Improving physical movement during stroke rehabilitation: investigating associations between sleep measured by wearable actigraphy technology, fatigue, and key biomarkers.

BACKGROUND: Sleep disturbance and fatigue are common in individuals undergoing inpatient rehabilitation following stroke. Understanding the relationships between sleep, fatigue, motor performance, and key biomarkers of inflammation and neuroplasticity could provide valuable insight into stroke recovery, possibly leading to personalized rehabilitation strategies. This study aimed to investigate the influence of sleep quality on motor function following stroke utilizing wearable technology to obtain objective sleep measurements. Additionally, we aimed to determine if there were relationships between sleep, fatigue, and motor function. Lastly, the study aimed to determine if salivary biomarkers of stress, inflammation, and neuroplasticity were associated with motor function or fatigue post-stroke. METHODS: Eighteen individuals who experienced a stroke and were undergoing inpatient rehabilitation participated in a cross-sectional observational study. Following consent, participants completed questionnaires to assess sleep patterns, fatigue, and quality of life. Objective sleep was measured throughout one night using the wearable Philips Actiwatch. Upper limb motor performance was assessed on the following day and saliva was collected for biomarker analysis. Correlation analyses were performed to assess the relationships between variables. RESULTS: Participants reported poor sleep quality, frequent awakenings, and difficulties falling asleep following stroke. We identified a significant negative relationship between fatigue severity and both sleep quality (r=-0.539, p = 0.021) and participants experience of awakening from sleep (r=-0.656, p = 0.003). A significant positive relationship was found between grip strength on the non-hemiplegic limb and salivary gene expression of Brain-derived Neurotrophic Factor (r = 0.606, p = 0.028), as well as a significant negative relationship between grip strength on the hemiplegic side and salivary gene expression of C-reactive Protein (r=-0.556, p = 0.048). CONCLUSION: The findings of this study emphasize the importance of considering sleep quality, fatigue, and biomarkers in stroke rehabilitation to optimize recovery and that interventions may need to be tailored to the individual. Future longitudinal studies are required to explore these relationships over time. Integrating wearable technology for sleep and biomarker analysis can enhance monitoring and prediction of outcomes following stroke, ultimately improving rehabilitation strategies and patient outcomes.

Leukocyte telomere length in multiple sclerosis: relationship between disability severity and pregnancy history.

BACKGROUND: Aging-related processes contribute to neurodegeneration and disability in multiple sclerosis (MS). Biomarkers of biological aging such as leukocyte telomere length (LTL) could help personalise prognosis. Pregnancy has been shown to be protective against disability accumulation in women with MS, though it is unclear if this effect relates to aging mechanisms or LTL. OBJECTIVES: This study aimed to cross-sectionally characterise LTL in a cohort of individuals with MS, and to correlate LTL with disability severity and pregnancy history. METHODS: We extracted DNA from the whole blood of 501 people with MS in Melbourne, Australia. Expanded Disability Status Scale (EDSS) score and demographic data, as well as pregnancy history for 197 females, were obtained at sample collection. Additional data were extracted from the MSBase Registry. LTL was determined in base pairs (bp) using real-time quantitative polymerase chain reaction. RESULTS: A relationship between EDSS score and shorter LTL was robust to multivariable adjustment for demographic and clinical factors including chronological age, with an adjusted LTL reduction per 1.0 increase in EDSS of 97.1 bp (95 % CI = 9.7-184.5 bp, p = 0.030). Adjusted mediation analysis found chronological age accounted for 33.6 % of the relationship between LTL and EDSS score (p = 0.018). In females with pregnancy data, history of pregnancy was associated with older age (median 49.7 vs 33.0 years, p < 0.001). There were no significant relationships between adjusted LTL and any history of pregnancy (LTL increase of 65.3 bp, 95 % CI = -471.0-601.5 bp, p = 0.81) or number of completed pregnancies (LTL increase of 14.6 bp per pregnancy, 95 % CI = -170.3-199.6 bp, p = 0.87). CONCLUSIONS: The correlation between LTL and disability independent of chronological age and other factors points to a link between neurological reserve in MS and biological aging, and a potential research target for pathophysiological and therapeutic mechanisms. Although LTL did not significantly differ by pregnancy history, longitudinal analyses could help identify interactions with prospectively captured pregnancy effects.

