Autism Spectrum DisorderNCT06069323
Therapeutic Use of rTMS in Pediatric ASD and ADHD Cohorts
A study testing repetitive Transcranial Magnetic Stimulation in people with Autism Spectrum Disorder and ADHD, run by Ospedali Riuniti di Foggia at 1 site in Italy.
Trial 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… Read more about this study
- Who is it for?
- Ages 6 to 18 yearsHealthy volunteers can take part
- Conditions the study is for
- Autism Spectrum Disorder, ADHD, Neurodevelopmental Disorders
- What is being tested?
- repetitive Transcranial Magnetic Stimulation
- Type of treatment
- Medical device
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 80 participants
- Where
- 1 siteItaly
- Study dates
- 1 Jun 2023to Jun 2026
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 6 to 18 years
- All sexes
- Healthy volunteers accepted
- Child, Adult
Who may be able to join
- 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
Who cannot join
- 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.
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- vision and auditory impairment.
- presence of diagnosed chronic or acute inflammation and/or infection.
- lack of consent.
Trial locations and contacts
1 site in 1 country.
Italy1 site, 1 recruiting
- Recruiting
Neuropsychiatric Unit for Child and Adolescent, at General Hospital "Riuniti" of Foggia, University of Foggia
Foggia, 71122
Rosa Savino, MD, + 39 0881732363, rosa.savino@unifg.it
About this study
Official title: Therapeutic Use of Repetitive Transcranial Magnetic Stimulation (rTMS) in Pediatric Autism Spectrum Disorder (ASD) and Attention Deficit Hyperactivity Cohorts (ADHD): a Randomized, Sham-controlled Study.
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.
Read the detailed description
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:
- Evaluating TMS impact on core symptoms, cognition, and executive functions.
- Analyzing changes in peripheral biomarkers, such as neurotransmitters, kynurenines, and neurotrophins following TMS.
- Investigating the role of BDNF gene polymorphism (Val66Met) in TMS individual susceptibility.
- Identifying clinical profiles and individual factors influencing TMS efficacy (such as cognitive level, ongoing therapies, age, sex, neuropsychiatric comorbidities, clinical severity, etc.).
- 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:
- 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).
- 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.
- 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.
- Conditions
- Autism Spectrum Disorder, ADHD, Neurodevelopmental Disorders
- Being tested
- repetitive Transcranial Magnetic Stimulation
- Keywords
- TMS, NEUROMODULATION, ASD, ADHD, NEUROSTIMULATION, COGNITION, EXECUTIVE FUNCTIONS, DLPFC
- Medical subject headings
- Autism Spectrum Disorder, Attention Deficit Disorder with Hyperactivity, Neurodevelopmental Disorders
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
repetitive Transcranial Magnetic StimulationDevice
Also called rTMS, Neurostimulation, Neuromodulation
Pediatric patients with ASD and ADHD will be randomized both in active and sham groups.
| Study group | Role | What they receive |
|---|---|---|
| Active ASD group | Active comparator | The rTMS will be administered 18 times, twice per week, with the following stimulation parameters: 1.0 Hz frequency, 90% MT, 180 pulses per session with 9 trains of 20 pulses each with 20-30s intervals between the trains. Receives: Device: repetitive Transcranial Magnetic Stimulation |
| Sham ASD group | Sham comparator | 18 rTMS sessions will be administered, placing the coil perpendicular to the scalp of the stimulation site, to avoid stimulation. Receives: Device: repetitive Transcranial Magnetic Stimulation |
| Active ADHD group | Active comparator | The rTMS will be administered 18 times, twice per week, with the following parameters: 5-10 Hz frequency, 90% MT, 180 pulses per session with 9 trains of 20 pulses each with 20-30 s intervals between the trains. Receives: Device: repetitive Transcranial Magnetic Stimulation |
| Sham ADHD group | Sham comparator | 18 rTMS sessions will be administered, placing the coil perpendicular to the scalp of the stimulation site, to avoid stimulation. Receives: Device: repetitive Transcranial Magnetic Stimulation |
What is being measured
The primary outcome is the main question the study is designed to answer.
Determining the impact of rTMS on Cognitive Functioning in Real Groups versus Sham Groups, through changes in scores of NEPSY-II sub-scales
The NEPSY-II is a comprehensive neuropsychological battery for children and adolescents ages 3-16. It contains 32 subtests, which are divided into six domains of cognitive functioning: Attention and Executive Functioning; Language; Memory and Learning; Sensorimotor; Social Perception; and Visuospatial Processing. Scores are categorized into standard scores (which usually range from 1 to 19 for each subtest), percentile ranks, and age-equivalent scores.
Results are compared to a normative sample to assess a child's performance. Higher scores generally indicate better performance, while lower scores may suggest areas of concern or developmental delay.
