Motor cortex FMRI activation changes in schizophrenia

Reduced cortical gray matter density in human MDMA (Ecstasy) users: a voxel-based morphometry study

To measure the volumetric changes of gray and white matters in patients with temporal lobe epilepsy(TLE)using voxel-based morphometric study(VBM)and correlate the changes with clinical parameters. A total of 71 TLE patients were enrolled in the study,and 22 healthy subjects served as normal controls. Routine brain MRI and 3D fast spoiled gradient echo(FSPGR)T1-weighted images of all the subjects were acquired. The 3D structural images were co-registered,segmented and smoothed,and then the images were analyzed using the optimized VBM with preprocessed using Diffeomorphic Anatomical Registration using Exponentiated Lie algebra(DARTEL)algorithm. The global and local gray matter and white matter volume of each subject were calculated and compared between the TLE patients and normal controls. The potential correlations between the changes of the global and local gray and white matters in the TLE patients and the clinical parameters including the age at onset and the duration of epilepsy were explored. Compared to the normal controls,the TLE patients had diffuse volumetric reduction of gray and white matters in cerebrum both ipsilateral and contralateral to the seizure focus(P<0.05). Local gray matter reduction was found extensively in bilateral cerebral lobes,especially in the temporal and frontal lobes. Local white matter reduction was found in bilateral temporal,parietal and frontal lobes,in addition to the cingulate gyrus. The global gray matter volume(Global GMV)and the global white matter volume(Global WMV)were negatively correlated to the duration of epilepsy with the most significant change occurring in the first year of epilepsy. Global WMV dropped more quickly than Global GMV during the prolonged disease course. TLE patients have diffuse gray matter and white matter reduction,particularly in the early stage of epilepsy. The reduction of the white matter is more obvious than the gray matter.

The purpose of this study was to examine the relationship between signal hyperintensities--a probable marker of underlying pathology--on T2-weighted magnetic resonance brain scans and neuropsychological test findings in elderly depressed and normal subjects. Elderly subjects with a DSM-III-R diagnosis of major depression (N=41) and normal elderly comparison subjects (N=38) participated in a magnetic resonance imaging study (1.0-T) of signal hyperintensities in periventricular, deep white matter, and subcortical gray matter. Hard copies of scans were rated in random order by research psychiatrists blind to diagnosis; the modified Fazekas hyperintensity rating scale was used. Cognitive performance was independently assessed with a comprehensive neuropsychological battery. Clinical and demographic differences between groups were assessed by t tests and chi-square analysis. Relationships between neuropsychological performance and diagnosis and hyperintensities and their interaction were analyzed by using analysis of covariance, with adjustment for age and education. Elderly depressed subjects manifested poorer cognitive performance on several tests than normal comparison subjects. A significant interaction between hyperintensity location/severity and presence/absence of depression on cognitive performance was found: depressed patients with moderate-to-severe deep white matter hyperintensities demonstrated worse performance on general and delayed recall memory indices, executive functioning and language testing than depressed patients without such lesions and normal elderly subjects with or without deep white matter changes. Findings validate cognitive performance decrements in geriatric depression and suggest possible neuroanatomic vulnerabilities to developing particular neuropsychological dysfunction in depressed subjects.

Absence of regional brain volume change in schizophrenia associated with short-term atypical antipsychotic treatment

