Focal gray matter changes in schizophrenia across the course of the illness: a 5-year follow-up study.

Recent volumetric magnetic resonance imaging (MRI) studies have suggested brain volume changes in schizophrenia to be progressive in nature. Whether this is a global process or some brain areas are more affected than others is not known. In a 5-year longitudinal study, MRI whole brain scans were obtained from 96 patients with schizophrenia and 113 matched healthy comparison subjects. Changes over time in focal gray and white matter were measured with voxel-based morphometry throughout the brain. Over the 5-year interval, excessive decreases in gray matter density were found in patients in the left superior frontal area (Brodmann areas 9/10), left superior temporal gyrus (Brodmann area 42), right caudate nucleus, and right thalamus as compared to healthy individuals. Excessive gray matter density decrease in the superior frontal gray matter was related to increased number of hospitalizations, whereas a higher cumulative dose of clozapine and olanzapine during the scan interval was related to lesser decreases in this area. In conclusion, gray matter density loss occurs across the course of the illness in schizophrenia, predominantly in left frontal and temporal cortices. Moreover, the progression in left frontal density loss appears to be related to an increased number of psychotic episodes, with atypical antipsychotic medication attenuating these changes.     

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.     

Effect of chronic exposure to antipsychotic medication on cell numbers in the parietal cortex of macaque monkeys.

Both in vivo and post-mortem investigations have demonstrated smaller volumes of the whole brain and of certain brain regions in individuals with schizophrenia. It is unclear to what degree such smaller volumes are due to the illness or to the effects of antipsychotic medication treatment. Indeed, we recently reported that chronic exposure of macaque monkeys to haloperidol or olanzapine, at doses producing plasma levels in the therapeutic range in schizophrenia subjects, was associated with significantly smaller total brain weight and volume, including an 11.8-15.2% smaller gray matter volume in the left parietal lobe. Consequently, in this study we sought to determine whether these smaller volumes were associated with lower numbers of the gray matter's constituent cellular elements. The use of point counting and Cavalieri's principle on Nissl-stained sections confirmed a 14.6% smaller gray matter volume in the left parietal lobe from antipsychotic-exposed monkeys. Use of the optical fractionator method to estimate the number of each cell type in the gray matter revealed a significant 14.2% lower glial cell number with a concomitant 10.2% higher neuron density. The numbers of neurons and endothelial cells did not differ between groups. Together, the findings of smaller gray matter volume, lower glial cell number, and higher neuron density without a difference in total neuron number in antipsychotic-exposed monkeys parallel the results of post-mortem schizophrenia studies, and raise the possibility that such observations in schizophrenia subjects might be due, at least in part, to antipsychotic medication effects.     

Cannabis use and progressive cortical thickness loss in areas rich in CB1 receptors during the first five years of schizophrenia

Cerebral grey matter volume reductions are progressive in schizophrenia, with larger grey matter volume decreases associated with cannabis use. It is unknown whether this grey matter loss is globally distributed over the entire brain or more pronounced in specific cortical brain regions. Fifty-one patients with recent-onset schizophrenia and 31 matched healthy subjects were included. For all subjects, magnetic resonance imaging scans were obtained at inclusion and at 5-year follow-up. Nineteen patients (ab-)used cannabis but no other illicit drugs; 32 patients and the healthy comparison subjects did not use any drugs during the 5-year follow-up. At follow-up, clinical outcome was measured. To evaluate the local differences in cortical thickness change over five years between the two groups regression analysis was carried out over the cortical surface. At inclusion cortical thickness did not differ between patients and controls and between cannabis-using and non-using patients. Over the follow-up period we found excessive thinning of the right supplementary motor cortex, inferior frontal cortex, superior temporal gyrus, angular gyrus, occipital and parietal lobe in patients relative to controls after controlling for cannabis use. Patients who used cannabis showed additional thinning in the left dorsolateral prefrontal cortex (DLPFC), left anterior cingulate cortex (ACC) and left occipital lobe as compared to those patients that did not use cannabis during the scan interval. First-episode schizophrenia patients who use cannabis show a more pronounced cortical thinning than non-using patients in areas known for their high density of CB1 receptors, such as the ACC and the DLPFC.     

