Decreased homotopic functional connectivity in traumatic brain injury.

INTRODUCTION: Homotopic functional connectivity (HoFC), the synchrony in activity patterns between homologous brain regions, is a fundamental characteristic of resting-state functional connectivity (RsFC). METHODS: We examined the difference in HoFC, computed as the correlation between atlas-based regions and their counterpart on the opposite hemisphere, in 16 moderate-severe traumatic brain injury patients (msTBI) and 36 healthy controls. Regions of decreased HoFC in msTBI patients were further used as seeds for examining differences between groups in correlations with other brain regions. Finally, we computed logistic regression models of regional HoFC and fractional anisotropy (FA) of the corpus callosum (CC). RESULTS: TBI patients exhibited decreased HoFC in the middle and posterior cingulate cortex, thalamus, superior temporal pole, and cerebellum III. Furthermore, decreased RsFC was found between left cerebellum III and right parahippocampal cortex and vermis, between superior temporal pole and left caudate and medial left and right frontal orbital gyri. Thalamic HoFC and FA of the CC discriminate patients as msTBI with a high accuracy of 96%. CONCLUSION: TBI is associated with regionally decreased HoFC. Moreover, a multimodality model of interhemispheric connectivity allowed for a high degree of accuracy in disease discrimination and enabled a deeper understanding of TBI effects on brain interhemispheric reorganization post-TBI.

Treatment-Resistant Depression (TRD): Is the Opioid System Involved?

About 30% of major depression disorder patients fail to achieve remission, hence being diagnosed with treatment-resistant major depression (TRD). Opium had been largely used effectively to treat depression for centuries, but when other medications were introduced, its use was discounted due to addiction and other hazards. In a series of previous studies, we evaluated the antinociceptive effects of eight antidepressant medications and their interaction with the opioid system. Mice were tested with a hotplate or tail-flick after being injected with different doses of mianserin, mirtazapine, trazodone, venlafaxine, reboxetine, moclobemide, fluoxetine, or fluvoxamine to determine the effect of each drug in eliciting antinociception. When naloxone inhibited the antinociceptive effect, we further examined the effect of the specific opioid antagonists of each antidepressant drug. Mianserin and mirtazapine (separately) induced dose-dependent antinociception, each one yielding a biphasic dose-response curve, and they were antagonized by naloxone. Trazodone and venlafaxine (separately) induced a dose-dependent antinociceptive effect, antagonized by naloxone. Reboxetine induced a weak antinociceptive effect with no significant opioid involvement, while moclobemide, fluoxetine, and fluvoxamine had no opioid-involved antinociceptive effects. Controlled clinical studies are needed to establish the efficacy of the augmentation of opiate antidepressants in persons with treatment-resistant depression and the optimal dosage of drugs prescribed.

Unexpected role of stress as a possible resilience mechanism upon mild traumatic brain injury (mTBI) in mice.

INTRODUCTION: Mild traumatic brain injury (mTBI) is common and associated with cognitive impairment. Stress and mTBI are known to modulate the neural function. The present study aims at exploring the effect of prior stress exposure on cognitive function following mTBI. METHODS: Eight weeks old male ICR mice were subjected to either stress induced by forced swimming stress alone, stress followed by an immediate mTBI, or stress followed by 30 min break and then mTBI. We had two control groups: SHAM group - a control group which was not exposed to stress nor to mTBI and control mTBI group - a control group which was exposed only to TBI with no stress. Mice were weighed prior and at 12, 24 h and 1 week following interventions. Motor evaluation was conducted by rotarod. Behavioral changes were evaluated using open field, Y maze, elevated plus maze and staircase tests, at 12 h and 1 week following interventions. Brain levels of NMDAR subunits (R1, R2A, R2B), GABABR1, glucocorticoid and mineralocorticoid receptors (GR, MR) were evaluated using western blot. RESULTS: Stress alone, mTBI alone, and stress followed by immediate mTBI resulted in a significant weight loss compared to control (p < 0.05). Stress 30 min prior to mTBI had a protective effect on weight (p = 0.14 compared to control). The stress and mTBI alone groups showed reduced time at the center of the open field arena 1 week after intervention (p < 0.05 for both). Time in the novel arm of the Y maze was significantly shorter in the mTBI and stress followed by delayed mTBI (p = 0.02). Immediate stress prior to mTBI had normalized times in the novel arm (p = 0.95 compared to control). Combination of stress and mTBI significantly modified NMDAR subunits levels (increased NMDAR1, p < 0.008, decreased NMDAR2A p = 0.02) as well as increased MR levels (p = 0.04). CONCLUSION: Exposure to stress prior to mTBI may improve the cognitive consequences of mTBI. These data may point towards a novel, unexpected role of stress as a possible resilience mechanism in the setting of mTBI.

