Response to SSRI intervention and amygdala activity during self-referential processing in major depressive disorder.

There are conflicting reports on the impact of antidepressants on neural reactions for positive information. We thus hypothesized that there would be clinically important individual differences in neural reactivity to positive information during SSRI therapy. We further predicted that only those who responded to SSRIs would show increased amygdala reactivity to positive information following treatment to a level similar to that seen in healthy participants. Depressed individuals (n = 17) underwent fMRI during performance of a task involving rating the self-relevance of emotionally positive and negative cue words before and after receiving 12 weeks of SSRI therapy. At post-treatment, SSRI responders (n = 11) had increased amygdala activity in response to positive stimuli, and decreased activity in response to negative stimuli, compared to non-responders (n = 6). Results suggest that normalizing amygdala responses to salient information is a correlate of SSRI efficacy. Second line interventions that modulate amygdala activity, such as fMRI neurofeedback, may be beneficial in those who do not respond to SSRI medications.

Consensus on the reporting and experimental design of clinical and cognitive-behavioural neurofeedback studies (CRED-nf checklist).

Neurofeedback has begun to attract the attention and scrutiny of the scientific and medical mainstream. Here, neurofeedback researchers present a consensus-derived checklist that aims to improve the reporting and experimental design standards in the field.

Effect of deactivation of activity patterns related to smoking cue reactivity on nicotine addiction.

With approximately 75% of smokers resuming cigarette smoking after using the Gold Standard Programme for smoking cessation, investigation into novel therapeutic approaches is warranted. Typically, smoking cue reactivity is crucial for smoking behaviour. Here we developed a novel closed-loop, smoking cue reactivity patterns EEG-based neurofeedback protocol and evaluated its therapeutic efficacy on nicotine addiction. During an evoked smoking cue reactivity task participants' brain activity patterns corresponding to smoking cues were obtained with multivariate pattern analysis of all EEG channels data, then during neurofeedback the EEG activity patterns of smoking cue reactivity were continuously deactivated with adaptive closed-loop training. In a double-blind, placebo-controlled, randomized clinical trial, 60 nicotine-dependent participants were assigned to receive two neurofeedback training sessions (∼1 h/session) either from their own brain (n = 30, real-feedback group) or from the brain activity pattern of a matched participant (n = 30, yoked-feedback group). Cigarette craving and craving-related P300 were assessed at pre-neurofeedback and post-neurofeedback. The number of cigarettes smoked per day was assessed at baseline, 1 week, 1 month, and 4 months following the final neurofeedback visit. In the real-feedback group, participants successfully deactivated EEG activity patterns of smoking cue reactivity. The real-feedback group showed significant decrease in cigarette craving and craving-related P300 amplitudes compared with the yoked-feedback group. The rates of cigarettes smoked per day at 1 week, 1 month and 4 months follow-up decreased 30.6%, 38.2%, and 27.4% relative to baseline in the real-feedback group, compared to decreases of 14.0%, 13.7%, and 5.9% in the yoked-feedback group. The neurofeedback effects on craving change and smoking amount at the 4-month follow-up were further predicted by neural markers at pre-neurofeedback. This novel neurofeedback training approach produced significant short-term and long-term effects on cigarette craving and smoking behaviour, suggesting the neurofeedback protocol described herein is a promising brain-based tool for treating addiction.

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 factors.

Amygdala real-time functional magnetic resonance imaging neurofeedback for major depressive disorder: A review.

Advances in imaging technologies have allowed for the analysis of functional magnetic resonance imaging data in real-time (rtfMRI), leading to the development of neurofeedback (nf) training. This rtfMRI-nf training utilizes functional magnetic resonance imaging (fMRI) tomographic localization capacity to allow a person to see and regulate the localized hemodynamic signal from his or her own brain. In this review, we summarize the results of several studies that have developed and applied neurofeedback training to healthy and depressed individuals with the amygdala as the neurofeedback target and the goal to increase the hemodynamic response during positive autobiographical memory recall. We review these studies and highlight some of the challenges and advances in developing an rtfMRI-nf paradigm for broader use in psychiatric populations. The work described focuses on our line of research aiming to develop the rtfMRI-nf into an intervention, and includes a discussion of the selection of a region of interest for feedback, selecting a control condition, behavioral and cognitive effects of training, and predicting which participants are most likely to respond well to training. While the results of these studies are encouraging and suggest the clinical potential of amygdala rtfMRI-nf in alleviating symptoms of major depressive disorder, larger studies are warranted to confirm its efficacy.

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.

Real-Time Functional Magnetic Resonance Imaging Amygdala Neurofeedback Changes Positive Information Processing in Major Depressive Disorder.

