Traumatic Brain Injury

Approximately half of all Americans have sustained at least one traumatic brain injury (TBI) due to major accidents, assault, military trauma and sports injuries. It is estimated that each year there are 2.8 million TBIs in the United States and 69 million worldwide, at a financial cost of $4 billion in the United States and $400 billion globally. Recent national focus on TBIs has been the result of the press coverage given to the long-term significance of frequently sustained concussions in the game of football.

Acute TBIs (concussions) can be relatively mild in outcomes with transient confusion, memory loss, dizziness, and reduced attention span and concentration, but with no long-term sequelae in 80% to 90% of those affected. Immediate post-trauma diagnostic assessment is usually limited to testing cognitive function, coordination of movement and ocular alterations; there are no available diagnostic or prognostic indices, including brain CT. On the athletic field, saliva testing for microRNAs is under assessment in several sport venues. Therapy for acute TBIs consists of the recommendation for physical and mental rest.

Of individuals with a severe single TBI or multiple acute TBIs, 10% to 20% will exhibit chronic TBI. Beyond the primary mechanical insult to the brain, prolonged metabolic damage can affect neurons, cerebral blood vessels and glia, which, in turn, may initiate chronic inflammation causing prolongation of neurogenic symptoms, as well as cardiovascular, gastrointestinal and sexual dysfunction.

The CDC groups the symptomatology of TBI sequelae into four domains:

Domain I: Thinking/remembering deficiency, ranging from mild to severe, eventually progressing to dementia.

Domain II: Physical symptoms of migraine headaches, blurred vision, dizziness, nausea, light and noise sensitivity, fatigue, and balance problems. Headaches are the most characteristic physical impairment of TBI, markedly diminishing quality of life.

Domain III: Mood and emotional symptoms of progressive depression and post-traumatic stress disorder, the latter most frequent in individuals subjected to violent trauma. The end stage of this impairment is suicidal ideation and progression to suicide.

Domain IV: Sleep disturbances, often in association with obstructive sleep apnea, especially in the obese.

There is no blood, x-ray or other signature marker for the presence, progression or resolution of chronic TBI.

There is no prophylactic therapy to prevent acute TBI from progressing to chronic TBI, and chronic TBI to chronic traumatic encephalopathy (CTE).

The unfortunate end result of worsening TBI is CTE, today an incurable progressive form of neurodegenerative disease culminating in dementia and early death. Subjective symptomatology provides diagnosis during life; definitive diagnosis of CTE is made only on autopsy by the presence of characteristic tau proteins in the sulci of a shrunken brain. There are two staggering public autopsy series in football players demonstrating tauopathy in 99% (110/111) of professional, and 91% (48/53) of college, football players.

The time course of severe TBI to CTE to death can be relatively brief: two to three years. However, the time from the initial traumatic event or events to end-stage TBI is relatively long: 10 years or more. This offers a window of opportunity for deleterious risk factors to accelerate the process, as well as for therapeutic intervention to retard or halt progression.

Three studied risk factors for progression of TBI are inflammation, cardiovascular disease or risk factors, and obesity. Of note, they are reciprocally causative. TBI leads to inflammation, and inflammation, even from unrelated causes (e.g., rheumatoid arthritis), accelerates TBI progression. Cardiovascular disease and cardiovascular disease risk factors are known to promote TBI symptoms, and TBI reciprocally accentuates cardiovascular impairment. Patients with TBI tend to become obese, and obese persons sustaining acute brain injury are more likely than lean individuals to exhibit TBI progression.

In a cohort of great public interest, former NFL football players, studies have demonstrated statistically significant correlations of obesity, cardiovascular disease and TBI. In light of this knowledge, patients with TBI should be counseled on avoiding cardiovascular disease risk factors and weight gain.

Inclusion of TBI among the multitude of obesity comorbidities or secondary diseases has not been well appreciated, although there is excellent evidence in the literature that obesity, particularly morbid obesity, impairs multiple functional parameters: global cognition, attention span, executive function and memory, and promotion and progression of depression. These functional parameters are associated with adverse structural brain changes: hypoperfusion, atrophy, dysfunction of microglia and astrocytes, neuronal injury and death, cerebral vascular insufficiency, formation of neurofibrillary tangles, and increased tau expression. There is also reputable literature evidence demonstrating mitigation or reversal of these functional and anatomic changes by significant and sustained weight loss.

