Modulation of corticospinal excitability by transcranial magnetic stimulation in children and adolescents with autism spectrum disorder

The developmental pathophysiology of autism spectrum disorders (ASD) is currently not fully understood. However, multiple lines of evidence suggest that the behavioral phenotype may result from dysfunctional inhibitory control over excitatory synaptic plasticity. Consistent with this claim, previous studies indicate that adults with Asperger’s Syndrome show an abnormally extended modulation of corticospinal excitability following a train of repetitive transcranial magnetic stimulation (rTMS). As ASD is a developmental disorder, the current study aimed to explore the effect of development on the duration of modulation of corticospinal excitability in children and adolescents with ASD. Additionally, as the application of rTMS to the understanding and treatment of pediatric neurological and psychiatric disorders is an emerging field, this study further sought to provide evidence for the safety and tolerability of rTMS in children and adolescents with ASD. Corticospinal excitability was measured by applying single pulses of TMS to the primary motor cortex both before and following a 40 s train of continuous theta burst stimulation. 19 high-functioning males ages 9–18 with ASD participated in this study. Results from this study reveal a positive linear relationship between age and duration of modulation of rTMS after-effects. Specifically we found that the older participants had a longer lasting response. Furthermore, though the specific protocol employed typically suppresses corticospinal excitability in adults, more than one third of our sample had a paradoxical facilitatory response to the stimulation. Results support the safety and tolerability of rTMS in pediatric clinical populations. Data also support published theories implicating aberrant plasticity and GABAergic dysfunction in this population

Use of Transcranial Magnetic Stimulation in Autism Spectrum Disorders

The clinical, social and financial burden of autism spectrum disorder (ASD) is staggering. We urgently need valid and reliable biomarkers for diagnosis and effective treatments targeting the often debilitating symptoms. Transcranial magnetic stimulation (TMS) is beginning to be used by a number of centers worldwide and may represent a novel technique with both diagnostic and therapeutic potential. Here we critically review the current scientific evidence for the use of TMS in ASD. Though preliminary data suggests promise, there is simply not enough evidence yet to conclusively support the clinical widespread use of TMS in ASD, neither diagnostically nor therapeutically. Carefully designed and properly controlled clinical trials are warranted to evaluate the true potential of TMS in ASD

Associative learning alone is insufficient for the evolution and maintenance of the human mirror neuron system

AbstractCook et al. argue that mirror neurons originate from associative learning processes, without evolutionary influence from social-cognitive mechanisms. We disagree with this claim and present arguments based upon cross-species comparisons, EEG findings, and developmental neuroscience that the evolution of mirror neurons is most likely driven simultaneously and interactively by evolutionarily adaptive psychological mechanisms and lower-level biological mechanisms that support them.</jats:p

Developmental changes in mu suppression to observed and executed actions in autism spectrum disorders

There has been debate over whether disruptions in the mirror neuron system (MNS) play a key role in the core social deficits observed in autism spectrum disorders (ASD). EEG mu suppression during the observation of biological actions is believed to reflect MNS functioning, but understanding of the developmental progression of the MNS and EEG mu rhythm in both typical and atypical development is lacking. To provide a more thorough and direct exploration of the development of mu suppression in individuals with ASD, a sample of 66 individuals with ASD and 51 typically developing individuals of 6-17 years old were pooled from four previously published studies employing similar EEG methodology. We found a significant correlation between age and mu suppression in response to the observation of actions, both for individuals with ASD and typical individuals. This relationship was not seen during the execution of actions. Additionally, the strength of the correlation during the observation of actions did not significantly differ between groups. The results provide evidence against the argument that mirror neuron dysfunction improves with age in individuals with ASD and suggest, instead, that a diagnosis-independent developmental change may be at the root of the correlation of age and mu suppression

an international symposium held in Pavia on July 4th, 2014

New progresses into the molecular and cellular mechanisms of autism spectrum disorders (ASDs) have been discussed in 1 day international symposium held in Pavia (Italy) on July 4th, 2014 entitled “synapses as therapeutic targets for autism spectrum disorders” (satellite of the FENS Forum for Neuroscience, Milan, 2014). In particular, world experts in the field have highlighted how animal models of ASDs have greatly advanced our understanding of the molecular pathways involved in synaptic dysfunction leading sometimes to “synaptic clinical trials” in children

Changes in Cortical Plasticity Across the Lifespan

Deterioration of motor and cognitive performance with advancing age is well documented, but its cause remains unknown. Animal studies dating back to the late 1970s reveal that age-associated neurocognitive changes are linked to age-dependent changes in synaptic plasticity, including alterations of long-term potentiation and depression (LTP and LTD). Non-invasive brain stimulation techniques enable measurement of LTP- and LTD-like mechanisms of plasticity, in vivo, in humans, and may thus provide valuable insights. We examined the effects of a 40-s train of continuous theta-burst stimulation (cTBS) to the motor cortex (600 stimuli, three pulses at 50 Hz applied at a frequency of 5 Hz) on cortico-spinal excitability as measured by the motor evoked potentials (MEPs) induced by single-pulse transcranial magnetic stimulation before and after cTBS in the contralateral first dorsal interosseus muscle. Thirty-six healthy individuals aged 19–81 years old were studied in two sites (Boston, USA and Barcelona, Spain). The findings did not differ across study sites. We found that advancing age is negatively correlated with the duration of the effect of cTBS (r = −0.367; p = 0.028) and the overall amount of corticomotor suppression induced by cTBS (r = −0.478; p = 0.003), and positively correlated with the maximal suppression of amplitude on motor evoked responses in the target muscle (r = 0.420; p = 0.011). We performed magnetic resonance imaging (MRI)-based individual morphometric analysis in a subset of subjects to demonstrate that these findings are not explained by age-related brain atrophy or differences in scalp-to-brain distance that could have affected the TBS effects. Our findings provide empirical evidence that the mechanisms of cortical plasticity area are altered with aging and their efficiency decreases across the human lifespan. This may critically contribute to motor and possibly cognitive decline

