Revisiting the NPcis mouse model: A new tool to model plexiform neurofibroma.

Neurofibromatosis Type I (NF1) is a rare genetic disorder. NF1 patients frequently develop a benign tumor in peripheral nerve plexuses called plexiform neurofibroma. In the past two decades, tissue-specific Nf1 knockout mouse models were developed using commercially available tissue-specific Cre recombinase and the Nf1 flox mice to mimic neurofibroma development. However, these models develop para-spinal neurofibroma, recapitulating a rare type of neurofibroma found in NF1 patients. The NPcis mouse model developed a malignant version of neurofibroma called malignant peripheral nerve sheath tumor (MPNST) within 3 to 6 months but intriguingly without apparent benign precursor lesion. Here, we revisited the NPcis model and discovered that about 20% display clinical signs similar to Nf1 tissue-specific knockout mice models. However, a systematic histological analysis could not explain the clinical signs we observed although we noticed lesions reminiscent of a neurofibroma in a peripheral nerve, a cutaneous neurofibroma, and para-spinal neurofibroma on rare occasions in NPcis mice. We also observed that 10% of the mice developed a malignant peripheral nerve sheath tumor (MPNST) spontaneously, coinciding with their earring tag identification. Strikingly, half of the sciatic nerves from NPcis mice developed plexiform neurofibroma within 1-6 months when intentionally injured. Thus, we provided a procedure to turn the widely used NPcis sarcoma model into a model recapitulating plexiform neurofibroma.

The Contribution of Sleep Quality and Psychological Factors to the Experience of Within-Day Pain Fluctuations Among Individuals With Temporomandibular Disorders.

We assessed the impact of day-to-day sleep quality and psychological variables (catastrophizing, negative affect, and positive affect) to within-day pain fluctuations in 42 females with painful temporomandibular disorders (TMD) using electronic diaries. More specifically, we examined the contribution of these variables to the likelihood of experiencing pain exacerbations defined as 1) an increase of 20 points (or more) in pain intensity on a 0 to 100 visual analog scale from morning to evening, and/or 2) a transition from mild-to-moderate pain over the course of the day; and pain decreases defined as 3) a decrease of 20 points (or more) in pain intensity (visual analog scale) from morning to evening, and/or 4) a reduction from moderate-to-mild pain over the day. The results indicated significantly main effects of sleep on both pain exacerbation outcomes (both P's < .05), indicating that nights with better sleep quality were less likely to be followed by clinically meaningful pain exacerbations on the next day. The results also indicated that days characterized by higher levels of catastrophizing were associated with a greater likelihood of pain exacerbations on the same day (both P's < .05). Daily catastrophizing was the only variable significantly associated with within-day pain decrease indices (both P's < .05). None of the other variables were associated with these outcomes (all P's > .05). These results underscore the importance of addressing patients' sleep quality and psychological states in the management of painful TMD. PERSPECTIVES: These findings highlight the significance of sleep quality and pain catastrophizing in the experience of within-day pain fluctuations among individuals with TMD. Addressing these components through tailored interventions may help to alleviate the impact of pain fluctuations and enhance the overall well-being of TMD patients.

One session of repetitive transcranial magnetic stimulation induces mild and transient analgesic effects among female individuals with painful temporomandibular disorders.

