Cortical Gray Matter Volume Deficits Research Articles

Frontal Lobe Synaptic Plasticity in Development and Disease: Modulation by the Dopamine D1 Receptor

Synaptic plasticity is now known to occur at glutamate synapses throughout the brain, including the neocortex, and to play a role in neurodevelopment as well as in a broad spectrum of adult neural functions. Here the hypothesis that synaptic plasticity, specifically long term depression, is the neural substrate that mediates adolescent synaptic pruning is re-examined in the context of its ramifications for neuropsychiatric illnesses. Stress, which in part is mediated by dopamine acting via the D1 receptor, may disrupt normal synaptic plasticity in adolescence resulting in excessive synaptic elimination. In this manner elevated dopamine levels due to stress could contribute to deficits in gray matter volume and reduced neural connectivity in diseases such as major depressive disorder and schizophrenia. Attention deficit hyperactivity disorder, another developmental illness associated with cortical gray matter volume deficits, may represent a state of diminished dopamine stimulation that is equally disruptive to normal mechanisms of synaptic plasticity. In post-traumatic stress disorder, long term potentiation necessary for conditioned fear extinction, is thought to be impaired. Recent evidence suggests that genotypes related to dopamine neurotransmission confer vulnerability to post-traumatic stress disorder, perhaps indicating that low dopamine levels are less permissive of the synaptic plasticity that underlies consolidation and retention of fear extinction. Further understanding of the role that dopamine-modulated synaptic plasticity plays in development and, when disrupted, in precipitating neuropsychiatric illness could lead to novel drug treatments, and ultimately to preventative pharmacotherapeutic interventions, for these disorders.

Gray matter volume deficits are associated with motor and attentional impairments in adolescents with schizophrenia

Cognitive deficits have been well described in adolescents with schizophrenia, but little is known about the neuroanatomical basis of these abnormalities. The authors examined whether neuropsychological deficits observed in adolescents with schizophrenia were associated with cortical gray matter volume deficits. Volumes of the superior frontal gyrus, anterior cingulate gyrus and orbital frontal lobe were outlined manually from contiguous MR images and automatically segmented into gray and white matter in 52 patients and 48 healthy volunteers. Subjects received a comprehensive neuropsychological test battery, assessing five different functional domains: executive, attention, verbal memory, motor and sensory motor. Children and adolescents with schizophrenia were found to have lower total cortical and lower superior frontal gyrus gray matter volumes and lower test scores across all functional domains compared to healthy volunteers. Among patients, the lower total cortical gray matter volume was associated with worse functioning on the attention and motor domains. Our findings point to widespread, perhaps multifocal, pathology as contributing to cognitive dysfunction in adolescents with schizophrenia.

49. Cognitive deficits predict prefrontal volume decline in schizophrenia

Schizophrenia is associated with neurocognitive impairment and cortical gray matter volume deficits, particularly in prefrontal and temporal cortical regions. In an earlier longitudinal analysis, we examined MRI brain volume changes over an average interval of four years in 24 schizophrenic men (age = 39.4 ± 6.4 years) and 25 normal control men (age = 40.7 ± 8.5 years). Patients exhibited faster rates of cortical gray matter volume decline than controls, particularly in fronto-temporal regions, and greater symptom severity was associated with faster rates of volume decline among patients. In this report, we examined whether neurocognitive function assessed at Scan 1 predicted the rate of regional cortical gray matter loss over time in a subgroup of these subjects (patients n = 10 to 17, controls n = 20 to 22, depending on availability of cognitive measures). Neurocognitive composite scores derived from individual measures representing executive functions, declarative memory, short-term memory/fluency, visuospatial function, and upper limb motor function were correlated with MRI slopes (volume change/interscan interval) for six cortical gray matter regions in both groups. In patients, deficits in executive and memory functions, but not visuospatial or motor functions, selectively predicted the rate of volume decline in prefrontal gray matter; these relationships were not observed in the controls. Additional analyses based on individual neuropsychological measures showed that deficits in working memory, attention, psychomotor speed, fluency, and overall declarative memory predicted the rate of prefrontal gray matter decline in patients, but not controls. Thus, cognitive, but not motor, impairment in schizophrenia is associated with progressive volume loss in the prefrontal cortex.

In vivo brain concentrations of N-acetyl compounds, creatine, and choline in Alzheimer disease.