Transcranial Magnetic Stimulation Provides Means to Assess Cortical Plasticity and Excitability in Humans with Fragile X Syndrome and Autism Spectrum Disorder

Fragile X Syndrome (FXS) is the most common heritable cause of intellectual disability. In vitro electrophysiologic data from mouse models of FXS suggest that loss of fragile X mental retardation protein affects intracortical excitability and synaptic plasticity. Specifically, the cortex appears hyperexcitable, and use-dependent long-term potentiation (LTP) and long-term depression (LTD) of synaptic strength are abnormal. Though animal models provide important information, FXS and other neurodevelopmental disorders are human diseases and as such translational research to evaluate cortical excitability and plasticity must be applied in the human. Transcranial magnetic stimulation paradigms have recently been developed to non-invasively investigate cortical excitability using paired pulse stimulation, as well as LTP- and LTD-like synaptic plasticity in response to theta burst stimulation (TBS) in vivo in the human. TBS applied on consecutive days can be used to measure metaplasticity (the ability of the synapse to undergo a second plastic change following a recent induction of plasticity). The current study investigated intracortical inhibition, plasticity and metaplasticity in full mutation females with FXS, participants with autism spectrum disorders (ASD), and neurotypical controls. Results suggest that intracortical inhibition is normal in participants with FXS, while plasticity and metaplasticity appear abnormal. ASD participants showed abnormalities in plasticity and metaplasticity, as well as heterogeneity in intracortical inhibition. Our findings highlight the utility of non-invasive neurophysiological measures to translate insights from animal models to humans with neurodevelopmental disorders, and thus provide direct confirmation of cortical dysfunction in patients with FXS and ASD

Continuous Theta-Burst Stimulation in Children With High-Functioning Autism Spectrum Disorder and Typically Developing Children

Objectives : A neurophysiologic biomarker for autism spectrum disorder (ASD) is highly desirable and can improve diagnosis, monitoring, and assessment of therapeutic response among children with ASD. We investigated the utility of continuous theta-burst stimulation (cTBS) applied to the motor cortex (M1) as a biomarker for children and adolescents with high-functioning (HF) ASD compared to their age- and gender-matched typically developing (TD) controls. We also compared the developmental trajectory of long-term depression- (LTD-) like plasticity in the two groups. Finally, we explored the influence of a common brain-derived neurotrophic factor (BDNF) polymorphism on cTBS aftereffects in a subset of the ASD group. Methods : Twenty-nine children and adolescents (age range 10-16) in ASD (n = 11) and TD (n = 18) groups underwent M1 cTBS. Changes in MEP amplitude at 5-60 min post-cTBS and their cumulative measures in each group were calculated. We also assessed the relationship between age and maximum cTBS-induced MEP suppression (ΔMEP) in each group. Finally, we compared cTBS aftereffects in BDNF Val/Val (n = 4) and Val/Met (n = 4) ASD participants. Results : Cumulative cTBS aftereffects were significantly more facilitatory in the ASD group than in the TD group (P 's 0.18). Conclusions : The results support the utility of cTBS measures of cortical plasticity as a biomarker for children and adolescents with HF-ASD and an aberrant developmental trajectory of LTD-like plasticity in ASD

Test–Retest Reliability of the Effects of Continuous Theta-Burst Stimulation

ObjectivesThe utility of continuous theta-burst stimulation (cTBS) as index of cortical plasticity is limited by inadequate characterization of its test–retest reliability. We thus evaluated the reliability of cTBS aftereffects, and explored the roles of age and common single-nucleotide polymorphisms in the brain-derived neurotrophic factor (BDNF) and apolipoprotein E (APOE) genes.MethodsTwenty-eight healthy adults (age range 21–65) underwent two identical cTBS sessions (median interval = 9.5 days) targeting the motor cortex. Intraclass correlation coefficients (ICCs) of the log-transformed, baseline-corrected amplitude of motor evoked potentials (ΔMEP) at 5–60 min post-cTBS (T5–T60) were calculated. Adjusted effect sizes for cTBS aftereffects were then calculated by taking into account the reliability of each cTBS measure.ResultsΔMEP at T50 was the most-reliable cTBS measure in the whole sample (ICC = 0.53). Area under-the-curve (AUC) of ΔMEPs was most reliable when calculated over the full 60 min post-cTBS (ICC = 0.40). cTBS measures were substantially more reliable in younger participants (&lt; 35 years) and in those with BDNF Val66Val and APOE ε4– genotypes.ConclusioncTBS aftereffects are most reliable when assessed 50 min post-cTBS, or when cumulative ΔMEP measures are calculated over 30–60 min post-cTBS. Reliability of cTBS aftereffects is influenced by age, and BDNF and APOE polymorphisms. Reliability coefficients are used to adjust effect-size calculations for interpretation and planning of cTBS studies