Investigating the Association Between Extended Participation in Collision Sports and Fluid Biomarkers Among Masters Athletes.

Traumatic brain injuries (TBIs) and concussions are prevalent in collision sports, and there is evidence that levels of exposure to such sports may increase the risk of neurological abnormalities. Elevated levels of fluid-based biomarkers have been observed after concussions or among athletes with a history of participating in collision sports, and certain biomarkers exhibit sensitivity toward neurodegeneration. This study investigated a cohort of 28 male amateur athletes competing in "Masters" competitions for persons >35 years of age. The primary objective of this study was to compare the levels of blood and saliva biomarkers associated with brain injury, inflammation, aging, and neurodegeneration between athletes with an extensive history of collision sport participation (i.e., median = 27 years; interquartile range = 18-44, minimum = 8) and those with no history. Plasma proteins associated with neural damage and neurodegeneration were measured using Simoa® assays, and saliva was analyzed for markers associated with inflammation and telomere length using quantitative real-time polymerase chain reaction. There were no significant differences between collision and non-collision sport athletes for plasma levels of glial fibrillary acidic protein, neurofilament light, ubiquitin C-terminal hydrolase L1, tau, tau phosphorylated at threonine 181, and brain-derived neurotrophic factor. Moreover, salivary levels of genes associated with inflammation and telomere length were similar between groups. There were no significant differences between groups in symptom frequency or severity on the Sport Concussion Assessment Tool-5th Edition. Overall, these findings provide preliminary evidence that biomarkers associated with neural tissue damage, neurodegeneration, and inflammation may not exhibit significant alterations in asymptomatic amateur athletes with an extensive history of amateur collision sport participation.

Gene expression changes in the cerebellum are associated with persistent post-injury pain in adolescent rats exposed to early life stress.

Chronic pain develops following injury in approximately 20% of adolescents, at twice the rate in females than males. Adverse childhood experiences also increase the risk for poor health outcomes, such as chronic pain. Emerging literature suggests the cerebellum to be involved in pain processing, however detailed explorations into how the cerebellum contributes to pain are lacking. Therefore, this study aimed to characterise chronic pain outcomes and cerebellar gene expression changes following early life stress and injury in both sexes. The adverse childhood experience of neglect was modelled using a maternal separation (MS) paradigm, which was combined with a subsequent injury (mild traumatic brain injury (mTBI) or plantar incision surgery) in adolescent male and female Sprague-Dawley rats. We measured behavioural nociceptive sensitivity, systemic modulators of pain such as calcitonin gene-related protein (CGRP) and Substance P, as well as gene expression of IL1ß, GFAP, GR, MR, GABRA1, CNR1, MAOA, and DAT1 in the cerebellum to examine associations between pain and neuroinflammation, the stress response, inhibitory neurotransmission, and monoaminergic function. We found increases in mechanical nociceptive sensitivity following plantar incision surgery. Sex differences were observed in anxiety-like behaviour and neuroinflammation, whereas systemic pain modulators showed cumulative effects with the addition of stressors. Most interestingly however, the increases in nociceptive sensitivity were associated with the suppressed expression of cerebellar genes that regulate stress, inhibition, cannabinoid function, and dopaminergic function, alongside sex-dependent distinctions for genes involved in inflammation and injury. This study highlights a novel link between nociception and molecular function in the cerebellum. Further investigation into how the cerebellum contributes to pain in males and females will facilitate novel therapeutic insights and opportunities.

Gut instinct: Sex differences in the gut microbiome are associated with changes in adolescent nociception following maternal separation in rats.