Nano-PSO Administration Attenuates Cognitive and Neuronal Deficits Resulting from Traumatic Brain Injury.

Traumatic Brain Injury (TBI), is one of the most common causes of neurological damage in young populations. It is widely considered as a risk factor for neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's (PD) disease. These diseases are characterized in part by the accumulation of disease-specific misfolded proteins and share common pathological features, such as neuronal death, as well as inflammatory and oxidative damage. Nano formulation of Pomegranate seed oil [Nano-PSO (Granagard TM)] has been shown to target its active ingredient to the brain and thereafter inhibit memory decline and neuronal death in mice models of AD and genetic Creutzfeldt Jacob disease. In this study, we show that administration of Nano-PSO to mice before or after TBI application prevents cognitive and behavioral decline. In addition, immuno-histochemical staining of the brain indicates that preventive Nano-PSO treatment significantly decreased neuronal death, reduced gliosis and prevented mitochondrial damage in the affected cells. Finally, we examined levels of Sirtuin1 (SIRT1) and Synaptophysin (SYP) in the cortex using Western blotting. Nano-PSO consumption led to higher levels of SIRT1 and SYP protein postinjury. Taken together, our results indicate that Nano-PSO, as a natural brain-targeted antioxidant, can prevent part of TBI-induced damage.

Sexual dimorphism of the posterior cervical spine muscle attachments.

Cervical spinal injury and neck pain are common disorders with wide physical implications. Neck pain and disability are reported to occur in females more often than in males, and chronic or persistent neck pain after whiplash is twice as common in females. Female athletes also sustain a higher percentage of concussions compared to male athletes. Still, while sexual differences in clinical presentation and outcome are well-established, the underlying etiology for the disparity remains less clear. It is well-established that the origin and insertion landmarks of posterior neck muscles are highly variable, but we do not know if these interindividual differences are associated with sex. Expanding our knowledge on sexual dimorphism in the anatomy of the cervical muscles is essential to our understanding of the possible biomechanical differences between the sexes and hence improves our understanding as to why females suffer from cervical pain more than males. It is also of paramount importance for accurate planning of posterior cervical spine surgery, which cuts through the posterior cervical musculature. Therefore, our main objective is to characterize the anatomy of posterior neck musculature and to explore possible sexual differences in the location of their attachment points. Meticulous posterior neck dissection was performed on 35 cadavers, 19 females, and 16 males. In each specimen, 8 muscle groups were examined bilaterally at 45 osseous anatomical landmarks. Muscles and their attachment sites were evaluated manually then photographed and recorded using Microscribe Digitizer technology built into 3D models. A comparison of attachment landmarks between males and females for each muscle was conducted. Out of the eight muscles that were measured, only two muscles demonstrated significant sex-related anatomical differences-Spinotranversales (splenius capitis and cervicis) and Multifidus. Male Spinotransversales muscle has more attachment points than female. It showed more cranial insertion points in the upper cervical attachments (superior nuchal line, C1 posterior tubercle, and mastoid process) and more caudal insertion points in the spinous processes and transverse processes of the lower cervical and upper thoracic vertebrae. Thus, the male subjects in this study exhibited a greater coverage of the posterior neck both cranially and caudally. Female Multifidus has more attachment points on the spinous processes and articular processes at middle and lower cervical vertebrae and at the transverse processes of the upper thoracic vertebrae. All remaining muscles exhibited no sexual differences. Our findings highlight, for the first time, a sexual dimorphism in attachment points of posterior cervical musculature. It reinforces the notion that the female neck is not a scaled version of the male neck. These differences in muscle attachment could partially explain differences in muscle torque production and range of motion and thus biomechanical differences in cervical spine stabilization between sexes. It sheds a much-needed light on the reason for higher whiplash rates, concussion, and chronic cervical pain among females. Surgeons should take these sexual morphological differences into consideration when deliberating the best surgical approach for posterior cervical surgery.

