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Emotion self-regulation training in major depressive disorder using simultaneous real-time fMRI and EEG neurofeedback.

ABSTRACT: Simultaneous real-time fMRI and EEG neurofeedback (rtfMRI-EEG-nf) is an emerging neuromodulation approach, that enables simultaneous volitional regulation of both hemodynamic (BOLD fMRI) and electrophysiological (EEG) brain activities. Here we report the first application of rtfMRI-EEG-nf for emotion self-regulation training in patients with major depressive disorder (MDD). In this proof-of-concept study, MDD patients in the experimental group (n = 16) used rtfMRI-EEG-nf during a happy emotion induction task to simultaneously upregulate two fMRI and two EEG activity measures relevant to MDD. The target measures included BOLD activities of the left amygdala (LA) and left rostral anterior cingulate cortex (rACC), and frontal EEG asymmetries in the alpha band (FAA, [7.5-12.5] Hz) and high-beta band (FBA, [21-30] Hz). MDD patients in the control group (n = 8) were provided with sham feedback signals. An advanced procedure for improved real-time EEG-fMRI artifact correction was implemented. The experimental group participants demonstrated significant upregulation of the LA BOLD activity, FAA, and FBA during the rtfMRI-EEG-nf task, as well as significant enhancement in fMRI connectivity between the LA and left rACC. Average individual FAA changes during the rtfMRI-EEG-nf task positively correlated with depression and anhedonia severities, and negatively correlated with after-vs-before changes in depressed mood ratings. Temporal correlations between the FAA and FBA time courses and the LA BOLD activity were significantly enhanced during the rtfMRI-EEG-nf task. The experimental group participants reported significant mood improvements after the training. Our results suggest that the rtfMRI-EEG-nf may have potential for treatment of MDD.

SUBMITTER: Zotev V

PROVIDER: S-EPMC7334611 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Emotion self-regulation training in major depressive disorder using simultaneous real-time fMRI and EEG neurofeedback.

Zotev Vadim V Mayeli Ahmad A Misaki Masaya M Bodurka Jerzy J

NeuroImage. Clinical 20200627

Simultaneous real-time fMRI and EEG neurofeedback (rtfMRI-EEG-nf) is an emerging neuromodulation approach, that enables simultaneous volitional regulation of both hemodynamic (BOLD fMRI) and electrophysiological (EEG) brain activities. Here we report the first application of rtfMRI-EEG-nf for emotion self-regulation training in patients with major depressive disorder (MDD). In this proof-of-concept study, MDD patients in the experimental group (n = 16) used rtfMRI-EEG-nf during a happy emotion i ...[more]