Despite the many neuroimaging studies that suggest gray matter volume reductions in schizophrenia, there is no compelling postmortem evidence to suggest neuronal loss, nor is there a distinctive or specific signature of gray matter abnormalities in schizophrenia. Instead, there appears to be no observed focal lesion that characterizes gray matter pathology in schizophrenia. This state of affairs has led to a movement away from conceptualizing schizophrenia as resulting from a single lesion, to conceptualizing schizophrenia as arising from abnormal communication between brain regions. Abnormal connectivity between brain regions is not a new concept, as Bleuler (1911) postulated such abnormalities. What is new, however, is an appreciation that brain regions that are not spatially proximal may be connected functionally into neural networks and that to understand altered neural connectivity we need to have a better understanding of the connections between brain regions which are made possible by white matter, the main infrastructure in the brain that makes possible long distance communication among neurons. Accordingly, a focus on white matter connections in the brain has become increasingly of interest in schizophrenia, particularly in the areas of imaging studies, postmortem studies, and new animal models of schizophrenia. This special issue focuses on schizophrenia and oligodendrocytes, the latter a class of neuroglia that give rise to myelin. The primary aim of this special issue is to understand and to clarify further white matter pathology in schizophrenia and how it may contribute to disconnectivity among brain regions, which results in the observed cognitive, behavioral, and clinical symptoms in this disorder. The first paper begins with a description of the theory that schizophrenia reflects a disorder of connectivity. The proposition put forth is that schizophrenia is, at least in part, the result of abnormal communication between brain regions that may be spatially distant but nonetheless functionally connected. As white matter is the main infrastructure for brain connectivity, this paper focuses on the use of a magnetic resonance imaging (MRI) technique called diffusion tensor imaging (DTI) to gain insight into the role of white matter abnormalities in schizophrenia. This paper also focuses on the functional implications of white matter abnormalities, particularly with regard to the possible role of myelin in modulating the transmission velocity of neural discharges. The paper ends with a speculative hypothesis about the relationship between gray matter and white matter abnormalities in schizophrenia. The second paper also focuses on altered neuronal connectivity. Here, however, the focus is on altered connectivity and impaired myelination in a postmortem study of schizophrenia and normal controls, where electron microscopy is used to study myelinated fibers and oligodendrocytes. This morphometric study examines myelinated fibers in the prefrontal cortex in both gray and white matter. Six types of abnormal fibers and ultrastructural alterations are described in the schizophrenia sample. The study reveals increased pathological fibers in gray matter in both young and elderly patients that are associated with positive symptoms, while in elderly patients, the frequency of pathological fibers in white matter is increased and these changes are associated with more negative symptoms. The key implication here is that altered myelinated fibers in white matter in schizophrenia likely follow alterations of myelinated fibers in gray matter that occur earlier in the course of illness. The third paper is a postmortem study on age-related changes in the number of oligodendrocytes in prefrontal cortex in schizophrenia, bipolar disorder and major depression. The study reveals an age-related increase in numerical density of oligodendrocytes in layer VI and adjacent white matter of BA9 and 10 that is seen only in normal controls and not in schizophrenia or in mood disorders. The absence of the normal age-related increase in oligodendrocytes in patients suggests that this aspect of normal brain development is dysregulated in schizophrenia and in mood disorders, and confirms postmortem and imaging data, further highlighting the fact that the absence of a normal age-related increase in oligodendrocytes is a key shared feature in these psychiatric populations. The fourth paper reviews white matter abnormalities in schizophrenia, including imaging and postmortem findings on the disconnectivity theory of schizophrenia, a major theme that underlies the three previous papers in this special issue. This paper then reviews some of the white matter diseases that commonly lead to psychotic symptoms and then reviews transgenic and mutant mouse models of schizophrenia. More specifically, genetic mouse models such as Plp1 transgenic mice and mutant mice heterogeneous for either NRG1 or its receptor erbB4, as well as Nogo-A- deficient mice are reviewed. This is followed by a focus on the myelin toxicity model of mice fed cuprizone. In the early stage (the second and third week) of the cuprizone feeding, mice show higher dopamine levels and lower norepinephrine levels in their prefrontal cortex, along with behavioral changes indicative of increased CNS activity. In the late stage (weeks 4–6), when demyelination and oligodendrocyte loss are obvious, mice display cognitive deficits as well as deficits in social interactions that are reminiscent of social withdrawal seen in patients with schizophrenia. Importantly, this cuprizone-feeding mouse may be used as an in vivo platform for psychopharmacological studies testing the effects of antipsychotic drugs on white matter alterations and associated behavioral changes, in addition to providing a new animal model of schizophrenia. The fifth and final paper of this special issue focuses on abnormal behavior and microstructural changes in juvenile mice that are repeatedly exposed to nonneurotoxic levels of amphetamine. These mice are compared with nonamphetamine treated mice. Oligodendrocyte numbers and three proteins expressed in mature oligodendrocytes are investigated in these young male mice at sacrifice. Treated mice showed higher locomotion and impaired spatial working memory, along with lowered Noga-A and GST-pi proteins, and lower MBP proteins, in frontal cortex and hippocampus and fewer mature oligodendrocytes in frontal cortex and corpus callosum, as well as lower MBP staining in frontal cortex, corpus callosum, and hippocampus, than untreated mice. These differences suggest that in wild-type mice late developing white matter is vulnerable to amphetamine and may lead to compromised white matter with increased dopamine in specific brain regions. Not only do these findings explain well the increased locomotion and impaired spatial working memory observed in amphetamine-treated mice, but also may serve as a principle for the amphetamine-treated mouse being used as a novel animal model of schizophrenia. To summarize, compared to the focus on gray matter and neurons, research on white matter and myelin/glial has been sparse in schizophrenia. In this special issue, neuroimaging findings are presented that suggest that myelin abnormalities in schizophrenia may underlie the white matter abnormalities observed using diffusion tensor imaging techniques. Data from postmortem studies also confirm the presence of oligodendrocyte and myelin abnormalities in schizophrenia as well as mood disorders. Oligodendrocytes provide protection and improve communication between brain regions and the oligodendroglia-producing myelin is approaching maturity in the same time frame as the onset of symptoms. Further, normal age-related white matter increases and related gray matter changes that likely predate the white matter changes are dysregulated in schizophrenia and may contribute to the clinical symptomatology of the disease. Finally, the recently developed animal models are not only of help in understanding connectivity abnormalities in schizophrenia but also provide novel platforms to test novel therapeutic approaches for schizophrenic patients. Treatments specifically targeting white matter, for example, may improve on the efficacy of those treatments currently in use. Martha E. Shenton Haiyun Xu Vahram Haroutunian George Bartzokis

