Re-examining the Mysterious Role of the Cerebellum in Pain.

Pain is considered a multidimensional experience that embodies not merely sensation, but also emotion and perception. As is appropriate for this complexity, pain is represented and processed by an extensive matrix of cortical and subcortical structures. Of these structures, the cerebellum is gaining increasing attention. Although association between the cerebellum and both acute and chronic pain have been extensively detailed in electrophysiological and neuroimaging studies, a deep understanding of what functions are mediated by these associations is lacking. Nevertheless, the available evidence implies that lobules IV-VI and Crus I are especially pertinent to pain processing, and anatomical studies reveal that these regions connect with higher-order structures of sensorimotor, emotional, and cognitive function. Therefore, we speculate that the cerebellum exerts a modulatory role in pain via its communication with sites of sensorimotor, executive, reward, and limbic function. On this basis, in this review, we propose numerous ways in which the cerebellum might contribute to both acute and chronic pain, drawing particular attention to emotional and cognitive elements of pain. In addition, we emphasise the importance of advancing our knowledge about the relationship between the cerebellum and pain by discussing novel therapeutic opportunities that capitalize on this association.

A pre-existing Toxoplasma gondii infection exacerbates the pathophysiological response and extent of brain damage after traumatic brain injury in mice.

Traumatic brain injury (TBI) is a key contributor to global morbidity that lacks effective treatments. Microbial infections are common in TBI patients, and their presence could modify the physiological response to TBI. It is estimated that one-third of the human population is incurably infected with the feline-borne parasite, Toxoplasma gondii, which can invade the central nervous system and result in chronic low-grade neuroinflammation, oxidative stress, and excitotoxicity-all of which are also important pathophysiological processes in TBI. Considering the large number of TBI patients that have a pre-existing T. gondii infection prior to injury, and the potential mechanistic synergies between the conditions, this study investigated how a pre-existing T. gondii infection modified TBI outcomes across acute, sub-acute and chronic recovery in male and female mice. Gene expression analysis of brain tissue found that neuroinflammation and immune cell markers were amplified in the combined T. gondii + TBI setting in both males and females as early as 2-h post-injury. Glutamatergic, neurotoxic, and oxidative stress markers were altered in a sex-specific manner in T. gondii + TBI mice. Structural MRI found that male, but not female, T. gondii + TBI mice had a significantly larger lesion size compared to their uninfected counterparts at 18-weeks post-injury. Similarly, diffusion MRI revealed that T. gondii + TBI mice had exacerbated white matter tract abnormalities, particularly in male mice. These novel findings indicate that a pre-existing T. gondii infection affects the pathophysiological aftermath of TBI in a sex-dependent manner, and may be an important modifier to consider in the care and prognostication of TBI patients.

Infraorbital nerve injury triggers sex-specific neuroimmune responses in the peripheral trigeminal pathway and common pain behaviours.

Trigeminal neuropathic pain is emotionally distressing and disabling. It presents with allodynia, hyperalgesia and dysaesthesia. In preclinical models it has been assumed that cephalic nerve constriction injury shows identical molecular, cellular, and sex dependent neuroimmune changes as observed in extra-cephalic injury models. This study sought empirical evidence for such assumptions using the infraorbital nerve chronic constriction model (ION-CCI). We compared the behavioural consequences of nerve constriction with: (i) the temporal patterns of recruitment of macrophages and T-lymphocytes at the site of nerve injury and in the trigeminal ganglion; and (ii) the degree of demyelination and axonal reorganisation in the injured nerve. Our data demonstrated that simply testing for allodynia and hyperalgesia as is done in extra-cephalic neuropathic pain models does not provide access to the range of injury-specific nociceptive responses and behaviours reflective of the experience of trigeminal neuropathic pain. Similarly, trigeminal neuroimmune changes evoked by nerve injury are not the same as those identified in models of extra-cephalic neuropathy. Specifically, the timing, magnitude, and pattern of ION-CCI evoked macrophage and T-lymphocyte activity differs between the sexes.

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.

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.

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.

E2730, an uncompetitive γ-aminobutyric acid transporter-1 inhibitor, suppresses epileptic seizures in a rat model of chronic mesial temporal lobe epilepsy.

