Experimental Neurology 317 (2019) 191–201

Contents lists available at ScienceDirect

Experimental Neurology
journal homepage: www.elsevier.com/locate/yexnr

Review Article

Brain interrupted: Early life traumatic brain injury and addiction T

vulnerability
⁎
Lee Anne Cannellaa,b, Hannah McGarya, Servio H. Ramireza,b,c,
a
Department of Pathology and Laboratory Medicine, The Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
b
Center for Substance Abuse Research, The Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
c
Shriners Hospitals Pediatric Research Center, The Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA

A R T I C LE I N FO A B S T R A C T

Keywords: Recent reports provide evidence for increased risk of substance use disorders (SUD) among patients with a
Early-life traumatic brain injury history of early-life traumatic brain injury (TBI). Preclinical research utilizing animal models of TBI have
Neuroinflammation identified injury-induced inflammation, blood-brain barrier permeability, and changes to synapses and neuronal
Substance use disorders networks within regions of the brain associated with the perception of reward. Importantly, these reward
Addiction
pathway networks are underdeveloped during childhood and adolescence, and early-life TBI pathology may
Animal models of addiction
interrupt ongoing maturation. As such, maladaptive changes induced by juvenile brain injury may underlie
increased susceptibility to SUD. In this review, we describe the available clinical and preclinical evidence that
identifies SUD as a persistent psychiatric consequence of pediatric neurotrauma by discussing (1) the incidence
of early-life TBI, (2) how preclinical studies model TBI and SUD, (3) TBI-induced neuropathology and neu-
roinflammation in the corticostriatal regions of the brain, and (4) the link between childhood or adolescent TBI
and addiction in adulthood. In summary, preclinical research utilizes an innovative combination of models of
early-life TBI and SUD to recapitulate clinical features and to determine how TBI promotes a risk for the de-
velopment of SUD. However, causal processes that link TBI and SUD remain unclear. Additional research to
identify and therapeutically target underlying mechanisms of aberrant reward pathway development will pro-
vide a launching point for TBI and SUD treatment strategies.

1. Introduction estimated economic cost of TBI being over $48 billion per year (Corso
et al., 2006; Langlois et al., 2006). Therefore, following efforts to in-
Trauma is the leading cause of death among children and adoles- crease awareness of TBI, recent research in the field of brain injury has
cents aged zero to 18 years old. This includes, but is not limited to identified physical, cognitive, emotional, and behavioral deficits as
shaken baby syndrome and falls in the first years of life, bicycle and some of the adverse outcomes associated with pediatric TBI that persist
transportation-related injuries in childhood, and sports and motor ve- into adulthood (Frieden et al., 2015; Haarbauer-Krupa et al., 2017).
hicle accidents during adolescence (Frieden et al., 2015). In fact, using Prominent examples include the potentially life-long psychological
the Healthcare Cost and Utilization Project's National Emergency De- consequences that can develop following a brain injury event. In ad-
partment Sample and National Inpatient Sample, Taylor et al. reported dition to depression and anxiety, a link to substance abuse has been
that more than one million emergency department visits related to observed. Several studies have indicated that the younger the patient is
concussion or traumatic brain injury (TBI) among children (aged 0–4 at the time of injury and also increased severity of injury are associated
and 4–14 years old) and adolescents/young adults (aged 15–24 years with increased risk for problematic alcohol and drug use behavior and
old) occurred in 2013 alone (Taylor et al., 2017). Notably, the number the development of substance use disorders (SUD) later in life (Whelan-
of TBI-related fatalities does not compare to the majority of TBI patients Goodinson et al., 2009; Corrigan et al., 2013).
that survive and suffer lifelong consequences of their injuries. Non-fatal While SUD affects approximately 11% of the general population, the
TBIs result in longer hospital stays, loss of productivity, extensive re- rate of SUD among TBI patients ranges between 37 and 66% (Corrigan,
habilitation and patient care, which taken together contribute to the 1995; Parry-Jones et al., 2006). Notably, data from the 2014 National

⁎
Corresponding author at: Department of Pathology and Laboratory Medicine, The Lewis Katz School of Medicine at Temple University, 3500 N. Broad St. MERB
844, Philadelphia, PA 19140, USA.
E-mail address: [email protected] (S.H. Ramirez).

https://doi.org/10.1016/j.expneurol.2019.03.003
Received 7 December 2018; Received in revised form 27 February 2019; Accepted 8 March 2019
Available online 09 March 2019
0014-4886/ © 2019 Elsevier Inc. All rights reserved.
L.A. Cannella, et al. Experimental Neurology 317 (2019) 191–201

