Transdiagnostic alterations in neural emotion regulation circuits - neural substrates of cognitive reappraisal in patients with depression and post-traumatic stress disorder.

BACKGROUND: Impaired cognitive reappraisal, associated with the social functioning and well-being of patients affected by mood or anxiety disorders, is characterized by distinct neural activation patterns across clinical populations. To date, studies dedicated to identifying common and distinct neural activation profiles need to be clarified. The aim of the present study was to investigate transdiagnostic differences and commonalities in brain activation patterns during reappraisal-mediated downregulation of emotions. METHODS: Cognitive reappraisal of negative images was contrasted with maintaining emotions during a control viewing condition. Brain activation in 35 patients with major depressive disorder (MDD), 20 patients with post-traumatic stress disorder (PTSD), and 34 healthy controls (HC) during cognitive reappraisal was compared. Moreover, the neural circuitry of emotion regulation in these clinical populations was examined using seed-to-voxel and voxel-to-voxel functional connectivity analyses. RESULTS: Whole-brain fMRI analyses showed less right-lateralized activation of the inferior, middle, and superior frontal gyrus during cognitive reappraisal compared to viewing of negative images in MDD and PTSD patients compared to HCs. Right IFG activation was negatively correlated with the severity of anxiety and depressive symptomatology. In addition, increased seed-to-voxel connectivity of the right IFG as well as increased voxel-to-voxel connectivity was observed in PTSD patients compared to HCs and MDD patients. CONCLUSIONS: FMRI results therefore suggested a common deficit of depression and anxiety symptomatology reflected by reduced activation in right IFG during cognitive reappraisal as well as diagnosis specific effects in patients with PTSD based on seed-to-voxel and voxel-to-voxel connectivity showing an overactive and hyperconnected salience network. Findings highlight the role of transdiagnostic research to identify disorder specific brain patterns as well as patterns common across disorders.

Shared network-level functional alterations across substance use disorders: A multi-level kernel density meta-analysis of resting-state functional connectivity studies.

An increasing number of neuroimaging studies indicate functional alterations in cortico-striatal loops in individuals with substance use disorders (SUD). Dysregulations in these circuits may contribute to drug-seeking and drug-consuming behaviour by impeding inhibitory control, habit formation, and reward processing. Despite evidence of network-level changes in SUD, a shared pattern of functional alterations within and between spatially distributed brain networks has not been systematically investigated. The present meta-analytic investigation aims at identifying common alterations in resting-state functional connectivity patterns across different SUD, including stimulant, heroin, alcohol, cannabis, and nicotine use. To this aim, seed-based whole-brain connectivity maps for different functional networks were extracted and subjected to multi-level kernel density analysis to identify dysfunctional networks in individuals with SUD compared with healthy controls. In addition, an exploratory analysis examined substance-specific effects as well as the influence of drug use status on the main findings. Our findings indicate a hypoconnectivity pattern for the limbic, salience, and frontoparietal networks in individuals with SUD as compared with healthy controls. The default mode network additionally exhibited a complex pattern of hypo- and hyperconnectivity across the studies. The observed disrupted connectivity between networks in SUD may associate with deficient inhibitory control mechanisms that are thought to contribute to excessive craving and automatic drug-related behaviour as well as failure in substance use cessation. The identified network-based alterations in SUD represent potential treatment targets for neuromodulation, for example, network-based real-time functional magnetic resonance imaging (fMRI) neurofeedback. Such interventions can evaluate the behavioural relevance of the identified neural circuits.

Putamen volume predicts real-time fMRI neurofeedback learning success across paradigms and neurofeedback target regions.

Real-time fMRI guided neurofeedback training has gained increasing interest as a noninvasive brain regulation technique with the potential to modulate functional brain alterations in therapeutic contexts. Individual variations in learning success and treatment response have been observed, yet the neural substrates underlying the learning of self-regulation remain unclear. Against this background, we explored potential brain structural predictors for learning success with pooled data from three real-time fMRI data sets. Our analysis revealed that gray matter volume of the right putamen could predict neurofeedback learning success across the three data sets (n = 66 in total). Importantly, the original studies employed different neurofeedback paradigms during which different brain regions were trained pointing to a general association with learning success independent of specific aspects of the experimental design. Given the role of the putamen in associative learning this finding may reflect an important role of instrumental learning processes and brain structural variations in associated brain regions for successful acquisition of fMRI neurofeedback-guided self-regulation.

