Right Anterior Theta Hypersynchrony as a Quantitative Measure Associated with Autistic Traits and K-Cl Cotransporter KCC2 Polymorphism.

Our aim was to use theta coherence as a quantitative trait to investigate the relation of the polymorphisms in NKCC1 (rs3087889) and KCC2 (rs9074) channel protein genes to autistic traits (AQ) in neurotypicals. Coherence values for candidate connection regions were calculated from eyes-closed resting EEGs in two independent groups. Hypersynchrony within the right anterior region was related to AQ in both groups (p < 0.05), and variability in this hypersynchrony was related to the rs9074 polymorphism in the total group (p < 0.05). In conclusion, theta hypersynchrony within the right anterior region during eyes-closed rest can be considered a quantitative measure for autistic traits. Replicating our findings in two independent populations with different backgrounds strengthens the validity of the current study.

Auditory Processing Differences Correlate With Autistic Traits in Males.

Autism spectrum disorder (ASD) has high prevalence among males compared to females but mechanisms underlying the differences between sexes are poorly investigated. Moreover, autistic symptoms show a continuity in the general population and are referred to as autistic traits in people without an ASD diagnosis. One of the symptoms of ASD is sensory processing differences both in sensitivity and perception. To investigate sensory processing differences in autistic traits, we examined auditory and visual processing in a healthy population. We recruited 75 individuals (39 females and 36 males, mean age = 23.01 years, SD = 3.23 years) and assessed autistic traits using the Autism Spectrum Quotient, and sensory sensitivity using the Sensory Sensitivity Scales. Sensory processing in the visual domain was examined with the radial motion stimulus and the auditory domain was assessed with the 1,000 Hz pure tone stimulus with electroencephalography-evoked potentials. The results showed that the auditory sensitivity scores of the males (r aud (34) = 0.396, p aud = 0.017) and the visual sensitivity scores of females were correlated with autistic traits (r vis (37) = 0.420, p vis = 0.008). Moreover, the P2 latency for the auditory stimulus was prolonged in the participants with a higher level of autistic traits (r s (61) = 0.411, p = 0.008), and this correlation was only observed in males (r s (31) = 0.542, p = 0.001). We propose that auditory processing differences are related to autistic traits in neurotypicals, particularly in males. Our findings emphasize the importance of considering sex differences in autistic traits and ASD.

Development of Sensory Sensitivity Scales (SeSS): Reliability and validity analyses.

BACKGROUND: Although adults are known to have sensory sensitivity differences, existing sensitivity scales have been mostly developed for children. The limited number of adult scales measure social/emotional features and modalities together. AIMS: To develop scales for adults that evaluate visual, auditory and somatosensory sensitivities as separate domains and independent of social/emotional features. METHODS AND PROCEDURES: Two consecutive studies (visual-auditory part and somatosensory part) were conducted using the same methods. Both studies included a pilot (n1 = 405 and n2 = 294) and a main group (n1 = 425 and n2 = 603). An exploratory factor analysis produced a single-factor solution for the visual and auditory domains and a three-factor solution for the somatosensory domain (touch, pain, and itch) of Sensory Sensitivity Scales. OUTCOMES AND RESULTS: A confirmatory factor analysis revealed good construct validity in the the visual (CFI = .973, TLI = .965, and RMSEA = .075) auditory (CFI = .943, TLI = .927, and RMSEA = .074) and somatosensory (CFI = .955, TLI = .946, and RMSEA = .048) scales. The categories were internally consistent (αv = .86, αa = .79, αs = .69). As an indicator of convergent validity, higher autistic traits were related to higher sensitivity (rs-v = .17, rs-a = .25, rs-s = .14). CONCLUSIONS AND IMPLICATIONS: Sensory Sensitivity Scales (SeSS) can be used to screen sensory sensitivity variability or identify and follow up the outcome of sensory interventions in adults.

Assessing Theory of Mind by Humor: The Humor Comprehension and Appreciation Test (ToM-HCAT).

