were acquired using a Picker 1.5 Tesla MRI scanner. Right and left cerebellar hemisphere volumes and vermal areas V1 (lobules I-V), V2 (lobules VI-VII), and V3 (lobules VIII-X) were measured. ANCOVA comparing each ROI, adjusting for race, sex, age, total cerebral volume, and substance abuse duration, revealed a significant group effect for vermal V3 area. Specifically, V3 area was significantly smaller in multiple-episode patients than in first-episode patients or healthy volunteers. Number of previous episodes of depression may contribute to this finding. These results suggest that cerebellar vermal atrophy may be a later neurodegenerative event in patients with bipolar disorder who have had multiple affective episodes. The confounding effects of medications are considered.     

Bridging the genomic approach and the neurodevelopmental and neurodenerative hypothesis of schizophrenia]

Schizophrenia is hypothesized as a neurodevelopmental and neurodegenerative disorder based on the following findings. 1. MRI studies have revealed brain structural abnormalities from the onset of schizophrenia and the progress of these structural abnormalities. 2. Histopathological studies have elucidated cytoarchitectural abnormalities in schizophrenic brains without gliosis. 3. Obstetric complications are one of the risk factors for schizophrenia. 4. Relapse of schizophrenia results in a deteriorating progress of the disorder. Furthermore, data from family, twin and adoption studies show evidence of a substantial genetic component in schizophrenia, Thus, a molecular genetic study combined with a neurodevelopmental and neurodegenerative hypothesis is required to elucidate the pathophysiology of schizophrenia. The positive association between neuregulin 1 and Icelandic schizophrenia that has been reproduced in Scottish and North European schizophrenia is one of the intriguing examples of this type of research. Neuregulin 1 regulates the cytoarchitecture of brain. Mice mutated for neuregulin 1 show a behavioral phenotype that overlaps with mouse models for schizophrenia. Furthermore, the behavioral phenotypes of the neuregulin 1 hypomorphs are reversible with clozapine. We also demonstrated a positive association between schizophrenia and a 5-HT5A receptor polymorphism, Pro15Ser, that may have role in cell differentiation in the brain.     

Cortical white matter microstructural abnormalities in bipolar disorder.

This article reports on preliminary findings describing microstructural abnormalities in the white matter of cortical areas thought to be associated with bipolar disorder. In all, 14 patients with bipolar disorder and 21 nonpsychiatrically ill control subjects underwent MR imaging including a diffusion tensor imaging (DTI) pulse sequence (six directions, b=1000 mm(2)/s). DTI data were analyzed on a workstation using a program that allowed calculation of apparent diffusion coefficient (ADC) and fractional anisotropy (FA) within the following three white matter fiber tracts bilaterally: the orbital frontal cortex, and the superior and middle frontal gyri. These values were compared across patient groups. The left and right orbital frontal white matter exhibited significantly higher ADC values in bipolar subjects than control subjects on both the left (p=0.028) and right (p=0.011). Microstructural changes in the white matter of the orbital frontal areas as reflected by increased ADC values appear to be associated with bipolar disorder. Further research is needed to better understand the interaction of microstructural changes and bipolar symptoms and whether these changes are specific to bipolar disorder.     

Decreased frontal white-matter volume in chronic substance abuse

There is quite a body of work assessing functional brain changes in chronic substance abuse, much less is known about structural brain abnormalities in this patient population. In this study we used magnetic resonance imaging (MRI) to determine if structural brain differences exist in patients abusing illicit drugs compared to healthy controls. Sixteen substance abusers who abused heroin, cocaine and cannabis but not alcohol and 16 age-, sex- and race-matched controls were imaged on a MRI scanner. Contiguous, 5-mm-thick axial slices were acquired with simultaneous T2 and proton density sequences. Volumes were estimated for total grey and white matter, frontal grey and white matter, ventricles, and CSF using two different methods: a conventional segmentation and a stereological method based on the Cavalieri principle. Overall brain volume differences were corrected for by expressing the volumes of interest as a percentage of total brain volume. Volume measures obtained with the two methods were highly correlated (r=0.65, p<0.001). Substance abusers had significantly less frontal white-matter volume percentage than controls. There were no significant differences in any of the other brain volumes measured. This difference in frontal lobe white matter might be explained by a direct neurotoxic effect of drug use on white matter, a pre-existing abnormality in the development of the frontal lobe or a combination of both effects. This last explanation might be compelling based on the fact that newer concepts on shared aspects of some neuropsychiatric disorders focus on the promotion and inhibition of the process of myelination throughout brain development and subsequent degeneration.     

Introduction to the special section: Myelin and oligodendrocyte abnormalities in schizophrenia

A central tenet of modern views of the neurobiology of schizophrenia is that the symptoms of schizophrenia arise from a failure of adequate communication between different brain regions and disruption of the circuitry that underlies behaviour and perception. Historically this disconnectivity syndrome has been approached from a neurotransmitter-based perspective. However, efficient communication between brain circuits is also contingent on saltatory signal propagation and salubrious myelination of axons. The papers in this Special Section examine the neuroanatomical and molecular biological evidence for abnormal myelination and oligodendroglial function in schizophrenia through studies of post-mortem brain tissue and animal model systems. The picture that emerges from the studies described suggests that although schizophrenia is not characterized by gross abnormalities of white matter such as those evident in multiple sclerosis, it does involve a profound dysregulation of myelin-associated gene expression, reductions in oligodendrocyte numbers, and marked abnormalities in the ultrastructure of myelin sheaths.