OBJECTIVE: More than one third of mesial temporal lobe epilepsy (MTLE) patients are resistant to current antiseizure medications (ASMs), and half experience mild-to-moderate adverse effects of ASMs. There is therefore a strong need to develop and test novel ASMs. The objective of this work is to evaluate the pharmacokinetics and neurological toxicity of E2730, a novel uncompetitive inhibitor of γ-aminobutyric acid transporter-1, and to test its seizure suppression effects in a rat model of chronic MTLE. METHODS: We first examined plasma levels and adverse neurological effects of E2730 in healthy Wistar rats. Adult male rats were implanted with osmotic pumps delivering either 10, 20, or 100 mg/kg/day of E2730 subcutaneously for 1 week. Blood sampling and behavioral assessments were performed at several timepoints. We next examined whether E2730 suppressed seizures in rats with chronic MTLE. These rats were exposed to kainic acid-induced status epilepticus, and 9 weeks later, when chronic epilepsy was established, were assigned to receive one of the three doses of E2730 or vehicle for 1 week in a randomized crossover design. Continuous video-electroencephalographic monitoring was acquired during the treatment period to evaluate epileptic seizures. RESULTS: Plasma levels following continuous infusion of E2730 showed a clear dose-related increase in concentration. The drug was well tolerated at all doses, and any sedation or neuromotor impairment was mild and transient, resolving within 48 h of treatment initiation. Remarkably, E2730 treatment in chronically epileptic rats led to seizure suppression in a dose-dependent manner, with 65% of rats becoming seizure-free at the highest dose tested. Mean seizure class did not differ between the treatment groups. SIGNIFICANCE: This study shows that continuous subcutaneous infusion of E2730 over 7 days results in a marked, dose-dependent suppression of spontaneous recurrent seizures, with minimal adverse neurological effects, in a rat model of chronic MTLE. E2730 shows strong promise as an effective new ASM to be translated into clinical trials.

Making migraine easier to stomach: the role of the gut-brain-immune axis in headache disorders.

BACKGROUND AND PURPOSE: Headache disorders place a significant burden on the healthcare system, being the leading cause of disability in those under 50 years. Novel studies have interrogated the relationship between headache disorders and gastrointestinal dysfunction, suggesting a link between the gut-brain-immune (GBI) axis and headache pathogenesis. Although the exact mechanisms driving the complex relationship between the GBI axis and headache disorders remain unclear, there is a growing appreciation that a healthy and diverse microbiome is necessary for optimal brain health. METHODS: A literature search was performed through multiple reputable databases in search of Q1 journals within the field of headache disorders and gut microbiome research and were critically and appropriately evaluated to investigate and explore the following; the role of the GBI axis in dietary triggers of headache disorders and the evidence indicating that diet can be used to alleviate headache severity and frequency. The relationship between the GBI axis and post-traumatic headache is then synthesized. Finally, the scarcity of literature regarding paediatric headache disorders and the role that the GBI axis plays in mediating the relationship between sex hormones and headache disorders are highlighted. CONCLUSIONS: There is potential for novel therapeutic targets for headache disorders if understanding of the GBI axis in their aetiology, pathogenesis and recovery is increased.

Repeat mild traumatic brain injuries (RmTBI) modify nociception and disrupt orexinergic connectivity within the descending pain pathway.

Repeat mild traumatic brain injuries (RmTBI) result in substantial burden to the public health system given their association with chronic post-injury pathologies, such as chronic pain and post-traumatic headache. Although this may relate to dysfunctional descending pain modulation (DPM), it is uncertain what mechanisms drive changes within this pathway. One possibility is altered orexinergic system functioning, as orexin is a potent anti-nociceptive neuromodulator. Orexin is exclusively produced by the lateral hypothalamus (LH) and receives excitatory innervation from the lateral parabrachial nucleus (lPBN). Therefore, we used neuronal tract-tracing to investigate the relationship between RmTBI and connectivity between lPBN and the LH, as well as orexinergic projections to a key site within the DPM, the periaqueductal gray (PAG). Prior to injury induction, retrograde and anterograde tract-tracing surgery was performed on 70 young-adult male Sprague Dawley rats, targeting the lPBN and PAG. Rodents were then randomly assigned to receive RmTBIs or sham injuries before undergoing testing for anxiety-like behaviour and nociceptive sensitivity. Immunohistochemical analysis identified distinct and co-localized orexin and tract-tracing cell bodies and projections within the LH. The RmTBI group exhibited altered nociception and reduced anxiety as well as a loss of orexin cell bodies and a reduction of hypothalamic projections to the ventrolateral nucleus of the PAG. However, there was no significant effect of injury on neuronal connectivity between the lPBN and orexinergic cell bodies within the LH. Our identification of structural losses and the resulting physiological changes in the orexinergic system following RmTBI begins to clarify acute post-injury mechanistic changes that drive may drive the development of post-traumatic headache and the chronification of pain.

