We aimed to extend our knowledge on the relationship between physical fitness (PF) and both white matter microstructure and cognition through in-depth investigation of various cognitive domains while ...accounting for potentially relevant nuisance covariates in a well-powered sample. To this end, associations between walking endurance, diffusion-tensor-imaging (DTI) based measures of fractional anisotropy (FA) within brain white matter and cognitive measures included in the NIH Toolbox Cognition Battery were investigated in a sample of n = 1206 healthy, young adults (mean age = 28.8; 45.5% male) as part of the human connectome project. Higher levels of endurance were associated with widespread higher FA (p
< 0.05) as well as with enhanced global cognitive function (p < 0.001). Significant positive relationships between endurance and cognitive performance were similarly found for almost all cognitive domains. Higher FA was significantly associated with enhanced global cognitive function (p < 0.001) and FA was shown to significantly mediate the association between walking endurance and cognitive performance. Inclusion of potentially relevant nuisance covariates including gender, age, education, BMI, HBA1c, and arterial blood pressure did not change the overall pattern of results. These findings support the notion of a beneficial and potentially protective effect of PF on brain structure and cognition.
Alterations in regional subcortical brain volumes have been investigated as part of the efforts of an international consortium, ENIGMA, to identify reliable neural correlates of major depressive ...disorder (MDD). Given that subcortical structures are comprised of distinct subfields, we sought to build significantly from prior work by precisely mapping localized MDD‐related differences in subcortical regions using shape analysis. In this meta‐analysis of subcortical shape from the ENIGMA‐MDD working group, we compared 1,781 patients with MDD and 2,953 healthy controls (CTL) on individual measures of shape metrics (thickness and surface area) on the surface of seven bilateral subcortical structures: nucleus accumbens, amygdala, caudate, hippocampus, pallidum, putamen, and thalamus. Harmonized data processing and statistical analyses were conducted locally at each site, and findings were aggregated by meta‐analysis. Relative to CTL, patients with adolescent‐onset MDD (≤ 21 years) had lower thickness and surface area of the subiculum, cornu ammonis (CA) 1 of the hippocampus and basolateral amygdala (Cohen's d = −0.164 to −0.180). Relative to first‐episode MDD, recurrent MDD patients had lower thickness and surface area in the CA1 of the hippocampus and the basolateral amygdala (Cohen's d = −0.173 to −0.184). Our results suggest that previously reported MDD‐associated volumetric differences may be localized to specific subfields of these structures that have been shown to be sensitive to the effects of stress, with important implications for mapping treatments to patients based on specific neural targets and key clinical features.
Objective
The absence of neurobiological diagnostic markers of bipolar disorder (BD) leads to its frequent misdiagnosis as unipolar depression (UD). We investigated if changes in fractional ...anisotropy (FA) could help to differentiate BD from UD in the state of depression.
Methods
Using diffusion tensor imaging (DTI) we employed a voxel‐based analysis approach to examine fractional anisotropy (FA) in 86 patients experiencing an acute major depressive episode according to DSM‐IV (N=39 BD, mean age 39.2 years; N=43 UD, mean age 39.0 years), and 42 healthy controls (HC, mean age 36.1 years). The groups did not differ in sex, age or total education time. FA was investigated in white matter (FA >.2) and hypothesis‐driven anatomically defined tracts (region‐of‐interest ROI analysis). Additionally, an exploratory gray matter FA analysis was performed.
Results
White matter analysis showed decreased FA in the right corticospinal tract in UD vs HC and in the right corticospinal tract/superior longitudinal fascicle in BD vs HC and also in BD vs UD. ROI analysis revealed decreased FA in BD vs UD in the corpus callosum and in the cingulum. Gray matter exploratory analysis revealed decreased FA in the left middle frontal gyrus and in the right inferior frontal gyrus in UD vs HC, and in the left superior medial gyrus in BD vs HC.
Conclusion
This is one of very few studies directly showing differences in FA between BD and UD. Gray matter FA changes in prefrontal areas might be precursors for future prefrontal gray matter abnormalities in these disorders.