Survey on Drug Use and Health demonstrates a significant increase in stratified using clinical guidelines such as the Glasgow Coma Scale
SUD rates from ages 12 to 18 (SAMHSA, 2015). Therefore, adolescents (GCS), sports-related concussions often seen in child and adolescent
represent a population at risk of both experiencing early-life TBI and athletes can occur in the absence of skull fracture or external bruising or
SUD development with the potential for TBI and SUD comorbidities. bleeding, making accurate diagnosis of mild TBI a clinical challenge.
Significant advancements in the understanding of the development of Compounding the problem, 10–20% of mild TBI patients continue to
SUD among TBI patients can be attributed to the recent increase in report detrimental symptoms for months and even years post-injury
interdisciplinary preclinical investigations between neurotrauma and (Prince and Bruhns, 2017). The extent and manifestation of psychiatric,
addiction research fields. Molecular changes in the mesolimbic nuclei cognitive, and affective disorders may present differently following
that occur after neurotrauma that may affect processing of drug eu- childhood and adolescent TBI due to ongoing neural development.
phoria and lead to increased risk for SUD following TBI. As such, animal Therefore, standardized measures for outcomes unique to pediatric TBI
models of TBI have identified chronic inflammation, blood-brain bar- also include academic performance, family, environmental, and daily-
rier permeability, and changes to synapses and neuronal networks living skills, language proficiency, and social cognition (McCauley
within the regions of the brain associated with perception of reward et al., 2012).
that are distant from the initial area of impact (Merkel et al. 2016a,
2016b; Cannella et al., 2019). 2.2. Preclinical studies (animal models of TBI)
This review will focus on key aspects of brain development that are
affected when brain injury is experienced during the early stages of life Preclinical research offers valuable resources to investigate me-
that consequently could lead to an increased risk of SUD development. chanisms underlying the link between early-life TBI and subsequent
Thus, the following related topics will be discussed: the incidence of behavioral and molecular outcomes. The combination of inter-
early-life TBI, how preclinical studies model TBI and SUD, TBI-induced disciplinary animal models offers many opportunities for novel ex-
neuropathology and neuroinflammation in the corticostriatal regions of perimental designs that can help to elucidate poorly understood
the brain, and the link between TBI and addiction. First, epidemiolo- pathologies and phenotypes seen clinically. Validated models of brain
gical evidence identifying early-life TBI as an eminent health problem injury have been comprehensively described previously by our group as
and how preclinical research can be used to help advance treatment well as Xiong and colleagues (Xiong et al., 2013; Merkel et al., 2017). In
approaches available to these patients will be addressed. Then, an brief, the four models widely used in research are the weight drop, fluid
overview of what is known regarding the ensuing pathology and in- percussion injury (FPI), controlled cortical impact (CCI), and models of
flammatory profile in brain regions anatomically distal from the initial blast-induced injury. Each of these models have unique advantages and
area of impact that mediate the behavioral responses to rewarding translational applications. The availability of multiple injury models
stimuli will be provided. Finally, the association of TBI and increased grants preclinical researchers the opportunity to simulate both severity
vulnerability to develop SUD during adulthood will be discussed. and type of TBI seen in patients. Notably, each of these models can be
Notably, this review will call attention to the need for further pre- applied to juvenile and adolescent aged animals, with the advantage
clinical research to better understand the molecular underpinnings that that studies can easily assess outcomes in adulthood that would
contribute to addiction liabilities in the context of TBI; such knowledge otherwise require longitudinal clinical studies which are burdened by
will provide a launching pad for the investigation of novel treatment considerable expense and issues with patient retention.
strategies for patients with comorbid TBI and SUD. Clinical studies have demonstrated that experiencing TBI early in
life is associated with poorer behavioral outcomes later in life and that
2. TBI and the young brain psychiatric disorders are more common after childhood TBI (Max et al.,
2015; Kennedy et al., 2017). Preclinical research can be used to re-
A key finding by the CDC revealed that the incidence of TBI peaks capitulate the psychological outcomes as a consequence of experiencing
across three developmental periods: infants aged 0–4, adolescents aged TBI early in life. For example, following administration of the CCI
15–19 (or youths aged 15–24), and adults over the age of 65 (Faul et al., model of TBI, Washington et al. used a battery of behavioral assays to
2010; Taylor et al., 2017). Importantly, it is well established that many assess cognitive and emotional deficits including the elevated plus maze
of the brain's neuronal networks continue to undergo developmental for evaluation of anxiety-like behavior, the forced swim test for de-
changes well into adulthood. Therefore, the damage inflicted by TBI pression-like phenotypes, and the Morris water maze to examine defi-
under the age of 19 can result in disruption of ongoing maturation and cits in spatial learning and memory (Washington et al., 2012). Using
changes to ongoing development of specialized neuronal circuitry. juvenile exposure to a closed-head mild modification to the CCI, Ro-
Several studies have found that TBI-induced inflammation can persist driguez-Grande et al. also report long-term cognitive deficits including
for months or even years beyond when the initial injury occurs increased anxiety behavior assessed by the open-field test (Rodriguez-
(Johnson et al., 2013; Howell et al., 2018). Yet, how chronic in- Grande et al., 2018). Several studies have reproduced social deficits
flammation affects the developing brain remains poorly understood. observed after early-life TBI (Meadows et al., 2017; Ryan et al., 2018).
For instance, Mychasiuk and colleagues recorded and analyzed play/
2.1. Clinical and epidemiological data on early-life TBI fight behaviors following juvenile exposure to the weight drop TBI
model and found that rats with a history of brain injury exhibited re-
Demographically TBIs are more common in males than females with ductions in play behaviors (Mychasiuk et al., 2014). Similarly, utilizing
some reports of ratios as high as 3:1, however both sexes follow similar a three-chamber apparatus to measure social interaction, Yu et al. re-
age-related peaks in incidence, identifying those under the age of 19 at ported that injured mice with a history of repeated, mild CCI injury
highest risk (Faul et al., 2010; Taylor et al., 2017). The most common demonstrated deficits in social interaction (Yu et al., 2017). Behavioral
causes of TBI-related emergency visits from 2007 and 2013 were falls, assays such as the five-choice serial reaction time task (SRTT) can also
being struck by or against an object, and car accidents (Taylor et al., be combined with TBI models and used to characterize deficits in im-
2017). Although the incidence of TBI and concussions during partici- pulsivity which are commonly reported following TBI during childhood
pation in contact sports during childhood and adolescence is difficult to (Wade et al., 2017; Rhine et al., 2018). The findings of Mychasiuk as
quantify, the CDC reports the activities of children < 19 years old most well as Hehar and colleagues showed that after juvenile weight drop
associated with early-life TBI related injuries are bicycling, football, exposure, inaccurate responding and reduced control of inhibitory re-
basketball, soccer, and general playground activity. sponding in the SRTT task were higher among injured rats, indicative of
Unlike more severe brain injuries, which typically results in loss of increased impulsivity (Mychasiuk et al., 2014; Hehar et al., 2015).
consciousness and observable neurological impairment that can be Recent studies have begun to combine the prevailing models of TBI

