Adverse childhood experiences exacerbate peripheral symptoms of autism spectrum disorder in adults.

AIM: Adverse childhood experiences are potentially traumatic events with long-lasting effects on the health and well-being of patients with autism spectrum disorder (ASD). It is important to clarify which types of long-lasting autism-related symptoms are influenced by childhood experiences to design future intervention studies. However, few studies have examined the association between childhood experiences and autistic symptoms in large samples of adults with ASD and individuals with typical development (TD). In this study, we evaluate the effects of adverse childhood experiences on multiple ASD phenotypes among both individuals with ASD and those with TD. METHOD: We combined questionnaire evaluations; Childhood Abuse and Trauma Scale, the Japanese version of the Autism-Spectrum Quotient, Conners' Adult ADHD Rating Scale, the Japanese version of the Impact of Event Scale-Revised, and the Japanese version of the Adolescent/Adult Sensory Profile. RESULTS: Individuals with ASD and those with TD (n = 205 and 104, respectively) were included. There were significant correlations between the extent of adverse childhood experiences and severity of attention-deficit/hyperactivity disorder symptoms, posttraumatic stress disorder symptoms, and hypersensitivity in both participants with ASD and those with TD. By contrast, ASD core symptoms showed no significant correlation with adverse childhood experiences in either group. These results remained consistent after adjusting for age, sex, and the estimated intelligence quotient. CONCLUSION: These findings suggest the need for a detailed disentanglement of ASD-related core and peripheral symptoms of adverse childhood experiences, which may help to appropriately set outcomes for future early interventions for the childhood experiences of individuals with ASD.

Objectifying subjective memory complaints: VR-based Verbal Word Learning Test in chronic stroke patients.

Memory impairment imposes a great burden on stroke patients and can be divided into Objective Memory Problems (OMPs) and Subjective Memory Complaints (SMCs). Studies have shown that these do not always co-occur. Possibly, the gap between SMCs and OMPs can be bridged when using a more ecologically valid memory test and considering the impact of other common stroke symptoms such as sensory hypersensitivity (SHS) and fatigue. In the present study, we applied Virtual Reality (VR) to create a sensory-rich environment with real-life stimuli. Memory performance was tested with the 15-Verbal Word Learning Test (VLT). Furthermore, we assessed SMCs (Everyday Memory Questionnaire), and the levels of SHS (Multi-Modal Evaluation of Sensory Sensitivity) and fatigue in the previous month. 31 chronic stroke patients and 32 healthy controls participated. The results showed that participants' memory performance decreased in a sensory-rich compared to a neutral environment. This decrease did not significantly differ between the groups. Interestingly, fatigue and SHS are related to the level of SMC in stroke patients but no such evidence was found in healthy controls. Last, for stroke patients, we found a significant negative correlation between SMCs and memory performance in a sensory-rich environment, but not in a neutral environment. In conclusion, our study implicates that in stroke patients, fatigue and SHS are related to SMCs and that using a sensory-rich VR environment might be a more ecologically valid way to objectify SMCs. However, interpretative caution is warranted due to the absence of sex and age-matched controls and potential selection bias.

Discordant dry eye disease and chronic pain: A systematic review and meta-analysis.

