ZNF804A genetic variation (rs1344706) affects brain grey but not white matter in schizophrenia and healthy subjects.

BACKGROUND: Genetic variation in the gene encoding ZNF804A, a risk gene for schizophrenia, has been shown to affect brain functional endophenotypes of the disorder, while studies of white matter structure have been inconclusive. METHOD: We analysed effects of ZNF804A single nucleotide polymorphism rs1344706 on grey and white matter using voxel-based morphometry (VBM) in high-resolution T1-weighted magnetic resonance imaging scans of 62 schizophrenia patients and 54 matched healthy controls. RESULTS: We found a significant (p < 0.05, family-wise error corrected for multiple comparisons) interaction effect of diagnostic group x genotype for local grey matter in the left orbitofrontal and right and left lateral temporal cortices, where patients and controls showed diverging effects of genotype. Analysing the groups separately (at p < 0.001, uncorrected), variation in rs1344706 showed effects on brain structure within the schizophrenia patients in several areas including the left and right inferior temporal, right supramarginal/superior temporal, right and left inferior frontal, left frontopolar, right and left dorsolateral/ventrolateral prefrontal cortices, and the right thalamus, as well as effects within the healthy controls in left lateral temporal, right anterior insula and left orbitofrontal cortical areas. We did not find effects of genotype of regional white matter in either of the two cohorts. CONCLUSIONS: Our findings demonstrate effects of ZNF804A genetic variation on brain structure, with diverging regional effects in schizophrenia patients and healthy controls in frontal and temporal brain areas. These effects, however, might be dependent on the impact of other (genetic or non-genetic) disease factors.

Individualized Gaussian process-based prediction and detection of local and global gray matter abnormalities in elderly subjects.

Structural imaging based on MRI is an integral component of the clinical assessment of patients with potential dementia. We here propose an individualized Gaussian process-based inference scheme for clinical decision support in healthy and pathological aging elderly subjects using MRI. The approach aims at quantitative and transparent support for clinicians who aim to detect structural abnormalities in patients at risk of Alzheimer's disease or other types of dementia. Firstly, we introduce a generative model incorporating our knowledge about normative decline of local and global gray matter volume across the brain in elderly. By supposing smooth structural trajectories the models account for the general course of age-related structural decline as well as late-life accelerated loss. Considering healthy subjects' demography and global brain parameters as informative about normal brain aging variability affords individualized predictions in single cases. Using Gaussian process models as a normative reference, we predict new subjects' brain scans and quantify the local gray matter abnormalities in terms of Normative Probability Maps (NPM) and global z-scores. By integrating the observed expectation error and the predictive uncertainty, the local maps and global scores exploit the advantages of Bayesian inference for clinical decisions and provide a valuable extension of diagnostic information about pathological aging. We validate the approach in simulated data and real MRI data. We train the GP framework using 1238 healthy subjects with ages 18-94 years, and predict in 415 independent test subjects diagnosed as healthy controls, Mild Cognitive Impairment and Alzheimer's disease.

Partial least squares correlation of multivariate cognitive abilities and local brain structure in children and adolescents.

Intelligent behavior is not a one-dimensional phenomenon. Individual differences in human cognitive abilities might be therefore described by a 'cognitive manifold' of intercorrelated tests from partially independent domains of general intelligence and executive functions. However, the relationship between these individual differences and brain morphology is not yet fully understood. Here we take a multivariate approach to analyzing covariations across individuals in two feature spaces: the low-dimensional space of cognitive ability subtests and the high-dimensional space of local gray matter volume obtained from voxel-based morphometry. By exploiting a partial least squares correlation framework in a large sample of 286 healthy children and adolescents, we identify directions of maximum covariance between both spaces in terms of latent variable modeling. We obtain an orthogonal set of latent variables representing commonalities in the brain-behavior system, which emphasize specific neuronal networks involved in cognitive ability differences. We further explore the early lifespan maturation of the covariance between cognitive abilities and local gray matter volume. The dominant latent variable revealed positive weights across widespread gray matter regions (in the brain domain) and the strongest weights for parents' ratings of children's executive function (in the cognitive domain). The obtained latent variables for brain and cognitive abilities exhibited moderate correlations of 0.46-0.6. Moreover, the multivariate modeling revealed indications for a heterochronic formation of the association as a process of brain maturation across different age groups.