Progressive Brain Atrophy and Cortical Thinning in Schizophrenia after Commencing Clozapine Treatment

Despite evidence that clozapine may be neuroprotective, there are few longitudinal magnetic resonance imaging (MRI) studies that have specifically explored an association between commencement of clozapine treatment for schizophrenia and changes in regional brain volume or cortical thickness. A total of 33 patients with treatment-resistant schizophrenia and 31 healthy controls matched for age and gender underwent structural MRI brain scans at baseline and 6–9 months after commencing clozapine. MRI images were analyzed using SIENA (Structural Image Evaluation, using Normalization, of Atrophy) and FreeSurfer to investigate changes over time in brain volume and cortical thickness respectively. Significantly greater reductions in volume were detected in the right and left medial prefrontal cortex and in the periventricular area in the patient group regardless of treatment response. Widespread further cortical thinning was observed in patients compared with healthy controls. The majority of patients improved symptomatically and functionally over the study period, and patients who improved were more likely to have less cortical thinning of the left medial frontal cortex and the right middle temporal cortex. These findings demonstrate on-going reductions in brain volume and progressive cortical thinning in patients with schizophrenia who are switched to clozapine treatment. It is possible that this gray matter loss reflects a progressive disease process irrespective of medication use or that it is contributed to by switching to clozapine treatment. The clinical improvement of most patients indicates that antipsychotic-related gray matter volume loss may not necessarily be harmful or reflect neurotoxicity.     

Current Smoking and Reduced Gray Matter Volume—a Voxel-Based Morphometry Study

Nicotine modulates prefrontal processing when tested with functional imaging. Previous studies on changes in regional brain volumes in small samples, reporting different life-time exposure to nicotine, identified reduced volume in smokers in prefrontal areas but reported controversial results for other areas. We investigated the association of cigarette smoking and regional gray and white matter volume by using voxel-based morphometry (VBM) for T1-weighted high-resolution magnetic resonance imaging in 315 current-smokers and 659 never-smokers from the representative Study of Health in Pomerania (SHIP). Our study showed that in current-smokers smoking is significantly associated with gray matter volume loss in the prefrontal cortex, the anterior cingulate cortex, the insula, and the olfactory gyrus. White matter volumes were not relevantly reduced in current-smokers. In current-smokers, we found associations of gray matter loss and smoking exposure (pack-years) in the prefrontal cortex, the anterior and middle cingulate cortex, and the superior temporal and angular gyrus, which however did not stand corrections for multiple testing. We confirmed associations between smoking and gray matter differences in the prefrontal cortex, the anterior cingulate cortex and the insula in the general population of Pomerania (Germany). For the first time, we identified differences in brain volumes in the olfactory gyrus. Other cerebral regions did not show significant differences when correcting for multiple comparisons within the whole brain. The regions of structural deficits might be involved in addictive behavior and withdrawal symptoms, whereas further investigations have to show if the observed atrophies were caused by smoking itself or are preexisting differences between smoking and non-smoking individuals.     

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 structural changes associated with chronicity and antipsychotic treatment in schizophrenia

Accumulating evidence suggest a life-long impact of disease related mechanisms on brain structure in schizophrenia which may be modified by antipsychotic treatment. The aim of the present study was to investigate in a large sample of patients with schizophrenia the effect of illness duration and antipsychotic treatment on brain structure. Seventy-one schizophrenic patients and 79 age and gender matched healthy participants underwent brain magnetic resonance imaging (MRI). All images were processed with voxel based morphometry, using SPM5. Compared to healthy participants, patients showed decrements in gray matter volume in the left medial and left inferior frontal gyrus. In addition, duration of illness was negatively associated with gray matter volume in prefrontal regions bilaterally, in the temporal pole on the left and the caudal superior temporal gyrus on the right. Cumulative exposure to antipsychotics correlated positively with gray matter volumes in the cingulate gyrus for typical agents and in the thalamus for atypical drugs. These findings (a) indicate that structural abnormalities in prefrontal and temporal cortices in schizophrenia are progressive and, (b) suggest that antipsychotic medication has a significant impact on brain morphology.     