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with assays that measure operant and drug-seeking behavior such as the stop there. Months and even years after the initial injury there can be
conditioned place preference and intravenous self-administration changes in gene expression as well as alterations in ion channels and
(Merkel et al. 2016b; Vonder Haar et al., 2018). Therefore, pre-clinical processes of cellular signaling. Even regenerative processes can alter the
models of early-life TBI represent a powerful tool that can be used to myelination and stability of neurocircuitry resulting in continued cell
continue to study injury-induced susceptibility to psychiatric disorders death and synaptic dysfunction (Johnson et al., 2013; Perez et al.,
seen in childhood TBI including depression, anxiety, conduct disorders, 2016b). Importantly, these injury processes have recently been reported
and drug addiction as causal mechanisms underlying this association to occur not only at the initial site of injury, but also in distal brain
remain unknown. nuclei such as the corticostriatal regions comprising the reward
pathway (Merkel et al. 2016b).
2.3. Development and maturation of the reward pathway
3.1. Anatomical alterations following TBI in the maturing brain
Cognitive, emotional, and behavioral deficits seen in humans and
recapitulated by animal models of early-life TBI can be attributed to Additional long-term consequences seen after pediatric brain injury
immaturity of brain systems within the prefrontal cortex (PFC) asso- include structural changes to brain regions beyond the area of impact.
ciated with executive functioning and higher-order thinking, changes Damage to both grey and white matter in brain areas distal from the
induced by the injury itself, or both. In fact, adolescence is a develop- point of impact can affect ongoing maturation of neuronal networks
mental period classically known to be characterized by increases in being developed. Unfortunately, these structural deviations are often
sensation-seeking, poor impulse-control, and deficient problem-solving associated with long-term deficits since the changes do not occur or are
(Walker et al., 2017; Williams et al., 2018). Anatomical and functional not detectable immediately. Advances in neuroimaging technologies
brain networks that connect PFC with mesolimbic nuclei such as the allow both clinical and preclinical researchers to visualize disruptions
nucleus accumbens (NAc) and the ventral tegmental area (VTA) com- and alterations following early-life TBI and address adverse behaviors
prise the network affected by the pathophysiology of substance abuse, correlated with these gross anatomical differences. For example, mag-
have been implicated in deficits of processing rewarding stimuli, and netic resonance (MR) diffusion tensor imaging (DTI) is a neuroimaging
remain underdeveloped during adolescence (Hartley and Somerville, technique that can be applied to both human TBI patients and pre-
2015). Maturation of dopaminergic projections that innervate the PFC clinical animal models of TBI. DTI creates contrasted MR images of the
is associated with linear increases in white matter tract volume from brain based on the diffusion pattern of water along the brain's white
childhood to adulthood (Naneix et al., 2012; Walker et al., 2017). White matter tracts.
matter connectivity is associated with strengthening of neural signaling, In clinical studies of pediatric brain injury, DTI has been a useful
executive control, and higher order cognitive functions (Schmithorst imaging technique in identifying brain regions vulnerable to white
and Yuan, 2010). matter damage. Specifically, Ryan and colleagues determined that in a
Likewise, grey matter maturation is another ongoing process during population of 95 children, 53 of which suffered pediatric TBI, injury-
adolescence. However, grey matter volume is reported to peak earlier in induced microstructural damage to white matter and abnormalities in
life and begins to decline during adolescence due to processes of sy- diffusion patterns in the corpus callosum (CC), middle and superior
naptic pruning (Gogtay et al., 2004; Tau and Peterson, 2010). Neuronal cerebellar peduncles, uncinate fasciculus, sagittal stratum, and dorsal
synapse formation and elimination by pruning is an important aspect cingulum were predictive of poorer social and cognitive performance at
normal synaptic development (Paolicelli et al., 2011; Wake et al., both 6- and 24-months post injury. Ultimately, these authors concluded
2013). that forces of acceleration and deceleration of childhood TBI lead to
Particularly within the reward pathway (PFC, NAc, VTA), we re- vulnerability of white matter tracts within fronto-temporal, limbic, and
cently reported aberrant microglial engulfment of synaptic proteins and projection fibers (Ryan et al., 2018). Fronto-temporal and limbic pro-
decreased synaptic spine density following adolescent TBI in mice jections are known to be involved in several cognitive processes in-
(Cannella et al., 2019). Plasticity changes within the NAc during ado- cluding learning, memory, and emotional regulation, likely con-
lescence involves microglial-mediated synaptic pruning and maturation tributing to social and cognitive deficits that persist long-term following
of dopaminergic signaling in response to reward-motivated behaviors. early-life TBI. Furthermore, in a study of young adults (mean age 22),
In adolescent rodents, Kopec et al. reported microglial involvement in Shah et al. tested the relationship between cognitive performance and
changes in dopamine receptor expression in the NAc (Kopec et al., DTI at 6 months post TBI. Their findings demonstrated asymmetrical
2018). Therefore, when TBI occurs during adolescence, the dynamic white matter micro-tears, discontinuity, and ultimately decreased vo-
maturation of anatomical and functional brain networks, such as the lume of the left ventral striatum in TBI patients, indicative of damage to
reward pathway, are interrupted. This likely contributes to cognitive deeper brain structures important for processing rewarding and re-
and behavioral deficits such as SUD reported in patients with history of inforcing stimuli (Shah et al., 2012). In fact, white matter tracts known
early-life TBI. as the anterior commissure project directly through the NAc. Together,
these results highlight the impact of TBI on brain regions distal from the
3. TBI neuropathology and neuroinflammation in the addiction area of impact. This research implies that damage at the impact and in
pathway these distal regions related to the pathophysiology of SUD contribute to
long-term psychiatric disorders seen in patients with a history of early-
When TBI occurs, the inflicted damage occurs at different stages. life TBI. However, further clinical research that considers both the
The first stage encompasses the initial impact and the damage occurs damage to the area directly insulted and projecting to areas of the brain
within seconds to minutes. During this time, there can be fracture of the that are associated with psychiatric disorders and TBI-related SUD, is
skull, axonal shearing, disruption of the vasculature and cell death at critical.
the site of impact. This is known as the primary injury. Then, after Using DTI in mice, Rodriguez-Grande and colleagues found that
minutes and up to several weeks following the initial injury, patients distortions to white-matter tracts following exposure to juvenile mild
experience a secondary stage of injury (Walker and Tesco, 2013). Me- CCI were not detectable at acute time points post injury, indicating
tabolic changes begin to occur which can include an increase in the their primary injury model was not severe enough to induce white
production of free radicals, oxidative stress, and inflammation. Sec- matter alterations directly. However, their study reported breakdown
ondary injury can initiate remodeling of the vasculature and pro- and fragmentation of myelin as measured by increased quantification of
grammed cell death by apoptosis and astrogliosis continues (Lozano myelin basic protein at 7 days post injury and significant white matter
et al., 2015; Lutton et al., 2017). Unfortunately, the damage does not alteration in the CC 30 days post injury. Interestingly, white matter

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Fig. 1. Graphical representation of TBI-induced disruption of

the neurovascular unit (NVU) within reward pathway nuclei
and subsequent cellular and behavioral consequences linked
to increased risk of substance use disorders. A: Under normal
conditions, endothelial cells (red) lining the vasculature and
expressing tight junction proteins (TJP) (grey) remain intact,
with no indications of blood-brain-barrier (BBB) permeability,
or immune cell infiltration (Yellow: Ly6C low/patrolling
monocytes; Orange: Ly6C intermediate/pro-inflammatory
monocytes; Red: Ly6C high/classical monocytes). Astrocytes
(green) and microglia (blue) remain quiescently surveilling
the environment, with some microglia involved in adolescent
synaptic pruning of neuronal proteins (engulfed purple cir-
cles). Magnification shows the synapse of interneurons/
medium spiny neurons residing in the NAc. Dopamine (pink)
release mediates reward-motivated behaviors that underlie
substance use disorders. B. Following early-life TBI, neuro-
pathology includes endothelial activation, disruption of TJP,
BBB hyperpermeability, and infiltration of immune cells with
persistent Ly6C pro-inflammatory monocytes reported in
adolescent brain injury. Activated microglia phagocytose
neuronal proteins resulting in adverse changes to medium
spiny neuron morphology and spine density. Magnification
shows adolescent TBI-induced hypodopaminergic state and
changes to spine length. Long thin spines are unstable and
associated with dynamic changes and increased excitability. C.
Proposed behavioral consequences seen in preclinical research
models of early-life TBI and cocaine conditioned place pre-
ference. Adolescent animals show increased sensitivity to
subthreshold doses of cocaine (green) compared to adults
(blue). TBI during adulthood (blue, striped) augments the
magnitude of CPP shift to high cocaine doses, which is further
exacerbated in adolescent TBI (green, striped). (For inter-
pretation of the references to colour in this figure legend, the
reader is referred to the web version of this article.)

