Neuroleptic-Induced Catalepsy: Electrophysiological Mechanisms of Functional Recovery Induced by High-Frequency Stimulation of the Subthalamic Nucleus

Abstract

High-frequency stimulation (HFS) of the subthalamic nucleus (STN) remarkably alleviates motor disorders in parkinsonian patients. The mechanisms by which STN HFS exerts its beneficial effects were investigated in anesthetized rats, using a model of acute interruption of dopaminergic transmission. Combined systemic injections of SCH-23390 [R(ϩ)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5,-tetrahydro-1H-3-benzazepine] and raclopride, antagonists of the D 1 and D 2 classes of dopaminergic receptors, respectively, were performed, and the parameters of STN HFS that reversed the neuroleptic-induced catalepsy were determined in freely moving animals. The effects of neuroleptics and the impact of STN HFS applied at parameters alleviating neuroleptic-induced catalepsy were analyzed in the substantia nigra pars reticulata (SNR), a major basal ganglia output structure, by recording the neuronal firing pattern and the responses evoked by cortical stimulation. Neuroleptic injection altered the tonic and regular mode of discharge of SNR neurons, most of them becoming irregular with bursts of spikes and pauses. The inhibitory component of the cortically evoked response, which is attributable to the activation of the direct striatonigral circuit, was decreased, whereas the late excitatory response resulting from the indirect striatopallido-subthalamo-nigral circuit was reinforced. During STN HFS, the spontaneous firing of SNR cells was either increased or decreased with a global enhancement of the firing rate in the overall population of SNR cells recorded. However, in all of the cases, SNR firing pattern was regularized, and the bias between the trans-striatal and trans-subthalamic circuits was reversed. By these effects, STN HFS restores the functional properties of the circuits by which basal ganglia contribute to motor activity.

Mechanisms of Deep Brain Stimulation in Movement Disorders as Revealed by Changes in Stimulus Frequency

“…3B); the mean firing rates of GPe and GPi neurons in MPTP monkeys were higher during STN HFS than before STN HFS, 27 and the mean firing rates of SNr neurons increased during STN HFS in rats with neurolepticinduced catalepsy. 37 These results suggest that HFS drives seemingly opposite changes in synaptic activity and firing rates in the basal ganglia, which is a difference that may be exacerbated by differences in the duration of HFS in the previously described experiments. The divergence in 2-DG accumulation and firing rate trends with and without high frequency DBS may indicate that 2-DG accumulation depends not only on the firing rate of neurons and synapses in the nucleus of interest, but also on complex changes in the patterns of activity that take place in the same nucleus.…”

“…The percent of SNr cells contributing to burst activity increased from 60% to 90% after neuroleptic injections in rats, and then decreased back to 62% during high-frequency STN stimulation. 37 Similarly, the frequency and duration of thalamic bursts were reduced in response to HFS of the GPi in monkeys. 26 Simulations of model thalamocortical relay neurons during 65 Hz and 130 Hz stimulation also indicate that intrinsic bursts were disrupted more by 130 Hz DBS than by 65 Hz DBS.…”

“…27 Similarly, firing rates in the SNr of rats with neurolepticinduced catalepsy, which receives excitatory inputs from the STN, increased from ϳ29 Hz to ϳ42 Hz during HFS. 37 Functional magnetic resonance imaging revealed that primary areas of activation during STN DBS were the ipsilateral thalamus and GP, 38 and more specifically the GPe 39 , which are all downstream targets of the STN. Furthermore, glutamate levels in healthy rats increased in GP and SNr as a function of STN DBS frequency up to a plateau at 130 Hz.…”

“…However, "in all of the cases, the SNr firing pattern was regularized." 37 In addition, the entropy of interspike intervals (i.e., a measure of the irregularity or disorder of neuronal spiking) is decreased in GPi and GPe during HFS of the STN in MPTP monkeys, but increased by low-frequency stimulation. 65 During low-frequency stimulation in these monkeys, interspike interval distributions returned to the pre-stimulation state around 10 ms after stimulus pulses, which demonstrated a failure to override pathological activity with low-frequency DBS.…”

Behavioral Electrophysiology of Psychostimulants

“…Unlike striatal output cells, which are silent in the absence of excitatory input, SNr neurons discharge at roughly the same rate whether excitatory input is present or not. In fact, activity remains relatively stable even during DA receptor blockade in awake animals (Degos et al, 2005). Adjustments in the SNr autoactive rate depend instead on fluctuations in the level of inhibitory GABA input, which may arise from several sources including axon collaterals of SNr projection neurons (Fallon and Loughlin, 1995;Gulacsi et al, 2003;Rick and Lacey, 1994).…”