Abstract
The mechanism by which deep brain stimulation (DBS) improves dystonia is not understood, partly heterogeneity of the underlying disorders leads to differing effects of stimulation in different locations. Similarity between the effects of DBS and the effects of lesions has led to biophysical models of blockade or reduced transmission of involuntary activity in individual cells in the pathways responsible for dystonia. Here, we expand these theories by modeling the effect of DBS on populations of neurons. We emphasize the important observation that the DBS signal itself causes surprisingly few side effects and does not normally appear in the electromyographic signal. We hypothesize that, at the population level, massively synchronous rhythmic firing caused by DBS is only poorly transmitted through downstream populations. However, the high frequency of stimulation overwhelms incoming dystonic activity, thereby substituting an ineffectively transmitted exogenous signal for the endogenous abnormal signal. Changes in sensitivity can occur not only at the site of stimulation, but also at downstream sites due to synaptic and homeostatic plasticity mechanisms. The mechanism is predicted to depend strongly on the stimulation frequency. We provide preliminary data from simultaneous multichannel recordings in basal ganglia and thalamus in children with secondary dystonia. We also provide illustrative simulations of the effect of stimulation frequency on the transmission of the DBS pulses through sequential populations of neurons in the dystonia pathway. Our experimental results and model provide a new hypothesis and computational framework consistent with the clinical features of DBS in childhood acquired dystonia.
Highlights
Deep brain stimulation (DBS) is a neuromodulatory intervention that has had profound impact on several adult-onset movement disorders, including parkinsonism, tremor, and dystonia (Montgomery, 2010)
This model is based on the pattern of excitatory and inhibitory connections between cortex, basal ganglia, and thalamus, and it posits that parkinsonism and dystonia are associated with very high and very low activity in globus pallidus (GPi), respectively
Because the output of GPi is carried by inhibitory synapses, and because the output of thalamus is often excitatory to cortex, the rate model suggests that high GPi activity in parkinsonism leads to decreased cortical activity, whereas low GPi activity in dystonia leads to increased cortical activity
Summary
Deep brain stimulation (DBS) is a neuromodulatory intervention that has had profound impact on several adult-onset movement disorders, including parkinsonism, tremor, and dystonia (Montgomery, 2010). Much of clinical care has been guided by the “rate model” (Vitek and Giroux, 2000) This model is based on the pattern of excitatory and inhibitory connections between cortex, basal ganglia, and thalamus, and it posits that parkinsonism and dystonia are associated with very high and very low activity in GPi, respectively. Because the output of GPi is carried by inhibitory synapses, and because the output of thalamus is often excitatory to cortex, the rate model suggests that high GPi activity in parkinsonism leads to decreased cortical activity, whereas low GPi activity in dystonia leads to increased cortical activity. The most likely candidate is corticothalamic projections (Rovo et al, 2012), an alternative possibility is that the thalamic response to input from GPi includes a rapid rebound excitation so that the net effect of GPi on thalamus might be excitatory (Rovo et al, 2012; Herrington et al, 2016)
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