Adolescent chronic pain is a growing public health epidemic. Our understanding of its etiology is limited; however, several factors can increase susceptibility, often developing in response to an acute pain trigger such as a surgical procedure or mild traumatic brain injury (mTBI), or an adverse childhood experience (ACE). Additionally, the prevalence and manifestation of chronic pain is sexually dimorphic, with double the rates in females than males. Despite this, the majority of pre-clinical pain research focuses on males, leaving a gap in mechanistic understanding for females. Given that emerging evidence has linked the gut microbiome and the brain-gut-immune axis to various pain disorders, we aimed to investigate sex-dependent changes in taxonomic and functional gut microbiome features following an ACE and acute injury as chronic pain triggers. Male and female Sprague Dawley rat pups were randomly assigned to either a maternal separation (MS) or no stress paradigm, then further into a sham, mTBI, or surgery condition. Chronically, the von Frey test was used to measure mechanical nociception, and fecal samples were collected for 16S rRNA sequencing. Animals in the surgery group had an increase in pain sensitivity when compared to mTBI and sham groups, and this was complemented by changes to the gut microbiome. In addition, significant sex differences were identified in gut microbiome composition, which were exacerbated in response to MS. Overall, we provide preliminary evidence for sex differences and ACE-induced changes in bacterial composition that, when combined, may be contributing to heterogeneity in pain outcomes.

Persistent Changes in Mechanical Nociception in Rats With Traumatic Brain Injury Involving Polytrauma.

Traumatic brain injury (TBI) survivors often experience debilitating consequences. Due to the high impact nature of TBI, patients often experience concomitant peripheral injuries (ie, polytrauma). A common, yet often overlooked, comorbidity of TBI is chronic pain. Therefore, this study investigated how common concomitant peripheral injuries (ie, femoral fracture and muscle crush) can affect long-term behavioral and structural TBI outcomes with a particular focus on nociception. Rats were randomly assigned to 1 of 4 groups: polytrauma (POLY; ie, fracture + muscle crush + TBI), peripheral injury (PERI; ie, fracture + muscle crush + sham TBI), TBI (ie, sham fracture + sham muscle crush + TBI), and sham-injured (SHAM; ie, sham fracture + sham muscle crush + sham TBI). Rats underwent behavioral testing at 3-, 6-, and 11-weeks postinjury, and were then euthanized for postmortem magnetic resonance imaging (MRI). POLY rats had a persisting increase in pain sensitivity compared to all groups on the von Frey test. MRI revealed that POLY rats also had abnormalities in the cortical and subcortical brain structures involved in nociceptive processing. These findings have important implications and provide a foundation for future studies to determine the underlying mechanisms and potential treatment strategies for chronic pain in TBI survivors. PERSPECTIVE: Rats with TBI and concomitant peripheral trauma displayed chronic nociceptive pain and MRI images also revealed damaged brain structures/pathways that are involved in chronic pain development. This study highlights the importance of polytrauma and the affected brain regions for developing chronic pain.

The waiting game: investigating the neurobiological transition from acute to persistent pain in adolescent rats.

Persistent postsurgical pain affects 20% of youth undergoing a surgical procedure, with females exhibiting increased prevalence of chronic pain compared with males. This study sought to examine the sexually-dimorphic neurobiological changes underlying the transition from acute to persistent pain following surgery in adolescence. Male and female Sprague Dawley rats were randomly allocated to a sham or injury (plantar-incision surgery) condition and assessed for pain sensitivity while also undergoing magnetic resonance imaging at both an acute and chronic timepoint within adolescence. We found that injury resulted in persistent pain in both sexes, with females displaying most significant sensitivity. Injury resulted in significant gray matter density increases in brain areas including the cerebellum, caudate putamen/insula, and amygdala and decreases in the hippocampus, hypothalamus, nucleus accumbens, and lateral septal nucleus. Gray matter density changes in the hippocampus and lateral septal nucleus were driven by male rats whereas changes in the amygdala and caudate putamen/insula were driven by female rats. Overall, our results indicate persistent behavioral and neurobiological changes following surgery in adolescence, with sexually-dimorphic and age-specific outcomes, highlighting the importance of studying both sexes and adolescents, rather than extrapolating from male adult literature.