Measured: Baseline; Post rTMS (9 weeks after baseline); One month follow-up (4 weeks after rTMS)
Determining the impact of rTMS on Depression in Real Groups vs. Sham Groups, through changes in CDI and MASC scores
The CDI is a self-report questionnaire designed to assess depressive symptoms in children and adolescents. Each item is rated on a scale, often from 0 to 2 or 0 to 3, with higher scores indicating more severe depressive symptoms. The total score is calculated by summing the individual item scores. Cutoff scores are used to categorize depression severity (e.g., mild, moderate, severe).
Measured: Baseline; Post rTMS (9 weeks after baseline); One month follow-up (4 weeks after rTMS)
Determining the impact of rTMS on Motor Skills and Coordination in Real Groups vs. Sham Groups, through changes in M-ABC scores
The Movement Assessment Battery for Children (M-ABC) is a motor assessment tool for children aged 3 to 16. The test includes various motor tasks grouped into three categories: manual dexterity, aiming and catching, and balance. Trained examiners administer the tasks and assign scores based on the child's performance. Scores are typically assigned on a scale of 0 to 5 for each task, with higher scores indicating better motor performance. The overall score is calculated by summing the individual task scores within each category. Lower overall scores may suggest motor skill difficulties or delays. The M-ABC results are often interpreted in conjunction with the child's age and gender, as motor development can vary among children.
Measured: Baseline; Post rTMS (9 weeks after baseline); One month follow-up (4 weeks after rTMS)
Determining the impact of rTMS on Emotional and Behavioral Problems in Real Groups vs. Sham Groups, through changes in CBCL scores
The Child Behavior Checklist (CBCL) is a questionnaire completed by parents or caregivers to assess a child's behavioral and emotional problems. Parents or caregivers provide responses to a series of questions about the child's behavior and emotions. Each item is assigned a numerical value based on the caregiver's responses. These values are summed to create raw scores for different scales and subscales within the CBCL. The raw scores are then converted into T-scores. T-scores are standardized scores with a mean (average) of 50 and a standard deviation of 10. These scores allow for comparisons with a normative sample of children of the same age and gender. Typically, scores falling within the range of 30 to 70 are considered within the average range. Scores below 30 may indicate below-average functioning, while scores above 70 suggest above-average or potentially concerning behavior.
Measured: Baseline; Post rTMS (9 weeks after baseline); One month follow-up (4 weeks after rTMS)
Determining the impact of rTMS on Adaptive Behaviors in Real Groups vs. Sham Groups, through changes in Vineland Scale scores
The Vineland is a structured interview with a parent or caregiver, which assesses adaptive behaviors in four main domains: Communication, Daily Living Skills, Socialization, and Motor Skills (optional). The Vineland uses standard scores percentile ranks, and age-equivalent scores to quantify an individual's level of adaptive functioning. Ratings are typically on a scale with options like "unable," "sometimes," "usually," and "always. These scores are based on the person's performance relative to a normative sample of individuals of the same age. The Vineland provides an overall summary score known as the Adaptive Behavior Composite (ABC) score. It represents an individual's general adaptive functioning across all domains. In addition to the ABC score, the Vineland provides subdomain scores for each of the four main domains, allowing for a more detailed assessment of specific areas.
Measured: Baseline; Post rTMS (9 weeks after baseline); One month follow-up (4 weeks after rTMS)
Determining the impact of rTMS on ADHD symptoms in Real Groups vs. Sham Groups, through changes in Conners scores
The Conners-3 (Conners 3rd Edition) is a widely used questionnaire for evaluating and measuring ADHD symptoms in children and adolescents. It may be administered to parents, teachers, and sometimes the child or adolescent themselves, depending on their age.
The Conners-3 generates standard scores for various scales and indices. These scores are typically presented as T-scores, with a mean of 50 and a standard deviation of 10. T-scores help compare the child's behavior to a normative sample of children of the same age and gender. Higher T-scores indicate more severe symptoms or concerns.
Measured: Baseline; Post rTMS (9 weeks after baseline); One month follow-up (4 weeks after rTMS)
Determining the impact of rTMS on Anxiety in Real Groups vs. Sham
MASC is a self-report questionnaire designed to assess anxiety symptoms in children and adolescents. Patients rate the frequency of their experiences on a 4-point scale, with higher scores indicating greater anxiety. MASC provides a total anxiety score, reflecting the overall level of anxiety symptoms. Subscale scores may also be considered to examine specific domains of anxiety ( including physical symptoms, harm avoidance, social anxiety, and separation/panic). Higher total scores on MASC indicate more significant anxiety symptoms.
Measured: Baseline; Post rTMS (9 weeks after baseline); One month follow-up (4 weeks after rTMS)
Secondary outcomes (11)
Determining the impact of rTMS on BDNF in Real Groups vs. Sham Groups, through changes in BDNF serum concentration.
BDNF levels in the plasma will be measured using laboratory techniques such as enzyme-linked immunosorbent assay (ELISA) or immunoassay. These assays use antibodies that specifically bind to BDNF, allowing for quantification. The results of the assay will be analyzed to determine the concentration of BDNF in the plasma sample. This concentration will be reported in picograms per milliliter (pg/mL).
