Traumatic brain injury and methamphetamine: A double-hit neurological insult

Journal Pre-proof Traumatic brain injury and methamphetamine: A double-hit neurological insult

Samer El Hayek, Farah Allouch, Mahdi Razafsha, Farid Talih, Mark S. Gold, Kevin K. Wang, Firas Kobeissy PII:

S0022-510X(20)30047-2

DOI:

https://doi.org/10.1016/j.jns.2020.116711

Reference:

JNS 116711

To appear in:

Journal of the Neurological Sciences

Received date:

3 August 2019

Revised date:

27 November 2019

Accepted date:

29 January 2020

Please cite this article as: S. El Hayek, F. Allouch, M. Razafsha, et al., Traumatic brain injury and methamphetamine: A double-hit neurological insult, Journal of the Neurological Sciences (2020), https://doi.org/10.1016/j.jns.2020.116711

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© 2020 Published by Elsevier.

Journal Pre-proof

Traumatic Brain Injury and Methamphetamine: A Double-Hit Neurological Insult Samer El Hayek*1 , Farah Allouch2 , Mahdi Razafsha3 , Farid Talih1 , Mark S Gold4 , Kevin K

Department of Psychiatry, Faculty of Medicine, American University of Beirut, Beirut,

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1

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Wang5 , and Firas Kobeissy*5,6

Lebanon

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3

School of Public Health, University of California, Berkeley, USA Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston,

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2

4

Department of Psychiatry, Washington University School of Medicine, St. Louis, USA Program for Neurotrauma, Neuroproteomics, and Biomarkers Research, Department of

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5

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USA

6

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Emergency Medicine, University of Florida, Gainesville, Florida, USA Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American

University of Beirut, Beirut, Lebanon

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*Corresponding authors: Samer El Hayek, MD E-mail: [email protected] Third-year postgraduate year Department of Psychiatry, American University of Beirut

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Beirut, Lebanon

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Firas Kobeissy, Ph.D.

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E-mail: [email protected] Assistant Professor

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Program for Neurotrauma, Neuroproteomics, and Biomarkers Research

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Gainesville, FL, 32611, USA

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Department of Emergency Medicine, University of Florida

Journal Pre-proof Abstract Traumatic brain injury (TBI) is one of the leading causes of morbidity and mortality in the world. TBI causes permanent physical, cognitive, social, and functional impairments.

Substance

use and intoxication are established risk factors for TBI. Data are emerging that also suggest that brain injury might be a risk factor for substance use. Methamphetamine (METH), a highly addictive psychostimulant, has not been thoroughly investigated in the context of TBI exposure.

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The interplay between the two has been of interest as their pathophysiology intertwines on many

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levels. However, the knowledge concerning the association between TBI-METH and the impact

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of chronic METH use on short and long-term TBI outcomes is equivocal at best. In this review

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of the literature, we postulate that, when combined, these two conditions synergize to result in more significant neuronal damage. As such, chronic exposure to METH before brain trauma may the

pathophysiological signs

of injury,

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accentuate

worsening

TBI outcomes.

Similarly,

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individuals with a history of TBI would be more vulnerable to METH misuse and harmful effects. We, therefore, review the most recent preclinical and clinical data tackling the significant

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overlap in the pathophysiology of TBI and METH at three levels: the structural level, the

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biochemical level, and the cellular level. We also highlight some controversial results of studies investigating the outcomes of the interaction between TBI and METH.

Keywords: traumatic brain injury; methamphetamine; addiction; interplay, neurological outcomes.

Journal Pre-proof 1. Introduction Traumatic brain injury (TBI) is one of the leading causes of morbidity and mortality in the world. In the United States, about 3.5 million individuals are annually affected by TBI (1), with an incidence rate of 153 cases per day (2). In 2013, TBI accounted for approximately 2.8 million emergency department (ED) visits, hospitalizations, and deaths (2). Falls and intentional selfharm are the leading causes of all TBI-related hospitalizations (52%) and deaths (33%),

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respectively (3). Figure 1 is a display of the causes and ratio of severity of TBI in the United

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States, along with a depiction of the pathophysiology for primary and secondary injuries (2, 4).

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Brain injury is broadly categorized as mild, moderate, or severe. The criteria employed for this

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classification are presented in Table 1 (5). They are based upon the detection of specific clinical features (loss of consciousness and amnesia), neurological impairment on objective testing, or

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abnormal laboratory imaging (6). Mild TBI is the most commonly diagnosed form, accounting

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for approximately 80% of all cases. Injury can also be differentiated into penetrating open-head trauma in which the skull is broken or fractured secondary to the impact of a foreign object, or

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non-penetrating closed-head injury where brain damage occurs without the entry of any material

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through the head (7). TBI causes permanent physical, cognitive, social, and functional impairments. Overall, recent estimates suggest that around 5.3 million individuals in the United States struggle with a long-term disability secondary to TBI (6). Compared to the general population, individuals sustaining TBI have substantially higher mortality (8). Life expectancy after brain trauma ranges from 40% to over 85% less than that of the general population (9). Several studies have shown that brain trauma can also cause chronic pain disorders (10) and cognitive deficits (11, 12). A recently published meta-analysis of 57 pooled studies reinforced the association between TBI and neuropsychiatric disorders (average odds ratio of 1.67) (13).

Journal Pre-proof Of interest, substance use and intoxication are established risk factors for TBI (14-16). For instance, psychostimulants can cause aggressive behavior (17) and a decline in psychomotor performance (18), which increase the risk of brain trauma. The most common mechanisms of injury post substance misuse are traffic collision or falls (19). Data are emerging that not only relate TBI and substance use as comorbidities but also suggest that brain injury might be a risk factor for substance use (7, 20-23), including alcohol use disorder (23-25). Substance use post-

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TBI is adopted as a coping mechanism for the psychosocial stressors of disability (22, 26). Other

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data attributes drug use post-TBI to physiological changes in the brain that make patients with

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brain trauma more likely to engage in drug-seeking and addictive behaviors (20).