The Opioid Interactions of the Antipsychotic Medications Risperidone and Amisulpride in Mice and Their Potential Use in the Treatment of Other Non-Psychotic Medical Conditions.

Pain is defined as an unpleasant sensory and emotional experience associated with actual or potential tissue damage. The opioid epidemic in the USA has highlighted the need for alternative treatments for pain. Following reports on the opioid interactions of various antipsychotic medications, we speculated that the involvement of the opioid system in some of the antipsychotics' mechanism of action may suggest their potential use in the treatment of pain. Risperidone is a neuroleptic with a potent dopamine D2 and serotonin 5-HT2 receptor-blocking activity as well as a high affinity for adrenergic and histamine H1 receptors. Amisulpride is a neuroleptic which selectively blocks dopamine D2 and D3 receptors. Both had a potent antinociceptive effect on ICR mice tested with a tail flick assay. That effect on both medications was antagonized by naloxone, indicating that at least some of the antinociceptive effects were mediated by an opioid mechanism of action. Further investigation found that ß-Funaltrexamine hydrochloride (ß-FNA), naloxonazine, and nor-Binaltorphimine dihydrochloride (nor-BNI) reversed the antinociceptive effect of both risperidone and amisulpride. Naltrindole at a dose that blocked [D-Pen2,D-Pen5]enkephalin (DPDPE, δ analgesia) blocked notably amisplride effect and only partially reversed that of risperidone. Risperidone induced an antinociceptive effect, implying involvement of µ and κ-opioid and δ-opioid mechanisms. Amisulpride-induced antinociception was mediated through selective involvement of all three opioid receptor subtypes. These findings emphasize the need for clinical trials to assess the possibility of extending the spectrum of medications available for the treatment of pain.

Social isolation in mice: behavior, immunity, and tumor growth.

The aim of this study was to investigate the behavioral, immunological, and neurological effects of long-term isolation in an animal model. Male C3H/eB mice wereraised in either social isolation or standard conditions for 6 weeks. At 10 weeks, each group was further divided into 3 sets. (A) Physical strength and behavior were evaluated with the grip strength, hot plate, staircase, and elevated plus-maze tests. Natural-killer cell activity and lymphocyte proliferation were measured. (B) Half the animals were subjected to electric shock with 3 reminders, and freezing time was evaluated at each reminder. Cortisone levels were evaluated after 16 weeks. (C)Mice were injected with 38 C-13 B lymphoma cells and followed for tumor size and survival. Strength evaluation yielded asignificantly lower body weight and grip strength in the socially isolated mice. Behavioral test results were similar in the two groups. The pattern of reactions to stress conditioning differed significantly, with the socially isolated mice showing an incline in freezing with each successive reminder, and the control mice showing a decline. The socially isolated mice had significantly attenuated tumor growth, with no significant difference in survival from control mice. There were no significant between-group differences in immunological parameters. In conclusion, social isolation serves as a model for chronic stress. It was associated with significant changes in stress conditioning reaction, resembling symptoms of post-traumatic stress disorder, and attenuated tumor development. No differences from controls were found in behavior tests, immune parameters, or survival after tumor cell inoculation.Lay summaryThis article explores biological and behavioral consequences of social isolation in a mice model. Our results show that social isolation leads to changes in the Hypothalamic-hypophyseal-adrenal axis, which in turn alter the response to stress. Additionally, social isolation was shown to impact tumor progression.

Different clinical phenotypes of persistent post-traumatic headache exhibit distinct sensory profiles.

