Neuromodulation Integrating rTMS and Neurofeedback for the Treatment of Autism Spectrum Disorder: An Exploratory Study

Autism spectrum disorder (ASD) is a pervasive developmental disorder characterized by deficits in social interaction, language, stereotyped behaviors, and restricted range of interests. In previous studies low frequency repetitive transcranial magnetic stimulation (rTMS) has been used, with positive behavioral and electrophysiological results, for the experimental treatment in ASD. In this study we combined prefrontal rTMS sessions with electroencephalographic (EEG) neurofeedback (NFB) to prolong and reinforce TMS-induced EEG changes. The pilot trial recruited 42 children with ASD (~14.5 years). Outcome measures included behavioral evaluations and reaction time test with event-related potential (ERP) recording. For the main goal of this exploratory study we used rTMS-neurofeedback combination (TMS-NFB, N = 20) and waitlist (WTL, N = 22) groups to examine effects of 18 sessions of integrated rTMS-NFB treatment or wait period) on behavioral responses, stimulus and response-locked ERPs, and other functional and clinical outcomes. The underlying hypothesis was that combined TMS-NFB will improve executive functions in autistic patients as compared to the WTL group. Behavioral and ERP outcomes were collected in pre- and post-treatment tests in both groups. Results of the study supported our hypothesis by demonstration of positive effects of combined TMS-NFB neurotherapy in active treatment group as compared to control WTL group, as the TMS-NFB group showed significant improvements in behavioral and functional outcomes as compared to the WTL group.     

Altered Heavy Metals and Transketolase Found in Autistic Spectrum Disorder

Autism and autism spectrum disorder (ASD) are developmental brain disorders with complex, obscure, and multifactorial etiology. Our recent clinical survey of patient records from ASD children under the age of 6?years and their age-matched controls revealed evidence of abnormal markers of thiol metabolism, as well as a significant alteration in deposition of several heavy metal species, particularly arsenic, mercury, copper, and iron in hair samples between the groups. Altered thiol metabolism from heavy metal toxicity may be responsible for the biochemical alterations in transketolase, and are mechanisms for oxidative stress production, dysautonomia, and abnormal thiamine homeostasis. It is unknown why the particular metals accumulate, but we suspect that children with ASD may have particular trouble excreting thiol-toxic heavy metal species, many of which exist as divalent cations. Accumulation or altered mercury clearance, as well as concomitant oxidative stress, arising from redox-active metal and arsenic toxicity, offers an intriguing component or possible mechanism for oxidative stress-mediated neurodegeneration in ASD patients. Taken together, these factors may be more important to the etiology of this symptomatically diverse disease spectrum and may offer insights into new treatment approaches and avenues of exploration for this devastating and growing disease.     

Traits Contributing to the Autistic Spectrum

Background

It is increasingly recognised that traits associated with autism reflect a spectrum with no clear boundary between typical and atypical behaviour. Dimensional traits are needed to investigate the broader autism phenotype.

Methods and Principal Findings

Ninety-three individual measures reflecting components of social, communication and repetitive behaviours characterising autistic spectrum disorder (ASD) were identified between the ages of 6 months and 9 years from the ALSPAC database. Using missing value imputation, data for 13,138 children were analysed. Factor analysis suggested the existence of 7 factors explaining 85% of the variance. The factors were labelled: verbal ability, language acquisition, social understanding, semantic-pragmatic skills, repetitive-stereotyped behaviour, articulation and social inhibition. Four factors (1, 3, 5 and 7) were specific to ASD being more strongly associated with this phenotype than other co-morbid conditions while other factors were more associated with learning difficulties and specific language impairment. Nevertheless, all 7 factors contributed independently to the explanation of ASD (p<0.001). Exploration of putative genetic causal factors such as variants in the CNTNAP2 gene showed a varying pattern of associations with these traits. An alternative predictive model of ASD was derived using four individual measures: the coherence subscale of the Children''s Communication Checklist (9y), the Social and Communication Disorders Checklist (91 m), repetitive behaviour (69 m) and the sociability subscale of the Emotionality Activity and Sociability measure (38 m). Although univarably these traits performed better than some factors, their combined explanations of ASD were similar (R² = 0.48).

Conclusions and Significance

These results support the fractional nature of ASD with different aetiological origins for these components despite pleiotropic genetic effects being observed. These traits are likely to be useful in the exploration of ASD.     