Measured: Baseline; Post rTMS (9 weeks after baseline); One month follow-up (4 weeks after rTMS)
Determining the impact of rTMS on GABA in Real Groups vs. Sham Groups, through changes in serum concentration.
Neurotransmitter GABA will be dosed in serum at three different points in time (baseline, post-treatment, and 1 month later), to evaluate the effect of rTMS in modulating its concentration. This neurotransmitter will be quantified by HPLC and mass spectrometry. Concentrations will be reported in nanograms per milliliter (ng/mL) or picomoles per milliliter (pmol/mL), depending on the assay's sensitivity.
Measured: Baseline; Post rTMS (9 weeks after baseline); One month follow-up (4 weeks after rTMS)
Determining the impact of rTMS on glutamate in Real Groups vs. Sham Groups, through changes in serum concentration.
Glutamate will be dosed in serum at three different points in time (baseline, post-treatment, and 1 month later), to evaluate the effect of rTMS in modulating its concentration. This neurotransmitter will be quantified by HPLC and mass spectrometry. Concentrations will be reported in nanograms per milliliter (ng/mL) or picomoles per milliliter (pmol/mL), depending on the assay's sensitivity.
Measured: Baseline; Post rTMS (9 weeks after baseline); One month follow-up (4 weeks after rTMS)
Determining the impact of rTMS on dopamine in Real Groups vs. Sham Groups, through changes in serum concentration.
Dopamine will be dosed in serum at three different points in time (baseline, post-treatment, and 1 month later), to evaluate the effect of rTMS in modulating its concentration. This neurotransmitter will be quantified by HPLC and mass spectrometry. Concentrations will be reported in nanograms per milliliter (ng/mL) or picomoles per milliliter (pmol/mL), depending on the assay's sensitivity.
Measured: Baseline; Post rTMS (9 weeks after baseline); One month follow-up (4 weeks after rTMS)
Determining the impact of rTMS on serotonin in Real Groups vs. Sham Groups, through changes in serum concentration.
Serotonin will be dosed in serum at three different points in time (baseline, post-treatment, and 1 month later), to evaluate the effect of rTMS in modulating its concentration. This neurotransmitter will be quantified by HPLC and mass spectrometry. Concentrations will be reported in nanograms per milliliter (ng/mL) or picomoles per milliliter (pmol/mL), depending on the assay's sensitivity.
Measured: Baseline; Post rTMS (9 weeks after baseline); One month follow-up (4 weeks after rTMS)
Determining the impact of rTMS on Kynurenines Pathway in Real Groups vs. Sham Groups, through changes in kynurenines serum and urine concentration.
Kynurenines will be extracted from urine, saliva, and plasma, at three different points in time (baseline, post-treatment, and 1 month later). The main goal is to evaluate how TMS intervention influences the Kynurenines pathway, involved in neuroinflammation. Kynurenines level will be measured using high-performance liquid chromatography (HPLC) or mass spectrometry. The results of the assay will provide the concentration of kynurenines in the respective samples, reported in micromoles per liter (µmol/L) or picomoles per milliliter (pmol/mL) depending on the assay's sensitivity.
Measured: Baseline; Post rTMS (9 weeks after baseline); One month follow-up (4 weeks after rTMS)
Determining the impact of rTMS on inflammatory protein IL-1 in Real Groups vs. Sham Groups, through changes in serum concentration.
IL-1 will be assessed in the serum to evaluate if TMS impacts its level, as ASD and ADHD pathogenesis involves neuroinflammation. To measure IL-1 enzyme-linked immunosorbent assay (ELISA) will be performed. Concentrations will be reported in nanograms per milliliter (ng/mL) or picomoles per milliliter (pmol/mL), depending on the assay's sensitivity.
Measured: Baseline; Post rTMS (9 weeks after baseline); One month follow-up (4 weeks after rTMS)
Determining the impact of rTMS on inflammatory protein IL-6 in Real Groups vs. Sham Groups, through changes in serum concentration.
IL-6 will be assessed in the serum to evaluate if TMS impacts its level, as ASD and ADHD pathogenesis involves neuroinflammation. To measure interleukin enzyme-linked immunosorbent assay (ELISA) will be performed. Concentrations will be reported in nanograms per milliliter (ng/mL) or picomoles per milliliter (pmol/mL), depending on the assay's sensitivity.
Measured: Baseline; Post rTMS (9 weeks after baseline); One month follow-up (4 weeks after rTMS)
Determining the impact of rTMS on inflammatory protein TNF-a in Real Groups vs. Sham Groups, through changes in serum concentration.
Inflammatory proteins, including TNF-a, will be assessed in the serum to evaluate if TMS impacts its levels, as ASD and ADHD pathogenesis involves neuroinflammation. To measure interleukin enzyme-linked immunosorbent assay (ELISA) will be performed. Concentrations will be reported in nanograms per milliliter (ng/mL) or picomoles per milliliter (pmol/mL), depending on the assay's sensitivity.
