Neeltje E.M. van Haren

Brain volume abnormalities in major depressive disorder: A meta-analysis of magnetic resonance imaging studies

Objective. So far, there have been no attempts to integrate the growing number of all brain volumetric magnetic resonance imaging studies in depression. In this comprehensive meta‐analysis the magnitude and extent of brain volume differences between 2,418 patients with major depressive disorder and 1,974 healthy individuals from 64 studies was determined. Methods. A systematic research was conducted for volumetric magnetic resonance imaging studies of patients with major depressive disorder in relation to healthy control subjects. Studies had to report sufficient data for computation of effect sizes. For each study, the Cohens d was calculated. All analyses were performed using the random effects model. Additionally, meta‐regression analyses were done to explore the effects of potential sources of heterogeneity. Results. Patients showed large volume reductions in frontal regions, especially in the anterior cingulate and orbitofrontal cortex with smaller reductions in the prefrontal cortex. The hippocampus, the putamen and caudate nucleus showed moderate volume reductions. Conclusions. This is the first comprehensive meta‐analysis in major depressive disorder demonstrating structural brain abnormalities, particularly in those brain areas that are involved in emotion processing and stress‐regulation. Hum Brain Mapp, 2009.

Brain Volumes in Schizophrenia: A Meta-Analysis in Over 18 000 Subjects

Although structural brain alterations in schizophrenia have been demonstrated extensively, their quantitative distribution has not been studied over the last 14 years despite advances in neuroimaging. Moreover, a volumetric meta-analysis has not been conducted in antipsychotic-naive patients. Therefore, meta-analysis on cross-sectional volumetric brain alterations in both medicated and antipsychotic-naive patients was conducted. Three hundred seventeen studies published from September 1, 1998 to January 1, 2012 comprising over 9000 patients were selected for meta-analysis, including 33 studies in antipsychotic-naive patients. In addition to effect sizes, potential modifying factors such as duration of illness, sex composition, current antipsychotic dose, and intelligence quotient matching status of participants were extracted where available. In the sample of medicated schizophrenia patients (n = 8327), intracranial and total brain volume was significantly decreased by 2.0% (effect size d = -0.17) and 2.6% (d = -0.30), respectively. Largest effect sizes were observed for gray matter structures, with effect sizes ranging from -0.22 to -0.58. In the sample of antipsychotic-naive patients (n = 771), volume reductions in caudate nucleus (d = -0.38) and thalamus (d = -0.68) were more pronounced than in medicated patients. White matter volume was decreased to a similar extent in both groups, while gray matter loss was less extensive in antipsychotic-naive patients. Gray matter reduction was associated with longer duration of illness and higher dose of antipsychotic medication at time of scanning. Therefore, brain loss in schizophrenia is related to a combination of (early) neurodevelopmental processes-reflected in intracranial volume reduction-as well as illness progression.

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.

Progressive Brain Volume Loss in Schizophrenia Over the Course of the Illness: Evidence of Maturational Abnormalities in Early Adulthood

BACKGROUND Considering the magnitude of the reported changes in brain volume over time in first-episode patients it is unlikely that these changes are constant over the life-span of the schizophrenic illness. Thus, one would expect the progression in brain volume change in schizophrenia to follow a more complex trajectory over time. METHODS Two magnetic resonance imaging brain scans were obtained over a 5-year interval of 96 schizophrenia patients and 113 healthy subjects between ages 16 to 56. RESULTS The trajectory of brain volume change differed between patients with schizophrenia and healthy individuals. Before the age of 45 years cerebral and gray matter loss and lateral ventricle increase were excessive in patients relative to controls, representing approximately the first 20 years of illness. Patients showed an excessive third ventricle volume increase over time. In addition, poor outcome patients showed more brain tissue loss during the follow-up interval than good outcome patients. CONCLUSIONS Cerebral (gray) matter volume loss in the patients was mainly characterized by the absence of the normal curved trajectory of volume change with age that was present in healthy subjects. Later in life, the degree of volume change in patients is similar to that observed with normal aging. Independently of age, larger brain volume changes appear clinically relevant.

