Biennial Review of Pain

Pain and sleep in post-concussion/mild traumatic brain injury Gilles Lavignea,b,*, Samar Khourya,b,c, Jean-Marc Chaunya,b, Alex Desautelsa,b,d

Abstract Concussion after a force to the head is called mild traumatic brain injury (mTBI). Approximately 1 in 5 patients with mTBI will develop chronic pain (headache and widespread pain, possibly of central origin) and/or sleep problems (insomnia, disordered breathing, periodic limb movements). However, the predisposing mechanisms for chronic pain in patients with mTBI are unknown. Mild traumatic brain injury is a rare model to prospectively assess the risk factors and mechanisms for pain chronification from the injury onset in the absence of pretrauma comorbidity or medication. In the acute phase, headaches and sleep disturbances seem to predict the poorest long-term cognitive and mood outcomes. Although recent studies suggest that certain brain biomarkers and mood alterations (eg, anxiety, depression) contribute, the causality of chronic pain remains unclear. In mTBI patients with pain, poor sleep quality was correlated with fast beta and gamma electroencephalographic activity in frontal, central, and occipital electroencephalographic (EEG) derivations in all sleep stages. Sleep recuperative function seems to be disturbed by persistent wake EEG activity, corroborating patient complaints such as feeling awake when asleep. Pain and sleep management in mTBI is not yet evidence-based. Treatments include cognitive behavioral and light therapies, medications, and continuous positive airway pressure (CPAP) or oral appliances for disordered sleep breathing. Customized approaches are indicated for mTBI, pain, and sleep complaints. Further studies in pediatric, sport, and transportation populations are needed to prevent TBI chronification. Improvements are emerging in biomarker sensitivity and specificity and management strategies for TBI, pain, and sleep comorbidities. Keywords: Pain, Widespread pain, Diffuse pain, Central pain, Sleep, Minor traumatic brain injury, Biomarkers, BDNF genotype, Depression, Anxiety, Hyperarousal, Chronification

1. Introduction 1.1. Definition and indicators Concussion, also called as mild traumatic brain injury (mTBI), is a brain injury that alters brain functioning (http://www.mayoclinic.org/ diseases-conditions/concussion/basics/definition/con-20019272). The debate on whether mTBI is as serious condition as concussion remains unresolved.146 Traumatic brain injury is consequent to sports, work, vehicle, or transportation accidents, as well as assaults in younger persons and falls in the elderly (.75 years). Traumatic brain injury is an acute brain injury resulting from mechanical energy to the head from external physical forces. Classical operational criteria for clinical identification of mTBI include (1) 1 or more of the following: confusion or disorientation, loss of consciousness for 30 minutes or less, posttraumatic amnesia for less than 24 hours, and/or other transient Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article. a

Departments of Medicine Family Medicine/Emergency Medicine and Neurosciences, Universite´ de Montreal, ´ b Research Centre, Trauma Unit and Centre for Advanced Study in Sleep Medicine, Hopital ˆ du Sacre´ Cœur de Montreal, ´ c Department of Anesthesia, McGill University, d Service of Neurologie, Faculty of Medicine, Hopital ˆ du Sacre´ Cœur de Montreal, ´ Canada *Corresponding author. Address: Universite´ de Montreal, ´ CP 6128, succursale Centre-Ville, Montreal, QC H3C 3J7, Canada. Tel.: 514-343-6005. E-mail address: [email protected] (G. Lavigne). PAIN 156 (2015) S75–S85 © 2015 International Association for the Study of Pain http://dx.doi.org/10.1097/j.pain.0000000000000111

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neurological abnormalities such as focal signs, seizure, and intracranial lesion not requiring surgery, (2) Glasgow Coma Scale score of 13 to 15 after 30 minutes after injury or later on presentation for health care. These must not be due to drugs, alcohol, medications, other injuries or treatment for other injuries (eg, systemic injuries, facial injuries, or intubation), other problems (eg, psychological trauma, language barrier, or coexisting medical conditions), or penetrating craniocerebral injury.17,18 A recent systematic literature review reported the following evidence-based indicators for concussion, observed in alert state and with a Glasgow Coma Scale of 13 to 15 after force to the head: (1) disorientation and confusion immediately after injury, (2) impaired body balance within 1 day after injury, (3) slower reaction time and impaired verbal learning and memory within 2 days after injury (Table 1).17 This article focuses on mTBI with a score of 13 to 15 on the Glasgow Coma Scale (where 15 indicates a fully awake person). The Glasgow Coma Scale assesses visual, verbal, and motor responses, with scores inversely related to severity: moderate (9-12) and severe (3-8). A score of 3 or more indicates deep coma or death.18,98

1.2. Public health issues In New Zealand, the TBI incidence is 790 cases per 100,000 persons per year, with predominantly mTBI, and higher incidence in males and rural residents.50 In the United States from 2002 to 2006, an estimated 1.7 million civilians had TBI, with an 11.4% reduction in mortality rate from 1997 to 2007 after awareness and www.painjournalonline.com