Measured: Baseline; Post rTMS (9 weeks after baseline); One month follow-up (4 weeks after rTMS)
Determining the impact of rTMS on inflammatory protein CRP (c-reactive protein) in Real Groups vs. Sham Groups, through changes in serum concentration.
Inflammatory proteins, including CRP, will be assessed in the serum to evaluate if TMS impacts its levels, as ASD and ADHD pathogenesis involves neuroinflammation. To measure interleukin enzyme-linked immunosorbent assay (ELISA) will be performed. Concentrations will be reported in nanograms per milliliter (ng/mL) or picomoles per milliliter (pmol/mL), depending on the assay's sensitivity.
Measured: Baseline; Post rTMS (9 weeks after baseline); One month follow-up (4 weeks after rTMS)
Determining the impact of rTMS on cortisol in Real Groups vs. Sham Groups, through changes in serum and saliva concentration.
Cortisol will be assessed in the serum and saliva at three different points in time. Immunoassays (ELISA) will be used to quantify it. Results will be typically reported in nanograms per milliliter (ng/mL).
Measured: Baseline; Post rTMS (9 weeks after baseline); One month follow-up (4 weeks after rTMS)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted5 Oct 2023
- Study start1 Jun 2023
- Primary completionDec 2024 (estimated)
- Study completionJun 2026 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (29)Papers the sponsor has linked to this study.
- Other trials for Autism Spectrum DisorderStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- A double-blind randomized, placebo-controlled study
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 80 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Ospedali Riuniti di Foggia
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Rosa Savino, Ospedali Riuniti di Foggia
- Investigators
- Anna N Polito, MD, Study chair, Neuropsychiatric Unit for Child and Adolescent, at General Hospital "Riuniti" of Foggia
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06069323
- Sponsor's protocol ID
- 50/CE/2023
- Status last verified
- Sep 2023
- First submitted
- 30 Aug 2023
- Last updated
- 5 Oct 2023
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: Individual participant data that underlie the results reported in future articles, after deidentification (text, tables, figures, and appendices).
Publications
Casanova MF, Buxhoeveden D, Gomez J. Disruption in the inhibitory architecture of the cell minicolumn: implications for autism. Neuroscientist. 2003 Dec;9(6):496-507. doi: 10.1177/1073858403253552.
PubMed 14678582Casanova MF, Sokhadze EM, Casanova EL, Li X. Transcranial Magnetic Stimulation in Autism Spectrum Disorders: Neuropathological Underpinnings and Clinical Correlations. Semin Pediatr Neurol. 2020 Oct;35:100832. doi: 10.1016/j.spen.2020.100832. Epub 2020 Jun 24.
PubMed 32892959Hart H, Radua J, Nakao T, Mataix-Cols D, Rubia K. Meta-analysis of functional magnetic resonance imaging studies of inhibition and attention in attention-deficit/hyperactivity disorder: exploring task-specific, stimulant medication, and age effects. JAMA Psychiatry. 2013 Feb;70(2):185-98. doi: 10.1001/jamapsychiatry.2013.277.
PubMed 23247506Norman LJ, Carlisi C, Lukito S, Hart H, Mataix-Cols D, Radua J, Rubia K. Structural and Functional Brain Abnormalities in Attention-Deficit/Hyperactivity Disorder and Obsessive-Compulsive Disorder: A Comparative Meta-analysis. JAMA Psychiatry. 2016 Aug 1;73(8):815-825. doi: 10.1001/jamapsychiatry.2016.0700.
PubMed 27276220Rubio B, Boes AD, Laganiere S, Rotenberg A, Jeurissen D, Pascual-Leone A. Noninvasive Brain Stimulation in Pediatric Attention-Deficit Hyperactivity Disorder (ADHD): A Review. J Child Neurol. 2016 May;31(6):784-96. doi: 10.1177/0883073815615672. Epub 2015 Dec 10.
PubMed 26661481Anderson G, Maes M. Interactions of Tryptophan and Its Catabolites With Melatonin and the Alpha 7 Nicotinic Receptor in Central Nervous System and Psychiatric Disorders: Role of the Aryl Hydrocarbon Receptor and Direct Mitochondria Regulation. Int J Tryptophan Res. 2017 Feb 16;10:1178646917691738. doi: 10.1177/1178646917691738. eCollection 2017.
PubMed 28469467Savino R, Carotenuto M, Polito AN, Di Noia S, Albenzio M, Scarinci A, Ambrosi A, Sessa F, Tartaglia N, Messina G. Analyzing the Potential Biological Determinants of Autism Spectrum Disorder: From Neuroinflammation to the Kynurenine Pathway. Brain Sci. 2020 Sep 11;10(9):631. doi: 10.3390/brainsci10090631.
PubMed 32932826Lim CK, Essa MM, de Paula Martins R, Lovejoy DB, Bilgin AA, Waly MI, Al-Farsi YM, Al-Sharbati M, Al-Shaffae MA, Guillemin GJ. Altered kynurenine pathway metabolism in autism: Implication for immune-induced glutamatergic activity. Autism Res. 2016 Jun;9(6):621-31. doi: 10.1002/aur.1565. Epub 2015 Oct 24.
