Characterizing cognitive subtypes in schizophrenia using cortical curvature.

Cognitive deficits are a core symptom of schizophrenia, but research on their neural underpinnings has been challenged by the heterogeneity in deficits' severity among patients. Here, we address this issue by combining logistic regression and random forest to classify two neuropsychological profiles of patients with high (HighCog) and low (LowCog) cognitive performance in two independent samples. We based our analysis on the cortical features grey matter volume (VOL), cortical thickness (CT), and mean curvature (MC) of N = 57 patients (discovery sample) and validated the classification in an independent sample (N = 52). We investigated which cortical feature would yield the best classification results and expected that the 10 most important features would include frontal and temporal brain regions. The model based on MC had the best performance with area under the curve (AUC) values of 76% and 73%, and identified fronto-temporal and occipital brain regions as the most important features for the classification. Moreover, subsequent comparison analyses could reveal significant differences in MC of single brain regions between the two cognitive profiles. The present study suggests MC as a promising neuroanatomical parameter for characterizing schizophrenia cognitive subtypes.

The multimodal Munich Clinical Deep Phenotyping study to bridge the translational gap in severe mental illness treatment research.

Introduction: Treatment of severe mental illness (SMI) symptoms, especially negative symptoms and cognitive dysfunction in schizophrenia, remains a major unmet need. There is good evidence that SMIs have a strong genetic background and are characterized by multiple biological alterations, including disturbed brain circuits and connectivity, dysregulated neuronal excitation-inhibition, disturbed dopaminergic and glutamatergic pathways, and partially dysregulated inflammatory processes. The ways in which the dysregulated signaling pathways are interconnected remains largely unknown, in part because well-characterized clinical studies on comprehensive biomaterial are lacking. Furthermore, the development of drugs to treat SMIs such as schizophrenia is limited by the use of operationalized symptom-based clusters for diagnosis. Methods: In line with the Research Domain Criteria initiative, the Clinical Deep Phenotyping (CDP) study is using a multimodal approach to reveal the neurobiological underpinnings of clinically relevant schizophrenia subgroups by performing broad transdiagnostic clinical characterization with standardized neurocognitive assessments, multimodal neuroimaging, electrophysiological assessments, retinal investigations, and omics-based analyzes of blood and cerebrospinal fluid. Moreover, to bridge the translational gap in biological psychiatry the study includes in vitro investigations on human-induced pluripotent stem cells, which are available from a subset of participants. Results: Here, we report on the feasibility of this multimodal approach, which has been successfully initiated in the first participants in the CDP cohort; to date, the cohort comprises over 194 individuals with SMI and 187 age and gender matched healthy controls. In addition, we describe the applied research modalities and study objectives. Discussion: The identification of cross-diagnostic and diagnosis-specific biotype-informed subgroups of patients and the translational dissection of those subgroups may help to pave the way toward precision medicine with artificial intelligence-supported tailored interventions and treatment. This aim is particularly important in psychiatry, a field where innovation is urgently needed because specific symptom domains, such as negative symptoms and cognitive dysfunction, and treatment-resistant symptoms in general are still difficult to treat.

Associations between aerobic fitness, negative symptoms, cognitive deficits and brain structure in schizophrenia-a cross-sectional study.

Negative symptoms and cognitive deficits are common in individuals with schizophrenia, greatly affect their outcome, and have been associated with alterations in cerebral gray and white matter volume (GMV, WMV). In the last decade, aerobic endurance training has emerged as a promising intervention to alleviate these symptoms and improved aerobic fitness has been suggested as a key moderator variable. In the present study, we investigated, whether aerobic fitness is associated with fewer cognitive deficits and negative symptoms and with GMVs and WMVs in individuals with schizophrenia in a cross-sectional design. In the largest study to date on the implications of fitness in individuals with schizophrenia, 111 participants at two centers underwent assessments of negative symptoms, cognitive functioning, and aerobic fitness and 69 underwent additional structural magnetic resonance imaging. Multilevel Bayesian partial correlations were computed to quantify relationships between the variables of interest. The main finding was a positive association of aerobic fitness with right hippocampal GMV and WMVs in parahippocampal and several cerebellar regions. We found limited evidence for an association of aerobic fitness with cognitive functioning and negative symptoms. In summary, our results strengthen the notion that aerobic fitness and hippocampal plasticity are interrelated which holds implications for the design of exercise interventions in individuals with schizophrenia.

