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.
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 发起方
- 入组人数
- 80
- 试验地点
- 2
- 主要终点
- Determining the impact of rTMS on Cognitive Functioning in Real Groups versus Sham Groups, through changes in scores of NEPSY-II sub-scales
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 6 Years 至 18 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •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
排除标准
- •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.
结局指标
主要结局
Determining the impact of rTMS on Cognitive Functioning in Real Groups versus Sham Groups, through changes in scores of NEPSY-II sub-scales
时间窗: 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 Emotional and Behavioral Problems in Real Groups vs. Sham Groups, through changes in CBCL scores
时间窗: 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 Depression in Real Groups vs. Sham Groups, through changes in CDI and MASC scores
时间窗: 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
时间窗: 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 ADHD symptoms in Real Groups vs. Sham Groups, through changes in Conners scores
时间窗: 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
时间窗: 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.
Determining the impact of rTMS on Adaptive Behaviors in Real Groups vs. Sham Groups, through changes in Vineland Scale scores
时间窗: 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.
次要结局
- Determining the impact of rTMS on BDNF in Real Groups vs. Sham Groups, through changes in BDNF serum concentration.(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.(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.(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.(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.(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.(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.(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.(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.(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.(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.(Baseline; Post rTMS (9 weeks after baseline); One month follow-up (4 weeks after rTMS))
研究者
Rosa Savino
Principal Investigator
Ospedali Riuniti di Foggia