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Neurological soft signs (NSS) are related to grey matter and functional brain abnormalities in schizophrenia. Studies in healthy subjects suggest, that NSS are also linked to white matter. However, the association between NSS and white matter abnormalities in schizophrenia remains to be elucidated. The present study investigated, if NSS are related to white matter alterations in patients with schizophrenia. The total sample included 42 healthy controls and 41 patients with schizophrenia. We used the Neurological Evaluation Scale (NES), and we acquired diffusion weighted magnetic resonance imaging to assess white matter on a voxel-wise between subject statistic. In patients with schizophrenia, linear associations between NES with fractional anisotropy (FA), radial, axial, and mean diffusivity were analyzed with tract-based spatial statistics while controlling for age, medication dose, the severity of the disease, and motion. The main pattern of results in patients showed a positive association of NES with all diffusion measures except FA in important motor pathways: the corticospinal tract, internal capsule, superior longitudinal fascicle, thalamocortical radiations and corpus callosum. In addition, exploratory tractography analysis revealed an association of the right aslant with NES in patients. These results suggest that specific white matter alterations, that is, increased diffusivity might contribute to NSS in patients with schizophrenia.

Axonal myelination and repair, critical processes for brain development, maturation, and aging, remain controlled by sexual hormones. Whether this influence is reflected in structural brain differences between sexes, and whether it can be quantified by neuroimaging, remains controversial. Diffusion-weighted magnetic resonance imaging (dMRI) is an in vivo method that can track myelination changes throughout the lifespan. We utilize a large, multisite sample of harmonized dMRI data (n = 551, age = 9–65 years, 46% females/54% males) to investigate the influence of sex on white matter (WM) structure. We model lifespan trajectories of WM using the most common dMRI measure fractional anisotropy (FA). Next, we examine the influence of both age and sex on FA variability. We estimate the overlap between male and female FA and test whether it is possible to label individual brains as male or female. Our results demonstrate regionally and spatially specific effects of sex. Sex differences are limited to limbic structures and young ages. Additionally, not only do sex differences diminish with age, but tracts within each subject become more similar to one another. Last, we show the high overlap in FA between sexes, which implies that determining sex based on WM remains open.

Catatonia is a complex psychomotor symptom frequently observed in schizophrenia. Neural activity within the motor system is altered in catatonia. Likewise, white matter (WM) is also expected to be abnormal. The aim of this study was to test, if schizophrenia patients with catatonia show specific WM alterations. Forty-eight patients with schizophrenia and 43 healthy controls were included. Catatonia was currently present in 13 patients with schizophrenia. Tract-Based Spatial Statistics was used to test for differences in fractional anisotropy (FA) in the whole brain between the three groups. We detected a group effect (F-test) of WM within the corpus callosum (CC). In the t-test, patients with catatonia showed higher FA in many left lateralized WM clusters involved in motor behaviour compared to patients without catatonia, including the CC, internal and external capsule, superior longitudinal fascicle (SLF) and corticospinal tract (CST). Similarly, patients with catatonia showed also higher FA in the left internal capsule and left CST compared to healthy controls. In contrast, the group comparison between patients without catatonia and healthy controls revealed lower FA in many right lateralized clusters, comprising the CC, internal capsule, SLF, and inferior longitudinal fascicle in patients without catatonia. Our results are in line with the notion of an altered motor system in catatonia. Thus, our study provides evidence for increased WM connectivity, especially in motor tracts in schizophrenia patients with catatonia.

Diffusion MRI studies consistently report group differences in white matter between individuals diagnosed with schizophrenia and healthy controls. Nevertheless, the abnormalities found at the group‐level are often not observed at the individual level. Among the different approaches aiming to study white matter abnormalities at the subject level, normative modeling analysis takes a step towards subject‐level predictions by identifying affected brain locations in individual subjects based on extreme deviations from a normative range. Here, we leveraged a large harmonized diffusion MRI dataset from 512 healthy controls and 601 individuals diagnosed with schizophrenia, to study whether normative modeling can improve subject‐level predictions from a binary classifier. To this aim, individual deviations from a normative model of standard (fractional anisotropy) and advanced (free‐water) dMRI measures, were calculated by means of age and sex‐adjusted z‐scores relative to control data, in 18 white matter regions. Even though larger effect sizes are found when testing for group differences in z‐scores than are found with raw values (p, We use a large (n = 1113) harmonized diffusion MRI dataset of individuals diagnosed with schizophrenia and healthy controls, in order to study the predictive performance of a normative modeling approach. This approach compares each individual with distribution derived from healthy controls to derive measures of deviation from the normal distribution. Our results show that combining deviation information from different white matter tracts, while using multiple imaging measures simultaneously, improves prediction performance, and could therefore aid in subject‐level classification.

