Mild Traumatic Brain Injury-Induced Augmented Postsurgical Pain Is Driven by Central Serotonergic Pain-Facilitatory Signaling.

BACKGROUND: Individuals recovering from mild traumatic brain injury (mTBI) have increased rates of acute and chronic pain. However, the mechanism through which mTBI triggers heightened pain responses and the link between mTBI and postsurgical pain remain elusive. Recent data suggest that dysregulated serotonergic pain-modulating circuits could be involved. We hypothesized that mTBI triggers dysfunction in descending serotonergic pain modulation, which exacerbates acute pain and delays pain-related recovery after surgery. METHODS: Using mouse models of mTBI and hindpaw incision for postsurgical pain in C57BL/6J mice, mechanical withdrawal thresholds were assessed throughout the postsurgical period. To determine whether mTBI leads to persistent alteration of endogenous opioid tone, mu-opioid receptors (MORs) were blocked with naloxone. Finally, the role of descending serotonergic signaling on postsurgical allodynia in animals with mTBI was examined using ondansetron (5-HT 3 receptor antagonist) or a serotonin-specific neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT), to ablate descending serotonergic fibers. The treatment effects on withdrawal thresholds were normalized to baseline (percentage of maximum possible effect, MPE%), and analyzed using paired t -test or 2-way repeated-measures ANOVA with post hoc multiple comparisons. RESULTS: Post-mTBI mice demonstrated transient allodynia in hindpaws contralateral to mTBI, while no nociceptive changes were observed in sham-mTBI animals (mean difference, MD, MPE%, post-mTBI day 3: -60.9; 95% CI, -88.7 to -35.0; P < .001). After hindpaw incision, animals without mTBI exhibited transient allodynia, while mice with prior mTBI demonstrated prolonged postsurgical allodynia (MD-MPE% postsurgical day 14: -65.0; 95% CI, -125.4 to -4.5; P = .04). Blockade of MORs using naloxone transiently reinstated allodynia in mTBI animals but not in sham-mTBI mice (MD-MPE% post-naloxone: -69.9; 95% CI, -94.8 to -45.1; P < .001). Intrathecal administration of ondansetron reversed the allodynia observed post-mTBI and postincision in mTBI mice (compared to vehicle-treated mTBI mice, MD-MPE% post-mTBI day 3: 82.7; 95% CI, 58.5-106.9; P < .001; postsurgical day 17: 62.5; 95% CI, 38.3-86.7; P < .001). Both the acute allodynia after TBI and the period of prolonged allodynia after incision in mTBI mice were blocked by pretreatment with 5,7-DHT (compared to sham-mTBI mice, MD-MPE% post-mTBI day 3: 0.5; 95% CI, -18.5 to 19.5; P = .99; postsurgical day 14: -14.6; 95% CI, -16.7 to 45.9; P = .48). Similar behavioral patterns were observed in hindpaw ipsilateral to mTBI. CONCLUSIONS: Collectively, our results show that descending serotoninergic pain-facilitating signaling is responsible for nociceptive sensitization after mTBI and that central endogenous opioid tone opposes serotonin's effects. Understanding brain injury-related changes in endogenous pain modulation may lead to improved pain control for those with TBI undergoing surgery.

A Scoping Review of the Complementary Feeding Practices and Early Eating Experiences of Children With Down Syndrome.

OBJECTIVE: Children with Down syndrome may experience more challenges in their early feeding and may be introduced to complementary foods comparatively later than typically developing (TD) children. This scoping review aimed to identify and synthesize the existing literature that describes feeding problems and early eating experiences relating to the period of complementary feeding for children with Down syndrome. METHODS: Scopus, PubMed, Medline, Web of Science, and PsycInfo were searched. Journal articles published between January 1991 and June 2022 that reported on the complementary feeding period with children with Down syndrome were included. RESULTS: Eighteen journal articles met the inclusion criteria. Children with Down syndrome were introduced to complementary foods later than TD children and progressed to more challenging food textures at a slower rate. Gross and fine motor skill delays and sensory difficulties contributed to secondary feeding problems such as difficulties chewing, biting, and reduced awareness of food on lips and tongue. Parents of children with Down syndrome reported exercising more caution and employing more controlling feeding practices compared to TD and had higher levels of concern regarding their child's weight. CONCLUSIONS: Guidelines and early feeding support specific to children with Down syndrome should be available before the first complementary foods are introduced and throughout this period. Feeding support should aim to address parental concerns and provide assistance when feeding problems occur, to minimize delays and encourage the optimum development of eating abilities. Future research should address the development of feeding problems during this period and explore possible interventions.

