The Neuropathology of Autism

Casanova, Manuel F.

doi:10.1111/j.1750-3639.2007.00100.x

Cited by 189 publications

(136 citation statements)

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“…These phenomena may reflect the daytime cortical hyperarousal that was found among patients comorbid with MDD and insomnia. Background: The study is based on an underlying neuropathological model of autism, which emphasizes "minicolumnar" pathology (Casanova, 2007;Casanova et al, 2006) and cortical lateral inhibition deficits resulting in behavioral abnormalities and executive dysfunctions. We propose that neuromodulation based on lowfrequency repetitive TMS over prefrontal area will enhance lateral inhibition through activation of inhibitory double bouquet interneurons and will be accompanied by EEG alteration that can be operantly conditioned using neurofeedback (NFB) immediately after rTMS session.…”

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confidence: 99%

Proceedings of the 2015 ISNR Conference: Poster Presentations

2015

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Background: Insomnia is common in patients with major depressive disorder (MDD); they complain of falling asleep and awakening in the daytime. One of the neuropsychopathological mechanisms of insomnia is cortical hyperarousal. Previous studies explored cortical activities at pre-sleep and sleep stages among patients with primary insomnia and MDD, as well as the physiological arousal in the daytime among patients with chronic insomnia. There were few studies that explored clearly the psychopathological mechanism among patients comorbid with MDD and insomnia. The purpose of this study was to explore the daytime cortical arousal among patients comorbid with MDD and insomnia.Methods: Fifty patients comorbid with MDD and insomnia were the MDD group that was compared with 35 healthy controls in beta power of electroencephalogram (EEG). All of the participants filled out the Pittsburgh Sleep Quality Index (PSQI). The resting EEG with eye-closed were measured for 5 min via 19-channel BrainMaster equipment (BrainMaster Technologies, Inc., Bedford, Ohio), where the spectrum analyses showed the beta power (13-32 Hz; as a cortical hyperarousal index) at Fz and Cz.Results: This study found that: (1) After controlling the medication effects, there were positive correlations between PSQI total score, the habitual sleep efficiency, use of sleep medications, and beta power at Fz and Cz.(2) There were higher absolute and relative beta power at Fz and Cz in the MDD group than that of in healthy controls. (3) After controlling the medication effect, the MDD group with high sleep disturbance had higher relative beta power at Fz and Cz than that of the MDD group with low sleep disturbance. Conclusion:This study indicated that poor sleep quality was associated with daytime cortical arousal. Patients with MDD had higher cortical arousal at the frontal and central areas than that of healthy controls. These phenomena may reflect the daytime cortical hyperarousal that was found among patients comorbid with MDD and insomnia. Background: The study is based on an underlying neuropathological model of autism, which emphasizes "minicolumnar" pathology (Casanova, 2007;Casanova et al., 2006) and cortical lateral inhibition deficits resulting in behavioral abnormalities and executive dysfunctions. We propose that neuromodulation based on lowfrequency repetitive TMS over prefrontal area will enhance lateral inhibition through activation of inhibitory double bouquet interneurons and will be accompanied by EEG alteration that can be operantly conditioned using neurofeedback (NFB) immediately after rTMS session. In prior studies in children with ASD we demonstrated post-TMS improvements in executive functions Sokhadze, El-Baz, Sears, Opris, & Casanova, 2014), as well as positive effects of prefrontal neurofeedback in ASD (Wang et al., 2014). In the current study each rTMS session was followed by NFB training that we predicted to result in a synergetic response. References Objectives:The overall aim of the study was to investigate behavioral respon...

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confidence: 99%

Proceedings of the 2015 ISNR Conference: Poster Presentations

2015

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“…A common theme in autism research is the multiple hit hypothesis. Casanova (2007) proposed that ASD etiology includes (1) inheritance of genetic susceptibility and (2) an environmental agent or endogenous stressor that (3) occurs during a critical time period in brain development (Casanova, 2007), also known as the triple hit hypothesis. Another 3-hit theory for contributions to ASD, developed by Davis and Pfaff (2014), includes androgenic hormone effects as one of the hits (Davis & Pfaff, 2014).…”

Section: Organization Of Dissertationmentioning

confidence: 99%

“…The prevalence of this disease has been on the rise over the last decade (Center for Disease Control and Prevention, 2016). In many cases the cause of ASD is unknown, with numerous causal mechanisms under investigation, but most researchers agree that autism is a multifactorial condition (Casanova, 2007;Rutter, 2005). ASD is heavily biased towards males (Auyeung et al, 2010), with ratios ranging from 4:1 for classic autism to 11:1 in individuals with Asperger Syndrome ( Baron-Cohen et al, 2011).…”

Section: Fig 1 Wheel Running Behavior (A-c) Latency Of Mice To Runmentioning

confidence: 99%

“…Research into the reasons for this disparity has been limited, but tends to focus on factors that could increase vulnerability in males or, conversely, are protective in females (Alycia K. Halladay, 2015;Baron-Cohen et al, 2011). A common theme in autism research is the 3-hit or triple hit hypothesis (Casanova, 2007;Davis & Pfaff, 2014). As ASD is proposed to result from multiple, variable factors, the sex bias in autism is likely the result of more than one factor that either increases the vulnerability of males or protects females.…”

Section: Fig 1 Wheel Running Behavior (A-c) Latency Of Mice To Runmentioning

confidence: 99%

“…Note that TP was administered on postnatal day 2 because the critical period when male rodents produce testosterone occurs immediately after birth, rather than prenatally as in humans (Hines, 2006). The within-litter and between-litter treatments can also be thought of in accordance with previous "3-hit" or "multiple-hit" hypotheses of autism etiology (Casanova, 2007;Pfaff, Rapin, & Goldman, 2011;Schaafsma & Pfaff, 2014), wherein in our study the hits are 1)VPA treatment, 2) TP treatment, and 3) "maleness." Hence, a VPA-TP treated male would be considered to have 3 hits, while a Veh1-Veh2 treated female would have 0 hits.…”

Section: Animalsmentioning

confidence: 99%

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Using a mouse model to investigate male bias in autism spectrum disorder incidence.