Today, the most effective and lasting therapy for morbid obesity, or severe obesity with life-threatening comorbidities, is, of course, metabolic/bariatric surgery. There is also a growing literature substantiating mitigation, arrest or even reversal of TBI symptomatology by metabolic/bariatric surgery. Among the 35 affirmative peer-reviewed publications, three noteworthy papers bear on cognitive dysfunction, the cardinal TBI impairment. Alosco et al (Am J Surg 2014;207[6]:870-876) showed improvement in cognitive function up to three years after metabolic/bariatric surgery, in contrast to the rapid deterioration of cognition usually found in patients with progressive TBI. Thiara et al (Psychosomatics 2017;58[3]:217-227) in a systematic review documented improvement in a neurocognitive domain in 10 of 10 studies. And Marques et al (J Clin Endocrinol Metab 2014;99[11]:E2347-E2352), at 24 weeks after metabolic/bariatric surgery, linked improvement in executive function with increased cerebral metabolism and decreased inflammatory parameters. A full review, in three parts, of metabolic surgery, obesity and TBI has been published by McGlennon et al (Obes Surg 2020;30[12]:4704-4714; 2021;31:4802-4814; 2021;31:4920-4907.

Two questions raised by the mitigating effects of metabolic/bariatric surgery on symptoms common to TBI in a cohort of obese individuals are: First, can these benefits be extended to the nonobese patient with TBI? Second, can elucidation of the metabolic mechanisms responsible for the outcomes of metabolic/bariatric surgery provide insight into the causative and enabling metabolic processes culpable for TBI?

With resolution of type 2 diabetes by metabolic/bariatric surgery firmly documented and accepted by the global medical community, a search for a non-, or minimal, weight loss/metabolic operation was initiated worldwide. Modifications of bariatric surgery and bariatric surgery unrelated, extraperitoneal operations to treat type 2 diabetes, were suggested and tested. Today these investigations are in their infancy but are being vigorously pursued. It is reasonable to predict that a similar initiative to treat TBI by modified metabolic/bariatric surgery, or by totally new metabolic surgery interventions in the nonobese, will be proposed once it is definitively demonstrated by Level I evidence (i.e., a randomized controlled trial) that metabolic surgery is effective therapy for TBI in the obese.

Slowly but progressively, the metabolic processes responsible for the effects of metabolic/bariatric surgery in obesity are being elucidated, and, thereby, are providing not only insights into the underlying mechanisms of surgical therapy but for the disease of obesity itself. These insights may also help us to understand the metabolic mechanisms responsible for TBI and the way in which metabolic surgery may ameliorate TBI. The basis for this perspective is the well-established, literature-documented evidence for a highly active gut–brain axis. Certain areas of the brain, in white and in gray matter, show alterations in both obesity and TBI. These areas demonstrate improvement in structural integrity and functional connectivity after metabolic/bariatric surgery, with corresponding clinical improvement in neurocognitive functioning. The metabolic processes independent of weight responsible for the resolution of type 2 diabetes, hypertension and dyslipidemia after metabolic/bariatric surgery may also affirmatively affect the anatomic and clinical aspects of TBI. The underlying mechanisms of the gut–brain axis involving the rich parasympathetic (e.g., vagal), sympathetic (e.g., celiac axis) and submucosal neural syncytium, as well as the gut-elaborated hormones, are dramatically altered by metabolic/bariatric surgery–induced changes in gut structure, the microbiome and bile acid composition. Once we fully understand these perturbations, we may come to recognize why TBI affects the gut, and, more importantly, why the gut affects the genesis of TBI and can play a major role in treating TBI.

Nearly all human afflictions are metabolic in origin or severity. In the realm of therapeutics, the role of metabolic surgery has become a reality. We have established metabolic surgery for hyperlipidemia, obesity, type 2 diabetes, metastatic cancer, hypertension and depression, as well as other less frequent diseases. To this list, we may soon be able to add TBI.

---

Dr. Buchwald is a professor of surgery and biomedical engineering, and the Owen H. and Sarah Davidson Wangensteen Chair in Experimental Surgery (emeritus), at the University of Minnesota, in Minneapolis. His articles appear every other month.

This article is from the April 2021 print issue.