Common neurofunctional dysregulations characterize obsessive-compulsive, substance use, and gaming disorders-An activation likelihood meta-analysis of functional imaging studies.

Compulsivity and loss of behavioral control represent core symptoms in obsessive-compulsive disorder (OCD), substance use disorder (SUD), and internet gaming disorder (IGD). Despite elaborated animal models suggesting that compulsivity is mediated by cortico-striatal circuits and a growing number of neuroimaging case-control studies, common neurofunctional alterations in these disorders have not been systematically examined. The present activation likelihood estimation (ALE) meta-analysis capitalized on previous functional magnetic resonance imaging (fMRI) studies to determine shared neurofunctional alterations among the three disorders. Task-based fMRI studies of individuals with SUD, OCD, or IGD were obtained. ALE was performed within each disorder. Next, contrast and conjunction meta-analyses were performed to determine differential and common alterations. Task-paradigm classes were group according to Research Domain Criteria (RDoC) domains to determine contributions of underlying behavioral domains. One hundred forty-four articles were included representing data from n = 6897 individuals (SUD = 2418, controls = 2332; IGD = 361, controls = 360; OCD = 715, controls = 711) from case-control studies. Conjunction meta-analyses revealed shared alterations in the anterior insular cortex between OCD and SUDs. SUD exhibited additionally pronounced dorsal-striatal alterations compared with both, OCD and IGD. IGD shared frontal, particularly cingulate alterations with all SUDs, while IGD demonstrated pronounced temporal alterations compared with both, SUD and OCD. No robust overlap between IGD and OCD was observed. Across the disorders, neurofunctional alterations were mainly contributed by cognitive systems and positive valence RDoC domains. The present findings indicate that neurofunctional dysregulations in prefrontal regions engaged in regulatory-control represent shared neurofunctional alterations across substance and behavioral addictions, while shared neurofunctional dysregulations in the anterior insula may mediate compulsivity in substance addiction and OCD.

Tracking of Mental Workload with a Mobile EEG Sensor.

The aim of the present investigation was to assess if a mobile electroencephalography (EEG) setup can be used to track mental workload, which is an important aspect of learning performance and motivation and may thus represent a valuable source of information in the evaluation of cognitive training approaches. Twenty five healthy subjects performed a three-level N-back test using a fully mobile setup including tablet-based presentation of the task and EEG data collection with a self-mounted mobile EEG device at two assessment time points. A two-fold analysis approach was chosen including a standard analysis of variance and an artificial neural network to distinguish the levels of cognitive load. Our findings indicate that the setup is feasible for detecting changes in cognitive load, as reflected by alterations across lobes in different frequency bands. In particular, we observed a decrease of occipital alpha and an increase in frontal, parietal and occipital theta with increasing cognitive load. The most distinct levels of cognitive load could be discriminated by the integrated machine learning models with an accuracy of 86%.

Common and separable neural alterations in substance use disorders: A coordinate-based meta-analyses of functional neuroimaging studies in humans.

Delineating common and separable neural alterations in substance use disorders (SUD) is imperative to understand the neurobiological basis of the addictive process and to inform substance-specific treatment strategies. Given numerous functional MRI (fMRI) studies in different SUDs, a meta-analysis could provide an opportunity to determine robust shared and substance-specific alterations. The present study employed a coordinate-based meta-analysis covering fMRI studies in individuals with addictive cocaine, cannabis, alcohol, and nicotine use. The primary meta-analysis demonstrated common alterations in primary dorsal striatal, and frontal circuits engaged in reward/salience processing, habit formation, and executive control across different substances and task-paradigms. Subsequent sub-analyses revealed substance-specific alterations in frontal and limbic regions, with marked frontal and insula-thalamic alterations in alcohol and nicotine use disorders respectively. Examining task-specific alterations across substances revealed pronounced frontal alterations during cognitive processes yet stronger striatal alterations during reward-related processes. Finally, an exploratory meta-analysis revealed that neurofunctional alterations in striatal and frontal reward processing regions can already be determined with a high probability in studies with subjects with comparably short durations of use. Together the findings emphasize the role of dysregulations in frontostriatal circuits and dissociable contributions of these systems in the domains of reward-related and cognitive processes which may contribute to substance-specific behavioral alterations.