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Furthermore, substance misuse before brain injury can modulate the outcomes of TBI. A recent meta-analysis of 22 studies comparing TBI outcomes in patients with and without a history of

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substance misuse showed that the former group had poorer radiological outcomes (decrease in

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hippocampus and gray matter volumes and increase in size of ventricles) along with a moderate decrease in executive functioning and memory (27). Even though other cognitive outcomes were

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either unaffected or had inconclusive evidence, postinjury substance misuse and emotional

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functioning were worse in those with a history of drug addiction prior to TBI incidence (27). Along the same lines, another meta-analysis of 27 studies comparing TBI outcomes of individuals depending on their day-of-injury blood alcohol level (positive versus zero, high versus low), showed that a positive blood alcohol level was associated with poorer cognitive outcomes and higher levels of disability. Most effect sizes were, however, small or bidirectional, concluding that alcohol misuse increases the risk of sustaining a brain injury, yet is not consistently associated with better or worse outcomes, other than subtle cognitive deficits (28).

Journal Pre-proof While alcohol misuse accounts for 43% of TBI-related ED presentations, 34% are related to other recreational substances, including methamphetamine (METH) (29). METH is the most commonly abused synthetic drug worldwide, as shown in Figure 2 (30). METH is a highly addictive psychostimulant, typically self-administered in a binge manner (29). There are an estimated 10 million users of METH in the United States (31) and 35.7 million users worldwide (i.e., 0.59% of the world population) (30, 32). METH-related hospital admissions increased from

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68,000 in 2007 to 103,000 in 2011, with 569,000 individuals using METH each month in the

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United States (29). In a recent study examining the effect of premorbid substance effect on injury

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severity in patients admitted for trauma, approximately 2.7% of the sample were misusing

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stimulants, including METH (19). TBI patients who screened positive for METH are more likely to have had a violent incident of brain trauma compared to those who test negative (33, 34).

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Having this in mind, there is a common mutual background, at least on the neurocellular and

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neurochemical levels, between TBI and METH use. However, little is known about the interplay between these two insults on short and long-term neurological outcomes. In this review, we

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postulate that these two brain insult conditions can, when combined, synergize to result in more

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significant neuronal damage and subsequent more addictive behavior than if experienced separately; this updated work builds on our previous studies discussing the molecular events of METH abuse and TBI (35, 36). We conclude that chronic exposure to METH before brain trauma may accentuate the pathophysiological signs of injury and worsen the cognitive and behavioral outcomes of TBI via several molecular pathways. Similarly, individuals with a history of TBI may be more vulnerable to the effects of METH and predisposed to lower thresholds of tolerance and addiction. We also present a summary of preclinical and clinical studies

Journal Pre-proof highlighting the interaction between METH and TBI and provide recommendations for future research. 2. The crosstalk between TBI and METH To put into perspective the complex interactions between TBI and METH, the next subsections will discuss how these two entities crosstalk at three primary levels: the structural (i.e., brain anatomical structures and the reward pathways), the biochemical (i.e., the dopaminergic and

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glutamatergic systems), and the cellular levels (i.e., inflammation, apoptosis, and necrosis synergism between TBI and

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processes). Shown in Figure 3 is the postulated mechanistic

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METH.

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2.1. The structural level 2.1.1. Physical damage

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TBI inflicts damage to different brain regions, including the prefrontal cortex (PFC), the nucleus

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accumbens (NAc), and the ventral tegmental area (VTA) (37, 38). Together, these structures make up a series of neural circuits that mediate substance use behaviors (37, 38). Therefore,

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injury to these regions may alter the brain’s reward center in a way that makes it akin to that of

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substance users, thereby increasing the risk for drug dependence (39). Most radiological abnormalities following brain trauma occur in the frontal and temporal cortices, suggesting that anterior regions such as the PFC brain regions are highly susceptible to injury of varying severity (40, 41). The midbrain, which includes the VTA, represents another critical site of injury that sustains a decrease in white matter integrity post-TBI (42). In addition, the hippocampus is one more highly vulnerable structural post brain trauma, with neurophysiological changes occurring weeks to months after TBI (see reviews (43, 44)).

Journal Pre-proof Interestingly, it has been observed that the structures damaged in TBI are commonly affected in the setting of METH administration (45, 46). In animal models of METH misuse (see the review of available rodent paradigms (47)), METH induces neurostructural damage in a dose-dependent fashion (see review (48)), particularly at high dosages, with an enduring reduction in the hippocampal volume (49-52). Studies on rats and nonhuman primates show an increase in striatal volume during chronic METH treatment (46, 50).

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Similarly, in humans, chronic METH use causes an increase in the brain’s striatal volume (53,

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54). White matter in the frontoparietal and temporal lobes of chronic METH users exhibits an

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increase in signal intensity on magnetic resonance FLAIR imaging (55). Also, compared to

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controls, METH users have severe frontal white matter and gray-matter deficits in the cingulate, limbic, and paralimbic cortices. These deficits tend to be most prominent in the right hemisphere

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(56-58). Users also display a dysfunctional orbitofrontal cortex (59, 60) and a smaller

(61).

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hippocampal size (56) with a maintained reduction in its volume in recent female abstinent users

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On the TBI front, recent studies have observed that focal penetrating injuries to the PFC lead to

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executive dysfunction and marked impulsivity, two traits implicated in addiction (62, 63). Also, high-level cognitive functions that regulate impulsivity,

such as response inhibition, are

compromised in diffuse axonal injury (64), a key feature of pathology seen following TBI (65, 66). This diffuse axonal injury leads to abnormal connectivity in the default mode functions carried by white matter tracts (67, 68), possibly explaining the impulsivity described in TBI populations. Alternatively, METH exposure during development and adolescence affects the central nervous system (CNS) (69, 70) in a way that a significant decrease in the putamen, caudate nucleus, and hippocampal volumes correlate with abnormal executive functioning (70).

Journal Pre-proof A recent meta-analysis assessing the magnitude of cognitive deficits associated with METH use found that, relative to healthy controls, METH users have deficits in multiple functions, including social cognition, and impulsivity (71). While impulsivity may be a direct result of TBI or METH use, the reverse can be correct in that risk-taking behaviors predispose individuals to either sustain brain trauma or continue drug consumption (14). Even though the main concept of impulsivity is not well dissected, the

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cumulative impact of the three conditions (TBI, METH/substance use, and impulsivity)

TBI patients receiving a single dose of methylphenidate, a psychostimulant,

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Clinically,

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culminates into poorer outcomes when combined (72).