Morphine Exacerbates Postfracture Nociceptive Sensitization, Functional Impairment, and Microglial Activation in Mice.

BACKGROUND: Emerging evidence suggests that opioid use immediately after surgery and trauma may worsen outcomes. In these studies, the authors aimed to determine whether morphine administered for a clinically relevant time period (7 days) in a tibia fracture orthopedic surgery model had adverse effects on postoperative recovery. METHODS: Mice were given morphine twice daily for 7 days after unilateral tibial fracture and intramedullary pin fixation to model orthopedic surgery and limb trauma. Mechanical allodynia, limb-specific weight bearing, gait changes, memory, and anxiety were measured after injury. In addition, spinal cord gene expression changes as well as glial activation were measured. Finally, the authors assessed the effects of a selective Toll-like receptor 4 antagonist, TAK-242, on nociceptive and functional changes after injury. RESULTS: Tibial fracture caused several weeks of mechanical nociceptive sensitization (F(1, 216) = 573.38, P < 0.001, fracture + vehicle vs. sham + vehicle, n = 10 per group), and this change was exacerbated by the perioperative administration of morphine (F(1, 216) = 71.61, P < 0.001, fracture + morphine vs. fracture + vehicle, n = 10 per group). In additional testing, injured limb weight bearing, gait, and object location memory were worse in morphine-treated fracture mice than in untreated fracture mice. Postfracture expression levels of several genes previously associated with opioid-induced hyperalgesia, including brain-derived neurotrophic factor and prodynorphin, were unchanged, but neuroinflammation involving Toll-like receptor 4 receptor-expressing microglia was observed (6.8 ± 1.5 [mean ± SD] cells per high-power field for fracture + vehicle vs. 12 ± 2.8 fracture + morphine, P < 0.001, n = 8 per /group). Treatment with a Toll-like receptor 4 antagonist TAK242 improved nociceptive sensitization for about 2 weeks in morphine-treated fracture mice (F(1, 198) = 73.36, P < 0.001, fracture + morphine + TAK242 vs. fracture + morphine, n = 10 per group). CONCLUSIONS: Morphine treatment beginning at the time of injury impairs nociceptive recovery and other outcomes. Measures preventing glial activation through Toll-like receptor 4 signaling may reduce the adverse consequences of postoperative opioid administration.

Pharmacological Characters of Oliceridine, a µ-Opioid Receptor G-Protein-Biased Ligand in Mice.

BACKGROUND: A major advancement in the field of analgesic pharmacology has been the development of G-protein-biased opioid agonists that display less respiratory depression than conventional drugs. It is uncertain, however, whether these new drugs cause less tolerance, hyperalgesia, and other maladaptations when administered repeatedly. METHODS: The archetypical µ-opioid receptor agonist morphine and, separately, the G-protein-biased µ-opioid receptor agonist oliceridine were administered to mice. These drugs were used in models of acute analgesia, analgesic tolerance, opioid-induced hyperalgesia, reward, and physical dependence. In addition, morphine and oliceridine were administered for 7 days after tibia fracture and pinning; mechanical allodynia and gait were followed for 3 weeks. Finally, the expression of toll-like receptor-4 and nacht domain-, leucine-rich repeat-, and pyrin domain-containing protein 3 (NALP3) and interleukin-1ß mRNA were quantified in spinal tissue to measure surgical and drug effects on glia-related gene expression. RESULTS: We observed using the tail flick assay that oliceridine was a 4-fold more potent analgesic than morphine, but that oliceridine treatment caused less tolerance and opioid-induced hyperalgesia than morphine after 4 days of ascending-dose administration. Using similar analgesic doses, morphine caused reward behavior in the conditioned place preference assay while oliceridine did not. Physical dependence was, however, similar for the 2 drugs. Likewise, morphine appeared to more significantly impair the recovery of nociceptive sensitization and gait after tibial fracture and pinning than oliceridine. Furthermore, spinal cord toll-like receptor-4 levels 3 weeks after fracture were higher in fracture mice given morphine than those given oliceridine. CONCLUSIONS: Aside from reduced respiratory depression, G-protein-biased agonists such as oliceridine may reduce opioid maladaptations and enhance the quality of surgical recovery.

