Abstract
Deep brain stimulation of the subthalamic nucleus (STN-DBS) alleviates motor symptoms in Parkinson’s disease (PD) but also affects the prefrontal cortex (PFC), potentially leading to cognitive side effects. The present study tested alterations within the rostro-caudal hierarchy of neural processing in the PFC induced by STN-DBS in PD. Granger-causality analyses of fast functional near-infrared spectroscopy (fNIRS) measurements were used to infer directed functional connectivity from intrinsic PFC activity in 24 PD patients treated with STN-DBS. Functional connectivity was assessed ON stimulation, in steady-state OFF stimulation and immediately after the stimulator was switched ON again. Results revealed that STN-DBS significantly enhanced the rostro-caudal hierarchical organization of the PFC in patients who had undergone implantation early in the course of the disease, whereas it attenuated the rostro-caudal hierarchy in late-implanted patients. Most crucially, this systematic network effect of STN-DBS was reproducible in the second ON stimulation measurement. Supplemental analyses demonstrated the significance of prefrontal networks for cognitive functions in patients and matched healthy controls. These findings show that the modulation of prefrontal functional networks by STN-DBS is dependent on the disease duration before DBS implantation and suggest a neurophysiological mechanism underlying the side effects on prefrontally-guided cognitive functions observed under STN-DBS.
Highlights
Deep brain stimulation of the subthalamic nucleus (STN-deep brain stimulation (DBS)) alleviates motor symptoms in Parkinson’s disease (PD) and affects the prefrontal cortex (PFC), potentially leading to cognitive side effects
Given that STN-DBS is assumed to shift the balance between inhibitory and excitatory network activity to restore functionality of the diseased motor system[10,11], currents spreading beyond the stimulation target can likely compromise the balance in associative and limbic cortico-basal ganglia loops connected with the STN12
The outcome of STN-DBS significantly relies on the integrity of the PFC, which is possibly influenced by the stimulation of the limbic hyperdirect pathway that was recently found to be confluent with the superolateral medial forebrain bundle in h umans[2]
Summary
Deep brain stimulation of the subthalamic nucleus (STN-DBS) alleviates motor symptoms in Parkinson’s disease (PD) and affects the prefrontal cortex (PFC), potentially leading to cognitive side effects. Given that STN-DBS is assumed to shift the balance between inhibitory and excitatory network activity to restore functionality of the diseased motor system[10,11], currents spreading beyond the stimulation target can likely compromise the balance in associative and limbic cortico-basal ganglia loops connected with the STN12. Benefits of STN-DBS for the alleviation of motor symptoms are unquestioned[13,14,15], cognitive and psychiatric side effects like impaired verbal fluency[16,17,18], impulsive b ehavior[19] and even a possibly increased suicidal tendency[20] have been reported These impairments indicate far-reaching implications of modulating basal-ganglia networks, suggesting that STN-DBS may impact on the functional integrity of the PFC12,21. The remote impact of STN-DBS on cortical regions is likely to differ between Parkinson’s patients that undergo surgery early and late after disease onset
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