Deep brain stimulation for the treatment of disorders of consciousness and cognition in traumatic brain injury patients: a review

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Traumatic brain injury (TBI) is a looming epidemic, growing most rapidly in the elderly population. Some of the most devastating sequelae of TBI are related to depressed levels of consciousness (e.g., coma, minimally conscious state) or deficits in executive function. To date, pharmacological and rehabilitative therapies to treat these sequelae are limited. Deep brain stimulation (DBS) has been used to treat a number of pathologies, including Parkinson disease, essential tremor, and epilepsy. Animal and clinical research shows that targets addressing depressed levels of consciousness include components of the ascending reticular activating system and areas of the thalamus. Targets for improving executive function are more varied and include areas that modulate attention and memory, such as the frontal and prefrontal cortex, fornix, nucleus accumbens, internal capsule, thalamus, and some brainstem nuclei. The authors review the literature addressing the use of DBS to treat higher-order cognitive dysfunction and disorders of consciousness in TBI patients, while also offering suggestions on directions for future research.

ABBREVIATIONS CNS = central nervous system; DBS = deep brain stimulation; DR = dorsal raphe; EEG = electroencephalography; MCS = minimally conscious state; MR = median raphe; MSN = medial septal nucleus; TBI = traumatic brain injury; TMS = transcranial magnetic stimulation; VS = vegetative state.

Abstract

Traumatic brain injury (TBI) is a looming epidemic, growing most rapidly in the elderly population. Some of the most devastating sequelae of TBI are related to depressed levels of consciousness (e.g., coma, minimally conscious state) or deficits in executive function. To date, pharmacological and rehabilitative therapies to treat these sequelae are limited. Deep brain stimulation (DBS) has been used to treat a number of pathologies, including Parkinson disease, essential tremor, and epilepsy. Animal and clinical research shows that targets addressing depressed levels of consciousness include components of the ascending reticular activating system and areas of the thalamus. Targets for improving executive function are more varied and include areas that modulate attention and memory, such as the frontal and prefrontal cortex, fornix, nucleus accumbens, internal capsule, thalamus, and some brainstem nuclei. The authors review the literature addressing the use of DBS to treat higher-order cognitive dysfunction and disorders of consciousness in TBI patients, while also offering suggestions on directions for future research.

Traumatic brain injury (TBI) is a medical and surgical epidemic affecting at least 1.7 million individuals yearly in the United States and causing 1.5 million hospitalizations in the European Union yearly.18,21 Its incidence is growing, from an estimated incidence of 521 per 100,000 in 2001 in the US21 (and 235 per 100,000 in Europe70) to 824 per 100,000 people in the US in 2010.21 The most common causes for TBI are falls (35%) and motor vehicle accidents (17%), and males sustain 1.4 times more brain injuries than females.18 Although TBI affects individuals of all ages, there has been a relative increase in incidence in older populations, abetted by the increased use of anticoagulation therapy.

Some of the most devastating sequelae of TBI are related to depressed levels of consciousness or deficits in higher-order cognitive functions.21 Levels of consciousness are separated clinically into different states: the minimally conscious state (MCS), the vegetative state (VS), and coma.26 Approximately 14% of patients admitted for trauma are discharged in a VS, and 52% will regain consciousness within 1 year.44 Patients typically transition out of coma within weeks to a VS or MCS.22

Conservative treatment has had limited success in treating disorders of consciousness. Central nervous system (CNS) stimulators (e.g., levodopa, amantadine) and depressants (zolpidem) have had minimal and inconsistent effects.24,45,71 Electrical stimulation of the brain is a potential alternative treatment for the sequelae of TBI. Although noninvasive methods such as transcranial magnetic stimulation (TMS) and transcranial direct-current stimulation have been widely studied,45 there are far fewer reports of deep brain stimulation (DBS) of subcortical targets.

DBS targets deep brain nuclei and white matter tracts with millimetric accuracy. The cognitive and consciousness sequelae of TBI are related to direct loss of cortical neurons, disconnection of distant cortical areas, and local neuronal circuit dysregulation in the form of dysregulated neurotransmitter levels and cellular damage.25 Neuropathological autopsy reports1,27 and whole brain imaging28 have shown that direct thalamic damage from injury or postinjury degeneration may also be a primary mechanism causing disorders of conciousness.28,63 Importantly, certain thalamic nuclei are required for arousal and attention.63 Thus, thalamic nuclei and connected white matter tracts and nuclei have become important targets for DBS to treat disorders of consciousness.

DBS has proven efficacy for cognitive and movement disorders20,52 and potential for the treatment of other disorders, such as depression.17 TBI patients often develop these same clinical diseases (e.g., tremor, depression) because of direct structural brain damage or secondary damage from the injury.4,16 DBS has shown efficacy in treating subpopulations of TBI patients with such comorbidities,37,65 yet the effect of DBS on higher-order functions is unclear. We review the literature addressing the use of DBS to treat higher-order cognitive dysfunction and disorders of consciousness in TBI patients (see Table 1).

TABLE 1.

