Striato-pallidal oscillatory connectivity correlates with symptom severity in dystonia patients. 

Lofredi R, Feldmann LK, Krause P, Scheller U, Neumann WJ, Krauss JK, Saryyeva A, Schneider GH, Faust K, Sander T, Kühn AA.

 

Nat Commun. 2024; 15(1): 8475.
doi: 10.1038/s41467-024-52814-4.
Download summary: ReTune PoM 2024 Oct

Dystonia is a hyperkinetic movement disorder characterized by involuntary muscle contractions, leading to abnormal movements and body postures. The exact causes are not known, but it is believed that there is an imbalance between the two main signaling pathways within the basal ganglia loop. This loop includes a direct pro-kinetic pathway from the striatum to the internal pallidum, which promotes movement, and an indirect, movement-inhibiting pathway via the external pallidum. In dystonia, one hypothesis put forward is that the direct signaling pathway may overweight the indirect pathway, leading to involuntary excessive movements.
However, this hypothesis could not yet be directly investigated because the basal ganglia, located deep in the brain, are difficult to access for neurophysiological measurements. Although deep brain stimulation electrodes (DBS) can measure activity in individual nuclei of the basal ganglia, conventional electrode models are limited to a single target region, which has so far made a detailed analysis of network activity between different basal ganglia nuclei impossible.
In this study, we utilized a new DBS electrode model, which, due to its larger number of DBS-contacts, allows for the recording of neuronal activity in three central basal ganglia nuclei: the striatum, as well as the internal and external pallidum. This enabled us to simultaneously measure and analyze the activity of both the direct and indirect pathways in ten dystonia patients treated with pallidal DBS. Our measurements showed that all three nuclei exhibited activity in the low-frequency range (3-12 Hz) and that these activities were strongly coupled with each other. Particularly significant was that both the strength of activity in the internal pallidum (R=0.88, P=0.001) and the coupling between the striatum and the internal pallidum as measured via the imaginary part of coherence (R=0.75, P=0.009) were closely correlated with the severity of dystonic symptoms.
As coherence supports effective neuronal communication across brain regions, this finding suggests disruptions in basal ganglia input-output coupling. Low-frequency activity may be amplified at striato-pallidal synapses, causing excessive synchrony that impairs motor circuits and triggers dystonia. Notably, this correlation was strong for the striatum-GPi (direct pathway) but absent for the striatum-GPe (indirect pathway), suggesting excessive D1-mediated direct pathway activity in GPi, known to be upregulated in dystonia. Future studies with cell-type-specific recordings in patients or animal models could further clarify this hypothesis.
The insights gained during the acute, post-operative period may inspire the development of advanced neurotechnological devices capable of chronic recordings across multiple basal ganglia nuclei. Such advancements could enable a circuit-based approach to neuromodulation therapies, integrating pathophysiological network signatures as feedback signals to guide novel, demand-adapted treatment strategies.

 

Dr. Roxanne Lofredi

Roxanne Lofredi is a neurology resident at Charité with a focus on movement disorders. She is a postdoc in Andrea Kühns Lab and her research focuses on the oscillatory signatures and DBS-effects on voluntary and involuntary movement patterns in PD and dystonia patients.

Prof. Andrea Kühn

Andrea Kühn is the director of the Movement Disorders and Neuromodulation Unit at Charité Berlin and the ReTune Spokesperson. Her research on basal ganglia electrophysiology has majorly contributed to the understanding of the pathophysiology of movement disorders and the mechanisms of action of DBS.

 

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