Hugo G. Schnack

Magnetic resonance imaging of boys with attention-deficit/hyperactivity disorder and their unaffected siblings

OBJECTIVE To study the influence of increased familial risk for attention-deficit/hyperactivity disorder (ADHD) on brain morphology. METHOD Volumetric cerebral measures based on whole brain magnetic resonance imaging scans from 30 boys with ADHD, 30 of their unaffected siblings, and 30 matched controls were compared. RESULTS Both subjects with ADHD and their unaffected siblings displayed reductions in right prefrontal gray matter and left occipital gray and white matter of up to 9.1% (p < 0.05). Right cerebellar volume was reduced by 4.9% in subjects with ADHD (p = 0.026) but not in their unaffected siblings (p = 0.308). A 4.0% reduction in intracranial volume was found in subjects with ADHD (p = 0.031), while a trend was observed in their unaffected siblings (p = 0.068). CONCLUSIONS The volumetric reductions in cortical gray and white matter in subjects with ADHD are also present in their unaffected siblings, suggesting that they are related to an increased familial risk for the disorder. In contrast, the cerebellum is unaffected in siblings, suggesting that the reduction in volume observed in subjects with ADHD may be more directly related to the pathophysiology of this disorder.

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.

Changes in the developmental trajectories of striatum in autism.

BACKGROUND Repetitive and stereotyped behavior has been associated with striatum in various neuropsychiatric disorders. However, striatal involvement has not yet been shown conclusively in autism. Issues include the use of neuroleptic medication and differences in mean age between samples, where conflicting results may reflect differences in developmental stage between samples. The objective was to examine brain development in a homogeneous sample of subjects with high-functioning autism. METHODS Magnetic resonance measures of brain structure of 188 individuals (99 subjects with high-functioning autism and 89 typically developing, matched control subjects) aged between 6 years and 25 years were compared. Measurements included the volume of brain structures, including striatum, as well as voxel-based assessment of gray matter density. RESULTS Developmental trajectories of the caudate nucleus, putamen, and nucleus accumbens differed between subjects with autism and control subjects. Results were not accounted for by overall changes in brain volume or neuroleptic medication. The development of the caudate nucleus differed from typical most, as its volume increased with age in autism, while it decreased for control subjects. Voxel-based analysis showed that changes in striatum localized to the head of the caudate nucleus. Overall, caudate nucleus volume was associated with repetitive behavior in autism. CONCLUSIONS We report changes in striatal development in autism, while caudate volume is associated with repetitive behaviors. This emphasizes the importance of striatum in the etiology of autism, in particular in the development of repetitive behavior that characterizes the disorder.

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.

Focal white matter density changes in schizophrenia: reduced inter-hemispheric connectivity.

Gray matter changes have been demonstrated in several regions in schizophrenia. Particularly, the frontal and temporal cortices and amygdala-hippocampal region have been found decreased in volume and density in magnetic resonance imaging (MRI) studies. These abnormalities may reflect an aberrant neuronal network in schizophrenia, suggesting that white matter fibers connecting these regions may also be affected. However, it is unclear if particular white matter areas are (progressively) affected in schizophrenia and if these are related to the gray matter changes. Focal white matter changes in schizophrenia were studied in whole brain magnetic resonance images acquired from 159 patients with schizophrenia or schizophreniform disorder and 158 healthy comparison subjects using voxel-based morphometry. White matter density changes in the patients with schizophrenia were correlated to gray matter density changes and to illness severity. In the patients with schizophrenia, significant decreases in white matter density were found in the genu and truncus of the corpus callosum in the left and right hemisphere, in the right anterior internal capsule and in the right anterior commissure. No interactions between diagnosis and age were found. Increased illness severity was correlated with low density of the corpus callosum and anterior commissure. Decreased corpus callosum density correlated with decreased density of thalamus, lateral inferior frontal and insular gray matter in patients and controls and with decreased density of medial orbitofrontal and superior temporal gyri in patients. Decreased internal capsule and anterior commissure density correlated with increased caudate, and globus pallidus density in patients and controls. These findings suggest aberrant inter-hemispheric connectivity of anterior cortical and sub-cortical brain regions in schizophrenia, reflecting decreased hemispheric specialisation in schizophrenia.

Increased gray-matter volume in medication-naive high-functioning children with autism spectrum disorder

BACKGROUND To establish whether high-functioning children with autism spectrum disorder (ASD) have enlarged brains in later childhood, and if so, whether this enlargement is confined to the gray and/or to the white matter and whether it is global or more prominent in specific brain regions. METHOD Brain MRI scans were acquired from 21 medication-naive, high-functioning children with ASD between 7 and 15 years of age and 21 comparison subjects matched for gender, age, IQ, height, weight, handedness, and parental education, but not pubertal status. RESULTS Patients showed a significant increase of 6% in intracranium, total brain, cerebral gray matter, cerebellum, and of more than 40% in lateral and third ventricles compared to controls. The cortical gray-matter volume was evenly affected in all lobes. After correction for brain volume, ventricular volumes remained significantly larger in patients. CONCLUSIONS High-functioning children with ASD showed a global increase in gray-matter, but not white-matter and cerebellar volume, proportional to the increase in brain volume, and a disproportional increase in ventricular volumes, still present after correction for brain volume. Advanced pubertal development in the patients compared to the age-matched controls may have contributed to the findings reported in the present study.

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.