Social Skills Training and Generalization of Skills in Children with Autism Spectrum Disorder

The social deficits observed in individiuals with autism spectrum disorder (ASD) can often be improved with social skills training. The current study evaluated the effects of the Superheroes Social Skills training program which uses animated superheroes, video modeling, and comic books to teach social skills training. Three participants with ASD were trained in Conversation, Responding to Questions, and Body Basics over ten sessions, with sessions occurring twice a week in a non-school setting at the Arc of Southeast Mississippi. A multiple baseline across skills design across participants was used to examine the effects of the intervention on skill accuracy across both training and generalization probes. All participants demostrated improvements in skill accuracy for the training probes and two of the participants demonstrated improvements in skill accuracy in the generalization probes

Repeated Zolpidem Treatment Effects on Sedative Tolerance, Withdrawal, mRNA Levels, and Protein Expression

Zolpidem and benzodiazepines (BZs) potentiate the inhibitory action of gamma-Aminobutyric acid (GABA) by allosterically binding to GABAA receptors (GABAAR). Prolonged use of GABAAR positive allosteric modulators (PAM) can lead to behavioral tolerance, the diminished response to the same drug dose with repeated use, and withdrawal, a group of symptoms that occur due to abrupt end of drug treatment. Zolpidem is a short-acting, non-BZ GABAAR PAM whose potential for tolerance and withdrawal is unclear. Zolpidem demonstrates sedative efficacy similar to BZs and has become a main treatment of insomnia in lieu of BZs. Zolpidem replaced BZs due to lower incidences of tolerance and withdrawal after prolonged treatment and discontinuation. Despite reported lower incidences, some studies find the occurrence of tolerance and withdrawal similar between zolpidem and BZs. Tolerance and withdrawal symptoms are likely caused by drug-induced neuroadaptive changes in central nervous system (CNS) functioning, and these alterations may be similar between zolpidem and BZ. Past rodent research suggests that long term use of zolpidem and BZs may produce alterations in normal inhibitory GABAergic and excitatory glutamatergic functioning in the cortex, hippocampus, amygdala, and PFC and that these alterations may underlie sedative tolerance and withdrawal symptoms. The purpose of this project was to examine the molecular mechanisms involved in the tolerance cross-tolerance, and withdrawal of zolpidem and diazepam in C57/BL6J mice after different treatment durations. Elucidating the mechanisms behind zolpidem tolerance and withdrawal is necessary due to the ongoing usage of subunit specific GABAAR PAMs and, to a broader extent, an understanding of GABAARs themselves. In Study 1, we measured sedative tolerance, cross-tolerance, and GABAAR associated mRNA levels in 4 regions of interest (ROI; the cortex, prefrontal cortex (PFC), hippocampus, and amygdala) after 3 days of intraperitoneal (i.p.) injections of diazepam and zolpidem in comparison to vehicle. We expected that this “short-term” exposure duration to diazepam and zolpidem would not result is tolerance, cross-tolerance, or changes in mRNA levels. Study 2 examined the same measures as in Study 1, in addition to AMPAR subunits, NDMAR subunits mRNA levels in the ROI, and total, surface, and intracellular GABAAR subunits protein expression due to 7 days of i.p. injections of diazepam and zolpidem compared to vehicle. Based on previous research both groups should become tolerant to zolpidem’s sedative effects and show decreases of GABAAR subunits and increases in NMDAR subunits in the ROI. It is also expected that there will be decreases in total α1 and γ2 in the cortex, a decrease of surface α1 in the cortex, and increases in GluR1 in the hippocampus after zolpidem and diazepam treatment. Study 3 measured the same measures as in Study 