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damage detected at later time points was correlated with long-term pathological consequence of secondary injury after TBI (Lozano et al.,
cognitive and anxiety behavioral deficits (Rodriguez-Grande et al., 2015). Biomechanical forces and biochemical insults of TBI induce
2018). Yu et al. also used DTI in their animal model of repetitive mild vascular disruptions which breach the neuronal microenvironment and
TBI. This study looked at the chronic effects of repetitive injuries on foster the propagation of injury resulting in hyperpermeability, micro-
white matter integrity by administering TBI in 8-week-old mice and hemorrhages, and rupture of capillaries. Age differences in indicators of
examining longitudinal outcomes at 3, 6, and 42 days post injury. In BBB permeability after TBI, such as brain edema and water content,
addition to anisotropic alterations to the CC, their data also demon- demonstrate more progressive pathology in patients who experience
strated white matter damage to cortical brain regions 6 weeks post in- early-life TBI (Fukuda et al., 2012). Unresolved BBB damage can lead to
jury. The cortical damage encapsulated the anterior cingulate cortex continued and proliferative inflammation and put patients at prolonged
which is a brain region implicated in social behaviors. The chronic risk for serious CNS consequences after the initial injury (Ichkova et al.,
white matter changes were correlated with the functional deficits in 2017). Clinically, CT scans used to assess TBI severity typically present
social interaction as described above (Yu et al., 2017). These findings as normal in patients with mild TBI and concussions due to the limited
further support the notion that the vulnerability to structural damage ability for these scans to reveal ultrastructural damage to the vascu-
induced by TBI is long-lasting and can be brain region dependent. As lature in deeper brain regions (Gill et al., 2018).
this area of research has not been fully explored, prospective preclinical Preclinical studies utilize a plethora of techniques to quantify BBB
research will continue to benefit from utilizing advances in neuroima- hyperpermeability following TBI including extravasation of molecules
ging techniques to better understand TBI pathology in deeper brain that are too large to cross the BBB in the absence of damage (Fig. 1). For
structures including the mesolimbic reward pathway of drug addiction. example, Rodriguez-Grande et al. quantified the extravasation of im-
munoglobulin G (IgG) 24 h post juvenile mild CCI and reported an in-
3.2. Induction of inflammatory markers crease in BBB permeability in the CC (Rodriguez-Grande et al., 2018).
Similarly, we also observed BBB leakage in brain parenchyma 48 h post
A key secondary mechanism of TBI pathology is neuroinflammation adolescent CCI by immunohistochemical detection of fibrinogen, a
(Walker and Tesco, 2013). The neuroinflammatory response is a well- plasma protein that does not cross the BBB under normal conditions
established consequence of TBI that can be robust and persist for years (Lutton et al., 2017). The expression of tight junction protein (TJP)
after a single injury (Johnson et al., 2013). The inflammatory response complexes that line cerebral vessels and form the physical barrier be-
to the initial injury itself is well characterized by activation of glial cells tween the blood and the brain, has also been utilized as an indicator of
at the area of impact. Microglia, the primary source for immune defense BBB breakdown. Using CCI in juvenile rats, Badaut et al. found that the
in the central nervous system (CNS), use phagocytic and cytotoxic TJP claudin-5 exhibited a bi-phasic response that correlated with IgG
mechanisms to maintain homeostasis during immune responses to in- extravasation. Specifically, they report a 21% decrease of expression of
jury conditions such as TBI. Recently, glial activation following early- claudin-5 which coincided with peak IgG extravasation at 3 days post
life TBI has also been reported in distal brain regions including the PFC, injury. However, at 7 days post injury, IgG extravasation normalized
NAc, and VTA (Merkel et al. 2016a, 2016b). Specifically, the presence and was associated with a 39% increase in claudin-5 expression (Badaut
of distinct pro-inflammatory genes upregulated in the NAc 2 weeks et al., 2015). Although there are many techniques for quantifying da-
following adolescent CCI in mice was observed. Subsequent studies mage to the BBB, more studies are needed to fully understand TBI in-
demonstrated that administration of an anti-inflammatory synthetic duced BBB permeability. In this case, preclinical research identifying
corticosteroid reduced microglial and astroglial activation in the NAc damage to vasculature in deeper brain regions would greatly increase
(Merkel et al. 2016a). Similarly, at 2 weeks following adolescent CCI translatability clinical studies of human TBI patients. Damage to brain
TBI, Karelina et al. found that treatment with minocycline, a tetra- vasculature and loss of BBB integrity can also be inferred from in-
cycline antibiotic commonly used to inhibit microglial activation, at- creased concentrations of proteins in peripheral blood that are typically
tenuated production of cytokines such as IL-1β as well as microglial expressed intracellularly by cells of the CNS. For example, in a study
activation within the NAc (Karelina et al., 2018). examining blood-based biomarkers for diagnostic efficacy in mild TBI,
Prior to the peak activation of microglia, TBI stimulates the release Gill and colleagues found that blood levels of CNS cellular proteins such
of inflammatory cytokines and chemokines which then stimulate the as tau, glial fibrillary acidic protein, and neurofilament light chain,
infiltration of immune cells such as neutrophils and monocytes/mac- demonstrated good discriminatory power to detect MRI abnormalities
rophages (Beschorner et al., 2002; Loane and Byrnes, 2010). The even when CT scans were unable to detect ultrastructural damage to
functional role of neutrophil and monocyte subtypes is not well un- mild TBI and concussion patients (Gill et al., 2018). Preclinical and
derstood, and long-term inflammatory cellular accumulation can be clinical research on BBB hyperpermeability in additional brain regions
detrimental. Following inhibition of neutrophil elastase, a proteolytic and long-term consequences is imperative.
enzyme secreted by activated neutrophils, Semple et al. demonstrated
attenuated inflammatory profiles of the cortex and hippocampus as 3.4. Synaptic alterations
measured by decreased cell death and rescued cognitive behaviors after
administration of CCI in juvenile mice (Semple et al., 2015). Recently, Acute neuronal cell death contributes to the known pathology of the
using flow cytometry to characterize infiltrating monocytes 2 weeks primary stage of injury following TBI. Furthermore, chronic changes in
following CCI, we found that compared to the adult inflammatory re- neuronal morphology and synaptic characterization in the absence of
sponse that resolved by 14 days after TBI, mice that experienced TBI cell death also occur after TBI (Perez et al., 2016a). Preclinical studies
during adolescence demonstrated persistent immune cell infiltration offer a distinct advantage of studying synaptic alterations following
that was still markedly detectable at 28 days post injury both globally in early-life TBI as cellular changes can only be evaluated post-mortem in
the injured hemisphere as well as in isolated NAc regions (Cannella clinical TBI cases. Using the FPI model of mild TBI in rats, Zhao et al.
et al., 2019). Taken together, these results support the notion that reported that in the absence of neuronal cell loss, TBI resulted in re-
persistent inflammation within the reward pathway induced by TBI duced spine density of pyramidal neurons in the infralimbic cortex of
may then contribute to increased drug-seeking behaviors seen in TBI- the PFC by golgi-cox analysis (Zhao et al., 2018). Comparably, Semple
related SUD. et al. evaluated morphological alterations of pyramidal neurons in the
PFC and granule cells of the hippocampus and described reduced
3.3. Blood-brain barrier hyperpermeability dendritic complexity associated with deficits in social interaction be-
haviors after pediatric CCI (Semple et al., 2017). In contrast, following
Loss of blood-brain barrier (BBB) integrity is another hallmark juvenile exposure to the weight drop TBI model, Mychasiuk et al.