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developed partial restoration of the neural circuitry involved in response inhibition (73). The described results can be explained by increased dopamine and noradrenaline levels post-injection

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yet does not provide insight into the long-term effects on response inhibition. We will further

review.

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2.1.2. Perfusion damage

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allude to the particular use of METH in the treatment of TBI, discussed in Section 3 of the

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Dopaminergic neurons cause vasomotor changes in brain microvasculature (74). In METH users, dopamine receptor activation largely accounts for cerebral vasoconstriction (75), with a marked reduction in regional blood flow in the insular cortex (76, 77). A decrease in striatal and cortical perfusion is maintained in abstinent users (57, 78). On the other hand, TBI has been shown to change the peri-contusional blood flow (79). In response to brain injury, the change in cerebral perfusion follows a triphasic response (hypo-hyper-hypo), is region-dependent, correlates with TBI severity, and may persist chronically even after clinical symptoms resolution (see review (80)).

Journal Pre-proof Furthermore, alterations in regional tissue perfusion are even more significant when both conditions coexist, with a 60% lower peri-contusional cerebral blood flow in METH users who sustained TBI compared to non-users (81). Apoptotic and necrotic cellular deaths, consequently, follow a decrease in tissue perfusion (82). In repeated experimental METH administration models, this is portrayed as an elevation of axonal injury marker, involving the breakdown products of αII-spectrin and MAP-tau proteins in the axonal regions of neurons localized within

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the cortical brain regions (83). These breakdown products are thought to be indicative of

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apoptotic and necrotic neuronal cell death processes (84, 85) and mimic the characteristic

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changes observed in TBI rat models (35). The cellular level of interplay between TBI and METH

2.1.3. Blood-brain barrier disruption

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use will be detailed in Section 2.3.

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There is a growing body of evidence describing the blood-brain barrier (BBB) disruption

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following TBI (86, 87). This process is thought to be biphasic. An initial rapid breakdown of the BBB due to the acute mechanical nature of the injury occurs; it is characterized by disruption of

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the tight junctions, enlargement of the intercellular spaces, and cellular swelling (88, 89). This

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damage results in the infiltration of peripheral leukocytes into the CNS, leading to an exaggerated neuroinflammatory response (90). A delayed disruption of the BBB occurs 3–7 days later (91). BBB disruption can last up to years, mainly mediated by chronic neuroinflammation and neuronal loss (92-94). The extent and time course of such disruption remain, however, poorly understood (see review (80)). Similarly, the administration of METH in animal models increases BBB permeability (95-100). Such activity is mediated by decreasing the expression of tight junction proteins (101, 102), enhancing the production of reactive oxygen species (101, 103), and interfering with vesicular transport across endothelial cells (99). The BBB breakdown

Journal Pre-proof generally occurs in the septal area, hippocampus, and amygdala and is amplified when accompanied with increased brain temperature (see review (104)). Exercise protects against this increased BBB permeability in rat models post METH injection; this mainly occurs by increasing the expression of junction proteins, stabilizing the BBB integrity, and enhancing neural differentiation (105). As both insults affect BBB integrity, we can hypothesize that once co-existing, subsequent outcomes would be worse. Since many other insults, including exposure

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to other substances, can alter BBB permeability, would additive physical damage of the BBB be

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always expected? This is not necessarily true, as METH has been shown to exert particular

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effects on the CNS, structurally and molecularly, even when compared to other related

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stimulants such as cocaine (106-108). If the results of the initial brain insult (being exposure to METH, cocaine, or other categories of substances and injuries) are very specific in nature, the

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outcomes subsequent to a co-occuring TBI would diverge and not necessarily be alike.

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2.2. The biochemical level

2.2.1. Dopaminergic system dysfunction

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A recent study by Shen et al. described a temporal interaction between METH and TBI,

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particularly at the level of the dopaminergic system (109). In this study, striatal dopamine (DA) levels, 3,4-dihydroxyphenylacetic acid (DOPAC) levels, and DOPAC/DA turnover ratios were measured acutely (within hours) and subacutely (within days) after injury. TBI alone did not affect DA levels hours after trauma but increased them, similarly to METH treatment, within days of the injury. Alternatively, TBI or METH treatment alone significantly reduced DOPAC and DOPAC/DA turnover ratios acutely and subacutely, with further reduction being observed when the two insults co-existed. These results suggest that a small dose of METH exacerbates the suppression of striatal dopamine turnover after mild TBI(109).

Journal Pre-proof Additionally, Gold et al. emphasized the analogous proteome changes occurring between TBI and METH treatment (36), proposing the presence of common underlying biochemical events, leading to long-term neuropsychiatric sequelae seen in these types of injuries. The dopaminergic changes observed in TBI go along with the effects of METH on the dopaminergic system, as will be discussed below. As such, TBI may neurochemically prime the brain in a manner analogous to chronic METH use, creating a state where individuals with a history of METH abuse are more

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susceptible to drug reinforcement post-TBI. This can be attributed to a double hit insult affecting

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the mesocorticolimbic system.

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The mesocorticolimbic system functions in behavioral reward and is heavily implicated in drug

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use behaviors (110, 111). Its activity is mediated by dopaminergic neurons that originate in the VTA and synapse onto medium spiny neurons in the NAc and PFC (37, 39, 112, 113). During

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acute drug administration, the concentration of dopamine increases in the NAc and PFC (39,

monoamine

transporters,

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112). METH acts as an indirect agonist of dopamine by reversing the function of vesicular and

dopamine cell surface transporters (DAT) expressed

on

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dopaminergic neurons (114). Furthermore, METH inhibits monoamine oxidase enzymes, which

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attenuates the metabolism of dopamine and prolongs neuronal signaling (115, 116). TBI affects dopamine neurotransmission in a manner like drug use (117-119), and the role of the dopaminergic system in brain trauma has indeed been extensively studied (check review (120)). Preclinical studies showed an increase in striatal dopamine levels shortly after TBI (121). However, two weeks post brain injury, rats exhibited a significant decrease in dopaminergic transmission in the striatum, along with downregulation of striatal DAT expression (118). This decline is also seen in METH exposure: following abstinence from repeated drug administration, the dopaminergic transmission decreases in the NAc (111, 122).