BACKGROUND: In participants with major depressive disorder who are trained to upregulate their amygdalar hemodynamic responses during positive autobiographical memory recall with real-time functional magnetic resonance imaging neurofeedback (rtfMRI-nf) training, depressive symptoms diminish. This study tested whether amygdalar rtfMRI-nf also changes emotional processing of positive and negative stimuli in a variety of behavioral and imaging tasks. METHODS: Patients with major depressive disorder completed two rtfMRI-nf sessions (18 received amygdalar rtfMRI-nf, 16 received control parietal rtfMRI-nf). One week before and following rtfMRI-nf training, participants performed tasks measuring responses to emotionally valenced stimuli including a backward-masking task, which measures the amygdalar hemodynamic response to emotional faces presented for traditionally subliminal duration and followed by a mask, and the Emotional Test Battery in which reaction times and performance accuracy are measured during tasks involving emotional faces and words. RESULTS: During the backward-masking task, amygdalar responses increased while viewing masked happy faces but decreased to masked sad faces in the experimental versus control group following rtfMRI-nf. During the Emotional Test Battery, reaction times decreased to identification of positive faces and during self-identification with positive words and vigilance scores increased to positive faces and decreased to negative faces during the faces dot-probe task in the experimental versus control group following rtfMRI-nf. CONCLUSIONS: rtfMRI-nf training to increase the amygdalar hemodynamic response to positive memories was associated with changes in amygdalar responses to happy and sad faces and improved processing of positive stimuli during performance of the Emotional Test Battery. These results may suggest that amygdalar rtfMRI-nf training alters responses to emotional stimuli in a manner similar to antidepressant pharmacotherapy.

Randomized Clinical Trial of Real-Time fMRI Amygdala Neurofeedback for Major Depressive Disorder: Effects on Symptoms and Autobiographical Memory Recall.

OBJECTIVE: Patients with depression show blunted amygdala hemodynamic activity to positive stimuli, including autobiographical memories. The authors examined the therapeutic efficacy of real-time functional MRI neurofeedback (rtfMRI-nf) training aimed at increasing the amygdala's hemodynamic response to positive memories in patients with depression. METHOD: In a double-blind, placebo-controlled, randomized clinical trial, unmedicated adults with depression (N=36) were randomly assigned to receive two sessions of rtfMRI-nf either from the amygdala (N=19) or from a parietal control region not involved in emotional processing (N=17). Clinical scores and autobiographical memory performance were assessed at baseline and 1 week after the final rtfMRI-nf session. The primary outcome measure was change in score on the Montgomery-Åsberg Depression Rating Scale (MADRS), and the main analytic approach consisted of a linear mixed-model analysis. RESULTS: In participants in the experimental group, the hemodynamic response in the amygdala increased relative to their own baseline and to the control group. Twelve participants in the amygdala rtfMRI-nf group, compared with only two in the control group, had a >50% decrease in MADRS score. Six participants in the experimental group, compared with one in the control group, met conventional criteria for remission at study end, resulting in a number needed to treat of 4. In participants receiving amygdala rtfMRI-nf, the percent of positive specific memories recalled increased relative to baseline and to the control group. CONCLUSIONS: rtfMRI-nf training to increase the amygdala hemodynamic response to positive memories significantly decreased depressive symptoms and increased the percent of specific memories recalled on an autobiographical memory test. These data support a role of the amygdala in recovery from depression.

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 the 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. The average asymmetry changes also significantly correlated with the amygdala BOLD laterality. 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 during emotion regulation. Our EEG asymmetry results indicate that the rtfMRI-nf training targeting the amygdala is beneficial to MDD patients. They further suggest that EEG-nf based on frontal EEG asymmetry in the alpha band would be compatible with the amygdala-based rtfMRI-nf. Combination of the two could enhance emotion regulation training and benefit MDD patients.

Resting-state functional connectivity modulation and sustained changes after real-time functional magnetic resonance imaging neurofeedback training in depression.

Amygdala hemodynamic responses to positive stimuli are attenuated in major depressive disorder (MDD) and normalize with remission. Real-time functional magnetic resonance imaging neurofeedback (rtfMRI-nf) training with the goal of upregulating amygdala activity during recall of happy autobiographical memories (AMs) has been suggested, and recently explored, as a novel therapeutic approach that resulted in improvement in self-reported mood in depressed subjects. In this study, we assessed the possibility of sustained brain changes as well as the neuromodulatory effects of rtfMRI-nf training of the amygdala during recall of positive AMs in MDD and matched healthy subjects. MDD and healthy subjects went through one visit of rtfMRI-nf training. Subjects were assigned to receive active neurofeedback from the left amygdale (LA) or from a control region putatively not modulated by AM recall or emotion regulation, that is, the left horizontal segment of the intraparietal sulcus. To assess lasting effects of neurofeedback in MDD, the resting-state functional connectivity before and after rtfMRI-nf in 27 depressed subjects, as well as in 27 matched healthy subjects before rtfMRI-nf was measured. Results show that abnormal hypo-connectivity with LA in MDD is reversed after rtfMRI-nf training by recalling positive AMs. Although such neuromodulatory changes are observed in both MDD groups receiving feedback from respective active and control brain regions, only in the active group are larger decreases of depression severity associated with larger increases of amygdala connectivity and a significant, positive correlation is found between the connectivity changes and the days after neurofeedback. In addition, active neurofeedback training of the amygdala enhances connectivity with temporal cortical regions, including the hippocampus. These results demonstrate lasting brain changes induced by amygdala rtfMRI-nf training and suggest the importance of reinforcement learning in rehabilitating emotion regulation in depression.

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.

Prefrontal control of the amygdala during real-time fMRI neurofeedback training of emotion regulation.

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).