Objective Individuals with depression exhibit numerous interpersonal deficits. As effective use of gestures is critical for social communication, it is possible that depressed individuals’ interpersonal deficits may be due to deficits in gesture performance. The present study thus compared gesture performance of depressed patients and controls and examined whether these deficits relate to cognitive and other domains of dysfunction. Methods Gesture performance was evaluated in 30 depressed patients and 30 controls using the Test of Upper Limb Apraxia (TULIA). Clinical rating scales were assessed to determine if gesture deficits were associated with motor, cognitive or functional outcomes. Results Compared to controls, depressed patients exhibited impaired gesture performance with 2/3 of the patients demonstrating gesture deficits. Within depressed patients, gesture performance was highly correlated with working memory abilities. In contrast, no association between gesture performance and gestural knowledge, psychomotor retardation, depression severity, or frontal dysfunction was observed in patients. Limitations This is a cross-sectional study and a larger size would have allowed for confident detection of more subtle, but potentially relevant effects. Conclusion Gesture performance is impaired in depressed patients, and appears to be related to poor working memory abilities, suggesting a disruption in the retrieval of gestural cues indicative of a distinct clinical phenomenon that might be related to social functioning.

Paranoia is a frequent and highly distressing experience in psychosis. Models of paranoia suggest limbic circuit pathology. Here, we tested whether resting-state functional connectivity (rs-fc) in the limbic circuit was altered in schizophrenia patients with current paranoia. We collected MRI scans in 165 subjects including 89 patients with schizophrenia spectrum disorders (schizophrenia, schizoaffective disorder, brief psychotic disorder, schizophreniform disorder) and 76 healthy controls. Paranoia was assessed using a Positive And Negative Syndrome Scale composite score. We tested rs-fc between bilateral nucleus accumbens, hippocampus, amygdala and orbitofrontal cortex between groups and as a function of paranoia severity. Patients with paranoia had increased connectivity between hippocampus and amygdala compared to patients without paranoia. Likewise, paranoia severity was linked to increased connectivity between hippocampus and amygdala. Furthermore, paranoia was associated with increased connectivity between orbitofrontal and medial prefrontal cortex. In addition, patients with paranoia had increased functional connectivity within the frontal hubs of the default mode network compared to healthy controls. These results demonstrate that current paranoia is linked to aberrant connectivity within the core limbic circuit and prefrontal cortex reflecting amplified threat processing and impaired emotion regulation. Future studies will need to explore the association between limbic hyperactivity, paranoid ideation and perceived stress.

Abnormal fine motor function is a frequent finding in schizophrenia and has been linked to structural and functional brain alterations. However, whether fine motor function is related to functional alterations within the motor system remains unclear. The aim of this study was to assess whether abnormalities in resting-state functional connectivity are present in schizophrenia patients and to investigate how these abnormalities may be related to fine motor function. We examined 19 schizophrenia patients and 16 healthy controls using resting-state functional connectivity for 11 bilateral regions of interest. Fine motor function was assessed on a set of copying tasks and the Symbol-Digit-Substitution Test. We found significantly reduced functional connectivity between the left caudate nucleus and bilateral dorsolateral prefrontal cortex (DLPFC) and between the left putamen and bilateral supplementary motor area (SMA) proper in patients compared to controls. Altered connectivity from DLPFC to caudate nucleus was related to fine motor tasks, which are sensitive to psychomotor speed, whereas aberrant connectivity between the SMA proper and putamen was associated to both, fine motor task, which are sensitive to psychomotor speed and to speed of information processing. Our findings emphasize the role of fronto-striatal connections in the pathogenesis of fine motor impairments in schizophrenia.

Hand gestures are an integral part of social interactions and communication. Several imaging studies in healthy subjects and lesion studies in patients with apraxia suggest the praxis network for gesture production, involving mainly left inferior frontal, posterior parietal and temporal regions. However, little is known about the structural connectivity underlying gesture production. We recruited 41 healthy participants and 39 patients with schizophrenia. All participants performed a gesture production test, the Test of Upper Limb Apraxia, and underwent diffusion tensor imaging. We hypothesized that gesture production is associated with structural network connectivity as well as with tract integrity. We defined the praxis network as an undirected graph comprised of 13 bilateral regions of interest and derived measures of local and global structural connectivity and tract integrity from Finsler geometry. We found an association of gesture deficit with reduced global and local efficiency of the praxis network. Furthermore, reduced tract integrity, for example in the superior longitudinal fascicle, arcuate fascicle or corpus callosum were related to gesture deficits. Our findings contribute to the understanding of structural correlates of gesture production as they first present diffusion tensor imaging data in a combined sample of healthy subjects and a patient cohort with gestural deficits.

Patients with schizophrenia frequently present deficits in gesture production and interpretation, greatly affecting their communication skills. As these gesture deficits can be found early in the course of illness and as they can predict later outcomes, exploring their neural basis may lead to a better understanding of schizophrenia. While gesturing has been reported to rely on a left lateralized network of brain regions, termed praxis network, in healthy subjects and lesioned patients, studies in patients with schizophrenia are sparse. It is currently unclear whether within-network connectivity at rest is linked to gesture deficit. Here, we compared the functional connectivity between regions of the praxis network at rest between 46 patients and 44 healthy controls. All participants completed a validated test of hand gesture performance before resting-state functional magnetic resonance imaging (fMRI) was acquired. Patients performed gestures poorer than controls in all categories and domains. In patients, we also found significantly higher resting-state functional connectivity between left precentral gyrus and bilateral superior and inferior parietal lobule. Likewise, patients had higher connectivity from right precentral gyrus to left inferior and bilateral superior parietal lobule (SPL). In contrast, they exhibited lower connectivity between bilateral superior temporal gyrus (STG). Connectivity between right precentral gyrus and left SPL, as well as connectivity between bilateral STG, correlated with gesture performance in healthy controls. We failed to detect similar correlations in patients. We suggest that altered resting-state functional connectivity within the praxis network perturbs correct gesture planning in patients, reflecting the gesture deficit often seen in schizophrenia.

