Correlation between amygdala BOLD activity and frontal EEG asymmetry during real-time fMRI neurofeedback training in patients with depression

Real-time fMRI neurofeedback (rtfMRI-nf) is an emerging approach for studies and novel treatments of major depressive disorder (MDD). EEG performed simultaneously with an rtfMRI-nf procedure allows an independent evaluation of rtfMRI-nf brain modulation effects. Frontal EEG asymmetry in the alpha band is a widely used measure of emotion and motivation that shows profound changes in depression. However, it has never been directly related to simultaneously acquired fMRI data. We report the first study investigating electrophysiological correlates of the rtfMRI-nf procedure, by combining rtfMRI-nf with simultaneous and passive EEG recordings. In this pilot study, MDD patients in the experimental group (n=13) learned to upregulate BOLD activity of the left amygdala using an rtfMRI-nf during a happy emotion induction task. MDD patients in the control group (n=11) were provided with a sham rtfMRI-nf. Correlations between frontal EEG asymmetry in the upper alpha band and BOLD activity across the brain were examined. Average individual changes in frontal EEG asymmetry during the rtfMRI-nf task for the experimental group showed a significant positive correlation with the MDD patients' depression severity ratings, consistent with an inverse correlation between the depression severity and frontal EEG asymmetry at rest. Temporal correlations between frontal EEG asymmetry and BOLD activity were significantly enhanced, during the rtfMRI-nf task, for the amygdala and many regions associated with emotion regulation. Our findings demonstrate an important link between amygdala BOLD activity and frontal EEG asymmetry. Our EEG asymmetry results suggest that the rtfMRI-nf training targeting the amygdala is beneficial to MDD patients, and that alpha-asymmetry EEG-nf would be compatible with the amygdala rtfMRI-nf. Combination of the two could enhance emotion regulation training and benefit MDD patients.Comment: 28 pages, 16 figures, to appear in NeuroImage: Clinica

Low Cost MR Compatible Haptic Stimulation with Application to fMRI Neurofeedback

The most common feedback displays in the fMRI environment are visual, e.g., in which participants try to increase or decrease the level of a thermometer. However, haptic feedback is increasingly valued in computer interaction tasks, particularly for real-time fMRI feedback. fMRI-neurofeedback is a clinical intervention that has not yet taken advantage of this trend. Here we describe a low-cost, user-friendly, MR-compatible system that can provide graded haptic vibrotactile stimulation in an initial application to fMRI neurofeedback. We also present a feasibility demonstration showing that we could successfully set up the system and obtain data in the context of a neurofeedback paradigm. We conclude that vibrotactile stimulation using this low-cost system is a viable method of feedback presentation, and encourage neurofeedback researchers to incorporate this type of feedback into their studies

Control freaks: Towards optimal selection of control conditions for fMRI neurofeedback studies

fMRI Neurofeedback research employs many different control conditions. Currently, there is no consensus as to which control condition is best, and the answer depends on what aspects of the neurofeedback-training design one is trying to control for. These aspects can range from determining whether participants can learn to control brain activity via neurofeedback to determining whether there are clinically significant effects of the neurofeedback intervention. Lack of consensus over criteria for control conditions has hampered the design and interpretation of studies employing neurofeedback protocols. This paper presents an overview of the most commonly employed control conditions currently used in neurofeedback studies and discusses their advantages and disadvantages. Control conditions covered include no control, treatment-as-usual, bidirectional-regulation control, feedback of an alternative brain signal, sham feedback, and mental-rehearsal control. We conclude that the selection of the control condition(s) should be determined by the specific research goal of the study and best procedures that effectively control for relevant confounding factor

Prefrontal Control of the Amygdala during Real-Time fMRI Neurofeedback Training of Emotion Regulation