A high-fat high-sugar diet and adversity early in life modulate pain outcomes at the behavioural and molecular level in adolescent rats: The role of sex.

Given that adolescence is a significant period of brain plasticity and development, early life factors have the potential to alter long term outcomes. For instance, adversities such as consumption of a high-fat high-sugar (HFHS) diet and adverse childhood experiences (ACEs; e.g., neglect), and their resulting inflammation and microglial activation can influence pain outcomes by priming the neuroimmune system to overrespond to stressors. Chronic pain is highly prevalent amongst the adolescent population, with the prevalence and manifestation being sexually dimorphic. Although clinical studies show that females are twice as likely to report pain problems compared to males, the majority of pre-clinical work uses male rodents. Therefore, our aim was to examine the effects of sex, a HFHS diet, and an ACE on chronic pain outcomes following a stressor in adolescence. Rat dams were randomly assigned to a Standard or HFHS diet, with pups maintained on their respective diets then randomly allocated to a No Stress or ACE paradigm, and a Sham or Injury condition as a stressor. Results showed that early life adversities increased nociceptive sensitivity, inflammation, and microglial activation systemically and within the brain. Behaviourally, pain outcomes were more prominent in females, however the neuroimmune response was exacerbated in males. These results demonstrate the sexual dimorphism of chronic pain outcomes following early life adversities and provide insight into the mechanisms driving these changes, which will inform more targeted and effective treatment strategies for youth living with chronic pain.

Examining Parent Adverse Childhood Experiences as a Distal Risk Factor in Pediatric Chronic Pain.

OBJECTIVES: Adverse childhood experiences (ACEs; ie, exposure to abuse, neglect, household dysfunction in childhood) are associated with poor mental and physical health outcomes across the lifespan. Emerging research suggests parent ACEs also confer risk for poor child outcomes. The relation between parent ACEs and child pain in youth with chronic pain has not yet been examined. The aim of the current longitudinal study was to examine the associations among parent ACEs, parent health, and child pain, in a clinical sample of youth with chronic pain. METHODS: In total, 192 youth (75.5% female, 10 to 18 y old) and one of their parents (92.2% female) were recruited from tertiary pediatric chronic pain clinics in Canada. At baseline, parents completed self-report measures of ACEs, chronic pain status, anxiety and depressive symptoms, and posttraumatic stress disorder symptoms. At a 3-month follow-up, youth completed self-report measures of pain intensity and pain interference. RESULTS: Regression and mediation analyses revealed that parent ACEs significantly predicted parent chronic pain status and depressive symptoms, but not parent anxiety or posttraumatic stress disorder symptoms. Moreover, parent ACEs were not significantly related to youth pain, either directly or indirectly through parent health variables. DISCUSSION: Findings suggest that an intergenerational cascade from parent ACEs to parent health to child pain was not present in the current sample. Further research that examines the role of parent ACEs in the development of child chronic pain, as well as other risk and resiliency factors that may mediate or moderate the association between parent ACEs and child chronic pain, is needed.

Pain in the Developing Brain: Early Life Factors Alter Nociception and Neurobiological Function in Adolescent Rats.