Association between aerobic fitness and the functional connectome in patients with schizophrenia.

BACKGROUND: Schizophrenia is accompanied by widespread alterations in static functional connectivity associated with symptom severity and cognitive deficits. Improvements in aerobic fitness have been demonstrated to ameliorate symptomatology and cognition in people with schizophrenia, but the intermediary role of macroscale connectivity patterns remains unknown. OBJECTIVE: Therefore, we aim to explore the relation between aerobic fitness and the functional connectome in individuals with schizophrenia. Further, we investigate clinical and cognitive relevance of the identified fitness-connectivity links. METHODS: Patients diagnosed with schizophrenia were included in this cross-sectional resting-state fMRI analysis. Multilevel Bayesian partial correlations between aerobic fitness and functional connections across the whole brain as well as between static functional connectivity patterns and clinical and cognitive outcome were performed. Preliminary causal inferences were enabled based on mediation analyses. RESULTS: Static functional connectivity between the subcortical nuclei and the cerebellum as well as between temporal seeds mediated the attenuating relation between aerobic fitness and total symptom severity. Functional connections between cerebellar seeds affected the positive link between aerobic fitness and global cognition, while the functional interplay between central and limbic seeds drove the beneficial association between aerobic fitness and emotion recognition. CONCLUSION: The current study provides first insights into the interactions between aerobic fitness, the functional connectome and clinical and cognitive outcome in people with schizophrenia, but causal interpretations are preliminary. Further interventional aerobic exercise studies are needed to replicate the current findings and to enable conclusive causal inferences. TRIAL REGISTRATION: The study which the manuscript is based on is registered in the International Clinical Trials Database (ClinicalTrials.gov identifier [NCT number]: NCT03466112) and in the German Clinical Trials Register (DRKS-ID: DRKS00009804).

Differences in electric field strength between clinical and non-clinical populations induced by prefrontal tDCS: A cross-diagnostic, individual MRI-based modeling study.

INTRODUCTION: Prefrontal cortex (PFC) regions are promising targets for therapeutic applications of non-invasive brain stimulation, e.g. transcranial direct current stimulation (tDCS), which has been proposed as a novel intervention for major depressive disorder (MDD) and negative symptoms of schizophrenia (SCZ). However, the effects of tDCS vary inter-individually, and dose-response relationships have not been established. Stimulation parameters are often tested in healthy subjects and transferred to clinical populations. The current study investigates the variability of individual MRI-based electric fields (e-fields) of standard bifrontal tDCS across individual subjects and diagnoses. METHOD: The study included 74 subjects, i.e. 25 patients with MDD, 24 patients with SCZ, and 25 healthy controls (HC). Individual e-fields of a common tDCS protocol (i.e. 2 mA stimulation intensity, bifrontal anode-F3/cathode-F4 montage) were modeled by two investigators using SimNIBS (2.0.1) based on structural MRI scans. RESULT: On a whole-brain level, the average e-field strength was significantly reduced in MDD and SCZ compared to HC, but MDD and SCZ did not differ significantly. Regions of interest (ROI) analysis for PFC subregions showed reduced e-fields in Sallet areas 8B and 9 for MDD and SCZ compared to HC, whereas there was again no difference between MDD and SCZ. Within groups, we generally observed high inter-individual variability of e-field intensities at a higher percentile of voxels. CONCLUSION: MRI-based e-field modeling revealed significant differences in e-field strengths between clinical and non-clinical populations in addition to a general inter-individual variability. These findings support the notion that dose-response relationships for tDCS cannot be simply transferred from healthy to clinical cohorts and need to be individually established for clinical groups. In this respect, MRI-based e-field modeling may serve as a proxy for individualized dosing.

Functional and clinical outcomes of FMRI-based neurofeedback training in patients with alcohol dependence: a pilot study.