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demonstrated increased dendritic length, increased spine density, and increased risk for SUD development is needed.
overall greater complexity of neurons analyzed from the anterior cin-
gulate region of the PFC. Whereas typically these neuronal character- 4. TBI and addiction
izations would be considered neuroprotective, the authors describe
maladaptive synaptic pruning during adolescent development as a 4.1. Clinical history of TBI and susceptibility to SUD
consequence of brain injury in mice (Mychasiuk et al., 2015). Aberrant
synaptic pruning has been linked to neurological dysfunction and seen Several studies have demonstrated an increased risk for SUD in
in psychiatric disorders such as schizophrenia, autism, and SUD adults with a history of TBI (Whelan-Goodinson et al., 2009; Corrigan
(Forsyth and Lewis, 2017; Kim et al., 2017; Kogachi et al., 2017) et al., 2012). For example, recent data from the 2012–2013 National
Hehar et al. examined morphology and synaptic alterations of Epidemiologic Survey on Alcohol and Related Conditions revealed that
medium spiny neurons in the NAc 2 weeks following the weight drop of TBI was significantly associated with past year SUD (Vaughn et al.,
mild TBI in juvenile rats and demonstrated injury-dependent reductions 2018). McHugo et al. assessed the rate and severity of TBI among 295
in both dendritic length and spine density associated with increased people in an outpatient mental health facility diagnosed with comorbid
impulsivity behaviors (Hehar et al., 2015). Likewise, we measured mental health disorders and SUD and found that 80% of these patients
changes in morphology and arborization of medium spiny neurons in tested positive for a history of TBI according to the Ohio State Uni-
the NAc 2 weeks following either adolescent or adult CCI TBI. We found versity TBI Identification Method (McHugo et al., 2017). Additionally,
that only moderate adolescent CCI induced significant reductions in in a study of electronic data of U.S. Military personnel, Miller et al.
dendritic length, dendritic complexity and arborization, and spine reported higher rates of comorbid addiction-related disorders among
density compared to either mild CCI or adult CCI. Notably, we also soldiers with history of mild TBI across all three periods post injury
reported increased spine length following adolescent CCI in the NAc, (1–30 days, 31–179 days, and > 180 days post injury) (Miller et al.,
indicative of increased long, thin spines known to be easily excitable. 2013).
These neuronal morphological changes in the NAc were associated with Clinical studies have recently identified TBI experienced during
increased sensitivity to the rewarding effects of cocaine (Cannella et al., childhood and/or adolescence as a risk factor for being vulnerable to
2019). problematic drug use (Corrigan et al., 2013; Ilie et al., 2016). However,
it is not known whether the specific age of injury (early childhood vs
3.5. Changes to the dopaminergic system adolescence) can differentiate which population is at greatest risk of
SUD development (see Section 4.4.2 for more details). Furthermore,
Dopamine (DA) is the primary CNS neurotransmitter that underlies Kennedy et al. performed a longitudinal study of 14,541 patients re-
reward-motivated behaviors. The DA pathway is comprised of anato- cruited in England followed since birth and assessed the association of
mical and functional connectivity between dopamine neurons that TBI with psychiatric symptoms at age 17. Their findings demonstrated
project from the VTA and release DA into the NAc. In a clinical setting, an increased risk of problematic alcohol use in participants with a
Donnemiller and colleagues showed that even several months after the history of TBI compared to those who experienced an orthopedic injury
initial injury, adults with TBI demonstrated detectable deficits in or no injury (Kennedy et al., 2017). In another longitudinal birth cohort
striatal DA signaling using single-photon emission tomography imaging study of 1265 children by McKinlay et al., SUD assessed between ages
and radio-labeled tracers that bind to the DA transporter (DAT) 14–16 were significantly more prevalent in children with a history of
(Donnemiller et al., 2000). The effect of brain injury on DA signaling being hospitalized for TBI before the age of 5 (McKinlay et al., 2009).
has been implicated in the negative psychiatric sequelae afflicting TBI Similarly, in a study of 636 inmates of the South Carolina Department
patients. Therefore, DA has been a targetable system with therapeutic of Corrections showed that those who had experienced their first TBI
potential for recovery. Treatment with DA agonists has shown im- prior to age 13 reported a higher percentage of illicit drug use, com-
proved executive cognitive function in humans (Kraus et al., 2005) and pared to those that had a TBI after 13 or had no injury (Fishbein et al.,
improved neuronal modulation in animals (Goldstein, 1993). 2016). While such longitudinal findings implicate early-life TBI in ad-
Preclinically, several studies have demonstrated changes to the DA verse neurodevelopmental changes that could then increase suscept-
system in animal models of early-life TBI. For example, using fast-scan ibility to SUD, more research is needed to better understand the long-
cyclic voltammetry, Chen et al. reported that adolescent rats exposed to term effects of childhood and adolescent injury.
the FPI model of brain injury demonstrated significant deficits in both
DA release and reuptake within the NAc for up to 2-weeks post TBI, 4.2. Preclinical evidence of SUD risk following early-life TBI
with greater effects in the NAc core (Chen et al., 2017). These deficits
normalized and returned to baseline DA levels at 4 weeks post injury Although preclinical TBI research has advanced our understanding
suggestive of a temporal hypodopaminergic state following adolescent of the progression of brain injury pathology and its impact on various
TBI. These authors expanded upon these findings in an additional study aspects of behavior, studies on how TBI affects addiction vulnerability
where they again found that DA release was suppressed by FPI and in are lacking. In fact, only a limited number of reports investigate assays
the presence of nicotine desensitization, DA release remained pro- of drug reward and reinforcement despite SUD being the third most
portionally suppressed after FPI (Chen et al., 2018). Taken together frequent neuropsychiatric diagnoses among individuals with TBI
these results suggest drug sensitivity was affected by TBI-suppressed DA (Whelan-Goodinson et al., 2009). Further, the majority of these studies
release and a reward response required a significantly stronger sti- have only examined SUD in the context of adult brain injury and have
mulus. Further, Karelina et al. also report a hypodopaminergic state as produced conflicting results. For example, using a two-bottle choice
assessed by decreased quantification of tyrosine hydroxylase, the pre- assay to quantify differences in alcohol consumption, Lim et al. report
cursor enzyme in DA synthesis, in the VTA, and reduced expression of comparable rates of alcohol intake in rats exposed to a blast model of
DAT in the NAc DR2 in the striatum following juvenile CCI that per- mild TBI compared to controls (Lim et al., 2015). By contrast, work by
sisted into adulthood when analyzed 7 weeks post injury (Karelina Mayeux et al. revealed augmented alcohol self-administration in adult
et al., 2017). The findings of these studies highlight the importance of rats following TBI induced by the FPI model (Mayeux et al., 2015).
considering deficits in DA release and reuptake in juvenile and pediatric Recent work extends SUD after adult TBI research beyond the scope of
TBI patients in order to assess long-term consequences and vulner- alcohol and has tested the effects of brain injury on psychostimulant
ability to SUD mediated by dysfunction of the DA system. However, self-administration using cocaine. Specifically, Muelbl et al. analyzed
since the effects of TBI on the DA system are not fully understood, cocaine self-administration following exposure to mild blast TBI and
further research investigating TBI-induced DA dysfunction and while they did not report differences in cocaine intake, the authors