Neurofeedback: An Alternative and Efficacious Treatment for Attention Deficit Hyperactivity Disorder

Current research has shown that neurofeedback, or EEG biofeedback as it is sometimes called, is a viable alternative treatment for Attention Deficit Hyperactivity Disorder (ADHD). The aim of this article is to illustrate current treatment modalities(s), compare them to neurofeedback, and present the benefits of utilizing this method of treatment to control and potentially alleviate the symptoms of ADHD. In addition, this article examines the prevalence rates and possible etiology of ADHD, the factors associated with ADHD and brain dysfunction, the current pharmacological treatments of ADHD, Ritalin, and the potential risks and side effects. Behavior modification and cognitive behavioral treatment for ADHD is discussed as well. Lastly, a brief history of the study of neurofeedback, treatment successes and clinical benefits, comparisons to medication, and limitations are presented.     

Parental and Grandparental Ages in the Autistic Spectrum Disorders: A Birth Cohort Study

Background

A number of studies have assessed ages of parents of children with autistic spectrum disorders (ASD), and reported both maternal and paternal age effects. Here we assess relationships with grandparental ages.

Methods and Findings

We compared the parental and grandparental ages of children in the population-based Avon Longitudinal Study of Parents and Children (ALSPAC), according to their scores in regard to 4 autistic trait measures and whether they had been given a diagnosis of ASD. Mean maternal and paternal ages of ASD cases were raised, but this appears to be secondary to a maternal grandmother age effect (P = 0.006): OR = 1.66[95%CI 1.16, 2.37] for each 10-year increase in the grandmother''s age at the birth of the mother. Trait measures also revealed an association between the maternal grandmother''s age and the major autistic trait–the Coherence Scale (regression coefficient b = 0.142, [95%CI = 0.057, 0.228]P = 0.001). After allowing for confounders the effect size increased to b = 0.217[95%CI 0.125, 0.308](P<0.001) for each 10 year increase in age.

Conclusions

Although the relationship between maternal grandmother''s age and ASD and a major autistic trait was unexpected, there is some biological plausibility, for the maternal side at least, given that the timing of female meiosis I permits direct effects on the grandchild''s genome during the grandmother''s pregnancy. An alternative explanation is the meiotic mismatch methylation (3 M) hypothesis, presented here for the first time. Nevertheless the findings should be treated as hypothesis generating pending corroborative results from other studies.     

LCA for Site Remediation: A Literature Review

Remediation of contaminated sites provides a cleaner local environment, but may also have negative environmental impacts on the local, regional, and global scales. Methods based on Life Cycle Assessment (LCA) are designed to take the negative effects into consideration when deciding how to treat a site, and to improve the environmental efficiency of remediation techniques. This paper reviews nine case studies that use LCA tools to evaluate alternative remediation techniques to summarize the findings of methodologies and results. The methodologies were found to differ in the limitation of the LCA for space, time and secondary processes. This strongly influenced the results. Bioremediation was the worst when the secondary process of producing electron acceptors was included; otherwise it was the best. The choice of impact categories heavily affected the results. Inclusion of land use was especially important in site remediation studies. In general, the negative impact of site remediation was due to energy consumption. For excavation combined with ex-situ treatment, the transport of contaminated soil to the treatment facility or landfill required the most energy. For in-situ treatment of soil and groundwater, pumping consumed the most energy. It is proposed that different methods be applied to the same site.     

Genetic Studies of Autistic Disorder and Chromosome 7

Genome-wide scans have suggested that a locus on 7q is involved in the etiology of autistic disorder (AD). We have identified an AD family in which three sibs inherited from their mother a paracentric inversion in the chromosome 7 candidate region (inv(7)(q22-q31.2)). Clinically, the two male sibs have AD, while the female sib has expressive language disorder. The mother carries the inversion, but does not express AD. Haplotype data on the family suggest that the chromosomal origin of the inversion was from the children's maternal grandfather. Based on these data, we have genotyped 76 multiplex (>/=2 AD affecteds/family) families for markers in this region of 7q. Two-point linkage analysis yielded a maximum heterogeneity lod score of 1.47 and maximum lod score (MLS) of 1.03 at D7S495. Multipoint MLS and NPL analyses resulted in peak scores of 1.77 at D7S2527 and 2.01 at D7S640. Examination of affected sibpairs revealed significant paternal (P = 0.007), but not maternal (P = 0. 75), identity-by-descent sharing at D7S640. Significant linkage disequilibrium was detected with paternal (P = 0.02), but not maternal (P = 0.15), transmissions at D7S1824 in multiplex and singleton families. There was also evidence for an increase in recombination in the region (D7S1817 to D7S1824) in the AD families versus non-AD families (P = 0.03, sex-averaged; and P = 0.01, sex-specific). These results provide further evidence for the presence of an AD locus on chromosome 7q, as well as provide evidence suggesting that this locus may be paternally expressed.     

