Emerging Treatments for Traumatic Brain Injury, Including Virtual Reality & Therapeutic Ultrasound

Written by Rita Hitching, MSc
ReachMD Contributor

Emerging Treatments for Traumatic Brain Injury, Including Virtual Reality & Therapeutic Ultrasound

One of neuroscience’s most infamous traumatic brain injury (TBI) patients - Phineas P. Gage (1823-1860) is a classic case study on the complex neurological sequelae of the injured brain. Gage, a well-respected and liked American railroad foreman, was using a tampering iron rod to pack explosive powder into a hole, when an accidental explosion resulted in the rod shooting upward to pierce his jaw and exit through the top of his skull, destroying most of his frontal lobe. The medical report by Dr. John Martyn Harlow, the physician that Gage was referred to, depicted an incredible transformation. Gage was “no longer Gage, with little deference for his fellows, an angry raging alcoholic”^1,2. Gage’s presenting symptom cluster remains ubiquitous in TBI patients ─ impaired executive function, memory, attention, chronic headaches, personality changes, and mood changes. Like Gage, many TBI patients remain chronically impaired and unable to resume work or their life before the injury.

Neural Correlates
In a valiant effort to determine the likely brain regions associated with Gage’s TBI, researchers used his preserved skull and modern neuroimaging techniques to reconstruct a map of his brain. As anticipated, the reconstruction showed damage to the left and right prefrontal cortices³, left frontal lobe, and superior sagittal sinus⁴, and cerebral cortex⁵. Regions are associated with rational decision-making and emotional processing and commensurate with Gage’s presenting symptoms, and those of many TBI patients.

In the close to three decades since then, our understanding of the neural correlates of TBI have greatly increased. The addition of computer tomography (CT), diffusion-weighted imaging (DWI), and magnetic resonance imaging (MRI) is providing new insights into brain function and connectivity. Using these strategies and fiducial landmarks in Gage’s preserved skull, researchers have been able to recreate a map of his brain following the injury. The results showed neuronal damage at the impact site, damage to cortical gray matter (GM) and to white matter (WM) fiber pathways in addition to disruption to network connectedness and aberrant brain function. All probable contributors to the reported acute and long-term functional and behavioral impairments that Gage and others with TBI report⁵.

Public Health Concern
As Dr. Maheen Mausoof Adamson, Clinical Associate Professor of Neurosurgery (affiliated) at Stanford School of Medicine and Clinical Research Director for Rehabilitation Services at VA Palo Alto, and Director of the Adamson Lab explained, “Impairment following a traumatic brain injury is not predicated on a substantial or penetrative injury, such as a gunshot wound. TBIs are inherently heterogeneous in nature. No two accidents are identical nor two brains. Most TBIs are associated with a blow to the head or a harsh bump but can also result from whiplash. In addition, you can sustain a TBI from the aftershock of an explosion, as is often the case in military personnel.”

A TBI can range in severity from mild to severe, and statistics from the National Concussion Surveillance System (NCSS) indicate that in 2019 TBIs account for 2.87 million emergency department visits and hospital admissions, resulting in 61,000 American deaths. The equivalent of 166 deaths daily⁶.

TBI results in observable and persistent structural brain alterations and is not limited to severe TBI. Patients with a mild TBI (mTBI), the most prevalent type of brain injury, often associated with sport or other recreational activities show the same pattern of neuronal damage. The Centers for Disease Control and Prevention (CDC) consider TBI a serious public health concern. In part because an mTBI is a known risk factor for Alzheimer’s disease (AD)⁷.

In addition, the associated mortality and morbidity risks of TBI differ by subpopulation. Those at particular risk for TBIs and more severe outcomes include domestic violence survivors⁸, racial and ethnic minorities⁹, military service members and Veterans⁷, as well as those in unstable living situations or the homeless¹⁰, correctional or detention facilities¹¹, and living in rural communities¹². The chronic and mercurial nature of the health concerns that follow a TBII pose significant treatment challenges. Particularly, the accompanying psychological sequelae ─ depression, anxiety, post-traumatic stress disorder (PTSD), suicidal ideation and behavior, substance use, anger, and insomnia¹³.