Studies evaluating DBS to treat arousal and executive function in TBI patients or TBI animal models

Authors & YearPopulationStimulation LocationFrequency of StimulationResults
Arousal
 Hassler et al., 19691 VS ptLt ventral ant thalamus & rt pallidumVentral ant thalamus at 50 Hz & pallidum at 8 HzIncreased arousal
 Tsubokawa et al., 19908 VS ptsMedian reticular formation (n = 2), central thalamic nuclei (unilat, n = 6)50 Hz4 pts emerged; EEG desynchronization, increased CBF & regional metabolism
 Cohadon & Richer, 199325 VS ptsCentral nucleus of the thalamus50 Hz13 showed clinical improvement
 Yamamoto et al., 201021 VS psCentromedian nucleus of the thalamus (n = 19) & midbrain reticular formation (n = 2)25 Hz8 had emerged at 16-mo mark, no others emerged over 10 yrs
 Schiff et al., 20071 MCS ptCentral thalamic nuclei (bilat)100 HzThe pt showed increased signs of arousal, better feeding & motor behaviors
 Magrassi et al., 20162 VS pts & 1 MCS ptAnt intralaminar nuclei & paralaminar areas (bilat)80–110 HzIncreased arousal
 Chudy et al., 201714 pts (MCS & VS)Central thalamic nuclei (unilat)25 Hz4 pts emerged (3 MCS pts & 1 VS pt); increased level of consciousness, some returned to independent life w/ disability
Executive function
 Carballosa Gonzalez et al., 201379 ratsMedian & dorsal raphe nucleiImproved spatial working memory, reduced cortical vol loss
 Lee et al., 201356 ratsMedial septal nucleusImproved spatial working memory
 Lee et al., 2015136 ratsMedial septal nucleus cont stimImproved object exploration & spatial working memory
 Rezai et al., 20164 ptsNucleus accumbens & ant limb of int capsule (bilat)80–210 HzImproved functional (encompassing self-awareness, ability to perform ADL, & communication) & cognitive (encompassing executive function, working memory, & attention) composite scores

ADL = activities of daily living; ant = anterior; CBF = cerebral blood flow; cont stim = continuous stimulation; int = internal; NR = not reported; pt = patient.

DBS for Arousal in TBI

Reticulothalamic System Stimulation and Modulation of Arousal in Animal Models

In normal physiology, the midbrain reticular formation within the brainstem drives thalamic nuclei through cholinergic as well as glutaminergic connections.67 From thalamic relay nuclei, thalamocortical fibers synapse on layer IV cells in the cortex, driving arousal.53,67 Moruzzi and Magoun53 showed that “high-frequency” (300-Hz) stimulation of cat reticular formation results in electroencephalography (EEG) “desynchronization.” Desynchronization is a hallmark of cortical activation and arousal in animals and humans.

The first cellular-level evidence of intralaminar thalamic nuclei transfer input from the brainstem reticular formation to the cortex and striatum was demonstrated in cats by using electrode recordings and horseradish peroxidase fiber tracking.68 In these experiments, the rostral pontine tegmentum was lesioned and degeneration of the fibers en passage was allowed in order to prevent artifactual recordings. High-frequency (100-Hz) stimulation of the central thalamus in intact rodents66 resulted in increased arousal and improved behavioral performance on tasks using attention and memory. Low-frequency (10-Hz) stimulation decreased arousal and led to sleep spindle formation and even absence seizures.46 Some of these early animal studies led to the first case studies using DBS to treat brain injury patients.

DBS to Treat Disorders of Consciousness in TBI Patients

One of the first clinical descriptions of DBS for treatment of disorders of consciousness was a case report published in 1969.31 The authors described a 26-year-old man in a persistent VS after TBI. Stimulation of electrodes implanted in the left ventral anterior nucleus of the thalamus (at 50 Hz) and the right pallidum (at 8 Hz) produced increased spontaneous limb and eye movements and increased duration of arousal. Post-stimulation, the EEG showed decreased slow waves in the left temporal cortex and increased fast spiking in the bilateral cortex as well as thalamus and pallidum.

In 1990, Tsubokawa et al.72 published an early case series addressing stimulation and arousal in coma patients implanted with electrodes in the mesencephalic reticular formation or nonspecific thalamus. By 6 months, 4 of 8 patients had emerged from the VS state to follow commands and exhibited EEG desynchronization and increased regional cerebral blood flow. In that study, stimulation was delivered every 2 hours for 30 minutes at a time (off at night) at 50 Hz. In a follow-up study,74 21 patients (2 with TBI, 19 with vascular injuries, including stroke) had electrodes implanted 3 months after injury. After 19 months, 8 patients (38%) could follow commands. Stimulation was delivered every 2–3 hours for 30 minutes at a time (off at night) at 25 Hz in the centromedian nucleus of the thalamus or midbrain reticular formation. After 10 years, no additional patients emerged from coma. Note that these studies have been criticized for not giving patients adequate time to recover consciousness on their own prior to implantation.73

With the aim of activating the cortex and producing some degree of functional recovery, Cohadon and Richer12 stimulated the central nucleus of the thalamus in 25 patients 3 months after injury. Bipolar stimulation at 50 Hz was delivered 12 hours per day for 2 months. Twelve patients showed clinical improvement, but all remained moderately to severely disabled. This cohort study illustrates a central challenge in linking DBS to recovery of consciousness because, as the authors note, up to 35% of VS patients and 81% of MCS patients will recover spontaneously within 6 months to 1 year.23,41,63

Cognitive testing during stimulation-on and stimulation-off periods is necessary to discern the arousal effects of DBS versus a “lesion effect” from implantation. Schiff et al.62 placed bilateral thalamic intralaminar and paralaminar leads in a 38-year-old man who had experienced a TBI 6 years earlier. The patient showed improved arousal behavior and improved limb movement and oral feeding responses during periods when 100-Hz DBS was on. Although this was a case study, because the experiment used a blinded, crossover design with multiple DBS on and off periods (each period was 1 month long), it shows that DBS can drive behavioral improvement. Stimulation frequency and amplitude were titrated to obtain the best response for this patient.

