A Pilot Trial Examining the Merits of Combining Amantadine and Repetitive Transcranial Magnetic Stimulation as an Intervention for Persons With Disordered Consciousness After TBI

Pape, Theresa; Herrold, Amy A.; Livengood, Sherri L.; Guernon, Ann; Weaver, Jennifer; Higgins, James; Rosenow, Joshua M.; Walsh, Elyse; Bhaumik, Runa; Pacheco, Marilyn; Patil, Vijaya; Kletzel, Sandra; Conneely, Mark; Bhaumik, Dulal K.; Mallinson, Trudy; Parrish, Todd B.

doi:10.1097/htr.0000000000000634

Cited by 18 publications

(11 citation statements)

References 70 publications

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“…The continuous data for time from injury to TMS was dichotomized by patients who received TMS at three or more months post-injury vs. prior to 3 months. Stimulation site was also grouped by studies stimulating M1 vs. studies stimulating cortical areas that lead to modification of DMN connectivity, such as DLPFC, angular gyrus, and inferior parietal lobe, which we have grouped as non-M1 ( 7 , 25 ).…”

Section: Methodsmentioning

confidence: 99%

Patient Outcomes in Disorders of Consciousness Following Transcranial Magnetic Stimulation: A Systematic Review and Meta-Analysis of Individual Patient Data

et al. 2021

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Background: There are few treatments with limited efficacy for patients with disorders of consciousness (DoC), such as minimally conscious and persistent vegetative state (MCS and PVS).Objective: In this meta-analysis of individual patient data (IPD), we examine studies utilizing transcranial magnetic stimulation (TMS) as a treatment in DoC to determine patient and protocol-specific factors associated with improved outcomes.Methods: We conducted a systematic review of PubMed, Ovid Medline, and Clinicaltrials.gov through April 2020 using the following terms: “minimally conscious state,” or “persistent vegetative state,” or “unresponsive wakefulness syndrome,” or “disorders of consciousness” and “transcranial magnetic stimulation.” Studies utilizing TMS as an intervention and reporting individual pre- and post-TMS Coma Recovery Scale-Revised (CRS-R) scores and subscores were included. Studies utilizing diagnostic TMS were excluded. We performed a meta-analysis at two time points to generate a pooled estimate for absolute change in CRS-R Index, and performed a second meta-analysis to determine the treatment effect of TMS using data from sham-controlled crossover studies. A linear regression model was also created using significant predictors of absolute CRS-R index change.Results: The search yielded 118 papers, of which 10 papers with 90 patients were included. Patients demonstrated a mean pooled absolute change in CRS-R Index of 2.74 (95% CI, 0.62–4.85) after one session of TMS and 5.88 (95% CI, 3.68–8.07) at last post-TMS CRS-R assessment. The standardized mean difference between real rTMS and sham was 2.82 (95% CI, −1.50 to 7.14), favoring rTMS. The linear regression model showed that patients had significantly greater CRS-R index changes if they were in MCS, had an etiology of stroke or intracranial hemorrhage, received 10 or more sessions of TMS, or if TMS was initiated within 3 months from injury.Conclusions: TMS may improve outcomes in MCS and PVS. Further evaluation with randomized, clinical trials is necessary to determine its efficacy in this patient population.

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Section: Methodsmentioning

confidence: 99%

Patient Outcomes in Disorders of Consciousness Following Transcranial Magnetic Stimulation: A Systematic Review and Meta-Analysis of Individual Patient Data

et al. 2021

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“…Repetitive TMS (rTMS) has shown minor EEG changes and a single case report of behavioral improvement [74]. Similar improvements were also observed in a pilot trial in patients with chronic DoCs treated with rTMS and amantadine [75]. The most significant adverse effect associated with rTMS is induction of seizures [76].…”

Section: Non-invasive Brain Stimulationmentioning

confidence: 65%

“…Interestingly, cerebral glucose metabolism can be used to differentiate MCS− and MCS+ patients, with MCS+ patients showing higher metabolism in left cortical areas crucial for language as well as in the posterior parietal, sensorimotor, premotor, and pre-supplementary motor cortices [30], some of which have direct cortico-thalamic projections from the central thalamus [16]. Projections from the central thalamus also innervate the striatum (caudate, putamen, and nucleus accumbens) and project onto medium spiny neurons [86], which are sensitive to dopamine deficiency [87], and may contribute to positive results seen with amantadine [47][48][49]75] and apomorphine [52,53]. Medium spiny neurons normally function to dis-inhibit the central thalamus by inhibiting the globus pallidus internus.…”

