Susanne Karch

Background: There is a certain degree of overlap between persistent postural-perceptual dizziness (PPPD) (ICD-11) and anxiety disorders (ANX) with regard to the phenomenological, pathological and neurobiological characteristics of both conditions. The implementation of an integrative psychotherapy programme may potentially result in the generation of synergistic effects across both patient groups. Objectives: This study assessed (1) whether psychological mechanisms similarly influence symptom severity in PPPD and ANX group, (2) the effectiveness of psychotherapy, and (3) potential neurofunctional biomarkers. Methods: Patients with PPPD (n = 14) and ANX (n = 20) underwent an integrative psychotherapy programme with balance training and mindfulness-based interventions. Emotional and neutral pictures were presented during MRI scans before and after therapy, with healthy controls (HC = 29) for comparison. Clinical and psychological questionnaires were administered, and brain activity was analysed in key regions. Results: The only diagnostic difference in the direct comparison between patients with PPPD and with ANX were the vertigo intensity values before and after therapy. PPPD with comorbid anxiety disorder had significantly more fear of physical symptoms than patients without comorbid anxiety disorder. PPPD showed no change regarding vertigo intensity (VSS), anxiety, or depression scores, but reported decreased impact of vertigo on social functioning (VHQ), and improved personal control after therapy (IPQ). By contrast, anxiety, dizziness, depression, alexithymia, and IPQ scores were significantly reduced after therapy in the ANX group. Neuroimaging revealed decreased activity in the hippocampus and superior temporal gyri (STG) in the PPPD group post-therapy as compared to the pre-therapy measurement, while the ANX group showed reduced activity in the insula, thalamus, hippocampus, and inferior frontal gyrus. Compared to the ANX and HC groups, patients with PPPD showed increased activity in the supramarginal gyrus and STG, both of which could serve as biomarkers for PPPD patients but need to be further validated. Conclusions: Anxiety and vertigo may reinforce each other in PPPD, as symptoms persisted post-therapy, whereas ANX patients improved significantly. Nevertheless, there is some evidence for a successful management of symptoms in the PPPD group. Findings are limited by small sample size and require further research.

Emotion dysregulation has long been considered a key symptom in multiple psychiatric disorders. Difficulties in emotion regulation have been associated with neural dysregulation in fronto-limbic circuits. Real-time fMRI-based neurofeedback (rt-fMRI-NFB) has become increasingly popular as a potential treatment for emotional dysregulation in psychiatric disorders, as it is able to directly target the impaired neural circuits. However, the clinical impact of these rt-fMRI-NFB protocols in psychiatric populations is still largely unknown. Here we provide a comprehensive overview of primary studies from 2010 to 2023 that used rt-fMRI-NFB to target emotion regulation. We assessed 41 out of 4001 original studies for methodological quality and risk of bias and synthesised concerning the frequency of significant rt-fMRI-NFB-related effects on the neural and behaviour level. Successful modulation of brain activity was reported in between 25 and 50 percent of study samples, while neural effects in clinical samples were more diverse than in healthy samples. Interestingly, the frequency of rt-fMRI-NFB-related behavioural improvement was over 75 percent in clinical samples, while healthy samples showed behavioural improvements between 0 and 25 percent. Concerning clinical subsamples, rt-fMRI-NFB-related behavioural improvement was observed in up to 100 percent of major depressive disorder (MDD) and post-traumatic stress disorder (PTSD) samples. Substance use samples showed behavioural benefits ranging between 50 and 75 percent. Neural effects appeared to be less frequent than behavioural improvements: most neural outcomes ranged between 25 and 50 percent for MDD and substance use and between 0 and 25 percent for PTSD. Using multiple individualised regions of interest (ROIs) for rt-fMRI-NFB training resulted in more frequent behavioural benefits than rt-fMRI-NFB solely based on the amygdala or the prefrontal cortex. While a significant improvement in behavioural outcomes was reported in most clinical studies, the study protocols were heterogeneous, which limits the current evaluation of rt-fMRI-NFB as a putative treatment for emotional dysregulation.

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.

Cognitive impairment in patients suffering from schizophrenia spectrum disorders has been discussed as a strong predictor for multiple disease outcome variables, such as response to psychotherapy, stable relationships, employment, and longevity. However, the consistency and severity of cognitive deficits across multiple domains in individuals with first-episode and chronic psychotic disorders is still undetermined. We provide a comprehensive overview of primary research from the years 2009 to 2022. Based on a Cochrane risk assessment, a systematic synthesis of 51 out of 3669 original studies was performed. Impairment of cognitive functioning in patients diagnosed with first-episode psychotic disorders compared with healthy controls was predicted to occur in all assessed cognitive domains. Few overall changes were predicted for chronically affected patients relative to those in the first-episode stage, in line with previous longitudinal studies. Our research outcomes support the hypothesis of a global decrease in cognitive functioning in patients diagnosed with psychotic disorders, i.e., the occurrence of cognitive deficits in multiple cognitive domains including executive functioning, memory, working memory, psychomotor speed, and attention. Only mild increases in the frequency of cognitive impairment across studies were observed at the chronically affected stage relative to the first-episode stage. Our results confirm and extend the outcomes from prior reviews and meta-analyses. Recommendations for psychotherapeutic interventions are provided, considering the broad cognitive impairment already observed at the stage of the first episode. Based on the risk of bias assessment, we also make specific suggestions concerning the quality of future original studies.

