Deep brain stimulation that abolishes parkinsonian activity in basal ganglia improves thalamic relay fidelity in a computational circuit

Abstract

Deep brain stimulation (DBS) of the subthalamic nucleus reduces the severity of parkinsonian motor symptoms, but the therapeutic mechanisms are not understood. We hypothesize that clinically effective high frequency DBS suppresses disordered neuronal activity in the globus pallidus internus (GPi), a primary output structure of the basal ganglia. In a computational model of the basal ganglia thalamic circuit, periodic high frequency (>100Hz) stimulation of the subthalamic nucleus reduced the incidence of thalamic cell errors, from the high error rates seen in the parkinsonian case back to the low error rates seen in the normal-healthy case. In contrast, both low frequency (<70Hz) DBS and high frequency aperiodic DBS failed to alleviate thalamic errors. In high error rate conditions, disordered patterns of GPi activity lead to irregular synaptic inhibition of thalamus. In low error rate conditions, ordered patterns of GPi activity lead to regular synaptic inhibition of thalamus. Linear regression revealed that the variance of the GPi synaptic output accounted for 87-97% of the changes in thalamic error rate. In contrast, the average GPi synaptic output – a measure of total GPi activity – accounted for only 25-50% of the changes in thalamic error rate. Thus, while the firing rate of GPi cells may play some minor role, regularizing the pathological patterns of GPi activity is the mechanism by which DBS treats parkinsonian motor symptoms.

The effects of DBS patterns on basal ganglia activity and thalamic relay

“…Such suppression of pathological patterns in the BG circuit may minimize PD motor symptoms. This intuition is supported by experimental data in monkeys and humans (Dorval et al 2009;Galvan and Wichmann 2008;Guo et al 2008).…”

“…The variance of the ensemble GPi output (Dorval et al 2009) captures stricter temporal dependencies between spiking patterns of pairs of neurons. In Dorval et al (2009), the RT model was used to show that variability in the ensemble GPi output is low in healthy conditions and high in PD conditions.…”

“…We applied square pulse train DBS waveforms into the STN at frequencies ranging from 0-140 Hz, and searched for waveforms that (i) restored thalamic relay reliability and (ii) that generated neuronal activity in all BG structures modeled and thalamus that resemble activity observed under healthy conditions, and (iii) that maintained restoration for all stages of PD. Thalamic relay reliability is an important variable and is thought to quantify the degree of Parkinsonianism by several authors (Dorval et al 2009;Schiff 2010;Rubin and Terman 2004;Guo et al 2008;Feng et al 2007). To achieve our three goals, we defined (i), (ii) and (iii) we defined normality measures that quantified the level of bursting (successive spikes within 2-10 ms apart), 10-30 Hz oscillations and synchronization in the BG structures and computed these measures for each DBS frequency along with the reliability of thalamic cells to relay cortical inputs.…”

“…One hypothesis is based on the similarity of clinical results between DBS and ablative surgeries, where lesions are made in particular basal ganglia (BG) nuclei in the latter (Montgomery and Baker 2000;Obeso et al 1997). In 2004, Rubin and Terman constructed a biophysical model of the BG and proposed that DBS works by replacing the pathological rhythmic output of basal ganglia with high-frequency tonic firing (Rubin and Terman 2004;Guo et al 2008;Dorval et al 2009;Cagnan et al 2009;Feng et al 2007). Due to high-frequency tonic firing, basal ganglia neurons lose their ability to modulate neuronal activity of neighboring structures, including its output to the thalamus, and thus in a way mimic a lesion in the area.…”

64 Channel ASIC for Neurobiology Experiments

“…All of these researches are conducted since people like to delve into nervous system in order to understand how it works. This knowledge can be then very helpful in building artificial prosthesis for disabled persons, in finding cures for diseases such as Parkinson or Alzheimer or in reusing it for coding the large amount of information [2], [3].…”