Journal Pre-proof Clinical research has also been instrumental in the understanding of dopaminergic modulation during METH misuse and TBI. Post-mortem analyses of the basal ganglia of chronic METH users revealed a significant decrease in the levels of DA and DAT (123). Several neuroimaging studies have shown a downregulation of dopaminergic D2 receptors and a decline in the DAT in the striatum (124-126) and PFC (127) of METH users, with evidence of some recovery of DAT levels after protracted detoxification (128, 129). Similarly, imaging studies of TBI patients substantially

lower

levels

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2-β-carbomethoxy-3-β-(-4-iodophenyl)tropane

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revealed

and

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iodobenzamide striatal/cerebellar binding on single-photon emission tomography of the striatum

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several months post-injury (130-133); this phenomenon is highly suggestive of impaired

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dopaminergic transmission in patients sustaining TBI (130). This disturbance produces a dysfunctional reward circuit that facilitates drug relapse (134). The decrease of DAT expression

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post-TBI and the minimal DA release during periods of METH abstinence may reflect a

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compensatory adaptation to boost striatal dopamine concentrations (118, 135, 136). In METH use, this triggers a cycle of drug-seeking behavior, as METH administration becomes the most

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direct way of restoring DA levels.

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2.2.2. Glutamatergic system dysfunction TBI causes an acute imbalance in the normal excitatory and inhibitory synaptic transmissions within the circuits of the brain (64, 137, 138). After brain injury, neuronal tissues become deprived of oxygen and glucose, pushing cells into anaerobic metabolism (139). Lack of sufficient energy sources to maintain cellular function creates an acidotic environment (140), which subsequently triggers extensive neuronal depolarization and the release of excitotoxic glutamate (141). For instance, rats sustaining post-fluid percussion injury display a significant increase in striatal glutamate levels (142). This is mediated by the downregulation of glutamate

Journal Pre-proof transporter subtype 1 (GLT-1), which is responsible for extracellular glutamate reuptake (142). Along the same lines, patients sustaining TBI exhibit elevated levels of glutamate in their striatum directly after injury (130). Decreased levels of glutamate have been, however, reported in the PFC 3 days and 2 weeks later (143). Therefore, glutamate changes after brain injury are likely region-specific and time-dependent (80). These perturbations are associated with the clinical features of TBI, including migraine symptoms and the previously alluded to cognitive

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impairment (see review (144)).

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Chronically increased extracellular glutamate levels are implicated in drug and alcohol addiction

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(145). In fact, substance-seeking behaviors are partially mediated by the corticolimbic

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glutamatergic circuit connecting the prelimbic cortex to the NAc (146). During acute drug administration, activation of glutamatergic neurons in the PFC leads to excessive glutamate

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release in the NAc (147). This disruption in homeostasis is partially counterbalanced by a

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decrease in GLT-1 expression (38), similar to what is described in TBI. In METH rodent paradigms, the effects of acute METH administration on the glutamatergic

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system are analogous to that of acute brain injury (117-119). Compared to controls, mice injected

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with a single dose of METH display a significant increase in their glutamate level in the frontal cortex (148). Since such excitability has been described post-TBI, a combination of both insults may overly disturb the excitatory/inhibitory neuronal homeostasis. Acute abstinence, on the other hand, decreases corticolimbic activity, which leads to a decline in extracellular glutamate levels in the NAc (38). This can theoretically trigger subsequent drug craving. In contrast, chronic METH exposure in rats causes a substantial alteration in the hippocampal glutamate receptor signaling (149). Indeed, repeated exposure to the drug triggers a widespread degeneration of glutamatergic neurons, including those in the somatosensory cortex (150). This

Journal Pre-proof comes in parallel to a decrease in mGlu2 receptor availability in the PFC (151). Alternatively, in clinical studies, an investigation of the differences in glutamate concentration, among other metabolites,

between

untreated

METH

users

and

healthy

individuals

showed

higher

concentrations in the brainstem of the former group. These elevated levels were positively correlated with the duration and the total dose of drug use (152). The glutamatergic upregulation observed post-TBI mimics the neurochemical state described in METH consumers and can

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possibly prime the brain for drug-seeking behaviors in prior users.

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Interestingly, the dopaminergic system in the PFC can affect glutamate homeostasis (38).

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Dopamine prevents glutamate excitotoxicity via the activation of D1 and D2 receptors and the

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inhibition of monoamine oxidase (MAO) enzyme (153). One study postulated that METH, when administered 8 hours post severe TBI, may exert a neuroprotective effect by indirectly

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preventing glutamate excitotoxicity via dopamine release in the extracellular space and inhibition

2.3.1. Inflammation

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2.3. The cellular level

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of MAO (154). The results of this study will be further discussed in Section 3.

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Astrocytes and microglia constitute the glial cells that play crucial functions in CNS homeostasis, BBB maintenance, as well as inflammation (155, 156). Their expression has a profound effect on the dopaminergic and glutamate pathways in the brain (157), which are heavily implicated in METH and TBI (109), as previously discussed. METH and TBI stimulate similar series of neuronal cascades that mediate inflammation, specifically through microglial and astrocytic activation, which is an attribute of their neurotoxic effects (24, 157-160). The effects of METH on neuronal inflammatory and immune cells have been recently reviewed (see review (161)). Several preclinical studies have observed significant astrogliosis, microglial

Journal Pre-proof activation, and increased pro-inflammatory molecules (TNF-α, IL-1β, and metalloproteinase-9) in the brains of rats trained to self-administer METH (102, 116). In clinical studies, abstinent METH users display a significant decrease in CNS glial C-bicarbonate production rate, which equates with glial cell failure and neuroimmune injury (162). Such reduction is mediated by the redistribution of DA from vesicular storage vesicles to the extracellular space, the subsequent formation of reactive oxygen species and quinine by-products (163), and the lipid peroxidation

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of dopaminergic terminal membranes (164). Alternatively, a recent study utilizing proton

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magnetic resonance spectroscopy compared METH users to healthy controls and demonstrated

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that after acute to short term abstinence, METH users display prominent damage of integrity in

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neuronal tissues, suggestive of maintained neuroinflammation in the PFC and anterior cingulate cortex (165).