Objective Repetitive subconcussive head impacts (RSHI) may lead to structural, functional, and metabolic alterations of the brain. While differences between males and females have already been suggested following a concussion, whether there are sex differences following exposure to RSHI remains unknown. The aim of this study was to identify and to characterize sex differences following exposure to RSHI. Methods Twenty-five collegiate ice hockey players (14 males and 11 females, 20.6 ± 2.0 years), all part of the Hockey Concussion Education Project (HCEP), underwent diffusion-weighted magnetic resonance imaging (dMRI) before and after the Canadian Interuniversity Sports (CIS) ice hockey season 2011–2012 and did not experience a concussion during the season. Whole-brain tract-based spatial statistics (TBSS) were used to compare pre- and postseason imaging in both sexes for fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD). Pre- and postseason neurocognitive performance were assessed by the Immediate Post-Concussion Assessment and Cognitive Test (ImPACT). Results Significant differences between the sexes were primarily located within the superior longitudinal fasciculus (SLF), the internal capsule (IC), and the corona radiata (CR) of the right hemisphere (RH). In significant voxel clusters (p, Highlights • This study explores sex differences following repetitive subconcussive head impacts. • Decreases in FA were observed in females over the course of one ice hockey season. • Females also showed increases in MD, AD, and RD over the course of the season. • In contrast, males showed no significant changes in these diffusion measures. • The results suggest sex differences in structural alterations following subconcussion.

Schizophrenia is characterized by deficits in gesturing that is important for nonverbal communication. Research in healthy participants and brain-damaged patients revealed a left-lateralized fronto-parieto-temporal network underlying gesture performance. First evidence from structural imaging studies in schizophrenia corroborates these results. However, as of yet, it is unclear if cortical thickness abnormalities contribute to impairments in gesture performance. We hypothesized that patients with deficits in gesture production show cortical thinning in 12 regions of interest (ROIs) of a gesture network relevant for gesture performance and recognition. Forty patients with schizophrenia and 41 healthy controls performed hand and finger gestures as either imitation or pantomime. Group differences in cortical thickness between patients with deficits, patients without deficits, and controls were explored using a multivariate analysis of covariance. In addition, the relationship between gesture recognition and cortical thickness was investigated. Patients with deficits in gesture production had reduced cortical thickness in eight ROIs, including the pars opercularis of the inferior frontal gyrus, the superior and inferior parietal lobes, and the superior and middle temporal gyri. Gesture recognition correlated with cortical thickness in fewer, but mainly the same, ROIs within the patient sample. In conclusion, our results show that impaired gesture production and recognition in schizophrenia is associated with cortical thinning in distinct areas of the gesture network., Highlights • Impairments in gesture production and recognition in schizophrenia are related to altered brain structure. • Brain alterations in schizophrenia are located in areas that are generally damaged in apraxia. • Schizophrenia patients with gesture deficits show cortical thinning of several regions in the gesture network. • Deficits of gesture production and recognition are both related to a fronto-parieto-temporal gesture network.

Motor abnormalities are frequently observed in schizophrenia and structural alterations of the motor system have been reported. The association of aberrant motor network function, however, has not been tested. We hypothesized that abnormal functional connectivity would be related to the degree of motor abnormalities in schizophrenia. In 90 subjects (46 patients) we obtained resting stated functional magnetic resonance imaging (fMRI) for 8 minutes 40 seconds at 3T. Participants further completed a motor battery on the scanning day. Regions of interest (ROI) were cortical motor areas, basal ganglia, thalamus and motor cerebellum. We computed ROI-to-ROI functional connectivity. Principal component analyses of motor behavioral data produced 4 factors (primary motor, catatonia and dyskinesia, coordination, and spontaneous motor activity). Motor factors were correlated with connectivity values. Schizophrenia was characterized by hyperconnectivity in 3 main areas: motor cortices to thalamus, motor cortices to cerebellum, and prefrontal cortex to the subthalamic nucleus. In patients, thalamocortical hyperconnectivity was linked to catatonia and dyskinesia, whereas aberrant connectivity between rostral anterior cingulate and caudate was linked to the primary motor factor. Likewise, connectivity between motor cortex and cerebellum correlated with spontaneous motor activity. Therefore, altered functional connectivity suggests a specific intrinsic and tonic neural abnormality in the motor system in schizophrenia. Furthermore, altered neural activity at rest was linked to motor abnormalities on the behavioral level. Thus, aberrant resting state connectivity may indicate a system out of balance, which produces characteristic behavioral alterations.

