The role of neurotransmitter systems in mediating deep brain stimulation effects in Parkinson’s disease

Abstract

Deep brain stimulation (DBS) is among the most successful paradigms in both translational and reverse translational neuroscience. DBS has developed into a standard treatment for movement disorders such as Parkinson’s disease (PD) in recent decades, however, specific mechanisms behind DBS’s efficacy and side effects remain unrevealed. Several hypotheses have been proposed, including neuronal firing rate and pattern theories that emphasize the impact of DBS on local circuitry but detail distant electrophysiological readouts to a lesser extent. Furthermore, ample preclinical and clinical evidence indicates that DBS influences neurotransmitter dynamics in PD, particularly the effects of subthalamic nucleus (STN) DBS on striatal dopaminergic and glutamatergic systems; pallidum DBS on striatal dopaminergic and GABAergic systems; pedunculopontine nucleus DBS on cholinergic systems; and STN-DBS on locus coeruleus (LC) noradrenergic system. DBS has additionally been associated with mood-related side effects within brainstem serotoninergic systems in response to STN-DBS. Still, addressing the mechanisms of DBS on neurotransmitters’ dynamics is commonly overlooked due to its practical difficulties in monitoring real-time changes in remote areas. Given that electrical stimulation alters neurotransmitter release in local and remote regions, it eventually exhibits changes in specific neuronal functions. Consequently, such changes lead to further modulation, synthesis, and release of neurotransmitters. This narrative review discusses the main neurotransmitter dynamics in PD and their role in mediating DBS effects from preclinical and clinical data.

Wireless Stimulation of the Subthalamic Nucleus with Nanoparticles Modulates Key Monoaminergic Systems Similar to Contemporary Deep Brain Stimulation

“…However, magnetoelectric stimulation did not show a significant difference in the co-expression of ChAT/c-Fos cells in the PPN. Those histological and behavioral findings are somewhat similar to the known effects of high frequency STN-DBS [21].…”

“…Clarifying whether this approach induces similar changes in the brain could help establish magnetoelectric DBS as a suitable alternative to conventional DBS. In PD research, subthalamic nucleus (STN)-DBS has been shown to alter the activity of dopaminergic, serotonergic, and cholinergic systems in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc), dorsal raphe nucleus (DRN), and pedunculopontine nucleus (PPN) both in healthy and PD conditions [17][18][19][20]; reviewed in [21].…”

Multi-scale and cross-dimensional TMS mapping: A proof of principle in patients with Parkinson’s disease and deep brain stimulation

“…Considering the inhibitory role of IFG in motor control ( Kenner et al, 2010 ; Rae et al, 2015 ; Aron et al, 2016 ; Chen et al, 2020 ), it is possible that the abnormal IFG over-excitability found in the OFF mode reflects excessive inhibitory inputs coming from the IFG to M1. STN-DBS has been shown to trigger GABA modulation in the basal ganglia and thalamus ( Stefani et al, 2011 ; Buchanan et al, 2014 ; Alosaimi et al, 2022 ). Our results suggest that clinically efficient STN-DBS might also partially exert its beneficial effects through a transient GABAergic disinhibition propagating to the cortex.…”

“…An exploratory grid of 5×5 targets spaced by 7 mm centered on the anatomical hotspot was used. Once the experimenter found the hotspot, defined as the point eliciting the most reliable and the highest MEP, the resting motor threshold (rMT) was assessed using TMSMTAT ( Awiszus, 2011 ). The first experimental stimulation condition was then set (DBS ON or OFF) and the TMS-EMG motor mapping began.…”

The grand challenge at the frontiers of neurotechnology and its emerging clinical applications

“…Neurotechnology already has the potential to alter the brain's chemistry and future developments predict that it will soon be able to create new neural connections between different parts of the nervous system ( 23 ). This will have huge therapeutic benefits for people with a range of neurological conditions, for example, stroke, chronic pain, paralysis, or psychological disorders, including anxiety and post-traumatic stress disorder.…”