Chronic Pain After Traumatic Brain Injury: Pathophysiology and Pain Mechanisms.

Background: Traumatic brain injury refers to a broad range of neurological, cognitive, and emotional factors that result from the application of an external force to the head. Individuals recovering from traumatic brain injury will frequently experience acute and chronic pain. Objective: The objective of this paper is to discuss the pathophysiological changes resulting from traumatic brain injury and how these may be involved in the development and persistence of pain after injury. Methods: We based our review on articles retrieved from the MEDLINE database of references and abstracts on life sciences and biomedical topics (1966 to present) using the search engine PubMed (United States National Library of Medicine). The published literature focused on traumatic brain injury and pain. Conclusions: This review presents evidence that pain is common after traumatic brain injury. However, while there are many potential mechanisms explaining this problem such as neuroinflammation, excitotoxicity, and axonal degeneration, we have no clear understanding of which of them contribute in individual patients. The authors highlight the priorities for research that will expand our knowledge and that may lead to the rational design of therapies that both reduce pain and provide optimal overall outcomes after traumatic brain injury.

Dysregulation of the Wnt pathway inhibits timely myelination and remyelination in the mammalian CNS.

The progressive loss of CNS myelin in patients with multiple sclerosis (MS) has been proposed to result from the combined effects of damage to oligodendrocytes and failure of remyelination. A common feature of demyelinated lesions is the presence of oligodendrocyte precursors (OLPs) blocked at a premyelinating stage. However, the mechanistic basis for inhibition of myelin repair is incompletely understood. To identify novel regulators of OLP differentiation, potentially dysregulated during repair, we performed a genome-wide screen of 1040 transcription factor-encoding genes expressed in remyelinating rodent lesions. We report that approximately 50 transcription factor-encoding genes show dynamic expression during repair and that expression of the Wnt pathway mediator Tcf4 (aka Tcf7l2) within OLPs is specific to lesioned-but not normal-adult white matter. We report that beta-catenin signaling is active during oligodendrocyte development and remyelination in vivo. Moreover, we observed similar regulation of Tcf4 in the developing human CNS and lesions of MS. Data mining revealed elevated levels of Wnt pathway mRNA transcripts and proteins within MS lesions, indicating activation of the pathway in this pathological context. We show that dysregulation of Wnt-beta-catenin signaling in OLPs results in profound delay of both developmental myelination and remyelination, based on (1) conditional activation of beta-catenin in the oligodendrocyte lineage in vivo and (2) findings from APC(Min) mice, which lack one functional copy of the endogenous Wnt pathway inhibitor APC. Together, our findings indicate that dysregulated Wnt-beta-catenin signaling inhibits myelination/remyelination in the mammalian CNS. Evidence of Wnt pathway activity in human MS lesions suggests that its dysregulation might contribute to inefficient myelin repair in human neurological disorders.

How much is enough? Using Delphi to explore the clinical-contact-time and return-to-practice needs of military nurses.

Aim Military nurses are required to deploy worldwide at any time to support British forces. They must maintain military and clinical skills, and fulfil other military commitments as required. These diverse responsibilities make it challenging for military nurses to maintain the level of clinical expertise they require for short-notice deployments. A service evaluation was conducted to investigate issues related to clinical contact time (CCT) and to return to practice (RTP) for military nurses. Method A consultative approach was taken in the form of a modified Delphi study, followed by a military judgement panel (focus group). Results Two aspects of the study are reported here: CCT and RTP. Panellists considered that policy rather than guidance is needed to ensure military nurses achieve the requisite CCT to prepare them for operational deployment. Additionally, there was a broad consensus on a range of issues, including minimum CCT for specific groups and mechanisms to support those returning to practice. Conclusion Maintaining clinical skills, and the challenges of returning to practice, require careful consideration in a mobile workforce with wide-ranging commitments. Prescribing CCT, ensuring assignment orders specify CCT and the introduction of job plans should help military nurses maintain their core and specialist nursing skills, guide commanders and reinforce the culture of 'hands-on nursing' as a valid use of time.