PMID: 32623140

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Project description:Real-time fMRI neurofeedback (rtfMRI-nf) left amygdala (LA) training is a promising intervention for major depressive disorder (MDD). We have previously proposed that rtfMRI-nf LA training may reverse depression-associated regional impairments in neuroplasticity and restore information flow within emotion-regulating neural circuits. Inflammatory cytokines as well as the neuroactive metabolites of an immunoregulatory pathway, i.e. the kynurenine pathway (KP), have previously been implicated in neuroplasticity. Therefore, in this proof-of-principle study, we investigated the association between rtfMRI-nf LA training and circulating inflammatory mediators and KP metabolites. Based on our previous work, the primary variable of interest was the ratio of the NMDA-receptor antagonist, kynurenic acid to the NMDA receptor agonist, quinolinic acid (KynA/QA), a putative neuroprotective index. We tested two main hypotheses. i. Whether rtfMRI-nf acutely modulates KynA/QA, and ii. whether baseline KynA/QA predicts response to rtfMRI-nf. Twenty-nine unmedicated participants who met DSM-5 criteria for MDD based on the Mini-International Neuropsychiatric Interview and had current depressive symptoms (Montgomery-Åsberg Depression Rating Scale (MADRS) score > 6) completed two rtfMRI-nf sessions to upregulate LA activity (Visit1 and 2), as well as a follow-up (Visit3) without rtfMRI-nf. All visits occurred at two-week intervals. At all three visits, the MADRS was administered to participants and serum samples for the quantification of inflammatory cytokines and KP metabolites were obtained. First, the longitudinal changes in the MADRS score and immune markers were tested by linear mixed effect model analysis. Further, utilizing a linear regression model, we investigated the relationship between rtfMRI-nf performance and immune markers. After two sessions of rtfMRI-nf, MADRS scores were significantly reduced (t[58] = -4.07, p = 0.009, d = 0.56). Thirteen participants showed a ≥ 25% reduction in the MADRS score (the partial responder group). There was a significant effect of visit (F[2,58] = 3.17, p = 0.05) for the neuroprotective index, KynA to 3-hydroxykynurenine (3-HK), that was driven by a significant increase in KynA/3-HK between Visit1 and Visit3 (t[58] = 2.50, p = 0.03, d = 0.38). A higher baseline level of KynA/QA (β = 5.23, p = 0.06; rho = 0.49, p = 0.02) was associated with greater ability to upregulate the LA. Finally, for exploratory purposes correlation analyses were performed between the partial responder and the non-responder groups as well as in the whole sample including all KP metabolites and cytokines. In the partial responder group, greater ability to upregulate the LA was correlated with an increase in KynA/QA after rtfMRI-nf (rho = 0.75, p = 0.03). The results are consistent with the possibility that rtfMRI-nf decreases metabolism down the so-called neurotoxic branch of the KP. Nevertheless, non-specific effects cannot be ruled out due to the lack of a sham control. Future, controlled studies are needed to determine whether the increase in KynA/3HK and KynA/QA is specific to rtfMRI-nf or whether it is a non-specific correlate of the resolution of depressive symptoms. Similarly, replication studies are needed to determine whether KynA/QA has clinical utility as a treatment response biomarker.

Project description:We have previously shown that in participants with major depressive disorder (MDD) trained to upregulate their amygdala hemodynamic response during positive autobiographical memory (AM) recall with real-time fMRI neurofeedback (rtfMRI-nf) training, depressive symptoms diminish. Here, we assessed the effect of rtfMRI-nf on amygdala functional connectivity during both positive AM recall and rest.The current manuscript consists of a secondary analysis on data from our published clinical trial of neurofeedback. Patients with MDD completed two rtfMRI-nf sessions (18 received amygdala rtfMRI-nf, 16 received control parietal rtfMRI-nf). One-week prior-to and following training participants also completed a resting-state fMRI scan. A GLM-based functional connectivity analysis was applied using a seed ROI in the left amygdala. We compared amygdala functional connectivity changes while recalling positive AMs from the baseline run to the final transfer run during rtfMRI-nf training, as well during rest from the baseline to the one-week follow-up visit. Finally, we assessed the correlation between change in depression scores and change in amygdala connectivity, as well as correlations between amygdala regulation success and connectivity changes.Following training, amygdala connectivity during positive AM recall increased with widespread regions in the frontal and limbic network. During rest, amygdala connectivity increased following training within the fronto-temporal-limbic network. During both task and resting-state analyses, amygdala-temporal pole connectivity decreased. We identified increased amygdala-precuneus and amygdala-inferior frontal gyrus connectivity during positive memory recall and increased amygdala-precuneus and amygdala-thalamus connectivity during rest as functional connectivity changes that explained significant variance in symptom improvement. Amygdala-precuneus connectivity changes also explain a significant amount of variance in neurofeedback regulation success.Neurofeedback training to increase amygdala hemodynamic activity during positive AM recall increased amygdala connectivity with regions involved in self-referential, salience, and reward processing. Results suggest future targets for neurofeedback interventions, particularly interventions involving the precuneus.