OBJECTIVE: Temporomandibular disorders (TMD) are characterised by chronic pain and dysfunction in the jaw joint and masticatory muscles. Repetitive transcranial magnetic stimulation (rTMS) has emerged as a potential non-invasive treatment for chronic pain; however, its effectiveness in individuals with TMD has not been thoroughly investigated. This study aimed to evaluate the immediate and sustained (over seven consecutive days) effects of a single session of active rTMS compared to sham stimulation on pain intensity and pain unpleasantness in individuals with TMD. METHODS: A randomised, double-blind, sham-controlled trial enrolled 41 female participants with chronic TMD. Pain intensity and pain unpleasantness were assessed immediately pre- and post-intervention, as well as twice daily for 21 days using electronic diaries. Secondary outcomes included pain interference, sleep quality, positive and negative affect and pain catastrophizing. Adverse effects were monitored. Repeated measures ANOVA and multilevel modelling regression analyses were employed for data analysis. RESULT: Active rTMS demonstrated a significant immediate mild reduction in pain intensity and pain unpleasantness compared to sham stimulation. However, these effects were not sustained over the 7-day post-intervention period. No significant differences were observed between interventions for pain interference, sleep quality and negative affect. A minority of participants reported minor and transient side effects, including headaches and fatigue. CONCLUSION: A single session of active rTMS was safe and led to immediate mild analgesic effects in individuals with TMD compared to sham stimulation. However, no significant differences were observed between interventions over the 7-day post-intervention period. Based on this study, rTMS stimulation appears to be a promising safe approach to be tested in TMD patients with longer stimulation protocols.

Females with painful temporomandibular disorders present higher intracortical facilitation relative to pain-free controls.

OBJECTIVES: This study aimed to investigate cortical excitability differences in the primary motor cortex (M1) hand representation between individuals with temporomandibular disorders (TMD) and healthy controls. We assessed resting motor thresholds, motor-evoked potentials (MEPs), intracortical inhibition, and intracortical facilitation and explored potential associations with clinical and psychosocial characteristics in the TMD group. MATERIALS AND METHODS: We recruited 36 female participants with TMD and 17 pain-free controls. Transcranial magnetic stimulation (TMS) was used to assess M1 cortical excitability. Correlations between clinical and psychosocial factors and cortical excitability measures were also evaluated. RESULTS: Patients with TMD showed significantly higher intracortical facilitation at 12 ms (z = 1.98, p = 0.048) and 15 ms (z = 2.65, p = 0.008) when compared to controls. Correlations revealed associations between intracortical facilitation and pain interference, sleep quality, depressive symptoms, and pain catastrophizing in the TMD group. CONCLUSIONS: Females with TMD exhibit heightened motor cortex intracortical facilitation in the hand representation, potentially indicating altered cortical excitability beyond the motor face area. This suggests a role for cortical excitability in TMD pathophysiology, influenced by psychosocial factors. CLINICAL RELEVANCE: Understanding cortical excitability in TMD may inform targeted interventions. Psychosocial variables may play a role in cortical excitability, emphasizing the multidimensional nature of TMD-related pain. Further research is needed to confirm and expand upon these findings, with potential implications for the management of TMD and related pain conditions.

Whole Central and Peripheral Nervous System Mice Dissection.

Animal models represent the workhorse of the neuroscience field. Despite this, today, there is still no step-by-step protocol to dissect a complete rodent nervous system, nor is there a complete schematic representing it that is freely available. Only methods to harvest the brain, the spinal cord, a specific dorsal root ganglion, and the sciatic nerve (separately) are available. Here, we provide detailed pictures and a schematic of the central and peripheral murine nervous system. More importantly, we outline a robust procedure to perform its dissection. The 30 min pre-dissection step allows isolating the intact nervous system within the vertebra with muscles free of viscera and skin. A 2-4 h dissection follows it under a micro-dissection microscope to expose the spinal cord and the thoracic nerves, and finally peel the whole central and peripheral nervous system off the carcass. This protocol represents a significant step forward in studying the anatomy and pathophysiology of the nervous system globally. For example, the dissected dorsal root ganglions from a neurofibromatosis type I mice model can be further processed for histology to unravel changes in tumor progression.

The Putative Role of Neuroinflammation in the Interaction between Traumatic Brain Injuries, Sleep, Pain and Other Neuropsychiatric Outcomes: A State-of-the-Art Review.

