Immune, Autonomic, and Endocrine Dysregulation in Autism and Ehlers-Danlos Syndrome/Hypermobility Spectrum Disorders Versus Unaffected Controls

Background: A growing body of literature suggests etiological overlap between Ehlers-Danlos syndrome (EDS)/hypermobility spectrum disorders (HSD) and some cases of autism, although this relationship is poorly delineated. In addition, immune, autonomic, and endocrine dysregulation are reported in both conditions and may be relevant to their respective etiologies. Aims: To study symptom overlap in these two comorbid spectrum conditions. Methods and Procedures: We surveyed 702 adults aged 25+ years on a variety of EDS/HSD-related health topics, comparing individuals with EDS/HSD, autism, and unaffected controls. Outcomes and Results: The autism group reported similar though less severe symptomology as the EDS/HSD group, especially in areas of immune/autonomic/endocrine dysregulation, connective tissue abnormalities (i.e., skin, bruising/bleeding), and chronic pain. EDS/HSD mothers with autistic children reported more immune symptoms than EDS/HSD mothers without, suggesting the maternal immune system could play a heritable role in these conditions (p = 0.0119). Conclusions and Implications: These data suggest that EDS/HSD and autism share aspects of immune/autonomic/endocrine dysregulation, pain, and some tissue fragility, which is typically more severe in the former. This overlap, as well as documented comorbidity, suggests some forms of autism may be hereditary connective tissue disorders (HCTD)

Relative Power of Specific EEG Bands and Their Ratios during Neurofeedback Training in Children with Autism Spectrum Disorder

Neurofeedback is a mode of treatment that is potentially useful for improving self-regulation skills in persons with autism spectrum disorder. We proposed that operant conditioning of EEG in neurofeedback mode can be accompanied by changes in the relative power of EEG bands. However, the details on the change of the relative power of EEG bands during neurofeedback training course in autism are not yet well explored. In this study, we analyzed the EEG recordings of children diagnosed with autism and enrolled in a prefrontal neurofeedback treatment course. The protocol used in this training was aimed at increasing the ability to focus attention, and the procedure represented the wide band EEG amplitude suppression training along with upregulation of the relative power of gamma activity. Quantitative EEG analysis was completed for each session of neurofeedback using wavelet transform to determine the relative power of gamma and theta/beta ratio, and further to detect the statistical changes within and between sessions. We found a linear decrease of theta/beta ratio and a liner increase of relative power of gamma activity over 18 weekly sessions of neurofeedback in 18 high functioning children with autism. The study indicates that neurofeedback is an effective method for altering EEG characteristics associated with the autism spectrum disorder. Also, it provides information about specific changes of EEG activities and details the correlation between changes of EEG and neurofeedback indexes during the course of neurofeedback. This pilot study contributes to the development of more effective approaches to EEG data analysis during prefrontal neurofeedback training in autism.Key word: Electroencephalography, Neurofeedback, Autism Spectrum Disorder, Gamma activity, EEG bands’ ratio

Transcranial Magnetic Stimulation in Autism Spectrum Disorders: Modulating Brainwave Abnormalities and Behaviors

Neuropathological studies in autism spectrum disorder (ASD) suggest the presence of a neuronal migrational disorder that alters the excitatory–inhibitory bias of the cerebral cortex. More specifically, in ASD, there appears to be widespread loss of parvalbumin (PV)-positive interneurons manifested as abnormalities in gamma oscillations (neural network instabilities), epileptogenesis, and impaired cognitive functions. Transcranial magnetic stimulation (TMS) is one of the first treatment to target this putative core pathological feature of ASD. Studies show that low-frequency TMS over the dorsolateral prefrontal cortex (DLPC) of individuals with ASD decreases the power of gamma activity while improving both executive function skills related to self-monitoring behaviors as well as the ability to apply corrective actions. Studies from our group have also shown that low-frequency TMS in ASD provides a reduction of stimulus-bound behaviors and diminished sympathetic arousal. Results become more significant with an increasing number of sessions and bear synergism when used along with neurofeedback

Exploratory Study of rTMS Neuromodulation Effects on Electrocortical Functional Measures of Performance in an Oddball Test and Behavioral Symptoms in Autism