Urinary Methylxanthine and Autistic Disorder: Absence of Previously Reported Correlation

We were unable to reveal significant difference in the levels of xanthine and methylxanthines in the urine samples from 59 patients diagnosed with autistic symptoms and 64 age‐ and sex‐matched normal volunteers. Our data suggest that abnormalities in xanthine and methylxanthine excretion (US Patent 20020019406 A1, Feb. 12, 2002) represent distincly uncommon symptoms in autism.     

Childhood Intussusception: A Literature Review

Background

Postlicensure data has identified a causal link between rotavirus vaccines and intussusception in some settings. As rotavirus vaccines are introduced globally, monitoring intussusception will be crucial for ensuring safety of the vaccine programs.

Methods

To obtain updated information on background rates and clinical management of intussusception, we reviewed studies of intussusception in children <18 years of age published since 2002. We assessed the incidence of intussusception by month of life among children <1 year of age, seasonality, method of diagnosis, treatment, and case-fatality.

Findings

We identified 82 studies from North America, Asia, Europe, Oceania, Africa, Eastern Mediterranean, and Central & South America that reported a total of 44,454 intussusception events. The mean incidence of intussusception was 74 per 100,000 (range: 9–328) among children <1 year of age, with peak incidence among infants 5–7 months of age. No seasonal patterns were observed. A radiographic modality was used to diagnose intussusception in over 95% of the cases in all regions except Africa where clinical findings or surgery were used in 65% of the cases. Surgical rates were substantially higher in Africa (77%) and Central and South America (86%) compared to other regions (13–29%). Case-fatality also was higher in Africa (9%) compared to other regions (<1%). The primary limitation of this review relates to the heterogeneity in intussusception surveillance across different regions.

Conclusion

This review of the intussusception literature from the past decade provides pertinent information that should facilitate implementation of intussusception surveillance for monitoring the postlicensure safety of rotavirus vaccines.     

Weight Cycling: A Review of the Animal Literature

This review critically evaluates the animal literature concerning the effects of weight cycling on factors related to development of obesity, diabetes, hypertension, and hyperlipidemia. Although human studies have been used to retrospectively examine the relationship between fluctuations in body weight and a variety of disease markers, direct causal links between weight cycling and negative health effects have been inferred from a series of scientific publications using animals as subjects. We use data from 24 such publications to evaluate evidence for and against a series of hypotheses that have been suggested regarding weight cycling and health. Although there are some intriguing results, there is currently little evidence to support any of these hypotheses. However, methodological limitations were identified in many of these studies, and caution should be used in making definitive decisions about weight cycling. Weight cycling studies could be improved by including more appropriate controls, comparing controls to weight cycling animals at more appropriate time points, and giving more attention to potential effects of diet composition. While more careful research is needed, at this time we conclude that the published animal literature does not justify any warnings about the hazards of weight cycling.     

Drug Withdrawal Syndromes: A Literature Review

Drug withdrawal syndromes reportedly have been caused by numerous pharmacological agents, but only a few drugs have been adequately studied in this regard. Criteria for evaluating drug withdrawal syndromes have been proposed. Sedative-hypnotic agents, opiates, corticosteroids, clonidine, tricyclic antidepressant medications and beta-adrenergic blocking agents meet the criteria for such syndromes. Gradual tapering of the dose of these drugs is recommended when therapy must be discontinued. Whether or not other drugs cause rebound reactions is questionable, but caution should be used when discontinuing drugs for which numerous reports of withdrawal syndromes exist.     

Future Prospects for Epigenetics in Autism Spectrum Disorder

Molecular Diagnosis & Therapy - Despite decades of investigation into the genetics of autism spectrum disorder (ASD), a current consensus in the field persists that ASD risk is too...     

Bioelectric Brain Activity in Children with Autistic Spectrum Disorders: Population Heterogeneity

During the discriminant analysis of the bioelectric brain activity, we found that there is a separate subgroup of children with autistic spectrum disorders that is close to the group of schizophrenia spectrum disorders but does not coincide with it. Differences between the experimental groups indicate the significance of impairments in the left frontal-temporal region, i.e., in the area responsible for speech development. When comparing the group of children with autistic spectrum disorders with other groups, we observed the significance of high-frequency rhythms.     

