Stimulation of subgenual cingulate area decreases limbic top-down effect on ventral visual stream: A DBS-EEG pilot study

Highlights

• CG25 DBS does not modulate significantly the emotional Stroop effect in depression.

• CG25 decreases N170 event related potential amplitude.

• CG25 DBS decreases activity in occipital face processing areas.

• CG25 DBS decreases connection strength to and from temporal pole.

Abstract

Deep brain stimulation (DBS) of the subgenual cingulate gyrus (area CG25) is beneficial in treatment resistant depression. Though the mechanisms of action of Cg25 DBS remain largely unknown, it is commonly believed that Cg25 DBS modulates limbic activity of large networks to achieve thymic regulation of patients. To investigate how emotional attention is influenced by Cg25 DBS, we assessed behavioral and electroencephalographic (EEG) responses to an emotional Stroop task in 5 patients during ON and OFF stimulation conditions. Using EEG source localization, we found that the main effect of DBS was a reduction of neuronal responses in limbic regions (temporal pole, medial prefrontal and posterior cingulate cortices) and in ventral visual areas involved in face processing. In the dynamic causal modeling (DCM) approach, the changes of the evoked response amplitudes are assumed to be due to changes of long range connectivity induced by Cg25 DBS. Here, using a simplified neural mass model that did not take explicitly into account the cytoarchitecture of the considered brain regions, we showed that the remote action of Cg25 DBS could be explained by a reduced top-down effective connectivity of the amygdalo-temporo-polar complex. Overall, our results thus indicate that Cg25 DBS during the emotional Stroop task causes a decrease of top-down limbic influence on the ventral visual stream itself, rather than a modulation of prefrontal cognitive processes only. Tuning down limbic excitability in relation to sensory processing might be one of the biological mechanisms through which Cg25 DBS produces positive clinical outcome in the treatment of resistant depression.

Introduction

Treatments for major depression are sparse and limited, only 67% of patients achieving remission after up to 4 therapeutic steps (Rush et al., 2006). For very severe patients resistant to conventional treatments, deep brain stimulation (DBS) of targets along the medial forebrain bundle (Coenen et al., 2012), such as the nucleus accumbens, the anterior limb of the internal capsule and the subgenual cingulate gyrus (area CG25), is being evaluated (Morishita et al., 2014). In particular, CG25 DBS shows high response rates (up to 75%) (Kennedy et al., 2011). Depression is associated with hyperactive limbic areas, including the subgenual region due to impaired down-regulating control from prefrontal areas (Anand et al., 2005). CG25 DBS has been shown to induce a reduction in resting cerebral blood flow in the subgenual region and in the medial prefrontal areas (Lozano et al., 2008, Mayberg et al., 2005). Given the observed clinical effects in TDR patients, DBS may mitigate an abnormally weak down-regulation of the excitability of limbic circuits by frontal control systems.

The emotional Stroop paradigm is well suited to specifically activate prefrontal-limbic circuits (Etkin et al., 2006) and to further asses the mechanisms of action of DBS in those patients. Emotional Stroop consists in inducing a conflict between a task goal of emotion recognition from facial expressions and a simultaneously presented prepotent distractor word. For example, when faces showing happy or angry emotions are presented with an emotional word overlapped (‘happy’ or ‘angry’), the automatic and unconscious reading of the word induces a conflict when its emotional valence is opposite to the one expressed by the face and slowing down the response. Conflict would be first detected in the posterior medial frontal cortex (pMFC), notably in the dorsal anterior cingulate cortex (Botvinick et al., 1999, Critchley et al., 2003). Conflict would then be resolved through the inhibitory action of the rostral ACC (rACC) and the subgenual ACC on autonomic limbic processing of the emotional distractor (particularly in the amygdala) (Egner et al., 2008). These limbic regions are implicated in shaping in real-time the routing and traffic of information (and corresponding attentional biases) within the ventral visual stream. Indeed, these structures have been consistently shown to mediate, in the context of visual processing of emotionally loaded information, an ongoing tuning of activity in striate and extrastriate visual regions, specifically for faces in the lateral occipital cortex (LOC), the fusiform gyrus (FG) and the superior temporal sulcus (STS) (Nguyen and Cunnington, 2014). Critically, feedforward and backward interactions take place between the ventral visual areas and the anterior affective system for emotional processing of faces and emotional words (Breiter et al., 1996, Sabatinelli et al., 2005).

Concurrent measurement of event-related potentials (ERP) can serve to evaluate the impact of CG25 DBS on underlying neural processing within the targeted circuits. ERP recorded during the emotional Stroop task (Zhu et al., 2010) feature several components, including the N170, an occipito-temporal wave from the FG and STS (Nguyen and Cunnington, 2014), and the P300 probably generated by the medial orbitofrontal cortex (OFC) (O’doherty et al., 2003) and ACC (Beckmann et al., 2009). On this basis, we hypothesized that studying ERP modulation by CG25 DBS during the Stroop task would be relevant to investigate, on the one hand how CG25 DBS may alleviate depressive symptoms and thus functionally regulate the limbic system, and on the other hand whether emotional conflict may depend on a modulation of the limbic system per se. To that end, we acquired behavioral and electroencephalographic (EEG) responses in 5 TRD patients treated with CG25 DBS, while they performed an emotional and a control Stroop tasks in conditions of DBS turned ON versus OFF. A recent fMRI study on a similar task in TRD patients concluded that further work was necessary to investigate the involved networks between amygdala, lateral frontal cortex and extrastriate visual region (Chechko et al., 2013). With EEG we could go forward and look at effective connections between these areas, using standard behavioral and ERP analysis across conditions, and refining analyses for selected conditions to study the modulation by CG25 DBS of cortical current densities and effective connectivity. Overall, our results put forward a decrease by CG25 DBS of limbic top-down influence on high-level visual ventral areas, rather than a modulation limited to prefrontal cognitive processes. This is a potential biological underpinning through which CG25 DBS produces clinical outcome in TRD.