INTRODUCTION: Persistent post-traumatic headache remains a poorly understood clinical entity. Although there are currently no accepted therapies for persistent post-traumatic headache, its clinical symptoms, which primarily resemble those of migraine or tension-type headache, often serve to guide treatment. However, evidence-based justification for this treatment approach remains lacking given the paucity of knowledge regarding the characteristics of these two major persistent post-traumatic headache phenotypes and their etiology. METHODS: We compared clinical features and quantitative sensory testing profiles between two distinct cohorts of persistent post-traumatic headache subjects that exhibited symptoms resembling either migraine (n = 15) or tension-type headache (n = 13), as well as to headache-free subjects that had suffered traumatic brain injury (n = 19), and to healthy controls (n = 10). We aimed to determine whether the two persistent post-traumatic headache subgroups could be discriminated based on additional clinical features, distinct quantitative sensory testing profiles, or the interaction of pain severity with the level of post-traumatic stress disorder. RESULTS: Persistent post-traumatic headache subjects with migraine-like symptoms reported that bright light and focused attention aggravated their pain, while stress and nervousness were reported to aggravate the headache in subjects with tension-type headache-like symptoms. Quietness was better in alleviating migraine-like persistent post-traumatic headache, while anti-inflammatory medications provided better relief in tension-type headache-like persistent post-traumatic headache. The two persistent post-traumatic headache subgroups exhibited distinct quantitative sensory testing profiles with subjects exhibiting tension-type headache-like persistent post-traumatic headache displaying a more pronounced cephalic and extracephalic thermal hypoalgesia that was accompanied by cephalic mechanical hyperalgesia. While both persistent post-traumatic headache subgroups had high levels of post-traumatic stress disorder, there was a positive correlation with pain severity in subjects with tension-type headache-like symptoms, but a negative correlation in subjects with migraine-like symptoms. CONCLUSIONS: Distinct persistent post-traumatic headache symptoms and quantitative sensory testing profiles may be linked to different etiologies, potentially involving various levels of neuropathic and inflammatory pain, and if confirmed in a larger cohort, could be used to further characterize and differentiate between persistent post-traumatic headache subgroups in studies aimed to improve treatment.

(-)-Phenserine and the prevention of pre-programmed cell death and neuroinflammation in mild traumatic brain injury and Alzheimer's disease challenged mice.

Mild traumatic brain injury (mTBI) is a risk factor for neurodegenerative disorders, such as Alzheimer's disease (AD) and Parkinson's disease (PD). TBI-derived neuropathologies are promoted by inflammatory processes: chronic microgliosis and release of pro-inflammatory cytokines that further promote neuronal dysfunction and loss. Herein, we evaluated the effect on pre-programmed cell death/neuroinflammation/synaptic integrity and function of (-)-Phenserine tartrate (Phen), an agent originally developed for AD. This was studied at two clinically translatable doses (2.5 and 5.0 mg/kg, BID), in a weight drop (concussive) mTBI model in wild type (WT) and AD APP/PSEN1 transgenic mice. Phen mitigated mTBI-induced cognitive impairment, assessed by Novel Object Recognition and Y-maze behavioral paradigms, in WT mice. Phen fully abated mTBI-induced neurodegeneration, evaluated by counting Fluoro-Jade C-positive (FJC+) cells, in hippocampus and cortex of WT mice. In APP/PSEN1 mice, degenerating cell counts were consistently greater across all experimental groups vs. WT mice. mTBI elevated FJC+ cell counts vs. the APP/PSEN1 control (sham) group, and Phen similarly mitigated this. Anti-inflammatory effects on microglial activation (IBA1-immunoreactivity (IR)) and the pro-inflammatory cytokine TNF-α were evaluated. mTBI increased IBA1-IR and TNF-α/IBA1 colocalization vs. sham, both in WT and APP/PSEN1 mice. Phen decreased IBA1-IR throughout hippocampi and cortices of WT mice, and in cortices of AD mice. Phen, likewise, reduced levels of IBA1/TNF-α-IR colocalization volume across all areas in WT animals, with a similar trend in APP/PSEN1 mice. Actions on astrocyte activation by mTBI were followed by evaluating GFAP, and were similarly mitigated by Phen. Synaptic density was evaluated by quantifying PSD-95+ dendritic spines and Synaptophysin (Syn)-IR. Both were significantly reduced in mTBI vs. sham in both WT and APP/PSEN1 mice. Phen fully reversed the PSD-95+ spine loss in WT and Syn-IR decrease in both WT and APP/PSEN1 mice. To associate immunohistochemical changes in synaptic markers with function, hippocampal long term potentiation (LTP) was induced in WT mice. LTP was impaired by mTBI, and this impairment was mitigated by Phen. In synopsis, clinically translatable doses of Phen ameliorated mTBI-mediated pre-programmed cell death/neuroinflammation/synaptic dysfunction in WT mice, consistent with fully mitigating mTBI-induced cognitive impairments. Phen additionally demonstrated positive actions in the more pathologic brain microenvironment of AD mice, further supporting consideration of its repurposing as a treatment for mTBI.