PURPOSE: To evaluate the relative contributions of objective and subjective indicators of dry eye disease (DED) in individuals with chronic pain conditions compared with controls. METHODS: A systematic review and meta-analysis was conducted of studies that reported the signs and symptoms of DED and/or their prevalence in individuals with chronic pain compared with controls. International Association for the Study of Pain (IASP) International Classification of Diseases (ICD)-11 codes for chronic pain conditions were applied, and outcomes defined as DED signs and symptoms. A search strategy utilised the EMBASE, Web of Science, Cochrane Library and MEDLINE databases. Risk of bias assessment was performed with the Newcastle-Ottawa scale. Random effects meta-analysis calculated mean differences (MD) and odds ratios (OR), while subgroup analysis of different chronic pain conditions explored their relative association with the signs and symptoms of DED. Evidence certainty was evaluated using Grades of Recommendation, Assessment, Development, and Evaluation (GRADE). RESULTS: Fourteen observational studies comprising 3,281,882 individuals were included. Meta-analysis found high quality evidence that individuals with chronic pain were more likely to experience symptoms of DED than controls (OR = 3.51 [95 %CI: 3.45,3.57]). These symptoms were more severe (MD = 18.53 [95 %CI: 11.90, 25.15]) than controls with a clinically meaningful effect size. Individuals with chronic pain had more rapid tear film disruption (MD = -2.45 [95 %CI: -4.20, -0.70]) and reduced tear production (MD = -5.57 [95 %CI: -9.56, -1.57]) compared with controls (with moderate evidence quality). High quality evidence revealed individuals with chronic pain had lower basal tear production (anaesthetised) than controls (MD = -2.59 [95 %CI: -3.60, -1.58]). Tear film osmolarity showed no significant differences between the chronic pain and pain-free groups. Group differences for DED signs were not considered clinically meaningful. CONCLUSION: More severe, clinically meaningful symptoms of DED were reported in individuals with chronic pain than controls, however group differences for the signs of DED were typically of limited or questionable clinical relevance. This ocular phenotype where DED is felt more than it is seen in chronic pain may reflect underlying sensory hypersensitivity, shared by both conditions and contributing to their frequent comorbidity. Advancing understanding of this potential pathophysiological mechanism may guide clinical management.

Why am I overwhelmed by bright lights? The behavioural mechanisms of post-stroke visual hypersensitivity.

After stroke, patients can experience visual hypersensitivity, an increase in their sensitivity for visual stimuli as compared to their state prior to the stroke. Candidate behavioural mechanisms for these subjective symptoms are atypical bottom-up sensory processing and impaired selective attention, but empirical evidence is currently lacking. In the current study, we aimed to investigate the relationship between post-stroke visual hypersensitivity and sensory thresholds, sensory processing speed, and selective attention using computational modelling of behavioural data. During a whole/partial report task, participants (51 stroke patients, 76 orthopedic patients, and 77 neurotypical adults) had to correctly identify a single target letter that was presented alone (for 17-100 ms) or along a distractor (for 83ms). Performance on this task was used to estimate the sensory threshold, sensory processing speed, and selective attention abilities of each participant. In the stroke population, both on a group and individual level, there was evidence for impaired selective attention and -to a lesser extent- lower sensory thresholds in patients with post-stroke visual hypersensitivity as compared to neurotypical adults, orthopedic patients, or stroke patients without post-stroke sensory hypersensitivity. These results provide a significant advancement in our comprehension of post-stroke visual hypersensitivity and can serve as a catalyst for further investigations into the underlying mechanisms of sensory hypersensitivity after other types of acquired brain injury as well as post-injury hypersensitivity for other sensory modalities.

Phenotypic analysis of multielectrode array EEG biomarkers in developing and adult male Fmr1 KO mice.

Fragile X Syndrome (FXS) is a leading known genetic cause of intellectual disability with symptoms that include increased anxiety and social and sensory processing deficits. Recent electroencephalographic (EEG) studies in humans with FXS have identified neural oscillation deficits that include increased resting state gamma power, increased amplitude of auditory evoked potentials, and reduced phase locking of sound-evoked gamma oscillations. Similar EEG phenotypes are present in mouse models of FXS, but very little is known about the development of such abnormal responses. In the current study, we employed a 30-channel mouse multielectrode array (MEA) system to record and analyze resting and stimulus-evoked EEG signals in male P21 and P91 WT and Fmr1 KO mice. This led to several novel findings. First, P91, but not P21, Fmr1 KO mice have significantly increased resting EEG power in the low- and high-gamma frequency bands. Second, both P21 and P91 Fmr1 KO mice have markedly attenuated inter-trial phase coherence (ITPC) to spectrotemporally dynamic auditory stimuli as well as to 40 Hz and 80 Hz auditory steady-state response (ASSR) stimuli. This suggests abnormal temporal processing from early development that may lead to abnormal speech and language function in FXS. Third, we found hemispheric asymmetry of fast temporal processing in the mouse auditory cortex in WT but not Fmr1 KO mice. Together, these findings define a set of EEG phenotypes in young and adult mice that can serve as translational targets for genetic and pharmacological manipulation in phenotypic rescue studies.