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Table 1

Clinical characteristics of concussion related to mild traumatic brain injury. A. Short-term evidence-based indicators of a concussive event after a force to the head (see Ref. 17 for more information) Observed in alert state with a Glasgow Coma Scale of 13-15: Disorientation and confusion immediately after the event Impaired balance (body equilibrium) within 1 d after injury Slower reaction time within 2 d after injury Impaired verbal learning and memory within 2 d after injury Note: Neurologic and cognitive deficits assessed in the 48 h after injury. Although positive findings on computed tomography scan imaging were associated with the above early indicators, their value is debatable, as discussed in the full text B. Clinical signs and symptoms* (most are not yet evidence-based) of a concussion may include Headache or a feeling of pressure in the head Temporary loss of consciousness Confusion or feeling as if in a fog Amnesia surrounding the traumatic event Dizziness or “seeing stars” Ringing in the ears Nausea Vomiting Slurred speech Delayed response to questions Appearing dazed Fatigue * Adapted from http://www.mayoclinic.org/diseases-conditions/concussion/basics/symptoms/con-20019272.

safety campaigns and improved management in sports and warfare.32 Traumatic brain injury became a major concern because of media coverage.40,105,122,138,146 1.3. Pain and sleep chronification in mild traumatic brain injury After mTBI, patients may develop acute or chronic pain and/or sleep problems such as insomnia (difficulty in initiating or maintaining sleep, or waking up earlier than desired), disordered breathing (eg, obstructive sleep apnea: apnea/10 seconds of breathing cessation; hypopnea: shallow breathing with oxygen desaturation), or periodic limb movements (repetitive leg and arm movements). Pain related to spinal cord injury is a serious neurological condition that can be concomitant to TBI, and is not addressed here.51,52 As reviewed below, the mechanisms for predisposition to chronic pain in mTBI are unknown. Based on risk factors for pain chronification (conversion of acute into chronic pain), we consider putative risk factors for pain chronification in mTBI (Table 2).20,71,125,126 Systematic investigations in mTBI populations have provided a rare model to prospectively assess the risk factors and investigate pain chronification mechanisms.

2. Pain and sleep disturbances post-concussion/mild traumatic brain injury 2.1. Acute and chronic headache complaints postconcussion/traumatic brain injury Complaints of acute headache and concomitant poor sleep after TBI are common.12,26,103,143 Complaints of acute and chronic headache are also frequent.12,26,36,48,103,143 Headache prevalence in patients with TBI across 12 studies was 58%, with 51% for chronic pain in civilians (higher in mTBI, at 75%) and 43% in veterans.103 Headache is a frequent complaint in the acute post-TBI period: 40% of patients at our hospital reported headache in the first 6 weeks,

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with impacts on mood and sleep quality.26 At 3 months after mTBI, 15% of patients still complained of headache compared with 2% of patients with minor injury (no brain injury).48 Over a 1-year period post-TBI, a telephone survey revealed that 1/3 of patients with mTBI still reported headache, either new headache or worsening of a preTBI headache (migraine or tension), at 3-, 6-, and 12-month followups.89 The specificity of posttraumatic headache vs the influence of concomitant cognitive and mood consequences remains controversial in complaints of persistent headache.36,44,48,107–109 2.2. Headache and widespread pain after mild traumatic brain injury As described above, headache is the most frequent pain type reported in the hours and days after TBI (Fig. 1). However, over months, headache and widespread neck and shoulder, limb, or back pain seem to become concomitant.17,26,73,79 At 1 month, the TBI-related pain observed in our prospective case–control cohort study was widespread-diffuse: over the lower back or head and neck area (reported frequency of 75% and 25%, respectively) and more rarely the leg and foot. Pain intensity was rated at 49 mm on a 100 mm visual analog scale.73 As described below, centralized pain may emerge with time after any TBI severity.110 The available data do not allow clarifying whether headache is a risk factor for chronic widespread pain or whether it is only concomitant, with a different time course. Central pain onset delay was reported at around 6.6 months (range, 0.5-30), which needs to be confirmed.110 Furthermore, patients with mTBI had more pain than that of patients with moderate or severe TBI, which remains to be confirmed in prospective studies using standardized concussion/TBI diagnostic criteria, and taking into account the lower vigilance state associated with lower Glasgow scores in patients with more severe TBI.12,79,103 2.3. Pain chronification risk due to high initial pain and influence of depression after traumatic brain injury Pain and mood changes after any TBI severity are frequent (Table 3). Patients with mTBI with the lowest pain intensity had a better outcome at 6 months (90% chance of returning to work).132 The risk of developing chronic pain after TBI was almost 6-fold with severe initial pain intensity in mTBI.74 In patients with mTBI with high pain intensity, more emotional aspects were noted (ie, aggressiveness, anxiety, depression, paranoia, and suspicion).146 In moderate-to-severe TBI with pain, the risk for persistent depression at 1 year was approximately 7-fold.133 The transition of acute posttraumatic pain to chronic pain involves complex interactions between neurobiological and psychosocial factors, probably comparable with those for chronic pain in patients with TBI. However, this remains to be established (see section 3 and Table 2).3,20,25,30,31,70,71,80,118,152 2.4. Emergence of centralized pain in traumatic brain injury In patients with moderate-to-severe TBI, 40% had pain onset in the first month and 50% in the 2 to 12 months after TBI, with a mean delay for pain onset of 6.6 months (range, 0.5-30). Chronic pain was described as centralized (ie, dysfunction that affects the brain, brainstem, or spinal cord), mainly located in 1 hemibody and spread over 5 sites. Pain was described as dysesthesia, painful paresthesia, or allodynia, using terms such as pricking, numb, or burning. Thermal quantitative sensory testing revealed significant sensitivity loss.110 In patients with mTBI with chronic headache, quantitative sensory testing