Brain development during early life in healthy individuals is rapid and dynamic, indicating that this period plays a very important role in neural and functional development. The frontal and temporal lobes are known to play a particularly important role in cognition. The study of healthy frontal and temporal lobe development in children is therefore of considerable importance. A better understanding of how these brain regions develop could also aid in the diagnosis and treatment of neurodevelopmental disorders. Some devel-opmental studies have used magnetic resonance imaging (MRI) to examine infant brains, but it remains the case that relatively little is known about cortical brain development in the first few years of life. In the present study we examined whole brain, temporal lobe and frontal lobe developmental trajectories from infancy to early adulthood in healthy individuals, considering gender and brain hemisphere differences. We performed a cross-sectional, longitudinal morphometric MRI study of 114 healthy individuals (54 females and 60 males) aged 1 month to 25 years old (mean age ± SD 8.8 ± 6.9). We measured whole brain, temporal and frontal lobe gray matter (GM)/white matter (WM) volumes, following previously used protocols. There were significant non-linear age-related volume changes in all regions. Peak ages of whole brain, temporal lobe and frontal lobe development occurred around pre-adolescence (9-12 years old). GM volumes for all regions increased significantly as a function of age. Peak age was nevertheless lobe specific, with a pattern of earlier peak ages for females in both temporal and frontal lobes. Growth change in whole brain GM volume was larger in males than in females. However, GM volume growth changes for the temporal and frontal lobes showed a somewhat different pattern. GM volume for both temporal and frontal lobes showed a greater increase in females until around 5-6 years old, at which point this tendency reversed (GM volume changes in males became greater), with male GM volume increasing for a longer time than that of females. WM volume growth changes were similar across regions, all increasing rapidly until early childhood but slowing down thereafter. All regions displayed significant rightward volumetric asymmetry regardless of sex. Furthermore, the right temporal and frontal lobes showed a greater volumetric increase than the left for the first several years, with this tendency reversing at around 6 years of age. In addition, the left frontal and temporal lobes increased in volume for a longer period of time. Taken together, these findings indicated that brain developmental trajectories differ depending on brain region, sex and brain hemisphere. Gender-related factors such as sex hormones and functional laterality may affect brain development.