PubMed 26497015Sathappan AV, Luber BM, Lisanby SH. The Dynamic Duo: Combining noninvasive brain stimulation with cognitive interventions. Prog Neuropsychopharmacol Biol Psychiatry. 2019 Mar 8;89:347-360. doi: 10.1016/j.pnpbp.2018.10.006. Epub 2018 Oct 9.
PubMed 30312634Cortese S. The neurobiology and genetics of Attention-Deficit/Hyperactivity Disorder (ADHD): what every clinician should know. Eur J Paediatr Neurol. 2012 Sep;16(5):422-33. doi: 10.1016/j.ejpn.2012.01.009. Epub 2012 Feb 2.
PubMed 22306277Cortese S, Holtmann M, Banaschewski T, Buitelaar J, Coghill D, Danckaerts M, Dittmann RW, Graham J, Taylor E, Sergeant J; European ADHD Guidelines Group. Practitioner review: current best practice in the management of adverse events during treatment with ADHD medications in children and adolescents. J Child Psychol Psychiatry. 2013 Mar;54(3):227-46. doi: 10.1111/jcpp.12036. Epub 2013 Jan 7.
PubMed 23294014Oberman LM, Enticott PG, Casanova MF, Rotenberg A, Pascual-Leone A, McCracken JT; TMS in ASD Consensus Group. Transcranial magnetic stimulation in autism spectrum disorder: Challenges, promise, and roadmap for future research. Autism Res. 2016 Feb;9(2):184-203. doi: 10.1002/aur.1567. Epub 2015 Nov 4.
PubMed 26536383Oberman LM, Enticott PG. Editorial: The safety and efficacy of noninvasive brain stimulation in development and neurodevelopmental disorders. Front Hum Neurosci. 2015 Oct 2;9:544. doi: 10.3389/fnhum.2015.00544. eCollection 2015. No abstract available.
PubMed 26483661Rossi S, Hallett M, Rossini PM, Pascual-Leone A; Safety of TMS Consensus Group. Safety, ethical considerations, and application guidelines for the use of transcranial magnetic stimulation in clinical practice and research. Clin Neurophysiol. 2009 Dec;120(12):2008-2039. doi: 10.1016/j.clinph.2009.08.016. Epub 2009 Oct 14.
PubMed 19833552Barahona-Correa JB, Velosa A, Chainho A, Lopes R, Oliveira-Maia AJ. Repetitive Transcranial Magnetic Stimulation for Treatment of Autism Spectrum Disorder: A Systematic Review and Meta-Analysis. Front Integr Neurosci. 2018 Jul 9;12:27. doi: 10.3389/fnint.2018.00027. eCollection 2018.
PubMed 30038561
Study at a glance
From the registry record, last updated by the sponsor on 5 Oct 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Therapeutic Use of Repetitive Transcranial Magnetic Stimulation (rTMS) in Pediatric Autism Spectrum Disorder (ASD) and Attention Deficit Hyperactivity Cohorts (ADHD): a Randomized, Sham-controlled Study.
- ClinicalTrials.gov ID
- NCT06069323
- Acronym / sponsor ID
- 50/CE/2023
- Conditions
- Autism Spectrum Disorder, ADHD, Neurodevelopmental Disorders
- Keywords
- TMS, NEUROMODULATION, ASD, ADHD, NEUROSTIMULATION, COGNITION, EXECUTIVE FUNCTIONS, DLPFC
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 80 participants (estimated)
- Lead sponsor
- Ospedali Riuniti di FoggiaUniversity, hospital or other
- Study start
- 1 Jun 2023 (actual)
- Primary completion
- Dec 2024 (estimated)
- Study completion
- Jun 2026 (estimated)
- First posted
- 5 Oct 2023 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
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:
- Evaluating TMS impact on core symptoms, cognition, and executive functions.
- Analyzing changes in peripheral biomarkers, such as neurotransmitters, kynurenines, and neurotrophins following TMS.
- Investigating the role of BDNF gene polymorphism (Val66Met) in TMS individual susceptibility.
- Identifying clinical profiles and individual factors influencing TMS efficacy (such as cognitive level, ongoing therapies, age, sex, neuropsychiatric comorbidities, clinical severity, etc.).
- 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:
- 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).
- 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.