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Table 2

Putative indicators of chronification from acute concussion/mild traumatic brain injury (mTBI) event toward chronic pain (chronification). Indicators for risk of pain chronification (based on cumulative evidence in the literature or opinion-driven) Pre-TBI indicators of chronification History of intense pain (presence of moderate-to-severe pain for more than 1 mo) History of repeated surgery History of repeated head trauma (sport, accident) Psychological vulnerability (eg, mood, anxiety, catastrophizing) Pretrauma anxiety Pretrauma depressive mood History of alcohol or drug abuse/ misuse Female gender Younger adult age Working compensation Genetic predisposition Dysfunctional pain modulation Hyperarousal/hypervigilance in wake time or sleep arousal History of insomnia Post-TBI indicators of chronification Trauma-related brain damage: inflammation, diffuse axonal injury, ischemia, synaptic loss, etc Postinjury circadian phase delay Postinjury depression Rise in psychological vulnerability Rise in postinjury anxiety Short-term or long-term neuropsychiatric impairments

mTBI and pain

Strength of the evidence

11

Strong

? 1

Low Low-to-moderate

1

Moderate

1 1 suggested

Moderate Moderate ?

1/? 11 ?/dogma 1 1 1 in sleep

Debatable Strong ? Moderate Experimental Low-to-moderate

1

Low-to-moderate

1 Brain insult

Moderate specificity?

1 11 1 11 11

Moderate Moderate Moderate Moderate Moderate*

* Hypervigilance/hyperarousal and posttraumatic stress disorder, and at the extreme: dementia pugilistica, chronic encephalopathy, and pugilistic parkinsonism.

performed 1 to 31 years after trauma confirmed sensitivity loss in cranial afferent but not forehand sites. Results on the reduced pain adaptation and dysfunctional pain modulation (described below) in patients with TBI further support a central pain origin.38 In the mTBI case–control prospective study by our group, no pain sensory abnormalities in thermal cold or heat difference on quantitative pain testing of the limb area was observed at 1 month.73,75 These inconsistent results may be due to time lags for pain assessments (ie, 1 month vs years)38,73 and differing TBI severity (mild, moderate-to-severe).110 2.5. Dysfunctional pain modulation mechanisms in traumatic brain injury In complaints of post-TBI headache or pain, dysfunctional pain modulation mechanisms (ie, no expectations of improvement under conditioned pain modulation testing) are thought to explain persistent pain.36–38 However, these findings should be reproduced in further laboratory studies. Pain onset and persistence in patients with TBI could also be due to the combined effect of several mechanisms: (1) centralized pain buildup due to brain insult (Table 2, Fig. 2, and section 3.1),37,110 (2) dysfunctional pain input modulation to reduce ascending sensory information to the central nervous system (CNS), or reduced activation or descending pain inhibition,37,38 (3) alterations in the midbrain periaqueductal gray (PAG) matter, cuneus, and prefrontal cortex after TBI insult, the prefrontal cortex being prominently involved in

cognition and pain perception and modulation (see section 3.2),4,58,131,139 or (4) cognitive, mood, or sleep–wake disturbances (SWCs), as described in the next section. Furthermore, it is unknown whether the initial headache that is frequent in mTBI triggers widespread pain or, as suggested above, whether it is followed by the emergence of centralized pain. Note that only 2% to 3% of our patients sample without initial pain developed new pain at 1 year follow-up.74 It remains to be demonstrated whether centralized pain is consequent to other non–pain-specific changes in the brain due to TBI (ie, widespread disruption of neural network/default node network) or whether there is a causal and temporal sequence.142 2.6. Sleep disturbances and insomnia after mild traumatic brain injury Sleep–wake disturbances are frequently reported by patients with TBI.10,72,130 Sleep–wake disturbances is defined as the presence of excessive daytime sleepiness, fatigue, and pleisomnia (ie, increased need for sleep/24-hours period), and can become chronic. After 3 years, almost 70% of patients with TBI presented SWD, with 33% fatigue and 10% insomnia or excessive daytime sleepiness. In this model, insomnia was not independent of depression.72 Based on community and sleep laboratory studies, it is difficult to accurately isolate the contribution of pain, anxiety, and depression to poor sleep quality in patients with TBI. A recent

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Figure 1. Mild traumatic brain injury/concussion and pain sequence. Figure 2. Single or repetitive traumatic brain injury.