[Volume alterations in the gray matter of anosmic subjects. Lessons we can learn from voxel-based morphometry]. / Volumenänderungen der grauen Hirnsubstanz bei Anosmikern. Erkenntnisse durch voxelbasierte Morphometrie.

Alterations in the central nervous system in patients with a loss of sense of smell are well documented for the olfactory bulb (OB). Here we present a voxel-based morphometry (VBM) study on cerebral alterations in the gray matter of patients with anosmia above the OB. 3-Tesla MRI datasets were obtained from 17 patients with anosmia as well as from 17 normosmic controls. Data processing and evaluation was performed using the SPM5 software package (Wellcome Department of Imaging Neuroscience Group, London, UK) and the implemented VBM5 toolbox. Patients with anosmia showed a significant volume decrease in the gray matter in the primary olfactory cortex as well as in secondary olfactory areas (insular cortex, orbitofrontal cortex, cingulate cortex and hippocampus). Furthermore, volume decreases in areas like the nucleus accumbens with adjacent subcallosal gyrus and the dorsolateral prefrontal cortex were found. Longer disease duration was associated with more profound alterations in the gray matter. VBM is appropriate to document brain alterations in patients with olfactory disorders.

Differential Effects of Fingolimod and Natalizumab on Magnetic Resonance Imaging Measures in Relapsing-Remitting Multiple Sclerosis.

Fingolimod and natalizumab are approved disease-modifying drugs in relapsing-remitting multiple sclerosis (RRMS). The two drugs have different modes of action and may therefore influence different aspects of MS-related tissue damage. In this retrospective cohort study, we longitudinally compared patients treated with fingolimod and patients treated with natalizumab by measures based on structural magnetic resonance imaging (MRI). We included patients with RRMS given that two standardized MRI scans under the same drug were available with an interval of at least 6 months both from therapy start to baseline scan and from baseline scan to follow-up scan. After matching for age, baseline and follow-up scans from 93 patients (fingolimod, 48; natalizumab, 45) were investigated. Mean follow-up time was 1.9 years. We determined the number of new white matter lesions as well as thalamic, cortical, and whole-brain atrophy. After scaling for time of the interscan interval, measures were analyzed by group comparisons and, to account for demographic and clinical characteristics, by multiple regression models and a binary logistic regression model. Compared to natalizumab, fingolimod treatment went along with more new white matter lesions (median [interquartile range, IQR] 0.0 [0.0; 0.7] vs. 0.0 [0.0; 0.0] /year; p < 0.01) whereas whole-brain atrophy was lower (median [IQR] 0.2 [0.0; 0.5] vs. 0.5 [0.2; 1.0] %/year; p = 0.01). These significant differences were confirmed by multiple regression models and the binary logistic regression model. In conclusion, our observation is compatible with stronger neuroprotective properties of fingolimod compared to natalizumab.

In vivo biomarkers of structural and functional brain development and aging in humans.

Brain aging is a major determinant of aging. Along with the aging population, prevalence of neurodegenerative diseases is increasing, therewith placing economic and social burden on individuals and society. Individual rates of brain aging are shaped by genetics, epigenetics, and prenatal environmental. Biomarkers of biological brain aging are needed to predict individual trajectories of aging and the risk for age-associated neurological impairments for developing early preventive and interventional measures. We review current advances of in vivo biomarkers predicting individual brain age. Telomere length and epigenetic clock, two important biomarkers that are closely related to the mechanistic aging process, have only poor deterministic and predictive accuracy regarding individual brain aging due to their high intra- and interindividual variability. Phenotype-related biomarkers of global cognitive function and brain structure provide a much closer correlation to age at the individual level. During fetal and perinatal life, autonomic activity is a unique functional marker of brain development. The cognitive and structural biomarkers also boast high diagnostic specificity for determining individual risks for neurodegenerative diseases.

Physically active life style is associated with increased grey matter brain volume in a medial parieto-frontal network.