In multiple sclerosis (MS), pronounced neurodegeneration manifests itself as cerebral gray matter (GM) atrophy, which is associated with cognitive and physical impairments. Microstructural changes in GM estimated by diffusion kurtosis imaging (DKI) may reveal neurodegeneration that is undetectable by conventional structural MRI and thus serve as a more sensitive marker of disease progression. The primary objective was to investigate the relationships between morphological and diffusional properties in cerebral GM and physical and cognitive performance in relapsing-remitting MS (RRMS) patients. A secondary objective was to investigate the relationship between GM microstructure and white matter (WM) injury, estimated by the volume of WM lesions. Sixty-seven RRMS patients performed the brief repeatable battery of neuropsychological tests (BRB-N), the 6-minute walk test (6MWT), the six spot step test (SSST), and underwent MRI scans using structural and DKI protocols. GM volumetrics and DKI measurements were analyzed in the cortex and deep GM structures using a general linear model with demographics, physical- and cognitive performance as covariates. Mean diffusivity (MD) in the cortex was associated with the SSST, 6MWT, information processing, global cognitive performance, and volume of WM lesions. In addition, thalamic volume was associated with SSST (r2 = 0.21, 6MWT (r2 = 0.18), information processing (r2 = 0.21), and WM lesion volume (r2 = 0.60). Cortical diffusion and thalamic volume are associated with walking and cognitive performance in RRMS patients and are highly affected by the presence of WM lesions.

1recently reported on the largest longitudinal study to date looking at brain volume changes over time in a cohort of patients with schizophrenia who had a mean age at first episode of 25 years. They found decreases in multiple grey and white matter regions, and these changes were most pro nounced early (2 yr) after intake for the first episode of psy chosis. In addition, a meta-analysis of studies involving persons at high risk for schizophrenia reported baseline de creases in grey matter in frontal and temporal regions of those who later transition to psychosis. 2 Almost invariably, any research paper discussing reasons for the age at onset of symptoms or the early grey matter changes during young adulthood in patients with schizophrenia will invoke abnor mal synaptic pruning as a potential mechanism. But what do we actually know about synaptic pruning in patients with schizophrenia? Early electron microscopy (EM) studies by Huttenlocher and Dabholkar 3,4 on postmortem brains from healthy humans showed that cortical synaptic density reaches a maximum at 2‐4 years of age, when it is about double adult levels, with re duction in the number of synapses toward adult levels occur ring mainly during adolescence. Synaptic pruning refers to this process of elimination of excess neuronal synapses. Con sistent with early EM studies, in a recent study profiling the expression pattern of thousands of genes (the so-called “tran scriptome”) in the prefrontal cortex across the human lifespan, Colantuoni and colleagues 5 reported that expression of many genes involved in axonal and synaptic function peak during fetal life then decrease during infancy with continuing reduc tions through the first decade of life. Interestingly, using an ex tensive series of brains of intermediate ages, Petanjek and colleagues 6 have recently provided evidence that synaptic elimination may be a more extended process continuing throughout the third decade of life before stabilization of synaptic density at adult levels. There is strong supporting evidence for the idea that developing synapses are selectively sta bilized by neuronal activity, while excess synapses are subse quently eliminated. 7 An abnormal increase in synaptic pruning generally implies that a normal complement of synapses is formed during development followed by an excess of elimina tion. But apparent “pruning” could also occur because of de creased development and stabilization of synapses. Neuropathologic studies in persons with schizophrenia in dicate that there is no actual loss of neurons but that alter ations in neuronal density, decreased neuronal size and/or decreases in the neuropil (axons+dendrites+glia) may ac count for the reductions in grey matter in persons with the disorder. In 1982, Feinberg 8 speculated that schizophrenia

Previous research has indicated the importance of the frontal lobe and its ‘executive’ connections to other brain structures as crucial in explaining primate neocortical adaptations. However, a representative sample of volumetric measurements of frontal connective tissue (white matter) has not been available. In this study, we present new volumetric measurements of white and grey matter in the frontal and non-frontal neocortical lobes from 18 anthropoid species. We analyze this data in the context of existing theories of neocortex, frontal lobe and white versus grey matter hyperscaling. Results indicate that the ‘universal scaling law’ of neocortical white to grey matter applies separately for frontal and non-frontal lobes; that hyperscaling of both neocortex and frontal lobe to rest of brain is mainly due to frontal white matter; and that changes in frontal (but not non-frontal) white matter volume are associated with changes in rest of brain and basal ganglia, a group of subcortical nuclei functionally linked to ‘executive control’. Results suggest a central role for frontal white matter in explaining neocortex and frontal lobe hyperscaling, brain size variation and higher neural structural connectivity in anthropoids.

