Neural correlates of temporal recalibration to delayed auditory feedback of active and passive movements.

When we perform an action, its sensory outcomes usually follow shortly after. This characteristic temporal relationship aids in distinguishing self- from externally generated sensory input. To preserve this ability under dynamically changing environmental conditions, our expectation of the timing between action and outcome must be able to recalibrate, for example, when the outcome is consistently delayed. Until now, it remains unclear whether this process, known as sensorimotor temporal recalibration, can be specifically attributed to recalibration of sensorimotor (action-outcome) predictions, or whether it may be partly due to the recalibration of expectations about the intersensory (e.g., audio-tactile) timing. Therefore, we investigated the behavioral and neural correlates of temporal recalibration and differences in sensorimotor and intersensory contexts. During fMRI, subjects were exposed to delayed or undelayed tones elicited by actively or passively generated button presses. While recalibration of the expected intersensory timing (i.e., between the tactile sensation during the button movement and the tones) can be expected to occur during both active and passive movements, recalibration of sensorimotor predictions should be limited to active movement conditions. Effects of this procedure on auditory temporal perception and the modality-transfer to visual perception were tested in a delay detection task. Across both contexts, we found recalibration to be associated with activations in hippocampus and cerebellum. Context-dependent differences emerged in terms of stronger behavioral recalibration effects in sensorimotor conditions and were captured by differential activation pattern in frontal cortices, cerebellum, and sensory processing regions. These findings highlight the role of the hippocampus in encoding and retrieving newly acquired temporal stimulus associations during temporal recalibration. Furthermore, recalibration-related activations in the cerebellum may reflect the retention of multiple representations of temporal stimulus associations across both contexts. Finally, we showed that sensorimotor predictions modulate recalibration-related processes in frontal, cerebellar, and sensory regions, which potentially account for the perceptual advantage of sensorimotor versus intersensory temporal recalibration.

Reduced hippocampal gray matter volume is a common feature of patients with major depression, bipolar disorder, and schizophrenia spectrum disorders.

Major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia spectrum disorder (SSD, schizophrenia, and schizoaffective disorder) overlap in symptomatology, risk factors, genetics, and other biological measures. Based on previous findings, it remains unclear what transdiagnostic regional gray matter volume (GMV) alterations exist across these disorders, and with which factors they are associated. GMV (3-T magnetic resonance imaging) was compared between healthy controls (HC; n = 110), DSM-IV-TR diagnosed MDD (n = 110), BD (n = 110), and SSD patients (n = 110), matched for age and sex. We applied a conjunction analysis to identify shared GMV alterations across the disorders. To identify potential origins of identified GMV clusters, we associated them with early and current risk and protective factors, psychopathology, and neuropsychology, applying multiple regression models. Common to all diagnoses (vs. HC), we identified GMV reductions in the left hippocampus. This cluster was associated with the neuropsychology factor working memory/executive functioning, stressful life events, and with global assessment of functioning. Differential effects between groups were present in the left and right frontal operculae and left insula, with volume variances across groups highly overlapping. Our study is the first with a large, matched, transdiagnostic sample to yield shared GMV alterations in the left hippocampus across major mental disorders. The hippocampus is a major network hub, orchestrating a range of mental functions. Our findings underscore the need for a novel stratification of mental disorders, other than categorical diagnoses.

Association of brain white matter microstructure with cognitive performance in major depressive disorder and healthy controls: a diffusion-tensor imaging study.

Cognitive deficits are central attendant symptoms of major depressive disorder (MDD) with a crucial impact in patients' everyday life. Thus, it is of particular clinical importance to understand their pathophysiology. The aim of this study was to investigate a possible relationship between brain structure and cognitive performance in MDD patients in a well-characterized sample. N = 1007 participants (NMDD = 482, healthy controls (HC): NHC = 525) were selected from the FOR2107 cohort for this diffusion-tensor imaging study employing tract-based spatial statistics. We conducted a principal component analysis (PCA) to reduce neuropsychological test results, and to discover underlying factors of cognitive performance in MDD patients. We tested the association between fractional anisotropy (FA) and diagnosis (MDD vs. HC) and cognitive performance factors. The PCA yielded a single general cognitive performance factor that differed significantly between MDD patients and HC (P < 0.001). We found a significant main effect of the general cognitive performance factor in FA (Ptfce-FWE = 0.002) in a large bilateral cluster consisting of widespread frontotemporal-association fibers. In MDD patients this effect was independent of medication intake, the presence of comorbid diagnoses, the number of previous hospitalizations, and depressive symptomatology. This study provides robust evidence that white matter disturbances and cognitive performance seem to be associated. This association was independent of diagnosis, though MDD patients show more pronounced deficits and lower FA values in the global white matter fiber structure. This suggests a more general, rather than the depression-specific neurological basis for cognitive deficits.

