Ventral Medial Thalamic Nucleus Promotes Synchronization of Increased High Beta Oscillatory Activity in the Basal Ganglia–Thalamocortical Network of the Hemiparkinsonian Rat

Abstract

Loss of dopamine is associated with increased synchronization and oscillatory activity in the subthalamic nucleus and basal ganglia (BG) output nuclei in both Parkinson's disease (PD) patients and animal models of PD. We have previously observed substantial increases in spectral power in the 25-40 Hz range in LFPs recorded in the substantia nigra pars reticulata (SNpr) and motor cortex (MCx) in the hemiparkinsonian rat during treadmill walking. The current study explores the hypothesis that SNpr output entrains activity in the ventral medial thalamus (VM) in this frequency range after loss of dopamine, which in turn contributes to entrainment of the MCx and BG. Electrode bundles were implanted in MCx, SNpr, and VM of rats with unilateral dopamine cell lesions. Spiking and LFP activity were recorded during epochs of rest and walking on a circular treadmill. After dopamine cell lesion, 30 -36 Hz LFP activity in the VM became more robust during treadmill walking and more coherent with LFP activity in the same range in MCx and SNpr. Infusion of the GABA A antagonist picrotoxin into the VM reduced both high beta power in MCx and SNpr and coherence between MCx and SNpr while temporarily restoring walking ability. Infusion of the GABA A agonist muscimol into the VM also reduced MCx-SNpr coherence and beta power but failed to improve walking. These results support the view that synchronized neuronal activity in the VM contributes to the emergence of high beta oscillations throughout the BG-thalamocortical network in the behaving parkinsonian rat.

Thalamocortical dynamics underlying spontaneous transitions in beta power in Parkinsonism

“…However, in our study, thalamic neurons exhibited activity in the beta band during both low and high beta power conditions (Fig.8). Our results are supported by recent experimental work showing a substantial and coherent enhancement of beta activity in the motor thalamus and motor cortex of behaving 6-OHDA-lesioned rats (Brazhnik et al, 2016). There is also evidence of aberrant beta synchrony in the thalamus of unmedicated PD patients (Kempf et al 2009) Taken together, these results emphasise that thalamic neural activity in the beta band is likely to be a contributing circuit feature for the generation of aberrant beta synchronization in PD, and highlight a functional coupling between the thalamus and deep layers of the motor cortex.…”

“…This rodent model is useful in capturing the chronic dopamine depletion that is common to 'late stage' PD, and has been widely used for studies of the mechanisms by which excessive beta synchrony arises and propagates within the BGTC circuit in Parkinsonism. Moreover, the abnormal beta oscillations present in the BGTC circuit in anesthetized and behaving 6-OHDA lesioned are similar in many respects to those present in unmedicated people with PD (Sharott et al, 2005;Mallet et al 2008aMallet et al , 2008bAvila et al 2010;Degos et al 2009;Nevado-Holgado et al 2014;Brazhnik et al 2016;Sharott et al 2017).…”

“…Motivated by these studies, we hypothesized that -in the Parkinsonian state -an alteration of interlaminar and laminar-specific connectivity in the Thalamocortical (TC) loop contributes to the mechanisms generating the parkinsonian spectral profile. We focused on the TC loop due to the anatomical and functional characteristics of this network: 1) the cortex is an optimal target for non-invasive therapeutic techniques such as TMS and TACS (Barker et al, 1985;Cantello et al, 2002;Kobayashi & Pascual-Leone, 2003;Herrmann et al, 2013); 2) the 6 thalamus is the only CBGTC node projecting directly to cortex, allowing for the integration of information from subcortical structures to the motor cortex (Wise & Donoghue, 1986;Brazhnik et al, 2016) and 3) cortex and thalamus establish a reciprocal relationship (Hooks et al, 2013), which is thought to play a key role in physiological and pathological sensory and motor computations (Sherman & Guillery, 2009). In PD, where motor impairments are the cardinal symptoms, understanding the synaptic dynamics and organization of the thalamocortical (TC) circuit could potentially shed light on pathophysiological mechanisms.…”

Synchronised spiking activity underlies phase amplitude coupling in the subthalamic nucleus of Parkinson’s disease patients

“…At the level of STN, our results suggest that this may be due to PAC being a proxy for the locking of local spiking activity to beta oscillations, which is supported by computational evidence (Sanders, 2016). The importance of this interpretation is that beta oscillations, as measured in basal ganglia LFPs or EEG/ECoG, are synchronised across the entire cortical basal ganglia network (Mallet et al, 2008a;Mallet et al, 2008b;Brazhnik et al, 2016;Sharott et al, 2017) and such spike-field locking is a robust marker of the Parkinsonian state across experimental animals and patients. Using the timing of cortical spiking activity locked to such network oscillations as a biomarker for closed-loop deep brain stimulation relieves motor impairment to a greater degree than conventional 130Hz stimulation (Rosin et al, 2011).…”

Parkinson’s disease uncovers an underlying sensitivity of subthalamic nucleus neurons to beta-frequency cortical input

“…In humans, the majority of studies have recorded oscillations either within the STN, or between cortex and STN. While investigations in experimental animals have clearly demonstrated these activities extend across the entire network (Mallet N, A Pogosyan, LF Marton, et al 2008;Pasquereau B and RS Turner 2011;Brazhnik E et al 2016;Deffains M et al 2016;Sharott A et al 2017), the STN likely has a pivotal role (Deffains M et al 2016). This stems, in part, from its position as the only group of excitatory neurons within the basal ganglia network.…”