Cerebral and extracerebral distribution of radioactivity associated with oxytocin in rabbits after intranasal administration: Comparison of TTA-121, a newly developed oxytocin formulation, with Syntocinon

Autism spectrum disorder (ASD) is a neurodevelopmental disorder associated with deficits in social interactions/communication. Despite the large number of ASD patients, there is no drug approved to treat its core symptoms. Recently, Syntocinon (oxytocin nasal spray) has been reported to have a therapeutic effect on ASD. However, the disadvantage of Syntocinon for ASD treatment is that 6 puffs/administration are required to achieve the effective pharmacological dose. Furthermore, there are no published reports evaluating the cerebral distribution profile of oxytocin after intranasal administration. TTA-121 is a newly developed intranasal oxytocin formulation with high bioavailability produced by optimizing the physicochemical properties. In this study, we prepared the same formula as Syntocinon as the control formulation (CF), and the cerebral and extracerebral distribution of oxytocin in rabbits after single intranasal administration of 3H-labeled oxytocin formulations—[3H]TTA-121 and [3H]CF were examined and compared. The area under the concentration-time curve to the time of the last quantifiable concentration (AUCt) in the whole brain was 3.6-fold higher in the [3H]TTA-121 group than in the [3H]CF group, indicating increased delivery of radioactivity to the brain by TTA-121 than by CF. Since the distribution profiles showed no notable differences in radioactivity between the olfactory bulb and trigeminal nerve, intranasally-administered oxytocin was probably transferred to the brain via both pathways. The results also showed an increase in radioactivity in the prefrontal area and the precuneus, which are probable sites of pharmacological action as shown in clinical studies using functional magnetic resonance imaging (fMRI), confirming that intranasally-administered oxytocin could reach these tissues.

Case Report: Christianson Syndrome Caused by SLC9A6 Mutation: From Case to Genotype-Phenotype Analysis

Christianson syndrome (CS) is an X-linked neurodevelopmental syndrome characterized by microcephaly, epilepsy, ataxia, and severe generalized developmental delay. Pathogenic mutations in the SLC9A6 gene, which encodes the Na+/H+ exchanger protein member 6 (NHE6), are associated with CS and autism spectrum disorder in males. In this study, whole exome sequencing (WES) and Sanger sequencing revealed a novel de novo frameshift variant c.1548_1549insT of SLC9A6 in a 14-month-old boy with early-onset seizures. According to The American College of Medical Genetics and Genomics (ACMG)/the Association for Molecular Pathology (AMP) guidelines, the variant was classified as pathogenic. The proband presented with several core symptoms of typical epilepsy, including microcephaly, motor delay, distal muscle weakness, micrognathia, occasional unprovoked laughter, swallowing and speech difficulties. Electroencephalography (EEG) showed spikes-slow waves in frontal pole, frontal, anterior temporal and frontal midline point areas. Gesell development schedules (GDS) indicated generalized developmental delay. We also summarized all the reported variants and analyzed the correlation of genotype and phenotype of CS. Our study extends the mutation spectrum of the SLC9A6 gene, and it might imply that the phenotypes of CS are not correlated with SLC9A6 genotypes.

Multimodal Interventions Are More Effective in Improving Core Symptoms in Children With ADHD

Objective: To investigate the effect of sensory integration training combined with EEG biofeedback on core symptoms in children with ADHD.Methods: Fifty-two children with attention-deficit, hyperactive-impulsive and combined ADHD were selected. They were randomly divided into control group, sensory integration training group, EEG biofeedback group, and sensory integration training + EEG biofeedback group, and after 4 months of intervention, concentration time and impulsive- hyperactivity and hyperactivity index scores on the PSQ scale were assessed.Results: Compared with that before the intervention, the attention time was significantly increased (P < 0.01), and the impulsive-hyperactivity and hyperactivity index scores were significantly decreased (P < 0.05, P < 0.01). After the intervention, the attention time was significantly higher than that of the control group (P < 0.05, P < 0.01), the attention time of the multimodal intervention group was significantly higher than that of the single intervention group (P < 0.01), and the impulsive-hyperactivity and hyperactivity index scores were significantly lower than those of the single intervention group (P < 0.05).Conclusion: Multimodal intervention can significantly improve the concentration level of children with ADHD, and significantly improve the behavioral symptoms of impulsive-hyperactivity and hyperactivity. Multimodal interventions were more effective than single interventions in improving core symptoms in children with ADHD. The results of this study provide a reference for related research and practical application.

Autism Spectrum Disorder and screen time during lockdown: an Italian study.

Background: Lockdown due to Covid-19 pandemic brought deep changes to the daily lives of children with Autism Spectrum Disorder (ASD), greatly increasing their amount of time spent at home. Methods: A cohort of 243 parents of children with ASD (2-15 years old) completed an original online survey regarding the child’s screen time and the modification of the ASD symptomatology during lockdown to investigate the relationship between them. Results: The data show that high solitary screen time is related with the worsening of ASD core symptoms. Conclusions: This study may help to increase awareness in the excessive use of screen in children with ASD during the lockdown, both during the pandemic as well as after it ends.

