Limbic Responses Following Shock Wave Exposure in Male and Female Mice.

Blast traumatic brain injury (bTBI) presents a serious threat to military personnel and often results in psychiatric conditions related to limbic system dysfunction. In this study, the functional outcomes for anxiety- and depressive-like behaviors and neuronal activation were evaluated in male and female mice after exposure to an Advanced Blast Simulator (ABS) shock wave. Mice were placed in a ventrally exposed orientation inside of the ABS test section and received primary and tertiary shock wave insults of approximately 15 psi peak pressure. Evans blue staining indicated cases of blood-brain barrier breach in the superficial cerebral cortex four, but not 24 h after blast, but the severity was variable. Behavioral testing with the elevated plus maze (EPM) or elevated zero maze (EZM), sucrose preference test (SPT), and tail suspension test (TST) or forced swim test (FST) were conducted 8 days-3.5 weeks after shock wave exposure. There was a sex difference, but no injury effect, for distance travelled in the EZM where female mice travelled significantly farther than males. The SPT and FST did not indicate group differences; however, injured mice were less immobile than sham mice during the TST; possibly indicating more agitated behavior. In a separate cohort of animals, the expression of the immediate early gene, c-Fos, was detected 4 h after undergoing bTBI or sham procedures. No differences in c-Fos expression were found in the cerebral cortex, but female mice in general displayed enhanced c-Fos activation in the paraventricular nucleus of the thalamus (PVT) compared to male mice. In the amygdala, more c-Fos-positive cells were observed in injured animals compared to sham mice. The observed sex differences in the PVT and c-Fos activation in the amygdala may correlate with the reported hyperactivity of females post-injury. This study demonstrates, albeit with mild effects, behavioral and neuronal activation correlates in female rodents after blast injury that could be relevant to the incidence of increased post-traumatic stress disorder in women.

Meningeal and Visual Pathway Magnetic Resonance Imaging Analysis after Single and Repetitive Closed-Head Impact Model of Engineered Rotational Acceleration (CHIMERA)-Induced Disruption in Male and Female Mice.

The consequences of forceful rotational acceleration on the central nervous system are not fully understood. While traumatic brain injury (TBI) research primarily has focused on effects related to the brain parenchyma, reports of traumatic meningeal enhancement in TBI patients may possess clinical significance. The objective of this study was to evaluate the meninges and brain for changes in dynamic contrast enhancement (DCE) magnetic resonance imaging (MRI) following closed-head impact model of engineered rotational acceleration (CHIMERA)-induced cerebral insult. Adult male and female mice received one (1 × ; n = 19 CHIMERA, n = 19 Sham) or four (4 × one/day; n = 18 CHIMERA, n = 12 Sham) injuries. Each animal underwent three MRI scans: 1 week before injury, immediately after the final injury, and 1 week post-injury. Compared with baseline readings and measures in sham animals, meningeal DCE in males was increased after single impact and repetitive injury. In female mice, DCE was elevated relative to their baseline level after a single impact. One week after CHIMERA, the meningeal enhancement returned to below baseline for single injured male mice, but compared with uninjured mice remained elevated in both sexes in the multiple impact groups. Pre-DCE meningeal T2-weighted relaxation time was increased only after 1 × CHIMERA in injured mice. Since vision is impaired after CHIMERA, visual pathway regions were analyzed through imaging and glial fibrillary acidic protein (GFAP) histology. Initial DCE in the lateral geniculate nucleus (LGN) and superior colliculus (SC) and T2 increases in the optic tract (OPT) and LGN were observed after injury with decreases in DCE and T2 1 week later. Astrogliosis was apparent in the OPT and SC with increased GFAP staining 7 days post-injury. To our knowledge, this is the first study to examine meningeal integrity after CHIMERA in both male and female rodents. DCE-MRI may serve as a useful approach for pre-clinical models of meningeal injury that will enable further evaluation of the underlying mechanisms.

