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.

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.

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.

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.

Rt-fMRI neurofeedback-guided cognitive reappraisal training modulates amygdala responsivity in posttraumatic stress disorder.

BACKGROUND: Traumatic experiences are associated with neurofunctional dysregulations in key regions of the emotion regulation circuits. In particular, amygdala responsivity to negative stimuli is exaggerated while engagement of prefrontal regulatory control regions is attenuated. Successful application of emotion regulation (ER) strategies may counteract this disbalance, however, application of learned strategies in daily life is hampered in individuals afflicted by posttraumatic stress disorder (PTSD). We hypothesized that a single session of real-time fMRI (rtfMRI) guided upregulation of prefrontal regions during an emotion regulation task enhances self-control during exposure to negative stimuli and facilitates transfer of the learned ER skills to daily life. METHODS: In a cross-over design, individuals with a PTSD diagnosis after a single traumatic event (n = 20) according to DSM-IV-TR criteria and individuals without a formal psychiatric diagnosis (n = 21) underwent a cognitive reappraisal training. In randomized order, all participants completed two rtfMRI neurofeedback (NF) runs targeting the left lateral prefrontal cortex (lPFC) and two control runs without NF (NoNF) while using cognitive reappraisal to reduce their emotional response to negative scenes. During the NoNF runs, two %%-signs were displayed instead of the two-digit feedback (FB) to achieve a comparable visual stimulation. The project aimed at defining the clinical potential of the training according to three success markers: (1) NF induced changes in left lateral prefrontal cortex and bilateral amygdala activity during the regulation of aversive scenes compared to cognitive reappraisal alone (primary registered outcome), (2) associated changes on the symptomatic and behavioral level such as indicated by PTSD symptom severity and affect ratings, (3) clinical utility such as indicated by perceived efficacy, acceptance, and transfer to daily life measured four weeks after the training. RESULTS: In comparison to the reappraisal without feedback, a neurofeedback-specific decrease in the left lateral PFC (d = 0.54) alongside an attenuation of amygdala responses (d = 0.33) emerged. Reduced amygdala responses during NF were associated with symptom improvement (r = -0.42) and less negative affect (r = -0.63) at follow-up. The difference in symptom scores exceeds requirements for a minimal clinically important difference and corresponds to a medium effect size (d = 0.64). Importantly, 75% of individuals with PTSD used the strategies in daily life during a one-month follow-up period and perceived the training as efficient. CONCLUSION: Our findings suggest beneficial effects of the NF training indicated by reduced amygdala responses that were associated with improved symptom severity and affective state four weeks after the NF training as well as patient-centered perceived control during the training, helpfulness and application of strategies in daily life. However, reduced prefrontal involvement was unexpected. The study suggests good tolerability of the training protocol and potential for clinical use in the treatment of PTSD.

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.