Ignite Creation Date:
2024-05-06 @ 7:36 PM
Last Modification Date:
2024-10-26 @ 3:10 PM
Study NCT ID:
NCT06069323
Status:
RECRUITING
Last Update Posted:
2023-10-05
First Post:
2023-08-30
Brief Title:
Therapeutic Use of rTMS in Pediatric ASD and ADHD Cohorts
Sponsor:
Ospedali Riuniti di Foggia
Organization:
Ospedali Riuniti di Foggia
Study Overview
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
Status:
RECRUITING
Status Verified Date:
2023-09
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief 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 individuals 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
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 individuals 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 EI 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 ValMet 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 eg 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
Childrens 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 disorders neurobiology - ASD Protocol The Casanova-Sokhadze research groups 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 PFCDLPFC 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 EI 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 childrens brains are more plastic than adults intervening in the pediatric population might result in more effective effects
Insights into neurotransmitter and biochemical modulation BDNFs 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
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 ValMet 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 eg 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
Childrens 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 disorders neurobiology - ASD Protocol The Casanova-Sokhadze research groups 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 PFCDLPFC 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 EI 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 childrens brains are more plastic than adults intervening in the pediatric population might result in more effective effects
Insights into neurotransmitter and biochemical modulation BDNFs 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 Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None