From syndromes to symptoms: Advancing our understanding of mental disorders

<p>Traditionally, psychiatric syndromes have formed the primary target of explanation in psychopathology research. However, these syndromes have been significantly criticised for their conceptual weakness and lack of validity. Ultimately, this limits our ability to create valid explanations of these categories; if the target is invalid then our explanations will suffer as a consequence. Using depression as extended example, this doctoral thesis explores the theoretical and methodological challenges associated with classifying and explaining mental disorders, and develops an alternative explanatory approach and associated methodology for advancing our understanding of mental disorders – the Phenomena Detection Method (PDM; Clack & Ward, 2020; Ward & Clack, 2019). This theoretical thesis begins by evaluating the current approaches to defining, classifying, and explaining mental disorders like depression, and explores the methodological and theoretical challenges with building theories of them. Next, in moving forward, I argue that the explanatory target in psychopathology research should shift from arbitrary syndromes to the central symptoms and signs of mental disorders. By conceptualising the symptoms of a disorder as clinical phenomena, and by adopting epistemic model pluralism as an explanatory strategy, we can build multi-faceted explanations of the processes and factors that constitute a disorder’s core symptoms. This core theoretical and methodological work is then followed by the development of the PDM. Unique in the field of psychopathology, the PDM links different phases of the inquiry process to provide a methodology for conceptualising the symptoms of psychopathology and for constructing multi-level models of the pathological processes that comprise them. Next, I apply the PDM to the two core symptoms of depression – ¬anhedonia and depressed mood – as an illustrative example of the advantages of this approach. This includes providing a more secure relationship between the pathology of depression and its phenotypic presentation, as well as greater insight into the relationship between underlying biological and psychological processes, and behavioural dysfunction. Next, I evaluate the PDM in comparison to existing metatheoretical approaches in the field and make some suggestions for future development. Finally, I conclude with a summary of the main contributions of this thesis. Considering the issues with current diagnostic categories, simply continuing to build explanations of syndromes is not a fruitful way forward. Rather, the complexity of mental disorders suggests we need to represent their key psychopathological phenomena or symptoms at different levels or aspects using multiple models. This thesis provides the metatheoretical and methodological foundations for this to successfully occur.</p>

From syndromes to symptoms: Advancing our understanding of mental disorders

<p>Traditionally, psychiatric syndromes have formed the primary target of explanation in psychopathology research. However, these syndromes have been significantly criticised for their conceptual weakness and lack of validity. Ultimately, this limits our ability to create valid explanations of these categories; if the target is invalid then our explanations will suffer as a consequence. Using depression as extended example, this doctoral thesis explores the theoretical and methodological challenges associated with classifying and explaining mental disorders, and develops an alternative explanatory approach and associated methodology for advancing our understanding of mental disorders – the Phenomena Detection Method (PDM; Clack & Ward, 2020; Ward & Clack, 2019). This theoretical thesis begins by evaluating the current approaches to defining, classifying, and explaining mental disorders like depression, and explores the methodological and theoretical challenges with building theories of them. Next, in moving forward, I argue that the explanatory target in psychopathology research should shift from arbitrary syndromes to the central symptoms and signs of mental disorders. By conceptualising the symptoms of a disorder as clinical phenomena, and by adopting epistemic model pluralism as an explanatory strategy, we can build multi-faceted explanations of the processes and factors that constitute a disorder’s core symptoms. This core theoretical and methodological work is then followed by the development of the PDM. Unique in the field of psychopathology, the PDM links different phases of the inquiry process to provide a methodology for conceptualising the symptoms of psychopathology and for constructing multi-level models of the pathological processes that comprise them. Next, I apply the PDM to the two core symptoms of depression – ¬anhedonia and depressed mood – as an illustrative example of the advantages of this approach. This includes providing a more secure relationship between the pathology of depression and its phenotypic presentation, as well as greater insight into the relationship between underlying biological and psychological processes, and behavioural dysfunction. Next, I evaluate the PDM in comparison to existing metatheoretical approaches in the field and make some suggestions for future development. Finally, I conclude with a summary of the main contributions of this thesis. Considering the issues with current diagnostic categories, simply continuing to build explanations of syndromes is not a fruitful way forward. Rather, the complexity of mental disorders suggests we need to represent their key psychopathological phenomena or symptoms at different levels or aspects using multiple models. This thesis provides the metatheoretical and methodological foundations for this to successfully occur.</p>

CBD-enriched cannabis for autism spectrum disorder: an experience of a single center in Turkey and reviews of the literature