Pharmacokinetics and efficacy of PT302, a sustained-release Exenatide formulation, in a murine model of mild traumatic brain injury.

Traumatic brain injury (TBI) is a neurodegenerative disorder for which no effective pharmacological treatment is available. Glucagon-like peptide 1 (GLP-1) analogues such as Exenatide have previously demonstrated neurotrophic and neuroprotective effects in cellular and animal models of TBI. However, chronic or repeated administration was needed for efficacy. In this study, the pharmacokinetics and efficacy of PT302, a clinically available sustained-release Exenatide formulation (SR-Exenatide) were evaluated in a concussive mild (m)TBI mouse model. A single subcutaneous (s.c.) injection of PT302 (0.6, 0.12, and 0.024 mg/kg) was administered and plasma Exenatide concentrations were time-dependently measured over 3 weeks. An initial rapid regulated release of Exenatide in plasma was followed by a secondary phase of sustained-release in a dose-dependent manner. Short- and longer-term (7 and 30 day) cognitive impairments (visual and spatial deficits) induced by weight drop mTBI were mitigated by a single post-injury treatment with Exenatide delivered by s.c. injection of PT302 in clinically translatable doses. Immunohistochemical evaluation of neuronal cell death and inflammatory markers, likewise, cross-validated the neurotrophic and neuroprotective effects of SR-Exenatide in this mouse mTBI model. Exenatide central nervous system concentrations were 1.5% to 2.0% of concomitant plasma levels under steady-state conditions. These data demonstrate a positive beneficial action of PT302 in mTBI. This convenient single, sustained-release dosing regimen also has application for other neurological disorders, such as Alzheimer's disease, Parkinson's disease, multiple system atrophy and multiple sclerosis where prior preclinical studies, likewise, have demonstrated positive Exenatide actions.

Functional effects of synthetic cannabinoids versus Δ9 -THC in mice on body temperature, nociceptive threshold, anxiety, cognition, locomotor/exploratory parameters and depression.

Synthetic cannabinoids are psychoactive substances designed to mimic the euphorigenic effects of the natural cannabis. Novel unregulated compounds appear once older compounds become illegal. It has been previously reported that synthetic cannabinoids are different than Δ9 -tetrahydrocannabinol (Δ9 -THC) as they have chemical structures unrelated to Δ9 -THC, different metabolism and, often, greater toxicity. This study aimed to investigate the effects of three novel synthetic cannabinoids and pure Δ9 -THC on body temperature, nociceptive threshold, anxiety, memory function, locomotor and exploratory parameters, and depression. We performed a battery of behavioural and motor tests starting 50 minutes post i.p. injection of each drug to adult ICR mice. The synthetic cannabinoids that were used are AB-FUBINACA, AB-CHMINACA and PB-22. All synthetic cannabinoids and Δ9 -THC caused hypothermia, but only Δ9 -THC induced a clear antinociceptive effect. All synthetic cannabinoids and Δ9 -THC caused decreased anxiety levels, spatial memory deficits and decreased exploratory behaviour as measured in the elevated plus maze, Y-maze and staircase paradigm, respectively. However, all synthetic cannabinoids but not Δ9 -THC demonstrated decreased locomotor activity in the staircase test. Moreover, only AB-FUBINACA and Δ9 -THC affected the gait balance and grip strength of the mice as was assessed by the latency time to fall from a rod. In the forced swimming test, PB-22 caused elevated depression-like behaviour while AB-FUBINACA induced a reversed effect. These results suggest varied effects among different synthetic cannabinoids and Δ9 -THC. Further studies are needed to characterize the overall effects and differences between these synthetic cannabinoids and Δ9 -THC.

Immediate and delayed hyperbaric oxygen therapy as a neuroprotective treatment for traumatic brain injury in mice.

