therapeutic use of rtms in pediatric asd and adhd cohorts

Conditions: Autism Spectrum Disorder; ADHD; Neurodevelopmental Disorders

Summary: in this interventional, pilot clinical trial investigators will stimulate the dorsolateral prefrontal cortex (dlpfc) in patients with autism and adhd. the goal of the study is to improve cognition and executive functions associated with this brain region and, consequently, ameliorate the core symptoms of the disorders. specifically, the primary purpose is to establish the efficacy, safety, and tolerability of tms in pediatric patients with asd and adhd. concurrently, the research aims to uncover the impact of tms on particular biomarkers associated with the development of these disorders and validate the hypothesis suggesting that the bdnf gene polymorphism (val66met) could influence an individual's susceptibility to tms. participants will be randomized into the active group and placebo group, to guarantee a real assessment of the impact of neurostimulation on the cognitive, behavioral, and biochemical parameters. participants will be asked to complete a neuropsychological evaluation and a biological sample collection before and after tms treatment, and 1-month post-treatment completion.

background asd and adhd are complex neurodevelopmental disorders with increasing prevalence worldwide. the neurobiology of asd and adhd reveals a complex picture of altered excitation-inhibition (e/i) balance, aberrant neuronal activity, and disorganization of brain networks. while cognitive and behavioral abnormalities in asd are related to excessive excitability (due to altered cortex cytoarchitecture), especially at the prefrontal lobes, adhd patients show reduced activation in the right vlpfc and dlpfc. neuroinflammation, glutamate imbalance, and kynurenines pathway (kp) dysfunction seem to play a key role in the pathogenesis of these disorders, creating a self-sustaining auto-toxic loop. treatment options for these disorders are limited, mainly focusing on early behavioral interventions. while for asd there are no specific pharmacological treatments to address the core symptoms, psychostimulants are considered the most effective therapy for patients with adhd. unfortunately, various side effects and the potential for abuse with no reduction in symptom severity in long-term use can restrict its administration. in this scenario, transcranial magnetic stimulation (tms) could emerge as a reliable therapeutic option. tms involves magnetic stimulation of the brain to cause long-term changes in excitability and neurochemical activity, healing the key neurobiological alterations described above. although shreds of evidence on its potential use in asd-adhd treatment, there are still critical challenges that limit its use in clinical practice. one of the big issues is the problem of heterogeneity of the results and the stimulation protocols used in current studies. many factors influence the efficacy of tms, including the stimulation parameters and the functional state of the targeted region during stimulation. also, the psychotropic drugs taken by enrolled patients may affect tms outcomes, as they cause long-term changes in synaptic and excitatory balance. the brain-derived neurotrophic factor (bdnf) gene polymorphism (val66met) has been considered a critical contributing factor to individual susceptibility to tms. bdnf is, indeed involved in early and long-term potentiation, particularly in hippocampal synapses, and its polymorphism has been shown to affect different cognitive functions. according to the most recent data, heterozygous val/met individuals were less susceptible to tms effects. finally, another crucial weakness is the lack of longitudinal follow-up, at a well-defined point in time, later neurostimulation. this avoids critical questions regarding possible predictors of outcome (e.g., genetic profiling), length of persistence of benefits, assessing outcome according to the severity of phenotypic presentation, and utility of booster session. aims and objectives the primary aim of the study is to establish the efficacy, safety, and tolerability of tms in pediatric patients with asd and adhd. key objectives include: 1. evaluating tms impact on core symptoms, cognition, and executive functions. 2. analyzing changes in peripheral biomarkers, such as neurotransmitters, kynurenines, and neurotrophins following tms. 3. investigating the role of bdnf gene polymorphism (val66met) in tms individual susceptibility. 4. identifying clinical profiles and individual factors influencing tms efficacy (such as cognitive level, ongoing therapies, age, sex, neuropsychiatric comorbidities, clinical severity, etc.). 