Evidence suggests that testicular cancer (TC) and its treatment are associated with cognitive impairment. However, the underlying neural substrate and biological mechanisms are poorly understood. This study aimed to investigate changes in cognition and brain grey matter (GM) morphology in TC patients undergoing treatment, and to explore associations with immune markers, endocrine markers, and genotype. Sixty-five patients with stage I-III TC underwent assessment after surgery but prior to further treatment and again 6months after. Twenty-two patients received chemotherapy (+CT), while 43 did not (-CT). Assessments included neuropsychological testing, whole-brain magnetic resonance imaging, and blood samples. Twenty-five healthy controls (HCs) underwent neuropsychological testing with a matching time interval. A regression-based approach was used to determine cognitive changes and longitudinal voxel-based morphometry (VBM) was performed to investigate changes in GM density in the TC groups. Compared with the HCs, both TC groups showed higher rates of cognitive decline (p < 0.05). A trend towards greater decline was observed in + CT (63.6%) compared with -CT patients(39.5%) (p = 0.07). VBM revealed widespread GM reductions in both TC groups, but a group-by-time interaction analysis revealed prefrontal reductions specific to the + CT group (p = 0.02), which were associated with poorer cognitive performance. Poorer cognitive performance was also associated with an increase in tumornecrosis factor alpha in + CTpatients. Furthermore, an interaction effect was found between the APOE ε4 genotype and chemotherapy on cognitive performance with ε4 carriers performing significantly worse. These findings provide novel evidence of changes in cognition and brain morphology in TC patients undergoing treatment.

Autism is a heritable neurodevelopmental disorder characterized biologically by enlargement of the head and brain and abnormalities of serotonin neurotransmission. To evaluate whether 5-HTTLPR, a functional promoter polymorphism of the serotonin transporter gene SLC6A4, influences cerebral cortical structure volumes in young male children with autism. Association study of a genetic variant with quantitative traits. Autism research centers at the University of North Carolina (UNC), Chapel Hill, and the University of Washington (UW), Seattle. Forty-four male children, 2 to 4 years old, with autism participating in longitudinal brain magnetic resonance imaging studies. Cerebral cortical and cerebellar gray and white matter volumes. We found that 5-HTTLPR genotype influenced gray matter volumes of the cerebral cortex (F(2,23) = 7.29, P = .004) and of 3 lobe-based subregions in the UNC sample of 29 children (frontal lobe gray matter: F(2,23) = 6.36, P = .01). The 5-HTTLPR short allele appeared to be additively associated with increasing gray matter volumes, an observation affirmed by tests of linear genotype effects (cortical gray matter: F(1,24) = 14.11, P = .001; frontal lobe gray matter: F(1,24) = 13.20, P = .001). Genotype did not influence cerebellar volumes. Confirmation was pursued by means of the UW sample of 15 children. While effects were not significant in the UW sample alone, the patterns of adjusted means resembled those found in the UNC sample. Positive Cochran-Mantel-Haenszel test results supported the concordance of relationships across the 2 sites, and analyses of covariance of the combined sample that included a site covariate showed significant linear genotype effects on structure volumes (cortical gray matter: F(1,38) = 5.73, P = .02; frontal lobe gray matter: F(1,38) = 11.73, P = .002). Effect sizes of 5-HTTLPR genotype on total cortical and frontal lobe gray matter volumes were 10% and 16%, respectively. The SLC6A4 promoter polymorphism 5-HTTLPR influences cerebral cortical gray matter volumes in young male children with autism.

Subcortical grey matter changes in untreated, early stage Parkinson's disease without dementia

