Moving toward a generalizable application of central thalamic deep brain stimulation for support of forebrain arousal regulation in the severely injured brain

Abstract

This review considers the challenges ahead for developing a generalizable strategy for the use of central thalamic deep brain stimulation (CT/DBS) to support arousal regulation mechanisms in the severely injured brain. Historical efforts to apply CT/DBS to patients with severe brain injuries and a proof-of-concept result from a single-subject study are discussed. Circuit and cellular mechanisms underlying the recovery of consciousness are considered for their relevance to the application of CT/DBS, to improve consciousness and cognition in nonprogressive brain injuries. Finally, directions for development, and testing of generalizable criteria for CT/DBS are suggested, which aim to identify neuronal substrates and behavioral profiles that may optimally benefit from support of arousal regulation mechanisms.

Figure 1

Single-subject study of central thalamic DBS in the minimally conscious state. (A). Study timeline. (B) Comparison of pre-surgical baselines and DBS ON and DBS OFF periods during a six cross-over trial of central thalamic DBS in a patient with severe traumatic brain injury (see text). Figure elements adapted from Ref. 21, with permission.

Figure 2

Mesocircuit model placing CT/DBS in the context of mechanisms underlying spontaneous and medication induced recovery of consciousness. A mesocircuit model organizing mechanisms underlying recovery of consciousness after severe brain injury [28]. Diffuse disfacilitation[30] across frontal cortical, central thalamic and striatal neurons arises from severe structural brain injuries. In particular, reduction of thalamocortical and thalamostriatal outflow following deafferentation and loss of neurons in central thalamus[31] withdraws important afferent drive to the medium spiny neurons (MSNs) of striatum that may then fail to reach firing threshold because of their requirement for high levels of synaptic background activity [45]. Loss of active inhibition from the striatum allows neurons of the globus pallidus interna (GPi) to tonically fire and provide an active inhibition to their synaptic targets including relay neurons of the already strongly disfacilitated central thalamus and possibly also the projection neurons of the pedunculopontine nucleus[78]. Amantadine,[14] L-DOPA,[57,58] and zolpidem[60] may reverse these conditions of marked down-regulation of anterior forebrain activity across frontal cortices, striatum, and central thalamus acting at different locations with the mesocircuit.[28] Collectively, restoration of thalamocortical and thalamostriatal outflow will depolarize neocortical neurons and facilitate long-range cortico-cortical, corticothalamic and corticostriatal outflow. CT/DBS can be considered as a final common pathway aggregating these effects and partial remediating the effects of strong deafferentation of these neurons in severe brain injuries.

Figure 3

Central thalamic DBS evoked potentials in the minimally conscious state. (A) Figure shows cortical evoked potentials recorded from left DBS electrode in single-subject study of Figure 1 (Ref. 21). Averaged waveforms of the evoked potentials are shown; a 250 ms baseline is shown prior to the onset of the approximately 100 ms stimulus electrical artifact induced by the stimulus train, followed by a 900 ms window containing the physiological response to the stimulation. Consistent, time-locked changes in EEG pattern are present for as long as 450 ms following the offset of stimulation. Two waveforms are shown for each recording site, with each representing half of the acquired data (first/second half) to demonstrate the neuronal origins of the response as opposed to volume conduction of the electrical field from the electrode cathodes. Bilateral activation is seen with a dominant effect over the ipsilateral (left) hemisphere and frontocentral midline, consistent with activation of frontal cortical regions involved in arousal regulation mechanisms. Magnetic resonance image inset shows electrode lead placements within central thalamus of patient's right (R) and left (L) hemispheres displayed in T1 weighted MRI coronal image. Figure elements adapted from Ref. 21, with permission. (B) Image shows classical pattern of bihemispheric EEG activation with spindle bursts seen in six different cortical areas in response to a single shock in the centromedian-parafasicularis nucleus of the cat under pentobarbital anesthesia, modified from Jasper.[54]

Figure 3

Central thalamic DBS evoked potentials in the minimally conscious state. (A) Figure shows cortical evoked potentials recorded from left DBS electrode in single-subject study of Figure 1 (Ref. 21). Averaged waveforms of the evoked potentials are shown; a 250 ms baseline is shown prior to the onset of the approximately 100 ms stimulus electrical artifact induced by the stimulus train, followed by a 900 ms window containing the physiological response to the stimulation. Consistent, time-locked changes in EEG pattern are present for as long as 450 ms following the offset of stimulation. Two waveforms are shown for each recording site, with each representing half of the acquired data (first/second half) to demonstrate the neuronal origins of the response as opposed to volume conduction of the electrical field from the electrode cathodes. Bilateral activation is seen with a dominant effect over the ipsilateral (left) hemisphere and frontocentral midline, consistent with activation of frontal cortical regions involved in arousal regulation mechanisms. Magnetic resonance image inset shows electrode lead placements within central thalamus of patient's right (R) and left (L) hemispheres displayed in T1 weighted MRI coronal image. Figure elements adapted from Ref. 21, with permission. (B) Image shows classical pattern of bihemispheric EEG activation with spindle bursts seen in six different cortical areas in response to a single shock in the centromedian-parafasicularis nucleus of the cat under pentobarbital anesthesia, modified from Jasper.[54]