Neurofeedback of core language network nodes modulates connectivity with the default-mode network: A double-blind fMRI neurofeedback study on auditory verbal hallucinations.

BACKGROUND: The experience of auditory verbal hallucinations in schizophrenia is associated with changes in brain network function. In particular, studies indicate altered functional coupling between nodes of the language and default mode networks. Neurofeedback based on real-time functional magnetic resonance imaging (rtfMRI) can be used to modulate such aberrant network connectivity. METHODS: We investigated resting-state connectivity changes after neurofeedback (NF) in 21 patients with schizophrenia and 35 healthy individuals. All participants underwent two days of neurofeedback training of important nodes of the left-hemispheric language network including the inferior frontal gyrus (IFG) and posterior superior temporal gyrus (pSTG). In a double-blind randomized cross-over design, participants learned to down- and up-regulate their brain activation in the designated target regions based on NF. Prior to and after each training day, a resting state measurement took place. RESULTS: Coupling between nodes of the language and the default mode network (DMN) selectively increased after down-as compared to up-regulation NF. Network analyses revealed more pronounced increases in functional connectivity between nodes of the language network and the DMN in patients compared to healthy individuals. In particular, down-regulation NF led to increased coupling between nodes of the language network and bilateral inferior parietal lobe (IPL) as well as posterior cingulate cortex (PCC)/precuneus in patients. Up-regulation strengthened connectivity with the medial prefrontal cortex (mPFC). Improved well-being four weeks after the training predicted increased functional coupling between the left IFG and left IPL. CONCLUSION: Modulatory effects emerged as increased internetwork communication, indicating that down-regulation NF selectively enhances coupling between language and DM network nodes in patients with AVH. RtfMRI NF may thus be used to modulate brain network function that is relevant to the phenomenology of AVH. Specific effects of self-regulation on symptom improvement have to be explored in therapeutic interventions.

Fronto-parietal and temporal brain dysfunction in depression: A fMRI investigation of auditory mismatch processing.

Mismatch responses reflect neural mechanisms of early cognitive processing in the auditory domain. Disturbances of these mechanisms on multiple levels of neural processing may contribute to clinical symptoms in major depression (MD). A functional magnetic resonance imaging (fMRI) study was conducted to identify neurobiological foundations of altered mismatch processing in MD. Twenty-five patients with major depression and 25 matched healthy individuals completed an auditory mismatch paradigm optimized for fMRI. Brain activity during mismatch processing was compared between groups. Moreover, seed-based connectivity analyses investigated depression-specific brain networks. In patients, mismatch processing was associated with reduced activation in the right auditory cortex as well as in a fronto-parietal attention network. Moreover, functional coupling between the right auditory cortex and frontal areas was reduced in patients. Seed-to voxel analysis on the whole-brain level revealed reduced connectivity between the auditory cortex and the thalamus as well as posterior cingulate. The present study indicates deficits in sensory processing on the level of the auditory cortex in depression. Hyposensitivity in a fronto-parietal network presumably reflects altered attention mechanisms in depression. The observed impairments may contribute to psychopathology by reducing the ability of the affected individuals to orient attention toward important environmental cues.

Multidimensional assessment of neuroendocrine and psychopathological profiles in maltreated youth.