The multi-institutional Cortical Activation by Thalamic Stimulation (CATS) study, which enrolled 3 of 40 screened TBI patients (all injured 2–8 years earlier), implemented bilateral stimulation of anterior intralaminar thalamic nuclei and adjacent areas from 18 to 48 months.48 Patients went through an initial testing phase during which optimal stimulation settings were determined based on behavior. The patients were stimulated on average at 100 Hz (range 80–110 Hz) during the daytime. The Coma Recovery Scale–Revised (CRS-R) scores improved from 6 and 8 for the 2 VS patients to 9 and 11 at 18 months, respectively, and from 14 to 15 in the MCS patient; however, none of the patients recovered to full consciousness.

Most recently, Chudy et al.11 used unilateral 50-Hz stimulation of the centromedian parafascicular complex to treat a group of 14 MCS and VS patients who had either traumatic or ischemic encephalopathy but had intact evoked potentials, positron emission tomography (PET)–detectable brain metabolism, and structural integrity of the brainstem grossly assessed using MRI. Three MCS patients and 1 VS patient emerged to consciousness—a 29% response rate. Treatment was started an average of 140 days after injury in those patients. Again, the authors agree that it is not possible to rule out that these patients were going to emerge spontaneously to consciousness without DBS, but they point out that the rates at which the patients recovered through rehabilitation were faster than previously reported rates of recovery in patients who were not treated with DBS.

How to Determine Whether DBS Will Work in Coma

Based on the experimental and clinical data described above, DBS to treat disorders of consciousness appears to require intact circuitry among the midbrain reticular formation, thalamus, and cortex to allow modulation of the global brain function. One challenge has been how to determine whether a coma patient has sufficient structural integrity within the thalamocortical loops to sustain brain function beyond simple arousal—and thereby allow DBS to be effective (Fig. 1A).63 In addition to the clinical examination discerning VS from MCS, most studies designed to test the effects of DBS on consciousness have radiographic criteria for inclusion—namely no radiographic evidence of damage to the thalamus, certain areas of the cortex, or the brainstem.

Fig. 1.
Fig. 1.

How to determine whether DBS will work in a patient in a coma. A: The theoretical arousal network targeted with DBS includes the cortex (orange overlay), thalamus (red overlay), and midbrain and pontine reticular formations (green overlay). The arousal generator originates from signals from the midbrain but may be modulated with stimulation of the thalamic relay centers. Thalamic relay centers project diffusely to cortex. B: The combination of structural measures (including MRI-based assessment of gray matter integrity, diffusion tensor imaging [DTI]–based assessment of white matter integrity), endogenously generated signals of global network integrity (such as in resting-state functional MRI [fMRI]), and newer stimulation-based connectivity measures (including TMS-based evoked response propagation as quantified by the perturbational complexity index [PCI]) may better predict which patients will benefit from DBS to bring about or facilitate arousal. C: The PCI is derived from recording the TMS-evoked response from scalp EEG (black trace is average TMS-evoked response across channels; gray traces are individual channel traces) and then projecting this signal to source space and deriving a measure of complexity based on the manner in which the evoked response propagates between brain structures of a particular patient. See Casali et al.10 for details of this methodology. Note that the TMS-evoked response can also be captured by the blood oxygen–dependent percent signal change from fMRI and thus measured in the thalamus as well as cortical structures. BAER = brainstem auditory evoked response; VEP = visual evoked potentials.

Some electrophysiological measures have been used to assess global brain function for both diagnosis and prognosis of recovery in patients with disorders of consciousness (Fig. 1B).59 Some of these evoked responses are the Vth wave of the auditory brainstem response, the N20 somatosensory evoked potential, desynchronization patterns of EEG, a pain-related P250 event-related potential > 7 μV, and more complex evoked potentials such as the P300 reflecting higher-order cognitive processing.59 Yamamoto et al.74 used these tests to predict which patients would recover after DBS. Of the 107 patients studied, 21 patients were implanted with DBS, 10 of whom met the above-mentioned electrophysiological criteria. Eight of those 10 patients (80%) eventually recovered. Of the remaining 86 patients who did not have electrodes implanted, 6 met electrophysiological criteria but none recovered consciousness. The significant difference in the rate of recovery suggests DBS is helpful for recovery in the setting of intact thalamocortical circuitry. Of the 13 who received DBS and did not recover, only 2 patients met criteria. Only 15% of patients met the electrophysiological criteria.

A novel measure that has been predictive of recovery from a VS and directly probes the structural connectivity of white matter tracts is the TMS-evoked response, which has been referred to as a measure of the causal interaction between 2 brain areas.50 Cortical connectivity as measured by the TMS-evoked response reliably changes as patients emerge from a VS to an MCS such that there is propagation of the response to more brain areas and in a more “complex” fashion (Fig. 1C).61 TMS stimulation of the brain in different cognitive states such as wakefulness, sleep,50 task,36 and levels of coma results in differential complexity of the TMS-evoked response.10,49,61 It may be that the complexity of the TMS-evoked response predicts the efficacy of DBS to treat that patient’s VS or MCS.