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described cognitive deficits in operant learning in the injured rats relationship in that hypothalamic orexin neurons project to dopamine
compared to controls as measured by increased errors during self-ad- neurons in the VTA, the orexin system may be a promising targetable
ministration acquisition (Muelbl et al., 2018). Although Muelbl et al. system to treat chronic psychiatric issues in TBI patients including risk
observed no distinctions in drug-seeking behavior in their brain injury for SUD (Fadel and Deutch, 2002).
model, a study by Vonder Haar et al. revealed significant increases in
cocaine infusions in the self-administration assay following both mild 4.4. Confounding variables of TBI-related SUD
and severe CCI TBI (Vonder Haar et al., 2018).
While these studies corroborate the link of increased risk of SUD 4.4.1. Sex as a biological variable underlying risk of SUD after early-life
following TBI that occurs during adulthood, investigations that model TBI
early-life TBI are nearly absent from the literature. Studies by Weil et al. One potential factor that could influence the risk of SUD following
have assessed the impact of juvenile TBI on alcohol consumption later early-life TBI and SUD susceptibility is biological sex. Unfortunately,
in life. Specifically, 21-day-old mice that suffered a closed-head injury TBI and the effect of sex is understudied and sex-dependent outcomes
demonstrated increased alcohol place preference in the conditioned following TBI remain controversial. The studies discussed in this section
place preference (CPP) assay and increased alcohol consumption highlight the need for further research to better understand how fe-
quantified in the two-bottle choice test during adulthood (Weil et al., males are affected by TBI compared to males, particularly in the context
2016b). Karelina et al. expanded these findings by replicating the effect of SUD vulnerability.
of juvenile TBI on increased alcohol intake which was attenuated by In the context of early-life TBI, sex-specific fluctuating hormones
minocycline treatment (Karelina et al., 2018). While these two studies can only be considered as a potential contributing factor of TBI-related
have demonstrated that juvenile TBI increases alcohol consumption, sex differences in outcomes after the onset of puberty, typically having
our previous report was the first to assess the effects of adolescent TBI occurred by age 13. For instance, using data from the National Trauma
on the rewarding effects of cocaine (Merkel et al.2016b). Our recent Data Bank Research Data Sets from 2007 to 2008, Ley et al. suggested
work extends these findings and suggests that TBI during adolescence, a that hormonal differences may contribute to sex differences in rates of
developmental period characterized by ongoing maturation of the re- mortality following isolated, moderate-to-severe TBI as they report
ward pathway, increased sensitivity to the rewarding efficacy of a lower mortality rates in postpubescent female TBI patients (aged
subthreshold dose of cocaine (Cannella et al., 2019). Collectively the 13–18 years old) compared to males, yet no difference in mortality rates
preclinical literature investigating the link between TBI and SUD de- between male and female pre-pubescent patients (aged 0–12 years old)
monstrates that early-life brain injury exacerbates alcohol and cocaine patients (Ley et al., 2013). However, when the outcomes evaluated
addiction vulnerability. However, whether this phenomenon gen- extend beyond rates of mortality and consider the development of long-
eralizes to other drugs of abuse is unknown as animal models have yet lasting psychiatric disorders such as SUD, clinical studies report sex-
to investigate the effects of juvenile TBI on the rewarding effects of specific effects but do not typically consider hormonal status at the time
other substances such as opioids or marijuana. Further, studies so far of early-life TBI. In a study of 9299 students enrolled in grades 7
have only tested SUD outcomes following a single TBI impact. There- through 12, Ilie and colleagues found that among long-term con-
fore, future studies may aim to investigate repetitive injury modeling, sequences examined, adolescent males with a history of TBI were more
representative of multiple concussions as commonly experienced in likely to report daily nicotine use while adolescent females with a
adolescent participation in contact sports and subsequent vulnerability history of TBI were more likely to report increased alcohol use in the
to SUD. past year (Ilie et al., 2016). Similarly, in an assessment of neu-
ropsychiatric outcomes among New Zealanders with a history of either
4.3. The possible mechanistic role of orexin in TBI and SUD moderate/severe childhood TBI (aged 0–17 years old), mild childhood
TBI, or an orthopedic childhood injury, Scott et al. found that males and
Orexin is a CNS peptide that regulates arousal and is known to play females displayed significant differences in internalizing versus ex-
a role in reward-motivated behaviors. Dysregulation of orexin systems ternalizing behaviors such that males were more likely to report sub-
has also been implicated in psychiatric disorders after TBI (Harris et al., stance abuse/dependence (DSM-IV-TR criteria) and females reported
2005; Gentile et al., 2018; Martin-Fardon et al., 2018). For example, higher rates of anxiety and depression, the effects of which were then
Baumann et al. found deficits in orexin levels measured by cerebral increased further in those with a history of childhood TBI (Scott et al.,
spinal fluid in patients with a history of TBI which was correlated with 2015). It is important to note that psychosocial norms related to re-
sleep-wake disturbances (Baumann et al., 2005; Baumann et al., 2007). porting symptoms of physical and mental health among females versus
Expanding upon these findings, Baumann et al. also evaluated post- males may also influence sex differences in internalizing and ex-
mortem tissue from patients who did not survive severe brain injuries ternalizing behaviors observed in TBI and SUD populations.
and found a 27% decrease in orexin neurons after TBI compared to The majority of the preclinical studies exploring the link between
control tissue (Baumann et al., 2009). early-life TBI and SUD discussed above included the use of only male
Alterations in sleep-wake behaviors, cognitive deficits, and reduced animals. Notably, preclinical studies that consider levels of fluctuating
orexin neurons were also reported in preclinical studies by Skopin et al. sex hormones in the extent that sex differences may mediate the risk of
1 month following the FPI model of TBI in rats (Skopin et al., 2015). SUD after early-life TBI are also limited by animal age. For example,
Thomasy et al. also found decreased wakefulness and fewer orexin- Weil et al. found increase alcohol consumption in female mice with a
producing neurons that persisted for at least 15 days post TBI, and history of juvenile CCI-TBI at post-natal day 21, prior to the age of onset
posited a role for chronic inflammation in orexin deficits after CCI in of the estrous cycle (Weil et al., 2016b). Our group has begun to assess
mice (Thomasy et al., 2017). The orexin system has also been con- estrous phase at the time of injury in adolescent female mice and de-
sidered for therapeutic efficacy in animal models of TBI. Following termine the effect on increased vulnerability to cocaine conditioned
juvenile exposure to FPI, Lim et al. demonstrated that dietary supple- preference. Unlike our observations in male mice discussed above,
ment of branch-chained amino acids (BCAA) that directly modulate preliminary results suggest that after adolescent CCI-TBI, females do
orexin neuron activity reinstated orexin neuron activation and im- not demonstrate increased drug-seeking behaviors and that higher le-
proved deficits in wakefulness mice with mild brain injury (Lim et al., vels of estrogen and progesterone at the time of injury may be pro-
2013). Elliott et al. expanded upon these findings, revealing that in tective against augmented cocaine CPP shifts. The role of sex-specific
mice with juvenile FPI, BCAA dietary modulation attenuated sleep- hormones, particularly progesterone and estrogen, has been extensively
wake disturbances and restored orexin neuronal activity through investigated preclinically and has reproducibly exhibited neuroprotec-
synthesis of GABA (Elliott et al., 2018). Thus, given the anatomical tive effects following experimental TBI. Independently, the work of