- 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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 4
- Model description
- A double-blind randomized, placebo-controlled study
| Arm | Type | Receives |
|---|---|---|
| Active ASD group | Active comparator | Device: repetitive Transcranial Magnetic StimulationThe rTMS will be administered 18 times, twice per week, with the following stimulation parameters: 1.0 Hz frequency, 90% MT, 180 pulses per session with 9 trains of 20 pulses each with 20-30s intervals between the trains. |
| Sham ASD group | Sham comparator | Device: repetitive Transcranial Magnetic Stimulation18 rTMS sessions will be administered, placing the coil perpendicular to the scalp of the stimulation site, to avoid stimulation. |
| Active ADHD group | Active comparator | Device: repetitive Transcranial Magnetic StimulationThe rTMS will be administered 18 times, twice per week, with the following parameters: 5-10 Hz frequency, 90% MT, 180 pulses per session with 9 trains of 20 pulses each with 20-30 s intervals between the trains. |
| Sham ADHD group | Sham comparator | Device: repetitive Transcranial Magnetic Stimulation18 rTMS sessions will be administered, placing the coil perpendicular to the scalp of the stimulation site, to avoid stimulation. |
Who may qualify
- Ages
- 6 to 18 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Child, Adult
Key inclusion criteria (2 listed)
- 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
Key exclusion criteria (9 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| repetitive Transcranial Magnetic StimulationAlso: rTMS, Neurostimulation, NeuromodulationPediatric patients with ASD and ADHD will be randomized both in active and sham groups. | Device | Active ADHD group, Active ASD group, Sham ADHD group, Sham ASD group |
Primary outcome
Determining the impact of rTMS on Cognitive Functioning in Real Groups versus Sham Groups, through changes in scores of NEPSY-II sub-scales
Time frame: Baseline; Post rTMS (9 weeks after baseline); One month follow-up (4 weeks after rTMS)
The NEPSY-II is a comprehensive neuropsychological battery for children and adolescents ages 3-16. It contains 32 subtests, which are divided into six domains of cognitive functioning: Attention and Executive Functioning; Language; Memory and Learning; Sensorimotor; Social Perception; and Visuospatial Processing. Scores are categorized into standard scores (which usually range from 1 to 19 for each subtest), percentile ranks, and age-equivalent scores. Results are compared to a normative sample to assess a child's performance. Higher scores generally indicate better performance, while lower scores may suggest areas of concern or developmental delay.
Determining the impact of rTMS on Depression in Real Groups vs. Sham Groups, through changes in CDI and MASC scores
Time frame: Baseline; Post rTMS (9 weeks after baseline); One month follow-up (4 weeks after rTMS)
The CDI is a self-report questionnaire designed to assess depressive symptoms in children and adolescents. Each item is rated on a scale, often from 0 to 2 or 0 to 3, with higher scores indicating more severe depressive symptoms. The total score is calculated by summing the individual item scores. Cutoff scores are used to categorize depression severity (e.g., mild, moderate, severe).
Determining the impact of rTMS on Motor Skills and Coordination in Real Groups vs. Sham Groups, through changes in M-ABC scores
Time frame: Baseline; Post rTMS (9 weeks after baseline); One month follow-up (4 weeks after rTMS)
The Movement Assessment Battery for Children (M-ABC) is a motor assessment tool for children aged 3 to 16. The test includes various motor tasks grouped into three categories: manual dexterity, aiming and catching, and balance. Trained examiners administer the tasks and assign scores based on the child's performance. Scores are typically assigned on a scale of 0 to 5 for each task, with higher scores indicating better motor performance. The overall score is calculated by summing the individual task scores within each category. Lower overall scores may suggest motor skill difficulties or delays. The M-ABC results are often interpreted in conjunction with the child's age and gender, as motor development can vary among children.
Determining the impact of rTMS on Emotional and Behavioral Problems in Real Groups vs. Sham Groups, through changes in CBCL scores
Time frame: Baseline; Post rTMS (9 weeks after baseline); One month follow-up (4 weeks after rTMS)
The Child Behavior Checklist (CBCL) is a questionnaire completed by parents or caregivers to assess a child's behavioral and emotional problems. Parents or caregivers provide responses to a series of questions about the child's behavior and emotions. Each item is assigned a numerical value based on the caregiver's responses. These values are summed to create raw scores for different scales and subscales within the CBCL. The raw scores are then converted into T-scores. T-scores are standardized scores with a mean (average) of 50 and a standard deviation of 10. These scores allow for comparisons with a normative sample of children of the same age and gender. Typically, scores falling within the range of 30 to 70 are considered within the average range. Scores below 30 may indicate below-average functioning, while scores above 70 suggest above-average or potentially concerning behavior.
Determining the impact of rTMS on Adaptive Behaviors in Real Groups vs. Sham Groups, through changes in Vineland Scale scores
Time frame: Baseline; Post rTMS (9 weeks after baseline); One month follow-up (4 weeks after rTMS)
The Vineland is a structured interview with a parent or caregiver, which assesses adaptive behaviors in four main domains: Communication, Daily Living Skills, Socialization, and Motor Skills (optional). The Vineland uses standard scores percentile ranks, and age-equivalent scores to quantify an individual's level of adaptive functioning. Ratings are typically on a scale with options like "unable," "sometimes," "usually," and "always. These scores are based on the person's performance relative to a normative sample of individuals of the same age. The Vineland provides an overall summary score known as the Adaptive Behavior Composite (ABC) score. It represents an individual's general adaptive functioning across all domains. In addition to the ABC score, the Vineland provides subdomain scores for each of the four main domains, allowing for a more detailed assessment of specific areas.