Electrographic seizures and brain hyperoxia may be key etiological factors for postconcussive deficits.

Repetitive mild traumatic brain injuries (RmTBIs) are increasingly recognized to have long-term neurological sequelae in a significant proportion of patients. Individuals that have had RmTBIs exhibit a variety of sensory, cognitive, or behavioral consequences that can negatively impact quality of life. Brain tissue oxygen levels ([Formula: see text]) are normally maintained through exquisite regulation of blood supply to stay within the normoxic zone (18-30 mmHg in the rat hippocampus). However, during neurological events in which brain tissue oxygen levels leave the normoxic zone, neuronal dysfunction and behavioral deficits have been observed, and are frequently related to poorer prognoses. The oxygenation response in the brain after RmTBIs/repeated concussions has been poorly characterized, with most preliminary research limited to the neocortex. Furthermore, the mechanisms by which RmTBIs impact changes to brain oxygenation and vice versa remain to be determined. In the current study, we demonstrate that upon receiving RmTBIs, rats exhibit posttraumatic, electrographic seizures in the hippocampus, without behavioral (clinical) seizures, that are accompanied by a long-lasting period of hyperoxygenation. These electrographic seizures and the ensuing hyperoxic episodes are associated with deficits in working memory and motor coordination that were reversible through attenuation of the posttraumatic and postictal (postseizure) hyperoxia, via administration of a vasoconstricting agent, the calcium channel agonist Bay K8644. We propose that the posttraumatic period characterized by brain oxygenation levels well above the normoxic zone, may be the basis for some of the common symptoms associated with RmTBIs.NEW & NOTEWORTHY We monitor oxygenation and electrographic activity in the hippocampus, immediately before and after mild traumatic brain injury. We demonstrate that as the number of injuries increases from 1 to 3, the proportion of rats that exhibit electrographic seizures and hyperoxia increases. Moreover, the presence of electrographic seizures and hyperoxia are associated with postinjury behavioral impairments, and if the hyperoxia is blocked with Bay K8644, the behavioral deficits are eliminated.

Diffusion Imaging Reveals Sex Differences in the White Matter Following Sports-Related Concussion.

Sports-related concussion (SRC) is a serious health concern. However, the temporal profile of neuropathophysiological changes after SRC and how these relate to biological sex are still poorly understood. This preliminary study investigated whether diffusion-weighted magnetic resonance imaging (dMRI) was sensitive to neuropathophysiological changes following SRC; whether these changes were sex-specific; and whether they persisted beyond the resolution of self-reported symptoms. Recently concussed athletes (n = 14), and age- and education-matched nonconcussed control athletes (n = 16), underwent MRI 24-48-h postinjury and again at 2-week postinjury (i.e., when cleared to return-to-play). Male athletes reported more symptoms and greater symptom severity compared with females. dMRI revealed white matter differences between athletes with SRC and their nonconcussed counterparts at 48-h postinjury. These differences were still present at 2-week postinjury, despite SRC athletes being cleared to return to play and may indicate increased cerebral vulnerability beyond the resolution of subjective symptoms. Furthermore, we identified sex-specific differences, with male SRC athletes having significantly greater white matter disruption compared with female SRC athletes. These results have important implications for the management of concussion, including guiding return-to-play decisions, and further improve our understanding regarding the role of sex in SRC outcomes.

White and Gray Matter Abnormalities in Australian Footballers With a History of Sports-Related Concussion: An MRI Study.