Corticospinal sprouting differs according to spinal injury location and cortical origin in macaque monkeys.

The primate corticospinal tract (CST), the major descending pathway mediating voluntary hand movements, comprises nine or more functional subdivisions. The role of subcomponents other than that from primary motor cortex, however, is not well understood. We have previously shown that following a cervical dorsal rhizotomy (Darian-Smith et al., 2013), CST projections originating from primary somatosensory (S1) and motor (M1) cortex responded quite differently to injury. Terminal projections from the S1 (areas 3b/1/2) shrank to <60% of the contralateral side, while M1 CST projections remained robust or expanded (>110%). Here, we asked what happens when a central lesion is added to the equation, to better simulate clinical injury. Monkeys (n = 6) received either a unilateral (1) dorsal root lesion (DRL), (2) or a combined DRL/dorsal column lesion (DRL/DCL), or (3) a DRL/DCL where the DCL was made 4 months following the initial DRL. Electrophysiological recordings were made in S1 4 months postlesion in the first two groups, and 6 weeks after the DCL in the third lesion group, to identify the reorganized region of D1-D3 (thumb, index finger, and middle finger) representation. Anterograde tracers were then injected bilaterally to assess spinal terminal labeling. Remarkably, in all DRL/DCL animals, terminal projections from the S1 and M1 extended bilaterally and caudally well beyond terminal territories in normal animals or following a DRL. These data were highly significant. Extensive sprouting from the S1 CST has not been reported previously, and these data raise important questions about S1 CST involvement in recovery following spinal injury.

Designer Receptor Exclusively Activated by Designer Drug (DREADD)-Mediated Activation of the Periaqueductal Gray Restores Nociceptive Descending Inhibition After Traumatic Brain Injury in Rats.

Traumatic brain injury (TBI) patients frequently experience chronic pain that can enhance their suffering and significantly impair rehabilitative efforts. Clinical studies suggest that damage to the periaqueductal gray matter (PAG) following TBI, a principal center involved in endogenous pain control, may underlie the development of chronic pain. We hypothesized that TBI would diminish the usual pain control functions of the PAG, but that directly stimulating this center using a chemogenetic approach would restore descending pain modulation. We used a well-characterized lateral fluid percussion model (1.3 ± 0.1 atm) of TBI in male rats (n = 271) and measured hindpaw mechanical nociceptive withdrawal thresholds using von Frey filaments. To investigate the role of the PAG in pain both before and after TBI, we activated the neurons of the PAG using a Designer Receptor Exclusively Activated by Designer Drug (DREADD) viral construct. Immunohistochemical analysis of brain tissue was used to assess the location and confirm the appropriate expression of the viral constructs in the PAG. Activation of the PAG DREADD using clozapine N-oxide (CNO) caused hindpaw analgesia that could be blocked using opioid receptor antagonist, naloxone, in uninjured but not TBI rats. Due to the importance of descending serotonergic signaling in modulating nociception, we ablated spinal serotonin signaling using 5,7-DHT. This treatment strongly reduced CNO-mediated anti-nociceptive effects in TBI but not uninjured rats. To define the serotonergic receptor(s) required for the CNO-stimulated effects in TBI rats, we administered 5-HT7 (SB-269970) and 5-HT1A (WAY-100635) receptor antagonists but observed no effects. The selective 5-HT2A receptor antagonist ketanserin, however, blocked CNO's effects in the DREADD expressing TBI but not DREADD expressing sham TBI animals. Blockade of alpha-1 adrenergic receptors with prazosin also had no effect after TBI. Descending pain control originating in the PAG is mediated through opioid receptors in uninjured rats. TBI, however, fundamentally alters the descending nociceptive control circuitry such that serotonergic influences predominate, and those are mediated by the 5-HT2A receptor. These results provide further evidence that the PAG is a key target for anti-nociception after TBI.

The lived experience of co-production: Reflective accounts from the InCLUDE project.

