Neuromodulation for treatment-resistant depression: Functional network targets contributing to antidepressive outcomes

Abstract

Non-invasive brain stimulation is designed to target accessible brain regions that underlie many psychiatric disorders. One such method, transcranial magnetic stimulation (TMS), is commonly used in patients with treatment-resistant depression (TRD). However, for non-responders, the choice of an alternative therapy is unclear and often decided empirically without detailed knowledge of precise circuit dysfunction. This is also true of invasive therapies, such as deep brain stimulation (DBS), in which responses in TRD patients are linked to circuit activity that varies in each individual. If the functional networks affected by these approaches were better understood, a theoretical basis for selection of interventions could be developed to guide psychiatric treatment pathways. The mechanistic understanding of TMS is that it promotes long-term potentiation of cortical targets, such as dorsolateral prefrontal cortex (DLPFC), which are attenuated in depression. DLPFC is highly interconnected with other networks related to mood and cognition, thus TMS likely alters activity remote from DLPFC, such as in the central executive, salience and default mode networks. When deeper structures such as subcallosal cingulate cortex (SCC) are targeted using DBS for TRD, response efficacy has depended on proximity to white matter pathways that similarly engage emotion regulation and reward. Many have begun to question whether these networks, targeted by different modalities, overlap or are, in fact, the same. A major goal of current functional and structural imaging in patients with TRD is to elucidate neuromodulatory effects on the aforementioned networks so that treatment of intractable psychiatric conditions may become more predictable and targeted using the optimal technique with fewer iterations. Here, we describe several therapeutic approaches to TRD and review clinical studies of functional imaging and tractography that identify the diverse loci of modulation. We discuss differentiating factors associated with responders and non-responders to these stimulation modalities, with a focus on mechanisms of action for non-invasive and intracranial stimulation modalities. We advance the hypothesis that non-invasive and invasive neuromodulation approaches for TRD are likely impacting shared networks and critical nodes important for alleviating symptoms associated with this disorder. We close by describing a therapeutic framework that leverages personalized connectome-guided target identification for a stepwise neuromodulation paradigm.

Keywords: deep brain stimulation; electroconvulsive therapy; epidural cortical stimulation; neuromodulation; salience network; transcranial magnetic stimulation (repetitive); treatment-resistant depression.

FIGURE 1

TRD neuromodulation clinical pathway. This schematic depicts the proposed stepwise pathway for optimizing individualized management of treatment-resistant depression sEEG, stereotactic electroencephalography; aDBS, adaptive deep brain stimulation.

FIGURE 2

Functional network modulation in TRD. Default mode network (DMN – blue), salience network (SN – purple), and central executive network (CEN – green) are accessible for modulation with transcranial magnetic stimulation (TMS) and deep brain stimulation (DBS). Dorsal lateral prefrontal cortex (DLPFC) TMS may modulate CEN via direct modulation of DLPFC and its projections to lateral parietal cortex (LPC) (A–C). DLPFC TMS could indirectly modulate SN via functional connections with anterior cingulate cortex (ACC), anterior insula (AI), or DMN via functional connections with medial prefrontal cortex (mPFC) and posterior cingulate cortex (PCC). DBS at the intersection of subcallosal cingulate cortex (SCC), the cingulum bundle (CB), uncinate fasciculus (UF), and forceps minor (FM) may modulate SN via projections to dorsal anterior cingulate cortex (dACC) and AI (C,D). Functional connections to DLPFC, mPFC, and PCC also present avenues for modulation of CEN and DMN. Please see Table 1 for full listing of network structures.