5. establishing a longitudinal follow-up to assess predictors of outcome, persistence of benefits, and the utility of booster sessions. methodology it is expected to recruit for this study at least 80 children, divided into 2 groups: 40 children with asd, and 40 children with adhd, both of them will be randomly divided into the active group (real tms stimulation) and the sham group (placebo stimulation). in case of the inferiority of the sample, due to the difficulty of recruitment, investigators will proceed to administer the active and sham stimulation to the same patients, alternatively, in two different moments, after a proper wash-out. it has been proposed 36-40 months to complete the whole study. recruitment of participants will be carried out at the neuropsychiatry unit for children and adolescents, general hospital "riuniti" of foggia. it has been planned to identify children among hospitalized patients who need a first diagnosis of adhd and asd or who need to be followed up. written informed consent will then be requested from parents, legal tutors, and children wherever possible. * study assessment this study will be articulated according to the following phases: 1. collecting and managing biomaterials peripheral blood, saliva, and urine samples will be collected before and after neurostimulation. to verify the impact of tms on serum and molecular profile in children with neurodevelopmental disorders, we will provide a third biological sample, one month after the last neurostimulation session. the following biomarkers will be assessed: • tryptophan and its catabolites: kina, quin, 3-hk, etc. • glutamate, gaba (γ-aminobutyric acid), serotonin, and dopamine. * plasmatic bdnf * inflammatory biomarkers: cortisol, il-6, il-1β, tnf-α, tsh, ft3, ft4, protein-c-reactive (pcr), ferritin. a small amount of blood will be used to genotype bdnf gene polymorphism (val66met). 2. clinical and neuropsychological assessment parents will be asked to complete a set of questionnaires and interview measures designed to assess symptoms of asd and adhd, such as: • vineland adaptive behavior scales - second edition. • conners 3 • the child behavior checklist (cbcl). • autism diagnostic interview-revised (adi-r) • social communication questionnaire (scq). participants will be asked to complete a battery of cognitive, neuropsychological, and play-based assessments, including: • autism diagnostic observation schedule-2 (ados-2). * wechsler intelligence scale for children iv ed. * leiter international performance scale-revised. * developmental neuropsychological assessment, second edition (nepsy-ii) * m-abc (movement assessment battery for children) * children's depression inventory 2™ (cdi 2) * multidimensional anxiety scale for children second edition™ (masc 2) neuropsychological evaluation will be conducted at three different moments, before and after the neurostimulation and 1 month after the last stimulation. 3. eeg data collection and neurostimulation the department of clinical and experimental medicine-university of foggia will perform tms neurostimulation. for all participants (both active and sham groups), eeg data will be recorded two times, 30 min before tms and within 30 min after the last stimulation. the participants will sit in a quiet room, awake and relaxed, with their eyes open. during the data-recording process, 5-10 minutes of resting-state eeg data will be recorded from 32 electrodes positioned according to the 10-10 international system (brainvision, brain products gmbh, germany). matlab and the package eeg lab will be used for offline data analysis. tms parameters will be tailored to each disorder's neurobiology. - asd protocol the casanova-sokhadze research group's tms protocol will be used because it is the most widely replicated protocol in the pediatric population, with good safety and tolerability as well as fair efficacy. for repetitive tms administration, we will use a magstim r2 stimulator (magstim co, uk) with a 70-mm wingspan figure-eight coil, handle oriented approximately 45° from the midline. the neuronavigation system will be utilized to correctly identify the stimulation site (pfc/dlpfc) for every subject. since it is difficult to treat patients with autism, to avoid their discomfort researchers hypothesize establishing the location of tms stimulation, through the use of anatomical landmarks corresponding to the scalp regions used for f3 and f4 eeg electrode placement in the 10-20 international system. individual mt will be assessed for each hemisphere at the beginning of treatment (l dlpfc, r dlpfc, l + r