Sleep disturbances are widely prevalent following a traumatic brain injury (TBI) and have the potential to contribute to numerous post-traumatic physiological, psychological, and cognitive difficulties developing chronically, including chronic pain. An important pathophysiological mechanism involved in the recovery of TBI is neuroinflammation, which leads to many downstream consequences. While neuroinflammation is a process that can be both beneficial and detrimental to individuals' recovery after sustaining a TBI, recent evidence suggests that neuroinflammation may worsen outcomes in traumatically injured patients, as well as exacerbate the deleterious consequences of sleep disturbances. Additionally, a bidirectional relationship between neuroinflammation and sleep has been described, where neuroinflammation plays a role in sleep regulation and, in turn, poor sleep promotes neuroinflammation. Given the complexity of this interplay, this review aims to clarify the role of neuroinflammation in the relationship between sleep and TBI, with an emphasis on long-term outcomes such as pain, mood disorders, cognitive dysfunctions, and elevated risk of Alzheimer's disease and dementia. In addition, some management strategies and novel treatment targeting sleep and neuroinflammation will be discussed in order to establish an effective approach to mitigate long-term outcomes after TBI.

Relevance of Sleep Disturbances to Orthopaedic Surgery: A Current Concepts Narrative and Practical Review.

➤: Sleep disturbances can increase the risk of falls and motor vehicle accidents and may reduce bone density. ➤: Poor sleep can lead to worse outcomes after fracture, such as chronic pain and delayed recovery. ➤: Orthopaedic surgeons can play an important role in the screening of sleep disorders among their patients.

Toward Understanding the Mechanisms of Malignant Peripheral Nerve Sheath Tumor Development.

Malignant peripheral nerve sheath tumors (MPNSTs) originate from the neural crest lineage and are associated with the neurofibromatosis type I syndrome. MPNST is an unmet clinical need. In this review article, we summarize the knowledge and discuss research perspectives related to (1) the natural history of MPNST development; (2) the mouse models recapitulating the progression from precursor lesions to MPNST; (3) the role of the tumor microenvironment in MPNST development, and (4) the signaling pathways linked to MPNST development.

Persistent implicit motor learning alterations following a mild traumatic brain injury sustained during late adulthood.

Introduction: The neurocognitive outcomes of sustaining a mild traumatic brain injury (mTBI) during late adulthood are vastly understudied. In young, asymptomatic adults, mTBI-related synaptic plasticity alterations have been associated with persistent implicit motor sequence learning impairments outlasting the usual cognitive recovery period. The current study examined whether uncomplicated mTBI sustained during late adulthood could exert persistent deleterious consequences on implicit motor sequence learning.Method: Thirty participants (aged 50-70 years) who experienced an uncomplicated mTBI within 3 to 24 months of testing, and 40 age-, sex- and education-equivalent healthy controls performed an implicit serial reaction time task (SRT task). The SRT task consisted of 10 blocks of a repeating sequence embedded among 4 random blocks. Participants also completed a battery of standardized neuropsychological tests of attention, memory and executive functioning.Results: While both mTBI participants and controls showed significant implicit motor sequence learning effects, the mTBI group achieved a lower level of competence at performing the SRT task as evidenced by smaller gains in reaction times across the 10 training blocks of the repeating sequence. The time elapsed since the injury was unrelated to implicit motor learning effects. There was no evidence of a persistent effect of mTBI on any neuropsychological domain compared to controls.Conclusions: Findings from this study suggest that a single mTBI sustained during older age may have persistent repercussions on training-dependent motor sequence learning capacity outlasting the recovery of mTBI symptoms and gold-standard neuropsychological tests performance.

Motor Learning Improvement Remains 3 Months After a Multisession Anodal tDCS Intervention in an Aging Population.

Healthy aging is associated with decline of motor function that can generate serious consequences on the quality of life and safety. Our studies aim to explore the 3-month effects of a 5-day multisession anodal transcranial direct current stimulation (a-tDCS) protocol applied over the primary motor cortex (M1) during motor sequence learning in elderly. The present sham-controlled aging study investigated whether tDCS-induced motor improvements previously observed 1 day after the intervention persist beyond 3 months. A total of 37 cognitively-intact aging participants performed five consecutive daily 20-min sessions of the serial-reaction time task (SRTT) concomitant with either anodal (n = 18) or sham (n = 19) tDCS over M1. All participants performed the Purdue Pegboard Test and transcranial magnetic stimulation (TMS) measures of cortical excitability were collected before, 1 day after and 3 months after the intervention. The last follow-up session also included the execution of the trained SRTT. The main findings are the demonstration of durable effects of a 5-day anodal tDCS intervention at the trained skill, while the active intervention did not differ from the sham intervention at both the untrained task and on measures of M1-disinhibition. Thus, the current article revealed for the first time the durability of functional effects of a-tDCS combined with motor training after only 5 days of intervention in an aging population. This finding provides evidence that the latter treatment alternative is effective in achieving our primary motor rehabilitation goal, that is to allow durable motor training effects in an aging population.