We would like to thank Dr. Gang Chen of the National Institute of Mental Health for his helpful advices regarding SVAR modeling.Conceived and designed the experiments: JB VZ WCD. Performed the experiments: VZ RP JB KDY. Analyzed the data: VZ. Contributed reagents/materials/analysis tools: JB VZ RP KDY. Wrote the paper: VZ JB WCD KDY RP.We observed in a previous study (PLoS ONE 6:e24522) that the self-regulation of amygdala activity via real-time fMRI neurofeedback (rtfMRI-nf) with positive emotion induction was associated, in healthy participants, with an enhancement in the functional connectivity between the left amygdala (LA) and six regions of the prefrontal cortex. These regions included the left rostral anterior cingulate cortex (rACC), bilateral dorsomedial prefrontal cortex (DMPFC), bilateral superior frontal gyrus (SFG), and right medial frontopolar cortex (MFPC). Together with the LA, these six prefrontal regions thus formed the functional neuroanatomical network engaged during the rtfMRI-nf procedure. Here we perform a structural vector autoregression (SVAR) analysis of the effective connectivity for this network. The SVAR analysis demonstrates that the left rACC plays an important role during the rtfMRI-nf training, modulating the LA and the other network regions. According to the analysis, the rtfMRI-nf training leads to a significant enhancement in the time-lagged effect of the left rACC on the LA, potentially consistent with the ipsilateral distribution of the monosynaptic projections between these regions. The training is also accompanied by significant increases in the instantaneous (contemporaneous) effects of the left rACC on four other regions – the bilateral DMPFC, the right MFPC, and the left SFG. The instantaneous effects of the LA on the bilateral DMPFC are also significantly enhanced. Our results are consistent with a broad literature supporting the role of the rACC in emotion processing and regulation. Our exploratory analysis provides, for the first time, insights into the causal relationships within the network of regions engaged during the rtfMRI-nf procedure targeting the amygdala. It suggests that the rACC may constitute a promising target for rtfMRI-nf training along with the amygdala in patients with affective disorders, particularly posttraumatic stress disorder (PTSD).Yeshttp://www.plosone.org/static/editorial#pee

Linguistic analysis of the autobiographical memories of individuals with major depressive disorder.

BACKGROUND:Major depressive disorder (MDD) is characterized by biases in memory, attention, and cognition. The present study utilized the Linguistic Inquiry and Word Count (LIWC) to examine the content of specific autobiographical memories (AMs) recalled by individuals with MDD during an autobiographical memory task. METHODS:We examined various features of the text (including use of affective, cognitive, and self-referential terms), as well as their associations with clinical and cognitive features of MDD (depression severity, autobiographical memory specificity, amygdala activity), in 45 unmedicated adults with MDD compared to 61 healthy controls. RESULTS:When recalling positive memories MDD individuals used the word "I" less, fewer positive words, more words indicating present focus (present tense verbs), and fewer words overall to describe memories compared to controls. When recalling negative memories, MDD individuals used "I" more, more words indicating present focus, and more words overall to describe memories relative to controls. Depression severity was correlated with word count, the use of "I", and words indicating present focus in negative memories and inversely correlated with word count and the use of "I" in positive memories. Autobiographical memory specificity was correlated with word count, the use of "I", and words indicating present focus for positive memories and inversely correlated with the use of "I" and words indicating present focus for negative memories. LIMITATIONS:Due to the nature of AM recall, we could not control for the number of memories which participants recalled in each mnemonic category. CONCLUSIONS:Results align with literature implicating rumination and intensive self-focus in depression and suggest that interventions targeting specific word use may be therapeutically beneficial in the treatment of MDD

Functional Neuroimaging Correlates of Autobiographical Memory Deficits in Subjects at Risk for Depression