dlpfc). participants will receive 18 rtms treatment with fig8 coil twice weekly (9 weeks). the rtms will be administered with the following stimulation parameters: 1hz frequency, 90% mt, 180 pulses per session with 9 trains of 20 pulses each with 20-30s intervals between the trains. the initial 6 times, rtms sessions will be administered over the left dlpfc, followed by 6 sessions targeting the right dlpfc, and an additional 6 treatments will be done bilaterally. the sham rtms group will receive the same process but the figure-eight coil will be placed vertically on the scalp with no magnetic field penetrated through the skull. the stimulation parameters will be the same as those of the real rtms. the environmental conditions will be the same for each test (comfortable armchair, quiet room, elbow positioned at 90◦ flexion). participants will be required to use earplugs during tms sessions. the selection of 90% of the motor threshold (mt) has been chosen as a precautionary measure to reduce the risk of seizure in this study population, while the choice of 1 hz of stimulation is based on the evidence that low-frequency improves cortex e/i imbalance. - adhd protocol participants will receive 18 rtms treatments with fig-8 coil twice per week (9 weeks). the rtms will be administered with the following stimulation parameters: 5 (or 10) hz frequency, 90% mt, 180 pulses per session with 9 trains of 20 pulses each with 20-30 s intervals between the trains. the initial six times, rtms sessions will be administered over the left dlpfc, followed by 6 sessions targeting the right dlpfc, and an additional 6 treatments will be done bilaterally (over the left and right dlpfc). for the sham rtms group, the coil will be simply placed perpendicular to the scalp of the stimulation site. the stimulation parameters will be the same as those of the real rtms. studies on children and adolescents with adhd are significantly fewer than those with asd. so it is difficult to find a validated and often replicated tms protocol. for the adhd population, high-frequency stimulation will be used since it was noted that high frequency can significantly improve adhd symptoms. it has been also shown that tms might produce a similar effect on the dopamine system as d-amphetamine a well-known psychostimulant. it has been decided to select 90% of the mt to avoid seizure risk to patients. at the end of every single session, a questionnaire regarding side effects will be administered to all participants. benefits and implications the study aims to establish a standardized tms protocol for pediatric asd and adhd, addressing heterogeneity in methodology and outcomes. since it has been demonstrated that younger age is a predictor of better response to tms therapy (as children's brains are more plastic than adults), intervening in the pediatric population might result in more effective effects. insights into neurotransmitter and biochemical modulation, bdnf's role, and tms susceptibility can guide personalized interventions. the research could modernize treatment approaches, offering a noninvasive, targeted therapy for these complex disorders. additionally, the study might identify potential biomarkers for diagnostic and therapeutic purposes. ethical considerations and confidentiality the study has received ethical approval and complies with the declaration of helsinki. personal data will be securely stored, anonymized, and accessible only to authorized personnel. stringent measures will be taken to ensure participant confidentiality throughout the study.

Eligibility criteria:
inclusion criteria: * patients must have received a diagnosis of "asd" or "adhd" according to the diagnostic and statistical manual of mental disorder-fifth edition. * patients must be older than 6-7 years of age, to obtain their collaboration easily exclusion criteria: * presence of known neurological or genetic conditions that are known to affect brain function and structure (i.e. brain tumors, x-fragile, tuberous sclerosis, etc.). * prescription of psychoactive medication(s) less than 4 weeks prior to joining the study. * medical history of head trauma associated with prolonged loss of consciousness. * presence of epilepsy, or history of previous epilepsy, seizures, and repeated febrile seizures. * presence of comorbidity with psychosis disorder. * presence of known endocrine, cardiovascular, pulmonary, liver, kidney, or other medical diseases. * vision and auditory impairment. * presence of diagnosed chronic or acute inflammation and/or infection. * lack of consent.

Keywords: tms neuromodulation asd adhd neurostimulation cognition executive functions dlpfc