Although adverse early experiences prime individuals to be at increased risk for chronic pain, little research has examined the trauma-pain relationship in early life or the underlying mechanisms that drive pathology over time. Given that early experiences can potentiate the nociceptive response, this study aimed to examine the effects of a high-fat, high-sugar (HFHS) diet and early life stress (maternal separation [MS]) on pain outcomes in male and female adolescent rats. Half of the rats also underwent a plantar-incision surgery to investigate how the pain system responded to a mildly painful stimuli in adolescence. Compared with controls, animals that were on the HFHS diet, experienced MS, or had exposure to both, exhibited increased anxiety-like behavior and altered thermal and mechanical nociception at baseline and following the surgery. Advanced magnetic resonance imaging demonstrated that the HFHS diet and MS altered the maturation of the brain, leading to changes in brain volume and diffusivity within the anterior cingulate, amygdala, corpus callosum, nucleus accumbens, and thalamus, while also modifying the integrity of the corticospinal tracts. The effects of MS and HFHS diet were often cumulative, producing exacerbated pain sensitivity and increased neurobiological change. As early experiences are modifiable, understanding their role in pain may provide targets for early intervention/prevention.

Adverse childhood experiences in parents of youth with chronic pain: prevalence and comparison with a community-based sample.

INTRODUCTION: Adverse childhood experiences (ACEs) are common occurrences that are related to poor health outcomes, including chronic pain, in youth and adults. Research suggests that children of parents exposed to ACEs are also at risk of poor outcomes. However, little is known about the risk that ACEs confer for chronic pain across generations. Parent ACEs may play an important role in pediatric chronic pain, given their association with key parent factors (eg, mental and physical health). OBJECTIVES: This study evaluated the prevalence of ACEs in parents of youth with chronic pain and compared these rates to a community-based sample. METHODS: One hundred seventy parents of youth (aged 10-18 years) with chronic pain, recruited from a tertiary-level chronic pain program at a pediatric hospital in Canada, completed a self-report measure of ACEs. A comparison sample (n = 3914) was drawn from a local, community-based study that examined ACEs among adults in primary care. RESULTS: Among parents of youth with chronic pain, 67.6% reported ≥1 ACE and 23.5% reported ≥4 ACEs. Controlling for sociodemographic factors, ACEs were similar across samples, except parents of youth with chronic pain reported significantly higher rates of physical neglect (odds ratio = 2.14; 95% confidence interval = 1.35-3.40) than the community-based sample. CONCLUSION: Adverse childhood experiences are prevalent among parents of youth with chronic pain, with physical neglect reported more frequently than the community-based sample. Further research that examines the association between parent ACEs and child chronic pain, as well as neurobiological and psychosocial factors that may mediate this potential relation, is needed.

Examining changes in rodent temperament following repetitive mild traumatic brain injury in adolescence.

Mild traumatic brain injuries are known to cause a host of symptoms, including headaches, nausea, and depression, that when persistent, are known as postconcussive syndrome. In addition to these overt symptomologies, individuals may experience changes in day-to-day behavior or temperament, which although not meeting criteria for postconcussive diagnosis, does cause distress to the individual. The aim of this study was to determine whether we could measure temperament in a rat and, if so, determine whether temperament is altered in response to repetitive mild traumatic brain injuries (RmTBI). Forty male and female adolescent Sprague-Dawley rats were same-sex pair housed and subjected to RmTBIs or sham injuries. The rats were recorded at 6 different time points throughout the study for the temperament assessment protocol, a measure of the complex behavioral profile of each rat within its dyadic home cage environment. The temperaments were quantified via a novel behavioral scoring algorithm. The rats were also tested on a battery of tests that were designed to measure symptoms of postconcussion syndrome. We determined that rodent temperament is quantifiable, is sex dependent, changes with age, and is modifiable in response to experiential factors such as RmTBI. Rats that received the RmTBIs were significantly less active and showed decreased levels of social interaction compared with their sham-injury counterparts. Moreover, both task switching and recovery patterns for RmTBI rats were dependent on the injury status of their cage mates. Future studies are now required to determine the mechanisms underlying these important changes in temperament. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Investigating the cumulative effects of Δ9-tetrahydrocannabinol and repetitive mild traumatic brain injury on adolescent rats.