To examine the association between the amount of sports activity performed during leisure time and gray matter volume (GMV) of the brain we investigated differences in GMV in a large cohort study of community-dwelling older adults. 967 individuals indicated their average weekly sports activity via a questionnaire, and underwent high resolution T1-weighted structural imaging of the brain. We used voxel based morphometry (CAT 12) in a region of interest approach for (1) comparing participants with higher versus lower sports activity (median split) and (2) calculating a linear regression on GMV and sports activity. We carefully corrected for other factors known to have an impact on GMV (sex, age, total brain volume, education, cigarettes and alcohol consumption, body mass index) and excluded pathology (history of psychiatric or neurological disease; visual inspection of brain scans). Those participants who spend more time performing sports activity per week (median split with > 1 h/week) showed higher GMV in the dorsomedial frontal lobe, the superior parietal lobe, and the precuneus/cuneus area. When splitting participants by their median (55.5 years) into two groups we found a stronger protective effect of sports against age related GMV decline for the older part of the cohort. Overall, a more active lifestyle was associated with increased GMV in areas associated with self-awareness and working memory. These cohort data support data on the protective role of sports activity for the GMV.

Structural brain alterations in subjects at high-risk of psychosis: a voxel-based morphometric study.

Forty Untreated high-risk (HR) individuals for psychosis and 75 healthy control subjects (HC) matched for age, gender, handedness and educational level were investigated by structural MRI. HR subjects were recruited at the Early Detection and Intervention Centre for Mental Crises (FETZ) of the Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University, Germany. Measurements of gray matter volumes were performed by voxel-based morphometry using SPM5. The sample of HR subjects showed GM volume reductions in frontal, lateral temporal and medial temporal regions compared to the healthy control group. These regions are compatible with structural findings in the clinically apparent disease of schizophrenia.

Disturbed glutathione antioxidative defense is associated with structural brain changes in neuroleptic-naïve first-episode psychosis patients.

BACKGROUND: Oxidative stress and impaired antioxidant defense are reported in schizophrenia and are thought to be associated with disturbed neurodevelopment, brain structural alterations, glutamatergic imbalance, negative symptomatology, and cognitive impairment. To test some of these assumptions we investigated the glutathione (GSH) antioxidant defense system (AODS) and brain structural abnormalities in drug-naïve individuals with first acute episode of psychosis (FEP). METHOD: The study involved 27 drug-naïve FEP patients and 31 healthy controls (HC). GSH AODS markers and TBARS (thiobarbituric acid reactive substances) were measured in blood plasma and erythrocytes. High-resolution T1-weighted 3T MRI were acquired from all subjects. To investigate brain structural abnormalities and effects of illness on interactions between GSH metabolites or enzyme activities and local grey matter density, voxel-based morphometry (VBM) with the computational anatomy toolbox (CAT12) was used. Symptomatology was assessed using the Positive and Negative Syndrome Scale (PANSS) and the Symptom Checklist 1990 revised (SCL-90-R). RESULTS: (i) In FEP patients, glutathione reductase activity (GSR) was lower than in the HC group. GSR activity in plasma was inversely correlated with SCL-90-R scores of depression and PANSS scores of the negative symptom subscale. (ii) A reduction of GM was observed in left inferior frontal, bilateral temporal, as well as parietal cortices of FEP patients. (iii) Interaction analyses revealed an influence of illness on GSR/GM associations in the left orbitofrontal cortex (BA 47). CONCLUSION: Our findings support the notion of altered GSH antioxidative defense in untreated acute psychosis as a potential pathomechanism for localized brain structural abnormalities. This pathology relates to a key brain region of social cognition, affective motivation control and decision making, and is clinically accompanied by depressive and negative symptoms.

Morphological basis for the spectrum of clinical deficits in spinocerebellar ataxia 17 (SCA17).