BACKGROUND: The value of co-produced research in health and social care is increasingly recognised, but accounts into the processes and individual experiences of co-producing research are lacking. This paper describes the personal journeys of four researchers (two experts by foster caring experience and two experts by profession) throughout the life course of a co-produced research project exploring the barriers and facilitators to inclusive research in foster caring, the InCLUDE project. METHODS: Each researcher kept a diary throughout the InCLUDE project of their personal reflections, questions, and learning. These were synthesised and reviewed by the researchers and two colleagues external to the team, and key themes were extracted. RESULTS: Narratives constructed from the diaries are presented in relation to distinct aspects of the co-production journey, alongside illustrative quotes. These aspects include: motivations for starting the project; making sense of the project; defining roles and responsibilities; challenges; and reflections on acquired knowledge and skills. From these insights, the researchers present recommendations for others endeavouring to engage in co-produced research. These include: recognising vulnerabilities and challenges during the early stages of a project; creating safe spaces; seeing the value of diversity; harnessing individual strengths; establishing a strong routine; and ensuring equal voice. CONCLUSIONS: This paper presents a novel perspective on the realities of co-produced research by documenting the lived experiences of researchers within the context of foster care research. It highlights the importance of both measurable, tangible project outcomes, and the personal and skills growth of team members. The consistent use of diaries is encouraged as a valuable practice to capture learning, progress and achievements throughout the co-production process.

Four researchers (two experts by foster caring experience and two experts by profession) reflect on their journey of being part of the InCLUDE project. InCLUDE looked at how to make research with foster and kinship carers more inclusive. Each researcher kept a diary throughout the project, to help them capture their learning, thoughts and feelings. In this paper, the diaries are collated together into themes, with illustrative quotes. These themes include motivations to get involved in the project, settling into the role, challenges, personal development, and new knowledge. The researchers then share their key learning which can help others who are hoping to co-produce a research project. This includes the importance of talking about feeling vulnerable, creating safe spaces, working to your individual strengths, setting up a strong routine, and making sure that everyone has an equal voice and role on the project. The researchers also discuss the benefits of using diaries as a way to capture learning, experiences and progress, and encourage other research teams to do the same.

Mechanisms and treatments of chronic pain after traumatic brain injury.

While pain after trauma generally resolves, some trauma patients experience pain for months to years after injury. An example, relevant to both combat and civilian settings, is chronic pain after traumatic brain injury (TBI). Headache as well as pain in the back and extremities are common locations for TBI-related chronic pain to be experienced. TBI-related pain can exist alone or can exacerbate pain from other injuries long after healing has occurred. Consequences of chronic pain in these settings include increased suffering, higher levels of disability, serious emotional problems, and worsened cognitive deficits. The current review will examine recent evidence regarding dysfunction of endogenous pain modulatory mechanisms, neuroplastic changes in the trigeminal circuitry and alterations in spinal nociceptive processing as contributors to TBI-related chronic pain. Key pain modulatory centers including the locus coeruleus, periaqueductal grey matter, and rostroventromedial medulla are vulnerable to TBI. Both the rationales and existing evidence for the use of monoamine reuptake inhibitors, CGRP antagonists, CXCR2 chemokine receptor antagonists, and interventional therapies will be presented. While consensus guidelines for the management of chronic post-traumatic TBI-related pain are lacking, several approaches to this clinically challenging situation deserve focused evaluation and may prove to be viable therapeutic options.

Preclinical characterization of the efficacy and safety of biologic N-001 as a novel pain analgesic for post-operative acute pain treatment.

Inhibition of actin remodeling in nerves modulates action potential propagation and therefore could be used to treat acute pain. N-001 is a novel protein analgesic engineered from several C. Botulinum toxins. N-001 targets sensory neurons through ganglioside GT1b binding and ADP-ribosylates G-actin reducing actin remodeling. The activity and efficacy of N-001 was evaluated previously in vitro and in a mouse inflammatory pain model. To assess the relevance of N-001 for treatment of acute post-surgical pain, the current study evaluated the efficacy of N-001 in a mouse hind-paw incision model by peri-incisional and popliteal nerve block administration combined with mechanical testing. N-001 provided relief of pain-like behavior over 3 days and 2 days longer than the conventional long-acting anesthetic bupivacaine. Preclinical safety studies of N-001 indicated the drug produced no toxic or adverse immunological reactions over multiple doses in mice. These results combined with past targeting results encourage further investigation of N-001 as an analgesic for post-operative pain management with the potential to function as a differential nociceptor-specific nerve block.