Finally, unilateral versus bilateral stimulation may affect how well DBS will activate arousal mechanisms. The literature to date does not show consistent results, and studies are confounded by the timing of DBS implantation. A meta-analysis demonstrated that of all the coma patients implanted with DBS leads who had at least 11 months to recover spontaneously, 1 of 1 unilateral and 5 of 6 bilateral stimulation patients recovered measurable degrees of consciousness.73

DBS for Cognition and Memory in TBI

Because of the widespread damage to white matter tracts and subcortical structures, including the thalamus, TBI causes profound disorders of cognition that result in disability from deficits in executive functioning.21 Few studies have tested cognitive function in the TBI patient population before and after DBS, but the cumulative data from animal and patient studies suggest that stimulation of the thalamus, frontal cortical areas, and components in the Papez circuit may be helpful for improving higher-order cognition. Recent studies from animal models and clinical data are addressing whether DBS can modulate cognitive performance in the brain-injured population.

DBS Modulation of Cognitive Performance in Animal Models of TBI

Hippocampal theta oscillations, which are thought to be related to learning and memory, particularly for spatial navigation,8,33 are decreased after TBI.54 It is hypothesized that the impaired cognition observed in TBI is related to altered oscillations, such as those seen in the hippocampus. If the desynchronization of brain oscillations mediates cognitive dysfunction, neuromodulation may be used to stimulate the injured brain to realign these oscillations and improve patient outcome.56 Prior reviews have described the use of electrical stimulation in modulating memory,6,38,64 but literature regarding the use of DBS specifically for altering cognition after TBI is more sparse.

TBI models showed a decrease in hippocampal theta oscillations in injured rats.19 Cells within the medial septal nucleus (MSN) modulate hippocampal pyramidal cells,2,35 making the MSN a target for neuromodulatory therapies to improve hippocampal function. Brief stimulation of the MSN in rats resulted in transient elevation of hippocampal theta activity and subsequent shorter escape latencies from the Barnes maze.42 Continuous 7.7-Hz theta stimulation of the MSN also increased hippocampal theta oscillations and resulted in normalized object exploration and improved performance in the Barnes maze.43

Other targets for DBS to improve memory after TBI are the midbrain median raphe (MR) and dorsal raphe (DR) nuclei,9 which were chosen because of serotonin’s potential neuroprotective and restorative effects.15 Carballosa Gonzalez et al.9 implanted electrodes into either the MR or DR nuclei and stimulated them at 8 or 24 Hz, beginning 4–6 hours or 7 days after a fluid percussion injury. When testing reference memory 5 weeks after injury, the authors found that 8-Hz MR- and DR-stimulated rats implanted within 4–6 hours showed significantly shorter latencies compared with their no-stimulation counterparts. It should be noted, however, that the differences between groups had decreased or disappeared by the third day of testing, which the authors attributed to underlying spontaneous recovery. When escape latency was used to measure working memory, only the 8-Hz MR-stimulated group implanted at 4–6 hours showed shorter escape latencies compared with the no-stimulation group.9

Thalamic damage has been correlated with decreased executive function in patients with mild TBI.28 Stimulation of the central thalamus in rodents resulted in improved performance on memory tasks as well as increased activation in the dentate gyrus, a connection node of the central thalamus.66

DBS Targets to Modulate Cognition in Patients

Although only one study to date, discussed below, directly addressed changes in memory function in TBI patients, DBS data from other patient populations point to alternative targets, including the pedunculopontine nucleus13 and the fornix,39,47,51 that may modulate memory function in humans. Mixed behavioral results have been seen with stimulation of the subthalamic nucleus, anterior nucleus of the thalamus, and hippocampus.6 Noninvasive stimulation of neocortical areas such as the dorsolateral prefrontal cortex may improve aspects of executive function.14,34

Importantly, what precludes functional independence in TBI patients is often not just the “granular” components of cognition, such as working memory and decision making, which can be objectively tested using trial-by-trial tasks, but broader abilities, such as excessive impulsive behavior and inability to regulate emotions. In the only study addressing the use of DBS to modulate cognition in TBI patients, Rezai et al.60 stimulated the bilateral nucleus accumbens and anterior limb of the internal capsule to modulate networks involved with motivation and processing of rewards. Deficits in initiating goal-directed behavior and problems of increased impulsiveness affect many of the patients with severe TBI who recover consciousness but are unable to live independently. Four TBI patients who could communicate and follow commands but were unable to live independently were included in Rezai and colleagues’ study. Performance on both functional and cognitive scores improved more with concurrent rehabilitation than with stimulation alone, leading the authors to suggest that DBS seems to work better when used concurrently with behavioral therapies. Continued therapy is important, since performance on tasks testing working memory and executive planning declined once formal practicing of those skills stopped.