Gordon¹

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The review (Chapter 1) overviews our current understanding of the sex bias in autism spectrum disorders (ASD), whereby males are 4 times more likely to develop the condition. The longstanding uncertainty surrounding the etiology of autism can be informed by inclusion of both sexes in future research to better understand the mechanism responsible for this sex bias. Both clinical studies and animal models are useful tools to elucidate the underlying cause(s) of sexual dimorphic morphological, physiological, and behavioral differences in the ASD phenotype.Sex differences in social behaviors are common across species, underscoring the importance of assessing baseline sex differences in behavior, especially when sexually dimorphic effects on behavior are expected. I examined pre-pubertal behavior (Chapter 2) in 3 strains of mice (C57BL/6, CFW, and CF1) using a wheel-running assay developed to be relevant to autism-like behaviors. The results indicated no sex differences in wheel running behaviors or social interaction with all mouse strains displaying typical wheel running behavior, i.e. more time running on the wheel when it would turn and increased performance of other activities when it was jammed. iv Studies have found that elevated levels of fetal testosterone (fT) are correlated with later ASD diagnosis. Prenatal valproic acid (VPA) treatment is a common animal model of ASD in rodents, mimicking many of the features of ASD including increased male vulnerability. I used the VPA model (Chapter 3) to evaluate sex-specific responses to prenatal VPA treatment, and to assess if masculinization of females with perinatal testosterone propionate (TP) after prenatal VPA treatment would masculinize their susceptibility for abnormalities in development relevant to ASD. My findings confirmed that VPA exposure results in impaired motor development abilities, and provide novel evidence that the combined effects of VPA, TP, and maleness (triple hit) led to more severe motor development deficiencies in some tasks. I also present evidence that the triple hit resulted in reduced anxiety, but elevated cognitive rigidity and self-grooming compared to control females. The results provide some evidence for increased vulnerability of triple hit males to behavioral deficits relevant to ASD, but more research is needed to better understand this effect.

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Increased Functional Connectivity Between Subcortical and Cortical Resting-State Networks in Autism Spectrum Disorder

et al. 2015

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Importance Individuals with autism spectrum disorder (ASD) exhibit severe difficulties in social interaction, motor coordination, behavioral flexibility, and atypical sensory processing, with considerable interindividual variability. This heterogeneous set of symptoms recently led to investigating the presence of abnormalities in the interaction across large-scale brain networks. To date, studies have focused either on constrained sets of brain regions or whole-brain analysis, rather than focusing on the interaction between brain networks. Objectives To compare the intrinsic functional connectivity between brain networks in a large sample of individuals with ASD and typically developing control subjects and to estimate to what extent group differences would predict autistic traits and reflect different developmental trajectories. Design, Setting, and Participants We studied 166 male individuals (mean age, 17.6 years; age range, 7-50 years) diagnosed as having DSM-IV-TR autism or Asperger syndrome and 193 typical developing male individuals (mean age, 16.9 years; age range, 6.5-39.4 years) using resting-state functional magnetic resonance imaging (MRI). Participants were matched for age, IQ, head motion, and eye status (open or closed) in the MRI scanner. We analyzed data from the Autism Brain Imaging Data Exchange (ABIDE), an aggregated MRI data set from 17 centers, made public in August 2012. Main Outcomes and Measures We estimated correlations between time courses of brain networks extracted using a data-driven method (independent component analysis). Subsequently, we associated estimates of interaction strength between networks with age and autistic traits indexed by the Social Responsiveness Scale. Results Relative to typically developing control participants, individuals with ASD showed increased functional connectivity between primary sensory networks and subcortical networks (thalamus and basal ganglia) (all t ≥ 3.13, P < .001 corrected). The strength of such connections was associated with the severity of autistic traits in the ASD group (all r ≥ 0.21, P < .0067 corrected). In addition, subcortico-cortical interaction decreased with age in the entire sample (all r ≤ −0.09, P < .012 corrected), although this association was significant only in typically developing participants (all r ≤ −0.13, P < .009 corrected). Conclusions and Relevance Our results showing ASD-related impairment in the interaction between primary sensory cortices and subcortical regions suggest that the sensory processes they subserve abnormally influence brain information processing in individuals with ASD. This might contribute to the occurrence of hyposensitivity or hypersensitivity and of difficulties in top-down regulation of behavior.

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The Neuropathology of Autism

Cited by 189 publications

References 123 publications

Proceedings of the 2015 ISNR Conference: Poster Presentations

Proceedings of the 2015 ISNR Conference: Poster Presentations

Using a mouse model to investigate male bias in autism spectrum disorder incidence.

Increased Functional Connectivity Between Subcortical and Cortical Resting-State Networks in Autism Spectrum Disorder

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