Alzheimer disease (AD) and normal aging result in cortical gray matter volume deficits. The extent to which the remaining cortex is functionally compromised can be estimated in vivo with magnetic resonance spectroscopic imaging. To assess the effects of age and dementia on gray matter and white matter concentrations of 3 metabolites visible in the proton spectrum: N-acetyl compounds, present only in living neurons; creatine plus phosphocreatine, reflecting high-energy phosphate metabolism; and choline, increasing with membrane synthesis and degradation. Fifteen healthy young individuals, 19 healthy elderly individuals, and 16 patients with AD underwent 3-dimensional magnetic resonance spectroscopic imaging and memory and language testing. Gray matter N-acetyl compound concentrations (signal intensity corrected for the amount of brain tissue contributing to the magnetic resonance spectroscopic imaging signal) was significantly reduced only in patients with AD, even though both the AD and elderly control groups had substantial gray matter volume deficits relative to the young control group. Both the healthy elderly and AD groups had abnormally high gray matter creatine plus phosphocreatine concentrations. Gray matter choline concentrations were higher in the elderly than the younger controls, and even higher in the AD group than in the elderly control group. Functional significance of these findings was supported by correlations between poorer performance on recognition memory tests and lower gray matter N-acetyl compounds in elderly controls and higher gray matter creatine plus phosphocreatine and choline concentrations in patients with AD. Cortical gray matter volume deficits in patients with AD are accompanied by disease-related increases in gray matter choline concentrations suggestive of cellular degeneration and reduced N-acetyl compound concentrations, with possible effects on behavioral function.

A profile of cortical gray matter volume deficits characteristic of schizophrenia.

Quantitative magnetic resonance imaging (MRI) studies from our laboratory have reported that patients with schizophrenia show a widespread cortical gray matter volume deficit, which is especially pronounced in the prefrontal and anterior superior temporal cortices. The present study compared two separate samples of schizophrenic patients -- 71 men from a Veterans Administration (VA) hospital and a sample of 57 severely ill men from a state hospital (SH) -- in an effort to test whether the pattern of brain volume abnormalities previously observed in VA schizophrenic patients can be generalized to other groups of schizophrenic patients. MRI-derived brain volumes of gray matter, white matter and sulcal cerebrospinal fluid (CSF) in six cortical regions, and CSF in the lateral and third ventricles were computed. All MRI volumes were adjusted for normal variation in head size and age and were expressed as standardized Z-scores, which also permitted structures of different sizes to be compared directly. The two schizophrenic groups displayed similar patterns of volume abnormalities: cortical gray matter but not white matter volume deficits that were widespread but especially notable in the prefrontal and temporal regions. The regional gray matter deficits in the SH group were generally greater than those in the VA group, particularly in the prefrontal and posterior superior temporal regions. Both schizophrenic groups had abnormally large volumes of the cortical sulci and lateral and third ventricles; however, the SH group showed greater enlargements, the most prominent occurring in the ventricles and temporal sulci. The overlapping patterns of cortical gray matter deficits in the two groups provide evidence for generality of this pattern of regional brain volume abnormalities in schizophrenia.

Patterns of regional cortical dysmorphology distinguishing schizophrenia and chronic alcoholism

This study used magnetic resonance imaging (MRI) to compare the extent and pattern of tissue volume deficit and cerebrospinal fluid volume enlargement in chronic alcoholics and schizophrenics. The subjects included 62 detoxified chronic alcoholics (26-63 years), 71 schizophrenics (23-63 years), and 73 controls spanning the adult age range (21-70 years). MRI volumes were adjusted for normal variation in head size and age established from the control group. Both patient groups showed widespread cortical gray matter volume deficits compared with controls, but only the alcoholics had white matter volume deficits. The schizophrenics had significantly greater volume deficits in the prefrontal and anterior superior temporal gray matter than in the more posterior cortical regions. By contrast, the deficits in the alcoholics were relatively homogeneous across the cortex. For white matter, the deficits in the alcoholics were greatest in the prefrontal and temporal-parietal regions. Although both patient groups had abnormally larger cortical sulci and lateral and third ventricles than the controls, the alcoholics had significantly larger sulcal volumes in the frontal, anterior, and posterior parietal-occipital regions than the schizophrenics. This quantitative MRI study revealed different patterns of regional cortical volume abnormalities in schizophrenics and alcoholics. The schizophrenic group exhibited cortical gray matter volume deficits of modestly greater magnitude than that observed in the alcoholic group, and the alcoholics but not the schizophrenics exhibited cortical white matter volume deficits.

