Parkinson’s disease as a somato-cognitive action network disorder, 2026, Ren et al.

[SNT Gatchaman]

Parkinson’s disease as a somato-cognitive action network disorder

Spoiler: Authors

Ren, Jianxun; Zhang, Wei; Dahmani, Louisa; Gordon, Evan M; Li, Shenshen; Zhou, Ying; Long, Yang; Huang, Jianting; Zhu, Yafei; Guo, Ning; Jiang, Changqing; Zhang, Feng; Bai, Yan; Wei, Wei; Wu, Yaping; Bush, Alan; Vissani, Matteo; Wei, Luhua; Oehrn, Carina R; Morrison, Melanie A; Zhu, Ying; Zhang, Chencheng; Hu, Qingyu; Yin, Yilin; Cui, Weigang; Fu, Xiaoxuan; Zhang, Ping; Wang, Weiwei; Ji, Gong-Jun; He, Ji; Wang, Kai; Fan, Dongsheng; Wang, Zhaoxia; Kimberley, Teresa; Little, Simon; Starr, Philip A; Richardson, Robert Mark; Li, Luming; Wang, Meiyun; Wang, Danhong; Dosenbach, Nico U F; Liu, Hesheng

Parkinson’s disease (PD) is an incurable neurological disorder that often begins insidiously with sleep disturbances and somatic symptoms, progressing to whole-body motor and cognitive symptoms1,2,3,4,5. Dysfunction of the somato-cognitive action network (SCAN)—which is thought to control action execution6,7 by coordinating arousal, organ physiology and whole-body motor plans with behavioural motivation—is a potential contributor to the diverse clinical manifestations of PD.

To investigate the role of the SCAN in PD pathophysiology and treatments (medications, deep-brain stimulation (DBS), transcranial magnetic stimulation (TMS) and MRI-guided focused ultrasound stimulation (MRgFUS)), we built a large (n = 863), multimodal, multi-intervention clinical imaging dataset.

Resting-state functional connectivity revealed that the substantia nigra and all PD DBS targets (subthalamic nucleus, globus pallidus and ventral intermediate thalamus) are selectively connected to the SCAN rather than to effector-specific motor regions.

Importantly, PD was characterized by specific hyperconnectivity between the SCAN and the subcortex. We therefore followed six PD cohorts undergoing DBS, TMS, MRgFUS and levodopa therapy using precision resting-state functional connectivity and electrocorticography recording.

Efficacious treatments reduced SCAN-to-subcortex hyperconnectivity. Targeting the SCAN instead of effector regions doubled the efficacy of TMS treatments. Focused ultrasound treatment benefits increased when the target was closer to the thalamic SCAN sweet spot.

Thus, SCAN hyperconnectivity is central to PD pathophysiology and its alleviation is a hallmark of successful neuromodulation. Targeting functionally defined subcortical SCAN nodes may improve existing therapies (DBS, MRgFUS), whereas cortical SCAN targets offer effective non-invasive or minimally invasive neuromodulation for PD.

Web | DOI | PDF | Nature | Open Access

 

[SNT Gatchaman]

See also last week's related —

The deep brain stimulation response network in Parkinson’s disease operates in the high beta band (2026)

Spoiler: Abstract

Deep brain stimulation (DBS) of the subthalamic nucleus improves motor symptoms in patients with Parkinson’s disease. Using functional MRI, optimal DBS response networks have been characterized. However, neural activity associated with Parkinsonian symptoms is magnitudes faster than what can be resolved by this method. Although both spatial and temporal domains of these networks appear crucial, no single study has yet investigated both domains simultaneously.

Here, we aimed at closing this gap by analysing electrophysiological data from a total of n = 127 hemispheres. Using subthalamic local field potentials that were recorded concurrently alongside whole-brain magnetoencephalography in a multi-centre cohort of patients who underwent subthalamic DBS for the treatment of Parkinson’s disease (n = 100 hemispheres), we analysed the DBS response network in both spatial and temporal domains. In every cortical vertex, cortico-subthalamic coupling was correlated with stimulation outcomes.