Background Semantic processing anomalies, clinically reflected by disorganized speech are a core symptom of schizophrenia. In the light of accumulating evidence on its prominent role in semantic processing, aberrant structural integrity of the ventral language stream may reflect impaired semantic processing in schizophrenia spectrum disorders (SSD). Methods Comparison of white matter tract integrity in SSD patients and healthy controls using diffusion tensor imaging combined with probabilistic fiber tractography. For the ventral language stream, we assessed the inferior fronto-occipital fasciculus [IFOF], inferior longitudinal fasciculus, and uncinate fasciculus. The arcuate fasciculus and corticospinal tract were used as control tracts. In SSD patients, the relationship between semantic processing impairments and tract integrity was analyzed separately. Three-dimensional tract reconstructions were performed in 45/44 SSD patients/controls (“Bern sample”) and replicated in an independent sample of 24/24 SSD patients/controls (“Basel sample”). Results Multivariate analyses of fractional anisotropy, mean, axial, and radial diffusivity of the left IFOF showed significant differences between SSD patients and controls (p Discussion This work provides direct evidence for the importance of the integrity of the ventral language stream, in particular the left IFOF, in semantic processing deficits in SSD.

Background The association of white matter (WM) abnormalities with clinical variables in schizophrenia (SCZ) is poorly understood. We investigated the clinical correlates of WM impairments using imaging data of 597 patients with SCZ and 490 healthy controls (HC). We focused on lifelong changes of WM (measured by Fractional Anisotropy [FA]) in SCZ and compared it to that of HC. We investigated how age, duration of illness, and medication influence WM trajectories, and examined how structural impairments are related to symptoms and cognition. Last, we tested for the role of sex in structure-function interactions. Methods Diffusion-weighted images and clinical measurements were collected as part of 13 independent studies, and data was harmonized across all sites. We registered images to the IIT Human Brain Atlas and averaged FA for forceps major, forceps minor, cingulum, inferior fronto-occipital fasciculus, inferior longitudinal fasciculus, superior longitudinal fasciculus (SLF) and uncinate fasciculus. First, we modeled the FA age trajectory of each tract in HC and used it to regress out the effect of age in patients. The residuals in the FA values were utilized for further analyses. We conducted mediator regression analyses with FA as the dependent variable, sex as a covariate, and age and duration of illness as the independent variables. Next, patients were grouped based on Chlorpromazine equivalent dosage (CPZ) and CPZ group was added to the regression model. To examine the association between structure and function, a structural equation model (SEM) was used, with cognition as a mediator. Last, all analyses were repeated for males and females separately. Results Regression analyses revealed a significant influence of duration of illness on the forceps major (T=3.24, p Adding CPZ to the model displayed a significant effect of medication on forceps major (T=3.93, p For SEM, FA of all tracts was used to represent structural impairment, and symptom scores were used to reflect functional impairment. All data paths were calculated with an asymptotically distribution-free model. The overall model fit was acceptable (RMSEA =.09) with a medium-strong effect of structural impairment on functional impairment (standardized estimate=.44). When separating sexes, males showed a significant association of duration of illness and FA. Females displayed a stronger influence of structural impairment on functional impairment (standardized estimate: males = .29, females =.52), and cognition had an impact on this relationship for females only. Discussion The effect of duration of illness on specific WM tracts suggests a progressive, neurodegenerative pathology, which might contribute to the devastating effects of chronicity. Medication seems to have only a small, localized effect on corpus callosum WM integrity. However, since our analysis used cross-sectional CPZ measures, future studies should include measurements of lifetime dosage. The observed impact of WM abnormalities on function further highlights the importance of WM for SCZ pathology. The association of structure and function seems sex-specific. Men show a stronger effect of chronicity. For females, cognition mediates the effect of structure on function, suggesting the role of cognitive reserve. Our approach provides the first step towards evidence-based medicine, by demonstrating the apparent relationship between structural pathology and functional outcome and suggesting possible mediators of this relationship, including duration of illness, cognition, medication, and sex.

Social interaction is impaired in schizophrenia, including the use of hand gestures, which is linked to poor social perception and outcome. Brain imaging suggests reduced neural activity in a left-lateralized frontoparietal network during gesture preparation; therefore, gesturing might be improved through facilitation of left hemispheric brain areas or via disruption of interhemispheric inhibition from the right homolog. This study tested whether repetitive transcranial magnetic stimulation (rTMS) protocols would improve gesture performance in schizophrenia. This randomized, placebo-controlled, double-blind, crossover trial applied 3 different protocols of rTMS separated by 48 h. Twenty right-handed schizophrenia patients and 20 matched healthy controls received facilitatory intermittent theta burst stimulation (iTBS) over the left inferior frontal gyrus (IFG), inhibitory continuous theta burst stimulation (cTBS) over right inferior parietal lobe (IPL), and placebo over left IPL in randomized order. Primary outcome was change in the test of upper limb apraxia (TULIA), rated from video recordings of hand gesture performance. Secondary outcome was change in manual dexterity using the coin rotation task. Participants improved on both tasks following rTMS compared with baseline. Only patients improved gesture performance following right IPL cTBS compared with placebo (P = .013). The results of the coin rotation parallel those of the TULIA, with improvements following right IPL cTBS in patients (P = .001). Single sessions of cTBS on the right IPL substantially improved both gesture performance accuracy and manual dexterity. The findings point toward an inhibition of interhemispheric rivalry as a potential mechanism of action.

