Cingulate-centered flexible control: physiologic correlates and enhancement by internal capsule stimulation

Abstract

Flexible cognitive control requires rapid adjustment when current demands diverge from the brains predictions. Deficits in control adjustment are prominent in psychiatric disorders, yet the neural mechanisms supporting such adjustment and their modifiability remain unclear. We analyzed two intracranial electroencephalography datasets, one with brief internal capsule stimulation (ICS), to identify a human circuit mechanism for flexible adjustment after control-demand change. We further used two clinical internal capsule deep brain stimulation (IC DBS) cohorts to validate our proposed mechanism. Across intracranial datasets, phase-amplitude coupling (PAC) anchored to the theta phase of right rostral anterior cingulate cortex (rACC-R), particularly theta-gamma coupling with dorsolateral prefrontal cortex and dorsal ACC, was associated with faster performance specifically when control demand changed. This effect generalized across datasets and tasks and was robust across analytic pipelines. An adaptive drift-diffusion model accounted for this adjustment cost in terms of unsigned control prediction error. In Dataset 1, brief ICS selectively enhanced the same rACC-R theta-centered PAC configuration on control-state-change trials, and computational modeling indicated that stimulation improved control flexibility under high-mismatch conditions. In a primarily treatment-resistant depression IC DBS cohort, stimulation-induced enhancement of the flexibility-related behavioral parameter, rather than a more general-control parameter, was associated with clinical response (N = 14; AUC = 0.90). In a separate treatment-resistant obsessive-compulsive disorder IC DBS cohort, clinically selected stimulation settings preferentially increased the same flexibility-related parameter across all patients (N = 5). These findings identify rACC-centered theta-phase coordination as a candidate human mechanism for flexible adjustment, show that capsule stimulation can augment this mechanism when flexibility is required, and suggest a causal link between flexibility-related behavioral and neural signals and psychiatric symptoms.