Identifying treatment options for patients with alcohol dependence is challenging. This study investigates the application of real-time functional MRI (rtfMRI) neurofeedback (NF) to foster resistance towards craving-related neural activation in alcohol dependence. We report a double-blind, placebo-controlled rtfMRI study with three NF sessions using alcohol-associated cues as an add-on therapy to the standard treatment. Fifty-two patients (45 male; 7 female) diagnosed with alcohol dependence were recruited in Munich, Germany. RtfMRI data were acquired in three sessions and clinical abstinence was evaluated 3 months after the last NF session. Before the NF training, BOLD responses and clinical data did not differ between groups, apart from anger and impulsiveness. During NF training, BOLD responses of the active group were decreased in medial frontal areas/caudate nucleus, and increased, e.g. in the cuneus/precuneus and occipital cortex. Within the active group, the down-regulation of neuronal responses was more pronounced in patients who remained abstinent for at least 3 months after the intervention compared to patients with a relapse. As BOLD responses were comparable between groups before the NF training, functional variations during NF cannot be attributed to preexisting distinctions. We could not demonstrate that rtfMRI as an add-on treatment in patients with alcohol dependence leads to clinically superior abstinence for the active NF group after 3 months. However, the study provides evidence for a targeted modulation of addiction-associated brain responses in alcohol dependence using rtfMRI.

Effects of bifrontal transcranial direct current stimulation on brain glutamate levels and resting state connectivity: multimodal MRI data for the cathodal stimulation site.

Transcranial direct current stimulation (tDCS) over prefrontal cortex (PFC) regions is currently proposed as therapeutic intervention for major depression and other psychiatric disorders. The in-depth mechanistic understanding of this bipolar and non-focal stimulation technique is still incomplete. In a pilot study, we investigated the effects of bifrontal stimulation on brain metabolite levels and resting state connectivity under the cathode using multiparametric MRI techniques and computational tDCS modeling. Within a double-blind cross-over design, 20 subjects (12 women, 23.7 ± 2 years) were randomized to active tDCS with standard bifrontal montage with the anode over the left dorsolateral prefrontal cortex (DLPFC) and the cathode over the right DLPFC. Magnetic resonance spectroscopy (MRS) was acquired before, during, and after prefrontal tDCS to quantify glutamate (Glu), Glu + glutamine (Glx) and gamma aminobutyric acid (GABA) concentration in these areas. Resting-state functional connectivity MRI (rsfcMRI) was acquired before and after the stimulation. The individual distribution of tDCS induced electric fields (efields) within the MRS voxel was computationally modelled using SimNIBS 2.0. There were no significant changes of Glu, Glx and GABA levels across conditions but marked differences in the course of Glu levels between female and male participants were observed. Further investigation yielded a significantly stronger Glu reduction after active compared to sham stimulation in female participants, but not in male participants. For rsfcMRI neither significant changes nor correlations with MRS data were observed. Exploratory analyses of the effect of efield intensity distribution on Glu changes showed distinct effects in different efield groups. Our findings are limited by the small sample size, but correspond to previously published results of cathodal tDCS. Future studies should address gender and efield intensity as moderators of tDCS induced effects.

The impact of endurance training and table soccer on brain metabolites in schizophrenia.

Higher glutamate and glutamine (together: Glx) and lower N-acetyl-aspartate (NAA) levels were reported in schizophrenia. Endurance training normalizes NAA in the hippocampus, but its effects on other metabolites in the brain and the relationship of metabolites to clinical symptoms remain unknown. For 12 weeks, 20 schizophrenia inpatients (14 men, 6 women) and 23 healthy controls (16 men, 7 women) performed endurance training and a control group of 21 schizophrenia inpatients (15 men, 6 women) played table soccer. A computer-assisted cognitive performance training program was introduced after 6 weeks. We assessed cognitive performance, psychopathological symptoms, and everyday functioning at baseline and after 6 and 12 weeks and performed single voxel magnetic resonance spectroscopy of the hippocampus, left dorsolateral prefrontal cortex (DLPFC), and thalamus. We quantified NAA, Glx, total creatine (tCr), calculated NAA/tCr and Glx/tCr and correlated these ratios with physical fitness, clinical and neurocognitive scores, and everyday functioning. At baseline, in both schizophrenia groups NAA/tCr was lower in the left DLPFC and left hippocampus and Glx/tCr was lower in the hippocampus than in the healthy controls. After 6 weeks, NAA/tCr increased in the left DLPFC in both schizophrenia groups. Brain metabolites did not change significantly in the hippocampus or thalamus, but the correlation between NAA/tCr and Glx/tCr normalized in the left DLPFC. Global Assessment of Functioning improvements correlated with NAA/tCr changes in the left DLPFC. In our study, endurance training and table soccer induced normalization of brain metabolite ratios in the brain circuitry associated with neuronal and synaptic elements, including metabolites of the glutamatergic system.