Project description:Posttraumatic stress disorder (PTSD) is a chronic and disabling neuropsychiatric disorder characterized by insufficient top-down modulation of the amygdala activity by the prefrontal cortex. Real-time fMRI neurofeedback (rtfMRI-nf) is an emerging method with potential for modifying the amygdala-prefrontal interactions. We report the first controlled emotion self-regulation study in veterans with combat-related PTSD utilizing rtfMRI-nf of the amygdala activity. PTSD patients in the experimental group (EG, n?=?20) learned to upregulate blood?oxygenation-level-dependent (BOLD) activity of the left amygdala (LA) using the rtfMRI-nf during a happy emotion induction task. PTSD patients in the control group (CG, n?=?11) were provided with a sham rtfMRI-nf. The study included three rtfMRI-nf training sessions, and EEG recordings were performed simultaneously with fMRI. PTSD severity was assessed before and after the training using the Clinician-Administered PTSD Scale (CAPS). The EG participants who completed the study showed a significant reduction in total CAPS ratings, including significant reductions in avoidance and hyperarousal symptoms. They also exhibited a significant reduction in comorbid depression severity. Overall, 80% of the EG participants demonstrated clinically meaningful reductions in CAPS ratings, compared to 38% in the CG. No significant difference in the CAPS rating changes was observed between the groups. During the first rtfMRI-nf session, functional connectivity of the LA with the orbitofrontal cortex (OFC) and the dorsolateral prefrontal cortex (DLPFC) was progressively enhanced, and this enhancement significantly and positively correlated with the initial CAPS ratings. Left-lateralized enhancement in upper alpha EEG coherence also exhibited a significant positive correlation with the initial CAPS. Reduction in PTSD severity between the first and last rtfMRI-nf sessions significantly correlated with enhancement in functional connectivity between the LA and the left DLPFC. Our results demonstrate that the rtfMRI-nf of the amygdala activity has the potential to correct the amygdala-prefrontal functional connectivity deficiencies specific to PTSD.

Project description:Neurofeedback (NFB) enables the voluntary regulation of brain activity, with promising applications to enhance and recover emotion and cognitive processes, and their underlying neurobiology. It remains unclear whether NFB can be used to aid and sustain complex emotions, with ecological validity implications. We provide a technical proof of concept of a novel real-time functional magnetic resonance imaging (rtfMRI) NFB procedure. Using rtfMRI-NFB, we enabled participants to voluntarily enhance their own neural activity while they experienced complex emotions. The rtfMRI-NFB software (FRIEND Engine) was adapted to provide a virtual environment as brain computer interface (BCI) and musical excerpts to induce two emotions (tenderness and anguish), aided by participants' preferred personalized strategies to maximize the intensity of these emotions. Eight participants from two experimental sites performed rtfMRI-NFB on two consecutive days in a counterbalanced design. On one day, rtfMRI-NFB was delivered to participants using a region of interest (ROI) method, while on the other day using a support vector machine (SVM) classifier. Our multimodal VR/NFB approach was technically feasible and robust as a method for real-time measurement of the neural correlates of complex emotional states and their voluntary modulation. Guided by the color changes of the virtual environment BCI during rtfMRI-NFB, participants successfully increased in real time, the activity of the septo-hypothalamic area and the amygdala during the ROI based rtfMRI-NFB, and successfully evoked distributed patterns of brain activity classified as tenderness and anguish during SVM-based rtfMRI-NFB. Offline fMRI analyses confirmed that during tenderness rtfMRI-NFB conditions, participants recruited the septo-hypothalamic area and other regions ascribed to social affiliative emotions (medial frontal / temporal pole and precuneus). During anguish rtfMRI-NFB conditions, participants recruited the amygdala and other dorsolateral prefrontal and additional regions associated with negative affect. These findings were robust and were demonstrable at the individual subject level, and were reflected in self-reported emotion intensity during rtfMRI-NFB, being observed with both ROI and SVM methods and across the two sites. Our multimodal VR/rtfMRI-NFB protocol provides an engaging tool for brain-based interventions to enhance emotional states in healthy subjects and may find applications in clinical conditions associated with anxiety, stress and impaired empathy among others.