BACKGROUND: Traumatic brain injury is the most common cause of death or chronic disability among people under-35-years-old. There is no effective pharmacological treatment currently existing for TBI. Hyperbaric oxygen therapy (HBOT) is defined as the inhalation of pure oxygen in a hyperbaric chamber that is pressurized higher than 1atm. HBOT offers physiological and mechanical effects by inducing a state of increased pressure and hyperoxia. HBOT has been proposed as an effective treatment for moderate traumatic brain injury (mTBI), yet the exact therapeutic window and mechanism that underlies this effect is not completely understood. METHODS: HBOT was administrated for 4 consecutive days, post a mouse closed head weight drop moderate TBI (mTBI) in 2 different time lines: immediate treatment - initiated 3h post-injury and delayed treatment - initiated 7days post-injury. Behavioral cognitive tests and biochemical changes were assessed. RESULTS: The results were similar for both the immediate and the delayed treatments. mTBI mice exhibited impairment in learning abilities, whereas mTBI mice treated with HBO displayed significant improvement compared with the mTBI group, performing similar to the sham groups. mTBI mice had a decline in myelin basic protein, an increase in neuronal loss (NeuN staining), and an increase in the number of reactive astrocytes (GFAP). The HBO treated mice in both groups did not exhibit these changes and remained similar to the sham group. CONCLUSIONS: The delayed HBOT has a potential to serve as a neuroprotective treatment for mTBI with a long therapeutic window. Further research is needed for fully understanding the cellular changes.

Repositioning drugs for traumatic brain injury - N-acetyl cysteine and Phenserine.

Traumatic brain injury (TBI) is one of the most common causes of morbidity and mortality of both young adults of less than 45 years of age and the elderly, and contributes to about 30% of all injury deaths in the United States of America. Whereas there has been a significant improvement in our understanding of the mechanism that underpin the primary and secondary stages of damage associated with a TBI incident, to date however, this knowledge has not translated into the development of effective new pharmacological TBI treatment strategies. Prior experimental and clinical studies of drugs working via a single mechanism only may have failed to address the full range of pathologies that lead to the neuronal loss and cognitive impairment evident in TBI and other disorders. The present review focuses on two drugs with the potential to benefit multiple pathways considered important in TBI. Notably, both agents have already been developed into human studies for other conditions, and thus have the potential to be rapidly repositioned as TBI therapies. The first is N-acetyl cysteine (NAC) that is currently used in over the counter medications for its anti-inflammatory properties. The second is (-)-phenserine ((-)-Phen) that was originally developed as an experimental Alzheimer's disease (AD) drug. We briefly review background information about TBI and subsequently review literature suggesting that NAC and (-)-Phen may be useful therapeutic approaches for TBI, for which there are no currently approved drugs.

Physiological and Behavioral Responses to Calibrated Noxious Stimuli Among Individuals with Cerebral Palsy and Intellectual Disability.

Objective: As individuals with intellectual disability (ID) due to cerebral palsy (CP) are at high risk of experiencing pain, measuring their pain is crucial for adequate treatment. While verbal reports are the gold standard in pain measurements, they may not be sufficient in ID. The aim was to detect behavioral/autonomic responses that may indicate the presence and intensity of pain in individuals with CP and ID, using calibrated stimuli, here for the first time. Subjects: Thirteen adults with CP and ID (CPID), 15 healthy controls (HC), and 5 adults with CP with no ID (CPNID). Methods: Subjects received pressure stimuli of various intensities. Self-reports (using a pyramid scale), facial expressions (retrospectively analyzed with Facial Action Coding System = FACS), and autonomic function (heart rate, heart rate variability, pulse, galvanic skin response) were analyzed. Results: Self-reports and facial expressions but not the autonomic function exhibited stimulus-response relationship to pressure stimulation among all groups. The CPID group had increased pain ratings and facial expressions compared with controls. In addition, the increase in facial expressions along the increase in noxious stimulation was larger than in controls. Freezing in response to pain was frequent in CPID. Conclusions: 1) Individuals with CP and ID have increased responses to pain; 2) facial expressions and self-reports, but not autonomic variables can reliably indicate their pain intensity; 3) the pyramid scale is suitable for self-report in this population. Although facial expressions may replace verbal reports, increased facial expressions at rest among these individuals may mask pain, especially at lower intensities.