Exercise therapy,cardiorespiratory fitness and their effect on brain volumes: A randomised controlled trial in patients with schizophrenia and healthy controls

The objective of this study was to examine exercise effects on global brain volume, hippocampal volume, and cortical thickness in schizophrenia patients and healthy controls. Irrespective of diagnosis and intervention, associations between brain changes and cardiorespiratory fitness improvement were examined. Sixty-three schizophrenia patients and fifty-five healthy controls participated in this randomised controlled trial. Global brain volumes, hippocampal volume, and cortical thickness were estimated from 3-Tesla MRI scans. Cardiorespiratory fitness was assessed with a cardiopulmonary ergometer test. Subjects were assigned exercise therapy or occupational therapy (patients) and exercise therapy or life-as-usual (healthy controls) for six months 2 h weekly. Exercise therapy effects were analysed for subjects who were compliant at least 50% of sessions offered. Significantly smaller baseline cerebral (grey) matter, and larger third ventricle volumes, and thinner cortex in most areas of the brain were found in patients versus controls. Exercise therapy did not affect global brain and hippocampal volume or cortical thickness in patients and controls. Cardiorespiratory fitness improvement was related to increased cerebral matter volume and lateral and third ventricle volume decrease in patients and to thickening in the left hemisphere in large areas of the frontal, temporal and cingulate cortex irrespective of diagnosis. One to 2 h of exercise therapy did not elicit significant brain volume changes in patients or controls. However, cardiorespiratory fitness improvement attenuated brain volume changes in schizophrenia patients and increased thickness in large areas of the left cortex in both schizophrenia patients and healthy controls.     

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.     

Schizophrenia: breakdown in the well-regulated lifelong process of brain development and maturation.

Recent evidence suggests that the temporal extent of brain development/maturation can be expanded into middle age when maximal white matter volume and myelination are reached in frontal lobes and association areas. This temporally expanded view of brain development underlies a more comprehensive conceptual model of schizophrenia that incorporates both the reduction of gray matter volume and the complementary expansion of white matter volume occurring from adolescence until middle age. The model posits that the brain is in a constant state of well-regulated structural and functional change roughly defined as periods of development continuing into middle age followed by degeneration. Multiple genetic and environmental factors can interfere with the developmental processes resulting in a dysregulation of the complementary changes occurring in gray and white matter. This dysregulation in development results in an insufficient capacity to maintain temporal synchrony of widely distributed neural networks and is manifested in the heterogeneity of symptoms and cognitive impairments of schizophrenia. The model highlights the contributory role of myelination to synchronous brain function, provides explanations for inconsistencies in the existing literature, and suggests testable hypotheses and novel approaches for intervention efforts.     

Tract-based diffusion tensor imaging in patients with schizophrenia and their non-psychotic siblings

Structural brain abnormalities have consistently been found in patients with schizophrenia. Diffusion tensor imaging (DTI) has been shown to be a useful method to measure white matter (WM) integrity in this illness, but findings in the earlier disease stages are inconclusive. Moreover, the relationship between WM microstructure and the familial risk for developing schizophrenia remains unresolved. From 126 patients with schizophrenia, 123 of their non-psychotic siblings and 109 healthy control subjects, DTI images were acquired on a 1.5 T MRI scanner. Mean fractional anisotropy (FA) was compared along averaged WM tracts, computed for the genu, splenium, left and right uncinate fasciculus, cingulum, inferior fronto-occipital fasciculus, fornix, arcuate fasciculus, and inferior longitudinal fasciculus. Fractional anisotropy (FA) was assessed for its unique environmental and familial (possibly heritable) aspects associated with schizophrenia, using structural equation modeling for these white matter tracts. The results of this study show that young adult (mean age 26.7 years) patients with schizophrenia did not differ in mean FA from healthy controls along WM fibers; siblings of patients showed higher mean FA in the left and right arcuate fasciculus as compared to patients and controls. With increasing age, an excessive decline in mean FA was found in patients as compared to siblings and healthy controls in the genu, left uncinate fasciculus, left inferior fronto-occipital fasciculus, and left inferior longitudinal fasciculus. Moreover, symptom severity was negatively correlated to mean FA in the arcuate fasciculus bilaterally in patients with schizophrenia. In young adult patients with schizophrenia integrity of individual tract-based (corticocortical) fibers can (still) be within normal limits. However, changes in the arcuate fasciculus may be relevant to (the risk to develop) psychosis, while a general and widespread loss of fiber integrity may be related to illness progression.     

