fMRI neurofeedback of amygdala response to aversive stimuli enhances prefrontal–limbic brain connectivity

Highlights

• Amygdala vs. sham feedback increases functional amygdala–vmPFC connectivity.

• Higher arousal is associated with increased amygdala–vmPFC coupling.

• Ventromedial, rostral and lateral PFC are associated with amygdala regulation.

Abstract

Down-regulation of the amygdala with real-time fMRI neurofeedback (rtfMRI NF) potentially allows targeting brain circuits of emotion processing and may involve prefrontal–limbic networks underlying effective emotion regulation. Little research has been dedicated to the effect of rtfMRI NF on the functional connectivity of the amygdala and connectivity patterns in amygdala down-regulation with neurofeedback have not been addressed yet.

Using psychophysiological interaction analysis of fMRI data, we present evidence that voluntary amygdala down-regulation by rtfMRI NF while viewing aversive pictures was associated with increased connectivity of the right amygdala with the ventromedial prefrontal cortex (vmPFC) in healthy subjects (N = 16). In contrast, a control group (N = 16) receiving sham feedback did not alter amygdala connectivity (Group × Condition t-contrast: p < .05 at cluster-level). Task-dependent increases in amygdala–vmPFC connectivity were predicted by picture arousal (β = .59, p < .05). A dynamic causal modeling analysis with Bayesian model selection aimed at further characterizing the underlying causal structure and favored a bottom-up model assuming predominant information flow from the amygdala to the vmPFC (xp = .90). The results were complemented by the observation of task-dependent alterations in functional connectivity of the vmPFC with the visual cortex and the ventrolateral PFC in the experimental group (Condition t-contrast: p < .05 at cluster-level).

Taken together, the results underscore the potential of amygdala fMRI neurofeedback to influence functional connectivity in key networks of emotion processing and regulation. This may be beneficial for patients suffering from severe emotion dysregulation by improving neural self-regulation.

Introduction

Real-time functional magnetic resonance imaging neurofeedback (rtfMRI NF) has attracted increasing interest from basic and clinical scientists. With rtfMRI NF, information on brain activation is fed back to the participant via a brain–computer interface (Weiskopf, 2012). Cumulative evidence is reported for a potential effect of rtfMRI NF on brain self-regulation in domains of high relevance for clinical psychology and psychiatry, such as emotion regulation (e.g. Brühl et al., 2014, Caria et al., 2010, Scheinost et al., 2013, Veit et al., 2012, Zotev et al., 2011), and an improved regulation of disturbed brain circuits supported by neurofeedback training may yield therapeutic benefits (Linden, 2014, Stoeckel et al., 2014).

There is initial evidence for an alteration of amygdala–prefrontal connectivity via amygdala neurofeedback when giving the instruction to upregulate (Yuan et al., 2014, Zotev et al., 2011, Zotev et al., 2013). Though, to date, it is unknown whether amygdala neurofeedback with the instruction to down-regulate involves similar neural mechanisms. This is of eminent interest for advancing rtfMRI NF towards the treatment of mental disorders involving limbic hyperactivation and aberrant prefrontal–limbic connectivity, that might become a therapeutic option in the future.

In a previous study, we recently demonstrated amygdala down-regulation with blood oxygenation level dependent (BOLD) signal feedback from the amygdala in healthy individuals (Paret et al., 2014). We adapted an established emotion regulation paradigm that involved viewing aversive and scrambled ‘neutral’ pictures in an fMRI environment. Participants were instructed to regulate a continuously updated biofeedback signal, obtained from the amygdala and displayed at both sides of the aversive picture (Fig. 1). They significantly decreased amygdala activation when instructed to regulate the feedback signal as compared to the instruction to respond naturally, i.e., to view the picture. In this recent report, however, changes in brain connectivity were not addressed. Hence, the major aim of the present paper is to delineate changes in functional amygdala connectivity with rtfMRI NF and the instruction to down-regulate the amygdala response to aversive pictures. This is not only necessary for advancing the development of the technique towards clinical application. It is also needed to scrutinize the present reports on connectivity with amygdala neurofeedback, which focused on amygdala up-regulation and interpret changes of prefrontal–limbic connectivity in terms of a top-down control model. Data from amygdala down-regulation are suited to test this model and deepen our understanding of the dialectic interplay of prefrontal cortex and amygdala in neurofeedback regulation. Addressing this point in this paper, it is expected, that amygdala neurofeedback compared to control region feedback would enhance functional connectivity of the amygdala with the prefrontal cortex. Functional connectivity is analyzed in the data set described above using psychophysiological interaction (PPI) analysis to identify prefrontal regions communicating with the amygdala in a task-dependent and (amygdala-feedback) specific manner. Connectivity with the ventromedial prefrontal cortex (vmPFC) region detected with this approach is further investigated for causal directionality using dynamic causal modeling (DCM) to inform the interpretation of connectivity changes in terms of top-down and bottom-up processes.