Increased Evoked Potentials and Behavioral Indices in Response to Pain Among Individuals with Intellectual Disability.

OBJECTIVE: Previous studies on the sensitivity and reactivity to pain of individuals with intellectual disability (ID) are inconsistent. The inconsistency may result from the reliance on self-reports and facial expressions of pain that are subject to internal and external biases. The aim was therefore to evaluate the reactivity to pain of individuals with ID by recording pain-evoked potentials (EPs), here for the first time, and testing their association with behavioral pain indices. SUBJECT: Forty-one healthy adults, 16 with mild-moderate ID and 25 controls. METHODS: Subjects received series of phasic heat stimuli and rated their pain on self-report scales. Changes in facial expressions and in pain EPs were recorded and analyzed offline. RESULTS: Pain self-reports, facial expressions, and the N2P2 amplitudes of the EPs exhibited stimulus-response relationship with stimulation intensity in both groups. The facial expressions and N2P2 amplitudes of individuals with ID were increased and N2P2 latency prolonged compared with controls. N2P2 amplitudes correlated with self-reports only in controls. CONCLUSIONS: Individuals with ID are hypersensitive/reactive to pain, a finding bearing clinical implications. Although pain EPs may reflect a somewhat different aspect of pain than the behavioral indices do, there is evidence to support their use to record pain in noncommunicative individuals, pending further validation.

Pomalidomide mitigates neuronal loss, neuroinflammation, and behavioral impairments induced by traumatic brain injury in rat.

BACKGROUND: Traumatic brain injury (TBI) is a global health concern that typically causes emotional disturbances and cognitive dysfunction. Secondary pathologies following TBI may be associated with chronic neurodegenerative disorders and an enhanced likelihood of developing dementia-like disease in later life. There are currently no approved drugs for mitigating the acute or chronic effects of TBI. METHODS: The effects of the drug pomalidomide (Pom), an FDA-approved immunomodulatory agent, were evaluated in a rat model of moderate to severe TBI induced by controlled cortical impact. Post-TBI intravenous administration of Pom (0.5 mg/kg at 5 or 7 h and 0.1 mg/kg at 5 h) was evaluated on functional and histological measures that included motor function, fine more coordination, somatosensory function, lesion volume, cortical neurodegeneration, neuronal apoptosis, and the induction of pro-inflammatory cytokines (TNF-α, IL-1ß, IL-6). RESULTS: Pom 0.5 mg/kg administration at 5 h, but not at 7 h post-TBI, significantly mitigated the TBI-induced injury volume and functional impairments, neurodegeneration, neuronal apoptosis, and cytokine mRNA and protein induction. To evaluate underlying mechanisms, the actions of Pom on neuronal survival, microglial activation, and the induction of TNF-α were assessed in mixed cortical cultures following a glutamate challenge. Pom dose-dependently ameliorated glutamate-mediated cytotoxic effects on cell viability and reduced microglial cell activation, significantly attenuating the induction of TNF-α. CONCLUSIONS: Post-injury treatment with a single Pom dose within 5 h significantly reduced functional impairments in a well-characterized animal model of TBI. Pom decreased the injury lesion volume, augmented neuronal survival, and provided anti-inflammatory properties. These findings strongly support the further evaluation and optimization of Pom for potential use in clinical TBI.

Responses of dural mast cells in concussive and blast models of mild traumatic brain injury in mice: Potential implications for post-traumatic headache.

BACKGROUND: Chronic post-traumatic headache (PTH) is one of the most common symptoms of mild traumatic brain injury (mTBI) but its underlying mechanisms remain unknown. Inflammatory degranulation of dural mast cells (MCs) is thought to promote headache, and may play a role in PTH. Whether mTBI is associated with persistent degranulation of dural MCs is yet to be determined. METHODS: Histochemistry was used to evaluate time course changes in dural MC density and degranulation level in concussive head trauma and blast mouse models of mTBI. The effects of sumatriptan and the MC stabilizer cromolyn sodium on concussion-evoked dural MC degranulation were also investigated. RESULTS: Concussive head injury evoked persistent MC degranulation for at least 30 days. Blast trauma gave rise to a delayed MC degranulation response commencing at seven days that also persisted for at least 30 days. Neither sumatriptan nor cromolyn treatment reduced concussion-evoked persistent MC degranulation. CONCLUSIONS: mTBI evoked by closed head injury or blast exposure is associated with persistent dural MC degranulation. Such a response in mTBI patients may contribute to PTH. Amelioration of PTH by sumatriptan may not involve inhibition of dural MC degranulation. If persistent dural MC degranulation contributes to PTH, then cromolyn treatment may not be effective.