1 due to 30 days of i.p. injections of diazepam and zolpidem compared to vehicle. It was expected that both groups would become tolerant to zolpidem’s sedative effects and show decreases of GABAAR subunits in the cortex, PFC, and hippocampus. The development of sedative tolerance and cross-tolerance to the locomotor impairing effects (measure of sedation) of zolpidem was measured by activity in the open field. Spontaneous withdrawal was also measured by activity and anxiety like behavior in the open field. Flumazenil- induced withdrawal was measured by anxiety- like behaviors in the elevated plus maze (EPM), activity, and anxiety like behavior in the open field. Messenger RNA levels were measured by quantitative real time quantitative reverse transcription polymerase chain reaction (qRT-PCR) and protein expression was measured by western blot. The surface and intracellular proteins were separated using bissulfosuccinimidyl suberate (BS3) cross-linking. Three days of diazepam but not zolpidem resulted in cross-tolerance to zolpidem in Study 1. Three days of zolpidem but not diazepam resulted in a decrease in the mRNA level of the α5 subunit in the hippocampus in Study 1. After 7 days of zolpidem or diazepam, mice were tolerant and cross-tolerant to zolpidem’s sedative effects. Spontaneous withdrawal resulted in anxiety-like behavior and decreased locomotor activity. Flumazenil did induce a robust withdrawal syndrome as measured in the EPM or open field. Seven days of zolpidem and diazepam caused significant decreases in the mRNA expression of α1, α3, β2, and δ GABAAR subunits in the cortex. Diazepam groups had significant decreases in the mRNA expression of α4, β1, γ2 subunits, GAT, and gephyrin in the cortex and significant decreases of α5- and β3-GABAAR subunits, and the GluN2A subunit in the hippocampus. Seven days of zolpidem resulted in a decrease in total α2 subunit protein level and 7 days of diazepam decreased total γ2 subunit protein levels. Thirty days of diazepam but not zolpidem resulted in cross-tolerance to zolpidem in Study 3. Thirty days of zolpidem but not diazepam resulted in a decrease in the mRNA levels of α1, α2, α3, β1, β2, β3, γ1, and γ2 subunits in the PFC. These results suggest that there is a window of time in which sedative tolerance to zolpidem is observed. The lack of zolpidem tolerance and minimal mRNA changes due to 3 days of zolpidem treatment may be due to its pharmacokinetic profile, zolpidem may not be in the system long enough to cause any changes. This may mean that sedative tolerance gradually develops and reaches detectable levels at later time points. Sedative tolerance and cross-tolerance to zolpidem is in line with other studies, however the spontaneous withdrawal is unique. Anxiety- like behavior and decreased activity were observed in our studies unlike other studies. The anxiety- like behavior is a common symptom of BZ withdrawal however the decrease in activity that was observed is not. It is unknown why this occurs though it may be due to a carryover sedative effect or more likely a placebo effect. Few studies have examined changes in protein levels. Study 2 found decreased protein expression of α2 and γ2 in the cortex due to zolpidem and diazepam respectively, indicate GABAARs containing those subunits are associated with tolerance and cross-tolerance to zolpidem’s sedative effects. This implies that the sedative effects of zolpidem is mediated by α1-GABAARs, the development of tolerance is mediated by α2-GABAARs due to zolpidem binding to both. There was also a decrease in the intracellular α1 subunit which may indicate degradation of an intracellular pool of α1 subunits or α1-GABAARs. The lack of zolpidem tolerance due to 30 days of zolpidem may be due to increased metabolism displayed as an increase in CYP3A enzymes. It is unclear what effect the decrease in GABAAR subunits in the PFC due to 30 days of zolpidem implicate. These may affect tolerance to zolpidem’s other effects such as amnesia