Cortical gray matter volume deficits in schizophrenia: a replication

We sought to replicate an earlier finding of widespread deficit in cortical gray matter in schizophrenia by testing new samples of 22 schizophrenic patients and 27 controls between the ages of 21–46 years. Brain values for both patients and controls were standardized against age and head size norms derived from a larger control group ( n=73) spanning a wider age range (21–70). Compared to the new age-matched controls, the new schizophrenic sample showed a deficit in gray matter volume affecting the cortex as a whole and enlargement of the lateral and third ventricles. Thus, widespread cortical gray matter deficit is a replicable feature of the brain dysmorphology of schizophrenia in young to middle-aged men.

Cognitive and motor impairments are related to gray matter volume deficits in schizophrenia

This study examined whether the neuropsychological deficits observed in patients with schizophrenia were related to cortical gray matter volume deficits in these patients. All subjects were men and included 34 patients with DSM-III-R Schizophrenia and 47 age-matched healthy controls. Subjects received a battery of 21 tests, assessing four different functional domains: executive functions, short-term memory and production, declarative memory, and motor ability. MRI volumes were corrected for normal variation in head size and age, and neuropsychological test scores were corrected for normal variation in age. The schizophrenic group had significantly smaller cortical gray matter volumes (p < .05) and lower test scores in all functional domain than the control group (p = .0001). Within the schizophrenic group, lower scores in each domain were significantly correlated with smaller total cortical gray matter volumes; however, no predictable relationships were observed between neuropsychological test performance and the volumes of specific cortical regions.

Gray matter deficits in schizophrenia-alcoholism comorbidity

Cortical gray matter volume deficits occur in schizophrenia and alcoholism. The degree and regional distribution of gray matter deficits may distinguish these diseases. When both diseases co-occur, which pattern will predominate is unknown. We used MRI to quantify the volumes of six cortical gray matter regions of interest (ROIs) in 78 schizophrenics, 65 alcoholics, and 26 patients comorbid for both diseases. Volumes were adjusted for normal variation in head size and age. A MANOVA revealed a significant group effect (p = 0.002), with the schizophrenic ROI profile exhibiting greater overall deficits than the alcoholic profile (p = 0.02), and the comorbid profile falling in between. The group-by-region interaction showed the configural pattern of ROI deficits to differ significantly (p 0.004) across the groups, independent of group differences in the profile elevations, suggesting relatively greater involvement of the frontal and temporal regions in the schizophrenics compared to the alcoholics. A discriminant function analysis, maximally discriminating the regional profile configurations of the schizophrenics and alcoholics, was used to generate discriminant scores for all groups, t tests on these scores showed the comorbid profile configuration to differ from the alcoholics (p = 0.008) hut not from the schizophrenics (p = 0.72). When the comorbids were divided according to which disease developed first, the schizophrenia-first group had ROI configurations more like the schizophrenics, and the alcoholism-first group were more like the alcoholics (p < 0.05, onetailed). Thus, alcohol-schizophrenia comorbidity may represent a biologically heterogeneous group of clinical entities, ranging from alcoholic drinking as a symptom of schizophrenia to an alcohol-induced chronic psychosis clinically indistinct from schizophrenia. (Supported by MH 30854, AA 05965, Department of Veterans Affairs.)

Regional profiles of cortical gray matter volume deficits in schizophrenia and alcoholism

The antisaccade task is a prominent tool to investigate the response inhibition component of cognitive control. Recent theoretical accounts explain performance in terms of parallel programming of exogenous and endogenous saccades, linked to the horse race metaphor. Previous studies have tested the hypothesis of competing saccade signals at the behavioral level by selectively slowing the programming of endogenous or exogenous processes e.g. by manipulating the probability of antisaccades in an experimental block. To gain a better understanding of inhibitory control processes in parallel saccade programming, we analyzed task-related eye movements and blood oxygenation level dependent (BOLD) responses obtained using functional magnetic resonance imaging (fMRI) at 3T from 16 healthy participants in a mixed antisaccade and prosaccade task. The frequency of antisaccade trials was manipulated across blocks of high (75%) and low (25%) antisaccade frequency. In blocks with high antisaccade frequency, antisaccade latencies were shorter and error rates lower whilst prosaccade latencies were longer and error rates were higher. At the level of BOLD, activations in the task-related saccade network (left inferior parietal lobe, right inferior parietal sulcus, left precentral gyrus reaching into left middle frontal gyrus and inferior frontal junction) and deactivations in components of the default mode network (bilateral temporal cortex, ventromedial prefrontal cortex) compensated increased cognitive control demands. These findings illustrate context dependent mechanisms underlying the coordination of competing decision signals in volitional gaze control.

Cortical gray matter volume deficits in women with schizophrenia

Cortical gray matter volume deficits in women with schizophrenia