Project description:Amygdala dysregulation has been shown to be central to the pathophysiology of posttraumatic stress disorder (PTSD) representing a critical treatment target. Here, amygdala downregulation was targeted using real-time fMRI neurofeedback (rt-fMRI-nf) in patients with PTSD, allowing us to examine further the regulation of emotional states during symptom provocation. Patients (n = 10) completed three sessions of rt-fMRI-nf with the instruction to downregulate activation in the amygdala, while viewing personalized trauma words. Amygdala downregulation was assessed by contrasting (a) regulate trials, with (b) viewing trauma words and not attempting to regulate. Training was followed by one transfer run not involving neurofeedback. Generalized psychophysiological interaction (gPPI) and dynamic causal modeling (DCM) analyses were also computed to explore task-based functional connectivity and causal structure, respectively. It was found that PTSD patients were able to successfully downregulate both right and left amygdala activation, showing sustained effects within the transfer run. Increased activation in the dorsolateral and ventrolateral prefrontal cortex (PFC), regions related to emotion regulation, was observed during regulate as compared with view conditions. Importantly, activation in the PFC, rostral anterior cingulate cortex, and the insula, were negatively correlated to PTSD dissociative symptoms in the transfer run. Increased functional connectivity between the amygdala- and both the dorsolateral and dorsomedial PFC was found during regulate, as compared with view conditions during neurofeedback training. Finally, our DCM analysis exploring directional structure suggested that amygdala downregulation involves both top-down and bottom-up information flow with regard to observed PFC-amygdala connectivity. This is the first demonstration of successful downregulation of the amygdala using rt-fMRI-nf in PTSD, which was critically sustained in a subsequent transfer run without neurofeedback, and corresponded to increased connectivity with prefrontal regions involved in emotion regulation during the intervention. Hum Brain Mapp 38:541-560, 2017. © 2016 Wiley Periodicals, Inc.

Project description:Despite the existence of several emotion regulation studies using neurofeedback, interactions among a small number of regions were evaluated, and therefore, further investigation is needed to understand the interactions of the brain regions involved in emotion regulation. We implemented electroencephalography (EEG) neurofeedback with simultaneous functional magnetic resonance imaging (fMRI) using a modified happiness-inducing task through autobiographical memories to upregulate positive emotion. Then, an explorative analysis of whole brain regions was done to understand the effect of neurofeedback on brain activity and the interaction of whole brain regions involved in emotion regulation. The participants in the control and experimental groups were asked to do emotion regulation while viewing positive images of autobiographical memories and getting sham or real (based on alpha asymmetry) EEG neurofeedback, respectively. The proposed multimodal approach quantified the effects of EEG neurofeedback in changing EEG alpha power, fMRI blood oxygenation level-dependent (BOLD) activity of prefrontal, occipital, parietal, and limbic regions (up to 1.9% increase), and functional connectivity in/between prefrontal, parietal, limbic system, and insula in the experimental group. New connectivity links were identified by comparing the brain functional connectivity between experimental conditions (Upregulation and View blocks) and also by comparing the brain connectivity of the experimental and control groups. Psychometric assessments confirmed significant changes in positive and negative mood states in the experimental group by neurofeedback. Based on the exploratory analysis of activity and connectivity among all brain regions involved in emotion regions, we found significant BOLD and functional connectivity increases due to EEG neurofeedback in the experimental group, but no learning effect was observed in the control group. The results reveal several new connections among brain regions as a result of EEG neurofeedback which can be justified according to emotion regulation models and the role of those regions in emotion regulation and recalling positive autobiographical memories.

Dataset Information

Emotion self-regulation training in major depressive disorder using simultaneous real-time fMRI and EEG neurofeedback.

Publications

Emotion self-regulation training in major depressive disorder using simultaneous real-time fMRI and EEG neurofeedback.

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