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Roof et al., O'Connor et al., and Garcia-Estrada et al. each demonstrated been shown to characterize this risk. Thus, more specific details re-
that female hormones reduced brain edema and inflammation in animal garding age at the time TBI occurred rather than binary history of TBI
models of contusion injury, diffuse axonal TBI, and penetrating brain or no history of TBI should be considered in future prospective and
injury, respectively (Garcia-Estrada et al., 1993; Roof et al., 1993; retrospective studies investigating the association of early-life TBI and
O'Connor et al., 2005). However, after being tested in phase 3 clinical SUD.
trials in human TBI patients, progesterone failed to demonstrate an
advantage in mortality rates compared to placebo and these trials were 4.4.3. Intrinsic versus extrinsic factors that may influence the likelihood of
discontinued (Lu et al., 2016; Goldstein et al., 2017). Additional re- TBI-related SUD
search investigating the influence of sex as a biological factor on out- Both intrinsic factors, such as comorbid neuropsychiatric disorders,
comes following early-life TBI such as SUD vulnerability is critical, and extrinsic factors including the patient's home and family environ-
particularly among post-pubescent adolescent patients where fluctu- ment exemplify additional confounding variables that can influence
ating hormone levels can be taken into consideration. Further studies SUD development following early-life TBI. Studies that have assessed
will improve the understanding and awareness of sex-specific vulner- diagnosis of SUD after history of TBI typically adjust the analysis using
abilities to TBI and interactions with persistent psychiatric problems confounding factors rather considering these as independent variables.
like SUD and will advance individual strategies for treatment. For example, in an adult population, Vaughn et al. report a significant
correlation of past year TBI with SUD after adjusting for age, sex, race/
4.4.2. The role of age of injury in risk of SUD after TBI ethnicity, socioeconomic status (SES), education, and parental history
Another factor that could potentially escalate SUD susceptibility of psychiatric disorders (Vaughn et al., 2018). In a population with
after early-life TBI is the age at the time the initial injury occurs. As childhood TBI, Kennedy and colleagues found TBI was associated with
discussed above, early childhood brain development and function may problematic alcohol use after adjusting for mother's age and education
represent a period of vulnerability to damage inflicted by TBI. Further, at birth, social class, self-reported parenting style, and maternal drug
dynamic alterations in plasticity and strengthening of brain networks use (Kennedy et al., 2017). These findings imply that SUD risk is in-
that mediate executive cognitive functions maturing throughout ado- creased following TBI if such confounding variables are controlled for.
lescence are likely also sensitive to external insults. A comprehensive However, intrinsic and extrinsic factors are important considerations
review of how age of injury can be considered as a factor for increased that can directly influence long-term outcomes.
risk of SUD or alcohol use disorder after TBI have been previously de- As mentioned above, the development of anxiety and depression
scribed by our group and Weil et al., respectively (Merkel et al. 2017; represent the most common neuropsychiatric disorders that TBI pa-
Weil et al., 2016a). Yet, research continues to support the notion that tients experience, and similar to the general population, often account
age at the time of injury can mediate risk of SUD after early-life TBI. For for comorbid diagnoses seen in TBI-SUD patients (Whelan-Goodinson
example, McKinlay et al. extended their analysis of the birth cohort of et al., 2009; Vaughn et al., 2018). Just as TBI has been shown to
children of the Christchurch Health and Development Study in New compromise areas of the brain important for the processing of reward
Zealand and found significant correlation between early childhood (age and drug-induced euphoria such as NAc, PFC, and VTA, childhood brain
0–5 years old) and adolescent (age 16–21 years old) TBI that required injury can also negatively impact areas involved in cognitive and
inpatient treatment and later alcohol and drug dependence (age 16–25 emotional regulation linked to anxiety and depression such as the
and 21–25, respectively) but no significant association if TBI occurred amygdala and hippocampus (Beauchamp et al., 2011). Risk of psy-
between ages 5–15 years old (McKinlay et al., 2014). Furthermore, chiatric disorders such anxiety and depression after early-life TBI is
Kennedy and colleagues also investigated the association between age likely regulated by a complex combination of injury-induced anato-
of injury and psychiatric symptoms, substance use, and criminal be- mical alterations, neurochemical dysfunction, and psychosocial factors.
haviors assessed at 17 years old and found that childhood (age Individuals diagnosed with mood disorders after experiencing TBI
0–11 years old) TBI was correlated with problematic cannabis use while during childhood could turn to drugs of abuse as a maladaptive coping
adolescent (age 12–16 years old) TBI was correlated with problematic strategy to manage symptoms of underlying psychiatric disorders. For
cannabis and alcohol use compared to controls who experienced age- instance, Wills and Filer suggested that in attempts to alleviate de-
matched orthopedic injuries (Kennedy et al., 2017). pressed or anxious symptoms, adolescents may participate in substance
Adolescence is a developmental period in animal models of SUD use as a coping strategy (Wills and Filer, 1996). However, even in
that is associated with increased sensitivity to the rewarding effects of adults, studies investigating the link between self-medicating to treat
drugs of abuse. For example, although not in the context of TBI, neuropsychiatric disorders and SUD development are limited and con-
Zakharova et al. found that adolescent male rats developed a significant troversial. In a study of 494 hospitalized drug abusers, Weiss and col-
cocaine CPP shift at lower cocaine doses than adult rats (Zakharova leagues reported the majority of patients used drugs to reduce symp-
et al., 2009). Badanich and colleagues also found that adolescent rats toms of depression (Weiss et al., 1992); however, in a study of 70
were more likely to establish CPP to subthreshold cocaine doses and patients undergoing methadone maintenance treatment, Hall and
that ontogenetic differences in DA release and reuptake, as measured by Queener failed to show an association between substance use as a
microdialysis, may account for age-specific sensitivities to the reinfor- means to cope with symptoms of anxiety and depression (Hall and
cing properties of cocaine, and ultimately increased vulnerability to Queener, 2007).
addiction during adolescence (Badanich et al., 2006). Similar to our Risk of Secondary Attention-Deficit/Hyperactivity Disorder
findings, in a neurochemical brain injury model induced by adminis- (SADHD) has also been reported following early-life TBI (Narad et al.,
tration of the dopaminergic neurotoxin 6-hydroxydopamine, Schenk 2018). In a study of 200 children (aged 5–17 years old), Schachar and
and colleagues reported that lesioned rats reliably responded for the colleagues found that SADHD and symptoms of anxiety were sig-
subthreshold intravenous doses of self-administered cocaine, suggestive nificantly more frequent among children that experienced TBI at least
of increased sensitivity to the rewarding effects of cocaine (Schenk 2 years prior and that the interaction of TBI and SADHD was predictive
et al., 1991). Our recent study is the first to report increased sensitivity of deficits in measurements of impulsivity and response inhibition
to subthreshold doses of cocaine if CCI-TBI occurred during adolescence (Schachar et al., 2004). Impulsivity and response inhibition deficits
but not if CCI-TBI occurred during adulthood (Cannella et al., 2019). have been extensively described as risk factors for the development of
Collectively, these studies suggest that age of injury is an important SUD (Groman et al., 2009; Lawrence et al., 2009; Kozak et al., 2018).
confounding variable to consider in the link between early-life TBI and Taken together, these findings suggest that individuals with a history of
SUD. Causal relationships between age of TBI and risk of problematic early-life TBI may be more likely to develop SUD as a consequence of
drug and alcohol use later in life is still unknown as several factors have confounding intrinsic factors such as comorbid neuropsychiatric