This network spatially resembled functional MRI-based findings (R = 0.40, P = 0.039) and explained significant amounts of variance in clinical outcomes (βstd = 0.30, P = 0.002), whereas theta–alpha and low beta coupling did not show significant associations with DBS response (theta–alpha: βstd = −0.02, P = 0.805; low beta: βstd = −0.08, P = 0.426). The ‘optimal’ high beta coupling map was robust when subjected to various cross-validation designs (10-fold cross-validation: R = 0.29, P = 0.009; split-half design: R = 0.31, P = 0.026) and was able to predict outcomes across DBS centres [R = 0.74; P(1) = 8.9 × 10−5].

We identified a DBS response network that resembles the previously defined MRI network and operates in the high beta band. Maximal connectivity to this network was associated with optimal DBS outcomes and was able to cross-predict clinical improvements across DBS surgeons and centres.

Web | PDF | Brain | Paywall

 

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A somato-cognitive action network alternates with effector regions in motor cortex (2023)

Spoiler: Abstract

Motor cortex (M1) has been thought to form a continuous somatotopic homunculus extending down the precentral gyrus from foot to face representations1,2, despite evidence for concentric functional zones3 and maps of complex actions4.

Here, using precision functional magnetic resonance imaging (fMRI) methods, we find that the classic homunculus is interrupted by regions with distinct connectivity, structure and function, alternating with effector-specific (foot, hand and mouth) areas. These inter-effector regions exhibit decreased cortical thickness and strong functional connectivity to each other, as well as to the cingulo-opercular network (CON), critical for action5 and physiological control6, arousal7, errors8 and pain9. This interdigitation of action control-linked and motor effector regions was verified in the three largest fMRI datasets. Macaque and pediatric (newborn, infant and child) precision fMRI suggested cross-species homologues and developmental precursors of the inter-effector system.

A battery of motor and action fMRI tasks documented concentric effector somatotopies, separated by the CON-linked inter-effector regions. The inter-effectors lacked movement specificity and co-activated during action planning (coordination of hands and feet) and axial body movement (such as of the abdomen or eyebrows).

These results, together with previous studies demonstrating stimulation-evoked complex actions4 and connectivity to internal organs10 such as the adrenal medulla, suggest that M1 is punctuated by a system for whole-body action planning, the somato-cognitive action network (SCAN). In M1, two parallel systems intertwine, forming an integrate–isolate pattern: effector-specific regions (foot, hand and mouth) for isolating fine motor control and the SCAN for integrating goals, physiology and body movement.

Web | PDF | Nature | Open Access

A motor association area in the depths of the central sulcus (2023)

Spoiler: Abstract

Cells in the precentral gyrus directly send signals to the periphery to generate movement and are principally organized as a topological map of the body. We find that movement-induced electrophysiological responses from depth electrodes extend this map three-dimensionally throughout the gyrus.

Unexpectedly, this organization is interrupted by a previously undescribed motor association area in the depths of the midlateral aspect of the central sulcus.

This ‘Rolandic motor association’ (RMA) area is active during movements of different body parts from both sides of the body and may be important for coordinating complex behaviors.

Web | PDF | Nature Neuroscience | Open Access

 

[SNT Gatchaman]

Roll on the day when ME/CFS papers read like this, following a newly discovered aspect of previously established biology (here the homunculus) leading to a list of low FDR-corrected p values.

It may not be brain centred, but the closing paragraph might be translated to something similar.

PD has traditionally been classified as a movement disorder on the basis of its most visible and debilitating symptoms, despite the well-recognized complex deficits in movement planning, coordination and cognitive abilities. Here we provide evidence that the SCAN lies at the core of network dysfunction in PD. With this updated understanding, we propose that PD may be better conceptualized and treated as a SCAN disorder. While SCAN dysfunction is not exclusive to a single condition—as it could also arise from stroke or multiple sclerosis—our findings position PD as a paradigmatic instance of a SCAN disorder. This reclassification of PD shifts the focus from complex and diverse phenotypic symptoms to specific circuit pathologies, encouraging future research on the associations between network dysfunction and the various symptom domains of PD.

"ME/CFS has traditionally been classified as a fatigue disorder on the basis of…"