Several prominent theories of schizophrenia suggest that structural white matter pathologies may follow a developmental, maturational, and/or degenerative process. However, a lack of lifespan studies has precluded verification of these theories. Here, we analyze the largest sample of carefully harmonized diffusion MRI data to comprehensively characterize age-related white matter trajectories, as measured by fractional anisotropy (FA), across the course of schizophrenia. Our analysis comprises diffusion scans of 600 schizophrenia patients and 492 healthy controls at different illness stages and ages (14-65 years), which were gathered from 13 sites. We determined the pattern of age-related FA changes by cross-sectionally assessing the timing of the structural neuropathology associated with schizophrenia. Quadratic curves were used to model between-group FA differences across whole-brain white matter and fiber tracts at each age; fiber tracts were then clustered according to both the effect-sizes and pattern of lifespan white matter FA differences. In whole-brain white matter, FA was significantly lower across the lifespan (up to 7%; p

The core symptoms of schizophrenia spectrum disorders (SSD) include abnormal semantic processing which may rely on the ventral language stream of the human brain. Thus, structural disruption of the ventral language stream may play an important role in semantic deficits observed in SSD patients. Therefore, we compared white matter tract integrity in SSD patients and healthy controls using diffusion tensor imaging combined with probabilistic fiber tractography. For the ventral language stream, we assessed the inferior fronto-occipital fasciculus [IFOF], inferior longitudinal fasciculus, and uncinate fasciculus. The arcuate fasciculus and corticospinal tract were used as control tracts. In SSD patients, the relationship between semantic processing impairments and tract integrity was analyzed separately. Three-dimensional tract reconstructions were performed in 45/44 SSD patients/controls ("Bern sample") and replicated in an independent sample of 24/24 SSD patients/controls ("Basel sample"). Multivariate analyses of fractional anisotropy, mean, axial, and radial diffusivity of the left IFOF showed significant differences between SSD patients and controls (p(FDR-corr) < 0.001, ηp2 = 0.23) in the Bern sample. Axial diffusivity (AD) of the left UF was inversely correlated with semantic impairments (r = -0.454, p(FDR-corr) = 0.035). In the Basel sample, significant group differences for the left IFOF were replicated (p < .01, ηp2 = 0.29), while the correlation between AD of the left IFOF and semantic processing decline (r = -0.376, p = .09) showed a statistical trend. No significant effects were found for the dorsal language stream. This is direct evidence for the importance of the integrity of the ventral language stream, in particular the left IFOF, in semantic processing deficits in SSD.

BACKGROUND: Evidence for age related brain white matter (WM) abnormalities in schizophrenia (SZ) has been observed using MRI, and interpreted by various studies as reflecting either developmental, maturational and/or degenerative pathology. Such conflicting findings, mostly due to lack of longitudinal data and statistical power, have hindered consensus on patterns and trajectories of brain dysfunction in SZ. ‘Big Data’ provides a new and powerful means to identify subtle abnormalities across the course of SZ. We have accumulated and processed, what we believe the biggest, to-date, sample of thoughtfully harmonized diffusion MRI (dMRI) cross sectional data, and performed the study aimed at comprehensively characterizing age-related WM changes (trajectories) through the course of SZ. METHODS: Our dMRI data comprises a total of 1092 participants, aged between 14 and 65. This includes 600 individuals with SZ at different illness stages (383 males, 217 females, age: 31.3+/- 12) and 492 healthy controls-HC (275 males, 217 females, age: 29.8+/-13), from 13 different sites. Preprocessing and dMRI data harmonization based on the rotation invariant spherical harmonics were used to remove the nonlinear scanner and sequence differences across sites. All harmonized data was registered to a common template. Fractional Anisotropy (FA) for Whole Brain (WB) and 14 individual WM regions of interest (ROIs) were computed using a probabilistic tractography atlas. We modeled FA changes over age by quadratic curves (the best fitted model: highest adjusted r^2) and fitted separately to SZ and HC. Peak age and upper and lower bounds of the model were estimated after 5000 bootstraps. FA% differences were modeled at each age between SZ and HC for WB and each ROI, while sex was treated as a confound. The effect sizes (Cohen’s d) between SZ and HC were also computed at each age. Finally, WM pathologies (i.e. based on between-group differences) were clustered into three groups according to d occurring along trajectory using kmeans. RESULTS: In WB, FA was lower in SZ comparing to HC at each age, but the percentage differences as well as d varied significantly by age (range of %FA change = [1.5 7], d = [.5 1.8]). Also, WB peaks of FA differed between groups, observed at the age of 33 in HC, shifted to the age of 27 in SZ. Three groups emerged from examining the degree of WM pathology across the age trajectories in ROIs, characterized by: 1) .3

