Understanding Parkinson’s Disease and the Brain’s Action Network

For decades, Parkinson’s disease has been framed primarily as a disorder of movement—an illness rooted in malfunctioning motor circuits and defined by tremor, rigidity, and slowness. A new large-scale study published in Nature challenges that view, proposing a more integrative explanation: Parkinson’s may be best understood as a disorder of a whole-body “action network” that links movement, cognition, arousal, and autonomic function.

The study focuses on the somato-cognitive action network (SCAN), a recently defined large-scale brain network described in prior work and further characterized in this investigation. SCAN coordinates voluntary action with internal bodily states and motivation. Unlike classical motor regions that control specific effectors such as the hand or foot, SCAN regions are interleaved throughout the motor cortex and link movement to cognition, attention, and physiological regulation. This architecture has made SCAN a compelling candidate for explaining why Parkinson’s symptoms extend far beyond tremor—affecting gait, sleep, autonomic control, and the initiation of voluntary action.

To test this hypothesis, the investigators assembled an unusually large and diverse dataset, analyzing multimodal brain imaging and electrophysiology from 863 participants across multiple Parkinson’s cohorts and treatment modalities. Using precision resting-state functional connectivity mapping, they found that brain structures long implicated in Parkinson’s disease—including the substantia nigra, subthalamic nucleus, globus pallidus, and thalamus—are preferentially connected to the SCAN rather than to effector-specific motor regions.

More strikingly, Parkinson’s disease was associated with a specific pattern of hyperconnectivity between subcortical nuclei and the SCAN. This abnormal coupling was not observed in other movement disorders used as controls, including essential tremor, dystonia, or amyotrophic lateral sclerosis. The degree of SCAN hyperconnectivity also tracked with clinical severity, correlating not only with motor impairment but with cognition, anxiety, and depressive symptoms—highlighting the network’s relevance to both motor and non-motor features of the disease.

The clinical relevance of this network became clearer when the authors examined how established Parkinson’s therapies interact with it. Across multiple treatment cohorts—deep brain stimulation (DBS), levodopa therapy, transcranial magnetic stimulation (TMS), and MRI-guided focused ultrasound—effective interventions were consistently associated with reductions in SCAN hyperconnectivity. In patients undergoing subthalamic nucleus DBS, normalization of SCAN connectivity paralleled improvements in Unified Parkinson’s Disease Rating Scale motor scores over a year of follow-up. Levodopa produced a similar, though more transient, reduction in SCAN hyperconnectivity.

Some of the most provocative findings emerged from the noninvasive neuromodulation arm of the study. In a randomized trial of patients receiving repetitive TMS, targeting cortical SCAN regions produced approximately double the motor benefit compared with stimulation of conventional motor cortex targets. Patients receiving SCAN-targeted stimulation experienced faster and larger improvements in bradykinesia, rigidity, tremor, and axial symptoms. These gains were accompanied by measurable reductions in cortico–subcortical SCAN hyperconnectivity, supporting a mechanistic link between network modulation and clinical response.

The implications extend beyond symptom relief. By reframing Parkinson’s disease as a disorder of an integrative action network rather than isolated motor pathways, the study identifies a network-level feature that may serve as a candidate biomarker for disease characterization, progression monitoring, and treatment optimization. SCAN hyperconnectivity, measurable with resting-state fMRI, may help distinguish Parkinson’s from other movement disorders and guide personalized targeting for neuromodulation therapies in research settings.

Clinically, this framework also helps explain longstanding paradoxes in Parkinson’s care—such as why movement can transiently improve with cognitive or emotional cues, or why invasive therapies aimed at deep nuclei can influence mood, motivation, and cognition. SCAN occupies a position at the intersection of these domains, linking internal state with action execution.

While the authors emphasize the need for larger, multicenter trials—particularly for SCAN-targeted TMS—the findings suggest a shift in how clinicians and researchers conceptualize Parkinson’s disease. Rather than treating tremor, gait, or cognition as separate problems, the SCAN model points to a shared circuit-level dysfunction underlying the disease’s diverse manifestations.