Effect of Voluntary Exercise on Endogenous Pain Control Systems and Post-traumatic Headache in Mice.

Traumatic brain injury (TBI) can cause acute and chronic pain along with motor, cognitive, and emotional problems. Although the mechanisms are poorly understood, previous studies suggest disruptions in endogenous pain modulation may be involved. Voluntary exercise after a TBI has been shown to reduce some consequences of injury including cognitive impairment. We hypothesized, therefore, that voluntary exercise could augment endogenous pain control systems in a rodent model of TBI. For these studies, we used a closed-head impact procedure in male mice modeling mild TBI. We investigated the effect of voluntary exercise on TBI-induced hindpaw nociceptive sensitization, diffuse noxious inhibitory control failure, and periorbital sensitization after bright light stress, a model of post-traumatic headache. Furthermore, we investigated the effects of exercise on memory, circulating markers of brain injury, neuroinflammation, and spinal cord gene expression. We observed that exercise significantly reduced TBI-induced hindpaw allodynia and periorbital allodynia in the first week following TBI. We also showed that exercise improved the deficits associated with diffuse noxious inhibitory control and reduced bright light stress-induced allodynia up to 2 months after TBI. In addition, exercise preserved memory and reduced TBI-induced increases in spinal BDNF, CXCL1, CXCL2, and prodynorphin expression, all genes previously linked to TBI-induced nociceptive sensitization. Taken together, our observations suggest that voluntary exercise may reduce pain after TBI by reducing TBI-induced changes in nociceptive signaling and preserving endogenous pain control systems. PERSPECTIVE: This article evaluates the effects of exercise on pain-related behaviors in a preclinical model of traumatic brain injury (TBI). The findings show that exercise reduces nociceptive sensitization, loss of diffuse noxious inhibitory control, memory deficits, and spinal nociception-related gene expression after TBI. Exercise may reduce or prevent pain after TBI.

The Reflective Fostering Programme-Adapting a group parenting programme for online delivery in response to the COVID-19 pandemic in the United Kingdom.

OBJECTIVE: In the context of the Covid-19 pandemic and subsequent lockdown restrictions, service providers faced significant challenges in delivering programmes to support their vulnerable service users. Foster carers-an already often isolated group of caregivers - were offered an adapted remote-delivery model of the Reflective Fostering Programme (Redfern et al., Adopt. Foster., 42, 2018, 234) from March 2020. METHOD: This paper outlines the adaptation process of the original programme to online-remote delivery and describes the feedback from participants in the programme. RESULTS: The adaptation of the Reflective Fostering programme to online, remote delivery had both strengths and weaknesses - including wider access to foster carers who might struggle to attend in person and challenge a to maintaining a Mentalizing space online and ensuring confidentiality within a therapeutic space. The programme was overwhelmingly well received by foster carers in this format. CONCLUSIONS: There are opportunities and challenges in the delivery of online therapeutic services, particularly those with a group format. This paper contributes initial reflections to what we hope will be a rapidly developing literature on best practice of supporting group services in an online format.

Monoamine control of descending pain modulation after mild traumatic brain injury.

Traumatic brain injury (TBI) is a significant public health concern, with the majority of injuries being mild. Many TBI victims experience chronic pain. Unfortunately, the mechanisms underlying pain after TBI are poorly understood. Here we examined the contribution of spinal monoamine signaling to dysfunctional descending pain modulation after TBI. For these studies we used a well-characterized concussive model of mild TBI. Measurements included mechanical allodynia, the efficacy of diffuse noxious inhibitory control (DNIC) endogenous pain control pathways and lumber norepinephrine and serotonin levels. We observed that DNIC is strongly reduced in both male and female mice after mild TBI for at least 12 weeks. In naïve mice, DNIC was mediated through α2 adrenoceptors, but sensitivity to α2 adrenoceptor agonists was reduced after TBI, and reboxetine failed to restore DNIC in these mice. The intrathecal injection of ondansetron showed that loss of DNIC was not due to excess serotonergic signaling through 5-HT3 receptors. On the other hand, the serotonin-norepinephrine reuptake inhibitor, duloxetine and the serotonin selective reuptake inhibitor escitalopram both effectively restored DNIC after TBI in both male and female mice. Therefore, enhancing serotonergic signaling as opposed to noradrenergic signaling alone may be an effective pain treatment strategy after TBI.