Future Directions

Stimulation Targeting Specific Anatomical Structures

Finite element models created to estimate the extent of activation of DBS in the brain, under different stimulation protocols, may be used to shape the area of activation to target specific anatomical structures.7 Most recently, Baker et al.5 have shown that stimulation of “the wing” of the central thalamus and medial dorsal thalamic tegmental tract (which contain efferent fibers to anterior forebrain structures and en passage fibers of the internal medullary lamina that encases the central thalamic nuclei) increases the duration of arousal and vigilance in cognitively fatigued nonhuman primates. Cognitive fatigue is a common feature of TBI, limiting patients’ ability to progress with rehabilitation therapies. The authors showed the best effect is derived with shaping the field of stimulation with adjacent DBS leads to match this “wing-shaped” area of the central thalamus.5

DBS for Network Modulation

Another avenue of exploration to treat decreased arousal or cognitive performance, based on the idea that DBS involves modulation of a large-scale brain network interconnected by white matter pathways,37 may be to target these white matter pathways instead of individual brainstem or thalamic nuclei.32 For example, stimulation of the corticothalamic projections or brainstem-to-thalamic projections may be more effective in increasing arousal. The zona incerta has been implicated in modulating central thalamic nuclei activation of the anterior forebrain.46 Cortical activation is decreased with 10-Hz stimulation of the central thalamus in anesthetized rats. This effect is amplified with inhibition of neurons constituting the zona incerta, implying that the zona incerta is a modulator of cortical activation and may be a novel target to stimulate arousal in patients with decreased levels of consciousness.

Recent investigations suggest that “cortical deafferentation” may be the mechanism of impaired consciousness in refractory epilepsy. Stimulation in intralaminar nuclei of the thalamus improves behavioral arousal in the postictal state in rats with induced hippocampal seizures.30 Combined stimulation of both the pontine nucleus oralis and the central lateral nucleus of the intralaminar thalamus bilaterally results in improved behavioral arousal during a focal limbic seizure, whereas stimulation of individual nuclei did not improve behavior, in a rat model.40 These data strongly suggest that intact connectivity is required for stimulation efficacy and that dual stimulation of multiple nodes in a network can significantly boost the efficacy of DBS for global cortical function.

Refining Open-Loop Stimulation

Stimulation amplitude and frequency parameters can be tailored to the individual based on clinical response. One interesting avenue of exploration has been trying alternative patterns of stimulation. Pfaff and Banavar57 suggested that a chaotic pattern of stimulation may be more efficacious in activating the CNS than a fixed linear stimulation rate. In both normal and closed head injury mouse models with electrodes implanted in the central thalamus, stimulation delivered in a chaotic pattern led to increased arousal and locomotion compared with stimulation delivered at random intervals or fixed intervals.58,69

Alternative Stimulation Targets Within the Network

There are numerous potential targets for modulating arousal and cognitive function, including the hippocampus, prefrontal cortex, or deeper brainstem nuclei to target global CNS neurotransmitter systems such as the dopaminergic or cholinergic systems. For example, the basal forebrain nuclei have emerged as a potential alternative target for treating decreased arousal. Activation of GABAergic neurons in the basal forebrain nuclei of mice and not the activation of cholinergic or glutaminergic neurons resulted in increased wakefulness as well as increased high gamma (60–100 Hz) power in frontoparietal electrodes, as measured by cortical EEG during slow-wave sleep.3 Inhibition of these neurons impaired wakefulness. Here GABAergic connections in the basal forebrain nuclei are necessary and sufficient for wakefulness in rats.3 Anterograde tracing from the basal forebrain showed connectivity to areas of the cortex, thalamus, hypothalamus, and pallidum. Gummadavelli et al.29 discussed alternative targets to modulate consciousness in the context of epilepsy, including the pedunculopontine tegmental nucleus, ventral tegmental area, lateral hypothalamus, tuberomammillary nucleus, globus pallidus internus, subthalamic nucleus, and cholinergic basal forebrain nuclei. Importantly, animals or patients with epilepsy probably have more intact underlying brain structure than patients with TBI.

Conclusions and Recommendations

TBI is an increasingly prevalent disease process that inherently affects multiple cortical and subcortical areas as well as the white matter tracts that connect these areas via processes that progress over months to years postinjury. DBS offers a means to jump-start dormant networks or modulate aberrant or desynchronized activity across brain areas to facilitate brain function. At this point, it is crucial to perform larger blinded prospective trials with TBI patients, targeting particular brain areas that have demonstrated potential for safely modulating cognition and arousal in other patient populations. Potential targets should involve one or more nodes of the “arousal network,” including brainstem and centromedian or centrolateral interlaminar thalamic nuclei. It will be important to allow for time periods where DBS is off to discern the effects of DBS from the natural progression of recovery from TBI. This will require that patients be given an adequate period of at least 6–12 months to spontaneously emerge from coma. Although numerous ethical considerations must be kept in mind when treating this patient population,55,73 DBS coupled with intensive behavioral therapy may offer a means for patients who have experienced devastating brain injury to recover cognitive function and a meaningful quality of life.

Disclosures

Dr. Butson reports a consultant relationship with Abbott and Functional Neuromodulation and direct stock ownership in Intelect Medical.

Author Contributions

Conception and design: Rolston, Kundu, Brock. Acquisition of data: Kundu, Brock. Analysis and interpretation of data: Kundu, Brock, Englot. Drafting the article: all authors. Critically revising the article: Rolston, Kundu, Englot, Butson. Reviewed submitted version of manuscript: Rolston, Kundu.