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In TBI, microglia promote the neuroinflammatory response through similar mediators, including

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TNF- α, interleukins (particularly IL-1B and IL-6 (166)), complement factors, chemokines, and reactive oxygen species (see review (167). Neuroinflammatory molecules leak through the

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damaged BBB acutely after TBI (168), and mediate subsequent second injury or post-

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inflammatory brain syndrome (see review (169)). The observed astrocytic inflammatory response can be transitory or chronic. For instance, two preclinical studies observed a chronic astrocytic reaction in the NAc and a significant increase in Bax and caspase-3 expression, known apoptosis markers, post-open-head controlled cortical impact (157, 159). Alternatively, Lowing et al. (2014) observed acute neuronal cell loss and astrocyte activation in the TBI-injured region using a closed-head injury model, which resolved 15 days post-injury (160). The discrepancy in astrocytic response duration is attributed to the model of TBI injury used (24). Not only that, the spatial location of the immune cells within the brain and the employed animal species also

Journal Pre-proof contribute to the immune cell behavior following TBI. Nevertheless, the inflammatory response remains an essential mediator of injury in TBI (see review (170)). Its association with addiction, in general, is further supported by the findings of Merkel et al., who observed normalized levels of drug-seeking behaviors after administration of anti-inflammatory molecules in animal models of brain injury (171). As previously discussed, a dysfunction in the NAc is implicated in drug addiction (172). Several

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studies have shown that acute METH administration is linked to an increased expression of c-

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Fos, an immediate-early response gene and marker of cellular activation (173, 174). c-Fos

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expression was also significantly increased in the NAc shell, a subdivision of the NAc, in the

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brains of animals exhibiting increased alcohol self-administration post-TBI, when compared to controls (172). Of note, no significant elevation in c-Fos expression was observed in the NAc

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core, another subdivision of the NAc (172). These findings are in concordance with one of the

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leading drug addiction theories, which claims that NAc shell activation drives increased drugseeking behavior while NAc core activation inhibits it (25). Alluding to this data and the

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commonly expressed c-Fos in both acute METH administration and TBI (25, 173, 174), the

misuse.

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inflammatory pathway represents another area of potential cross-talk between TBI and METH

2.3.2. Apoptosis and necrosis Along the same line, METH exposure has been correlated to an increase in the expression of caspase and calpain molecules, which are known markers of apoptotic cell death (36, 159, 175177). In particular, rodents injected with METH show an increase in their plasma levels of caspase-3, caspase-6, and caspase-12, followed by proteolysis of caspase substrates in neuronal tissue (DFF-45, lamin A, and PARP) and subsequent apoptosis (36). Similarly, TBI induces the

Journal Pre-proof expression of critical apoptotic markers in the brain, most notably Bax, caspase, and calpain molecules (36, 159, 175-177). Calpains are calcium-dependent proteases that play a role in mediating cell death (36, 178-180). Although calpains have traditionally been linked to proapoptotic effects, emerging literature is demonstrating the molecules’ important role in mediating pro-necrotic pathways as well (176, 177). TBI also causes significant white matter degeneration in the brains of victims along with reactive microglial accumulation in the corpus callosum,

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which may persist for years even after a single TBI (181). Distal white matter injury to sites of

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TBI is also observed, most notably in the PFC and the NAc at the anterior commissure (171,

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181-183). As previously discussed, both these structures are implicated in drug addiction. As

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such, a possible additive apoptotic effect, mediated via caspases and calpains, can maximize the brain injury in METH consumers who sustain TBI.

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3. The METH controversy and neuroprotection

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At high doses and in chronic misuse, METH causes dopamine-mediated neurotoxicity (116, 184). In contrast, short-term administration in controlled and low dosages have been implicated

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in specific neurotherapeutic outcomes. For instance, in non-TBI paradigms, young male rats

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injected with low-dose METH displayed better performance in spatial navigation tasks as compared to male controls. This effect was only short-lived. In contrast, female rats exposed to METH had a long-lasting improvement in acquisition and performance in navigation tasks, along with a more efficient working memory in adulthood, as compared to female controls (185). Alternatively, another study showed that low-dose METH provided to male rats during preadolescence but not adulthood led to a long-term improvement in the performance of spatial learning and memory tasks (186). These findings suggest that METH may enhance spatial

Journal Pre-proof learning only when administered during early life, at a time the central nervous system is highly susceptible to neurochemical modulation. In preclinical research of brain trauma, Shen et al. described a differential behavioral interaction between METH and TBI, that is timepoint dependent. In particular, during the acute phase of injury, TBI reduced METH-mediated increase in locomotor activity, whereas subacutely, both insults synergized to cause a further reduction in locomotion. This was paralleled by a significant

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decrease in DOPAC/DA turnover ratio in rats exposed to both injuries, both acutely and

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subacutely (109). Alternatively, in TBI models treated with METH (Table 2), Rau et al. reported

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that administering a low dose (0.25-0.5 mg/kg/h) 8 to 12 hours after severe TBI significantly

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improves behavioral and cognitive functioning compared to saline-treated controls (154, 187). After 12 hours post-injury, the administration of METH loses its characteristic neuroprotective

enhances

neurorestoration

(neuronal

and

functional

improvement)

rather

than

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METH

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effects, with no further positive impact on assessment tests (154). Another study showed that

neuroprotection after brain injury (188). Also, the effect of METH was maintained several weeks

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post-injury, which suggests that it may have long-term beneficial effects in brain trauma (188). A

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similar outcome has been described in rodents administered methylenedioxymethamphetamine (MDMA) prior to TBI. In fact, exposure to MDMA in these rats stabilized the cortico-striatal dopaminergic system, protected from neurodegeneration, and improved cognitive performance (189). In clinical studies (Table 3), a retrospective analysis showed that TBI patients testing positive for METH at the time of their hospital admission had a significantly lower odds ratio for mortality compared to those testing negative (190). A prospective observational study of adults with moderate and severe TBI showed that those who tested positive for METH had lower peri-

Journal Pre-proof contusional cerebral blood flow compared to nonusers. No differences in contralateral blood flow and tissue metabolism were found between the two groups (81). Another more recent retrospective study comparing the clinical outcomes after TBI in METH users versus non-METH users detected a more significant improvement in the Glasgow Coma Scale (GCS) and the Glasgow Outcome Scale (GOS) in the former group during hospital stay (191). Finally, in a cohort study of hospital patients admitted for traumatic injury, the presence of alcohol,

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stimulants (including METH), depressant drugs, and hallucinogens was analyzed. Drugs other

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than alcohol were found in 31.3% of patients, METH accounting for 2.7%. Depressants had a

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strong influence on injury severity in patients who screened positive for alcohol, whereas

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stimulants did not significantly affect injury outcomes (19).

