Abstract
Central thalamic deep brain stimulation (CT-DBS) is an investigational therapy to treat enduring cognitive dysfunctions in structurally brain injured (SBI) patients. However, the mechanisms of CT-DBS that promote restoration of cognitive functions are unknown, and the heterogeneous etiology and recovery profiles of SBI patients contribute to variable outcomes when using conventional DBS strategies,which may result in off-target effects due to activation of multiple pathways. To disambiguate the effects of stimulation of two adjacent thalamic pathways, we modeled and experimentally compared conventional and novel ‘field-shaping’ methods of CT-DBS within the central thalamus of healthy non-human primates (NHP) as they performed visuomotor tasks. We show that selective activation of the medial dorsal thalamic tegmental tract (DTTm), but not of the adjacent centromedian-parafascicularis (CM-Pf) pathway, results in robust behavioral facilitation. Our predictive modeling approach in healthy NHPs directly informs ongoing and future clinical investigations of conventional and novel methods of CT-DBS for treating cognitive dysfunctions in SBI patients, for whom no therapy currently exists.
Highlights
Central thalamic deep brain stimulation (CT-DBS) is an investigational therapy to treat enduring cognitive dysfunctions in structurally brain injured (SBI) patients
We developed a biophysical modeling framework[49] to study DBS within the non-human primates (NHP) thalamus to identify the central thalamic pathways associated with significant changes in behavioral performance
Our results demonstrate that selective activation of the dorsal thalamic tegmental tract (DTTm) fiber pathway that projects through the central lateral (CL) nucleus, and not the Cm-Pf complex fiber projections, facilitates performance
Summary
Central thalamic deep brain stimulation (CT-DBS) is an investigational therapy to treat enduring cognitive dysfunctions in structurally brain injured (SBI) patients. A unique aspect of this s tudy[35] was the use of two closely spaced DBS leads placed within CT and the discovery that both the precise location of the leads in CT and the orientation of the electric field established between the two leads were critical parameters for improving performance and enhancing frontostriatal activity patterns This discovery led us to hypothesize that the key target for stimulation is the local fiber tracts that traverse the CT and not a single nucleus. Patients with higher levels of consciousness and less structural injury of their thalamus, frontal lobe, and striatum are expected to be ideal candidates for DBS therapy as they often suffer from enduring cognitive d ysfunction[8] In such persons, improved targeting and activation of the arousal related pathways that minimizes OFF-target side effects, are critical to developing this potential therapy, as recently demonstrated[47]. The study presented here further establishes the DTTm fiber pathway as an optimal DBS target to facilitate performance in healthy NHPs and directly informs ongoing[47] and future clinical studies using DBS to treat the enduring fatigue and cognitive dysfunction experienced by the majority TBI patients
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