Let's face it: The lateralization of the face perception network as measured with fMRI is not clearly right dominant.

The neural face perception network is distributed across both hemispheres. However, the dominant role in humans is virtually unanimously attributed to the right hemisphere. Interestingly, there are, to our knowledge, no imaging studies that systematically describe the distribution of hemispheric lateralization in the core system of face perception across subjects in large cohorts so far. To address this, we determined the hemispheric lateralization of all core system regions (i.e., occipital face area - OFA, fusiform face area - FFA, posterior superior temporal sulcus - pSTS) in 108 healthy subjects using functional magnetic resonance imaging (fMRI). We were particularly interested in the variability of hemispheric lateralization across subjects and explored how many subjects can be classified as right-dominant based on the fMRI activation pattern. We further assessed lateralization differences between different regions of the core system and analyzed the influence of handedness and sex on the lateralization with a generalized mixed effects regression model. As expected, brain activity was on average stronger in right-hemispheric brain regions than in their left-hemispheric homologues. This asymmetry was, however, only weakly pronounced in comparison to other lateralized brain functions (such as language and spatial attention) and strongly varied between individuals. Only half of the subjects in the present study could be classified as right-hemispheric dominant. Additionally, we did not detect significant lateralization differences between core system regions. Our data did also not support a general leftward shift of hemispheric lateralization in left-handers. Only the interaction of handedness and sex in the FFA revealed that specifically left-handed men were significantly more left-lateralized compared to right-handed males. In essence, our fMRI data did not support a clear right-hemispheric dominance of the face perception network. Our findings thus ultimately question the dogma that the face perception network - as measured with fMRI - can be characterized as "typically right lateralized".

Association of disease course and brain structural alterations in major depressive disorder.

INTRODUCTION: The investigation of disease course-associated brain structural alterations in Major Depressive Disorder (MDD) have resulted in heterogeneous findings, possibly due to low reliability of single clinical variables used for defining disease course. The present study employed a principal component analysis (PCA) on multiple clinical variables to investigate effects of cumulative lifetime illness burden on brain structure in a large and heterogeneous sample of MDD patients. METHODS: Gray matter volumes (GMV) was estimated in n = 681 MDD patients (mean age: 35.87 years; SD = 12.89; 66.6% female) using voxel-based-morphometry. Five clinical variables were included in a PCA to obtain components reflecting disease course to associate resulting components with GMVs. RESULTS: The PCA yielded two main components: Hospitalization reflected by patients' frequency and duration of inpatient treatment and Duration of Illness reflected by the frequency and duration of depressive episodes. Hospitalization revealed negative associations with bilateral dorsolateral prefrontal cortex (DLPFC) and left insula volumes. Duration of Illness showed significant negative associations with left hippocampus and right DLPFC volumes. Results in the DLPFC and hippocampus remained significant after additional control for depressive symptom severity, psychopharmacotherapy, psychiatric comorbidities, and remission status. CONCLUSION: This study shows that a more severe and chronic lifetime disease course in MDD is associated with reduced volume in brain regions relevant for executive and cognitive functions and emotion regulation in a large sample of patients representing the broad heterogeneity of MDD disease course. These findings were only partly influenced by other clinical characteristics (e.g., remission status, psychopharmacological treatment).

Commonalities and differences in predictive neural processing of discrete vs continuous action feedback.

Sensory action consequences are highly predictable and thus engage less neural resources compared to externally generated sensory events. While this has frequently been observed to lead to attenuated perceptual sensitivity and suppression of activity in sensory cortices, some studies conversely reported enhanced perceptual sensitivity for action consequences. These divergent findings might be explained by the type of action feedback, i.e., discrete outcomes vs. continuous feedback. Therefore, in the present study we investigated the impact of discrete and continuous action feedback on perceptual and neural processing during action feedback monitoring. During fMRI data acquisition, participants detected temporal delays (0-417 ms) between actively or passively generated wrist movements and visual feedback that was either continuously provided during the movement or that appeared as a discrete outcome. Both feedback types resulted in (1) a neural suppression effect (active

Effects of polygenic risk for major mental disorders and cross-disorder on cortical complexity.