The prevalence of mild traumatic brain injury is highest amongst the adolescent population and can lead to complications including neuroinflammation and excitotoxicity. Also pervasive in adolescents is recreational cannabis use. Δ9-Tetrahydrocannabinol, the main psychoactive component of cannabis, is known to have anti-inflammatory properties and serves as a neuroprotective agent against excitotoxicity. Thus, we investigated the effects of Δ9-tetrahydrocannabinol on recovery when administered either prior to or following repeated mild brain injuries. Male and female Sprague-Dawley rats were randomly assigned to receive Δ9-tetrahydrocannabinol or vehicle either prior to or following the repeated injuries. Rats were then tested on a behavioural test battery designed to measure post-concussive symptomology. The hippocampus, nucleus accumbens and prefrontal cortex were extracted from all animals to examine mRNA expression changes (Bdnf, Cnr1, Comt, GR, Iba-1 and Vegf-2R). We hypothesized that, in both experiments, Δ9-tetrahydrocannabinol administration would provide neuroprotection against mild injury outcomes and confer therapeutic benefit. Δ9-Tetrahydrocannabinol administration following repeated mild traumatic brain injury was beneficial to three of the six behavioural outcomes affected by injury (reducing anxiety and depressive-like behaviours while also mitigating injury-induced deficits in short-term working memory). Δ9-Tetrahydrocannabinol administration following injury also showed beneficial effects on the expression of Cnr1, Comt and Vegf-2R in the hippocampus, nucleus accumbens and prefrontal cortex. There were no notable benefits of Δ9-tetrahydrocannabinol when administered prior to injury, suggesting that Δ9-tetrahydrocannabinol may have potential therapeutic benefit on post-concussive symptomology when administered post-injury, but not pre-injury.

The Development of Adolescent Chronic Pain following Traumatic Brain Injury and Surgery: The Role of Diet and Early Life Stress.

Pain is evolutionarily necessary for survival in that it reduces tissue damage by signaling the body to respond to a harmful stimulus. However, in many circumstances, acute pain becomes chronic, and this is often dysfunctional. Adolescent chronic pain is a growing epidemic with an unknown etiology and limited effective treatment options. Given that the relationship between acute pain and chronic pain is not straightforward, there is a need to better understand the factors that contribute to the chronification of pain. Since early life factors are critical to a variety of outcomes in the developmental and adolescent periods, they pose promise as potential mechanisms that may underlie the transition from acute to chronic pain. This review examines two early life factors: poor diet and adverse childhood experiences (ACEs); they may increase susceptibility to the development of chronic pain following surgical procedures or traumatic brain injury (TBI). Beyond their high prevalence, surgical procedures and TBI are ideal models to prospectively understand mechanisms underlying the transition from acute to chronic pain. Common themes that emerged from the examination of poor diet and ACEs as mechanisms underlying this transition included: prolonged inflammation and microglia activation leading to sensitization of the pain system, and stress-induced alterations to hypothalamic-pituitary-adrenal axis function, where cortisol is likely playing a role in the development of chronic pain. These areas provide promising targets for interventions, the development of diagnostic biomarkers, and suggest that biological treatment strategies should focus on regulating the neuroinflammatory and stress responses in an effort to modulate and prevent the development of chronic pain.

Clinical Relevance of Behavior Testing in Animal Models of Traumatic Brain Injury.

Traumatic brain injury (TBI) is a leading cause of morbidity worldwide, with patients often suffering from consequences such as cognitive deficits, social abnormalities, anxiety, depression, pain, and motor dysfunction. Given that these impairments often have a significant impact on the patient's quality of life, a key aim of therapeutic intervention in TBI is to mitigate these effects. Translational strategies to develop such interventions have heavily featured animal models of TBI. To assess the efficacy of interventions in these models, a range of behavioral outcomes are utilized. However, in light of the past translational failures that have plagued the TBI field, the clinical relevance of these preclinical behavioral tests is now being scrutinized. This article will summarize the behavioral consequences of TBI in humans; describe common methods available for testing cognition, social function, motor ability, pain, as well as depression- and anxiety-like behaviors in animal models of TBI; provide an overview of the results from TBI animal model studies that have utilized these methods; and discuss these pre-clinical behavior methods and findings in terms of their relevance to the clinical TBI setting. We conclude that there is translational value in these methods and their related findings, but also suggest strategies and future research to improve the clinical relevance of behavior testing in animal models of TBI.