Substance use and regional gray matter volume in individuals at high risk of psychosis

Individuals with an at risk mental state (ARMS) are at greatly increased risk of developing a psychotic illness. Risk of transition to psychosis is associated with regionally reduced cortical gray matter volume. There has been considerable interest in the interaction between psychosis risk and substance use. In this study we investigate the relationship between alcohol, cannabis and nicotine use with gray matter volume in ARMS subjects and healthy volunteers. Twenty seven ARMS subjects and 27 healthy volunteers took part in the study. All subjects underwent volumetric MRI imaging. The relationship between regional gray matter volume and cannabis use, smoking, and alcohol use in controls and ARMS subjects was analysed using voxel-based morphometry. In any region where a significant relationship with drug was present, data were analysed to determine if there was any group difference in this relationship. Alcohol intake was inversely correlated with gray matter volume in cerebellum, cannabis intake was use was inversely correlated with gray matter volume in prefrontal cortex and tobacco intake was inversely correlated with gray matter volume in left temporal cortex. There were no significant interactions by group in any region. There is no evidence to support the hypothesis of increased susceptibility to harmful effects of drugs and alcohol on regional gray matter in ARMS subjects. However, alcohol, tobacco and cannabis at low to moderate intake may be associated with lower gray matter in both ARMS subjects and healthy volunteers—possibly representing low-level cortical damage or change in neural plasticity.     

Hippocampal and striatal gray matter volume are associated with a smoking cessation treatment outcome: results of an exploratory voxel-based morphometric analysis

Rationale  

Compared to nonsmokers, smokers exhibit a number of potentially important differences in regional brain structure including reduced gray matter (GM) volume and/or density in areas including frontal and cingulate cortices, thalamus, and insula. However, associations between brain structure and smoking cessation treatment outcomes have not been reported.     

A behavioural and functional neuroimaging investigation into the effects of nicotine on sensorimotor gating in healthy subjects and persons with schizophrenia

Rationale Schizophrenia patients display an excessive rate of smoking compared to the general population. Nicotine increases acoustic prepulse inhibition (PPI) in animals as well as healthy humans, suggesting that smoking may provide a way of restoring deficient sensorimotor gating in schizophrenia. No previous study has examined the neural mechanisms of the effect of nicotine on PPI in humans. Objectives To investigate whether nicotine enhances tactile PPI in healthy subjects and patients with schizophrenia employing a double-blind, placebo-controlled, cross-over design and, if so, what are the neural correlates of nicotine-induced modulation of PPI. Materials and methods In experiment 1, 12 healthy smokers, 12 healthy non-smokers and nine smoking schizophrenia patients underwent testing for tactile PPI on two occasions, 14 days apart, once after receiving (subcutaneously) 12 μg/kg body weight of nicotine and once after receiving saline (placebo). In experiment 2, six healthy subjects and five schizophrenia patients of the original sample (all male smokers) underwent functional magnetic resonance imaging (fMRI) under the same drug conditions and the same tactile PPI paradigm as in experiment 1. Results Nicotine enhanced PPI in both groups. A comparison of patterns of brain activation on nicotine vs placebo conditions showed increased activation of limbic regions and striatum in both groups after nicotine administration. Subsequent correlational analyses demonstrated that the PPI-enhancing effect of nicotine was related to increased hippocampal activity in both groups. Conclusions Nicotine enhances tactile PPI in both healthy and schizophrenia groups. Our preliminary fMRI findings reveal that this effect is modulated by increased limbic activity. Jeffrey A. Gray is deceased.     

Cerebellar gray matter volume correlates with duration of cocaine use in cocaine-dependent subjects.