Background Aberrant motor function is an integral part of Schizophrenia. In fact, abnormalities are frequently found in patients, in populations at risk, and in unaffected relatives. Motor abnormalities are suspected to be relevant for the clinical outcome and could probably predict the conversion from at-risk individuals to schizophrenia. Furthermore, motor function and has been argued as endophenotype of the disorder. Yet, which particular motor domain may classify as a potential endophenotype is unknown. We aimed to compare schizophrenia patients, unaffected first degree relatives and healthy controls for different motor domains. We expected impairments in all domains in patients and in some domains in relatives. Methods We included 43 schizophrenia patients, 34 unaffected first degree relatives of schizophrenia patients and 29 healthy control subjects, matched for age, gender and education level. We compared motor function of five domains between the groups. The domains comprise neurological soft sings (NSS), abnormal involuntary movements (dyskinesia), Parkinsonism, complex fine motor function applying the coin rotation task as well as finger tapping. Furthermore, we tested the association of motor function of the five domains with working memory, frontal lobe function and nonverbal intelligence for each group separately using within-group bivariate correlations. Results Schizophrenia patients showed poorer motor function in all tested domains compared to healthy controls. First-degree relatives had intermediate ratings with aberrant function in two motor domains. In detail, relatives had significantly more NSS and performed poorer in the finger tapping task than controls. In contrast, in relatives complex fine motor function was intact. Relatives did not differ from controls in dyskinesia or Parkinsonism severity. Discussion Taken together, schizophrenia patients have motor abnormalities in all tested domains. Thus, motor abnormalities are a key element of the disorder. Likewise, first degree relatives presented motor deficits in two domains. A clear difference between relatives and healthy controls was found for NSS and finger tapping. Thus, NSS and finger tapping may be a potential marker of vulnerability for schizophrenia. The lack of association between genetic risk and dyskinesia or Parkinsonism suggests distinct pathobiological mechanisms in the various motor abnormalities in schizophrenia.

Introduction Aberrant motor function is an integral part of schizophrenia. In fact, abnormalities are frequently found in patients, in populations at risk, and in unaffected relatives. Motor abnormalities are suspected to be relevant for the clinical outcome and could probably predict the conversion from at-risk individuals to schizophrenia. Furthermore, motor function has been argued as endophenotype of the disorder. Yet, which particular motor domain may classify as a potential endophenotype is unknown. We aimed to compare schizophrenia patients, unaffected first-degree relatives and healthy controls for different motor domains. We expected impairments in all domains in patients and in some domains in relatives. Method We included 43 schizophrenia patients, 34 unaffected first-degree relatives of schizophrenia patients, and 29 healthy control subjects, matched for age, gender, and education level. We compared motor function of four motor domains between the groups. The domains comprise neurological soft signs (NSS), abnormal involuntary movements (dyskinesia), Parkinsonism, and fine motor function including simple [finger tapping (FT)] and complex fine motor function, (i.e., dexterity as measured with the coin rotation test). Furthermore, we tested the association of motor function of the four domains with working memory, frontal lobe function, and nonverbal intelligence for each group separately using within-group bivariate correlations. Results Schizophrenia patients showed poorer motor function in all tested domains compared to healthy controls. First-degree relatives had intermediate ratings with aberrant function in two motor domains. In detail, relatives had significantly more NSS and performed poorer in the FT task than controls. In contrast, complex fine motor function was intact in relatives. Relatives did not differ from controls in dyskinesia or Parkinsonism severity. Discussion Taken together, schizophrenia patients have motor abnormalities in all tested domains. Thus, motor abnormalities are a key element of the disorder. Likewise, first-degree relatives presented motor deficits in two domains. A clear difference between relatives and healthy controls was found for NSS and FT. Thus, NSS and FT may be potential markers of vulnerability for schizophrenia. The lack of association between genetic risk and dyskinesia or Parkinsonism suggests distinct pathobiological mechanisms in the various motor abnormalities in schizophrenia.

Background: Motor abnormalities are frequently observed in schizophrenia, providing hints on the outcome of the disorder. Motor signs are intrinsic to the disorder and associated with structural abnormalities in the cerebral motor system. This study investigated whether motor abnormalities were associated with aberrant functional connectivity.

Background Hand gestures are an integral part of social interactions and are involved in nonverbal and verbal communication. The convey language that is expressed by motor actions, and thus depend on the interplay of various brain regions. Several functional magnetic resonance imaging studies in healthy subjects suggest the praxis network for gesture production, involving distinct frontal, parietal and temporal regions. Lesions studies in subjects with apraxia, following left brain damage corroborate these findings. However, little is known about the structural connectivity underlying gesture production. We aimed to provide novel insights into the structural connectivity of the praxis network and how it is related to gesture production. Methods Our sample consisted of 41 healthy subjects and of 40 patients with schizophrenia, demonstrating gesture impairments and structural network abnormalities. All participants performed a gesture production test, the test of upper limb apraxia and underwent diffusion weighted magnetic resonance imaging. Finsler geometry was used to investigate structural connectivity and graph theory to estimate global and local efficiency of the praxis network, which consists of 13 bilateral regions of interest. Results Our findings showed an association of gesture production with network attributes and specific connections within the praxis network. Thus, global and local efficiency and most of the intra- and interhemispheric connections within the gesture network predicted gesture production across groups. Global efficiency of the praxis network further predicted gesture production only in the patient group. Local efficiency of many ROIs and connections of interest predicted production in patients at trend-level. In contrast, there were no significant or trend-level associations of gesture production with network attributes in controls. Discussion The results revealed an association of impaired gesture performance with structural alterations of the praxis network, including global and local efficiency and many connections of interest. Our findings are of great importance in the understanding of the structural correlates of gesture production and shed further light on the neural underpinnings of gesture deficits in a patient group with severe social deficits.