The above findings may suggest that the neuroprotective and/or neurorestorative properties of

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METH observed in preclinical models are dosage and time-dependent (192), and may exert a

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similar role in humans. It is hypothesized that the activation of the dopaminergic pathway post METH injection delays calcium deregulation and glutamate excitotoxicity (153); this may

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explain the prior findings. It is possible that when administered post-injury, METH decreases

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neuronal loss in the hippocampus, a structure mostly involved in the preservation of memories (154), and increases the expression of anti-inflammatory molecules and neurotensin, both highly involved in the dopaminergic system. METH also enhances the expression of the corticotropinreleasing hormone, a substance with an observed neuroprotective effect when administered postTBI (154, 193). Moreover, METH provision after brain trauma does not affect the expression of inflammatory molecules, such as CCL2, Myd88, or IL1β, which usually increase post-TBI (154). On that basis, METH may inhibit the upregulation of pro-inflammatory markers when administered post-TBI. Therefore, at a clinical level, individuals taking METH before or

Journal Pre-proof immediately after trauma may show improvement in specific domains of functioning during their recovery. This could arguably be a direct neuroprotective effect of the substance as both elements come into play sequentially. Regardless, the exact mechanisms underlying the protective and restorative effects of METH on brain trauma remain unclear and deserve further investigation. Of note, most of the aforementioned studies were mostly correlational, warranting further analysis to dissect the exact mechanisms of potential METH-incuded neuroprotection.

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4. Conclusions

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This review examines the intricate interplay between TBI and METH exposure. The two insults

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share similar mechanisms of injury at different levels. At a structural level, both are associated

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with a reduction in the hippocampal volume and damage to the PFC, limbic, and paralimbic cortices. Decrease peri-contusional cerebral blood flow and a breakdown of the BBB ensue. Co-

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occurring imbalance in the excitatory/inhibitory homeostasis of the CNS is observed, with

na

impairment of dopaminergic transmission and release of excitotoxic glutamate. Subsequently, inflammation and apoptosis occur, mediated by activation of microglia and astrocytes, the

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release of pro-inflammatory molecules, and initiation of cell death cascades. These structural,

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biochemical, and cellular changes represent essential meeting points in TBI and METH pathophysiology. It seems plausible that, when combined, these two brain insults cause more considerable neuronal damage. However, a bidirectional relationship of cause and effect between TBI and METH, or TBI and substance use in general, remains unclear. On the other hand, data describing an improvement in TBI outcomes following METH administration shed light on the other side of the coin. The potential beneficial role of METH following brain injury cannot be ignored as this substance seems, at times, to tweak the adverse neuropsychiatric sequelae of TBI. This divergence into positive and negative outcomes probably

Journal Pre-proof depends on several complex factors, including the timeline of insults, their characteristics, and their associated severity. On that account, this review carries a translational ability to experiment with a new postulation for therapeutic potential of METH in brain injury. Recent meta-analyses assessed the impact of other stimulants on TBI outcomes. In an analysis of 10 randomized controlled trials, methylphenidate demonstrated a significant benefit in enhancing attention after TBI, with no

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effect on memory or processing speed (194). However, a more recent review of 9 studies

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concluded that evidence for the use of methylphenidate in mild TBI is inconclusive due to the

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heterogeneity of the available research (195). The rising misuse of METH in patients with brain

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trauma can be partially explained by individuals trying to self-medicate in order to mitigate the neuropsychiatric sequelae of TBI. Nevertheless, the addictive potential and detrimental effects of

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therapeutic purposes in brain trauma.

lP

METH still overcome its dualistic properties, refraining from recommending its use for

Further research should be undertaken to unveil the likely short- and long-term consequences of

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head injury in the presence of METH. Understanding the pathways linking the two conditions,

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via more-in-depth experimental models, can help formulate a better formulation of their interaction. A key element previously alluded to is the critical period pre- or post-injury when METH can be administrated, which at a clinical level might be challenging to control or predict. Another imperative factor is the dosage of METH that should be employed to achieve significant beneficial outcomes without potentiating any underlying addictive predisposition.

Journal Pre-proof Acknowledgments None. Declarations of interest None. Funding This research did not receive any specific grant from funding agencies in the public, commercial,

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or not-for-profit sectors.

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Journal Pre-proof Figure captions Figure 1. Traumatic brain injury: a) distribution by cause in the United States, b) ratio of severity, c) pathophysiology and interplay between primary and secondary injuries (2, 4). Figure 2. Methamphetamine: a) structural formula, b) different methods of administration, c) adverse effects in acute exposure, d) adverse effects in chronic exposure. Figure 3. Hypothetical scheme portraying an additive effect of traumatic brain injury (TBI) on

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the addiction threshold in methamphetamine (METH) naïve and chronic mice users.

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Sham mice not previously exposed to METH or TBI have a regular addiction threshold (green

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line). Alternatively, mice that are chronically exposed to METH but never sustained TBI have a

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lower threshold for addiction (orange line). Mice never subjected to METH, which have a primary regular addiction threshold (green line), hypothetically display a decrease in their

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addiction threshold after sustaining TBI (orange line). Lastly, in mice that chronically misuse

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METH and display a low threshold for addiction (orange line), sustaining a TBI can theoretically cause a further decrease in the addiction threshold (red line), making these mice more prone to

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developing addictive behaviors.

Journal Pre-proof Tables Table 1. Criteria used to classify traumatic brain injury severity (5). Table 2. Major findings of basic studies assessing the effects of methamphetamine on outcomes after traumatic brain injury. Table 3. Major findings of clinical studies assessing the effects of methamphetamine on

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outcomes after traumatic brain injury.

