Stimulation-evoked orbitofrontal activity as a biomarker for DBS personalization in depression

Finding suitable therapies for treatment-refractory neuropsychiatric disorders constitutes a major goal for translational neuroscience. Deep brain stimulation shows promise for treatment resistant depression, but treatment efficacy varies substantially across patients. Objective, electrophysiologically driven strategies to optimize deep brain stimulation for treatment resistant depression could greatly improve clinical efficacy by minimizing the trial-and-error approach needed to personalize stimulation settings. This may not only reduce the delay between the start of the treatment and symptom improvement, but also enable acute, real-time verification of circuit engagement, advancing our understanding of the mechanism mediating antidepressant effects. Here, we investigate whether cerebro-cerebral evoked potentials elicited through different deep brain stimulation configurations could be used to guide stimulation personalization for treatment resistant depression. Cerebro-cerebral evoked potentials offer a fast, objective way to identify regions engaged by stimulation, revealing the effective connectivity pattern of the stimulated location. Data were collected from eight patients with treatment resistant depression who received dual bilateral deep brain stimulation devices targeting the subcallosal cingulate and ventral capsule/ventral striatum. During an initial in-hospital monitoring period, single-pulse electrical stimulation was delivered through the deep brain stimulation devices and cerebro-cerebral evoked potentials were recorded through temporary stereo-electroencephalography probes across fronto-temporal regions. Patients underwent several outpatient stimulation programming sessions over the course of 9 months to identify the stimulation configurations leading to the greatest improvement in depressive symptoms. We retrospectively analysed cerebro-cerebral evoked potentials obtained in response to stimulation of different stimulation configurations to identify features distinguishing the clinically effective configurations. The deep brain stimulation configurations leading to the greatest improvement in depressive symptoms were associated with significantly larger evoked potentials in the orbitofrontal cortex and showed an increased number of evoked potentials across dorsal and ventral prefrontal regions. Waveform similarity analysis revealed a gradient in therapeutic effects, such that multiple alternative stimulation configurations led to similar symptom improvement. The vast deep brain stimulation parameter space might contain a configuration subspace defined by comparable therapeutic effects. In addition, evoked potentials obtained from single-pulse and from bursts of high-frequency stimulation displayed similar spatial patterns, suggesting that either method might be able to identify the configuration best engaging the circuit mediating the clinical response. Together, these findings provide proof-of-principle evidence that stimulation-evoked prefrontal responses reflect network engagement associated with antidepressant effects. Cerebro-cerebral evoked potentials may offer an objective and acute strategy to guide contact selection in deep brain stimulation for treatment resistant depression.