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    Kim KEkstrom ADTandon N: A network approach for modulating memory processes via direct and indirect brain stimulation: toward a causal approach for the neural basis of memory. Neurobiol Learn Mem 134 (Pt A):1621772016

  • 39

    Koubeissi MZKahriman ESyed TUMiller JDurand DM: Low-frequency electrical stimulation of a fiber tract in temporal lobe epilepsy. Ann Neurol 74:2232312013

  • 40

    Kundishora AJGummadavelli AMa CLiu MMcCafferty CSchiff ND: Restoring conscious arousal during focal limbic seizures with deep brain stimulation. Cereb Cortex 27:196419752017

  • 41

    Lammi MHSmith VHTate RLTaylor CM: The minimally conscious state and recovery potential: a follow-up study 2 to 5 years after traumatic brain injury. Arch Phys Med Rehabil 86:7467542005

  • 42

    Lee DJGurkoff GGIzadi ABerman RFEkstrom ADMuizelaar JP: Medial septal nucleus theta frequency deep brain stimulation improves spatial working memory after traumatic brain injury. J Neurotrauma 30:1311392013

  • 43

    Lee DJGurkoff GGIzadi ASeidl SEEcheverri AMelnik M: Septohippocampal neuromodulation improves cognition after traumatic brain injury. J Neurotrauma 32:182218322015

  • 44

    Levin HSSaydjari CEisenberg HMFoulkes MMarshall LFRuff RM: Vegetative state after closed-head injury: a traumatic coma data bank report. Arch Neurol 48:5805851991

  • 45

    Li SZaninotto ALNeville ISPaiva WSNunn DFregni F: Clinical utility of brain stimulation modalities following traumatic brain injury: current evidence. Neuropsychiatr Dis Treat 11:157315862015

  • 46

    Liu JLee HJWeitz AJFang ZLin PChoy M: Frequency-selective control of cortical and subcortical networks by central thalamus. eLife 4:e092152015

  • 47

    Lozano AMFosdick LChakravarty MMLeoutsakos JMMunro COh E: A phase II study of fornix deep brain stimulation in mild Alzheimer’s disease. J Alzheimers Dis 54:7777872016

  • 48

    Magrassi LMaggioni GPistarini CDi Perri CBastianello SZippo AG: Results of a prospective study (CATS) on the effects of thalamic stimulation in minimally conscious and vegetative state patients. J Neurosurg 125:9729812016

  • 49

    Massimini MBoly MCasali ARosanova MTononi G: A perturbational approach for evaluating the brain’s capacity for consciousness. Prog Brain Res 177:2012142009

  • 50

    Massimini MFerrarelli FHuber REsser SKSingh HTononi G: Breakdown of cortical effective connectivity during sleep. Science 309:222822322005

  • 51

    Miller JPSweet JABailey CMMunyon CNLuders HOFastenau PS: Visual-spatial memory may be enhanced with theta burst deep brain stimulation of the fornix: a preliminary investigation with four cases. Brain 138:183318422015

  • 52

    Morrell MJHalpern C: Responsive direct brain stimulation for epilepsy. Neurosurg Clin N Am 27:1111212016

  • 53

    Moruzzi GMagoun HW: Brain stem reticular formation and activation of the EEG. Electroencephalogr Clin Neurophysiol 1:4554731949

  • 54

    Paterno RMetheny HXiong GElkind JCohen AS: Mild traumatic brain injury decreases broadband power in area CA1. J Neurotrauma 33:164516492016

  • 55

    Patuzzo SManganotti P: Deep brain stimulation in persistent vegetative states: ethical issues governing decision making. Behav Neurol 2014:6412132014

  • 56

    Pevzner AIzadi ALee DJShahlaie KGurkoff GG: Making waves in the brain: what are oscillations, and why modulating them makes sense for brain injury. Front Syst Neurosci 10:302016

  • 57

    Pfaff DBanavar JR: A theoretical framework for CNS arousal. BioEssays 29:8038102007

  • 58

    Quinkert AWPfaff DW: Temporal patterns of deep brain stimulation generated with a true random number generator and the logistic equation: effects on CNS arousal in mice. Behav Brain Res 229:3493582012

  • 59

    Ragazzoni ACincotta MGiovannelli FCruse DYoung GBMiniussi C: Clinical neurophysiology of prolonged disorders of consciousness: From diagnostic stimulation to therapeutic neuromodulation. Clin Neurophysiol 128:162916462017

  • 60

    Rezai ARSederberg PBBogner JNielson DMZhang JMysiw WJ: Improved function after deep brain stimulation for chronic, severe traumatic brain injury. Neurosurgery 79:2042112016

  • 61

    Rosanova MGosseries OCasarotto SBoly MCasali AGBruno MA: Recovery of cortical effective connectivity and recovery of consciousness in vegetative patients. Brain 135:130813202012

  • 62

    Schiff NDGiacino JTKalmar KVictor JDBaker KGerber M: Behavioural improvements with thalamic stimulation after severe traumatic brain injury. Nature 448:6006032007 (Erratum in Nature 452:120 2008)

  • 63

    Shah SASchiff ND: Central thalamic deep brain stimulation for cognitive neuromodulation - a review of proposed mechanisms and investigational studies. Eur J Neurosci 32:113511442010

  • 64

    Sharma MDeogaonkar MRezai A: Assessment of potential targets for deep brain stimulation in patients with Alzheimer’s disease. J Clin Med Res 7:5015052015