It has been debated whether children who have experienced early life stress (ELS), such as early caregiver separation show elevated risk for stress-related psychiatric disorders and a multi-symptom psychopathological profile that is not fully reflected in categorical assessments. In this study, we investigated dimensional measures of stress-related psychopathology in children in permanent out-of-home care, taking into account potential neuroendocrine interactions. In the current study, 25 children who had been placed in permanent out-of-home care before age 3 (years) and 26 controls (aged 10.6 ± 1.75 years) were investigated with categorical (DSM-IV) and dimensional assessments (CBCL) of psychopathology and diurnal salivary cortisol levels were assessed. Semi-structured interviews (K-DIPS) revealed no significant group differences in full-scale psychiatric diagnoses, whereas dimensional assessment (CBCL) revealed significant group differences in externalizing and total problem behaviours within the clinical range for children with ELS. Only children with ELS showed a combined symptom profile of clinical-range internalizing and externalizing problems. Lower morning cortisol values and subsequent flatter decline was found in subjects with ELS children compared to controls, showing group differences in diurnal cortisol secretion. Lower morning cortisol values were associated with more problem behaviour in the ELS group. Results show that ELS children exhibited increased psychopathological symptom severity and complexity associated with lower morning cortisol levels, which was not fully reflected in categorical assessments. This highlights the importance of incorporating dimensional assessments and neurobiological factors into psychopathological evaluations of children in out-of-home care in order to facilitate early identification of children at high risk for stress-related disorders.

Auditory neural correlates and neuroergonomics of driving assistance in a simulated virtual environment.

Objective.Driver assistance systems play an increasingly important role in modern vehicles. In the current level of technology, the driver must continuously supervise the driving and intervene whenever necessary when using driving assistance systems. The driver's attentiveness plays an important role in this human-machine interaction. Our aim was to design a simplistic technical framework for studying neural correlates of driving situations in a functional magnetic resonance imaging (fMRI) setting. In this work we assessed the feasibility of our proposed platform.Methods.We proposed a virtual environment (VE) simulation of driver assistance as a framework to investigate brain states related to partially automated driving. We focused on the processing of auditory signals during different driving scenarios as they have been shown to be advantageous as warning stimuli in driving situations. This provided the necessary groundwork to study brain auditory attentional networks under varying environmental demands in an fMRI setting. To this end, we conducted a study with 20 healthy participants to assess the feasibility of the VE simulation.Results.We demonstrated that the proposed VE can elicit driving related brain activation patterns. Relevant driving events evoked, in particular, responses in the bilateral auditory, sensory-motor, visual and insular cortices, which are related to perceptual and behavioral processes during driving assistance. Conceivably, attentional mechanisms increased somatosensory integration and reduced interoception, which are relevant for requesting interactions during partially automated driving.Significance.In modern vehicles, driver assistance technologies are playing an increasingly prevalent role. It is important to study the interaction between these systems and drivers' attentional responses to aid in future optimizations of the assistance systems. The proposed VE provides a foundational first step in this endeavor. Such simulated VEs provide a safe setting for experimentation with driving behaviors in a semi-naturalistic environment.

Functional connectivity signatures of NMDAR dysfunction in schizophrenia-integrating findings from imaging genetics and pharmaco-fMRI.

Both, pharmacological and genome-wide association studies suggest N-methyl-D-aspartate receptor (NMDAR) dysfunction and excitatory/inhibitory (E/I)-imbalance as a major pathophysiological mechanism of schizophrenia. The identification of shared fMRI brain signatures of genetically and pharmacologically induced NMDAR dysfunction may help to define biomarkers for patient stratification. NMDAR-related genetic and pharmacological effects on functional connectivity were investigated by integrating three different datasets: (A) resting state fMRI data from 146 patients with schizophrenia genotyped for the disease-associated genetic variant rs7191183 of GRIN2A (encoding the NMDAR 2 A subunit) as well as 142 healthy controls. (B) Pharmacological effects of the NMDAR antagonist ketamine and the GABA-A receptor agonist midazolam were obtained from a double-blind, crossover pharmaco-fMRI study in 28 healthy participants. (C) Regional gene expression profiles were estimated using a postmortem whole-brain microarray dataset from six healthy donors. A strong resemblance was observed between the effect of the genetic variant in schizophrenia and the ketamine versus midazolam contrast of connectivity suggestive for an associated E/I-imbalance. This similarity became more pronounced for regions with high density of NMDARs, glutamatergic neurons, and parvalbumin-positive interneurons. From a functional perspective, increased connectivity emerged between striato-pallido-thalamic regions and cortical regions of the auditory-sensory-motor network, while decreased connectivity was observed between auditory (superior temporal gyrus) and visual processing regions (lateral occipital cortex, fusiform gyrus, cuneus). Importantly, these imaging phenotypes were associated with the genetic variant, the differential effect of ketamine versus midazolam and schizophrenia (as compared to healthy controls). Moreover, the genetic variant was associated with language-related negative symptomatology which correlated with disturbed connectivity between the left posterior superior temporal gyrus and the superior lateral occipital cortex. Shared genetic and pharmacological functional connectivity profiles were suggestive of E/I-imbalance and associated with schizophrenia. The identified brain signatures may help to stratify patients with a common molecular disease pathway providing a basis for personalized psychiatry.

