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Background: Abnormalities in brain regions involved in the pathophysiology of schizophrenia (SCZ) may present insight into individual clinical symptoms. Specifically, functional connectivity irregularities may provide potential biomarkers for treatment response or treatment resistance, as such changes can occur before any structural changes are visible. We reviewed resting-state functional magnetic resonance imaging (rs-fMRI) findings from the last decade to provide an overview of the current knowledge on brain functional connectivity abnormalities and their associations to symptoms in treatment-resistant schizophrenia (TRS) and ultra-treatment-resistant schizophrenia (UTRS) and to look for support for the dysconnection hypothesis., Methods: PubMed database was searched for articles published in the last 10 years applying rs-fMRI in TRS patients, i.e., who had not responded to at least two adequate treatment trials with different antipsychotic drugs., Results: Eighteen articles were selected for this review involving 648 participants (TRS and control cohorts). The studies showed frontal hypoconnectivity before the initiation of treatment with CLZ or riluzole, an increase in frontal connectivity after riluzole treatment, fronto-temporal hypoconnectivity that may be specific for non-responders, widespread abnormal connectivity during mixed treatments, and ECT-induced effects on the limbic system., Conclusion: Probably due to the heterogeneity in the patient cohorts concerning antipsychotic treatment and other clinical variables (e.g., treatment response, lifetime antipsychotic drug exposure, duration of illness, treatment adherence), widespread abnormalities in connectivity were noted. However, irregularities in frontal brain regions, especially in the prefrontal cortex, were noted which are consistent with previous SCZ literature and the dysconnectivity hypothesis. There were major limitations, as most studies did not differentiate between TRS and UTRS (i.e., CLZ-resistant schizophrenia) and investigated heterogeneous cohorts treated with mixed treatments (with or without CLZ). This is critical as in different subtypes of the disorder an interplay between dopaminergic and glutamatergic pathways involving frontal, striatal, and hippocampal brain regions in separate ways is likely. Better definitions of TRS and UTRS are necessary in future longitudinal studies to correctly differentiate brain regions underlying the pathophysiology of SCZ, which could serve as potential functional biomarkers for treatment resistance., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Tuovinen and Hofer.)

The role of the limbic system in the acute phase and during the recovery of takotsubo syndrome needs further clarification. In this longitudinal study, anatomical and task-based functional magnetic resonance imaging of the brain was performed during an emotional picture paradigm in 19 postmenopausal female takotsubo syndrome patients in the acute and recovery phases in comparison to sex- and aged-matched 15 healthy controls and 15 patients presenting with myocardial infarction. Statistical analyses were performed based on the general linear model where aversive and positive picture conditions were included in order to reveal group differences during encoding of aversive versus positive pictures and longitudinal changes. In the acute phase, takotsubo syndrome patients showed a lower response in regions involved in affective and cognitive emotional processes (e.g., insula, thalamus, frontal cortex, inferior frontal gyrus) while viewing aversive versus positive pictures compared to healthy controls and patients presenting with myocardial infarction. In the recovery phase, the response in these brain regions normalized in takotsubo syndrome patients to the level of healthy controls, whereas patients 8-12 weeks after myocardial infarction showed lower responses in the limbic regions (mainly in the insula, frontal regions, thalamus, and inferior frontal gyrus) compared to healthy controls and takotsubo syndrome patients. In conclusion, compared to healthy controls and patients suffering from acute myocardial infarction, limbic responses to aversive visual stimuli are attenuated during the acute phase of takotsubo syndrome, recovering within three months. Reduced functional brain responses in the recovery phase after a myocardial infarction need further investigation.