BACKGROUND: MRI-derived cortical folding measures are an indicator of largely genetically driven early developmental processes. However, the effects of genetic risk for major mental disorders on early brain development are not well understood. METHODS: We extracted cortical complexity values from structural MRI data of 580 healthy participants using the CAT12 toolbox. Polygenic risk scores (PRS) for schizophrenia, bipolar disorder, major depression, and cross-disorder (incorporating cumulative genetic risk for depression, schizophrenia, bipolar disorder, autism spectrum disorder, and attention-deficit hyperactivity disorder) were computed and used in separate general linear models with cortical complexity as the regressand. In brain regions that showed a significant association between polygenic risk for mental disorders and cortical complexity, volume of interest (VOI)/region of interest (ROI) analyses were conducted to investigate additional changes in their volume and cortical thickness. RESULTS: The PRS for depression was associated with cortical complexity in the right orbitofrontal cortex (right hemisphere: p = 0.006). A subsequent VOI/ROI analysis showed no association between polygenic risk for depression and either grey matter volume or cortical thickness. We found no associations between cortical complexity and polygenic risk for either schizophrenia, bipolar disorder or psychiatric cross-disorder when correcting for multiple testing. CONCLUSIONS: Changes in cortical complexity associated with polygenic risk for depression might facilitate well-established volume changes in orbitofrontal cortices in depression. Despite the absence of psychopathology, changed cortical complexity that parallels polygenic risk for depression might also change reward systems, which are also structurally affected in patients with depressive syndrome.

Severity of current depression and remission status are associated with structural connectome alterations in major depressive disorder.

Major depressive disorder (MDD) is associated to affected brain wiring. Little is known whether these changes are stable over time and hence might represent a biological predisposition, or whether these are state markers of current disease severity and recovery after a depressive episode. Human white matter network ("connectome") analysis via network science is a suitable tool to investigate the association between affected brain connectivity and MDD. This study examines structural connectome topology in 464 MDD patients (mean age: 36.6 years) and 432 healthy controls (35.6 years). MDD patients were stratified categorially by current disease status (acute vs. partial remission vs. full remission) based on DSM-IV criteria. Current symptom severity was assessed continuously via the Hamilton Depression Rating Scale (HAMD). Connectome matrices were created via a combination of T1-weighted magnetic resonance imaging (MRI) and tractography methods based on diffusion-weighted imaging. Global tract-based metrics were not found to show significant differences between disease status groups, suggesting conserved global brain connectivity in MDD. In contrast, reduced global fractional anisotropy (FA) was observed specifically in acute depressed patients compared to fully remitted patients and healthy controls. Within the MDD patients, FA in a subnetwork including frontal, temporal, insular, and parietal nodes was negatively associated with HAMD, an effect remaining when correcting for lifetime disease severity. Therefore, our findings provide new evidence of MDD to be associated with structural, yet dynamic, state-dependent connectome alterations, which covary with current disease severity and remission status after a depressive episode.

Social support and hippocampal volume are negatively associated in adults with previous experience of childhood maltreatment.

Background: Childhood maltreatment has been associated with reduced hippocampal volume in healthy individuals, whereas social support, a protective factor, has been positively associated with hippocampal volumes. In this study, we investigated how social support is associated with hippocampal volume in healthy people with previous experience of childhood maltreatment. Methods: We separated a sample of 446 healthy participants into 2 groups using the Childhood Trauma Questionnaire: 265 people without maltreatment and 181 people with maltreatment. We measured perceived social support using a short version of the Social Support Questionnaire. We examined hippocampal volume using automated segmentation (Freesurfer). We conducted a social support × group analysis of covariance on hippocampal volumes controlling for age, sex, total intracranial volume, site and verbal intelligence. Results: Our analysis revealed significantly lower left hippocampal volume in people with maltreatment (left F1,432 = 5.686, p = 0.018; right F1,433 = 3.371, p = 0.07), but no main effect of social support emerged. However, we did find a significant social support × group interaction for left hippocampal volume (left F1,432 = 5.712, p = 0.017; right F1,433 = 3.480, p = 0.06). In people without maltreatment, we observed a trend toward a positive association between social support and hippocampal volume. In contrast, social support was negatively associated with hippocampal volume in people with maltreatment. Limitations: Because of the correlative nature of our study, we could not infer causal relationships between social support, maltreatment and hippocampal volume. Conclusion: Our results point to a complex dynamic between environmental risk, protective factors and brain structure - in line with previous evidence - suggesting a detrimental effect of maltreatment on hippocampal development.