Balancing Opinions: The Effects on an Individual\u27s Romantic Relationship When Third Parties\u27 Opinions Collide

Previous researchers have established that social networks can influence an individual’s romantic relationship. Two studies examined whether one third party’s opinion was more influential than another when multiple parties’ opinions conflict or concur. The first study was a 2 (Parent Opinion: approval, disapproval) x 2 (Friend Opinion: approval, disapproval) between-subjects factorial design experimental survey which examined how third party opinions influenced an individual’s current romantic relationship state. Analyses revealed that both friend and parent opinion had significant effects on an individual’s romantic relationship. The second study incorporated a virtual dating game in which participants received feedback about one of their interaction partners. The study employed a 2 (Parent Opinion: good match, bad match) x 2 (Friend Opinion: good match, bad match) x 2 (Interaction Partner: Target, Control – within-subjects) mixed factorial design. Friend opinion emerged as playing an important role in individuals’ perceptions and choices of a potential romantic partner

The Effects of Corticotomies on Frontonasal Suture Expansion and Bone Modeling in Mature Rabbits

The purpose of this split skull study was designed to evaluate whether corticotomies enhance bone modeling and reduces the resistance of surrounding articulations during expansion in mature rabbits. Nine adult female New Zealand White (NZW) rabbits, 8 to 9 months old, had miniscrew implant (MSI) supported expansion devices with 150 g open-coil nickel-titanium springs placed bilaterally across the frontonasal sutures. Corticotomies were performed on one randomly chosen side, anterior and posterior to the frontonasal suture; the other side served as the control. Sutural separation was measured bi-weekly for 7 weeks. Using microCT scans of each specimens, bone material density (mg HA/ccm) and bone volume fraction (BV/TV) were measured. Qualitative histologic analyses of the suture tissues were performed using H&E staining. Most (94.4%) of the MSIs remained stable throughout the experiment. There was significantly (p <.05) more sutural separation on the corticotomy side (3.73 mm) than the control side (2.83 mm). There was no statistically significant side difference in bone volume fraction (p =.26) and bone density (p=.11). The amount of expansion that occurred was negatively correlated (R=-.860; p=<.001) with bone density. Blinded histological examination showed an increased density of osteoblasts, with a blastema-like appearance, along the bone fronts on the corticotomy side. Numerous elongated Sharpey’s fiber insertions and a mixture of immature woven bone, with numerous osteocytes, were visible at the sutural margins on the corticotomy side, indicating the formation of new bone. In conclusion, mature sutures expanded with adjunctive corticotomies undergo 31% more separation than sutures expanded without corticotomies with the amount of expansion that occurs being inversely related to bone density

Dynamic Change of Awareness during Meditation Techniques: Neural and Physiological Correlates

Recent fndings illustrate how changes in consciousness accommodated by neural correlates and plasticity of the brain advance a model of perceptual change as a function of meditative practice. During the mindbody response neural correlates of changing awareness illustrate how the autonomic nervous system shifts from a sympathetic dominant to a parasympathetic dominant state. Expansion of awareness during the practice of meditation techniques can be linked to the Default Mode Network (DMN), a network of brain regions that is active when the one is not focused on the outside world and the brain is restful yet awake (Chen et al., 2008). A model is presented illustrating the dynamic mindbody response before and after mindfulness meditation, and connections are made with prefrontal cortex activity, the cardiac and respiratory center, the thalamus and amygdala, the DMN and cortical function connectivity. The default status of the DMN changes corresponding to autonomic modulation resulting from meditation practice

Lipid kinase regulation of nociceptive signaling and sensitization: Implications for analgesic drug development

Chronic pain affects approximately 35% of American adults resulting in annual treatment costs over $600 billion. Unfortunately, current therapeutics have harmful side effects while only providing partial relief, highlighting the need for novel therapeutic targets for analgesic drug development. Neuropathic pain and inflammatory pain are the two most common forms of chronic pain in humans. In these conditions, nerve injury and inflammation lead to the release of pronociceptive molecules that signal through pronociceptive (pain-promoting) G protein-coupled receptors (GPCRs) and ion channels to sensitize nociceptive neurons in the dorsal root ganglia (DRG). Sensitization of these neurons leads to hyperalgesia and allodynia, two common symptoms of chronic pain. The majority of these pronociceptive receptors and ion channels signal via phosphatidylinositol 4,5-bisphosphate (PIP2) hydrolysis. However, it is currently unknown which lipid kinases generate PIP2 in DRG neurons and if these kinases regulate pronociceptive receptor signaling. The aim of this dissertation is to fully characterize the regulatory role of the predominant PIP2-synthesizing enzyme in nociceptive signaling and sensitization using a combination of genetic and pharmacological approaches. Our studies reveal that lipid kinase (LK) is expressed at the highest levels in DRG and, based on experiments with LK+/- mice, generates at least half of all PIP2 in DRG neurons. Moreover, LK haploinsufficiency reduced pronociceptive receptor signaling and ion channel-mediated neuronal excitability in DRG neurons and reduced noxious thermal and mechanical sensitization in mouse models of chronic pain via PIP2-dependent mechanism(s). In parallel, we developed a high-throughput screening assay to identify the first reported small molecule inhibitor of LK, UNC1. UNC1 lowered PIP2 levels in DRG neurons, reduced pronociceptive receptor signaling, and attenuated noxious thermal and mechanical sensitization when administered intrathecally. Collectively, this work demonstrates that LK regulates PIP2-dependent nociceptive signaling and sensitization and validates LK as a novel therapeutic target for chronic pain.Doctor of Philosoph