EEG Spectral Changes Linked to Psychiatric Medications: Computational Pipeline for Data Mining and Analysis.

The presented computational pipeline is designed to analyze drug-induced changes in EEG data from the Temple University EEG Corpus. The data is cleaned from artifacts, pre-processed, the averaged absolute and relative frequency powers are calculated and compared to a control group. Thus, different research hypotheses can be tested with the intention to reuse accessible data collections.

The Interplay between Vitamin D, Exposure of Anticholinergic Antipsychotics and Cognition in Schizophrenia.

Vitamin D deficiency is a frequent finding in schizophrenia and may contribute to neurocognitive dysfunction, a core element of the disease. However, there is limited knowledge about the neuropsychological profile of vitamin D deficiency-related cognitive deficits and their underlying molecular mechanisms. As an inductor of cytochrome P450 3A4, a lack of vitamin D might aggravate cognitive deficits by increased exposure to anticholinergic antipsychotics. This cross-sectional study aims to assess the relationship between 25-OH-vitamin D-serum concentrations, anticholinergic drug exposure and neurocognitive functioning (Brief Assessment of Cognition in Schizophrenia, BACS, and Trail Making Test, TMT) in 141 patients with schizophrenia. The anticholinergic drug exposure was estimated by adjusting the concentration of each drug for its individual muscarinic receptor affinity. Using regression analysis, we observed a positive relationship between vitamin D levels and processing speed (TMT-A and BACS Symbol Coding) as well as executive functioning (TMT-B and BACS Tower of London). Moreover, a negative impact of vitamin D on anticholinergic drug exposure emerged, but the latter did not significantly affect cognition. When other cognitive items were included as regressors, the impact of vitamin D remained only significant for the TMT-A. Among the different cognitive impairments in schizophrenia, vitamin D deficiency may most directly affect processing speed, which in turn may aggravate deficits in executive functioning. This finding is not explained by a cytochrome P450-mediated increased exposure to anticholinergic antipsychotics.

fMRI Neurofeedback-Enhanced Cognitive Reappraisal Training in Depression: A Double-Blind Comparison of Left and Right vlPFC Regulation.

Affective disorders are associated with maladaptive emotion regulation strategies. In particular, the left more than the right ventrolateral prefrontal cortex (vlPFC) may insufficiently regulate emotion processing, e.g., in the amygdala. A double-blind cross-over study investigated NF-supported cognitive reappraisal training in major depression (n = 42) and age- and gender-matched controls (n = 39). In a randomized order, participants trained to upregulate either the left or the right vlPFC during cognitive reappraisal of negative images on two separate days. We wanted to confirm regional specific NF effects with improved learning for left compared to right vlPFC (ClinicalTrials.gov NCT03183947). Brain responses and connectivity were studied with respect to training progress, gender, and clinical outcomes in a 4-week follow-up. Increase of vlPFC activity was stronger after NF training from the left- than the right-hemispheric ROI. This regional-specific NF effect during cognitive reappraisal was present across patients with depression and controls and supports a central role of the left vlPFC for cognitive reappraisal. Further, the activity in the left target region was associated with increased use of cognitive reappraisal strategies (r = 0.48). In the 4-week follow-up, 75% of patients with depression reported a successful application of learned strategies in everyday life and 55% a clinically meaningful symptom improvement suggesting clinical usability.

Data-Driven Approach to the Analysis of Real-Time FMRI Neurofeedback Data: Disorder-Specific Brain Synchrony in PTSD.