Spinocerebellar ataxia 17 (SCA17) is a rare genetic disorder characterized by cerebellar, extrapyramidal, pyramidal as well as psychiatric signs. The pathoanatomical basis of this disorder is still not well known. A total of 12 patients and 12 age- and sex-matched controls were examined by in vivo MRI voxel-based morphometry (VBM). Besides general patterns of disease-related brain atrophy, characteristic syndrome-related morphological changes in SCA17 patients were studied. In comparison with normal controls, SCA17 patients showed a pattern of degeneration of the grey matter centred around mesial cerebellar structures, occipito-parietal structures, the anterior putamen bilaterally, the thalamus and other parts of the motor network, reflecting the cerebellar, pyramidal and extrapyramidal signs. A correlation analysis revealed a clear association between the clinical cerebellar, extrapyramidal and psychiatric scores and degeneration in specific areas. Two degeneration patterns were found as follows: regarding motor dysfunction, atrophy of the grey matter involved mainly the cerebellum and other motor networks, in particular the basal ganglia. In contrast, correlations with psychiatric scores revealed grey matter degeneration patterns in the frontal and temporal lobe, the cuneus and cingulum. Most interestingly, there was a highly significant correlation between the clinical Mini-Mental State Examination scores and atrophy of the nucleus accumbens, probably accounting for the leading psychiatric signs.

Volume versus surface-based cortical thickness measurements: A comparative study with healthy controls and multiple sclerosis patients.

The cerebral cortex is a highly folded outer layer of grey matter tissue that plays a key role in cognitive functions. In part, alterations of the cortex during development and disease can be captured by measuring the cortical thickness across the whole brain. Available software tools differ with regard to labor intensity and computational demands. In this study, we compared the computational anatomy toolbox (CAT), a recently proposed volume-based tool, with the well-established surface-based tool FreeSurfer. We observed that overall thickness measures were highly inter-correlated, although thickness estimates were systematically lower in CAT than in FreeSurfer. Comparison of multiple sclerosis (MS) patients with age-matched healthy control subjects showed highly comparable clusters of MS-related thinning for both methods. Likewise, both methods yielded comparable clusters of age-related cortical thinning, although correlations between age and average cortical thickness were stronger for FreeSurfer. Our data suggest that, for the analysis of cortical thickness, the volume-based CAT tool can be regarded a considerable alternative to the well-established surface-based FreeSurfer tool.

Bilateral grey-matter increase in the putamen in primary blepharospasm.

BACKGROUND: Primary blepharospasm is a focal dystonia characterised by excessive involuntary closure of the eyelids. The pathophysiology of primary blepharospasm is unresolved. AIM: To pinpoint grey-matter changes that are associated with primary blepharospasm. METHODS: 16 right-handed patients with primary blepharospasm (mean age 67.4 (SD 4.3) years; 12 women) were compared with 16 healthy volunteers matched for sex and age. High-resolution T1-weighted magnetic resonance imaging of each participant was obtained and analysed by voxel-based morphometry, a method to detect regionally specific differences in grey matter between patients and control group. To evaluate whether the identified grey-matter changes were correlated with the duration of primary blepharospasm or botulinum neurotoxin treatment (BoNT), separate regression analyses were carried out. RESULTS: In patients with primary blepharospasm, grey-matter increase in the putamina was observed, whereas regression analyses did not indicate a correlation between grey-matter increases and the duration of primary blepharospasm or BoNT. Grey-matter decrease was detected in the left inferior parietal lobule; here regression analyses of grey-matter decrease showed a significant (p = 0.013) correlation of grey-matter decrease with the duration of BoNT. CONCLUSIONS: The data suggest structural changes in primary blepharospasm and point to a crucial role of the putamen for the pathophysiology of this focal dystonia.

Hippocampal volume in chronic posttraumatic stress disorder (PTSD): MRI study using two different evaluation methods.