Pre-operative pain pressure threshold association with patient satisfaction following Total Knee Arthroplasty.

Background: Total knee arthroplasty (TKA) is commonly performed for the treatment of knee osteoarthritis (KOA). Poor satisfaction continues to be seen after TKA. Whilst reasons for poor patient satisfaction are multifactorial, there is a strong correlation with persistent pain following TKA. Studies have shown an association between local and remote mechanical hypersensitivity, measured using pressure pain thresholds (PPTs), and severity of knee osteoarthritis and functional status. We aimed to determine if the pre-operative PPTs were associated with patient satisfaction following TKA. Methods: A prospective longitudinal study of 77 individuals was undertaken. Regression modelling assessed the relationship between Patient Satisfaction using the Knee Society Score (satisfaction subscale) following TKA for KOA, and PPTs recorded pre-operatively locally and remote to the affected knee, while accounting for potentially confounding patient demographic and psychosocial factors. Results: Lower PPTs (indicating increased mechanical hypersensitivity) locally and remote to the operative knee were modestly associated with lower patient satisfaction in the short-term (six weeks) following TKA (ß 0.25-0.28, adjR2 = 0.14-0.15), independent of demographic or psychosocial influences. However, this relationship progressively diminished in the intermediate and long-term post TKA. Conclusion: While pre-operative PPT measures may provide some foresight to patient satisfaction post TKA in the short term, these measures appear to provide little insight to patient satisfaction in the intermediate and longer term.

The Multi-Modal Evaluation of Sensory Sensitivity (MESSY): Assessing a commonly missed symptom of acquired brain injury.

Objective: Sensory hypersensitivity is common after acquired brain injury. Since appropriate diagnostic tools are lacking, these complaints are overlooked by clinicians and available literature is limited to light and noise hypersensitivity after concussion. This study aimed to investigate the prevalence of sensory hypersensitivity in other modalities and after other types of brain injury. Method: We developed the Multi-Modal Evaluation of Sensory Sensitivity (MESSY), a patient-friendly questionnaire that assesses sensory sensitivity across multiple sensory modalities. 818 neurotypical adults (mean age = 49; 244 male) and 341 chronic acquired brain injury patients (including stroke, traumatic brain injury, and brain tumour patients) (mean age = 56; 126 male) completed the MESSY online. Results: The MESSY had a high validity and reliability in neurotypical adults. Post-injury sensory hypersensitivity (examined using open-ended questions) was reported by 76% of the stroke patients, 89% of the traumatic brain injury patients, and 82% of the brain tumour patients. These complaints occurred across all modalities with multisensory, visual, and auditory hypersensitivity being the most prevalent. Patients with post-injury sensory hypersensitivity reported a higher sensory sensitivity severity on the multiple-choice items of the MESSY as compared to neurotypical adults and acquired brain injury patients without post-injury sensory hypersensitivity (across all sensory modalities) (effect sizes (partial eta squared) ranged from .06 to .22). Conclusions: These results show that sensory hypersensitivity is prevalent after different types of acquired brain injury as well as across several sensory modalities. The MESSY can improve recognition of these symptoms and facilitate further research.

Cerebellar contribution to autism-relevant behaviors in fragile X syndrome models.

Cerebellar dysfunction has been linked to autism spectrum disorders (ASDs). Although cerebellar pathology has been observed in individuals with fragile X syndrome (FXS) and in mouse models of the disorder, a cerebellar functional contribution to ASD-relevant behaviors in FXS has yet to be fully characterized. In this study, we demonstrate a critical cerebellar role for Fmr1 (fragile X messenger ribonucleoprotein 1) in ASD-relevant behaviors. First, we identify reduced social behaviors, sensory hypersensitivity, and cerebellar dysfunction, with loss of cerebellar Fmr1. We then demonstrate that cerebellar-specific expression of Fmr1 is sufficient to impact social, sensory, cerebellar dysfunction, and cerebro-cortical hyperexcitability phenotypes observed in global Fmr1 mutants. Moreover, we demonstrate that targeting the ASD-implicated cerebellar region Crus1 ameliorates behaviors in both cerebellar-specific and global Fmr1 mutants. Together, these results demonstrate a critical role for the cerebellar contribution to FXS-related behaviors, with implications for future therapeutic strategies.

