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A novel head-neck cooling device for concussion injury in contact sports

Emerging research on the long-term impact of concussions on athletes has allowed public recognition of the potentially devastating effects of these and other mild head injuries. Mild traumatic brain injury (mTBI) is a multifaceted disease for which management remains a clinical challenge. Recent pre-clinical and clinical data strongly suggest a destructive synergism between brain temperature elevation and mTBI; conversely, brain hypothermia, with its broader, pleiotropic effects, represents the most potent neuro-protectant in laboratory studies to date. Although well-established in selected clinical conditions, a systemic approach to accomplish regional hypothermia has failed to yield an effective treatment strategy in traumatic brain injury (TBI). Furthermore, although systemic hypothermia remains a potentially valid treatment strategy for moderate to severe TBIs, it is neither practical nor safe for mTBIs. Therefore, selective head-neck cooling may represent an ideal strategy to provide therapeutic benefits to the brain. Optimizing brain temperature management using a National Aeronautics and Space Administration (NASA) spacesuit spinoff head-neck cooling technology before and/or after mTBI in contact sports may represent a sensible, practical, and effective method to potentially enhance recover and minimize post-injury deficits. In this paper, we discuss and summarize the anatomical, physiological, preclinical, and clinical data concerning NASA spinoff head-neck cooling technology as a potential treatment for mTBIs, particularly in the context of contact sports.


Introduction
"No head injury is too trivial to ignore" Hippocrates 4th century BC.
An estimated 1.6-3.8 million sports-related traumatic brain injuries (TBIs), including those not treated by a health care provider, occur in the United States annually [1]. However, 75-80% of TBIs are mild, involving only a brief alteration in consciousness or mental status [2]. The term mild traumatic brain injury (mTBI) is generally interchangeable with concussion. Clinical presentation includes loss of consciousness for less than 30 minutes, alteration of mental state for less than 24 hours, posttraumatic amnesia for less than 24 hours, and a Glasgow Coma Scale score of 13-15 [3]. However, mTBI represents not only an acute, but also a chronic process. Postconcussion syndrome is characterized by experiencing numerous cognitive, somatic, and/or affective symptoms for longer than three months [3]. Representing as many as 5-20% of all mTBIs, postconcussion syndrome can often lead to chronic disability [4][5][6]. Recently, emerging research on the longterm effects of mTBI has drawn intense media attention and Congressional scrutiny of current health policy in the United States. Repetitive head impacts add another level of complexity to the characterization of mTBI because the emergence and duration of pathogenic events can overlap. Further, the destructive effect of recurrent mTBIs is likely synergistic rather than additive; for example, chronic repetitive subconcussive head impacts, which individually may have little noticeable effect, may result in cumulative long-term deleterious effects [7][8][9][10][11]. Therefore, the summed effects of both concussive and subconcussive injuries may better represent the more complicated clinical landscape for mTBI.
Understanding the compounding effects of repetitive mTBI is of particular relevance to modern athletes. Common long-term health disorders associated with recurrent mTBIs include neurocognitive deficits (attention, memory, processing speed, etc.), posttraumatic stress disorder (PTSD), chronic traumatic encephalopathy, psychosocial health problems (e.g., binge drinking, major depression, impairment of social functioning and ability to work, suicide), epilepsy, pain, and other alterations in personality or behavior [9,[12][13][14].

Brief overview of brain temperature
Our group recently published an extensive review on brain temperature and its fundamental properties [35]. In general, deep brain temperature is higher than body temperature but correlates well with body temperature. Fluctuating in both physiological and pathological conditions, brain temperature itself largely depends on the summed effects of the following principle variables: brain metabolism, cerebral blood flow (CBF) and volume, and blood temperature [36].