community-based study in mild-to-severe TBI suggests that the contribution of pain, anxiety, and depression should be assessed before managing poor sleep (see section 4).116 More intense pain was associated with greater anxiety and depression. Furthermore, greater anxiety and depression, assessed with rating scales, were associated with greater daytime sleepiness, poorer sleep quality, and more naps in TBI vs controls. Regression analysis revealed that pain and anxiety, but not depression, accounted for 32% of the sleep quality variance (assessed with the Pittsburgh Sleep Quality Index—PSQI). Conversely, in our sleep laboratory study of mTBI vs controls, depression mainly explained poor sleep quality (PSQI) over ratings of pain intensity, pain catastrophizing, and anxiety (Beck).73 Others found that sleep disturbances in the acute TBI phase predicted persistent anxiety, depression, and apathy at 12 months.119 However, given the limited sample sizes and certain methodological shortcomings of these TBI studies, we cannot exclude or clarify various influences on mood variables (anxiety and depression) in the pain–sleep interaction in TBI.78,90,98 Because altered circadian rhythm may also exacerbate SWD in mild-to-severe TBI,7,10,23,46 other sleep disorders should be identified. More than 40% of patients with mild-to-severe TBI Table 3

Possible pretrauma vulnerability and post-concussion/ traumatic brain injury consequences in persons with concomitant pain and sleep complaints. Pretrauma vulnerability (V) and posttrauma cognitive consequences (C) Mood (depression, anxiety) (V and C) Memory alteration (C) Sensory impairments and chronic pain (V and C) Circadian cycle misalignment—phase delay (C) Sleep disturbances and chronic insomnia (V and C) Drug or medication misuse or abuse (V and C) Hypervigilance/hyperarousal (indirect evidence from sleep medicine studies) (V and C) Hypothalamic-pituitary-adrenal (HPA) axis dysfunction (higher risk if repetitive head contact; not present or debatable in mild traumatic brain injury) (C) Posttraumatic stress disorders (PTSD; intersecting incidence or comorbidity; debatable) (C) Long-term Dementia pugilistica (C) Chronic traumatic encephalopathy (C) Pugilistic parkinsonism (C) (higher risk if repeated head contact)

present several sleep disorders.23,24,93,112,143 Insomnia (ie, difficulty in initiating or maintaining sleep, or waking up earlier than desired) is reported by 25% to 50% of patients with TBI, with more awakenings and sleep disruptions. Again, the role of depression in insomnia cannot be excluded.12,113,114,143 In sleep medicine, insomnia is a state of frequent hyperarousal; in pain medicine, pain is a proxy for hypervigilance.13,80,95,111,135,136 Other sleep disorders associated with TBI are obstructive apnea–hypopnea syndrome (approximately 25% of patients; definition given in section 1.3), with 10% or less having posttraumatic hypersomnia (excessive sleep), periodic limb movement disorder, or narcolepsy (overwhelming drowsiness and sudden attacks of sleep during wake periods). More rarely, increased muscle tone in REM sleep has been reported, as seen in REM sleep behavior disorder (RBD), a neurological condition with the absence of muscle hypotonia in REM sleep and with dreamenacted movements.22,55,143 Further studies are needed to unravel the role of pain in sleep quality and the role of sleep quality in pain, alone or in interaction with other TBI consequences (eg, mood and cognitive functions).81,84,85 Despite the complex interplay between the influence of depression and mood on sleep and pain, separately or in combination, the interactions between mood, pain, and sleep and various treatments that target any of these have not been satisfactorily interpreted.85 In patients with chronic pain, presleep arousal, but not pain, seems to strongly predict sleep quality.135 Some treatments may be either concordant or have opposite effects on sleep or pain outcomes.45 Systematic studies using robust analytical methods are needed to identify the variance and impact of risk factors for TBI and its consequences before treatment guidelines can be developed.17,152

3. Pathophysiology of the pain–sleep interaction in mild traumatic brain injury 3.1. Changes in cerebral cellular activity, biomarkers, and gene expression related to the pain–sleep interaction in mild traumatic brain injury A limited number of cellular pathways have been described in the CNS and the serum or cerebral fluid biomarkers associated with the short-term and long-term consequences of TBI (see Fig. 2 and Table 4). Traditionally, TBI was thought to result from brain injury by

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rapid rotational acceleration, with or without impact, whereby the rotational force induces stretching of the white matter axons. The suggested cerebral damage cascade is: 1. Diffuse axonal injury and shear, efflux of K1/influx of Na1/rise in cellular Ca11, swelling (rise in interleukin 6, 8, and 10 in severe TBI), ischemia/hypoxia, synaptic loss. 2. Acute neuronal and astroglia injury and dysfunctions. 3. Impaired axonal transport and/or neuronal circuit disruption. 4. Edema, accumulation of abnormal protein aggregates, myeloid-related process, biomarkers expression. 5. Neurofibrillary tangles.39,154 Previously, a short-term sequence of alterations in the minute to hour to day range after brain injury was suggested. An update of the short-term time course of cellular events after TBI would be welcome.53 Proposed long-term consequences of single and repeated TBI, as in high impact risk sports, may include the development of dementia pugilistica, chronic traumatic encephalopathy (CTE), and pugilistic parkinsonism (Table 3). Whether these consequences actually arise remains debatable; however, to the best of our knowledge, these risks are not present with chronic pain alone.34,39,146,154 The link between TBI and lack of sleep is instructive. As described above in section 2.6, approximately 40% of patients with TBI reported pleisomnia, with excessive daytime sleepiness (a symptom) and posttraumatic hypersomnia (a diagnostic entity). This was associated with hypocretin (Hcrt; orexin) reduction; Hcrt is a neuropeptide essential for maintaining consolidated sleep/ wake states.10,11,130 No single gene can explain the complex interrelations between the risk factors and causes in TBI-related behavioral and cognitive changes, pain, and poor sleep chronification. Gene ontology involves multiple mechanisms and systems, including cellular homeostasis, ionic transport, synaptic transmission, regulation of biological and system processes up to local inflammatory responses, neuronal activity, and behaviors possibly associated