Determining the impact of rTMS on ADHD symptoms in Real Groups vs. Sham Groups, through changes in Conners scores
Time frame: Baseline; Post rTMS (9 weeks after baseline); One month follow-up (4 weeks after rTMS)
The Conners-3 (Conners 3rd Edition) is a widely used questionnaire for evaluating and measuring ADHD symptoms in children and adolescents. It may be administered to parents, teachers, and sometimes the child or adolescent themselves, depending on their age. The Conners-3 generates standard scores for various scales and indices. These scores are typically presented as T-scores, with a mean of 50 and a standard deviation of 10. T-scores help compare the child's behavior to a normative sample of children of the same age and gender. Higher T-scores indicate more severe symptoms or concerns.
Determining the impact of rTMS on Anxiety in Real Groups vs. Sham
Time frame: Baseline; Post rTMS (9 weeks after baseline); One month follow-up (4 weeks after rTMS)
MASC is a self-report questionnaire designed to assess anxiety symptoms in children and adolescents. Patients rate the frequency of their experiences on a 4-point scale, with higher scores indicating greater anxiety. MASC provides a total anxiety score, reflecting the overall level of anxiety symptoms. Subscale scores may also be considered to examine specific domains of anxiety ( including physical symptoms, harm avoidance, social anxiety, and separation/panic). Higher total scores on MASC indicate more significant anxiety symptoms.
11 secondary outcomes
Determining the impact of rTMS on BDNF in Real Groups vs. Sham Groups, through changes in BDNF serum concentration.
Time frame: Baseline; Post rTMS (9 weeks after baseline); One month follow-up (4 weeks after rTMS)
Determining the impact of rTMS on GABA in Real Groups vs. Sham Groups, through changes in serum concentration.
Time frame: Baseline; Post rTMS (9 weeks after baseline); One month follow-up (4 weeks after rTMS)
Determining the impact of rTMS on glutamate in Real Groups vs. Sham Groups, through changes in serum concentration.
Time frame: Baseline; Post rTMS (9 weeks after baseline); One month follow-up (4 weeks after rTMS)
Determining the impact of rTMS on dopamine in Real Groups vs. Sham Groups, through changes in serum concentration.
Time frame: Baseline; Post rTMS (9 weeks after baseline); One month follow-up (4 weeks after rTMS)
Determining the impact of rTMS on serotonin in Real Groups vs. Sham Groups, through changes in serum concentration.
Time frame: Baseline; Post rTMS (9 weeks after baseline); One month follow-up (4 weeks after rTMS)
Determining the impact of rTMS on Kynurenines Pathway in Real Groups vs. Sham Groups, through changes in kynurenines serum and urine concentration.
Time frame: Baseline; Post rTMS (9 weeks after baseline); One month follow-up (4 weeks after rTMS)
Determining the impact of rTMS on inflammatory protein IL-1 in Real Groups vs. Sham Groups, through changes in serum concentration.
Time frame: Baseline; Post rTMS (9 weeks after baseline); One month follow-up (4 weeks after rTMS)
Determining the impact of rTMS on inflammatory protein IL-6 in Real Groups vs. Sham Groups, through changes in serum concentration.
Time frame: Baseline; Post rTMS (9 weeks after baseline); One month follow-up (4 weeks after rTMS)
Determining the impact of rTMS on inflammatory protein TNF-a in Real Groups vs. Sham Groups, through changes in serum concentration.
Time frame: Baseline; Post rTMS (9 weeks after baseline); One month follow-up (4 weeks after rTMS)
Determining the impact of rTMS on inflammatory protein CRP (c-reactive protein) in Real Groups vs. Sham Groups, through changes in serum concentration.
Time frame: Baseline; Post rTMS (9 weeks after baseline); One month follow-up (4 weeks after rTMS)
Determining the impact of rTMS on cortisol in Real Groups vs. Sham Groups, through changes in serum and saliva concentration.
Time frame: Baseline; Post rTMS (9 weeks after baseline); One month follow-up (4 weeks after rTMS)
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 5 Oct 2023.
- Results publication: PubMed 14678582Casanova MF, Buxhoeveden D, Gomez J. Disruption in the inhibitory architecture of the cell minicolumn: implications for autism. Neuroscientist. 2003 Dec;9(6):496-507. doi: 10.1177/1073858403253552.
- Results publication: PubMed 32892959Casanova MF, Sokhadze EM, Casanova EL, Li X. Transcranial Magnetic Stimulation in Autism Spectrum Disorders: Neuropathological Underpinnings and Clinical Correlations. Semin Pediatr Neurol. 2020 Oct;35:100832. doi: 10.1016/j.spen.2020.100832. Epub 2020 Jun 24.
