Expedition for new symptom-specific TMS targets: Protocol for the first randomized causal circuit mapping trial

Abstract

Background: Functional neuroimaging has been used to map brain organization, but only identifies correlates of brain functions rather than causes. Causal brain mapping can be conducted by randomly applying transcranial magnetic stimulation (TMS) to different targets, as randomization controls for all confounders, and comparing clinical outcomes across different targeted circuits. Random targets can be systematically compared by mapping their functional connectivity to specific circuits. This study will build a multidimensional atlas of circuits that are causally involved in human brain function. We aim to identify TMS targets for a wide range of transdiagnostic constructs relevant to psychopathology from broad spectra (e.g., internalizing) to specific symptoms (e.g., worry) and processes (e.g. emotional regulation).

Methods/design: 90 participants with major depression, obsessive-compulsive disorder, generalized anxiety disorder, or schizophrenia will receive 40 total sessions of accelerated intermittent theta burst stimulation (aiTBS). The first 20 sessions will be applied over two days to a random target in the left prefrontal cortex (PFC). A deep circuit-based phenotyping battery pre- and post-aiTBS will be conducted. Six weeks later, participants will receive 20 sessions of aiTBS to a different random target in the left PFC. Patients with schizophrenia will be offered an open-label extension with aiTBS to the rostromedial prefrontal cortex (rmPFC), a previously proposed, novel target for schizophrenia.

Discussion: We aim to map circuitry connected to TMS sites that causally modify transdiagnostic and diagnosis-specific behaviors. This will complement prior retrospective studies using incidental lesions and stimulation sites and aim to define optimal TMS target circuits across diagnoses.

Keywords: Behavioral phenotyping measures; Causal brain mapping; Functional MRI; GAD; MDD; OCD; Prefrontal cortex; Rostromedial prefrontal cortex; Schizophrenia; Transcranial magnetic stimulation.