There is no accepted pathology to autism spectrum disorders (ASD) but research suggests the presence of an altered excitatory/inhibitory (E/I) bias in the cerebral cortex. Repetitive transcranial magnetic stimulation (rTMS) offers a non-invasive means of modulating the E/I cortical bias with little in terms of side effects. In this study, 124 high functioning ASD children (IQ > 80, <18 years of age) were recruited and assigned using randomization to either a waitlist group or one of three different number of weekly rTMS sessions (i.e., 6, 12, and 18). TMS consisted of trains of 1.0 Hz frequency pulses applied over the dorsolateral prefrontal cortex (DLPFC). The experimental task was a visual oddball with illusory Kanizsa figures. Behavioral response variables included reaction time and error rate along with such neurophysiological indices such as stimulus and response-locked event-related potentials (ERP). One hundred and twelve patients completed the assigned number of TMS sessions. Results showed significant changes from baseline to posttest period in the following measures: motor responses accuracy [lower percentage of committed errors, slower latency of commission errors and restored normative post-error reaction time slowing in both early and later-stage ERP indices, enhanced magnitude of error-related negativity (ERN), improved error monitoring and post-error correction functions]. In addition, screening surveys showed significant reductions in aberrant behavior ratings and in both repetitive and stereotypic behaviors. These differences increased with the total number of treatment sessions. Our results suggest that rTMS, particularly after 18 sessions, facilitates cognitive control, attention and target stimuli recognition by improving discrimination between task-relevant and task-irrelevant illusory figures in an oddball test. The noted improvement in executive functions of behavioral performance monitoring further suggests that TMS has the potential to target core features of ASD

rTMS neuromodulation improves electrocortical functional measures of information processing and behavioral responses in autism

Objectives: Reports in autism spectrum disorders (ASD) of a minicolumnopathy with consequent deficits of lateral inhibition help explain observed behavioral and executive dysfunctions. We propose that neuromodulation based on low frequency repetitive Transcranial Magnetic Stimulation (rTMS) will enhance lateral inhibition through activation of inhibitory double bouquet interneurons and will be accompanied by improvements in the prefrontal executive functions. In addition we proposed that rTMS will improve cortical excitation/inhibition ratio and result in changes manifested in event-related potential (ERP) recorded during cognitive tests. Materials and Methods: Along with traditional clinical behavioral evaluations the current study used ERPs in a visual oddball task with illusory figures. We compared clinical, behavioral and electrocortical outcomes in two groups of children with autism (TMS, wait-list group). We predicted that 18 session long course in autistic patients will have better behavioral and ERP outcomes as compared to age- and IQ-matched WTL group. We used 18 sessions of 1 Hz rTMS applied over the dorso-lateral prefrontal cortex in 27 individuals with ASD diagnosis. The WTL group was comprised of 27 age-matched subjects with ASD tested twice. Both TMS and WTL groups were assessed at the baseline and after completion of 18 weekly sessions of rTMS (or wait period) using clinical behavioral questionnaires and during performance on visual oddball task with Kanizsa illusory figures. Results: Post-TMS evaluations showed decreased irritability and hyperactivity on the Aberrant Behavior Checklist (ABC), and decreased stereotypic behaviors on the Repetitive Behavior Scale (RBS-R). Following rTMS course we found decreased amplitude and prolonged latency in the frontal and fronto-central N100, N200 and P300 (P3a) ERPs to non-targets in active TMS treatment group. TMS resulted in increase of P2d (P2a to targets minus P2a to non-targets) amplitude. These ERP changes along with increased centro-parietal P100 and P300 (P3b) to targets are indicative of more efficient processing of information post-TMS treatment. Another important finding was decrease of the latency and increase of negativity of error-related negativity (ERN) during commission errors that may reflect improvement in error monitoring and correction function. Enhanced information processing was also manifested in lower error rate. In addition we calculated normative post-error treaction time (RT) slowing response in both groups and found that rTMS treatment was accompanied by post-error RT slowing and higher accuracy of responses, whereas the WTL group kept on showing typical for ASD post-error RT speeding and higher commission and omission error rates. Conclusion: Results from our study indicate that rTMS improves executive functioning in ASD as evidenced by normalization of ERP responses and behavioral reactions (RT, accuracy) during executive function test, and also by improvements in clinical evaluations

Effects of rTMS on Behavioral and Electrocortical Measures of Error Monitoring and Correction Function in Children with Autism Spectrum Disorder