- Results publication: PubMed 23247506Hart H, Radua J, Nakao T, Mataix-Cols D, Rubia K. Meta-analysis of functional magnetic resonance imaging studies of inhibition and attention in attention-deficit/hyperactivity disorder: exploring task-specific, stimulant medication, and age effects. JAMA Psychiatry. 2013 Feb;70(2):185-98. doi: 10.1001/jamapsychiatry.2013.277.
- Results publication: PubMed 27276220Norman LJ, Carlisi C, Lukito S, Hart H, Mataix-Cols D, Radua J, Rubia K. Structural and Functional Brain Abnormalities in Attention-Deficit/Hyperactivity Disorder and Obsessive-Compulsive Disorder: A Comparative Meta-analysis. JAMA Psychiatry. 2016 Aug 1;73(8):815-825. doi: 10.1001/jamapsychiatry.2016.0700.
- Results publication: PubMed 26661481Rubio B, Boes AD, Laganiere S, Rotenberg A, Jeurissen D, Pascual-Leone A. Noninvasive Brain Stimulation in Pediatric Attention-Deficit Hyperactivity Disorder (ADHD): A Review. J Child Neurol. 2016 May;31(6):784-96. doi: 10.1177/0883073815615672. Epub 2015 Dec 10.
- Results publication: PubMed 28469467Anderson G, Maes M. Interactions of Tryptophan and Its Catabolites With Melatonin and the Alpha 7 Nicotinic Receptor in Central Nervous System and Psychiatric Disorders: Role of the Aryl Hydrocarbon Receptor and Direct Mitochondria Regulation. Int J Tryptophan Res. 2017 Feb 16;10:1178646917691738. doi: 10.1177/1178646917691738. eCollection 2017.
- Results publication: PubMed 32932826Savino R, Carotenuto M, Polito AN, Di Noia S, Albenzio M, Scarinci A, Ambrosi A, Sessa F, Tartaglia N, Messina G. Analyzing the Potential Biological Determinants of Autism Spectrum Disorder: From Neuroinflammation to the Kynurenine Pathway. Brain Sci. 2020 Sep 11;10(9):631. doi: 10.3390/brainsci10090631.
- Results publication: PubMed 26497015Lim CK, Essa MM, de Paula Martins R, Lovejoy DB, Bilgin AA, Waly MI, Al-Farsi YM, Al-Sharbati M, Al-Shaffae MA, Guillemin GJ. Altered kynurenine pathway metabolism in autism: Implication for immune-induced glutamatergic activity. Autism Res. 2016 Jun;9(6):621-31. doi: 10.1002/aur.1565. Epub 2015 Oct 24.
- Results publication: PubMed 30312634Sathappan AV, Luber BM, Lisanby SH. The Dynamic Duo: Combining noninvasive brain stimulation with cognitive interventions. Prog Neuropsychopharmacol Biol Psychiatry. 2019 Mar 8;89:347-360. doi: 10.1016/j.pnpbp.2018.10.006. Epub 2018 Oct 9.
- Results publication: PubMed 22306277Cortese S. The neurobiology and genetics of Attention-Deficit/Hyperactivity Disorder (ADHD): what every clinician should know. Eur J Paediatr Neurol. 2012 Sep;16(5):422-33. doi: 10.1016/j.ejpn.2012.01.009. Epub 2012 Feb 2.
- Results publication: PubMed 23294014Cortese S, Holtmann M, Banaschewski T, Buitelaar J, Coghill D, Danckaerts M, Dittmann RW, Graham J, Taylor E, Sergeant J; European ADHD Guidelines Group. Practitioner review: current best practice in the management of adverse events during treatment with ADHD medications in children and adolescents. J Child Psychol Psychiatry. 2013 Mar;54(3):227-46. doi: 10.1111/jcpp.12036. Epub 2013 Jan 7.
- Results publication: PubMed 26536383Oberman LM, Enticott PG, Casanova MF, Rotenberg A, Pascual-Leone A, McCracken JT; TMS in ASD Consensus Group. Transcranial magnetic stimulation in autism spectrum disorder: Challenges, promise, and roadmap for future research. Autism Res. 2016 Feb;9(2):184-203. doi: 10.1002/aur.1567. Epub 2015 Nov 4.
- Individual participant dataSharing planned: Yes. Individual participant data that underlie the results reported in future articles, after deidentification (text, tables, figures, and appendices).
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Autism
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Anna N Polito, MD study chair
Neuropsychiatric Unit for Child and Adolescent, at General Hospital "Riuniti" of Foggia
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing repetitive Transcranial Magnetic Stimulation in people with Autism Spectrum Disorder and ADHD, run by Ospedali Riuniti di Foggia at 1 site in Italy.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 2 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 5 Oct 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Rosa Savino, MD (+ 39 0881732363, rosa.savino@unifg.it), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Determining the impact of rTMS on Cognitive Functioning in Real Groups versus Sham Groups, through changes in scores of NEPSY-II sub-scales (time frame: Baseline; Post rTMS (9 weeks after baseline); One month follow-up (4 weeks after rTMS)). The study lists 7 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT06069323, which also lists 29 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 5 Oct 2023.