  • 65

    Shin SSDixon CEOkonkwo DORichardson RM: Neurostimulation for traumatic brain injury. J Neurosurg 121:121912312014

  • 66

    Shirvalkar PSeth MSchiff NDHerrera DG: Cognitive enhancement with central thalamic electrical stimulation. Proc Natl Acad Sci U S A 103:17007170122006

  • 67

    Steriade M: Arousal: revisiting the reticular activating system. Science 272:2252261996

  • 68

    Steriade MGlenn LL: Neocortical and caudate projections of intralaminar thalamic neurons and their synaptic excitation from midbrain reticular core. J Neurophysiol 48:3523711982

  • 69

    Tabansky IQuinkert AWRahman NMuller SZLofgren JRudling J: Temporally-patterned deep brain stimulation in a mouse model of multiple traumatic brain injury. Behav Brain Res 273:1231322014

  • 70

    Tagliaferri FCompagnone CKorsic MServadei FKraus J: A systematic review of brain injury epidemiology in Europe. Acta Neurochir (Wien) 148:2552682006

  • 71

    Thonnard MGosseries ODemertzi ALugo ZVanhaudenhuyse ABruno MA: Effect of zolpidem in chronic disorders of consciousness: a prospective open-label study. Funct Neurol 28:2592642013

  • 72

    Tsubokawa TYamamoto TKatayama YHirayama TMaejima SMoriya T: Deep-brain stimulation in a persistent vegetative state: follow-up results and criteria for selection of candidates. Brain Inj 4:3153271990

  • 73

    Vanhoecke JHariz M: Deep brain stimulation for disorders of consciousness: systematic review of cases and ethics. Brain Stimul 10:101310232017

  • 74

    Yamamoto TKatayama YKobayashi KOshima HFukaya CTsubokawa T: Deep brain stimulation for the treatment of vegetative state. Eur J Neurosci 32:114511512010

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Article Information

Correspondence John D. Rolston: University of Utah, Salt Lake City, UT. neuropub@hsc.utah.edu.

INCLUDE WHEN CITING DOI: 10.3171/2018.5.FOCUS18168.

Disclosures Dr. Butson reports a consultant relationship with Abbott and Functional Neuromodulation and direct stock ownership in Intelect Medical.

© AANS, except where prohibited by US copyright law.

Headings

Figures

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    How to determine whether DBS will work in a patient in a coma. A: The theoretical arousal network targeted with DBS includes the cortex (orange overlay), thalamus (red overlay), and midbrain and pontine reticular formations (green overlay). The arousal generator originates from signals from the midbrain but may be modulated with stimulation of the thalamic relay centers. Thalamic relay centers project diffusely to cortex. B: The combination of structural measures (including MRI-based assessment of gray matter integrity, diffusion tensor imaging [DTI]–based assessment of white matter integrity), endogenously generated signals of global network integrity (such as in resting-state functional MRI [fMRI]), and newer stimulation-based connectivity measures (including TMS-based evoked response propagation as quantified by the perturbational complexity index [PCI]) may better predict which patients will benefit from DBS to bring about or facilitate arousal. C: The PCI is derived from recording the TMS-evoked response from scalp EEG (black trace is average TMS-evoked response across channels; gray traces are individual channel traces) and then projecting this signal to source space and deriving a measure of complexity based on the manner in which the evoked response propagates between brain structures of a particular patient. See Casali et al.10 for details of this methodology. Note that the TMS-evoked response can also be captured by the blood oxygen–dependent percent signal change from fMRI and thus measured in the thalamus as well as cortical structures. BAER = brainstem auditory evoked response; VEP = visual evoked potentials.

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Karas PJMikell CBChristian ELiker MASheth SA: Deep brain stimulation: a mechanistic and clinical update. Neurosurg Focus 35(5):E12013

38

Kim KEkstrom ADTandon N: A network approach for modulating memory processes via direct and indirect brain stimulation: toward a causal approach for the neural basis of memory. Neurobiol Learn Mem 134 (Pt A):1621772016

39

Koubeissi MZKahriman ESyed TUMiller JDurand DM: Low-frequency electrical stimulation of a fiber tract in temporal lobe epilepsy. Ann Neurol 74:2232312013

40

Kundishora AJGummadavelli AMa CLiu MMcCafferty CSchiff ND: Restoring conscious arousal during focal limbic seizures with deep brain stimulation. Cereb Cortex 27:196419752017

41

Lammi MHSmith VHTate RLTaylor CM: The minimally conscious state and recovery potential: a follow-up study 2 to 5 years after traumatic brain injury. Arch Phys Med Rehabil 86:7467542005

42

Lee DJGurkoff GGIzadi ABerman RFEkstrom ADMuizelaar JP: Medial septal nucleus theta frequency deep brain stimulation improves spatial working memory after traumatic brain injury. J Neurotrauma 30:1311392013

43

Lee DJGurkoff GGIzadi ASeidl SEEcheverri AMelnik M: Septohippocampal neuromodulation improves cognition after traumatic brain injury. J Neurotrauma 32:182218322015

44

Levin HSSaydjari CEisenberg HMFoulkes MMarshall LFRuff RM: Vegetative state after closed-head injury: a traumatic coma data bank report. Arch Neurol 48:5805851991

45

Li SZaninotto ALNeville ISPaiva WSNunn DFregni F: Clinical utility of brain stimulation modalities following traumatic brain injury: current evidence. Neuropsychiatr Dis Treat 11:157315862015