This study was conducted to explore differences in gray and white matter volume between cocaine-dependent and healthy comparison subjects using optimized voxel-based morphometry (VBM). Brain magnetic resonance imaging (MRI) and neuropsychological function tests were performed for 40 cocaine-dependent subjects (41.4+/-6.9 years, 27 men) and 41 healthy age- and sex-matched comparison subjects (38.7+/-8.8 years, 26 men). Optimally normalized whole brain MR images were segmented, modulated, smoothed, and compared between groups with statistical parametric mapping. The cocaine-dependent group had lower gray matter volumes in bilateral premotor cortex (Brodmann area (BA) 6, 8; 16.6%), right orbitofrontal cortex (BA 10, 15.1%), bilateral temporal cortex (BA 20, 38; 15.9%), left thalamus (12.6%), and bilateral cerebellum (13.4%) as well as lower right cerebellar white matter volume (10.0%) relative to the comparison group at a corrected p<0.05 for multiple comparisons. Duration of cocaine use negatively correlated with right and left cerebellar gray matter volumes (r=-0.37, r=-0.39, respectively). In cocaine-dependent subjects, lower cerebellar hemispheric gray and white matter volumes were correlated with deficits in executive function and decreased motor performance. This study reports that cocaine-dependent subjects have lower gray matter volumes in cerebellar hemispheres as well as in frontal, temporal cortex, and thalamus. These findings are the first to suggest that the cerebellum may be vulnerable to cocaine-associated brain volume changes, and that cerebellar deficits may contribute to neuropsychological deficits and motor dysfunction frequently observed in cocaine-dependent subjects.     

Gray-matter volume in methamphetamine dependence: Cigarette smoking and changes with abstinence from methamphetamine

Background

Group differences in brain structure between methamphetamine-dependent and healthy research participants have been reported, but findings in the literature present discrepancies. Although most methamphetamine-abusing individuals also smoke cigarettes, the effects of smoking on brain structure have not been distinguished from those of methamphetamine. Changes with abstinence from methamphetamine have also been relatively unexplored. This study, therefore, attempted to account for effects of smoking and brief abstinence from methamphetamine on gray-matter measures in methamphetamine-dependent research participants.

Methods

Gray matter was measured using voxel-based morphometry in three groups: 18 Control Nonsmokers, 25 Control Smokers, and 39 Methamphetamine-dependent Smokers (methamphetamine-abstinent 4–7 days). Subgroups of methamphetamine-dependent and control participants (n = 12/group) were scanned twice to determine change in gray matter over the first month of methamphetamine abstinence.

Results

Compared with Control Nonsmokers, Control Smokers and Methamphetamine-dependent Smokers had smaller gray-matter volume in the orbitofrontal cortex and caudate nucleus. Methamphetamine-dependent Smokers also had smaller gray-matter volumes in frontal, parietal and temporal cortices than Control Nonsmokers or Smokers, and smaller gray-matter volume in insula than Control Nonsmokers. Longitudinal assessment revealed gray matter increases in cortical regions (inferior frontal, angular, and superior temporal gyri, precuneus, insula, occipital pole) in methamphetamine-dependent but not control participants; the cerebellum showed a decrease.

Conclusions

Gray-matter volume deficits in the orbitofrontal cortex and caudate of methamphetamine-dependent individuals may be in part attributable to cigarette smoking or pre-morbid conditions. Increase in gray matter with methamphetamine abstinence suggests that some gray-matter deficits are partially attributable to methamphetamine abuse.     

NCAN Cross-Disorder Risk Variant Is Associated With Limbic Gray Matter Deficits in Healthy Subjects and Major Depression