Introduction: Individual real-time functional magnetic resonance imaging neurofeedback (rtfMRI NF) might be a promising adjuvant in treating depressive symptoms. Further studies showed functional variations and connectivity-related changes in the dorsolateral prefrontal cortex (dlPFC) and the insular cortex. Objectives: The aim of this pilot study was to investigate whether individualized connectivity-based rtfMRI NF training can improve symptoms in depressed patients as an adjunct to a psychotherapeutic programme. The novel strategy chosen for this was to increase connectivity between individualized regions of interest, namely the insula and the dlPFC. Methods: Sixteen patients diagnosed with major depressive disorder (MDD, ICD-10) and 19 matched healthy controls (HC) participated in a rtfMRI NF training consisting of two sessions with three runs each, within an interval of one week. RtfMRI NF was applied during a sequence of negative emotional pictures to modulate the connectivity between the dlPFC and the insula. The MDD REAL group was divided into a Responder and a Non-Responder group. Patients with an increased connectivity during the second NF session or during both the first and the second NF session were identified as “MDD REAL Responder” (N = 6). Patients that did not show any increase in connectivity and/or a decreased connectivity were identified as “MDD REAL Non-Responder” (N = 7). Results: Before the rtfMRI sessions, patients with MDD showed higher neural activation levels in ventromedial PFC and the insula than HC; by contrast, HC revealed increased hemodynamic activity in visual processing areas (primary visual cortex and visual association cortex) compared to patients with MDD. The comparison of hemodynamic responses during the first compared to during the last NF session demonstrated significantly increased BOLD-activation in the medial orbitofrontal cortex (mOFC) in patients and HC, and additionally in the lateral OFC in patients with MDD. These findings were particularly due to the MDD Responder group, as the MDD Non-Responder group showed no increase in this region during the last NF run. There was a decrease of neural activation in emotional processing brain regions in both groups in the last NF run compared to the first: HC showed differences in the insula, parahippocampal gyrus, basal ganglia, and cingulate gyrus. Patients with MDD demonstrated deceased responses in the parahippocampal gyrus. There was no significant reduction of BDI scores after NF training in patients. Conclusions: Increased neural activation in the insula and vmPFC in MDD suggests an increased emotional reaction in patients with MDD. The activation of the mOFC could be associated with improved control-strategies and association-learning processes. The increased lOFC activation could indicate a stronger sensitivity to failed NF attempts in MDD. A stronger involvement of visual processing areas in HC may indicate better adaptation to negative emotional stimuli after repeated presentation. Overall, the rtfMRI NF had an impact on neurobiological mechanisms, but not on psychometric measures in patients with MDD.

EEG neurofeedback (EEG-NFB) is a promising tool for the treatment of depressive disorders. However, many methods for the presentation of neurobiological reactions are available and it is widely unknown which of these feedback options are preferrable. Moreover, the influence of motivation on NFB training success is insufficiently studied. This study analyzed the efficacy of a novel EEG protocol (FC3/Pz) based on findings for NFB in depression. The role of four feedback options (Rumination, Anxiety, Meditation Master, Moving Art) from the NFB software “Brain Assistant” and motivation in EEG-based NFB performance was studied. Regarding “Anxiety” and “Rumination” visual feedback was used to evoke emotions; reinforcement (both negative and positive operant conditioning) was continuous. Regarding “Meditation Master” visual feedback was combined with continuous positive reinforcement. Regarding “Moving Art” 20-min calm nature films with neutral character were used; both visual and auditive feedback were applied. The reinforcement was positive and continuous. 13 healthy participants completed 15 EEG sessions over four months combining simultaneous frontal (aims: reduction of theta-, alpha- and high beta-activity, increase of low and mid beta-activity) and parietal training (aims: reduction of theta-, alpha 1-, mid and high beta-activity, increase of alpha 2- and low beta-activity). We observed significantly more pronounced percentage change in the expected direction for Anxiety than Moving Art (mean difference = 3.32; p = 0.003). The association between motivation and performance was non-significant. Based on these results we conclude that feedback with both negative and positive operant conditioning and emotion evoking effects should be preferred.