Subthalamic deep brain stimulation reduces pathological information transmission to the thalamus in a rat model of parkinsonism

Abstract

The degeneration of dopaminergic neurons in the substantia nigra pars compacta leads to parkinsonian motor symptoms via changes in electrophysiological activity throughout the basal ganglia. High-frequency deep brain stimulation (DBS) partially treats these symptoms, but the mechanisms are unclear. We hypothesize that motor symptoms of Parkinson’s disease (PD) are associated with increased information transmission from basal ganglia output neurons to motor thalamus input neurons and that therapeutic DBS of the subthalamic nucleus (STN) treats these symptoms by reducing this extraneous information transmission. We tested these hypotheses in a unilateral, 6-hydroxydopamine-lesioned rodent model of hemiparkinsonism. Information transfer between basal ganglia output neurons and motor thalamus input neurons increased in both the orthodromic and antidromic directions with hemiparkinsonian (hPD) onset, and these changes were reversed by behaviorally therapeutic STN-DBS. Omnidirectional information increases in the parkinsonian state underscore the detrimental nature of that pathological information and suggest a loss of information channel independence. Therapeutic STN-DBS reduced that pathological information, suggesting an effective increase in the number of independent information channels. We interpret these data with a model in which pathological information and fewer information channels diminishes the scope of possible motor activities, driving parkinsonian symptoms. In this model, STN-DBS restores information-channel independence by eliminating or masking the parkinsonism-associated information, and thus enlarges the scope of possible motor activities, alleviating parkinsonian symptoms.

A Network Model of Local Field Potential Activity in Essential Tremor and the Impact of Deep Brain Stimulation

“…In future work, we could explicitly model the afferent connections, but in that case these connections would participate in the network activity even in the absence of DBS, and would change the entire dynamics of the model. Furthermore, this effect reflects a hypothesis about subthalamic DBS, which proposes that it acts to replace pathological synchrony with low amplitude activity and regain information flow through the thalamus [57–59]. Interestingly, while this hypothesis has been proposed for subthalamic DBS to treat Parkinson’s disease, our results indicate that a similar mechanism may apply for thalamic DBS for ET.…”

Modulation of Neuronal Activity in the Motor Thalamus during GPi-DBS in the MPTP Nonhuman Primate Model of Parkinson's Disease

“…Multiple other studies, however, have reported increased cGMP levels in the GPi [28] [29] [30] and in the SNr [30] during STN DBS suggesting increased levels of synaptic/metabolic activity consistent with activation of output from the stimulated structure. Regardless of whether one supports the inhibition or activation hypothesis, the far-reaching effect of DBS on other structures in the circuit is supported by a number of studies demonstrating alterations in cortical activity with STN [31] [32] or GPi DBS [33] as well as previous modeling [34,35] and animal studies recording from multiple structures in the circuit [9,24] [36–38]. Changes in extracellular concentrations of striatal GABA and glutamate during STN stimulation lend further support to the varied and complex changes that occur during DBS [39,40].…”

Do gap junctions regulate synchrony in the Parkinsonian basal ganglia?

“…To shed light into the importance of basal ganglia activity changes for PD, models of parkinsonism are needed to investigate how this information transmission changes after dopamine depletion. We expect that the communication between basal ganglia and thalamus differs in parkinsonism and potentially more information is transmitted to thalamus than in the healthy situation [Reitsma et al, 2011, Anderson et al, 2015. In particular, we are curious how average noise correlations change and what happens to the coherence at high beta frequency (Fig.…”

“…Most evidence comes from birds , and recently rodents [Anderson et al, 2015]. However, few data on the primate basal gangliathalamic connection is available [Kammermeier et al, 2014, Zimnik and.…”

“…Anderson et al [2015] described low spike-spike correlations between the rat SNr and the ventral anterior thalamus (VA) as well as low spike-LFP coupling. Also high-frequency stimulation of the GPi did not lead to entrainment of thalamic cells [Kammermeier et al, 2014], but only to subtle changes in oscillatory power.…”