Neural foundation of the diathesis-stress model: longitudinal gray matter volume changes in response to stressful life events in major depressive disorder and healthy controls.

Recurrences of depressive episodes in major depressive disorder (MDD) can be explained by the diathesis-stress model, suggesting that stressful life events (SLEs) can trigger MDD episodes in individuals with pre-existing vulnerabilities. However, the longitudinal neurobiological impact of SLEs on gray matter volume (GMV) in MDD and its interaction with early-life adversity remains unresolved. In 754 participants aged 18-65 years (362 MDD patients; 392 healthy controls; HCs), we assessed longitudinal associations between SLEs (Life Events Questionnaire) and whole-brain GMV changes (3 Tesla MRI) during a 2-year interval, using voxel-based morphometry in SPM12/CAT12. We also explored the potential moderating role of childhood maltreatment (Childhood Trauma Questionnaire) on these associations. Over the 2-year interval, HCs demonstrated significant GMV reductions in the middle frontal, precentral, and postcentral gyri in response to higher levels of SLEs, while MDD patients showed no such GMV changes. Childhood maltreatment did not moderate these associations in either group. However, MDD patients who had at least one depressive episode during the 2-year interval, compared to those who did not, or HCs, showed GMV increases in the middle frontal, precentral, and postcentral gyri associated with an increase in SLEs and childhood maltreatment. Our findings indicate distinct GMV changes in response to SLEs between MDD patients and HCs. GMV decreases in HCs may represent adaptive responses to stress, whereas GMV increases in MDD patients with both childhood maltreatment and a depressive episode during the 2-year interval may indicate maladaptive changes, suggesting a neural foundation for the diathesis-stress model in MDD recurrences.

Principal component analysis as an efficient method for capturing multivariate brain signatures of complex disorders-ENIGMA study in people with bipolar disorders and obesity.

Multivariate techniques better fit the anatomy of complex neuropsychiatric disorders which are characterized not by alterations in a single region, but rather by variations across distributed brain networks. Here, we used principal component analysis (PCA) to identify patterns of covariance across brain regions and relate them to clinical and demographic variables in a large generalizable dataset of individuals with bipolar disorders and controls. We then compared performance of PCA and clustering on identical sample to identify which methodology was better in capturing links between brain and clinical measures. Using data from the ENIGMA-BD working group, we investigated T1-weighted structural MRI data from 2436 participants with BD and healthy controls, and applied PCA to cortical thickness and surface area measures. We then studied the association of principal components with clinical and demographic variables using mixed regression models. We compared the PCA model with our prior clustering analyses of the same data and also tested it in a replication sample of 327 participants with BD or schizophrenia and healthy controls. The first principal component, which indexed a greater cortical thickness across all 68 cortical regions, was negatively associated with BD, BMI, antipsychotic medications, and age and was positively associated with Li treatment. PCA demonstrated superior goodness of fit to clustering when predicting diagnosis and BMI. Moreover, applying the PCA model to the replication sample yielded significant differences in cortical thickness between healthy controls and individuals with BD or schizophrenia. Cortical thickness in the same widespread regional network as determined by PCA was negatively associated with different clinical and demographic variables, including diagnosis, age, BMI, and treatment with antipsychotic medications or lithium. PCA outperformed clustering and provided an easy-to-use and interpret method to study multivariate associations between brain structure and system-level variables. PRACTITIONER POINTS: In this study of 2770 Individuals, we confirmed that cortical thickness in widespread regional networks as determined by principal component analysis (PCA) was negatively associated with relevant clinical and demographic variables, including diagnosis, age, BMI, and treatment with antipsychotic medications or lithium. Significant associations of many different system-level variables with the same brain network suggest a lack of one-to-one mapping of individual clinical and demographic factors to specific patterns of brain changes. PCA outperformed clustering analysis in the same data set when predicting group or BMI, providing a superior method for studying multivariate associations between brain structure and system-level variables.

Shared and distinct structural brain networks related to childhood maltreatment and social support: connectome-based predictive modeling.

Childhood maltreatment (CM) has been associated with changes in structural brain connectivity even in the absence of mental illness. Social support, an important protective factor in the presence of childhood maltreatment, has been positively linked to white matter integrity. However, the shared effects of current social support and CM and their association with structural connectivity remain to be investigated. They might shed new light on the neurobiological basis of the protective mechanism of social support. Using connectome-based predictive modeling (CPM), we analyzed structural connectomes of N = 904 healthy adults derived from diffusion-weighted imaging. CPM predicts phenotypes from structural connectivity through a cross-validation scheme. Distinct and shared networks of white matter tracts predicting childhood trauma questionnaire scores and the social support questionnaire were identified. Additional analyses were applied to assess the stability of the results. CM and social support were predicted significantly from structural connectome data (all rs ≥ 0.119, all ps ≤ 0.016). Edges predicting CM and social support were inversely correlated, i.e., positively correlated with CM and negatively with social support, and vice versa, with a focus on frontal and temporal regions including the insula and superior temporal lobe. CPM reveals the predictive value of the structural connectome for CM and current social support. Both constructs are inversely associated with connectivity strength in several brain tracts. While this underlines the interconnectedness of these experiences, it suggests social support acts as a protective factor following adverse childhood experiences, compensating for brain network alterations. Future longitudinal studies should focus on putative moderating mechanisms buffering these adverse experiences.

Handedness in schizophrenia and affective disorders: a large-scale cross-disorder study.