Table 4

Genetic and protein expression candidates in traumatic brain injury (TBI). Apolipoprotein E—APOE (action through inflammatory and cellular repair processes and/or amyloid deposition; higher risk if repeated head contact; role in sleep apnea, Alzheimer’s, etc; link to worst TBI prognosis) *Brain-derived neurotrophic factor—BDNF (role in synaptic plasticity and neuroprotection in inhibiting activation of caspase-3, reducing translocation of apoptosis-inducing factor; attenuates excitotoxicity of glutamate and increases antioxidant enzyme activity; relevance in learning, PTSD, pain, etc) Ephrin ligands—EphA4 (activated astrocyte-glial cells that inhibit axonal regeneration) Glial fibrillary acidic protein—GFAP (repair role after central nervous system injury; high prognostic value) Hypocretin/orexin—Hcrt (regulates arousal and wakefulness; may contribute to excessive sleepiness after TBI) S100B—(calcium-binding protein with neuronal apoptosis potential; biomarker in severe TBI; overly sensitive to extracranial injury; less specific to TBI) Tyrosine kinase receptor B—TrkB (BDNF/NT-3 growth factors receptor; transfers phosphate from ATP to intracellular proteins) *Ubiquitine—UCH-L1 (role in removing excessive, oxidized, or misfolded proteins; potential marker of worst prognostic; not specific) *Tau (interferes with cognition and the sleep–wake cycle; role as a signal of axonal damage; putative role in TBI by formation of neurofibrillary tangles; rapid rise in boxer/4-10 d after trauma; may indicate poor prognosis) Y enolase—NSE (glycolytic enzyme; unknown whether process is specific to TBI) *Putative role in mTBI.

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with pain and sleep disturbances.62,88,100 Table 4 presents the findings of recent studies demonstrating changes in the expression of a few biomarkers (eg, APOE, TrkB, S100B, GFAP, BDNF, UCH-L1, Tau, Y enolase) in the blood or cerebrospinal fluid (CSF) of patients with TBI.39,42,49,69,127,154 Except for the brain-derived neurotrophic factor (BDNF), suggested to be expressed in both posttraumatic stress disorder (PTSD) and TBI,69 none of these biomarkers have been specifically associated with mTBI, chronic pain, or poor sleep. BDNF is important for synaptic plasticity, and as presented in Table 4, is most likely involved in neuroprotection by inhibiting caspase-3 activation, reducing translocation of the apoptosisinducing factor, attenuating glutamate excitotoxicity, and increasing antioxidant enzyme activity. More recently, the expression of BDNF genetic variation (single-nucleotide polymorphisms rs6265 [val66met] and rs7124442 [T.C]) in elderly patients with severe TBI was associated with a lower survival probability.47 These findings in a severe TBI population have not been determined as directly relevant to mTBI or associated chronification of acute-phase mood or sensory complaints. Although some evidence supports the role of BDNF in the pain–sleep interaction in TBI, BDNF is probably neither a unique nor specific candidate. Animal and human studies have demonstrated many putative roles and functions for BDNF: (1) BDNF is a critical molecule in the rat spinal cord microglia and neuron in neuropathic pain onset and chronification,33,96 and may also contribute to opiate analgesia in the parabrachio-amygdaloid pathway in mice.124 (2) The mouse BDNF Met/Met allele variant has been suggested as dominant in predisposition to anxiety and depression.28 (3) After an experimental sleep deprivation protocol, human BDNF Val/Val homozygote subjects had better sleep memory recovery than Met allele carriers and presented more deep sleep (slow wave electroencephalographic activity) than Val-Met genotype carriers.8,63 Studies have also linked BDNF to cognitive and general intelligence performance, slower processing and memory during post-TBI recovery.94,121 However, BDNF function specificity has yet to be demonstrated as a marker or management tool for TBI. Could BDNF Met/Val predispose to cognitive and learning problems, with greater risk for developing chronic pain? This question remains unanswered for pain in TBI because learning remains a putative process in pain chronification and brain plasticity.3,35,91,92,94,101 Our group found that patients with mTBI who expressed the BDNF Val/Val allele had greater risk for chronic pain at 1-year follow-up than did patients carrying the Met genotype.74 The significance of this finding, based on a single-nucleotide polymorphism (SNP) in a small sample of highly selected subjects, remains to be determined for the TBI phenotype. 3.2. Cerebral sites in traumatic brain injury dysfunction In a provocative hypothesis-driven review, based mainly on animal findings, PTSD and TBI were suggested to be associated with brain neuroplasticity of the frontal and cingulated cortex (with the participation of BDNF) projecting to the hippocampus and basolateral amygdala, and indirectly to the hypothalamus.69 In a human psychophysiological functional magnetic resonance imaging (fMRI) study, patients with mTBI reporting severe pain presented reduced mid-dorsolateral prefrontal cortex (midDLPFC) activation during a working memory task and lower cognitive performance compared with sport injury patients with pain, who showed higher activation in the mid-DLPFC and no correlation with cognitive performance.58 This suggests that behavioral performance and cerebral functioning are affected by pain after mTBI. Other areas of interest are the midbrain PAG, the