Behavioral responses following repeated bilateral frontal region closed head impacts and fear conditioning in male and female mice.

The frontal lobes are among the most vulnerable sites in traumatic brain injuries. In the current study, a balanced 2 × 2 × 2 design (n = 18 mice/group), female and male C57Bl/6J mice received repeated bilateral frontal concussive brain injury (frCBI) and underwent fear conditioning (FC) to assess how injured mice respond to adverse conditions. Shocks received during FC impacted behavior on all subsequent tests except the tail suspension test. FC resulted in more freezing behavior in all mice that received foot shocks when evaluated in subsequent context and cue tests and induced hypoactivity in the open field (OF) and elevated zero maze (EZM). Mice that sustained frCBI learned the FC association between tone and shock. Injured mice froze less than sham controls during context and cue tests, which could indicate memory impairment, but could also suggest that frCBI resulted in hyperactivity that overrode the rodent's natural freezing response to threat, as injured mice were also more active in the OF and EZM. There were notable sex differences, where female mice exhibited more freezing behavior than male mice during FC context and cue tests. The findings suggest frCBI impaired, but did not eliminate, FC retention and resulted in an overall increase in general activity. The injury was characterized pathologically by increased inflammation (CD11b staining) in cortical regions underlying the injury site and in the optic tracts. The performance of male and female mice after injury suggested the complexity of possible sex differences for neuropsychiatric symptoms.

COVID-19 deaths in people with intellectual disability in the UK and Ireland: descriptive study.

BACKGROUND: Rapid spread of coronavirus disease 2019 (COVID-19) has affected people with intellectual disability disproportionately. Existing data does not provide enough information to understand factors associated with increased deaths in those with intellectual disability. Establishing who is at high risk is important in developing prevention strategies, given risk factors or comorbidities in people with intellectual disability may be different to those in the general population. AIMS: To identify comorbidities, demographic and clinical factors of those individuals with intellectual disability who have died from COVID-19. METHOD: An observational descriptive case series looking at deaths because of COVID-19 in people with intellectual disability was conducted. Along with established risk factors observed in the general population, possible specific risk factors and comorbidities in people with intellectual disability for deaths related to COVID-19 were examined. Comparisons between mild and moderate-to-profound intellectual disability subcohorts were undertaken. RESULTS: Data on 66 deaths in individuals with intellectual disability were analysed. This group was younger (mean age 64 years) compared with the age of death in the general population because of COVID-19. High rates of moderate-to-profound intellectual disability (n = 43), epilepsy (n = 29), mental illness (n = 29), dysphagia (n = 23), Down syndrome (n = 20) and dementia (n = 15) were observed. CONCLUSIONS: This is the first study exploring associations between possible risk factors and comorbidities found in COVID-19 deaths in people with intellectual disability. Our data provides insight into possible factors for deaths in people with intellectual disability. Some of the factors varied between the mild and moderate-to-profound intellectual disability groups. This highlights an urgent need for further systemic inquiry and study of the possible cumulative impact of these factors and comorbidities given the possibility of COVID-19 resurgence.

The closed-head impact model of engineered rotational acceleration (CHIMERA) as an application for traumatic brain injury pre-clinical research: A status report.

Closed-head traumatic brain injury (TBI) is a worldwide concern with increasing prevalence and cost to society. Rotational acceleration is a primary mechanism in TBI that results from tissue strains that give rise to diffuse axonal injury. The Closed-Head Impact Model of Engineered Rotational Acceleration (CHIMERA) was recently introduced as a method for the study of impact acceleration effects in pre-clinical TBI research. This review provides a survey of the published literature implementing the CHIMERA device and describes pathological, imaging, neurophysiological, and behavioral findings. Findings show CHIMERA inflicts damage in white matter tracts as a key area of injury. Behaviorally, repeated studies have shown motor deficits and more chronic cognitive effects after CHIMERA injury. Good progress with model application has been accomplished by investigators attending to what is required for model validation. However, the majority of CHIMERA studies only utilize adult male mice. To further establish this model, more work with female animals and various age groups need to be performed, as well as studies to further establish and standardize methodologies for validation of the models for clinical relevance. Common data elements to standardize the reporting methodology for the CHIMERA literature are suggested.