Overgeneral autobiographical memory (AM) manifests in individuals with major depressive disorder (MDD) tested during depressed (dMDD) or remitted phases (rMDD), and healthy individuals at high-risk (HR) for developing MDD. The current study aimed to elucidate differences in hemodynamic correlates of AM recall between rMDDs, HRs, and controls (HCs) to identify neural changes following previous depressive episodes without the confound of current depressed mood. HCs, HRs, and unmedicated rMDDs (n = 20/group) underwent fMRI while recalling AMs in response to emotionally valenced cue words. HRs and rMDDs recalled fewer specific and more categorical AMs relative to HCs. During specific AM recall, HRs had increased activity relative to rMDDs and HCs in left ventrolateral prefrontal cortex (VLPFC) and lateral orbitofrontal cortex. During positive specific AM recall, HRs and HCs had increased activity relative to rMDDs in bilateral dorsomedial prefrontal cortex (DMPFC) and left precuneus. During negative specific AM recall HRs and HCs had increased activity in left VLPFC and right DMPFC, while rMDDs had increased activity relative to HRs and HCs in right DLPFC and precuneus. Differential recruitment of medial prefrontal regions implicated in emotional control suggests experiencing a depressive episode may consequently reduce one’s ability to regulate emotional responses during AM recall

Real-time FMRI neurofeedback training of amygdala activity in patients with major depressive disorder.

BACKGROUND: Amygdala hemodynamic responses to positive stimuli are attenuated in major depressive disorder (MDD), and normalize with remission. Real-time functional MRI neurofeedback (rtfMRI-nf) offers a non-invasive method to modulate this regional activity. We examined whether depressed participants can use rtfMRI-nf to enhance amygdala responses to positive autobiographical memories, and whether this ability alters symptom severity. METHODS: Unmedicated MDD subjects were assigned to receive rtfMRI-nf from either left amygdala (LA; experimental group, n = 14) or the horizontal segment of the intraparietal sulcus (HIPS; control group, n = 7) and instructed to contemplate happy autobiographical memories (AMs) to raise the level of a bar representing the hemodynamic signal from the target region to a target level. This 40s Happy condition alternated with 40s blocks of rest and counting backwards. A final Transfer run without neurofeedback information was included. RESULTS: Participants in the experimental group upregulated their amygdala responses during positive AM recall. Significant pre-post scan decreases in anxiety ratings and increases in happiness ratings were evident in the experimental versus control group. A whole brain analysis showed that during the transfer run, participants in the experimental group had increased activity compared to the control group in left superior temporal gyrus and temporal polar cortex, and right thalamus. CONCLUSIONS: Using rtfMRI-nf from the left amygdala during recall of positive AMs, depressed subjects were able to self-regulate their amygdala response, resulting in improved mood. Results from this proof-of-concept study suggest that rtfMRI-nf training with positive AM recall holds potential as a novel therapeutic approach in the treatment of depression

Altered task-based and resting-state amygdala functional connectivity following real-time fMRI amygdala neurofeedback training in major depressive disorder

Background: 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. Method: 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. Results: 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. Conclusions: 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. Keywords: Neurofeedback, Amygdala, Functional connectivity, Depression, Positive memory recall, Resting-stat

Trends in the rACC and amygdala effects on the other network regions according to the multivariate SVAR analyses for seven ROIs.

<p>The table contains linear trend <i>t</i>-statistics for the SVAR path coefficients across the six experimental runs (RE…TR) with the corresponding group <i>P</i>-values. Each data row corresponds to a subplot in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0079184#pone-0079184-g006" target="_blank">Fig. 6</a>. Notations are the same as in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0079184#pone-0079184-g006" target="_blank">Fig. 6</a>.</p>*<p>indicate significant effect.</p

Interactions within the network suggested by the multivariate VAR analysis.

<p>Results of the multivariate first-order vector autoregression (VAR) analysis for the network of seven ROIs depicted in Fig. 1. The four subplots show meta-analytic group statistics for path coefficients for the following groups and contrasts. (A) Experimental group (EG), neurofeedback Run 3. (B) Control group (CG), Run 3. (C) Difference between Run 3 and Rest for EG. (D) Difference between Run 3 for EG and Run 3 for CG. Red arrows denote augmentation effects (path coefficient α>0), and blue arrows – inhibition effects (path coefficient α<0). In (A) and (B), solid arrows correspond to effects with FDR <i>q</i><0.05, and dotted arrows – to effects with 0.05≤<i>q</i><0.1. In (C) and (D), solid arrows correspond to results with uncorrected <i>P</i><0.05, and dotted arrows – to results with 0.05≤<i>P</i><0.1.</p