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cuneus, and the right dorsolateral prefrontal cortex, which were activated with pain anticipation in nondepressed mTBI subjects. This suggests that post-TBI cellular (Fig. 2) and CNS network disturbances may contribute to negatively modulate the natural and functional endogenous regulatory pain processes.38,131 Cognitive function, behavior, and brain imaging studies could investigate associations between TBI, biomarkers, chronic pain, and sleep to further characterize the mTBI phenotype.3,4,142 For more putative relationships to TBI (eg, endophenotype characterization), see Tracey’s work on the prefrontal cortex role in pain, analgesia, emotion, etc.139,140 3.3. Electroencephalography in the pain–sleep interaction in mild traumatic brain injury Although wake electroencephalography (EEG) is suboptimal for TBI diagnosis or prognostic assessment, it is useful for research purposes.54,99,117 Electroencephalography assesses indirect brain activity in experimental or clinical protocols, whereas laser-evoked potentials, experimental pain stimulation, and related arousal responses or sleep activity can deepen the understanding of the pain–sleep interaction in chronic widespread patients with pain.9,82,86 Most mTBI investigations did not correlate sleep complaints with either sleep macrostructure (eg, sleep stage duration and distribution) or the usual EEG spectral analysis using 30-second sleep stage scoring and 4-second EEG analysis epochs, respectively. Moreover, most TBI sleep studies were unable to isolate sleep from the influences of mood or insomnia problems.73,114,119 However, quantitative EEG (qEEG, performed using fast Fourier transform analysis of EEG signals with a 1 minute temporal resolution regardless of sleep stage and with artifact removal) better corroborated sleep complaints that were otherwise unobservable using sleep macrostructure measures: patients with TBI showed more beta and gamma EEG activity in the frontal cortical area.73 In an EEG data reanalysis in mTBI and sports injury patients, we found that, because of potential endophenotype differences, beta EEG at the occipital EEG derivation was a dominant feature of nonREM sleep compared with agematched controls.59,73 However, EEG activity and subjective poor sleep complaints were uncorrelated after controlling for concurrent anxiety and pain (Arbour C, et al, Sleep Medicine, in press) In patients with post-TBI pain, beta and gamma EEG activity were dominant in all sleep stages over the frontal, central, and occipital EEG derivations. These findings corroborate a small-sample EEG analysis in mTBI, suggesting high intrasubject variability in sigma.149 Perception of sleep recuperative function seems to be disturbed by persistent wake-related EEG activity, and pain seems to be an exacerbating covariable. Persistent high EEG activity in some patients with TBI with poor sleep recovery73 plus the observation that patients with TBI with excessive daytime sleepiness (Epworth Sleepiness Scale $10) presented cortex hypoexcitability after transcranial magnetic stimulation further suggest that sleep disturbances and daytime carryover influences merit greater attention in the understanding of the daytime cognitive consequences of mild-to-moderate TBI.46,58,104

4. Clinical recognition of pain and sleep disorders in patients with mild traumatic brain injury 4.1. Complaints and related assessment tools First days and weeks: The most frequent complaints are rapid headache onset, altered recent memory, poor sleep quality, and mood problems (Tables 1 and 3; Fig. 1).26,59

Mid-term and long-term consequences (3 and 12 months, respectively) include: 1. Pain and/or headache assessed with tools such as the Brief Pain Inventory, Pain Map, and visual analog scale to rate intensity.83,153 2. Circadian rhythm misalignment (mismatch between the endogenous clock and the external environment regarding sleep timing and duration) assessed using actigraphy and other methods.2,7,83 3. Unusual mood alterations, personality changes, or irritability assessed by interview. 4. Signs and symptoms of depression, measured with the Beck Depression Inventory or similar questionnaire or DSM 5 criteria.73,129,151 5. Sleep impairment or disturbances assessed with the Pittsburgh Sleep Quality Index (PSQI) or other sleep inventory to screen for insomnia, breathing disorders, and periodic limb movements (Insomnia Severity Index, Berlin Sleep Apnea). Further confirmation by home or sleep laboratory recordings may be useful.15,73,82,83,102 6. Severity and prognosis of headache and pain, altered memory, altered reasoning, impaired communication, inappropriate social behaviors, etc, should also be clinically assessed.17,150,151 4.2. Health consequences and prevention Table 3 presents several short-term and long-term health consequences of TBI. In the short term, PTSD as well as hypervigilance and sleep and mood disorders may be concomitant to TBI. BDNF is a candidate gene for modulating these associations.69 Dementia pugilistica, CTE, and pugilistic Parkinsonism are proposed long-term consequences of repetitive TBI, and are therefore serious research and public health concerns.39,40,154 Recently, a Swedish national cohort study found a very high longterm health risk (HR . 50) for young-onset dementia associated with TBI of varying severity.106 Many CNS alterations can be associated (or not) with genetic vulnerability for protein expression and neuropathological changes. Associations between TBI and neurological consequences need to be examined with valid tools.17,39,41,78,127 Crucially, a recent review of sport injuries highlighted the lack of a specific causal link with the long-term risk of dementia.146 It is critical to improve prevention and reduce brain injury in sport, transportation, and work environments.146 Improved methods to prevent or mitigate head impacts in sport need to be developed and better applied.125,137,146 Helmets can prevent head and face injuries and reduce brain injuries, but greater effectiveness in reducing TBI CNS insults is needed.56,87 4.3. Imaging, electroencephalography, and traumatic brain injury Functional and anatomical imagings as well as EEG are used for clinical TBI diagnosis and prognosis and in research. However, the available methods are suboptimal, being costly as well as insufficiently sensitive and/or specific.18,19,39,41,42,65,73,77 Currently, the strongest outcome predictors are age (for extracranial injuries) and day-of-injury alcohol intoxication.66 It remains debatable whether computed tomographic scanning (CT scanning) is helpful for prognosis. However, in the clinical context of acute TBI, CT scans are routinely used to exclude brain hematoma and skull fracture.117,146 Although a growing