Introduction Schizophrenia patients frequently suffer from complex motor abnormalities including fine and gross motor disturbances, abnormal involuntary movements, neurological soft signs and parkinsonism. These symptoms occur early in the course of the disease, continue in chronic patients and may deteriorate with antipsychotic medication ( Walther and Strik, 2012 ). Furthermore gesture performance is impaired in patients, including the pantomime of tool use. Whether schizophrenia patients would show difficulties of actual tool use has not yet been investigated. Human tool use is complex and relies on a network of distinct and distant brain areas. We therefore aim to test if schizophrenia patients had difficulties in tool use and to assess associations with structural brain imaging using voxel based morphometry (VBM) and tract based spatial statistics (TBSS). Methods In total, 44 patients with schizophrenia (DSM-5 criteria; 59% men, mean age 38) underwent structural MR imaging and performed the Tool-Use test ( Randerath et al., 2011 ). The test examines the use of a scoop and a hammer in three conditions: pantomime (without the tool), demonstration (with the tool) and actual use (with a recipient object). T1-weighted images were processed using SPM8 and DTI-data using FSL TBSS routines. To assess structural alterations of impaired tool use we first compared gray matter (GM) volume in VBM and white matter (WM) integrity in TBSS data of patients with and without difficulties of actual tool use. Next we explored correlations of Tool use scores and VBM and TBSS data. Group comparisons were family wise error corrected for multiple tests. Correlations were uncorrected (p Results Tool use was impaired in schizophrenia (43.2% pantomime, 11.6% demonstration, 11.6% use). Impairment was related to reduced GM volume and WM integrity. Whole brain analyses detected an effect in the SMA in group analysis. Correlations of tool use scores and brain structure revealed alterations in brain areas of the dorso-dorsal pathway (superior occipital gyrus, superior parietal lobule, and dorsal premotor area) and the ventro-dorsal pathways (middle occipital gyrus, inferior parietal lobule) the action network, as well as the insula and the left hippocampus. Furthermore, significant correlations within connecting fiber tracts - particularly alterations within the bilateral corona radiata superior and anterior as well as the corpus callosum - were associated with Tool use performance. Conclusions Tool use performance was impaired in schizophrenia, which was associated with reduced GM volume in the action network. Our results are in line with reports of impaired tool use in patients with brain lesions particularly of the dorso-dorsal and ventro-dorsal stream of the action network. In addition an effect of tool use on WM integrity was shown within fiber tracts connecting regions important for planning and executing tool use. Furthermore, hippocampus is part of a brain system responsible for spatial memory and navigation.The results suggest that structural brain alterations in the common praxis network contribute to impaired tool use in schizophrenia ( Fig. 1 ).

Background Schizophrenia is associated with poor nonverbal communication. Impairments in the performance of hand gestures have been shown in 67% of patients with schizophrenia. These deficits are similar to those seen in Apraxia, which is often due to lesions in the inferior parietal (IPL) lobe, insula and inferior frontal gyrus (IFG). In Schizophrenia however, the neural correlates are unknown. Therefore, we investigated structural correlates of impaired gesture performance in schizophrenia. Methods In 43 patients with schizophrenia spectrum disorders, gesture performance was assessed by the comprehensive Test of Upper Limb Apraxia (TULIA). Performance was video recorded and blindly rated for accuracy. Structural brain imaging was measured in all patients using a 3-T MR Scanner. Grey matter density was correlated with TULIA scores using Whole-Brain Voxel-Based Morphometry (VBM) and total intracranial volume as covariate. White matter integrity was correlated with TULIA scores using Tract-Based Spatial Statistics (TBSS) and age as covariate. Results The TULIA total score correlated with grey matter density in several clusters of the praxis network at p p Conclusions Aberrant brain structure is associated with poor gesture performance in schizophrenia. Particularly in key regions of the praxis network, i.e. insula, parietal cortex, we detected correlations of gesture performance and grey and white matter markers. In addition, the anterior cingulate cortex grey matter was correlated to gesture performance, a region implicated in action planning and control. Therefore, specific brain structural alterations may contribute to deficits in nonverbal communication in schizophrenia ( Fig. 1 ).

Background Higher order processes such as recognition of gestures rely on a network of distinct and distant brain areas. Particularly the role of key regions such as the left inferior frontal gyrus (IFG) and the inferior parietal lobe is subject to ongoing debate. Schizophrenia patients suffer from impaired gesture performance and recognition. However, neural correlates of impaired gesture recognition have not yet been investigated. We therefore aim to test associations between structural brain imaging and postural knowledge in schizophrenia using voxel based morphometry (VBM) and tract based spatial statistics (TBSS). Methods In total, 44 patients with schizophrenia (DSM-5 criteria; 59% men, mean age 38) underwent structural MR imaging and performed the comprehensive postural knowledge task (PKT) for hand gestures. All patients except four were treated with antipsychotics. T1-weighted images were processed using SPM8 and DTI-data using FSL TBSS routines. We explored correlations of PKT scores and gray matter (GM) volume in VBM data and correlations of PKT scores and white matter (WM) integrity in TBSS data. Results were corrected for multiple comparisons using family wise error correction. Results Impaired postural knowledge was related to reduced GM volume and WM integrity. Whole brain analyses revealed effects of postural knowledge on gray matter volume within the bilateral insula extending to the IFG, the left primary motor cortex, the left superior parietal lobe and the bilateral hippocampi. Furthermore, significant correlations within fiber tracts connecting these regions – particularly alterations within the bilateral cingulum bundle and cingulum, the right superior longitudinal fasciculus, the right anterior limb of internal capsule, and the left uncinated fasciculus – were associated with PKT performance. Conclusions Poor postural knowledge in schizophrenia was associated with GM volume reductions in the praxis network. Our results are in line with the literature as particularly lesions in the left IFG were found to predict poor gesture recognition in brain damaged patients. In addition an effect of postural knowledge on WM integrity was shown within fiber tracts connecting key regions of gesture processing. Furthermore, the hippocampus is engaged in spatial memory and navigation. The results suggest that structural brain alterations in the common gesture network contribute to impaired postural knowledge in schizophrenia ( Fig. 1 ).