46

Liu JLee HJWeitz AJFang ZLin PChoy M: Frequency-selective control of cortical and subcortical networks by central thalamus. eLife 4:e092152015

47

Lozano AMFosdick LChakravarty MMLeoutsakos JMMunro COh E: A phase II study of fornix deep brain stimulation in mild Alzheimer’s disease. J Alzheimers Dis 54:7777872016

48

Magrassi LMaggioni GPistarini CDi Perri CBastianello SZippo AG: Results of a prospective study (CATS) on the effects of thalamic stimulation in minimally conscious and vegetative state patients. J Neurosurg 125:9729812016

49

Massimini MBoly MCasali ARosanova MTononi G: A perturbational approach for evaluating the brain’s capacity for consciousness. Prog Brain Res 177:2012142009

50

Massimini MFerrarelli FHuber REsser SKSingh HTononi G: Breakdown of cortical effective connectivity during sleep. Science 309:222822322005

51

Miller JPSweet JABailey CMMunyon CNLuders HOFastenau PS: Visual-spatial memory may be enhanced with theta burst deep brain stimulation of the fornix: a preliminary investigation with four cases. Brain 138:183318422015

52

Morrell MJHalpern C: Responsive direct brain stimulation for epilepsy. Neurosurg Clin N Am 27:1111212016

53

Moruzzi GMagoun HW: Brain stem reticular formation and activation of the EEG. Electroencephalogr Clin Neurophysiol 1:4554731949

54

Paterno RMetheny HXiong GElkind JCohen AS: Mild traumatic brain injury decreases broadband power in area CA1. J Neurotrauma 33:164516492016

55

Patuzzo SManganotti P: Deep brain stimulation in persistent vegetative states: ethical issues governing decision making. Behav Neurol 2014:6412132014

56

Pevzner AIzadi ALee DJShahlaie KGurkoff GG: Making waves in the brain: what are oscillations, and why modulating them makes sense for brain injury. Front Syst Neurosci 10:302016

57

Pfaff DBanavar JR: A theoretical framework for CNS arousal. BioEssays 29:8038102007

58

Quinkert AWPfaff DW: Temporal patterns of deep brain stimulation generated with a true random number generator and the logistic equation: effects on CNS arousal in mice. Behav Brain Res 229:3493582012

59

Ragazzoni ACincotta MGiovannelli FCruse DYoung GBMiniussi C: Clinical neurophysiology of prolonged disorders of consciousness: From diagnostic stimulation to therapeutic neuromodulation. Clin Neurophysiol 128:162916462017

60

Rezai ARSederberg PBBogner JNielson DMZhang JMysiw WJ: Improved function after deep brain stimulation for chronic, severe traumatic brain injury. Neurosurgery 79:2042112016

61

Rosanova MGosseries OCasarotto SBoly MCasali AGBruno MA: Recovery of cortical effective connectivity and recovery of consciousness in vegetative patients. Brain 135:130813202012

62

Schiff NDGiacino JTKalmar KVictor JDBaker KGerber M: Behavioural improvements with thalamic stimulation after severe traumatic brain injury. Nature 448:6006032007 (Erratum in Nature 452:120 2008)

63

Shah SASchiff ND: Central thalamic deep brain stimulation for cognitive neuromodulation - a review of proposed mechanisms and investigational studies. Eur J Neurosci 32:113511442010

64

Sharma MDeogaonkar MRezai A: Assessment of potential targets for deep brain stimulation in patients with Alzheimer’s disease. J Clin Med Res 7:5015052015

65

Shin SSDixon CEOkonkwo DORichardson RM: Neurostimulation for traumatic brain injury. J Neurosurg 121:121912312014

66

Shirvalkar PSeth MSchiff NDHerrera DG: Cognitive enhancement with central thalamic electrical stimulation. Proc Natl Acad Sci U S A 103:17007170122006

67

Steriade M: Arousal: revisiting the reticular activating system. Science 272:2252261996

68

Steriade MGlenn LL: Neocortical and caudate projections of intralaminar thalamic neurons and their synaptic excitation from midbrain reticular core. J Neurophysiol 48:3523711982

69

Tabansky IQuinkert AWRahman NMuller SZLofgren JRudling J: Temporally-patterned deep brain stimulation in a mouse model of multiple traumatic brain injury. Behav Brain Res 273:1231322014

70

Tagliaferri FCompagnone CKorsic MServadei FKraus J: A systematic review of brain injury epidemiology in Europe. Acta Neurochir (Wien) 148:2552682006

71

Thonnard MGosseries ODemertzi ALugo ZVanhaudenhuyse ABruno MA: Effect of zolpidem in chronic disorders of consciousness: a prospective open-label study. Funct Neurol 28:2592642013

72

Tsubokawa TYamamoto TKatayama YHirayama TMaejima SMoriya T: Deep-brain stimulation in a persistent vegetative state: follow-up results and criteria for selection of candidates. Brain Inj 4:3153271990

73

Vanhoecke JHariz M: Deep brain stimulation for disorders of consciousness: systematic review of cases and ethics. Brain Stimul 10:101310232017

74

Yamamoto TKatayama YKobayashi KOshima HFukaya CTsubokawa T: Deep brain stimulation for the treatment of vegetative state. Eur J Neurosci 32:114511512010

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