Predictive perception of self-generated movements: Commonalities and differences in the neural processing of tool and hand actions.

Tool use is one of the most remarkable skills of the human species, enabling complex interactions with the environment. To establish such interactions, we predict the sensory consequences of our actions based on a copy of the motor command (efference copy), leading to an attenuated perception and neural suppression of the sensory input. Here, we investigated whether and how tools can be incorporated into these predictions. We hypothesized that similar predictive mechanisms are used for both hand and tool use actions, but that additional resources are needed to integrate the tool. During fMRI data acquisition, 19 healthy participants used either their right hand or a tool to hold the handle of a movement device. To manipulate the effect of the efference copy, the handle was moved either actively by participants or passively by the movement device. The sensory outcome, consisting of a real-time video of the hand or tool movement shown on a screen, was presented with varying delays (0-417 ms). Participants reported their perception of such delays. The processing of hand and tool movements yielded largely similar results when comparing active against passive conditions: Active movements were in both cases associated with worse delay detection performances. Moreover, during both hand and tool use actions, active movements led to a downregulation of sensory (somatosensory, visual) areas as well as the right cerebellum and right posterior parietal cortex, as assessed by a conjunction analysis. By contrast, an interaction analysis indicated differential processing of active vs. passive movements in hand vs. tool conditions in the left postcentral gyrus, right middle temporal gyrus (MTG), and bilateral caudate nuclei. Our findings provide behavioral and neural support that hand and tool actions share similar mechanisms for sensory predictions. We propose that the MTG and (sensori)motor areas (postcentral gyrus, caudate nuclei) contribute to these predictions by optimizing them to the physics of the end effector (hand or tool). Collectively, these results suggest that the brain dynamically adjusts sensorimotor predictive models to anticipate the dynamics of the end effector, be it a hand or a tool.

Seeing your own or someone else's hand moving in accordance with your action: The neural interaction of agency and hand identity.

Forward models can predict sensory consequences of self-action, which is reflected by less neural processing for actively than passively generated sensory inputs (BOLD suppression effect). However, it remains open whether forward models take the identity of a moving body part into account when predicting the sensory consequences of an action. In the current study, fMRI was used to investigate the neural correlates of active and passive hand movements during which participants saw either an on-line display of their own hand or someone else's hand moving in accordance with their movement. Participants had to detect delays (0-417 ms) between their movement and the displays. Analyses revealed reduced activation in sensory areas and higher delay detection thresholds for active versus passive movements. Furthermore, there was increased activation in the hippocampus, the amygdala, and the middle temporal gyrus when someone else's hand was seen. Most importantly, in posterior parietal (angular gyrus and precuneus), frontal (middle, superior, and medial frontal gyrus), and temporal (middle temporal gyrus) regions, suppression for actively versus passively generated feedback was stronger when participants were viewing their own compared to someone else's hand. Our results suggest that forward models can take hand identity into account when predicting sensory action consequences.

Interactive impact of childhood maltreatment, depression, and age on cortical brain structure: mega-analytic findings from a large multi-site cohort.

BACKGROUND: Childhood maltreatment (CM) plays an important role in the development of major depressive disorder (MDD). The aim of this study was to examine whether CM severity and type are associated with MDD-related brain alterations, and how they interact with sex and age. METHODS: Within the ENIGMA-MDD network, severity and subtypes of CM using the Childhood Trauma Questionnaire were assessed and structural magnetic resonance imaging data from patients with MDD and healthy controls were analyzed in a mega-analysis comprising a total of 3872 participants aged between 13 and 89 years. Cortical thickness and surface area were extracted at each site using FreeSurfer. RESULTS: CM severity was associated with reduced cortical thickness in the banks of the superior temporal sulcus and supramarginal gyrus as well as with reduced surface area of the middle temporal lobe. Participants reporting both childhood neglect and abuse had a lower cortical thickness in the inferior parietal lobe, middle temporal lobe, and precuneus compared to participants not exposed to CM. In males only, regardless of diagnosis, CM severity was associated with higher cortical thickness of the rostral anterior cingulate cortex. Finally, a significant interaction between CM and age in predicting thickness was seen across several prefrontal, temporal, and temporo-parietal regions. CONCLUSIONS: Severity and type of CM may impact cortical thickness and surface area. Importantly, CM may influence age-dependent brain maturation, particularly in regions related to the default mode network, perception, and theory of mind.