Introduction Motor symptoms are an integral part of the clinical presentation of schizophrenia and disturbances of fine motor function are frequent. However, only limited knowledge exists on the neural correlates of fine motor skills in schizophrenia. We implemented a complex fine motor task to test associations with whole brain gray matter (GM) volume as well as cerebral blood flow (CBF). We aimed to investigate whether patients with difficulties of fine motor performance would show structural and cerebral blood flow alterations in the motor loop. Methods In total 42 schizophrenia patients (59.5% men, mean age=38.6±11.4) diagnosed according to DSM-V underwent MR-neuroimaging. All patients but four received antipsychotic treatment. Parkinsonism was assessed using the motor part of the Unified Parkinson Disease Rating Scale (UPDRS). Fine motor skills were assessed using the coin rotation task. The task is to rotate a coin (.5 swiss francs) using three fingers of the left hand (thumb, index, middle) through serial 180-degree turns as rapidly as possible. Deficits are indicated by the reduced number of half turns and coin drops. We processed structural images using standard SPM8 procedures, in particular voxel-based morphometry (VBM) toolbox. Resting state CBF was measured by arterial spin labeling (ASL). ASL data was analyzed with our custom written MATLAB programs (Federspiel et al., 2006; Walther et al., 2011). The main emphasis was to explore the effect of task performance on GM volume and CBF. Correlations of task performance (mean=10.7±4.1) and GM volume (covariates total intracranial volume and UPDRS) as well as CBF (covariate UPDRS) were calculated. A threshold of p - uncorr 0.001 (min. cluster size=17: equivalent to a map-wise false positive rate of alpha Results We found significant correlations of coin rotation scores and GM volume in the bilateral pre-supplementary motor area (pre-SMA) extending to the SMA, in the left primary motor cortex, the right superior frontal gyrus, bilateral the cerebellum and the left putamen. The pre-SMA cluster survived family wise error correction at cluster level. Significant correlations of CBF and the coin rotation scores were detected in the right SMA, the left primary motor cortex and in the right superior frontal gyrus (Area Fp1), the left inferior frontal gyrus and the right precuneus. Two clusters survived family wise error correction: right superior frontal gyrus and the left inferior frontal gyrus. Discussion Difficulties of fine motor task performance were associated with structural gray matter volume reduction in the motor loop, particularly in cortical motor control areas. In addition fine motor function in schizophrenia patients was linked with cerebral blood flow. These findings were corrected for parkinsonism. In sum, the results argue for specific alterations of the motor system in schizophrenia as source of impaired fine motor function beyond parkinsonism.

Diffusion tensor imaging (DTI) studies have provided evidence of widespread white matter (WM) abnormalities in schizophrenia. Although these abnormalities appear clinically significant, the relationship to specific clinical symptoms is limited and heterogeneous. This study examined the association between WM microstructure and the severity of the five main DSM-5 schizophrenia symptom dimensions. DTI was measured in forty patients with schizophrenia spectrum disorders. Using Tract-Based Spatial Statistics controlling for age, gender and antipsychotic dosage, our analyses revealed significant negative relationships between WM microstructure and two DSM-5 symptom dimensions: Whereas abnormal psychomotor behavior was particularly related to WM of motor tracts, negative symptoms were associated with WM microstructure of the prefrontal and right temporal lobes. However, we found no associations between WM microstructure and delusions, hallucinations or disorganized speech. These data highlight the relevance of characteristic WM disconnectivity patterns as markers for negative symptoms and abnormal psychomotor behavior in schizophrenia and provide evidence for relevant associations between brain structure and aberrant behavior., Highlights • DTI study of brain-behavior associations of the new DSM-5 schizophrenia dimensions. • The severity of the DSM-5 abnormal psychomotor behavior dimension is related to white matter microstructure in motor tracts. • Associations of the DSM-5 negative symptom dimension with white matter microstructure are found in prefrontal and temporal clusters. • Characteristic patterns of white matter microstructure argue for relevant associations between brain structure and aberrant behavior in schizophrenia.

Disorganized speech is related to functional abnormalities in schizophrenia. To test the association between formal thought disorders (FTDs) and white matter microstructure, we applied a behavioral rating and diffusion tensor imaging in 61 patients with schizophrenia spectrum disorders. The Bern Psychopathology Scale was used to rate the dimension of language abnormalities ranging from negative FTDs, basically unaltered speech, to positive FTDs. Tract-based spatial statistics indicated increased fractional anisotropy in left hemispheric pathways of the language system in patients with negative FTDs. Thus, altered white matter properties in relevant fiber tracts may represent vulnerability to specific formal thought disorders.