Blast-induced axonal degeneration in the rat cerebellum in the absence of head movement.

Blast exposure can injure brain by multiple mechanisms, and injury attributable to direct effects of the blast wave itself have been difficult to distinguish from that caused by rapid head displacement and other secondary processes. To resolve this issue, we used a rat model of blast exposure in which head movement was either strictly prevented or permitted in the lateral plane. Blast was found to produce axonal injury even with strict prevention of head movement. This axonal injury was restricted to the cerebellum, with the exception of injury in visual tracts secondary to ocular trauma. The cerebellar axonal injury was increased in rats in which blast-induced head movement was permitted, but the pattern of injury was unchanged. These findings support the contentions that blast per se, independent of head movement, is sufficient to induce axonal injury, and that axons in cerebellar white matter are particularly vulnerable to direct blast-induced injury.

The use of social robots with children and young people on the autism spectrum: A systematic review and meta-analysis.

BACKGROUND: Robot-mediated interventions show promise in supporting the development of children on the autism spectrum. OBJECTIVES: In this systematic review and meta-analysis, we summarize key features of available evidence on robot-interventions for children and young people on the autism spectrum aged up to 18 years old, as well as consider their efficacy for specific domains of learning. DATA SOURCES: PubMed, Scopus, EBSCOhost, Google Scholar, Cochrane Library, ACM Digital Library, and IEEE Xplore. Grey literature was also searched using PsycExtra, OpenGrey, British Library EThOS, and the British Library Catalogue. Databases were searched from inception until April (6th) 2021. SYNTHESIS METHODS: Searches undertaken across seven databases yielded 2145 articles. Forty studies met our review inclusion criteria of which 17 were randomized control trials. The methodological quality of studies was conducted with the Quality Assessment Tool for Quantitative Studies. A narrative synthesis summarised the findings. A meta-analysis was conducted with 12 RCTs. RESULTS: Most interventions used humanoid (67%) robotic platforms, were predominantly based in clinics (37%) followed home, schools and laboratory (17% respectively) environments and targeted at improving social and communication skills (77%). Focusing on the most common outcomes, a random effects meta-analysis of RCTs showed that robot-mediated interventions significantly improved social functioning (g = 0.35 [95%CI 0.09 to 0.61; k = 7). By contrast, robots did not improve emotional (g = 0.63 [95%CI -1.43 to 2.69]; k = 2) or motor outcomes (g = -0.10 [95%CI -1.08 to 0.89]; k = 3), but the numbers of trials were very small. Meta-regression revealed that age accounted for almost one-third of the variance in effect sizes, with greater benefits being found in younger children. CONCLUSIONS: Overall, our findings support the use of robot-mediated interventions for autistic children and youth, and we propose several recommendations for future research to aid learning and enhance implementation in everyday settings. PROSPERO REGISTRATION: Our methods were preregistered in the PROSPERO database (CRD42019148981).

Childhood trauma and schizotypy in non-clinical samples: A systematic review and meta-analysis.

The association of early life adversities and psychosis symptoms is well documented in clinical populations; however, whether this relationship also extends into subclinical psychosis remains unclear. In particular, are early life adversities associated with increased levels of schizotypal personality traits in non-clinical samples? We conducted a systematic review and meta-analysis of associations between early life adversities and psychometrically defined schizotypal traits in non-clinical samples. The review followed PRISMA guidelines. The search using PubMed, Web of Science and EBSCO databases identified 1,609 articles in total. Twenty-five studies (N = 15,253 participants) met eligibility criteria for the review. An assessment of study quality showed that fewer than half of all studies were rated as methodologically robust. Meta-analyses showed that all forms of childhood abuse (emotional, physical and sexual) and neglect (emotional and physical) were significantly associated with psychometric schizotypy. The association of schizotypy traits with childhood emotional abuse (r = .33: 95%CI .30 to .37) was significantly larger than for all other form of abuse or neglect. Meta-regression analyses showed that the physical abuse-schizotypy relationship was stronger in samples with more women participants; and the sexual abuse-schizotypy relationship was stronger in younger samples. The current review identifies a dose-response relationship between all forms of abuse/neglect and schizotypy scores in non-clinical samples; however, a stronger association emerged for emotional abuse. More research is required to address the relationship of trauma types and specific symptom types. Future research should also address the under-representation of men.