Error monitoring and correction is one of the executive functions and is important for effective goal-directed behavior. Deficient executive functioning, including reduced error monitoring ability, is one of the typical features of such neurodevelopmental disorders as autism spectrum disorder (ASD), probably related to perseverative responding, stereotyped repetitive behaviors, and an inability to accurately monitor ongoing behavior. Our prior studies of behavioral and event-related potential (ERP) measures during performance on visual oddball tasks in high-functioning autistic children showed that despite only minor differences in reaction times (RT) children with autism committed significantly more errors. The chapter reviews behavioral (reaction time, accuracy, rate of omission and commission errors, post-error reaction time slowing) error monitoring in children with ASD and response-locked event-related potentials (ERP), in particular, the error-related negativity (ERN) and error-related positivity (Pe) recorded at the fronto-central EEG sites. The ERN reflects early error detection processes, whereas the Pe has been associated with later conscious error evaluation and attention reallocation. Our prior studies showed significant differences of behavioral and ERN indices between children with ASD and with ADHD as well as with typical developing peers. The goal of our chapter is to review effects of slow frequency repetitive TMS (rTMS) over dorsolateral prefrontal cortex (DLPFC) in high-functioning children with ASD on behavioral and electrocortical measures found in a series of studies conducted by our group. Our results show significant post-TMS differences in the response-locked ERPs such as ERN, as well as behavioral response-monitoring measures indicative of improved error monitoring and correction function. Our review suggests that TMS has the potential to become a viable therapeutic tool in ASD treatment and may play an important role in improving the quality of life of many children with the disorder. The chapter provides rationale to use ERN and Pe, along with behavioral performance measures as functional outcome measures, to assess the effectiveness of neuromodulation (e.g., rTMS and rTMS combined with neurofeedback) in children with autism, and thus, may have important practical implications

Abnormalities of EEG Functional Connectivity and Effective Connectivity in Children with Autism Spectrum Disorder

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder that interferes with normal brain development. Brain connectivity may serve as a biomarker for ASD in this respect. This study enrolled a total of 179 children aged 3−10 years (90 typically developed (TD) and 89 with ASD). We used a weighted phase lag index and a directed transfer function to investigate the functional and effective connectivity in children with ASD and TD. Our findings indicated that patients with ASD had local hyper-connectivity of brain regions in functional connectivity and simultaneous significant decrease in effective connectivity across hemispheres. These connectivity abnormalities may help to find biomarkers of ASD

Affective Virtual Reality Gaming for Autism

Emotional impairment is one of the common symptoms of many mental diseases. Being able to learn the emotional reactions from subjects using nonintrusive human-computer interactions (HCI) would provide a novel and efficient approach to assist existing intervention and therapy. Psychologists conducted research using virtual reality (VR) as a tool for exposure starting from decades ago. However, early VR equipment was cumbersome in size and inefficient, which can only be used to simulate limited scenes, such as car driving and phobia scenarios. With the evolution of affordable and portable VR hardware, we are now able to design systematic VR games that can precisely control variables for different stimuli and testing cases. Furthermore, the VR nowadays can serve not only as exposure methods, but also real games that seamlessly and nonintrusively interact with users. The experience of immersion and presence has made VR naturally suitable for triggering strong emotions. Moreover, the study of affective computing, known as the study and development of systems and devices that can recognize, interpret, process, and simulate human affects, is a trendy and challenging topic in HCI field. Given current research and potential development, affective computing is seeking to develop emotional intelligence in machines. Integrating the concept of affective computing into game design and development will lead to a new type of serious games that interact with users’ emotions. This chapter reviews the methodologies commonly used in affective computing and related research projects using VR exposure as an intervention for people with special needs. It also describes a series of studies conducted to collect and analyze data. Our goal is to propose a game framework that recognizes users’ emotional reactions in a multimodal approach, which, with ideal expectation, adapts according to the fluctuation of the users’ emotional states dynamically. The system provides a guideline for affective gaming design for mental healthcare purposes. The application of the framework is to assist in intervention for autistic spectrum disorder and can be extended to other emotion-related mental illness

Effects of Transcranial Magnetic Stimulation Therapy on Evoked and Induced Gamma Oscillations in Children with Autism Spectrum Disorder

Autism spectrum disorder (ASD) is a behaviorally diagnosed neurodevelopmental condition of unknown pathology. Research suggests that abnormalities of elecltroencephalogram (EEG) gamma oscillations may provide a biomarker of the condition. In this study, envelope analysis of demodulated waveforms for evoked and induced gamma oscillations in response to Kanizsa figures in an oddball task were analyzed and compared in 19 ASD and 19 age/gender-matched neurotypical children. The ASD group was treated with low frequency transcranial magnetic stimulation (TMS), (1.0 Hz, 90% motor threshold, 18 weekly sessions) targeting the dorsolateral prefrontal cortex. In ASD subjects, as compared to neurotypicals, significant differences in evoked and induced gamma oscillations were evident in higher magnitude of gamma oscillations pre-TMS, especially in response to non-target cues. Recordings post-TMS treatment in ASD revealed a significant reduction of gamma responses to task-irrelevant stimuli. Participants committed fewer errors post-TMS. Behavioral questionnaires showed a decrease in irritability, hyperactivity, and repetitive behavior scores. The use of a novel metric for gamma oscillations. i.e., envelope analysis using wavelet transformation allowed for characterization of the impedance of the originating neuronal circuit. The results suggest that gamma oscillations may provide a biomarker reflective of the excitatory/inhibitory balance of the cortex and a putative outcome measure for interventions in autism