A Novel Head-Fixed Assay for Social Touch in Mice Uncovers Aversive Responses in Two Autism Models.

Social touch, an important aspect of social interaction and communication, is essential to kinship across animal species. How animals experience and respond to social touch has not been thoroughly investigated, in part because of the lack of appropriate assays. Previous studies that examined social touch in freely moving rodents lacked the necessary temporal and spatial control over individual touch interactions. We designed a novel head-fixed assay for social touch in mice, in which the experimenter has complete control to elicit highly stereotyped bouts of social touch between two animals. The user determines the number, duration, context, and type of social touch interactions, while monitoring an array of complex behavioral responses with high resolution cameras. We focused on social touch to the face because of its high translational relevance to humans. We validated this assay in two different models of autism spectrum disorder (ASD), the Fmr1 knock-out (KO) model of Fragile X syndrome (FXS) and maternal immune activation (MIA) mice. We observed higher rates of avoidance running, hyperarousal, and aversive facial expressions (AFEs) to social touch than to object touch, in both ASD models compared with controls. Fmr1 KO mice showed more AFEs to mice of the same sex but whether they were stranger or familiar mice mattered less. Because this new social touch assay for head-fixed mice can be used to record neural activity during repeated bouts of social touch it could be used to uncover underlying circuit differences.SIGNIFICANCE STATEMENT Social touch is important for communication in animals and humans. However, it has not been extensively studied and current assays to measure animals' responses to social touch have limitations. We present a novel head-fixed assay to quantify how mice respond to social facial touch with another mouse. We validated this assay in autism mouse models since autistic individuals exhibit differences in social interaction and touch sensitivity. We find that mouse models of autism exhibit more avoidance, hyperarousal, and aversive facial expressions (AFEs) to social touch compared with controls. Thus, this novel assay can be used to investigate behavioral responses to social touch and the underlying brain mechanisms in rodent models of neurodevelopmental conditions, and to evaluate therapeutic responses in preclinical studies.

Sensory hypersensitivity after acquired brain injury: the patient perspective.

PURPOSE: Sensory hypersensitivity is a frequently reported complaint after acquired brain injury (ABI). This study explores patients' perceptions of sensory hypersensitivity following ABI and its impact on everyday life. MATERIALS AND METHODS: Semi-structured interviews were conducted with 18 patients with ABI (stroke, brain tumour, TBI) who reported complaints of sensory hypersensitivity. Interview data were analysed using qualitative thematic analysis. RESULTS: Six themes emerged from the data: (1) definition of sensory hypersensitivity, relating to individual perceptions of sensory hypersensitivity; (2) type of sensory stimuli, relating to the variety of stimuli that patients may be sensitive to; (3) course, relating to changes in sensory hypersensitivity following ABI; (4) fatigue, relating to its association with sensory hypersensitivity; (5) consequences of sensory hypersensitivity, relating to the physical, social and emotional impact of sensory hypersensitivity on patients' lives; and (6) coping strategies, relating to behaviours used to cope with sensory hypersensitivity. CONCLUSIONS: Sensory hypersensitivity can have a major impact on patients' physical well-being, return to work and (social) participation after ABI. Characteristics of sensory hypersensitivity vary between patients with ABI. To develop treatments for sensory hypersensitivity, future studies should focus on cognitive (e.g., filtering information) and psychological factors (e.g., coping) in relation to sensory hypersensitivity.

Sensory hypersensitivity occurs in all types of acquired brain injury (ABI).It is important to ask an ABI patient how sensory hypersensitivity is experienced.It is recommended to investigate the physical (e.g., headache) and emotional (e.g., irritability, anger, frustration) consequences of sensory hypersensitivity and its impact on return to work and social participation.When the patient mentions sensory hypersensitivity, also map cognition (with a focus on attention), fatigue, stress, and coping.