Behavioral Responses to Fevers and Other Medical Events in Children With and Without ASD

Byrne, Katherine; Zheng, Shuting; Bishop, Somer; Boucher, Juliana; Ghods, Sheila; Kim, So Hyun; Lord, Catherine

doi:10.1101/2022.05.23.22275374

Cited by 3 publications

(1 citation statement)

References 9 publications

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“…The LPS dose used by Reed et al, was lower than that used here (50 µg/Kg vs 250 µg/Kg) and this produced a more modest suppression of activity than we observed, which may facilitate a maintenance of social activity. The higher dose used in our study may have produced lethargy that was incompatible with observing improved performance on some motivated tasks (Figure 5) and which is consistent with illness providing limited benefit for ASD patients (Byrne et al, 2022). The current study is focussed on elevated temperature in the absence of acute illness.…”

Section: It Has Recently Been Shown That Acute Inflammation Induced B...mentioning

confidence: 74%

Hyperthermia elevates brain temperature and improves behavioural signs in animal models of Autism spectrum disorder

López-Rodríguez

Murray

Kealy

et al. 2022

Preprint

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Autism Spectrum Disorders (ASD) are predominantly developmental in nature and largely genetically determined. There are some human data supporting the idea that fever can improve symptoms in some individuals but the human data for this are limited and there are almost no data to support this from animal models. In the current study, we used a whole body hyperthermia (WBH) protocol and systemic inflammation induced by bacterial endotoxin (LPS) to dissociate temperature and inflammatory elements of fever in order to examine the impact of these environmental stressors on behavioural signs in two animal models relevant to ASD: C58BL/6 and Shank3B- mice. While only LPS induced inflammatory signatures in the brain, WBH and LPS induced both overlapping and distinct neuronal cFos activation in several brain regions and modest effects on heat shock gene expression. In behavioural experiments LPS significantly suppressed most activities over 24-48 hours while WBH reduced repetitive behaviours and improved social interaction in C58BL/6 mice. In Shank3B- mice WBH significantly reduced compulsive grooming. The data are the first, to our knowledge, to demonstrate that elevated body temperature, in the absence of underpinning inflammation, can improve some behavioural signs in two distinct animal models of ASD. Given the developmental and genetic nature of ASD, evidence that symptoms may be ameliorated by environmental perturbations indicates that there are possibilities for improving function in these individuals.

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Section: It Has Recently Been Shown That Acute Inflammation Induced B...mentioning

confidence: 74%

Hyperthermia elevates brain temperature and improves behavioural signs in animal models of Autism spectrum disorder

López-Rodríguez

Murray

Kealy

et al. 2022

Preprint

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Hyperthermia elevates brain temperature and improves behavioural signs in animal models of autism spectrum disorder

Lopez-Rodriguez,

Murray,

Kealy

et al. 2023

Molecular Autism

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Background Autism spectrum disorders (ASD) are predominantly neurodevelopmental and largely genetically determined. However, there are human data supporting the idea that fever can improve symptoms in some individuals, but those data are limited and there are almost no data to support this from animal models. We aimed to test the hypothesis that elevated body temperature would improve function in two animal models of ASD. Methods We used a 4 h whole-body hyperthermia (WBH) protocol and, separately, systemic inflammation induced by bacterial endotoxin (LPS) at 250 µg/kg, to dissociate temperature and inflammatory elements of fever in two ASD animal models: C58/J and Shank3B- mice. We used one- or two-way ANOVA and t-tests with normally distributed data and Kruskal–Wallis or Mann–Whitney with nonparametric data. Post hoc comparisons were made with a level of significance set at p < 0.05. For correlation analyses, data were adjusted by a linear regression model. Results Only LPS induced inflammatory signatures in the brain while only WBH produced fever-range hyperthermia. WBH reduced repetitive behaviours and improved social interaction in C58/J mice and significantly reduced compulsive grooming in Shank3B- mice. LPS significantly suppressed most activities over 5–48 h. Limitations We show behavioural, cellular and molecular changes, but provide no specific mechanistic explanation for the observed behavioural improvements. Conclusions The data are the first, to our knowledge, to demonstrate that elevated body temperature can improve behavioural signs in 2 distinct ASD models. Given the developmental nature of ASD, evidence that symptoms may be improved by environmental perturbations indicates possibilities for improving function in these individuals. Since experimental hyperthermia in patients would carry significant risks, it is now essential to pursue molecular mechanisms through which hyperthermia might bring about the observed benefits.

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Air Pollution and Maximum Temperature Are Associated with Neurodevelopmental Regressive Events in Autism Spectrum Disorder

Frye¹,

Cakir

McCarty

et al. 2022

JPM

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Neurodevelopmental regression (NDR) is an enigmatic event associated with autism spectrum disorder (ASD) during which a child loses previously acquired skills and develops ASD symptoms. In some, a trigger which precedes the NDR event, such as a fever, can be identified, but in many cases no trigger is obvious. We hypothesize that air pollution (PM2.5) may trigger NDR, especially in those children without an identified trigger. Average daily PM2.5, ozone, precipitation and maximum temperature (Tmax) were derived from Environmental Protection Agency models and National Oceanic and Atmospheric Administration monitors based on zip-code information from 83 ASD participants during the six-weeks following the onset month of an NDR event and a reference period defined as one year before and one year after the event. Seasonally adjusted logistic regression (LR) and linear mixed models (LMM) compared cases (with a history of NDR) and matched controls (without a history of NDR). LR models found that the risk of NDR was related to higher PM2.5 during 3 to 6 weeks of the NDR event period, particularly in those without a trigger. Overall, both models converged on NDR being related to a higher PM2.5 and lower Tmax both during the NDR event period as well as the reference period, particularly in those without a known trigger. This temporal pattern suggests that environmental triggers, particularly PM2.5, could be related to NDR, especially in those without an identifiable trigger. Further studies to determine the underlying biological mechanism of this observation could help better understand NDR and provide opportunities to prevent NDR.

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Behavioral Responses to Fevers and Other Medical Events in Children With and Without ASD

Cited by 3 publications

References 9 publications

Hyperthermia elevates brain temperature and improves behavioural signs in animal models of Autism spectrum disorder

Hyperthermia elevates brain temperature and improves behavioural signs in animal models of Autism spectrum disorder

Hyperthermia elevates brain temperature and improves behavioural signs in animal models of autism spectrum disorder

Air Pollution and Maximum Temperature Are Associated with Neurodevelopmental Regressive Events in Autism Spectrum Disorder

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