Psychiatric disorders show heterogeneous symptoms and trajectories, with current nosology not accurately reflecting their molecular etiology and the variability and symptomatic overlap within and ...between diagnostic classes. This heterogeneity impedes timely and targeted treatment. Our study aimed to identify psychiatric patient clusters that share clinical and genetic features and may profit from similar therapies. We used high-dimensional data clustering on deep clinical data to identify transdiagnostic groups in a discovery sample (N = 1250) of healthy controls and patients diagnosed with depression, bipolar disorder, schizophrenia, schizoaffective disorder, and other psychiatric disorders. We observed five diagnostically mixed clusters and ordered them based on severity. The least impaired cluster 0, containing most healthy controls, showed general well-being. Clusters 1-3 differed predominantly regarding levels of maltreatment, depression, daily functioning, and parental bonding. Cluster 4 contained most patients diagnosed with psychotic disorders and exhibited the highest severity in many dimensions, including medication load. Depressed patients were present in all clusters, indicating that we captured different disease stages or subtypes. We replicated all but the smallest cluster 1 in an independent sample (N = 622). Next, we analyzed genetic differences between clusters using polygenic scores (PGS) and the psychiatric family history. These genetic variables differed mainly between clusters 0 and 4 (prediction area under the receiver operating characteristic curve (AUC) = 81%; significant PGS: cross-disorder psychiatric risk, schizophrenia, and educational attainment). Our results confirm that psychiatric disorders consist of heterogeneous subtypes sharing molecular factors and symptoms. The identification of transdiagnostic clusters advances our understanding of the heterogeneity of psychiatric disorders and may support the development of personalized treatments.
Expression of polysialic acid (polySia) in the adult brain is enriched in areas of continuous neurogenesis and plasticity such as the hippocampus. Genome-wide association studies identified variants ...of glycosylation enzyme-encoding genes, required for the generation of polySia, to be associated with the development of schizophrenia and bipolar disorder. Here, we report that serum levels of polySia are increased in patients with schizophrenia spectrum disorder compared to patients with major depressive disorders or demographically matched healthy controls. Furthermore, elevated polySia serum levels are associated with structural hippocampal gray matter decline in schizophrenia spectrum and bipolar disorder. In patients with schizophrenia spectrum disorder, polySia serum levels correlate with the number, duration of disease-related hospitalizations, early retirement and medical leave as estimators of detrimental long-term disease trajectories. Our data show that polySia serum levels are linked to structural hippocampal brain changes in schizophrenia spectrum and bipolar disorders, and suggest a contribution of polySia to the pathophysiology of these diseases.
•Data-driven, multivariate statistical approach for structural MRI data.•Identification of gyrification cluster patterns beyond diagnostic categories.•Data-driven subgroups are discriminative in ...transdiagnostic disease risk factors.•Using DSM diagnoses had little power in discriminating global gyrification patterns.
Multivariate data-driven statistical approaches offer the opportunity to study multi-dimensional interdependences between a large set of biological parameters, such as high-dimensional brain imaging data. For gyrification, a putative marker of early neurodevelopment, direct comparisons of patterns among multiple psychiatric disorders and investigations of potential heterogeneity of gyrification within one disorder and a transdiagnostic characterization of neuroanatomical features are lacking.
In this study we used a data-driven, multivariate statistical approach to analyze cortical gyrification in a large cohort of N = 1028 patients with major psychiatric disorders (Major depressive disorder: n = 783, bipolar disorder: n = 129, schizoaffective disorder: n = 44, schizophrenia: n = 72) to identify cluster patterns of gyrification beyond diagnostic categories.
Cluster analysis applied on gyrification data of 68 brain regions (DK-40 atlas) identified three clusters showing difference in overall (global) gyrification and minor regional variation (regions). Newly, data-driven subgroups are further discriminative in cognition and transdiagnostic disease risk factors.
Results indicate that gyrification is associated with transdiagnostic risk factors rather than diagnostic categories and further imply a more global role of gyrification related to mental health than a disorder specific one. Our findings support previous studies highlighting the importance of association cortices involved in psychopathology. Explorative, data-driven approaches like ours can help to elucidate if the brain imaging data on hand and its a priori applied grouping actually has the potential to find meaningful effects or if previous hypotheses about the phenotype as well as its grouping have to be revisited.
Electroconvulsive therapy (ECT) is a fast-acting intervention for major depressive disorder. Previous studies indicated neurotrophic effects following ECT that might contribute to changes in white ...matter brain structure. We investigated the influence of ECT in a non-randomized prospective study focusing on white matter changes over time.
Twenty-nine severely depressed patients receiving ECT in addition to inpatient treatment, 69 severely depressed patients with inpatient treatment (NON-ECT) and 52 healthy controls (HC) took part in a non-randomized prospective study. Participants were scanned twice, approximately 6 weeks apart, using diffusion tensor imaging, applying tract-based spatial statistics. Additional correlational analyses were conducted in the ECT subsample to investigate the effects of seizure duration and therapeutic response.
Mean diffusivity (MD) increased after ECT in the right hemisphere, which was an ECT-group-specific effect. Seizure duration was associated with decreased fractional anisotropy (FA) following ECT. Longitudinal changes in ECT were not associated with therapy response. However, within the ECT group only, baseline FA was positively and MD negatively associated with post-ECT symptomatology.
Our data suggest that ECT changes white matter integrity, possibly reflecting increased permeability of the blood-brain barrier, resulting in disturbed communication of fibers. Further, baseline diffusion metrics were associated with therapy response. Coherent fiber structure could be a prerequisite for a generalized seizure and inhibitory brain signaling necessary to successfully inhibit increased seizure activity.