Personality traits have been linked with both brain structure and function. However, the exact relationship between personality traits and other behavioural measures with neurometabolites, measured with proton magnetic resonance spectroscopy, is not clear. Here we investigated the association between behavioural measures (i.e., personality traits, resilience, perceived stress, self-esteem, hopelessness, psychological distress) and metabolite ratios (i.e., of choline-containing compounds [Cho], creatine and phosphocreatine [Cr], and N-acetyl-aspartate [NAA]) in the posterior cingulate cortex (pCC) and the dorsal anterior cingulate cortex (dACC) and surrounding white matter (WM) regions in healthy emerging adults (N = 57, 26 women, mean age=23.40 years, SD=2.50). The pCC and the dACC were selected for their known involvement as important brain network hubs and their association to five factor personality dimensions and other psychological measures. Spectral analysis as well as statistics for demographic, clinical, and imaging data were performed. Correlation and multiple regression analyses were used to test the relationship between metabolite ratios and behavioural scores in the entire sample as well as in female and male participants separately. The entire sample showed significant (p<0.05) negative correlates of stress with the NAA/Cr ratio in the pCC, and of extraversion with WM metabolite ratios. In regards of sex differences, a significantly higher NAA/Cho ratio in the pCC (p<0.05), the dACC (p<0.01), and in the left and right posterior WM matter (p<0.05), and a lower Cho/Cr ratio in the dACC (p<0.01) was detected in women. Moreover, the two sexes differed in regards of metabolite correlates of openness, conscientiousness, extraversion, agreeableness, neuroticism, stress, hopelessness, and self-esteem, and in multiple regression model predictions. Our results point to a role of the ACC in conscientiousness through its involvement in higher-order cognitive control as part of the salience network and internally directed thoughts as part of the default mode network (DMN). Furthermore, the two sexes differ in terms of metabolite correlates of openness and conscientiousness in the pCC, suggesting mental process involvement through the DMN, and of agreeableness in the dACC, possibly through involvement in social cognitive processes, particularly in women. Additionally, our results suggest that the ACC is linked to the so-called Alpha-factor of personality. Our findings on stress correlates contribute to the existing literature of the involvement of the ACC as part of the limbic system. In addition, our results suggest a possible role of the pCC in stress-regulatory processes through a possible co-involvement of stress, hopelessness, and self-esteem in the pCC in men, where higher self-esteem may help to cope with stress., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Grey matter volume (GMV) decline is a frequent finding in multiple sclerosis (MS), the most common chronic neurological disease in young adults. Increases of GMV were detected in language related brain regions following second language (L2) learning in healthy adults. Effects of L2 learning in people with MS (pwMS) have not been investigated so far., Methods: This study prospectively evaluated the potential of an eight-week L2 training on grey matter plasticity measured by 3T-MRI, L2 proficiency and health-related quality of life (HRQoL) in people with relapsing-remitting MS (pwMS, n = 11) and healthy, sex- and age-matched controls (HCs; n = 12)., Results: Categorical voxel-based analysis revealed significantly less GMV bilaterally of the insula extending to the temporal pole in pwMS at baseline. Following L2 training, significant increases of GMV were evident in the right hippocampus, parahippocampus and putamen of pwMS and in the left insula of HCs. L2 training resulted in significant improvements of listening comprehension, speaking fluency and vocabulary knowledge in both pwMS and HCs. GMV increases of right hippocampus and parahippocampus significantly correlated with vocabulary knowledge gain and L2 learning was associated with a significant increase of HRQoL in pwMS., Conclusion: Our findings demonstrate distinct patterns of GMV increases of language related brain regions in pwMS and HCs and indicate disease-related compensatory cortical and subcortical plasticity to acquire L2 proficiency in pwMS., Competing Interests: The present study was funded by an unrestricted research grant of Merck Austria. None of the authors has an affiliation with Merck Austria. There are no patents, products in development or marketed products to declare. Further, this does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: The cognitive function of brain tumor patients is affected during the treatment. There is evidence that gliomas and surgery alter the functional brain connectivity but studies on the longitudinal effects are lacking., Methods: We acquired longitudinal (pre- and post-radiotherapy) resting-state functional magnetic resonance imaging on three selected glioblastoma patients. These cases were selected to study three models: a lesion involving a functional hub within a central system, a lesion involving a peripheral node within a central system and a lesion involving a peripheral node of a non-central system., Results: We found that, as expected, the tumor lesion affects connections in close vicinity, but when the lesion relates to a functional hub, these changes involve long-range connections leading to diverse connectivity profiles pre- and post-radiotherapy. In particular, a global but temporary improvement in the post-radiotherapy connectivity was obtained when treating a lesion close to a network hub, such as the posterior Cingulate Cortex., Conclusions: This suggests that this node re-establishes communication to nodes further away in the network. Eventually, these observed effects seem to be transient and on the long-term the tumor burden leads to an overall decline of connectivity following the course of the pathology. Furthermore, we obtained that the link between hubs, such as the Supplementary Motor Area and posterior Cingulate Cortex represents an important backbone by means of which within and across network communication is handled: the disruption of this connection seems to imply a strong decrease in the overall connectivity.