Genome-wide association studies have reported an association between NCAN rs1064395 genotype and bipolar disorder. This association was later extended to schizophrenia and major depression. However, the neurobiological underpinnings of these associations are poorly understood. NCAN is implicated in neuronal plasticity and expressed in subcortical brain areas, such as the amygdala and hippocampus, which are critically involved in dysfunctional emotion processing and regulation across diagnostic boundaries. We hypothesized that the NCAN risk variant is associated with reduced gray matter volumes in these areas. Gray matter structure was assessed by voxel-based morphometry on structural MRI data in two independent German samples (healthy subjects, n=512; depressed inpatients, n=171). All participants were genotyped for NCAN rs1064395. Hippocampal and amygdala region-of-interest analyses were performed within each sample. In addition, whole-brain data from the combined sample were analyzed. Risk (A)-allele carriers showed reduced amygdala and hippocampal gray matter volumes in both cohorts with a remarkable spatial overlap. In the combined sample, genotype effects observed for the amygdala and hippocampus survived correction for entire brain volume. Further effects were also observed in the left orbitofrontal cortex and the cerebellum/fusiform gyrus. We conclude that NCAN genotype is associated with limbic gray matter alterations in healthy and depressed subjects in brain areas implicated in emotion perception and regulation. The present data suggest that NCAN forms susceptibility to neurostructural deficits in the amygdala, hippocampus, and prefrontal areas independent of disease, which might lead to disorder onset in the presence of other genetic or environmental risk factors.     

The influence of chronic exposure to antipsychotic medications on brain size before and after tissue fixation: a comparison of haloperidol and olanzapine in macaque monkeys.

It is unclear to what degree antipsychotic therapy confounds longitudinal imaging studies and post-mortem studies of subjects with schizophrenia. To investigate this problem, we developed a non-human primate model of chronic antipsychotic exposure. Three groups of six macaque monkeys each were exposed to oral haloperidol, olanzapine or sham for a 17-27 month period. The resulting plasma drug levels were comparable to those seen in subjects with schizophrenia treated with these medications. After the exposure, we observed an 8-11% reduction in mean fresh brain weights as well as left cerebrum fresh weights and volumes in both drug-treated groups compared to sham animals. The differences were observed across all major brain regions (frontal, parietal, temporal, occipital, and cerebellum), but appeared most robust in the frontal and parietal regions. Stereological analysis of the parietal region using Cavalieri's principle revealed similar volume reductions in both gray and white matter. In addition, we assessed the subsequent tissue shrinkage due to standard histological processing and found no evidence of differential shrinkage due to drug exposure. However, we observed a pronounced general shrinkage effect of approximately 20% and a highly significant variation in shrinkage across brain regions. In conclusion, chronic exposure of non-human primates to antipsychotics was associated with reduced brain volume. Antipsychotic medication may confound post-mortem studies and longitudinal imaging studies of subjects with schizophrenia that depend upon volumetric measures.     

Non-treatment-seeking heavy drinkers: effects of chronic cigarette smoking on brain structure

We previously reported [Cardenas, V.A., Studholme, C., Meyerhoff, D.J., Song, E., Weiner, M.W., 2005. Chronic active heavy drinking and family history of problem drinking modulate regional brain tissue volumes. Psychiatry Res. 138, 115-130] that non-treatment-seeking, active heavy drinkers (HD) demonstrated smaller regional neocortical gray matter volumes compared to light drinking controls; however, the potential effects of chronic cigarette smoking on regional brain volumes were not addressed. The goal of this retrospective analysis was to determine if chronic smoking affected brain structure in the non-treatment-seeking heavy drinking sample from our earlier report (i.e., Cardenas et al., 2005). Regional volumetric comparisons were made among age-matched smoking HD (n=17), non-smoking HD (n=16), and non-smoking light drinkers (nsLD; n=20) from our original sample. Quantitative volumetric measures of neocortical gray matter (GM), white matter (WM), subcortical structures, and cerebral spinal fluid (CSF) were derived from high-resolution magnetic resonance imaging. Smoking HD demonstrated smaller volumes than nsLD in the frontal, parietal, temporal GM, and for total neocortical GM. Smoking HD also demonstrated smaller temporal and total GM volumes than non-smoking HD. Non-smoking HD and nsLD did not differ significantly on GM volumes. Further, the three groups did not differ on lobar WM, subcortical structures or regional CSF volumes. These retrospective analyses indicate neocortical GM volume reductions in non-treatment-seeking smoking HD, but not in non-smoking HD, which are consistent with our studies in recently detoxified treatment-seeking alcohol-dependent samples.