effects of exercise-induced hyperthermia on the brain-body thermal gradient
Physical exertion changes the physiological parameters of cerebral thermal regulation.
During significant periods of intense exercise or physical activities, body temperature elevates 1-2°C [39,40]. This temperature increase is critically important to understanding the acute effects of sports-related mTBI, which typically occurs during periods of intense physical exertion. As the body temperature rises, a window of increased cerebral vulnerability to injury may occur (Fig. 2).
Hyperthermia during exercise is associated with hyperventilation [41,42], which reduces blood levels of carbon dioxide, and carbon dioxide is a well-known potent mediator of CBF. For example, CO 2 produces cerebral vasodilatation, which enhances cerebral heat clearance and narrows the brain-blood temperature gradients. Similarly, hypocapnia, induced with hyperventilation, widens the brain-blood temperature gradients [36].
In addition, cerebral CO 2 reactivity (i.e. the magnitude of change in CBF for a given change in PaCO 2 ) appears to increase during hyperthermia [43]. Hyperventilation-induced hypocapnia combined with increased cerebral CO 2 reactivity lead to significant reduction in CBF [41,44,45]. Thus, a temperature-associated reduction in CO 2 levels compromises cerebral heat clearance capacity when heat clearance is most needed physiologically (Fig. 2).
Intense exercise increases cerebral metabolism and oxygen utilization, which subsequently increases cerebral metabolic heat production [46][47][48]. The increase in cerebral metabolic heat production with the concomitant decrease in CBF leads to a significant net cerebral heat storage [40], sustaining a widened brain-body thermal gradient ( Fig. 2).
At the termination of exercise, the cerebral venous to arterial temperature difference (v-a D temp ) markedly increases, indicating a thermal recovery process from the net cerebral heat storage accumulated during exercise [40]. However, the cerebral venous blood temperature decreases at a much slower rate than the drop in body temperature. Therefore, the cerebral thermal recovery response from exercise-induced hyperthermia is relatively slow (Fig. 2) [40].
In sum, intense physical exertion/exercise perturbs the thermal balance between cerebral heat production and heat removal via the cerebral circulation. Consequently, the brain-body thermal gradient widens, potentially creating a temporal window of greatly increased cerebral vulnerability to the deleterious effects from mTBIs both during and immediately after intense exercise [26].
However, this same temporal window may represent a window of opportunity for optimal selective brain temperature management to potentially lessen the cerebral vulnerability to concomitant concussive and subconcussive injuries.
In contact sports such as boxing and football, repeated blows to the head are inevitable.
Frequent head impacts are also common in soccer, ice hockey, lacrosse, basketball, etc. For male athletes, football and hockey have the highest number of sports-related concussions (SRC) [49,50]. For female athletes, hockey, soccer, and basketball are considered to be high-risk organized sports [49,50].

Experimental and clinical data
In the context of a single concussion, spontaneous and complete recovery is the general rule. However, the mild injury results in a temporal window of much increased cerebral vulnerability to more serious damage in the case of a second injury to produce greater damage if repeat injury occurs [51,52].
Analogously, although intense activity-induced hyperthermia (< 40°C), a common occurrence in contact sports, does not typically lead to any deleterious effects in athletes, recent evidence suggests that it may also significantly increase the cerebral vulnerability to any further mild traumatic injury [26].
In experimental studies to date, mild elevations in brain temperature (< 40°C) have consistently been demonstrated to worsen neurological outcome in moderate to severe TBI animal models [53]. A strong clinical associative relationship between the incidence of fever and poor outcome in patients with moderate to severe brain injuries has also been wellestablished [54,55]. However, there has been a relative dearth of information regarding the impact of brain temperature elevations on mTBI  as blood-brain-barrier (BBB) breakdown, mitochondria malfunction, apoptotic cell death, glutamate triggered excitotoxicity, energy demand-and-supply mismatch, cerebral autoregulation impairment, injury-induced oxidative stress and inflammation, and axonal injury. Although there does not appear to be histopathological consequences of induced mild hyperthermia by itself, the effect of combining mild hyperthermia and mTBIs (particularly recurrent concussions), is likely synergistic. mTBI/SRC = mild Traumatic Brain Injury / Sports-Related Concussion.
as well as delayed systemic hypothermia in brain injury patients (Fig. 4A)  There are direct temperature effects on the brain as the tissue is cooled, and there are with the cranium and neck, but also isolates the liquid cooling heat exchanger layer from the ambient environment (Fig. 5B).
In addition to the optimal thermal interactions with the brain, head-neck cooling may be particularly effective for activating temperature-sensitive skin afferents. Facial skin contains the highest concentration of the sensory receptors in the entire body [88]. More specifically, the face presents with the highest distribution density of free nerve endings with temperature sensory function [89]. Activation of temperature-sensitive fibers may have protective implications in contact sports.
The brain has a relatively slow recovery response from hyperthermia, as well as a low perfusion state early in the recovery [40,44]. Because CO 2 is a well-known potent mediator of CBF, CO 2 inhalation or voluntary hypoventilation has been proposed as a strategy for a faster restoration of CBF and dissipation of heat from the brain [40]. Such proposed strategies are not practical in contact sports. Skin cooling reduces minute ventilation and respiratory rate, a physiological response to reduce respiratory heat loss in cold environment [90,91].

clinical and practical considerations
Strategies to reduce body temperature before exercise and exertion have long been recognized and adopted by many athletes to decrease heat stress and improve performance [112]. However, pre-cooling may be impractical  induced changes in regional brain perfusion patterns and functional connectivity are also warranted.
To lessen the risks for and detrimental outcomes of mTBIs, a multidisciplinary scientific approach is required. Active and selective brain cooling using NASA spacesuit