UNLABELLED: The hippocampus is discussed as one of the key regions in the pathogenesis of Posttraumatic Stress Disorder (PTSD). MRI results concerning the volume of the hippocampus are, however, inconsistent. This may be due to the heterogeneity of patients' traumata or postprocessing of the imaging data. To overcome these problems, the present study investigates volume changes in well-characterized chronic PTSD patients in comparison to controls using two different evaluation methods. MATERIAL AND METHODS: 15 patients with chronic PTSD, traumatized at the same air show plane crash in 1988 (Ramstein, Germany), and 15 matched healthy controls participated in this study. All patients suffered from significant impairment by the PTSD; none had a history of drug or alcohol abuse. Hippocampus volume changes were processed by a semi-automated standard procedure performed with BRAINS2 as well as the voxel based morphometry (VBM) using SPM2. RESULTS: No differences in total brain grey or white matter were detected between patients and controls. No differences in total hippocampal volume or in right and left parts were seen, even when hippocampal volumes were corrected by total brain volume or correlated with clinical data. Finally, no significant differences were detected between patients and controls in hippocampal regions using VBM. DISCUSSION: This is the first study examining long-term changes in hippocampal volumes in chronic PTSD patients compared to matched controls using two different evaluation methods. Neither conventional volumetry nor VBM could detect any differences in the volume and structure. This supports the hypothesis that previously described hippocampal volume reduction is not necessarily due to PTSD or at least that, after 15 years, volume changes have been restored or have not yet developed.

Supporting evidence for the model of cognitive dysmetria in schizophrenia--a structural magnetic resonance imaging study using deformation-based morphometry.

The aim of the study was to investigate whether there is any structural evidence for the model of 'cognitive dysmetria' in schizophrenia if an automatic whole-brain analysis method is used. High-resolution magnetic resonance scans were obtained for 75 schizophrenic patients and 75 controls. These data were analysed using the recently developed deformation-based morphometry allowing the assessment of volumetric differences without a priori definition of regions of interest. When compared with controls, we found reduced volumes in patients with schizophrenia in the frontal lobe (gyrus frontalis superior, medius and medialis), the temporal lobe (gyrus temporalis superior and inferior), the thalamus, the left cerebellar hemisphere and the right cerebellar vermis. There was an increase in volume in the right putamen. To date, this is the first structural magnetic resonance imaging study to demonstrate that the three key-elements of the model of cognitive dysmetria--frontal lobe, thalamus, and cerebellum--are reduced in volume in schizophrenic patients. This highlights the importance of this concept for future investigations.

Time estimation in schizophrenia: an fMRI study at adjusted levels of difficulty.

fMRI was performed in nine male schizophrenia patients and 15 healthy male controls during an auditory time estimation (timing), a frequency (i.e. pitch) discrimination task, and rest. An adaptive psychophysical approach, the weighted up-down method, was used to adjust individual performance to a level of 75% probability for correct answers. Although performing on the same level of individual difficulty, schizophrenia patients revealed less activations in prefrontal cortex and caudate nucleus, comparing time vs rest. Timing specific differences (i.e. timing vs pitch) between patients and controls were found in the posterior putamen, anterior thalamus, and right medial prefrontal cortex, with patients showing relative hypoactivity. Impairment in time estimation in schizophrenia might be mediated by specific fronto-thalamo-striatal dysfunction.

Increased excitability in the primary motor cortex and supplementary motor area in patients with phantom limb pain after upper limb amputation.

Using functional magnetic resonance imaging and single slice FLASH technique, we investigated reorganization of the hand representation of the primary sensorimotor cortex (SMC) in 16 patients with upper extremity amputation. Patients were asked to perform finger tapping with the intact hand, repetitive eye closing and anteflexion of the amputation stump or intact shoulder. Six normal volunteers served as control. In the normal volunteers activations during shoulder anteflexion, finger tapping and eye closure were located within the central sulcus in a medio-lateral fashion. Patients demonstrated invasion of the face or shoulder representation into the hand representation of the amputated limb. Eight phantom limb pain patients showed significantly greater activation in SMC and supplementary motor area (SMA) in contrast to eight patients without phantom limb pain. We conclude, that different parts of the motor system are affected in patients with phantom limb pain--possibly in the sense of an up-regulation of excitability.

Brain activation during cognitive stimulation with the Wisconsin Card Sorting Test--a functional MRI study on healthy volunteers and schizophrenics.