While most people are right-handed, a minority are left-handed or mixed-handed. It has been suggested that mental and developmental disorders are associated with increased prevalence of left-handedness and mixed-handedness. However, substantial heterogeneity exists across disorders, indicating that not all disorders are associated with a considerable shift away from right-handedness. Increased frequencies in left- and mixed-handedness have also been associated with more severe clinical symptoms, indicating that symptom severity rather than diagnosis explains the high prevalence of non-right-handedness in mental disorders. To address this issue, the present study investigated the association between handedness and measures of stress reactivity, depression, mania, anxiety, and positive and negative symptoms in a large sample of 994 healthy controls and 1213 patients with DSM IV affective disorders, schizoaffective disorders, or schizophrenia. A series of complementary analyses revealed lower lateralization and a higher percentage of mixed-handedness in patients with major depression (14.9%) and schizophrenia (24.0%) compared to healthy controls (12%). For patients with schizophrenia, higher symptom severity was associated with an increasing tendency towards left-handedness. No associations were found for patients diagnosed with major depression, bipolar disorder, or schizoaffective disorder. In healthy controls, no association between hand preference and symptoms was evident. Taken together, these findings suggest that both diagnosis and symptom severity are relevant for the shift away from right-handedness in mental disorders like schizophrenia and major depression.

[Case Report of a 14-Year-Old Girl with Addison's Disease Under Initial Presumptive Diagnosis of Anorexia Nervosa: Confusingly Similar and Yet so Different?] / Kasuistik einer früh im Lebensverlauf an Morbus Addison erkrankten 14 Jahre alten Patientin bei Verdachtsdiagnose einer Anorexia nervosa.

Case Report of a 14-Year-Old Girl with Addison's Disease Under Initial Presumptive Diagnosis of Anorexia Nervosa: Confusingly Similar and Yet so Different? Abstract: Objective: Primary adrenal insufficiency (Addison's disease) is a rare differential diagnosis of anorexia nervosa. This case report presents important differential diagnostic aspects. Methods: We prepared a case report of a 14-year-old female patient according to the CARE guidelines, taking the patient's and the child's parents' view into consideration. Results: The diagnosis of primary adrenocortical insufficiency was reached using specific laboratory diagnostics approximately 9 months after the onset of symptoms, including sudden body weight loss. Significant differential diagnostic aspects were the absence of a body schema disorder and skin hyperpigmentation prominent in the physical examination. The patient experienced a high psychosocial burden because of the unclear diagnosis over 9 months. The diagnosis and substitution therapy with hydrocortisone led to a rapid improvement of the physical and psychological symptoms. Conclusions: This case report emphasizes the importance of a thorough somatic differential diagnosis in the context of a suspected anorexia nervosa.

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.

Long-term cortisol stress response in depression and comorbid anxiety is linked with reduced N-acetylaspartate in the anterior cingulate cortex.

OBJECTIVES: Major Depression (MDD) and anxiety disorders are stress-related disorders that share pathophysiological mechanisms. There is evidence for alterations of glutamate-glutamine, N-acetylaspartate (NAA) and GABA in the anterior cingulate cortex (ACC), a stress-sensitive region affected by hypothalamic-pituitary-adrenal axis (HPA). The aim was to investigate metabolic alterations in the ACC and whether hair cortisol, current stress or early life adversity predict them. METHODS: We investigated 22 patients with MDD and comorbid anxiety disorder and 23 healthy controls. Proton magnetic resonance spectroscopy was performed with voxels placed in pregenual (pg) and dorsal (d) ACC in 3 T. Analysis of hair cortisol was performed using liquid chromatography-tandem mass spectrometry (LC-MS/MS). RESULTS: The N-acetylaspartate/Creatin ratio (NAA/Cr) was reduced in patients in both pgACC (p = .040) and dACC (p = .016). A significant interactive effect of diagnosis and cortisol on both pg-NAA/Cr (F = 5.00, p = .033) and d-NAA/Cr (F = 7.86, p = .009) was detected, whereby in controls cortisol was positively correlated with d-NAA/Cr (r = 0.61, p = .004). CONCLUSIONS: Our results suggest a relationship between NAA metabolism in ACC and HPA axis activity as represented by long-term cortisol output.

Immunological changes following electroconvulsive therapy in multiple sclerosis.

INTRODUCTION: Electroconvulsive therapy (ECT) is a well-established treatment option in case of treatment-resistant depression (TRD). Only a few cases of ECT in depressed patients with multiple sclerosis (MS) were reported so far suggesting efficacy for the treatment of severe depression in MS, while data on possible neurological deterioration remained unclear. METHODS: In this case study we report on a case of a middle-aged man with MS. He was on dimethyl fumarate for relapse prevention since 2019 and without signs of active disease in a recent cerebral MRI. He suffered from treatment-resistant severe bipolar depression and thus received a total of 14 ECT sessions. We changed from right-unilateral to bilateral stimulation technique after the 7th session. We rated depression severity and measured biomarkers of neurodegeneration and inflammation before and after the ECT series to determine the impact of ECT on tolerance, response and neurobiology. RESULTS: The ECT series was tolerated well without neurological deterioration and any new neurological symptoms. The seizure quality was sufficient on average. We saw partial response corresponding to an improvement of about 35% in BDI-II and MADRS. The concentration of inflammation and neurodegeneration biomarkers was low both pre-treatment and post-treatment with increases from pre- to post ECT mainly in the CCL-2 pathway. CONCLUSION: In our patient with TRD and MS ECT was safe and feasible. We did not see any neurobiological signs of disease activation of MS or neurodegeneration during the course of ECT, which may even be beneficial as it led to increase in the neuroprotective CCL-2 pathway in the presented patient.