When Two Wrongs Make a Right: The Effect of Acute and Chronic Binge Drinking on Traumatic Brain Injury Outcomes in Young Adult Female Rats.

Alcohol is the most commonly abused drug by young adults across North America. Although alcohol consumption itself incurs a risk of neurological damage, it is also a significant risk factor for traumatic brain injury (TBI). TBI among young adults is described as a modern healthcare epidemic. The drastic changes occurring within their neurological networks put young adults at greater risk for developing long-term post-traumatic deficits. Contradictory findings have been indicated regarding the effects of alcohol consumption on TBI outcomes in adults, with some studies demonstrating detrimental effects, whereas others suggest neuroprotective abilities. However, little is known about the effects of alcohol consumption on TBI outcomes during the sensitive stage of early adulthood. Young adult female Sprague-Dawley rats were randomly assigned to one of six experimental conditions: Pre-injury alcohol+TBI; Pre-injury alcohol+Sham; Pre- and Post-injury alcohol+TBI; Pre- and Post-injury alcohol+Sham; No alcohol+TBI; No alcohol+Sham. Alcohol consumption groups received an amount of 10% v/v ethanol solution based on the animals' weight. Following the injury, the rats were subjected to a behavioral test battery to assess post-concussive symptomology. Overall, chronic binge drinking significantly improved TBI outcomes related to motor coordination and balance, whereas binge drinking in general significantly decreased anxiety-like behaviors. Additionally, in many cases, chronic binge drinking appears to return the TBI animal's behavioral outcomes to levels comparable to those of the no alcohol sham animals. Thus, the results suggest that alcohol may exhibit neuroprotective abilities in the context of early adulthood TBI.

Utilization of a rodent model to examine the neurological effects of early life adversity on adolescent pain sensitivity.

All children experience pain, and although many recover quickly, some go on to develop chronic pain. Adolescent chronic pain is a growing epidemic. It is unknown why some adolescents recover without incident and others experience persistent pain. Although unexplored, early life adversity may contribute to the development and maintenance of chronic pain. This study investigated the effects and underlying neurobiological mechanisms of an early life stressor on nociceptive (pain) sensitivity and emotional function in male and female Sprague-Dawley rats. Using maternal separation (MS) as an established model of early life stress, we addressed two aims: investigation of the effects of MS on behavior (anxiety and pain sensitivity), and investigation of the effects of MS on mRNA and pathophysiological changes associated with an acutely painful stimulus. Our results indicate that MS increased anxiety-like behavior and altered nociceptive responsivity in adolescent rats, with decreased mechanical withdrawal thresholds indicative of heightened and prolonged pain-related behavior. The MS groups also demonstrated increased expression of genes involved in regulating the stress and fight-or-flight response, mood, and neuroplasticity; as well as increased levels of inflammatory markers. We conclude that nociception, both at the behavioral and molecular level, is altered in response to the MS stressor.

Caffeine consumption during development alters spine density and recovery from repetitive mild traumatic brain injury in young adult rats.