The Effects of Corticotomies on Frontonasal Suture Expansion and Bone Modeling in Mature Rabbits

The purpose of this split skull study was designed to evaluate whether corticotomies enhance bone modeling and reduces the resistance of surrounding articulations during expansion in mature rabbits. Nine adult female New Zealand White (NZW) rabbits, 8 to 9 months old, had miniscrew implant (MSI) supported expansion devices with 150 g open-coil nickel-titanium springs placed bilaterally across the frontonasal sutures. Corticotomies were performed on one randomly chosen side, anterior and posterior to the frontonasal suture; the other side served as the control. Sutural separation was measured bi-weekly for 7 weeks. Using microCT scans of each specimens, bone material density (mg HA/ccm) and bone volume fraction (BV/TV) were measured. Qualitative histologic analyses of the suture tissues were performed using H&E staining. Most (94.4%) of the MSIs remained stable throughout the experiment. There was significantly (p <.05) more sutural separation on the corticotomy side (3.73 mm) than the control side (2.83 mm). There was no statistically significant side difference in bone volume fraction (p =.26) and bone density (p=.11). The amount of expansion that occurred was negatively correlated (R=-.860; p=<.001) with bone density. Blinded histological examination showed an increased density of osteoblasts, with a blastema-like appearance, along the bone fronts on the corticotomy side. Numerous elongated Sharpey’s fiber insertions and a mixture of immature woven bone, with numerous osteocytes, were visible at the sutural margins on the corticotomy side, indicating the formation of new bone. In conclusion, mature sutures expanded with adjunctive corticotomies undergo 31% more separation than sutures expanded without corticotomies with the amount of expansion that occurs being inversely related to bone density

Stream Water Quality Responses in a Tornado Damaged Residential Watershed

Tornado damage has the potential to impact stream water quality from seeping anthropogenic compounds and scattered debris in affected areas. On 3 March 2020, an EF4 tornado (~282 km h-1 winds) hit Putnam County, Tennessee, destroying structures, trees, and removing vegetation across the area. This study assessed the influence of tornado damage on the water quality of streams draining the damaged area. We compared physiochemical conditions, fecal contamination, and chemical water quality measures for affected and unaffected watersheds over three months. We found differences between stormflow and baseflow conditions between watersheds, with elevated nutrients, dissolved metals, and fecal coliform bacteria after rain events. However, there were no significant differences between affected and unaffected watersheds for any parameter. Similarly, there were no relationships among nutrients or contaminants and distance to, or density of tornado wreckage. This study provides evidence that unlike other natural disasters, such as earthquakes and hurricanes, tornados may have minimal effects on water quality when residential areas are hit, possibly due to the localized area of destruction that tornados leave. However, tornado influence may still be event-specific and depend on the type of structures damaged

Lipid kinases as therapeutic targets for chronic pain

Existing analgesics are not efficacious in treating all patients with chronic pain and have harmful side effects when used long-term. A deeper understanding of pain signaling and sensitization could lead to the development of more efficacious analgesics. Nociceptor sensitization occurs under conditions of inflammation and nerve injury where diverse chemicals are released and signal through receptors to reduce the activation threshold of ion channels, leading to an overall increase in neuronal excitability [98; 28]. Drugs that inhibit specific receptors have so far been unsuccessful in alleviating pain, possibly because they do not simultaneously target the diverse receptors that contribute to nociceptor sensitization. Hence, focus has shifted towards targeting downstream convergence points of nociceptive signaling [98]. Lipid mediators, including phosphatidylinositol 4,5-bisphosphate (PIP2), are attractive targets as these molecules are required for signaling downstream of G protein-coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs). Furthermore, PIP2 regulates the activity of various ion channels [80]. Thus, PIP2 sits at a critical convergence point for multiple receptors, ion channels and signaling pathways that promote and maintain chronic pain. Decreasing the amount of PIP2 in neurons was recently shown to attenuate pronociceptive signaling and could provide a novel approach for treating pain. Here, we review the lipid kinases that are known to regulate pain signaling and sensitization and speculate on which additional lipid kinases might regulate signaling in nociceptive neurons