Thalamic deep brain stimulation in traumatic brain injury: a phase 1, randomized feasibility study.

Converging evidence indicates that impairments in executive function and information-processing speed limit quality of life and social reentry after moderate-to-severe traumatic brain injury (msTBI). These deficits reflect dysfunction of frontostriatal networks for which the central lateral (CL) nucleus of the thalamus is a critical node. The primary objective of this feasibility study was to test the safety and efficacy of deep brain stimulation within the CL and the associated medial dorsal tegmental (CL/DTTm) tract.Six participants with msTBI, who were between 3 and 18 years post-injury, underwent surgery with electrode placement guided by imaging and subject-specific biophysical modeling to predict activation of the CL/DTTm tract. The primary efficacy measure was improvement in executive control indexed by processing speed on part B of the trail-making test.All six participants were safely implanted. Five participants completed the study and one was withdrawn for protocol non-compliance. Processing speed on part B of the trail-making test improved 15% to 52% from baseline, exceeding the 10% benchmark for improvement in all five cases.CL/DTTm deep brain stimulation can be safely applied and may improve executive control in patients with msTBI who are in the chronic phase of recovery.ClinicalTrials.gov identifier: NCT02881151 .

Presynaptic dopamine deficit in minimally conscious state patients following traumatic brain injury.

Dopaminergic stimulation has been proposed as a treatment strategy for post-traumatic brain injured patients in minimally conscious state based on a clinical trial using amantadine, a weak dopamine transporter blocker. However, a specific contribution of dopaminergic neuromodulation in minimally conscious state is undemonstrated. In a phase 0 clinical trial, we evaluated 13 normal volunteers and seven post-traumatic minimally conscious state patients using 11C-raclopride PET to estimate dopamine 2-like receptors occupancy in the striatum and central thalamus before and after dopamine transporter blockade with dextroamphetamine. If a presynaptic deficit was observed, a third and a fourth 11C-raclopride PET were acquired to evaluate changes in dopamine release induced by l-DOPA and l-DOPA+dextroamphetamine. Permutation analysis showed a significant reduction of dopamine release in patients, demonstrating a presynaptic deficit in the striatum and central thalamus that could not be reversed by blocking the dopamine transporter. However, administration of the dopamine precursor l-DOPA reversed the presynaptic deficit by restoring the biosynthesis of dopamine from both ventral tegmentum and substantia nigra. The advantages of alternative pharmacodynamic approaches in post-traumatic minimally conscious state patients should be tested in clinical trials, as patients currently refractory to amantadine might benefit from them.

Determination of awareness in patients with severe brain injury using EEG power spectral analysis.

OBJECTIVE: To determine whether EEG spectral analysis could be used to demonstrate awareness in patients with severe brain injury. METHODS: We recorded EEG from healthy controls and three patients with severe brain injury, ranging from minimally conscious state (MCS) to locked-in-state (LIS), while they were asked to imagine motor and spatial navigation tasks. We assessed EEG spectral differences from 4 to 24 Hz with univariate comparisons (individual frequencies) and multivariate comparisons (patterns across the frequency range). RESULTS: In controls, EEG spectral power differed at multiple frequency bands and channels during performance of both tasks compared to a resting baseline. As patterns of signal change were inconsistent between controls, we defined a positive response in patient subjects as consistent spectral changes across task performances. One patient in MCS and one in LIS showed evidence of motor imagery task performance, though with patterns of spectral change different from the controls. CONCLUSIONS: EEG power spectral analysis demonstrates evidence for performance of mental imagery tasks in healthy controls and patients with severe brain injury. SIGNIFICANCE: EEG power spectral analysis can be used as a flexible bedside tool to demonstrate awareness in brain-injured patients who are otherwise unable to communicate.

Mean-field modeling of thalamocortical dynamics and a model-driven approach to EEG analysis.

Higher brain function depends on task-dependent information flow between cortical regions. Converging lines of evidence suggest that interactions between cortical regions and the central thalamus play a key role in establishing the dynamic patterns of functional connectivity that normally support these processes. In patients with chronic disturbances of cognitive function due to severe brain injury, dysfunction of this circuitry likely plays a crucial role in pathogenesis. However, assaying thalamocortical interactions is challenging even in healthy subjects and more so in severely impaired patients. To approach this problem, we apply a dynamical-systems approach to motivate an analysis of the electroencephalogram (EEG). We begin with a model for a single thalamocortical module [Robinson PA, Rennie CJ, Rowe DL (2002) Phys Rev E Stat Nonlin Soft Matter Phys 65:041924; Robinson PA, Rennie CJ, Wright JJ, Bourke PD (1998) Phys Rev E Stat Nonlin Soft Matter Phys 58:3557-3571]. When two such modules interact via shared thalamic inhibition, multistable behavior emerges; each mode is characterized by a different pattern of coherence between cortical regions. This observation suggests that changing patterns of cortical coherence are a hallmark of normal thalamocortical dynamics. In a preliminary study, we test this idea by analyzing the EEG of a patient with chronic brain injury, who has a marked improvement in behavior and frontal brain metabolism in response to zolpidem. The analysis shows that following zolpidem administration, changing patterns of coherence are identified between the frontal lobes and between frontal and distant brain regions. These observations support the role of the central thalamus in the organization of patterns of cortical interactions and suggest how indexes of thalamocortical dynamics can be extracted from the EEG.

Dynamics of coupled thalamocortical modules.

We develop a model of thalamocortical dynamics using a shared population of thalamic neurons to couple distant cortical regions. Behavior of the model is determined as a function of the connection strengths with shared and unshared populations in the thalamus, either within a relay nucleus or the reticular nucleus. When the coupling is via the reticular nucleus, we locate solutions of the model where distant cortical regions maintain the same activity level, and regions where one region maintains an elevated activity level, suppressing activity in the other. We locate and investigate a region where both types of solutions exist and are stable, yielding a mechanism for spontaneous changes in global activity patterns. Power spectra and coherence are computed, and marked differences in the coherence are found between the two kinds of modes. When, on the other hand, the coupling is via a shared relay nuclei, the features seen with the reticular coupling are absent. These considerations suggest a role for the reticular nucleus in modulating long distance cortical communication.

A Bayesian statistical analysis of behavioral facilitation associated with deep brain stimulation.

Deep brain stimulation (DBS) is an established therapy for Parkinson's Disease and is being investigated as a treatment for chronic depression, obsessive compulsive disorder and for facilitating functional recovery of patients in minimally conscious states following brain injury. For all of these applications, quantitative assessments of the behavioral effects of DBS are crucial to determine whether the therapy is effective and, if so, how stimulation parameters can be optimized. Behavioral analyses for DBS are challenging because subject performance is typically assessed from only a small set of discrete measurements made on a discrete rating scale, the time course of DBS effects is unknown, and between-subject differences are often large. We demonstrate how Bayesian state-space methods can be used to characterize the relationship between DBS and behavior comparing our approach with logistic regression in two experiments: the effects of DBS on attention of a macaque monkey performing a reaction-time task, and the effects of DBS on motor behavior of a human patient in a minimally conscious state. The state-space analysis can assess the magnitude of DBS behavioral facilitation (positive or negative) at specific time points and has important implications for developing principled strategies to optimize DBS paradigms.