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body of research addresses the clinical use of diffusion tensor imaging, it is not the focus of this article. 4.4. Lack of standardization, evidence-based criteria, and indicators for traumatic brain injury diagnosis Unfortunately, most TBI studies on causes and risk factors, diagnosis, outcome prediction, mechanisms, and clinical trials include considerable methodological limitations, even 10 years after a World Health Organization task force consensus to improve standardization.17,18,78,90,98 Future TBI studies should focus on evidence-based diagnostic criteria and prognostic indicators, and they should validate the specificity of imaging, serum, and CFS biomarkers.17 Caution should therefore be taken in translating experimental or clinical results into daily practice.

5. Managing traumatic brain injury patients with pain and sleep conditions The management of mTBI symptoms per se is not yet strongly supported by evidence-based data (Table 5 and section 5.3 below).1,41 In a recent literature review of pharmacological treatments for various trauma types (orthopedic, thoracic, burn, spinal cord, TBI), we found little evidence on TBI-specific symptom treatments.60,118 Therefore, it is not surprising that 84% of pediatricians reported using nonguideline approaches to manage concussion in children and adolescents.76 Clinicians managing pain and/or sleep problems in patients with TBI should be aware that most medications used are off-label. Traumatic brain injury research on biomarkers offers new avenues for drug development, and clinicians should cross-reference pain and sleep disturbance management methods.10,41,118 5.1. Understanding temporal progression and prognosis in traumatic brain injury The temporal progression from injury to pathological changes after brain insult involves minutes, hours, and days. Currently, no links between therapy and temporal changes have been proposed to guide clinicians on the best preventive or palliative interventions.41,53,145,154 Hopefully, most patients with mTBI will recover within 6 to 12 weeks or 3 to 6 months after mTBI. Approximately 15% of patients present more severe cognitive, mood, pain, sleep, or wake disturbances after 1 year. Pain was present in almost 70% of our mTBI population (note a possible referral bias in our pain center) at the first assessment in the weeks after trauma, and persisted at moderate intensity in more than 50% at 1 year. As mentioned above (section 2.3), the greater the initial pain intensity, the greater the odds for pain chronification.74 Moreover, as described above, the odds for returning to work were 2.3 greater (ie, 90% more chance) when initial postinjury pain was absent compared with the presence of severe pain.132 Sleep problems and fatigue persist in 2 of 3 patients with TBI after 3 years. In 45% of cases, these conditions are associated with the trauma, not comorbidities.72 Adequate control of pain symptoms seems to better predict sleep quality outcomes over the first year after moderate-to-severe TBI.27 5.2. Overview of pain and sleep disorder management in patients with traumatic brain injury Table 5 presents the usual but non–evidence-based approaches in acute and chronic TBI phases.29,97 To summarize, these include:

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Table 5

Management of post-concussion/mild traumatic brain injury pain and sleep complaints/disorders (lack of direct evidence for traumatic brain injury). Acute phase Non–evidence-based use: acetaminophen, omega 3, melatonin (to restore circadian misalignment or promote neuroprotection) Plus: Control for concomitant anxiety, depression, pain, and related drug abuse or misuse (refer to psychiatry, psychology if too problematic) Exclude sleep comorbid apnea, limb movements, insomnia, narcolepsy (refer to sleep laboratory if too severe) Under phase 2 or 3 trials (see reference from R Diaz-Arristia 2014): central acetylcholinesterase inhibitors, huperzine A, CNS stimulants, HMG-CoA reductase inhibitors, N-acetyl plus amantadine, cyclosporine A, growth hormones, progesterone, and melatonin Chronic phase Cognitive and behavioural counseling and therapy (refer to a psychologist, neuropsychologist for more effective management) Medications for pain and sleep (off-label for mTBI) Mechanical pain Nonsteroidal anti-inflammatory drug Muscle relaxant Neuropathic/atypical pain Anticonvulsant Tricyclic antidepressant Serotonin reuptake inhibitor Insomnia (also see below) Sedative-hypnotics or H1 receptor specific antagonist Low-dose serotonin reuptake inhibitor Antidepressive/mood and sleep promoters: amitriptyline, duloxetine, or milnacipran For excessive daytime sleepiness unsuccessfully treated with the usual sleep and CBTs, psychostimulants can be used under close medical supervision If sleep breathing disorder (eg, obstructive sleep apnea) is present or suspected, refer to a sleep laboratory for assessment and management Respiratory devices such as a CPAP (continuous positive airway pressure device) or mandibular advancement oral appliance Note: Avoid opioids and benzodiazepines before or during sleep if sleep apnea is suspected; possible aggravation of central sleep apnea If insomnia (eg, delayed sleep onset by 20-30 min or difficulty resuming sleep after sudden awakening during sleep period) is concomitant, first consider CBT and medication for the transition period: benefits decrease over time If periodic limb movements (eg, leg or arm movements inducing sleep fragmentation) during sleep interfere with sleep: dopaminergic agonists, calcium channel alpha-2-delta subunit agonist, or hypnotics could be tried CBT, cognitive behavioral therapy.