Distinct Roles for the Cerebellum, Angular Gyrus, and Middle Temporal Gyrus in Action-Feedback Monitoring.

Action-feedback monitoring is essential to ensure meaningful interactions with the external world. This process involves generating efference copy-based sensory predictions and comparing these with the actual action-feedback. As neural correlates of comparator processes, previous fMRI studies have provided heterogeneous results, including the cerebellum, angular and middle temporal gyrus. However, these studies usually comprised only self-generated actions. Therefore, they might have induced not only action-based prediction errors, but also general sensory mismatch errors. Here, we aimed to disentangle these processes using a custom-made fMRI-compatible movement device, generating active and passive hand movements with identical sensory feedback. Online visual feedback of the hand was presented with a variable delay. Participants had to judge whether the feedback was delayed. Activity in the right cerebellum correlated more positively with delay in active than in passive trials. Interestingly, we also observed activation in the angular and middle temporal gyri, but across both active and passive conditions. This suggests that the cerebellum is a comparator area specific to voluntary action, whereas angular and middle temporal gyri seem to detect more general intersensory conflict. Correlations with behavior and cerebellar activity nevertheless suggest involvement of these temporoparietal areas in processing and awareness of temporal discrepancies in action-feedback monitoring.

Perceiving your hand moving: BOLD suppression in sensory cortices and the role of the cerebellum in the detection of feedback delays.

Sensory consequences of self-generated as opposed to externally generated movements are perceived as less intense and lead to less neural activity in corresponding sensory cortices, presumably due to predictive mechanisms. Self-generated sensory inputs have been mostly studied in a single modality, using abstract feedback, with control conditions not differentiating efferent from reafferent feedback. Here we investigated the neural processing of (a) naturalistic action-feedback associations of (b) self-generated versus externally generated movements, and (c) how an additional (auditory) modality influences neural processing and detection of delays. Participants executed wrist movements using a passive movement device (PMD) as they watched their movements in real time or with variable delays (0-417 ms). The task was to judge whether there was a delay between the movement and its visual feedback. In the externally generated condition, movements were induced by the PMD to disentangle efferent from reafferent feedback. Half of the trials involved auditory beeps coupled to the onset of the visual feedback. We found reduced BOLD activity in visual, auditory, and somatosensory areas during self-generated compared with externally generated movements in unimodal and bimodal conditions. Anterior and posterior cerebellar areas were engaged for trials in which action-feedback delays were detected for self-generated movements. Specifically, the left cerebellar lobule IX was functionally connected with the right superior occipital gyrus. The results indicate efference copy-based predictive mechanisms specific to self-generated movements, leading to BOLD suppression in sensory areas. In addition, our results support the cerebellum's role in the detection of temporal prediction errors during our actions and their consequences.

Brain Structural Network Connectivity of Formal Thought Disorder Dimensions in Affective and Psychotic Disorders.

BACKGROUND: The psychopathological syndrome of formal thought disorder (FTD) is not only present in schizophrenia (SZ), but also highly prevalent in major depressive disorder and bipolar disorder. It remains unknown how alterations in the structural white matter connectome of the brain correlate with psychopathological FTD dimensions across affective and psychotic disorders. METHODS: Using FTD items of the Scale for the Assessment of Positive Symptoms and Scale for the Assessment of Negative Symptoms, we performed exploratory and confirmatory factor analyses in 864 patients with major depressive disorder (n= 689), bipolar disorder (n = 108), or SZ (n = 67) to identify psychopathological FTD dimensions. We used T1- and diffusion-weighted magnetic resonance imaging to reconstruct the structural connectome of the brain. To investigate the association of FTD subdimensions and global structural connectome measures, we employed linear regression models. We used network-based statistic to identify subnetworks of white matter fiber tracts associated with FTD symptomatology. RESULTS: Three psychopathological FTD dimensions were delineated, i.e., disorganization, emptiness, and incoherence. Disorganization and incoherence were associated with global dysconnectivity. Network-based statistics identified subnetworks associated with the FTD dimensions disorganization and emptiness but not with the FTD dimension incoherence. Post hoc analyses on subnetworks did not reveal diagnosis × FTD dimension interaction effects. Results remained stable after correcting for medication and disease severity. Confirmatory analyses showed a substantial overlap of nodes from both subnetworks with cortical brain regions previously associated with FTD in SZ. CONCLUSIONS: We demonstrated white matter subnetwork dysconnectivity in major depressive disorder, bipolar disorder, and SZ associated with FTD dimensions that predominantly comprise brain regions implicated in speech. Results open an avenue for transdiagnostic, psychopathology-informed, dimensional studies in pathogenetic research.