Brain-computer interfaces (BCIs) can be used in real-time fMRI neurofeedback (rtfMRI NF) investigations to provide feedback on brain activity to enable voluntary regulation of the blood-oxygen-level dependent (BOLD) signal from localized brain regions. However, the temporal pattern of successful self-regulation is dynamic and complex. In particular, the general linear model (GLM) assumes fixed temporal model functions and misses other dynamics. We propose a novel data-driven analyses approach for rtfMRI NF using intersubject covariance (ISC) analysis. The potential of ISC was examined in a reanalysis of data from 21 healthy individuals and nine patients with post-traumatic stress-disorder (PTSD) performing up-regulation of the anterior cingulate cortex (ACC). ISC in the PTSD group differed from healthy controls in a network including the right inferior frontal gyrus (IFG). In both cohorts, ISC decreased throughout the experiment indicating the development of individual regulation strategies. ISC analyses are a promising approach to reveal novel information on the mechanisms involved in voluntary self-regulation of brain signals and thus extend the results from GLM-based methods. ISC enables a novel set of research questions that can guide future neurofeedback and neuroimaging investigations.

Altered functional connectivity during evaluation of self-relevance in women with borderline personality disorder.

Self-relevant functional abnormalities and identity disorders constitute the core psychopathological components in borderline personality disorder (BPD). Evidence suggests that appraising the relevance of environmental information to the self may be altered in BPD. However, only a few studies have examined self-relevance (SR) in BPD, and the neural correlates of SR processing has not yet been investigated in this patient group. The current study sought to evaluate brain activation differences between female patients with BPD and healthy controls during SR processing. A task-based fMRI paradigm was applied to evaluate SR processing in 23 female patients with BPD and 23 matched healthy controls. Participants were presented with a set of short sentences and were instructed to rate the stimuli. The differences in fMRI signals between SR rating (task of interest) and valence rating (control task) were examined. During SR rating, participants showed elevated activations of the cortical midline structures (CMS), known to be involved in the processing of self-related stimuli. Furthermore, we observed an elevated activation of the supplementary motor area (SMA) and the regions belonging to the mirror neuron system (MNS). Using whole-brain, seed-based connectivity analysis on the task-based fMRI data, we studied connectivity of networks anchored to the main CMS regions. We found a discrepancy in the connectivity pattern between patients and controls regarding connectivity of the CMS regions with the basal ganglia-thalamus complex. These observations have two main implications: First, they confirm the involvement of the CMS in SR evaluations of our stimuli and add evidence about the involvement of an extended network including the MNS and the SMA in this task. Second, the functional connectivity profile observed in BPD provides evidence for an altered functional interplay between the CMS and the brain regions involved in salience detection and reward evaluation, including the basal ganglia and the thalamus.

Auditory mismatch processing: Role of paradigm and stimulus characteristics as detected by fMRI.

Auditory mismatch processing is accompanied by activation of a distributed brain network which can be detected by fMRI. However, the impact of different experimental designs such as event-related or block designs and different stimulus characteristics on the auditory mismatch response and the activity of this network remains controversial. In the present study, we applied five auditory mismatch paradigms with standard experimental designs and recorded fMRI in 31 healthy participants. Brain activity was analyzed using general linear models as well as classification approaches. The results stress a greater role of the type of the applied deviant stimulus compared to the experimental design. Moreover, the absolute number of the deviants as well as the length of the experimental run seems to play a greater role than the experimental design. The present study promotes optimization of experimental paradigms in the context of mismatch research. In particular, our findings contribute to designing auditory mismatch paradigms for application in clinical settings.

Neural correlates of fluctuations in the intermediate band for heart rate and respiration are related to interoceptive perception.