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30 minutes to 24 hours

>24 hours

0–1 day

>1 and <7 days

>7 days

13–15

9–12

3–8

1-2

3

4-6

Normal or abnormal

Normal or abnormal

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Post-traumatic amnesia Glasgow coma scale (best available score in 24 hours) Abbreviated injury scale score: Head

Severe

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Loss of consciousness

Moderate

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Mild < 30 minutes, usually few seconds or minutes

Structural Imaging

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Normal

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Lab test

Objective scale

Clinical

Criteria

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Table 1. Criteria used to classify traumatic brain injury severity.

Journal Pre-proof Table 2. Major findings of basic studies assessing the effects of methamphetamine on outcomes after traumatic brain injury. Model of Model of traumatic Study

methamphetamine

Main results

brain injury administration

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In the acute phase (within hours of exposure to the insult), METH treatment significantly increased locomotor activity in non-TBI and TBI rats. In rats injected with METH, TBI reduced METH-mediated increase in locomotor activity.

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Intravenous injection of 5 mg/kg of METH 30 minutes prior to TBI.

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Methamphetamine potentiates behavioral and electrochemical responses after mild traumatic brain injury in mice

Mild TBI sustained by dropping a 30 grams metal projectile onto the temporal skull, anterior to the right ear.

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Shen et al. (2011)

Severe TBI sustained by a lateral fluid percussion injury model.

Intravenous injection of 0.845 mg/kg of METH 3 hours after TBI, followed by a continuous

In the subacute phase (within 2-3 days of exposure to the insult), METH treatment or TBI alone significantly reduced locomotor activity. In rats injected with METH, there was a further reduction in locomotor activity after TBI, suggesting a synergistic effect on behavior. In the acute phase, METH treatment significantly reduced striatal dopamine levels. METH treatment or TBI alone significantly reduced DOPAC and DOPAC/DA turnover ratios in the striatum. In rats injected with METH, there was a further reduction in DOPAC/DA turnover ratio after TBI, suggesting a synergistic effect on the dopaminergic system.

In the subacute phase, METH treatment or TBI alone increased striatal dopamine levels and reduced DOPAC/DA turnover ratios in the striatum. In rats injected with METH, there was a further reduction in DOPAC/DA turnover ratio after TBI. Compared to saline-treated rats, those exposed to METH had significantly reduced behavioral and cognitive dysfunction after TBI (scored fewer foot faults and had restored learning and memory functions,

Journal Pre-proof improves behavioral and cognitive function after severe traumatic brain injury

intravenous infusion at a rate of 0.5 mg/kg/h for 24 hours.

respectively). This improvement was sustained until day 30 post-TBI: the performance of METH-treated animals was no more different from uninjured sham controls, whereas saline-treated rats lagged behind. Compared to saline-treated rats, those exposed to METH after TBI had a significant reduction in their hippocampal apoptotic cell death.

Mild TBI sustained using a concussive head trauma device.

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A study of the mechanism by which MDMA protects against dopaminergic dysfunction after minimal traumatic brain injury

Intraperitoneal injection of 10 mg/kg of Methylenedioxymethamphetamine (MDMA) 1 hour prior to TBI.

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Edut et al. (2014)

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METH-treated rats displayed more hippocampal immature neurons with more extensive dendritic processes than salinetreated rats 48 hours after injury. Rats sustaining TBI displayed higher striatal D2 receptor and tyrosine hydroxylase (TH) levels, and lower cortical TH level 24 hours post-injury, as compared to sham controls.

Rau et al. (2014) Administration of low dose methamphetamine 12 h after a severe traumatic brain injury prevents neurological dysfunction and cognitive impairment in rats

Severe TBI sustained by a lateral fluid percussion injury model.

Administration of MDMA prior to TBI restored D2 receptor level and both striatal and cortical TH levels back to normal. Brain-derived neurotrophic factor levels were significantly elevated in rats subjected to MDMA prior to TBI compared to those subjected to saline.

Administration of MDMA prior to TBI improved the cognitive abilities of mice: better performance on spatial learning and visual memory tasks. Haloperidol reversed this neuroprotective effect. Intravenous injection Rats injected with METH at a dose of 0.5 of 0.106, 0.212, and mg/kg/h between 8 and 12 hours after TBI 0.425 mg/kg of exhibited significant behavioral (dexterity METH 8-12 hours and fine motor control) and cognitive after TBI, followed by (learning, spatial memory, and spatial a continuous recall) improvements compared to those intravenous infusion injected with saline or lower METH doses. at a rate of 0.125, 0.25, and 0.5 mg/kg/h Rats treated with METH beginning 12 hours for 24 hours, after TBI did not display any improvement respectively. in performance on behavioral and cognitive

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Severe TBI sustained using a controlled cortical impact model.

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Ding et al. (2013)

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A higher dose of METH (0.5 mg/kg/h) conferred a slightly greater effect on early recovery compared to lower doses (recovery as early as day 7 post-injury). Higher doses of METH (0.25 and 0.5 mg/kg/h) achieved better maintenance of recovery (up to day 40 post-injury). Delivering METH at a dose of 0.5 mg/kg/h, beginning at 8 or 12 hours after injury, significantly reduced neuronal loss within the CA1 region of the hippocampus when compared to saline-treated animals. Delivering METH at a dose of 0.5 mg/kg/h, only if beginning 8 hours after injury, significantly preserved neurofilament staining within the CA3 region of the hippocampus when compared to salinetreated animals.

MRI of neuronal recovery after lowdose methamphetamine treatment of traumatic brain injury in rats

Intravenous injection of 0.42 mg/kg of METH 8 hours after TBI, followed by a continuous intravenous infusion at a rate of 0.05 mg/kg/h for 24 hours.