Changes in Cortical Thickness During the Course of Illness in Schizophrenia

CONTEXT Whether cortical thickness changes in schizophrenia over time are more pronounced relative to the changes that can be attributed to normal aging has not been studied. OBJECTIVE To compare patients with schizophrenia and healthy control participants on cortical thickness change. DESIGN A 5-year longitudinal study comparing schizophrenic patients and healthy controls using 2 magnetic resonance images of the brain. SETTING Patients were recruited from the Department of Psychiatry at the University Medical Centre Utrecht and from other psychiatric hospitals in the Netherlands. Healthy controls were recruited via advertisement in newspapers and notice boards. PARTICIPANTS Ninety-six schizophrenic patients and 113 healthy controls aged 16 to 56 years. MAIN OUTCOME MEASURES Cortical thickness and change in cortical thickness on a vertex-by-vertex basis across the cortical mantle, measures of functional and symptomatic outcome, and cumulative intake of antipsychotics during the scan interval. RESULTS At baseline, the schizophrenic patients had thinner left orbitofrontal and right parahippocampal and superior temporal cortices and a thicker superior parietal lobule and occipital pole compared with the controls. Mean cortical thickness did not differ between the groups. Over time, excessive cortical thinning was found in widespread areas on the cortical mantle, most pronounced bilaterally in the temporal cortex and in the left frontal area. Poor outcome in patients was associated with more pronounced cortical thinning. Higher cumulative intake of typical antipsychotics during the scan interval was associated with more pronounced cortical thinning, whereas higher cumulative intake of atypical antipsychotic medication was associated with less pronounced cortical thinning. CONCLUSIONS In schizophrenia, the cortex shows excessive thinning over time in widespread areas of the brain, most pronounced in the frontal and temporal areas, and progresses across the entire course of the illness. The excessive thinning of the cortex appears related to outcome and medication intake.

Excessive Brain Volume Loss Over Time in Cannabis-Using First-Episode Schizophrenia Patients

OBJECTIVE Cerebral gray matter volume reductions have been found to progress over time in schizophrenia, with larger decreases related to poorer outcome, which has also been associated with cannabis use in schizophrenia patients. Progressive gray matter changes in patients who use cannabis may be more extensive than in those who do not. METHOD Patients with recent-onset schizophrenia (N=51) and matched healthy subjects (N=31) were included. For all subjects, magnetic resonance imaging scans were obtained at inclusion (T0) and at 5-year follow-up (T5). Nineteen patients used cannabis but no other illicit drugs; 32 patients did not use any drugs during the 5-year follow-up. At T5, clinical outcome was measured. Cumulative amount of antipsychotic medication during the interval was calculated. At T0 and T5, total brain, gray and white matter, and lateral and third ventricle volumes were measured. Univariate analysis of covariance and pairwise comparisons were performed. RESULT Schizophrenia patients showed a larger gray matter volume decrease over time than healthy subjects. They also showed larger increases in lateral and third ventricle volumes than healthy subjects and patients who did not use cannabis during follow-up. This decrement was significantly more pronounced in the patients who continued to use cannabis. These differences could not be attributed to outcome or baseline characteristics. CONCLUSIONS First-episode schizophrenia patients who use cannabis show a more pronounced brain volume reduction over a 5-year follow-up than patients with schizophrenia who do not use cannabis. These results may help explain some of the detrimental effects of cannabis use in schizophrenia.

Human brain changes across the life span: a review of 56 longitudinal magnetic resonance imaging studies.