Sports-related concussion (SRC) is a form of mild traumatic brain injury that has been linked to long-term neurological abnormalities. Australian rules football is a collision sport with wide national participation and is growing in popularity worldwide. However, the chronic neurological consequences of SRC in Australian footballers remain poorly understood. This study investigated the presence of brain abnormalities in Australian footballers with a history of sports-related concussion (HoC) using multimodal MRI. Male Australian footballers with HoC (n = 26), as well as noncollision sport athletes with no HoC (n = 27), were recruited to the study. None of the footballers had sustained a concussion in the preceding 6 months, and all players were asymptomatic. Data were acquired using a 3T MRI scanner. White matter integrity was assessed using diffusion tensor imaging. Cortical thickness, subcortical volumes, and cavum septum pellucidum (CSP) were analyzed using structural MRI. Australian footballers had evidence of widespread microstructural white matter damage and cortical thinning. No significant differences were found regarding subcortical volumes or CSP. These novel findings provide evidence of persisting white and gray matter abnormalities in Australian footballers with HoC, and raise concerns related to the long-term neurological health of these athletes.

The ketogenic diet raises brain oxygen levels, attenuates postictal hypoxia, and protects against learning impairments.

OBJECTIVES: A prolonged vasoconstriction/hypoperfusion/hypoxic event follows self-terminating focal seizures. The ketogenic diet (KD) has demonstrated efficacy as a metabolic treatment for intractable epilepsy and other disorders but its effect on local brain oxygen levels is completely unknown. This study investigated the effects of the KD on tissue oxygenation in the hippocampus before and after electrically elicited (kindled) seizures and whether it could protect against a seizure-induced learning impairment. We also examined the effects of the ketone ß-hydroxybutyrate (BHB) as a potential underlying mechanism. METHODS: Male and female rats were given access to one of three diet protocols 2 weeks prior to the initiation of seizures: KD, caloric restricted standard chow, and ad libitum standard chow. Dorsal hippocampal oxygen levels were measured prior to initiation of diets as well as before and after a 10-day kindling paradigm. Male rats were then tested on a novel object recognition task to assess postictal learning impairments. In a separate cohort, BHB was administered 30 min prior to seizure elicitation to determine whether it influenced oxygen dynamics. RESULTS: The KD increased dorsal hippocampal oxygen levels, ameliorated postictal hypoxia, and prevented postictal learning impairments. Acute BHB administration did not alter oxygen levels before or after seizures. INTERPRETATION: The ketogenic diet raised brain oxygen levels and attenuated severe postictal hypoxia likely through a mechanism independent of ketosis and shows promise as a non-pharmacological treatment to prevent the postictal state.

Behavioral, axonal, and proteomic alterations following repeated mild traumatic brain injury: Novel insights using a clinically relevant rat model.

A history of mild traumatic brain injury (mTBI) is linked to a number of chronic neurological conditions, however there is still much unknown about the underlying mechanisms. To provide new insights, this study used a clinically relevant model of repeated mTBI in rats to characterize the acute and chronic neuropathological and neurobehavioral consequences of these injuries. Rats were given four sham-injuries or four mTBIs and allocated to 7-day or 3.5-months post-injury recovery groups. Behavioral analysis assessed sensorimotor function, locomotion, anxiety, and spatial memory. Neuropathological analysis included serum quantification of neurofilament light (NfL), mass spectrometry of the hippocampal proteome, and ex vivo magnetic resonance imaging (MRI). Repeated mTBI rats had evidence of acute cognitive deficits and prolonged sensorimotor impairments. Serum NfL was elevated at 7 days post injury, with levels correlating with sensorimotor deficits; however, no NfL differences were observed at 3.5 months. Several hippocampal proteins were altered by repeated mTBI, including those associated with energy metabolism, neuroinflammation, and impaired neurogenic capacity. Diffusion MRI analysis at 3.5 months found widespread reductions in white matter integrity. Taken together, these findings provide novel insights into the nature and progression of repeated mTBI neuropathology that may underlie lingering or chronic neurobehavioral deficits.

Dysregulated phosphoinositide 3-kinase signaling in microglia: shaping chronic neuroinflammation.