Theory of Mind (ToM) may be defined as the ability to understand the mental states, such as beliefs, desires, intentions, and emotions, of others. Impairment of ToM ability leads to disorders with pathologies in social skills, such as autism spectrum disorder and schizophrenia. In addition to differences in ToM ability among patient populations, there is variation between neurotypical individuals. Unfortunately, ToM tasks are usually developed for children or patients with cognitive disorders and cannot detect variations in healthy adults. As an alternative tool, humor may be used. Humor plays a role in social communication and requires many different cognitive functions. Humor is believed to represent complex high-order cognitive processes. There are numerous types of humor; the most complex type is considered ToM humor, where an understanding of social/emotional content is necessary. Given the need for a ToM assessment test suitable for healthy adult populations, we developed a test for measuring humor comprehension and appreciation, with and without ToM content (ToM-HCAT). The present ToM-HCAT test is a performance test consisting of cartoons. The test measures perceived funniness, reaction time to perceived funniness decision, and meaning inference. Cartoons were selected after pilot studies involving 44 participants. Subscales were constituted according to expert views and confirmed by confirmatory factor analysis (N = 135). Goodness of fit values for the final 35-item test were acceptable to excellent: GFI = 0.97; AGFI = 0.97; NFI = 0.97; RFI = 0.97, and SRMR = 0.067. Both categories were internally consistent (α1 = 0.84, α2 = 0.94). External validity was assessed against autistic traits. One hundred and three participants completed the Autism Spectrum Quotient and were grouped by +0.5 standard deviations from the mean as high in autistic traits. The meaning-inference scores of the subscale with the ToM cartoons were significantly lower (p = 0.034) for the high autistic traits group, providing evidence of external validity. In conclusion, we developed and validated a test for assessment of ToM by humor comprehension and appreciation. We believe that the present test will be useful for the detection of variations in ToM ability in the healthy adult population.

Protective effects of methylxanthines on hypoxia-induced apoptotic neurodegeneration and long-term cognitive functions in the developing rat brain.

Aminophylline is widely used in the management of premature apnea. The methylxanthines aminophylline, theophylline and caffeine are nonspecific inhibitors of adenosine receptors. There are no proven effects of methylxanthines on acute brain injury and long-term cognitive functions. This study is aimed at investigating the effects of methylxanthines on brain injury and cognitive functions. Newborn rats were allocated to form four groups, which contained at least 21 pups: two groups were exposed to room air and two groups were exposed to intermittent hypoxia. Intraperitoneal aminophylline was administered to treatment groups during postnatal day 1 through postnatal day 7. All rats were sacrificed on postnatal day 8 via intraperitoneal pentobarbital and the effects of the administered drug on brain injury and adenosine receptor expression were determined. Cognitive functions of rats were evaluated via water maze test. Histopathological evaluation demonstrated that aminophylline significantly diminished the number of 'apoptotic cells' in the hippocampal CA1, CA2, CA3 and gyrus dentatus regions in the brain. Aminophylline treatment immediately after hypoxic insult significantly improved long-term neurobehavioral achievements. In conclusion, aminophylline administration immediately after neonatal hypoxic insult provides benefit over a prolonged period in the developing rat brain.

Erythropoietin attenuates lipopolysaccharide-induced white matter injury in the neonatal rat brain.