T1-MPRAGE and T2-FLAIR segmentation of cortical and subcortical brain regions-an MRI evaluation study.

PURPOSE: Development of a warp-based automated brain segmentation approach of 3D fluid-attenuated inversion recovery (FLAIR) images and comparison to 3D T1-based segmentation. METHODS: 3D FLAIR and 3D T1-weighted sequences of 30 healthy subjects (mean age 29.9 ± 8.3 years, 8 female) were acquired on the same 3T MR scanner. Warp-based segmentation was applied for volumetry of total gray matter (GM), white matter (WM), and 116 atlas regions. Segmentation results of both sequences were compared using Pearson correlation (r). RESULTS: Correlation of GM segmentation results based on FLAIR and T1 was overall good for cortical structures (mean r across all cortical structures = 0.76). Comparatively weaker results were found in the occipital lobe (r = 0.77), central region (mean r = 0.58), basal ganglia (mean r = 0.59), thalamus (r = 0.30), and cerebellum (r = 0.73). FLAIR segmentation underestimated volume of the central region compared to T1, but showed a better anatomic concordance with the occipital lobe on visual review and subcortical structures, when also compared to manual segmentation. Visual analysis of FLAIR-based WM segmentation revealed frequent misclassification of regions of high signal intensity as GM. CONCLUSION: Warp-based FLAIR segmentation yields comparable results to T1 segmentation for most cortical GM structures and may provide anatomically more congruent segmentation of subcortical GM structures. Selected cortical regions, especially the central region and total WM, seem to be underestimated on FLAIR segmentation.

Modulation of Craving Related Brain Responses Using Real-Time fMRI in Patients with Alcohol Use Disorder.

LITERATURE: One prominent symptom in addiction disorders is the strong desire to consume a particular substance or to display a certain behaviour (craving). Especially the strong association between craving and the probability of relapse emphasises the importance of craving in the therapeutic process. Neuroimaging studies have shown that craving is associated with increased responses, predominantly in fronto-striatal areas. AIM AND METHODS: The aim of the present study is the modification of craving-related neuronal responses in patients with alcohol addiction using fMRI real-time neurofeedback. For that purpose, patients with alcohol use disorder and healthy controls participated once in neurofeedback training; during the sessions neuronal activity within an individualized cortical region of interest (ROI) (anterior cingulate cortex, insula, dorsolateral prefrontal cortex) was evaluated. In addition, variations regarding the connectivity between brain regions were assessed in the resting state. RESULTS AND DISCUSSION: The results showed a significant reduction of neuronal activity in patients at the end of the training compared to the beginning, especially in the anterior cingulate cortex, the insula, the inferior temporal gyrus and the medial frontal gyrus. Furthermore, the results show that patients were able to regulate their neuronal activities in the ROI, whereas healthy subjects achieved no significant reduction. However, there was a wide variability regarding the effects of the training within the group of patients. After the neurofeedback-sessions, individual craving was slightly reduced compared to baseline. The results demonstrate that it seems feasible for patients with alcohol dependency to reduce their neuronal activity using rtfMRI neurofeedback. In addition, there is some evidence that craving can be influenced with the help of this technique. FUTURE PROSPECTS: In future, real-time fMRI might be a complementary neurophysiological-based strategy for the psychotherapy of patients with psychiatric or psychosomatic diseases. For that purpose, the stability of this effect and the generalizability needs to be assessed.