Supratentorial brain structures such as the insula and the cingulate cortex modulate the autonomic nervous system (ANS). The neural underpinnings of separate frequency bands for variability in cardiac and respiratory data have been suggested in explaining parasympathetic and sympathetic ANS modulation. As an extension, an intermediate (IM) band in peripheral physiology has been considered to reflect psychophysiological states during rest. Using functional magnetic resonance imaging (fMRI), we investigated the neural correlates associated with IM band variability in cardiac and respiratory rate and identified dissociable networks for LF, IM, and HF bands in both modalities. Cardiac and respiratory IM band fluctuations correlated with blood oxygen level-dependent (BOLD) signal in the mid and posterior insula and the secondary somatosensory area, that is, regions related to interoceptive perception. These data suggest that in addition to the commonly considered LF and HF bands, other frequency components represent relevant physiological constituents. The IM band may be instrumental for assessment of the CNS-ANS interaction. In particular, the relation between the IM band and interoception may be of physiological and clinical interest.

Impaired Subcortical Detection of Auditory Changes in Schizophrenia but Not in Major Depression.

The mismatch negativity is a cortical response to auditory changes and its reduction is a consistent finding in schizophrenia. Recent evidence revealed that the human brain detects auditory changes already at subcortical stages of the auditory pathway. This finding, however, raises the question where in the auditory hierarchy the schizophrenic deficit first evolves and whether the well-known cortical deficit may be a consequence of dysfunction at lower hierarchical levels. Finally, it should be resolved whether mismatch profiles differ between schizophrenia and affective disorders which exhibit auditory processing deficits as well. We used functional magnetic resonance imaging to assess auditory mismatch processing in 29 patients with schizophrenia, 27 patients with major depression, and 31 healthy control subjects. Analysis included whole-brain activation, region of interest, path and connectivity analysis. In schizophrenia, mismatch deficits emerged at all stages of the auditory pathway including the inferior colliculus, thalamus, auditory, and prefrontal cortex. In depression, deficits were observed in the prefrontal cortex only. Path analysis revealed that activation deficits propagated from subcortical to cortical nodes in a feed-forward mechanism. Finally, both patient groups exhibited reduced connectivity along this processing stream. Auditory mismatch impairments in schizophrenia already manifest at the subcortical level. Moreover, subcortical deficits contribute to the well-known cortical deficits and show specificity for schizophrenia. In contrast, depression is associated with cortical dysfunction only. Hence, schizophrenia and major depression exhibit different neural profiles of sensory processing deficits. Our findings add to a converging body of evidence for brainstem and thalamic dysfunction as a hallmark of schizophrenia.

A Novel Brain-Computer Interface Virtual Environment for Neurofeedback During Functional MRI.

Virtual environments (VEs), in the recent years, have become more prevalent in neuroscience. These VEs can offer great flexibility, replicability, and control over the presented stimuli in an immersive setting. With recent developments, it has become feasible to achieve higher-quality visuals and VEs at a reasonable investment. Our aim in this project was to develop and implement a novel real-time functional magnetic resonance imaging (rt-fMRI)-based neurofeedback (NF) training paradigm, taking into account new technological advances that allow us to integrate complex stimuli into a visually updated and engaging VE. We built upon and developed a first-person shooter in which the dynamic change of the VE was the feedback variable in the brain-computer interface (BCI). We designed a study to assess the feasibility of the BCI in creating an immersive VE for NF training. In a randomized single-blinded fMRI-based NF-training session, 24 participants were randomly allocated into one of two groups: active and reduced contingency NF. All participants completed three runs of the shooter-game VE lasting 10 min each. Brain activity in a supplementary motor area region of interest regulated the possible movement speed of the player's avatar and thus increased the reward probability. The gaming performance revealed that the participants were able to actively engage in game tasks and improve across sessions. All 24 participants reported being able to successfully employ NF strategies during the training while performing in-game tasks with significantly higher perceived NF control ratings in the NF group. Spectral analysis showed significant differential effects on brain activity between the groups. Connectivity analysis revealed significant differences, showing a lowered connectivity in the NF group compared to the reduced contingency-NF group. The self-assessment manikin ratings showed an increase in arousal in both groups but failed significance. Arousal has been linked to presence, or feelings of immersion, supporting the VE's objective. Long paradigms, such as NF in MRI settings, can lead to mental fatigue; therefore, VEs can help overcome such limitations. The rewarding achievements from gaming targets can lead to implicit learning of self-regulation and may broaden the scope of NF applications.