Periventricular leukomalacia (PVL), a common neonatal brain white matter (WM) lesion, is frequently associated with cerebral palsy. Growing evidence has indicated that in addition to ischemia/reperfusion injury, cytokine-induced brain injury associated with maternal or fetal infection may also play an important role in the pathogenesis of PVL. Recent studies have shown that administration of lipopolysaccharide (LPS) to pregnant rats causes enhanced expression of the cytokines, i.e., IL-1 beta, TNF-alpha, and IL-6, in fetal brains. In recent years, it has been shown that erythropoietin (EPO) has a critical role in the development, maintenance, protection and repair of the nervous system. In the present study we investigated the effect of EPO on LPS-induced WM injury in Sprague-Dawley rats. LPS (500 microg/kg) suspension in pyrogen-free saline was administered intraperitoneally to pregnant rats at 18 and 19 days of gestation. The control group was treated with pyrogen-free saline. They were given 5,000 U/kg recombinant human EPO. Seven-day-old Sprague-Dawley rat pups were divided into four groups: control group, LPS-treated group, prenatal maternal EPO-treated group (5,000 U/kg, intraperitoneally given to pregnant rats at 18 and 19 days of gestation), and postnatal EPO-treated group (5,000 U/kg, intraperitoneally given to 1-day-old rat pups). Cytokine induction in the postnatal 7-day-old (P7) rat brain after maternal administration of LPS was determined by the ELISA method. The proinflammatory cytokine levels (IL-1 beta, TNF-alpha, and IL-6) in P7 rat pup brains were significantly increased in the LPS-treated group as compared with the control group. Prenatal maternal EPO treatment significantly reduced the concentration of TNF-alpha and IL-6 in the newborn rat brain following LPS injection. The concentration of IL-1 beta was decreased in the intrauterine EPO treatment group. Postnatal EPO treatment significantly decreased only the IL-6 concentration in the newborn rat brain following LPS injection. The concentration of cytokines, IL-1 beta and TNF-alpha, was reduced in the postnatal EPO treatment group. We demonstrated here that LPS administration in pregnant rats at gestational day 18 and 19 induced WM injury in P7 progeny characterized by apoptosis. Prenatal maternal and postnatal EPO treatment significantly reduced the number of apoptotic cells in the periventricular WM. Using immunohistochemistry techniques, we investigated the effects of maternal administration of LPS on myelin basic protein (MBP) staining, as a marker of myelination in the periventricular area in the neonatal rat brain. MBP staining was significantly less and weaker in the brains of the LPS-treated group as compared with the prenatal maternal EPO-treated group. However, the postnatal EPO treatment did not prevent LPS-stimulated loss of MBP-positive staining. In conclusion, especially prenatal maternal EPO treatment attenuates LPS-induced injury by reducing the expression of inflammatory cytokines and sparing MBP in the neonatal rat brain. While the postnatal EPO treatment prevented LPS-induced brain injury this effect was partial. To our knowledge, this is the first study that demonstrates a protective effect of EPO on LPS-induced WM injury in the developing brain. Regarding the wide use of EPO in premature newborns, this agent maybe potentially beneficial in treating LPS-induced brain injury in the perinatal period.

Activated protein C reduces endotoxin-induced white matter injury in the developing rat brain.

Periventricular leukomalacia (PVL), the dominant form of brain injury in premature infants, is characterized by white matter injury (WMI) and is associated with cerebral palsy. The pathogenesis of PVL is complex and likely involves ischemia/reperfusion, free radical formation, excitotoxicity, impaired regulation of cerebral blood flow, a procoagulant state, and inflammatory mechanisms associated with maternal and/or fetal infection. Using an established animal model of human PVL, we investigated whether activated protein C (APC), an anti-coagulant factor with anti-inflammatory, anti-apoptotic, anti-oxidant, and cytoprotective activities, could reduce endotoxin-induced WMI in the developing rat brain. Intraperitoneal injections of lipopolysaccharide (LPS) (0.5 mg/kg body weight) were given at embryonic days 18 (E18) and 19 (E19) to pregnant Sprague-Dawley rats; control rats were injected with sterile saline. A single intravenous injection of recombinant human (rh) APC (0.2 mg /kg body weight) was given to pregnant rats following the second LPS dose on embryonic day 19 (E19). Reduced cell death in white matter and hypomyelination were shown on TUNEL and myelin basic protein (MBP) staining, respectively, on late postnatal days (P7) in APC-treated groups. There were significantly fewer TUNEL+nuclei in the periventricular WM in the APC+LPS group than in the untreated LPS group. Compared to the APC+LPS and control group, MBP expression was weak in the LPS group on P7, indicating endotoxin-induced hypomyelination in the developing rat brain. APC attenuated the LPS-induced protein expression of inflammatory cytokines, tumor necrosis factor-alpha, and interleukin-6, as evaluated by ELISA in neonatal rat brains. A single intraperitoneal injection of rhAPC (0.2 mg/kg body weight) to neonatal rats on P1 also had similar protective and anti-inflammatory effects against maternally administered LPS. Collectively, these data support the hypothesis that APC may provide protection against an endotoxin-evoked inflammatory response and WMI in the developing rat brain. Moreover, our results suggest that the possible use of APC in treatment of preterm infants and pregnant women with maternal or placental infection may minimize the risk of PVL and cerebral palsy.