Microglia are integral mediators of innate immunity within the mammalian central nervous system. Typical microglial responses are transient, intending to restore homeostasis by orchestrating the removal of pathogens and debris and the regeneration of damaged neurons. However, prolonged and persistent microglial activation can drive chronic neuroinflammation and is associated with neurodegenerative disease. Recent evidence has revealed that abnormalities in microglial signaling pathways involving phosphatidylinositol 3-kinase (PI3K) and protein kinase B (AKT) may contribute to altered microglial activity and exacerbated neuroimmune responses. In this scoping review, the known and suspected roles of PI3K-AKT signaling in microglia, both during health and pathological states, will be examined, and the key microglial receptors that induce PI3K-AKT signaling in microglia will be described. Since aberrant signaling is correlated with neurodegenerative disease onset, the relationship between maladapted PI3K-AKT signaling and the development of neurodegenerative disease will also be explored. Finally, studies in which microglial PI3K-AKT signaling has been modulated will be highlighted, as this may prove to be a promising therapeutic approach for the future treatment of a range of neuroinflammatory conditions.

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.

Microglia dynamics in adolescent traumatic brain injury.

Repetitive, mild traumatic brain injuries (RmTBIs) are increasingly common in adolescents and encompass one of the largest neurological health concerns in the world. Adolescence is a critical period for brain development where RmTBIs can substantially impact neurodevelopmental trajectories and life-long neurological health. Our current understanding of RmTBI pathophysiology suggests key roles for neuroinflammation in negatively regulating neural health and function. Microglia, the brain's resident immune population, play important roles in brain development by regulating neuronal number, and synapse formation and elimination. In response to injury, microglia activate to inflammatory phenotypes that may detract from these normal homeostatic, physiological, and developmental roles. To date, however, little is known regarding the impact of RmTBIs on microglia function during adolescent brain development. This review details key concepts surrounding RmTBI pathophysiology, adolescent brain development, and microglia dynamics in the developing brain and in response to injury, in an effort to formulate a hypothesis on how the intersection of these processes may modify long-term trajectories.

Catastrophic consequences: can the feline parasite Toxoplasma gondii prompt the purrfect neuroinflammatory storm following traumatic brain injury?

Traumatic brain injury (TBI) is one of the leading causes of morbidity and mortality worldwide; however, treatment development is hindered by the heterogenous nature of TBI presentation and pathophysiology. In particular, the degree of neuroinflammation after TBI varies between individuals and may be modified by other factors such as infection. Toxoplasma gondii, a parasite that infects approximately one-third of the world's population, has a tropism for brain tissue and can persist as a life-long infection. Importantly, there is notable overlap in the pathophysiology between TBI and T. gondii infection, including neuroinflammation. This paper will review current understandings of the clinical problems, pathophysiological mechanisms, and functional outcomes of TBI and T. gondii, before considering the potential synergy between the two conditions. In particular, the discussion will focus on neuroinflammatory processes such as microglial activation, inflammatory cytokines, and peripheral immune cell recruitment that occur during T. gondii infection and after TBI. We will present the notion that these overlapping pathologies in TBI individuals with a chronic T. gondii infection have the strong potential to exacerbate neuroinflammation and related brain damage, leading to amplified functional deficits. The impact of chronic T. gondii infection on TBI should therefore be investigated in both preclinical and clinical studies as the possible interplay could influence treatment strategies.

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 genetic ablation of tau improves long-term, but not short-term, functional outcomes after experimental traumatic brain injury in mice.

PRIMARY OBJECTIVE: This study characterized the acute and chronic effects of tau reduction in traumatic brain injury (TBI). RESEARCH DESIGN: A fluid percussion injury (FPI) or a sham-injury was administered to wild type (WT) or tau knockout (Tau-/-) mice. Mice were assigned to a one-week or twelve-week recovery period before behavioral testing and analysis of brain tissue. METHODS AND PROCEDURES: Mice were tested on the elevated-plus maze, the Y-maze, and rotarod. The twelve-week recovery mice underwent in vivo MRI. Phosphorylated tau in brain tissue was analyzed post-mortem using western blots. MAIN OUTCOMES AND RESULTS: FPI mice, regardless of genotype, had abnormalities on the elevated-plus maze (a task to assess anxiety-like behavior) at one-week post-injury. However, after twelve-weeks recovery, the Tau-/- mice that were given an FPI were less anxious and had improved motor function compared to their WT counterparts. MRI analysis found that while all FPI mice had brain damage, the Tau-/- mice had larger hippocampal volumes. The WT+FPI mice also had increased phosphorylated tau compared to WT+sham mice at both the one-week and twelve-week recovery times. CONCLUSION: These findings suggest that tau may play an important role in some of the consequences of TBI, particularly the long-term functional deficits.