Multisession anodal transcranial direct current stimulation induces motor cortex plasticity enhancement and motor learning generalization in an aging population.

OBJECTIVES: The present aging study investigated the impact of a multisession anodal-tDCS protocol applied over the primary motor cortex (M1) during motor sequence learning on generalization of motor learning and plasticity-dependent measures of cortical excitability. METHODS: A total of 32 cognitively-intact aging participants performed five consecutive daily 20-min sessions of the serial-reaction time task (SRTT) concomitant with either anodal (n = 16) or sham (n = 16) tDCS over M1. Before and after the intervention, all participants performed the Purdue Pegboard Test (PPT) and Transcranial Magnetic Stimulation (TMS) measures of cortical excitability were collected. RESULTS: Relative to sham, participants assigned to the anodal-tDCS intervention revealed significantly greater performance gains on both the trained SRTT and the untrained PPT as well as a greater disinhibition of long-interval cortical inhibition (LICI). Generalization effects of anodal-tDCS significantly correlated with LICI disinhibition. CONCLUSION: Anodal-tDCS facilitates motor learning generalisation in an aging population through intracortical disinhibition effects. SIGNIFICANCE: The current findings demonstrate the potential clinical utility of a multisession anodal-tDCS over M1 protocol as an adjuvant to motor training in alleviating age-associated motor function decline. This study also reveals the pertinence of implementing brain stimulation techniques to modulate age-associated intracortical inhibition changes in order to facilitate motor function gains.

Incidence rate of mild traumatic brain injury among patients who have suffered from an isolated limb fracture: Upper limb fracture patients are more at risk.

OBJECTIVES: This study compares the incidence rate of mild traumatic brain injury (mild TBI) detected at follow-up visits (retrospective diagnosis) in patients suffering from an isolated limb trauma, with the incidence rate held by the hospital records (prospective diagnosis) of the sampled cohort. This study also seeks to determine which types of fractures present with the highest incidence of mild TBI. PATIENTS AND METHODS: Retrospective assessment of mild TBI among orthopaedic monotrauma patients, randomly selected for participation in an Orthopaedic clinic of a Level I Trauma Hospital. Patients in the remission phase of a limb fracture were recruited between August 2014 and May 2015. No intervention was done (observational study). MAIN OUTCOME MEASUREMENTS: Standardized semi-structured interviews were conducted with all patients to retrospectively assess for mild TBI at the time of the fracture. Emergency room related medical records of all patients were carefully analyzed to determine whether a prospective mild TBI diagnosis was made following the accident. RESULTS: A total of 251 patients were recruited (54% females, Mean age=49). Study interview revealed a 23.5% incidence rate of mild TBI compared to an incidence rate of 8.8% for prospective diagnosis (χ(2)=78.47; p<0.0001). Patients suffering from an upper limb monotrauma (29.6%; n=42/142) are significantly more at risk of sustaining a mild TBI compared to lower limb fractures (15.6%; n=17/109) (χ(2)=6.70; p=0.010). More specifically, patients with a proximal upper limb injury were significantly more at risk of sustaining concomitant mild TBI (40.6%; 26/64) compared to distal upper limb fractures (20.25%; 16/79) (χ(2)=7.07; p=0.008). CONCLUSIONS: Results suggest an important concomitance of mild TBI among orthopaedic trauma patients, the majority of which go undetected during acute care. Patients treated for an upper limb fracture are particularly at risk of sustaining concomitant mild TBI.