Section: Neuroanatomy Of Consciousnessmentioning

confidence: 99%

Treating Traumatic Brain Injuries with Electroceuticals: Implications for the Neuroanatomy of Consciousness

et al. 2021

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According to the Centers for Disease Control and Prevention (CDC), traumatic brain injury (TBI) is the leading cause of loss of consciousness, long-term disability, and death in children and young adults (age 1 to 44). Currently, there are no United States Food and Drug Administration (FDA) approved pharmacological treatments for post-TBI regeneration and recovery, particularly related to permanent disability and level of consciousness. In some cases, long-term disorders of consciousness (DoC) exist, including the vegetative state/unresponsive wakefulness syndrome (VS/UWS) characterized by the exhibition of reflexive behaviors only or a minimally conscious state (MCS) with few purposeful movements and reflexive behaviors. Electroceuticals, including non-invasive brain stimulation (NIBS), vagus nerve stimulation (VNS), and deep brain stimulation (DBS) have proved efficacious in some patients with TBI and DoC. In this review, we examine how electroceuticals have improved our understanding of the neuroanatomy of consciousness. However, the level of improvements in general arousal or basic bodily and visual pursuit that constitute clinically meaningful recovery on the Coma Recovery Scale-Revised (CRS-R) remain undefined. Nevertheless, these advancements demonstrate the importance of the vagal nerve, thalamus, reticular activating system, and cortico-striatal-thalamic-cortical loop in the process of consciousness recovery.

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“…Just as no single therapy is likely to be efficacious in all patients, it is possible that more than one therapeutic modality is needed to stimulate neural networks via synergistic mechanisms. For example, electromagnetic stimulation (e.g., rTMS) may be combined with pharmacologic stimulation [ 222 ], or electromagnetic top-down stimulation (e.g., tES) with bottom-up approaches (e.g., transauricular VNS), administered either concurrently or consecutively. We encourage the development of adaptive clinical trial designs featuring conditional therapeutic additions or changes based on the patient’s clinical evolution.…”

Section: Discussion and Future Directionsmentioning

confidence: 99%

Therapies to Restore Consciousness in Patients with Severe Brain Injuries: A Gap Analysis and Future Directions

et al. 2021

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Background/Objective For patients with disorders of consciousness (DoC) and their families, the search for new therapies has been a source of hope and frustration. Almost all clinical trials in patients with DoC have been limited by small sample sizes, lack of placebo groups, and use of heterogeneous outcome measures. As a result, few therapies have strong evidence to support their use; amantadine is the only therapy recommended by current clinical guidelines, specifically for patients with DoC caused by severe traumatic brain injury. To foster and advance development of consciousness-promoting therapies for patients with DoC, the Curing Coma Campaign convened a Coma Science Work Group to perform a gap analysis. Methods We consider five classes of therapies: (1) pharmacologic; (2) electromagnetic; (3) mechanical; (4) sensory; and (5) regenerative. For each class of therapy, we summarize the state of the science, identify gaps in knowledge, and suggest future directions for therapy development. Results Knowledge gaps in all five therapeutic classes can be attributed to the lack of: (1) a unifying conceptual framework for evaluating therapeutic mechanisms of action; (2) large-scale randomized controlled trials; and (3) pharmacodynamic biomarkers that measure subclinical therapeutic effects in early-phase trials. To address these gaps, we propose a precision medicine approach in which clinical trials selectively enroll patients based upon their physiological receptivity to targeted therapies, and therapeutic effects are measured by complementary behavioral, neuroimaging, and electrophysiologic endpoints. Conclusions This personalized approach can be realized through rigorous clinical trial design and international collaboration, both of which will be essential for advancing the development of new therapies and ultimately improving the lives of patients with DoC.

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A Pilot Trial Examining the Merits of Combining Amantadine and Repetitive Transcranial Magnetic Stimulation as an Intervention for Persons With Disordered Consciousness After TBI

Cited by 18 publications

References 70 publications

Patient Outcomes in Disorders of Consciousness Following Transcranial Magnetic Stimulation: A Systematic Review and Meta-Analysis of Individual Patient Data

Patient Outcomes in Disorders of Consciousness Following Transcranial Magnetic Stimulation: A Systematic Review and Meta-Analysis of Individual Patient Data

Treating Traumatic Brain Injuries with Electroceuticals: Implications for the Neuroanatomy of Consciousness

Therapies to Restore Consciousness in Patients with Severe Brain Injuries: A Gap Analysis and Future Directions

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