Functional Connectivity of the Nucleus Accumbens and Changes in Appetite in Patients With Depression.

Importance: Major depressive disorder (MDD) is characterized by a substantial burden on health, including changes in appetite and body weight. Heterogeneity of depressive symptoms has hampered the identification of biomarkers that robustly generalize to most patients, thus calling for symptom-based mapping. Objective: To define the functional architecture of the reward circuit subserving increases vs decreases in appetite and body weight in patients with MDD by specifying their contributions and influence on disease biomarkers using resting-state functional connectivity (FC). Design, Setting, and Participants: In this case-control study, functional magnetic resonance imaging (fMRI) data were taken from the Marburg-Münster FOR 2107 Affective Disorder Cohort Study (MACS), collected between September 2014 and November 2016. Cross-sectional data of patients with MDD (n = 407) and healthy control participants (n = 400) were analyzed from March 2018 to June 2022. Main Outcomes and Measures: Changes in appetite during the depressive episode and their association with FC were examined using fMRI. By taking the nucleus accumbens (NAcc) as seed of the reward circuit, associations with opposing changes in appetite were mapped, and a sparse symptom-specific elastic-net model was built with 10-fold cross-validation. Results: Among 407 patients with MDD, 249 (61.2%) were women, and the mean (SD) age was 36.79 (13.4) years. Reduced NAcc-based FC to the ventromedial prefrontal cortex (vmPFC) and the hippocampus was associated with reduced appetite (vmPFC: bootstrap r = 0.13; 95% CI, 0.02-0.23; hippocampus: bootstrap r = 0.15; 95% CI, 0.05-0.26). In contrast, reduced NAcc-based FC to the insular ingestive cortex was associated with increased appetite (bootstrap r = -0.14; 95% CI, -0.24 to -0.04). Critically, the cross-validated elastic-net model reflected changes in appetite based on NAcc FC and explained variance increased with increasing symptom severity (all patients: bootstrap r = 0.24; 95% CI, 0.16-0.31; patients with Beck Depression Inventory score of 28 or greater: bootstrap r = 0.42; 95% CI, 0.25-0.58). In contrast, NAcc FC did not classify diagnosis (MDD vs healthy control). Conclusions and Relevance: In this study, NAcc-based FC reflected important individual differences in appetite and body weight in patients with depression that can be leveraged for personalized prediction. However, classification of diagnosis using NAcc-based FC did not exceed chance levels. Such symptom-specific associations emphasize the need to map biomarkers onto more confined facets of psychopathology to improve the classification and treatment of MDD.

Interaction of recent stressful life events and childhood abuse on orbitofrontal grey matter volume in adults with depression.

BACKGROUND: The diathesis-stress model of major depressive disorder (MDD) predicts interactions of recent stressful life events (SLEs) in adulthood and early developmental risk factors. We tested, for the first time, the diathesis stress model on brain structure in a large group of MDD patients. METHODS: Structural magnetic resonance imaging data of 1465 participants (656 with lifetime diagnosis MDD; 809 healthy controls) were analyzed using voxel-based morphometry to identify clusters associated with recent SLEs (Life Events Questionnaire). Those clusters were then examined for group (healthy/MDD) × early developmental risk (operationalized as childhood abuse [Childhood Trauma Questionnaire] and a major psychiatric disorder [i.e., MDD, bipolar disorder, schizophrenia, and schizoaffective disorder] in a first-degree relative) × recent SLEs three-way interactions on grey matter volume. RESULTS: There was a group × childhood abuse × recent SLEs interaction on left medial orbitofrontal cortex grey matter volume. This three-way interaction arose because childhood abuse and recent SLEs interacted in MDD subjects but not in healthy subjects. LIMITATIONS: We are not able to draw conclusions about the cause and effect relationship due to our cross-sectional study design. CONCLUSIONS: Our data provides evidence for an interplay between orbitofrontal cortex structure, childhood abuse and recent SLEs. These factors have previously been linked to MDD and their complex interaction contributes to the pathogenesis of MDD.