Rats injected with METH had no change in their gene expression of pro-inflammatory molecules (CCL2, Myd88, and interleukin 1β), whereas they displayed a significant increase in levels of anti-inflammatory chemokine CXCL12, corticotropin releasing hormone, and neurotensin, compared to saline-treated rats. Compared to saline, METH treatment significantly improved recovery of behavioral functions (reduction of modified neurological severity scores and foot-fault score errors up to 6 weeks after TBI). However, no differences were found on tasks of spatial learning and memory. Compared to saline, METH treatment did not significantly reduce cerebral tissue damage, lesion volumes, or ventricular volume during the 6 weeks after TBI. Compared to saline, METH treatment significantly increased neuronal density and

Journal Pre-proof axonal reorganization in the ipsilateral hemisphere of rats up to 6 weeks after TBI. However, no differences were found in the contralateral hemisphere.

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Compared to saline, METH treatment promoted neuronal recovery as detected by increased measurement of fractional anisotropy in the recovery regions-ofinterest on brain imaging up to 6 weeks after TBI. These results indicate a more reorganized white matter.

Journal Pre-proof Table 3. Major findings of clinical studies assessing the effects of methamphetamine on outcomes after traumatic brain injury.

Study

Aim

Methods

Main results

Limitations

O’phelan et al. (2008)

To assess the impact of METH use on mortality after TBI.

Retrospective review of the medical records of patients admitted to a trauma center for a diagnosis consistent with a head injury.

N = 483

Limited data regarding the clinical course during hospitalization.

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Patients with complete toxicology data were included in the subsequent analysis.

Toxicology results were available for 52.6% of patients, with the commonly detected substances being alcohol, cannabis, and amphetamines.

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The impact of substance abuse on mortality in patients with severe traumatic brain injury

O’phelan et al. (2013) Impact of methamphetamine on regional metabolism and

To assess if METH use would decrease pericontusional cerebral perfusion and N-acetyl-

Single center prospective observational study of patients with moderate or severe TBI.

Overall mortality was 50.9%. A toxicology screen positive for amphetamine was associated with decreased mortality (OR=0.25, CI 0.080.79, p<0.02).

The amphetamine positive group was more likely to use cannabis and less like to consume alcohol compared to the amphetamine negative group. N =17 41% (7 patients) tested positive for METH.

Lack of toxicology screen and detailed drug history in all patients. Inability to know the time or dose of drug use relative to the TBI event. Only 14 out of 47 positive urine tested exclusively positive for amphetamines.

Underpowered study. Heterogeneous TBI group with varying mechanisms of injury, severity, and affected

Journal Pre-proof cerebral blood flow after traumatic brain injury

aspartate concentration and increase lactate concentration in TBI patients.

Peri-contusional cerebral blood flood was 60% lower in METH users compared to nonusers (p=0.04).

All subjects underwent urine toxicology testing on admission.

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N = 320 METH group: 24 patients NONE group: 60 patients

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Retrospective review of the medical records of adult patients presenting with severe TBI to a trauma center.

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Patients with a toxicology profile were separated into two groups: METH group (positive for METH only) and NONE group

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The impact of methamphetamines in patients with traumatic brain injury, a retrospective review

To compare clinical outcomes after TBI in METH users versus nonMETH users.

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Duong et al. (2018)

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No difference between groups in contralateral cerebral blood flow or Nacetyl-aspartate and lactate concentrations.

(negative).

METH patients were younger on presentation (43.5 vs. 55.8, p=0.003). METH patients had a more significant improvement in mean Glasgow Coma Scale (GCS) and Glasgow Outcome Scale (GOS) during hospital stay (p=0.012 and p=0.0001, respectively). There was no association between METH use and length of hospital stay. There was no statistical difference for GCS and GOS scales between the two groups at discharge time.

brain regions. Limited METH use history: urine test cannot determine amount, time, or chronicity of misuse, and TBI patients were comatose. Variability in the time of brain imaging might have contributed to the variability of findings. Limited sample size. Short follow-up period of patients. Routine toxicology profiles not available for many individuals with severe TBI.

Journal Pre-proof N=1187 Drugs other than alcohol were found in 371 patients (31.3% of the sample). Stimulants, including METH, accounted for 2.7%.

All patients hospitalized for trauma were screened for alcohol and drug use independently of trauma severity.

The presence of depressant drugs, but not stimulants or hallucinogens, was associated with increased injury severity. This effect was sustained only in those also exposed to alcohol (for moderate injuries: OR=4.63, CI 1.37-15.60, p<0.013, for severe injuries: OR=7.83, CI 2.5324.21, p<0.001).

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To assess how alcohol might modify these effects.

Cohort study of patients admitted to a tertiary care hospital for traumatic injuries.

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The effect of central nervous system depressant, stimulant and hallucinogenic drugs on injury severity in patients admitted for trauma

To analyze the effects of stimulants, hallucinogens, and depressant drugs on injury severity.

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CordovillaGuardia et al. (2019)

Possible presence of false-negative results for alcohol in patients not tested for it at the time of admission and who denied misuse later on. Trauma patients who died at the scene of the accident not included in the analysis. Not all hospitalized patients screened for substance misuse.

Journal Pre-proof Figure 1. Traumatic brain injury: a) distribution by cause in the United States, b) ratio of

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severity, c) pathophysiology and interplay between primary and secondary injuries.

Journal Pre-proof Figure 2. Methamphetamine: a) structural formula, b) different methods of administration, c)

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adverse effects in acute exposure, d) adverse effects in chronic exposure.

Journal Pre-proof Figure 3. Hypothetical scheme portraying an additive effect of traumatic brain injury (TBI) on the addiction threshold in methamphetamine (METH) naïve and chronic mice users. Sham mice not previously exposed to METH or TBI have a regular addiction threshold (green line). Alternatively, mice that are chronically exposed to METH but never sustained TBI have a lower threshold for addiction (orange line). Mice never subjected to METH, which have a primary regular addiction threshold (green line), hypothetically display a decrease in their

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addiction threshold after sustaining TBI (orange line). Lastly, in mice that chronically misuse

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METH and display a low threshold for addiction (orange line), sustaining a TBI can theoretically

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cause a further decrease in the addiction threshold (red line), making these mice more prone to

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developing addictive behaviors.

Journal Pre-proof Highlights Traumatic brain injury is a leading cause of morbidity and mortality in the world.

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Methamphetamine is the most abused synthetic psychostimulant worldwide.

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These two brain insults crosstalk at structural, biochemical, and cellular levels.

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If combined, the two entities may synergize to cause significant neuronal damage.

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