It has been demonstrated by single photon emission computed tomography (SPECT) and positron emission tomography (PET) that frontal brain regions are stimulated during performance of the Wisconsin Card Sorting Test (WCST). The WCST is also regarded as one of the standard tests for the assessment of frontal activity in brain imaging studies of schizophrenia. In this study cerebral activation was assessed by means of functional magnetic resonance imaging (fMRI). In healthy volunteers WCST stimulation resulted in a right lateralized frontal activation. In 13 chronic schizophrenics on stable neuroleptic medication, a lack of activation in the right prefrontal cortex and--as a trend--an increased left temporal activity during execution of the WCST was noted compared to controls. Since a one-slice technique was used, no information about the activation pattern in adjacent brain regions was obtained. However, as fMRI possesses a superior spatial resolution compared to SPECT and PET, the anatomical localization of the activation effect in the measured slice can be defined more precisely. Beside these methodological considerations, the results are discussed in relation to prior findings of a reduced ability of schizophrenics to coordinate cerebral function.

Decreased frontal activation in schizophrenics during stimulation with the continuous performance test--a functional magnetic resonance imaging study.

The Continuous Performance Test (CPT) has become an essential constituent of the neuropsychological investigation of schizophrenia. Also, a vast number of brain imaging studies, mostly PET investigations, have employed the CPT as a cognitive challenge and established a relative hypofrontality in schizophrenics compared to controls. The aim of the present investigation was to clarify whether this predescribed hypofrontality could also be verified using functional magnetic resonance imaging (fMRI). 20 healthy volunteers and 14 schizophrenics on stable neuroleptic medication were included. Imaging was performed using the CPT-double-T-version and a clinical 1.5 T MRI-scanner with a single slice technique and a T(2)*-weighted gradient-echo-sequence. The schizophrenics exhibited a decreased activation in the right mesial prefrontal cortex, the right cingulate and the left thalamus compared to controls. These results obtained by fMRI are discussed in relation to published findings using PET.

Gray matter alterations in parosmia.

Parosmia is a common olfactory disorder. In this condition, odors are perceived in a different quality than usual. This distorted olfactory percept is typically reported to be unpleasant. Little is known about the pathophysiology of this phenomenon. Previous studies demonstrated smaller volumes of the olfactory bulbs in patients with parosmia compared to subjects without parosmia. In order to investigate structural brain alterations in areas beyond the olfactory bulb, in the current study voxel-based morphometry was applied. A group of 22 parosmic patients was compared with control subjects matched for age- and sex, who exhibited a similar performance in olfactory tests. Performing a whole brain analysis, we found profound gray matter volume loss in the left anterior insula in parosmic patients. In an additional volume of interest analysis including primary and secondary olfactory areas, we also found volume loss in the right anterior insula, the anterior cingulate cortex, the hippocampus bilaterally, and the left medial orbitofrontal cortex. Many of these areas are critically involved in olfactory quality discrimination and odor memory. The present results indicate that reduced gray matter volume in brain regions supporting odor discrimination and memory is related to disturbed olfactory sensation in parosmia.

Voxel-based morphometry in individual patients: a pilot study in early Huntington disease.

BACKGROUND AND PURPOSE: Voxel-based morphometry (VBM) has proved a powerful method to detect subtle changes of gray matter (GM) at the group level but the role of VBM for the detection of GM changes in single subjects, especially in those with suspected neurodegenerative disorder, remains uncertain. Here, we performed single subject analyses in 22 patients in early stages of Huntington disease (HD), a neurodegenerative disorder with a well-known and characteristic pattern of GM loss. MATERIALS AND METHODS: We applied an ANCOVA with age and gender as covariates and corrected for multiple statistical tests by false discovery rate (P < 0.05). Each patient was compared to 133 healthy controls. The same procedure was applied to 22 of the controls matched for age and gender in a pair-wise manner. RESULTS: Our analyses yielded biologically plausible results in HD patients in which GM decrease within the caudate nucleus could be identified in 15 of the 16 most affected patients while GM decrease was found in only 1 control subject. Lowering the size of the control group yielded comparable results with 99 and 66 control subjects whereas sensitivity decreased with 33 control subjects. CONCLUSIONS: Our pilot study demonstrates a potential role of VBM for the detection of cerebral GM changes in single subjects with suspected neurodegenerative disorder.