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disorders. and opiates. Third, addiction has phases that include: reinforcement,
The extrinsic factor SES can financially regulate a patient's access to drive, incentive, tolerance, dependence, and relapse. Therefore, future
innovative treatment approaches, state-of-the-art rehabilitation centers, studies could reveal how the stages of addiction are changed as a
and education about the care needed, which may then affect long-term function of brain injury. Fourth, it is essential to recognize that TBI
outcomes. However, the support systems available to patients, parti- severity (i.e. mild, repeated TBI, moderate, and severe) must be con-
cularly those that experience TBI during earlier childhood years, has sidered in all the above, since severity affects acute and chronic pa-
shown a strong correlation with prognosis as several studies support the thologic responses that undoubtedly will have different behavioral
notion that the home environment has a significant effect on outcome manifestations. Fifth, a closer look into the changes in molecular and
following early-life TBI (Anderson et al., 2006; Yeates et al., 2010; cellular pathways will aid in testing the notion that specific neuroin-
Wade et al., 2016). Specifically, in a study of 550 SUD patients entered flammatory responses disrupt the neurocircuitry within the reward
in an Alcohol-Drug Program, Felde and colleagues described extrinsic pathway which leads to aberrant neurotransmission such as that asso-
factors such as loss of a parent during childhood and childhood beha- ciated with the dopaminergic system.
vior problems (e.g. truancy, delinquency, vandalism, etc.) as strongly Overall, it is the hope that scientific research into TBI and its link to
associated with a history of TBI (Felde et al., 2006). Likewise, in a study SUD will: 1) help health care providers inform TBI patients about the
of 723 adolescent residents of the Missouri Division of Youth Services, risk for SUDs and 2) promote discoveries that can offer neuroprotection
Perron and Howard found that adolescents with a history of TBI were to this essential neural circuit, the reward pathway.
significantly more likely to have used drugs such as heroin, cocaine or
crack cocaine, marijuana, and ecstasy than those without a history of Acknowledgements
TBI. Adolescents with TBI and SUD were also more likely than those
without to report negative environmental experiences such as being hit The authors acknowledge funding support from the National
by someone, having had someone use a weapon or force against them, Institutes of Health/National Institute on Drug Abuse (NIH/NIDA) P30
and be attacked by someone who was otherwise trying to injure them DA013429-16 (SHR), R01DA046833 01 (SHR), T32 DA007237 (LAC),
(Perron and Howard, 2008). Vaughn et al. also found significantly NIH/National Institute of Neurological Disorders and Stroke (NINDS),
higher reporting of substance use, alcohol or drug abuse or dependence, R01 NS086570-01 (SHR), and the PA-CURE program (Pennsylvania
violent victimization and witnessing violence among adjudicated ado- Department of Health).
lescents with a history of TBI than those without (Vaughn et al., 2014).
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