Caffeine is the most commonly used psychostimulant throughout the world, with its consumption being especially prevalent among adolescents and young adults, as over 75% of this group consumes caffeine daily. Similarly, the adolescent and young adult age group exhibit the highest incidence of traumatic brain injury (TBI). Given that both caffeine consumption and mild TBI (mTBI) are more prevalent among the late adolescent/young adult age group and that changes in dendritic spine morphology during this developmental period are poorly understood, this study sought to examine the effects of caffeine consumption during late adolescence/early adulthood on recovery from repetitive mTBI (RmTBI). The study specifically focused on changes to neuronal dendritic morphology as synaptic changes likely underlie long-term behavioral outcomes. The results demonstrate that during young adulthood caffeine consumption differentially affects the RmTBI outcomes of males and females, where the effects of caffeine and RmTBI were often additive in males while being equally detrimental, but rarely additive, in females. In general, caffeine and RmTBI induced the greatest impairments in males on cognitive and motor tasks whereas in females the most significant detriments were on pain-related tasks. Both caffeine and RmTBI increased spine density in the Cg3 (medial prefrontal cortex [mPFC]), AID (orbitofrontal cortex [OFC]), and nucleus accumbens (NAc), which is proposed to reflect an impairment in the normal pruning processes. Overall, despite caffeine's neuroprotective abilities among other age groups, this study offers concerning results regarding the detrimental effects of caffeine and RmTBI, in isolation, and especially in combination, in this susceptible population.

The behavioural and pathophysiological effects of the ketogenic diet on mild traumatic brain injury in adolescent rats.

Mild traumatic brain injury (mTBI), caused by an insult to the head, results in a cascade of molecular imbalance that includes altered glucose metabolism, mitochondrial dysfunction, and increases in reactive oxygen species. Although glucose is the primary energy source for the brain, it becomes an inefficient substrate following injury, and the brain is primed to use alternative substrates (such as ketones). The ketogenic diet (KD), a high-fat, low-carbohydrate diet, forces the brain to utilize ketones over glucose for energy. Given that mTBIs are commonly experienced during adolescence, our study sought to examine the effects of the KD on recovery from mTBI in adolescent rats. This was done via two experiments; the first of which animals were fed the KD prior to a mTBI in order to investigate the neuroprotective potential of the diet, and the second the animals were fed the KD following a mTBI to examine the therapeutic potential. Male and female Sprague Dawley rats were assigned to receive a control standard diet or the KD (either pre-injury or post-injury), then further randomized to receive a sham or mTBI. Animals were tested on 6 behavioural measures designed to examine post-concussive symptomology, and mRNA analysis of the brain and small intestine were performed. Pre-injury exposure to the KD offered some neuroprotection, reducing balance and motor impairments while increasing exploratory behaviour and telomere length. Consumption of the KD following the injury also provided some therapeutic benefit, reducing both anxiety- and depressive-like behaviours. The timing of KD administration also differentially modified expression of prefrontal cortex, hippocampus, and intestinal mRNA for our genes of interest (Fgf2, Iba1, Opa1, Sirt1, Claudin3, OCC, and ZO1) This study demonstrates the neuroprotective and therapeutic potential of the KD for mTBI and warrants further investigation.

A Bump on the Head or Late to Bed: Behavioral and Pathophysiological Effects of Sleep Deprivation after Repetitive Mild Traumatic Brain Injury in Adolescent Rats.

An old wives' tale, and strongly held dogma, maintains that one should be kept awake after a mild traumatic brain injury (mTBI) to prevent a coma. This, however, conflicts with the known benefits of sleep: repair and restoration. We therefore sought to examine the effects of sleep deprivation (SD) in the post-traumatic sleep period on post-concussion symptomology (PCS). Adolescent male and female rats were administered repetitive mTBIs (RmTBI) or sham injuries and were then assigned to 5 h of SD or left undisturbed. All animals were then tested using seven behavioral tasks validated to examine PCS, followed by analysis of serum cytokines, and quantitative real-time PCR for messenger RNA (mRNA) expression. Exposure to 3 SD epochs significantly impaired behavior in 4 of 7 of the measures, while RmTBI also produced dysfunction in 5 of 7 tests, but the effects of SD and RmTBI were not cumulative. SD induced long-lasting changes in serum levels of Tnf-α, IL6, and IL-1ß. mRNA expression in the pre-frontal cortex, hippocampus, hypothalamus, and anterior cingulate cortex was modified in response to SD and RmTBI; but similar to the behavioral measures, the mRNA changes were not cumulative. Consequently, we report that SD often produced impairments similar or worse than RmTBI, and sleep hygiene should become a priority for adolescent health.