Blast traumatic brain injury-induced cognitive deficits are attenuated by preinjury or postinjury treatment with the glucagon-like peptide-1 receptor agonist, exendin-4.

INTRODUCTION: Blast traumatic brain injury (B-TBI) affects military and civilian personnel. Presently, there are no approved drugs for blast brain injury. METHODS: Exendin-4 (Ex-4), administered subcutaneously, was evaluated as a pretreatment (48 hours) and postinjury treatment (2 hours) on neurodegeneration, behaviors, and gene expressions in a murine open field model of blast injury. RESULTS: B-TBI induced neurodegeneration, changes in cognition, and genes expressions linked to dementia disorders. Ex-4, administered preinjury or postinjury, ameliorated B-TBI-induced neurodegeneration at 72 hours, memory deficits from days 7-14, and attenuated genes regulated by blast at day 14 postinjury. DISCUSSION: The present data suggest shared pathologic processes between concussive and B-TBI, with end points amenable to beneficial therapeutic manipulation by Ex-4. B-TBI-induced dementia-related gene pathways and cognitive deficits in mice somewhat parallel epidemiologic studies of Barnes et al. who identified a greater risk in US military veterans who experienced diverse TBIs, for dementia in later life.

Liraglutide is neurotrophic and neuroprotective in neuronal cultures and mitigates mild traumatic brain injury in mice.

Traumatic brain injury (TBI), a brain dysfunction for which there is no present effective treatment, is often caused by a concussive impact to the head and affects an estimated 1.7 million Americans annually. Our laboratory previously demonstrated that exendin-4, a long-lasting glucagon-like peptide 1 receptor (GLP-1R) agonist, has neuroprotective effects in cellular and animal models of TBI. Here, we demonstrate neurotrophic and neuroprotective effects of a different GLP-1R agonist, liraglutide, in neuronal cultures and a mouse model of mild TBI (mTBI). Liraglutide promoted dose-dependent proliferation in SH-SY5Y cells and in a GLP-1R over-expressing cell line at reduced concentrations. Pre-treatment with liraglutide rescued neuronal cells from oxidative stress- and glutamate excitotoxicity-induced cell death. Liraglutide produced neurotrophic and neuroprotective effects similar to those of exendin-4 in vitro. The cAMP/PKA/pCREB pathway appears to play an important role in this neuroprotective activity of liraglutide. Furthermore, our findings in cell culture were well-translated in a weight drop mTBI mouse model. Post-treatment with a clinically relevant dose of liraglutide for 7 days in mice ameliorated memory impairments caused by mTBI when evaluated 7 and 30 days post trauma. These data cross-validate former studies of exendin-4 and suggest that liraglutide holds therapeutic potential for the treatment of mTBI. Exendin-4, a long-lasting glucagon-like peptide 1 receptor (GLP-1R) agonist, has neuroprotective effects in cellular and animal models of traumatic brain injury (TBI). Here, we demonstrate neurotrophic and neuroprotective effects of a different GLP-1R agonist, liraglutide, in neuronal cultures and a mouse model of mild TBI (mTBI). Liraglutide promoted dose-dependent proliferation in SH-SY5Y cells and in a GLP-1R over-expressing cell line at reduced concentrations. Pretreatment with liraglutide rescued neuronal cells from oxidative stress- and glutamate excitotoxicity-induced cell death. Liraglutide produced neurotrophic and neuroprotective effects similar to those of exendin-4 in vitro, likely involving the cAMP/PKA/pCREB pathway. Our findings in cell culture were well-translated in a weight-drop mTBI mouse model. Post-treatment with a clinically relevant dose of liraglutide for 7 days in mice ameliorated memory impairments caused by mTBI.