Back to table of contents Previous article Next article EditorialFull AccessNeural Networks in SchizophreniaJohn G. Csernansky M.D.Will J. Cronenwett M.D.John G. Csernansky M.D.Search for more papers by this authorWill J. Cronenwett M.D.Search for more papers by this authorPublished Online:1 Aug 2008https://doi.org/10.1176/appi.ajp.2008.08050700AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail As methods for high-resolution MRI continue to develop, our understanding of changes in brain structure in patients with psychiatric disorders improves. In patients with schizophrenia, decreases in the gray matter volume of a variety of cortical and subcortical brain regions have been repeatedly observed (1) . Two articles in this issue of the Journal add to this literature and go further by strengthening the hypothesis that schizophrenia involves abnormalities in specific cortical-subcortical networks. Ellison-Wright et al. (2) present a meta-analysis of MRI studies that reveals different patterns of structural changes in first-episode and chronic schizophrenia. Adapting a technique developed to combine data from functional MRI studies (3) , the authors evaluated group differences in specific brain regions in reference to a three-dimensional coordinate system. The result of this adaptation, called anatomical likelihood estimation, adds to a growing literature on probabilistic approaches to neuroanatomical computation (4) . In patients with first-episode schizophrenia, Ellison-Wright et al. found evidence for decreased gray matter volume in the hippocampus, the caudate nucleus, the thalamus (mediodorsal nucleus), the insula, the anterior cingulate gyrus, the inferior frontal gyrus, and the cerebellum. Subcortical changes were similar in patients with chronic schizophrenia, but cortical changes were even more extensive. As Ellison-Wright et al. note, this pattern of abnormality implicates a neural circuit originating with limbic input to the striatum, then the thalamus, and finally to the prefrontal and cingulate cortex ( Figure 1 ). Abnormalities of thalamocortical circuitry have previously been implicated in schizophrenia, particularly in reference to the pathophysiological concept of cognitive dysmetria (5) . Figure 1. Gray Matter Deficits and Thalamocorticostriatal Circuit Dysfunction in Schizophrenia aa The diagram on the left illustrates the circuit pathways. On the right is a diagrammatic representation of thalamocorticostriatal circuits superimposed on regions of gray matter showing signal decrease in both first-episode schizophrenia (yellow) and chronic schizophrenia (red). The thalamus (blue triangle) sends thalamocortical projections to the cortex (blue arrow). Cortical regions project (green arrow) to the caudate (pink circle) and then back to the thalamus (orange arrow). Components of these circuits show anatomical changes in schizophrenia, with the caudate head showing gray matter deficits in first-episode schizophrenia and more widespread cortical changes in chronic schizophrenia. The thalamus shows gray matter deficits in both first-episode and chronic schizophrenia. Also in this issue, Friedman et al. (6) report on their use of diffusion tensor imaging to examine the pattern of white matter changes in patients with first-episode and chronic schizophrenia. Using fractional anisotropy (FA) to assess the integrity of white matter connections (7) , they found evidence in first-episode patients for decreased connectivity only in the inferior longitudinal fasciculus (at the trend level), while chronic patients showed a broader pattern of white matter disturbances ( Figure 2 ). Figure 2. Regions of Fractional Anisotropy (FA) Reductions in Schizophrenia aa Relative to healthy comparison subjects, patients with first-episode schizophrenia showed trend-level FA reductions in the left and right inferior longitudinal fasciculus. Patients with chronic schizophrenia showed significant FA reductions in the right forceps minor and the left inferior longitudinal fasciculus. ILF=inferior longitudinal fasciculus; GCC=genu of corpus callosum; SCC=splenium of corpus callosum. The results of Friedman’s study, to date the largest to directly examine FA in first-episode and chronic schizophrenia patients, suggest a number of intriguing interpretations. As they note, one explanation may be that pathological white matter abnormalities may be present but too subtle to detect with current imaging methods in first-episode schizophrenia. Alternatively, white matter changes may develop as the disease process of schizophrenia progresses.Taken together, the results of these two studies provide strong support for the hypothesis that schizophrenia involves abnormalities in networks of brain regions. They further suggest that such abnormalities may be progressive in at least some patients. If the “progression” hypothesis is confirmed in future studies, we must redouble our efforts at early and effective intervention for this potentially disabling disorder.Address correspondence and reprint requests to Dr. Csernansky, Department of Psychiatry and Behavioral Sciences, Feinberg School of Medicine, Northwestern University, 446 E. Ontario, Suite 7-200, Chicago, IL 60611; [email protected] (e-mail). Editorial accepted for publication May 2008 (doi: 10.1176/appi.ajp.2008.08050700).Dr. Csernansky has consulted for Eli Lilly, Sanofi-Aventis, and HoustonPharma. Dr. Freedman has reviewed this editorial and found no evidence of influence from these relationships. Dr. Cronenwett reports no competing interests.

Dynamic gray matter changes within cortex and striatum after short motor skill training are associated with their increased functional interaction

Classification of schizophrenia patients and healthy controls from structural MRI scans in two large independent samples