Dimensions of Formal Thought Disorder and Their Relation to Gray- and White Matter Brain Structure in Affective and Psychotic Disorders.

Factorial dimensions and neurobiological underpinnings of formal thought disorders (FTD) have been extensively investigated in schizophrenia spectrum disorders (SSD). However, FTD are also highly prevalent in other disorders. Still, there is a lack of knowledge about transdiagnostic, structural brain correlates of FTD. In N = 1071 patients suffering from DSM-IV major depressive disorder, bipolar disorder, or SSD, we calculated a psychopathological factor model of FTD based on the SAPS and SANS scales. We tested the association of FTD dimensions with 3 T MRI measured gray matter volume (GMV) and white matter fractional anisotropy (FA) using regression and interaction models in SPM12. We performed post hoc confirmatory analyses in diagnostically equally distributed, age- and sex-matched sub-samples to test whether results were driven by diagnostic categories. Cross-validation (explorative and confirmatory) factor analyses revealed three psychopathological FTD factors: disorganization, emptiness, and incoherence. Disorganization was negatively correlated with a GMV cluster comprising parts of the middle occipital and angular gyri and positively with FA in the right posterior cingulum bundle and inferior longitudinal fascicle. Emptiness was negatively associated with left hippocampus and thalamus GMV. Incoherence was negatively associated with FA in bilateral anterior thalamic radiation, and positively with the hippocampal part of the right cingulum bundle. None of the gray or white matter associations interacted with diagnosis. Our results provide a refined mapping of cross-disorder FTD phenotype dimensions. For the first time, we demonstrated that their neuroanatomical signatures are associated with language-related gray and white matter structures independent of diagnosis.

Association Between Genetic Risk for Type 2 Diabetes and Structural Brain Connectivity in Major Depressive Disorder.

BACKGROUND: Major depressive disorder (MDD) and type 2 diabetes mellitus (T2D) are known to share clinical comorbidity and to have genetic overlap. Besides their shared genetics, both diseases seem to be associated with alterations in brain structural connectivity and impaired cognitive performance, but little is known about the mechanisms by which genetic risk of T2D might affect brain structure and function and if they do, how these effects could contribute to the disease course of MDD. METHODS: This study explores the association of polygenic risk for T2D with structural brain connectome topology and cognitive performance in 434 nondiabetic patients with MDD and 539 healthy control subjects. RESULTS: Polygenic risk score for T2D across MDD patients and healthy control subjects was found to be associated with reduced global fractional anisotropy, a marker of white matter microstructure, an effect found to be predominantly present in MDD-related fronto-temporo-parietal connections. A mediation analysis further suggests that this fractional anisotropy variation may mediate the association between polygenic risk score and cognitive performance. CONCLUSIONS: Our findings provide preliminary evidence of a polygenic risk for T2D to be linked to brain structural connectivity and cognition in patients with MDD and healthy control subjects, even in the absence of a direct T2D diagnosis. This suggests an effect of T2D genetic risk on white matter integrity, which may mediate an association of genetic risk for diabetes and cognitive impairments.

Cortical swallowing processing in early subacute stroke.

BACKGROUND: Dysphagia is a major complication in hemispheric as well as brainstem stroke patients causing aspiration pneumonia and increased mortality. Little is known about the recovery from dysphagia after stroke. The aim of the present study was to determine the different patterns of cortical swallowing processing in patients with hemispheric and brainstem stroke with and without dysphagia in the early subacute phase. METHODS: We measured brain activity by mean of whole-head MEG in 37 patients with different stroke localisation 8.2+/-4.8 days after stroke to study changes in cortical activation during self-paced swallowing. An age matched group of healthy subjects served as controls. Data were analyzed by means of synthetic aperture magnetometry and group analyses were performed using a permutation test. RESULTS: Our results demonstrate strong bilateral reduction of cortical swallowing activation in dysphagic patients with hemispheric stroke. In hemispheric stroke without dysphagia, bilateral activation was found. In the small group of patients with brainstem stroke we observed a reduction of cortical activation and a right hemispheric lateralization. CONCLUSION: Bulbar central pattern generators coordinate the pharyngeal swallowing phase. The observed right hemispheric lateralization in brainstem stroke can therefore be interpreted as acute cortical compensation of subcortically caused dysphagia. The reduction of activation in brainstem stroke patients and dysphagic patients with cortical stroke could be explained in terms of diaschisis.