Activation of the Locus Coeruleus Mediated by Designer Receptor Exclusively Activated by Designer Drug Restores Descending Nociceptive Inhibition after Traumatic Brain Injury in Rats.

Disruption of endogenous pain control mechanisms including descending pain inhibition has been linked to several forms of pain including chronic pain after traumatic brain injury (TBI). The locus coeruleus (LC) is the principal noradrenergic (NA) nucleus participating in descending pain inhibition. We therefore hypothesized that selectively stimulating LC neurons would reduce nociception after TBI. All experiments used a well-characterized rat lateral fluid percussion model of TBI. NA neurons were stimulated by administering clozapine N-oxide (CNO) to rats selectively expressing a designer receptor exclusively activated by designer drug (DREADD) viral construct in their LC's. Mechanical nociceptive thresholds were measured using von Frey fibers. The efficacy of diffuse noxious inhibitory control (DNIC), a critical endogenous pain control mechanism, was assessed using the hindpaw administration of capsaicin. Immunohistochemical analyses demonstrated the selective expression of the DREADD construct in LC neurons after stereotactic injection. During the 1st week after TBI, when rats demonstrated hindlimb (HL) nociceptive sensitization, CNO administration provided transient anti-allodynia in DREADD-expressing rats but not in rats injected with control virus. Seven weeks after TBI we observed a complete loss of DNIC in response to capsaicin. However, CNO administration largely restored DNIC in TBI DREADD-expressing rats but not those injected with control virus. Unexpectedly, the effects of LC activation in the DREADD-expressing rats were blocked by the α-1 adrenergic receptor antagonist prazosin, but not the α-2 adrenergic receptor antagonist atipamezole. These results suggest that directly stimulating the LC after TBI can reduce both early and late manifestations of dysfunctional endogenous pain regulation. Clinical approaches to activating descending pain circuits may reduce suffering in those with pain after TBI.

Paranormal beliefs and cognitive function: A systematic review and assessment of study quality across four decades of research.

BACKGROUND: Research into paranormal beliefs and cognitive functioning has expanded considerably since the last review almost 30 years ago, prompting the need for a comprehensive review. The current systematic review aims to identify the reported associations between paranormal beliefs and cognitive functioning, and to assess study quality. METHOD: We searched four databases (Scopus, ScienceDirect, SpringerLink, and OpenGrey) from inception until May 2021. Inclusion criteria comprised papers published in English that contained original data assessing paranormal beliefs and cognitive function in healthy adult samples. Study quality and risk of bias was assessed using the Appraisal tool for Cross-Sectional Studies (AXIS) and results were synthesised through narrative review. The review adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and was preregistered as part of a larger registration on the Open Science Framework (https://osf.io/uzm5v). RESULTS: From 475 identified studies, 71 (n = 20,993) met our inclusion criteria. Studies were subsequently divided into the following six categories: perceptual and cognitive biases (k = 19, n = 3,397), reasoning (k = 17, n = 9,661), intelligence, critical thinking, and academic ability (k = 12, n = 2,657), thinking style (k = 13, n = 4,100), executive function and memory (k = 6, n = 810), and other cognitive functions (k = 4, n = 368). Study quality was rated as good-to-strong for 75% of studies and appears to be improving across time. Nonetheless, we identified areas of methodological weakness including: the lack of preregistration, discussion of limitations, a-priori justification of sample size, assessment of nonrespondents, and the failure to adjust for multiple testing. Over 60% of studies have recruited undergraduates and 30% exclusively psychology undergraduates, which raises doubt about external validity. Our narrative synthesis indicates high heterogeneity of study findings. The most consistent associations emerge for paranormal beliefs with increased intuitive thinking and confirmatory bias, and reduced conditional reasoning ability and perception of randomness. CONCLUSIONS: Although study quality is good, areas of methodological weakness exist. In addressing these methodological issues, we propose that authors engage with preregistration of data collection and analysis procedures. At a conceptual level, we argue poorer cognitive performance across seemingly disparate cognitive domains might reflect the influence of an over-arching executive dysfunction.