1. Cognitive behavioral therapy (CBT) to help recover good sleep hygiene and improve concomitant insomnia115; and hybrid treatments, or a combination of CBT for pain and sleep, proposed as better than unimodal CBT to modify misperceptions, misbelieves, or excessive expectations about pain relief and poor sleep improvement.115,134,144 2. Although melatonin and light therapy have little supporting and even inconsistent evidence for use in TBI, they may improve the circadian misalignment found in approximately 1 in 3 patients with TBI, suggesting a phenotype-driven effect.7,14,148 Based on animal findings, melatonin could be an avenue of interest in acute phase treatments for humans with circadian and sleep complaints.43,128 However, the neuroprotective effect of melatonin remains to be demonstrated in humans.141 3. For sleep and pain management, off-label medications are used to treat the TBI–pain–sleep interaction, including analgesics and muscle relaxants as well as hypnotics and

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sedatives for short (2- to 3-week) periods. Antidepressants can be used to improve mood alterations. 4. If periodic limb movements (eg, repetitive leg or arm movements) during sleep are suspected to contribute to sleep complaints in a patient with TBI, an initial PSG confirmation should be performed. If their role in sleep fragmentation is confirmed (index .10/h of sleep), a trial of dopaminergic agonist, calcium channel alpha-2-delta subunit agonist (eg, pregabalin or gabapentin) or hypnotic can be initiated.6,21,64 5. For obstructive sleep breathing disorders (eg, obstructive sleep apnea syndrome breathing cessation for 10 seconds with 4% oxygen desaturation), the usual treatments include a continuous positive airway pressure (CPAP) or mandibular advancement oral appliance.5,21,57 Note: Prescribing opioids or benzodiazepines runs the risk of more centralized sleep apnea. In such cases, advanced device technologies need to be prescribed (eg, automatic servoventilation).16,61,67,120 6. In patients with TBI where excessive sleepiness is not due to mood disorders or nocturnal sleep disorders such as sleep breathing, psychostimulants can be used under close medical supervision.21,68 5.3. Lack of evidence-based treatments for traumatic brain injury No guidelines have emerged for treating TBI. Most pharmaceutical tools are in the experimental stage, including central acethylcholinesterase inhibitors, huperzine A, CNS stimulants, HMG-CoA reductase inhibitors, N-acetyl plus amantadine, cyclosporine A, growth hormones, progesterone, and melatonin.1,10,41,150 In this emerging field, advances are needed so that the acute state can be managed before chronic post-concussion/ TBI consequences arise.

6. Conclusions and future directions Although mTBI has low incidence, it has high impact on the entire population, from children to the elderly. Traumatic brain injury is a major consequence of sport and transportation accidents, assault, and falls. The acute consequences, including headache, pain, and altered cognition or mood, are largely reversible. Nevertheless, they greatly affect quality of life and daily functioning, with potential long-term effects on cognition, mood, and sleep as well as pain or headache in at least 15% of patients. Single and/or repetitive TBI-related brain insults should be prevented because of the long-term risks, including dementia pugilistica, CTE, and pugilistic parkinsonism, although the causal relationship is debatable. More connections between TBI and spinal cord injury prevention (safety programs and campaigns, harm-reduction devices) and management could fuel innovations in the TBI field. Future studies should focus on TBI in children and people of all ages who suffer transportation and sport injuries. Other valuable avenues include the development of mechanical aids to reduce brain insult by reducing rotational–acceleration– deceleration impacts on cerebral tissue, the identification of better predictive biomarkers, improvements in diagnostic methods, and the production of evidence-based management guidelines to help clinicians manage the acute consequences of TBI on cognition, pain, sleep, and mood, with special attention paid to preventing chronification and the long-term risk of trauma-related dementia.

Conflict of interest statement The authors have no conflicts of interest to declare. The first author (GL) holds a Canada Research Chair in Pain, Sleep and Trauma. The author’s projects cited in this review were funded by the Fonds de Recherche du Quebec—Sant ´ e/Quebec ´ Pain Research Network partnership and the Ronald Denis Trauma Foundation, Montreal, Canada.

Acknowledgements The authors thank Margaret McKyes for English editing. Article history: Received 2 September 2014 Received in revised form 11 January 2015 Accepted 22 January 2015

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