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.

Clinical Application of Real-Time fMRI-Based Neurofeedback for Depression.

Real-time functional magnetic resonance imaging-based neurofeedback (rt-fMRI NF) is a recent technique used to train self-regulation of circumscribed brain areas or networks. For clinical applications in depression, NF training targets brain areas with disturbed activation patterns, such as heightened reactivity of amygdala in response to negative stimuli, in order to normalize the neurophysiology and their behavioral correlates. Recent studies have targeted emotion processing areas such as the amygdala, the salience network, and top-down control areas such as the lateral prefrontal cortex. Different methods of rt-fMRI-based NF in depression, their potential for clinical improvement, and most recent advancements of this technology are discussed considering their role for future clinical applications. Initial findings of randomized controlled trials show promising results. However, for lasting treatment effects, clinical efficiency and optimal target regions, tasks, control conditions, and duration of training need to be established.

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.

Autonomic nervous system responses in the intermediate band to cranial cutaneous stimulation.

Cardiovascular rhythms representing functional states of the autonomic nervous system (ANS) are insufficiently reflected by the current physiological model based on low and high frequency bands (LF, HF, resp.). An intermediate (IM) frequency band generated by a brainstem pacemaker was included in systemic physiological ANS analyses of forehead skin perfusion (SP), ECG, and respiration. Data of 38 healthy participants at T0 and T1 (+1 week) before, during, and following osteopathic cranial vault hold (CVH) stimulation were analyzed including momentary frequencies of highest amplitude, amplitudes in low (0.05-0.12 Hz), IM (0.12-0.18 Hz), and high (0.18-0.4 Hz) frequency bands, and established heart rate variability (HRV) metrics. During CVH, LF interval durations increased, whereas IM/HF band durations decreased significantly. Amplitudes increased significantly in all frequency bands. A cluster analysis found one response pattern dominated by IM activity (47% of participants) with highly stable 0.08 Hz oscillation to CVH, and one dominated by LF activity (0.10 Hz) at T0, increasing to IM activity at T1. Showing frequency ratios at ≈3:1, respiration was not responsible for oscillations in PPG during CVH. HRV revealed no significant responses. Rhythmic patterns in SP and respiration matched previous findings on a reticular "0.15 Hz rhythm". Involvement of baroreflex pathways is discussed as alternative explanation.

On the cardiorespiratory coordination assessed by the photoplethysmography imaging technique.

Cardiorespiratory coordination (CRC) probes the interaction between cardiac and respiratory oscillators in which cardiac and respiratory activity are synchronized, with individual heartbeats occurring at approximately the same temporal positions during several breathing cycles. An increase of CRC has previously been related to pathological stressful states. We studied CRC employing coordigrams computed from non-contact photoplethysmography imaging (PPGI) and respiratory data using the optical flow method. In a blocked study design, we applied the cold pressure test (CPT), water at ambient temperature (AWT), and intermittent resting conditions. In controls (no intervention), CRC remained on initial low levels throughout measurements. In the experimental group (AWT and CPT intervention), CRC decreased during AWT and CPT. Following both interventions, CRC increased significantly, with a rebound effect following AWT. In controls, HR increased steadily over time. CPT evoked a significant HR increase which correlated with subjective stress/pain ratings. The CRC increase following AWT correlated significantly with subjective pain (r = .79) and stress (r = .63) ratings. Furthermore, we observed a significant correlation (r = - .80) between mean RMSSD and mean duration of CRC, which further supports an association between autonomic state and CRC level. CRC analysis obtained from cutaneous tissue perfusion data therefore appears to be a sensitive and useful method for the study of CRC and ANS activity. Future studies need to investigate the physiological principles and clinical significance of these findings.

Validation of subjective manual palpation using objective physiological recordings of the cranial rhythmic impulse during osteopathic manipulative intervention.

Intermediate (IM) band physiology in skin blood flow exhibits parallels with the primary respiratory mechanism (PRM) or cranial rhythmic impulse (CRI), controversial concepts of osteopathy in the cranial field (OCF). Owing to inconsistent manual palpation results, validity of evidence of PRM/CRI activity has been questionable. We therefore tried to validate manual palpation combining instrumented tracking and algorithmic objectivation of frequencies, amplitudes, and phases. Using a standard OCF intervention, cranial vault hold (CVH), two OCF experts palpated and digitally marked CRI frequencies in 25 healthy adults. Autonomic nervous system (ANS) activity in low frequency (LF) and IM band in photoplethysmographic (PPG) forehead skin recordings was probed with momentary frequency of highest amplitude (MFHA) and wavelet amplitude spectra (WAS) in examiners and participants. Palpation errors and frequency expectation bias during CVH were analyzed for phases of MFHA and CRI. Palpated CRI frequencies (0.05-0.08 Hz) correlated highly with mean MFHA frequencies with 1:1 ratio in 77% of participants (LF-responders; 0.072 Hz) and with 2:1 ratio in 23% of participants (IM-responders; 0.147 Hz). WAS analysis in both groups revealed integer number (harmonic) waves in (very) low and IM bands in > 98% of palpated intervals. Phase analyses in participants and examiners suggested synchronization between MFHA and CRI in a subset of LF-responders. IM band physiology in forehead PPG may offer a sensible physiological correlate of palpated CRI activity. Possible coordination or synchronization effects with additional physiological signals and between examiners and participants should be investigated in future studies.

On the spatial phase distribution of cutaneous low-frequency perfusion oscillations.

Distributed cutaneous tissue blood volume oscillations contain information on autonomic nervous system (ANS) regulation of cardiorespiratory activity as well as dominating thermoregulation. ANS associated with low-frequency oscillations can be quantified in terms of frequencies, amplitudes, and phase shifts. The relative order between these faculties may be disturbed by conditions colloquially termed 'stress'. Photoplethysmography imaging, an optical non-invasive diagnostic technique provides information on cutaneous tissue perfusion in the temporal and spatial domains. Using the cold pressure test (CPT) in thirteen healthy volunteers as a well-studied experimental intervention, we present a method for evaluating phase shifts in low- and intermediate frequency bands in forehead cutaneous perfusion mapping. Phase shift changes were analysed in low- and intermediate frequency ranges from 0.05 Hz to 0.18 Hz. We observed that time waveforms increasingly desynchronised in various areas of the scanned area throughout measurements. An increase of IM band phase desynchronization observed throughout measurements was comparable in experimental and control group, suggesting a time effect possibly due to overshooting the optimal relaxation duration. CPT triggered an increase in the number of points phase-shifted to the reference that was specific to the low frequency range for phase-shift thresholds defined as π/4, 3π/8, and π/2 rad, respectively. Phase shifts in forehead blood oscillations may infer changes of vascular tone due to activity of various neural systems. We present an innovative method for the phase shift analysis of cutaneous tissue perfusion that appears promising to assess ANS change processes related to physical or psychological stress. More comprehensive studies are needed to further investigate the reliability and physiological significance of findings.

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.

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.

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.

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.