Transient disruption of mouse home cage activities and assessment of orexin immunoreactivity following concussive- or blast-induced brain injury.

The employment of explosive weaponry in modern warfare exposes populations to shock wave-induced and impact-related brain injuries. Among the most common clinical complaints resulting from traumatic brain injury (TBI) are sleep-wake disturbances. The current study assessed the acute effects of mild concussive brain injury (CBI) and mild blast wave-induced brain injury (BTBI) on mouse behavior and orexin-A expression. Male C57BL/6J mice were exposed to CBI, BTBI, or sham procedures. Injured animals and their shams were further divided into the following subgroups: 24-h survival in standard group (SG) housing, 72-h survival in SG housing, and 72-h survival in Any-Maze cages (AMc). AMc enabled continuous monitoring of home cage activities. BTBI caused significant but transient decreases in wheel running and ingestive behaviors 24 h post-injury (PI), while CBI transiently decreased running and water intake. BTBI resulted in general hypoactivity in the open field (OF) at both PI time points for SG-housed animals. In contrast, CBI did not cause hypoactivity. Mice subjected to CBI traveled more in the center of the OF at both time points PI, suggesting that CBI caused reduced anxiety in mice. Increased activity in the center of the OF was also seen at 24 h PI after BTBI. CBI treatment caused increased CD11b immunostaining. However, neither injury was accompanied by an alteration in the number of orexin-A hypothalamic neurons. Taken together, shock wave exposure and concussive injury transiently reduced mouse activities, but some differences between the two injuries were seen.

A feasibility randomised controlled trial of extended brief intervention for alcohol misuse in adults with mild to moderate intellectual disabilities living in the community; The EBI-LD study.

BACKGROUND: Extended brief interventions (EBIs) are effective in targeting alcohol misuse in the general population. However, little is known of the effects of EBI in adults with intellectual (also known as learning) disabilities. In this feasibility trial we compared EBI with usual care for alcohol misuse in adults with mild to moderate Intellectual Disability (ID). METHODS: The study took place in three community ID networks of services in England. Participants aged 18-65 years with reported alcohol problems, a score ≥8 on the Alcohol Use Disorder Identification Test (AUDIT), and IQ <70 (+/5%CI) were recruited and were randomly allocated to either EBI (five weekly sessions and one follow-up at 8 weeks) and usual care or usual care alone. Research assistants were blind to arm allocation. Research assessments took place at baseline, 2 and 3 months. The primary outcome was reduction in alcohol consumption measured by the AUDIT. Preliminary health economic analysis was performed to investigate the costs of delivering EBI and the feasibility of a cost-effectiveness analysis in a full trial. The trial is closed. RESULTS: Participants were recruited from January 2014 to August 2015. Thirty individuals were randomised (15 in each arm) and provided primary outcome data. In regard to harmful drinking, at baseline, all the participants exceeded the relevant threshold. At 8 weeks, the proportion of participants with harmful drinking had decreased to 60% for both groups, and at 12 weeks it had decreased by 66°7% and 46°7% for the intervention and the control groups, respectively. The unit cost for the delivery of EBI is £430. CONCLUSIONS: Recruitment to this trial has been proven challenging as prevalence of alcohol misuse in the targeted population was lower than anticipated. EBI may provide an effective low-intensity treatment for this population. Participants' and carers' feedback on their experience was overall positive. Further work needs to be undertaken to ascertain the group of participants that should be participating in a future definitive trial. TRIAL REGISTRATION: Psychological Intervention Alcohol Misuse Learning Disability; isrctn.com, identifier: ISRCTN58783633 . Registered on 17 December 2013.