A Contemplative Biofeedback Intervention for Adults with Autism Spectrum Disorder: Feasibility of a Community-Based Treatment

Applied Psychophysiology and Biofeedback - As the number of diagnosed adults living with autism spectrum disorder (ASD) continues to grow, a lack of resources and lack of available interventions...     

A Pilot Study of Neurofeedback for Chronic PTSD

EEG Biofeedback (also known as neurofeedback) has been in use as a clinical intervention for well over 30 years; however, it has made very little impact on clinical care. One reason for this has been the difficulty in designing research to measure clinical change in the real world. While substantial evidence exists for its efficacy in treating attention deficit/hyperactivity disorder, relatively little evidence exists for its utility in other disorders including posttraumatic stress disorder (PTSD). The current study represents a “proof-of-concept” pilot for the use of neurofeedback with multiply-traumatized individuals with treatment-resistant PTSD. Participants completed 40 sessions of neurofeedback training two times per week with sensors randomly assigned (by the study coordinator, who was not blind to condition) to sensor placements of either T4-P4 or T3-T4. We found that neurofeedback significantly reduced PTSD symptoms (Davidson Trauma Scale scores averaged 69.14 at baseline to 49.26 at termination), and preceded gains in affect regulation (Inventory of Altered Self-Capacities-Affect Dysregulation scores averaged 23.63 at baseline to 17.20 at termination). We discuss a roadmap for future research.     

Antifungal Dosing in Obesity: A Review of the Literature

Obesity is becoming a global pandemic that is projected to increase significantly over the next few decades. Unfortunately, studies of drug dosing and pharmacokinetics have largely excluded obese patients. Currently, literature inadequately characterizes drug disposition in these patients. Only a limited selection of literature addresses antibacterial dosing in obesity, and virtually none characterizes antifungal dosing in obesity. This review discusses the changes in pharmacokinetics that occur in obesity and the available in vitro and in vivo data describing the disposition of antifungal agents in obese animals and patients.     

Late-life Onset Bipolar Disorder Presenting as a Case of Pseudo-Dementia: A Case Discussion and Review of Literature

Depression and comorbid cognitive impairment in the elderly can be difficult todistinguish from dementia. Adding to the complex differential is that depressionmay be part of a bipolar illness rather than a unipolar mood disorder. Adiligent workup and close monitoring of patients can inform appropriatetreatment and can make the difference between recovery and persistence ofsymptoms. The present case will illustrate how a comprehensive workup utilizingextensive data gathering, laboratory workup, use of neuropsychological testing,neuroimaging, and timely treatment can lead to successful clinical outcomes thatcan be sustained for many years.     

The Efficacy of Neurofeedback in Patients with Major Depressive Disorder: An Open Labeled Prospective Study

The purpose of this study was to evaluate the effect of neurofeedback on depressive symptoms and electrophysiological disturbances in patients with major depressive disorder. We recruited participants suffering from depression to evaluate efficacy of left prefrontal beta with alpha/theta training. An 8-week, prospective, open-label study was undertaken. Twenty participants were recruited. The treatment protocol was twice or three times a week training of beta at F3 with alpha/theta at Pz for 8 weeks. When every visit, patients were received beta training for 30 min, and then alpha/theta training for 30 min. Baseline, 4 and 8 week scores of; the Hamilton rating scale for Depression (HAM-D), the Hamilton rating scale for Anxiety (HAM-A), the Beck Depression Inventory (BDI)-II, the Beck Anxiety Inventory (BAI), Clinical global impression-severity (CGI-S), and pre- and post-treatment resting state EEGs were compared. Interhemispheric alpha power asymmetry (A score) was computed for homologous sites F3–F4. Pre- and post-training clinical assessments revealed significant improvements in HAM–D, HAM-A, BDI, and CGI-S scores. Cumulative response rates by HAM-D were 35.0 and 75.0 % at 4 and 8 weeks, respectively, corresponding cumulative remission rates by HAM-D were 15.0 and 55.0 %, respectively. No significant differences were found between pre- and post-treatment A score. Neurofeedback treatment could improve depressive symptoms significantly. In addition, anxiety symptoms and clinical illness severity decreased significantly after neurofeedback treatment. Despite its several limitations, such as, small sample size and lack of a control group, this study suggested neurofeedback has significant effects in patients with major depressive disorder.