Modeling mechanisms of tremor reduction for essential tremor using symmetric biphasic DBS

Abstract

Essential tremor (ET) is the most common movement disorder, in which the primary symptom is a prominent, involuntary 4-10 Hz movement. For severe, medication refractory cases, deep brain stimulation (DBS) targeting the ventral intermediate nucleus of the thalamus (VIM) can be an effective treatment for cessation of tremor and is thought to work in part by disrupting tremor frequency oscillations (TFOs) in VIM. However, DBS is not universally effective and may be further disrupting cerebellar-mediated activity in the VIM. Here, we applied biophysically detailed computational modeling to investigate whether the efficacy of DBS is affected by the mechanism of generation of TFOs or by the pattern of stimulation. We simulated the effects of DBS using standard, asymmetric pulses as well as biphasic, symmetric pulses to understand biophysical mechanisms of how DBS disrupts TFOs generated either extrinsically or intrinsically. The model results suggested that the efficacy of DBS in the VIM is affected by the mechanism of generation of TFOs. Symmetric biphasic DBS reduced TFOs more than standard DBS in both networks, and these effects were stronger in the intrinsic network. For intrinsic tremor frequency activity, symmetric biphasic DBS was more effective at reducing TFOs. Simulated non-tremor signals were also transmitted during symmetric biphasic DBS, suggesting that this type of DBS may help to reduce side effects caused by disruption of the cerebellothalamocortical pathway. Biophysical details in the model provided a mechanistic interpretation of the cellular and network dynamics contributing to these effects that can be empirically tested in future studies. 2 Modeling biphasic DBS in ET S. Lee et al. Significance StatementEssential tremor (ET) is a common movement disorder, whose primary symptom is an involuntary rhythmic movement of the limbs or head. An area of the human thalamus demonstrates electrical activity that oscillates at the frequencies of tremor, and deep brain stimulation (DBS) in this area can reduce tremor. It is not fully understood how DBS affects tremor frequency activity in the thalamus, and studying different patterns of DBS stimulation may help to clarify these mechanisms. We created a computational model of different shapes of DBS and studied how they reduce different hypothesized generators of tremor frequency activity. A greater understanding of how DBS affects the thalamus may lead to improved treatments to reduce tremor and alleviate side effects in patients with ET.3 Modeling biphasic DBS in ET S. Lee et al.

Biophysical modeling of VIM to assess contributions of oscillatory activity to essential tremor

“…2). We extended the original models with additional axonal and dendritic compartments in particular to be suitable for simulations of extracellular electrical "deep brain" stimulation, a widely-used therapy for medication-refractory ET, which we addressed in a companion study [33]. We analyzed spike rate outputs at the distal axon terminal of the VIM cells to understand how tremor frequency activity in VIM might be transmitted to downstream areas such as primary motor cortex and also simulated the extracellular field potential.…”

“…If tremor frequency activity in VIM must cross a threshold to drive behavioral tremor expression, then DBS affecting cerebellothalamic fibers may be eliminating non-tremor inputs to VIM, still resulting in reduced tremor output despite not explicitly blocking tremor frequency input activity. In a companion paper, we investigate the influence of symmetric, biphasic DBS patterns on both extrinsic and intrinsic generation of tremor frequency activity [33].…”

“…Our goal was to assess the extent to which intrinsic versus extrinsic mechanisms may contribute to tremor and how differences in these networks respond differently to pharmacological manipulations or afferent inputs representing non-tremor signals. In a companion paper, we investigated the differential impact of deep brain stimulation on tremor frequency oscillations produced by extrinsic or intrinsic mechanisms [33].…”