Although highly effective on average, exposure-based treatments do not work equally well for all patients with anxiety disorders. The identification of pre-treatment response-predicting patient ...characteristics may enable patient stratification. Preliminary research highlights the relevance of inhibitory fronto-limbic networks as such. We aimed to identify pre-treatment neural signatures differing between exposure treatment responders and non-responders in spider phobia and to validate results through rigorous replication. Data of a bi-centric intervention study comprised clinical phenotyping and pre-treatment resting-state functional connectivity (rsFC) data of n = 79 patients with spider phobia (discovery sample) and n = 69 patients (replication sample). RsFC data analyses were accomplished using the Matlab-based CONN-toolbox with harmonized analyses protocols at both sites. Treatment response was defined by a reduction of >30% symptom severity from pre- to post-treatment (Spider Phobia Questionnaire Score, primary outcome). Secondary outcome was defined by a reduction of >50% in a Behavioral Avoidance Test (BAT). Mean within-session fear reduction functioned as a process measure for exposure. Compared to non-responders and pre-treatment, results in the discovery sample seemed to indicate that responders exhibited stronger negative connectivity between frontal and limbic structures and were characterized by heightened connectivity between the amygdala and ventral visual pathway regions. Patients exhibiting high within-session fear reduction showed stronger excitatory connectivity within the prefrontal cortex than patients with low within-session fear reduction. Whereas these results could be replicated by another team using the same data (cross-team replication), cross-site replication of the discovery sample findings in the independent replication sample was unsuccessful. Results seem to support negative fronto-limbic connectivity as promising ingredient to enhance response rates in specific phobia but lack sufficient replication. Further research is needed to obtain a valid basis for clinical decision-making and the development of individually tailored treatment options. Notably, future studies should regularly include replication approaches in their protocols.
To understand how cognitive dysfunction contributes to social cognitive deficits in depression, we investigated the relationship between executive function and social cognitive performance in ...adolescents and young adults during current and remitted depression, compared to healthy controls. Social cognition and executive function were measured in 179 students (61 healthy controls and 118 patients with depression; Mage = 20.60 years; SDage = 3.82 years). Hierarchical regression models were employed within each group (healthy controls, remitted depression, current depression) to examine the nature of associations between cognitive measures. Social cognitive and executive function did not significantly differ overall between depressed patients and healthy controls. There was no association between executive function and social cognitive function in healthy controls or in remitted patients. However, in patients with a current state of depression, lower cognitive flexibility was associated with lower performance in facial-affect recognition, theory-of-mind tasks and overall affect recognition. In this group, better planning abilities were associated with decreased performance in facial affect recognition and overall social cognitive performance. While we infer that less cognitive flexibility might lead to a more rigid interpretation of ambiguous social stimuli, we interpret the counterintuitive negative correlation of planning ability and social cognition as a compensatory mechanism.
•Executive function is associated with social cognition only during current depression.•Enhanced planning ability might compensate for social cognitive dysfunction.•Reduced cognitive flexibility might lead to a rigid interpretation of social stimuli.•The results cannot be attributed to age or chronicity of depression.•The method investigates prosody, facial affect recognition and theory of mind.
There is a lack of knowledge regarding the relationship between proneness to dimensional psychopathological syndromes and the underlying pathogenesis across major psychiatric disorders, i.e., Major ...Depressive Disorder (MDD), Bipolar Disorder (BD), Schizoaffective Disorder (SZA), and Schizophrenia (SZ). Lifetime psychopathology was assessed using the OPerational CRITeria (OPCRIT) system in 1,038 patients meeting DSM-IV-TR criteria for MDD, BD, SZ, or SZA. The cohort was split into two samples for exploratory and confirmatory factor analyses. All patients were scanned with 3-T MRI, and data was analyzed with the CAT-12 toolbox in SPM12. Psychopathological factor scores were correlated with gray matter volume (GMV) and cortical thickness (CT). Finally, factor scores were used for exploratory genetic analyses including genome-wide association studies (GWAS) and polygenic risk score (PRS) association analyses. Three factors (paranoid-hallucinatory syndrome, PHS; mania, MA; depression, DEP) were identified and cross-validated. PHS was negatively correlated with four GMV clusters comprising parts of the hippocampus, amygdala, angular, middle occipital, and middle frontal gyri. PHS was also negatively associated with the bilateral superior temporal, left parietal operculum, and right angular gyrus CT. No significant brain correlates were observed for the two other psychopathological factors. We identified genome-wide significant associations for MA and DEP. PRS for MDD and SZ showed a positive effect on PHS, while PRS for BD showed a positive effect on all three factors. This study investigated the relationship of lifetime psychopathological factors and brain morphometric and genetic markers. Results highlight the need for dimensional approaches, overcoming the limitations of the current psychiatric nosology.
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