Emerging Treatments
As Dr. John Coetzee, Postdoctoral Research Fellow at the Stanford School of Medicine and the VA’s Polytrauma & Traumatic Brain Injury Rehabilitation Center says “Regrettably, the current diagnostic models and treatment options for TBI patients have been ineffective at alleviating functional impairment or preventing long-term disability. Especially the often-debilitating chronic pain, persistent headaches, and cognitive impairment.”

Coetzee is part of the research team at the Adamson Lab investigating a range of diagnostic and treatment options for patients with mTBI ^14-18. The team is researching several non-invasive and non-pharmacological treatments, including Virtual (VR) and Augmented Reality (AR) for pain and PTSD-related symptoms such as depression and anxiety. In addition to neuromodulatory approaches like repetitive transcranial magnetic stimulation (rTMS) for cognitive impairment, the team is also researching two novel treatments for the chronic headaches associated with mTBI including calcitonin gene-related peptide (CGRP) inhibitors, a key neuropeptide that is central to migraine pathophysiology, and a potent vasodilator and low-intensity focused ultrasound (LIFU). Early results are extremely encouraging, and patients are responding well to treatment and reporting a significant reduction in symptoms.

Renewed Hope
Although no silver bullet is yet available for TBI, the emerging diagnostic and treatment tools researchers like Adamson and Coetzee are investigating are offering renewed hope to patients.

References

1. O'Driscoll K, Leach J P. “No longer Gage”: an iron bar through the head. Early observations of personality change after injury to the prefrontal cortex. BMJ 1998; 317 :1673 doi:10.1136/bmj.317.7174.1673a
2. Harlow JM. Recovery from the passage of an iron bar through the head. History of Psychiatry. 1993;4(14):274-281. doi:10.1177/0957154X9300401407
3. Damasio H, Grabowski T, Frank R, Galaburda AM, Damasio AR. The return of Phineas Gage: clues about the brain from the skull of a famous patient. Science. 1994 May 20;264(5162):1102-5.
4. Ratiu P, Talos IF, Haker S, Lieberman D, Everett P. The tale of Phineas Gage, digitally remastered. Journal of neurotrauma. 2004 May 1;21(5):637-43.
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6. Centers for Disease Control and Prevention. National Center for Health Statistics: Mortality Data on CDC WONDER. (NCSS, 2019) Available at: https://wonder.cdc.gov/mcd.html.
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8. Centers for Disease Control and Prevention, National Institutes of Health, Department of Defense, and Veterans Administration. Report to Congress on traumatic brain injury in the United States: Understanding the public health problem among current and former military personnel. Atlanta (GA): Centers for Disease Control and Prevention; 2013.
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13. Centers for Disease Control and Prevention. Report to Congress on Traumatic Brain Injury in the United States: Epidemiology and Rehabilitation. National Center for Injury Prevention and Control; Division of Unintentional Injury Prevention. 2014. Atlanta, GA
14. Tate DF, Dennis EL, Adams JT, Adamson MM, Belanger HG, Bigler ED, Bouchard HC, Clark AL, Delano-Wood LM, Disner SG, Eapen BC. Coordinating global multi-site studies of military-relevant traumatic brain injury: Opportunities, challenges, and harmonization guidelines. Brain imaging and behavior. 2021 Apr;15(2):585-613.
15. Adamson MM, Main KL, Milazzo AC, Soman S, Kong J, Kolakowsky-Hayner S, Furst AJ, Ashford JW, Kang X. Cortical Thickness and Diffusion Properties in the Injured Brain: The Influence of Chronic Health Complaints. Military medicine. 2020 Jan 7;185(Supplement_1):168-75.
16. Main KL, Soman S, Pestilli F, Furst A, Noda A, Hernandez B, Kong J, Cheng J, Fairchild JK, Taylor J, Yesavage J. DTI measures identify mild and moderate TBI cases among patients with complex health problems: a receiver operating characteristic analysis of US veterans. NeuroImage: Clinical. 2017 Jan 1; 16:1-6
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