There is consistent evidence that brain volume changes in early and late life. Most longitudinal studies usually only span a few years and include a limited number of participants. In this review, we integrate findings from 56 longitudinal magnetic resonance imaging (MRI) studies on whole brain volume change in healthy individuals. The individual longitudinal MRI studies describe only the development in a limited age range. In total, 2,211 participants were included. Age at first measurement varied between 4 and 88 years of age. The studies included in this review were performed using a large range of methods (e.g., different scanner protocols and different acquisition parameters). We applied a weighted regression analysis to estimate the age dependency of the rate of relative annual brain volume change across studies. The results indicate that whole brain volume changes throughout the life span. A wave of growth occurs during childhood/adolescence, where around 9 years of age a 1% annual brain growth is found which levels off until at age 13 a gradual volume decrease sets in. During young adulthood, between ∼18 and 35 years of age, possibly another wave of growth occurs or at least a period of no brain tissue loss. After age 35 years, a steady volume loss is found of 0.2% per year, which accelerates gradually to an annual brain volume loss of 0.5% at age 60. The brains of people over 60 years of age show a steady volume loss of more than 0.5%. Understanding the mechanisms underlying these plastic brain changes may contribute to distinguishing progressive brain changes in psychiatric and neurological diseases from healthy aging processes. Hum Brain Mapp, 2012.

Changes in Thickness and Surface Area of the Human Cortex and Their Relationship with Intelligence

Changes in cortical thickness over time have been related to intelligence, but whether changes in cortical surface area are related to general cognitive functioning is unknown. We therefore examined the relationship between intelligence quotient (IQ) and changes in cortical thickness and surface over time in 504 healthy subjects. At 10 years of age, more intelligent children have a slightly thinner cortex than children with a lower IQ. This relationship becomes more pronounced with increasing age: with higher IQ, a faster thinning of the cortex is found over time. In the more intelligent young adults, this relationship reverses so that by the age of 42 a thicker cortex is associated with higher intelligence. In contrast, cortical surface is larger in more intelligent children at the age of 10. The cortical surface is still expanding, reaching its maximum area during adolescence. With higher IQ, cortical expansion is completed at a younger age; and once completed, surface area decreases at a higher rate. These findings suggest that intelligence may be more related to the magnitude and timing of changes in brain structure during development than to brain structure per se, and that the cortex is never completed but shows continuing intelligence-dependent development.

Gray and white matter volume abnormalities in monozygotic and same-gender dizygotic twins discordant for schizophrenia.

Abstract Background Whole brain tissue volume decreases in schizophrenia have been related to both genetic risk factors and disease-related (possibly nongenetic) factors; however, whether genetic and environmental risk factors in the brains of patients with schizophrenia are differentially reflected in gray or white matter volume change is not known. Methods Magnetic resonance imaging (1.5 T) brain scans of 11 monozygotic and 11 same-gender dizygotic twin pairs discordant for schizophrenia were acquired and compared with 11 monozygotic and 11 same-gender dizygotic healthy control twin pairs. Results Repeated-measures volume analysis of covariance revealed decreased whole brain volume in the patients with schizophrenia as compared with their co-twins and with healthy twin pairs. Decreased white matter volume was found in discordant twin pairs compared with healthy twin pairs, particularly in the monozygotic twin pairs. A decrease in gray matter was found in the patients compared with their co-twins and compared with the healthy twins. Conclusions The results suggest that the decreases in white matter volume reflect the increased genetic risk to develop schizophrenia, whereas the decreases in gray matter volume are related to environmental risk factors. Study of genes involved in the (maintenance) of white matter structures may be particularly fruitful in schizophrenia.

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

The purpose of this study is to create a model that can classify schizophrenia patients and healthy controls based on whole brain gray matter densities (voxel-based morphometry, VBM) from structural magnetic resonance imaging (MRI) scans. In addition, we investigated the stability of the accuracy of the models, when built with different sample sizes. Using a support vector machine, we built a model from 239 subjects (128 patients and 111 healthy controls) and classified 71.4% correct (leave-one-out). We replicated and validated this result by testing the unaltered model on a completely independent sample of 277 subjects (155 patients and 122 healthy controls), scanned with a different scanner. The classification rate of the validation sample was 70.4%. The models discriminative pattern showed, amongst other differences, gray matter density decreases in frontal and superior temporal lobes and hippocampus in schizophrenia patients with respect to healthy controls and increases in gray matter density in basal ganglia and left occipital lobe and. Larger training samples gave more reliable models: Models based on sample sizes smaller than N=130 should be considered unstable and can even score below chance.