Introduction Autism spectrum disorder is a neurodevelopmental disorder characterized by deficits in communication, social interaction, restricted interest, and repetitive behaviors. Although more cases are being diagnosed, no drugs are approved to treat the core symptoms or cognitive and behavioral problems associated with autism. Therefore, there is an urgent need to develop an effective and safe treatment. Objective In this study, we aim to share our 2-year experience with CBD-enriched cannabis treatment in autism and review the latest studies. Materials and methods The study included 33 (27 males, six females) children diagnosed with autism spectrum disorder who were followed up between January 2018 and August 2020. The mean age was 7.7 ± 5.5 years. The average daily dosage of cannabidiol (CBD) was 0.7 mg/kg/day (0.3–2 mg/kg/day). The median duration of treatment was 6.5 months (3–28 months). The preparations used in this study contained full-spectrum CBD and trace elements tetrahydrocannabinol (THC) of less than 3%. Results The outcomes were evaluated before and after treatment based on clinical interviews. At each follow-up visit, parents were asked to evaluate the effectiveness of the CBD-enriched cannabis treatment. According to the parents’ reports, no change in daily life activity was reported in 6 (19.35%) patients. The main improvements of the treatment were as follows: a decrease in behavioral problems was reported in 10 patients (32.2%), an increase in expressive language was reported in 7 patients (22.5%), improved cognition was reported in 4 patients (12,9%), an increase in social interaction was reported in 3 patients (9.6%), and a decrease in stereotypes was reported in 1 patient (3.2%). The parents reported improvement in cognition among patients who adhered to CBD-enriched cannabis treatment for over two years. The antipsychotic drug could be stopped only in one patient who showed mild ASD symptoms. No change could be made in other drug use and doses. Additionally, this study includes an extensive review of the literature regarding CBD treatment in autism spectrum disorder. According to recent studies, the average dose of CBD was 3.8±2.6 mg/kg/day. The ratio of CBD to THC in the used preparations was 20:1. The most significant improvements were seen in the behavioral problems reported in 20–70% of the patients. Conclusion Using lower doses of CBD and trace THC seems to be promising in managing behavioral problems associated with autism. In addition, this treatment could be effective in managing the core symptoms and cognitive functions. No significant side effects were seen at the low doses of CBD-enriched cannabis when compared to other studies.

Assessment of behavioral, morphological and electrophysiological changes in prenatal and postnatal valproate induced rat models of autism spectrum disorder

Autism spectrum disorders (ASD) are neurodevelopmental disorders, that are characterized by core symptoms, such as alterations of social communication and restrictive or repetitive behavior. The etiology and pathophysiology of disease is still unknown, however, there is a strong interaction between genetic and environmental factors. An intriguing point in autism research is identification the vulnerable time periods of brain development that lack compensatory homeostatic corrections. Valproic acid (VPA) is an antiepileptic drug with a pronounced teratogenic effect associated with a high risk of ASD, and its administration to rats during the gestation is used for autism modeling. It has been hypothesized that valproate induced damage and functional alterations of autism target structures may occur and evolve during early postnatal life. Here, we used prenatal and postnatal administrations of VPA to investigate the main behavioral features which are associated with autism spectrum disorders core symptoms were tested in early juvenile and adult rats. Neuroanatomical lesion of autism target structures and electrophysiological studies in specific neural circuits. Our results showed that prenatal and early postnatal administration of valproate led to the behavioral alterations that were similar to ASD. Postnatally treated group showed tendency to normalize in adulthood. We found pronounced structural changes in the brain target regions of prenatally VPA-treated groups, and an absence of abnormalities in postnatally VPA-treated groups, which confirmed the different severity of VPA across different stages of brain development. The results of this study clearly show time dependent effect of VPA on neurodevelopment, which might be explained by temporal differences of brain regions’ development process. Presumably, postnatal administration of valproate leads to the dysfunction of synaptic networks that is recovered during the lifespan, due to the brain plasticity and compensatory ability of circuit refinement. Therefore, investigations of compensatory homeostatic mechanisms activated after VPA administration and directed to eliminate the defects in postnatal brain, may elucidate strategies to improve the course of disease.

Stimulus-Stimulus-Pairing to Reduce Stereotypes in Three Children with Autism during Movie Watching

Autism spectrum disorders represent a challenge for professionals, who must include in their individualized educational interventions goals for core symptoms (social–communication and stereotypies/restricted interests) and comorbidities. The narrowness of interests and the high frequency of repetitive behaviors in children with autism often constitute an obstacle for learning and the quality of life, and for their caregivers as well. In the scientific literature, behavioral interventions based on both aversive and, less commonly, positive procedures have been implemented to reduce the frequency of stereotypies. The following study was carried out with the intention of replicating a Stimulus-Stimulus Pairing procedure applied by Nuzzolo-Gomez, Leonard, Ortiz, Rivera and Greer (2002) in order to reduce stereotypies in children. This procedure was applied to three children diagnosed with autism aged five, almost six and seven years, in order to reduce stereotypies when children watched movies. An A-B-A experimental design with three subjects was used for this research. The results showed a decrease in stereotypies in favor of appropriate behaviors.