tRNS Combined to Cognitive Training in Children With Dyscalculia

Study Overview
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Brief Summary
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The present study grounds on the absence of evidence-based treatment in individuals with developmental dyscalculia (DD). At this topic, the present study will explore the potential effect of transcranial random noise stimulation (tRNS) over dorsolateral prefrontal cortex (DLPFC) or posterior parietal cortex (PPC), cerebral areas usually disrupted in individuals with DD, in addition to a usual treatment such as cognitive training. Therefore, the investigators hypothesized that active tRNS over DLPFC or PPC combined to cognitive training will boost math and math-related skills in children and adolescents with DD, modulating theta/beta ratio around stimulated cerebral network. On the contrary, sham tRNS (placebo) over DLPFC or PPC combined to cognitive training will not have significant effect in improving math skills. Further, both active and sham tRNS combined to cognitive training will be safe and well tolerated.

Detailed Description
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The study design is randomized stratified, double blind, placebo-controlled. A group of children and adolescents with DD will be selected and randomly assigned to three different conditions: 1. tRNS over bilateral DLPFC + cognitive training (Brainstim DLPFC); 2. tRNS over bilateral PPC (Brainstim PPC) + cognitive training; 3. sham tRNS (bilateral DLPFC/bilateral PPC; Brainstim Sham) + cognitive training. In this project, the investigators will work to understand whether a brain-based intervention, with the use of tRNS, combined to a usual treatment can improve the outcome of individual with DD. The protocol will allow the investigators to: testing the critical role of two brain regions (DLPFC or PPC) usually involved in numerical abilities and disrupted in individuals with DD; examining the neural changes (using EEG recordings) due to cognitive training without tRNS (Brainstim Sham) and with tRNS (Brainstim DLPFC; Brainstim PPC); predicting training outcomes based on math-related skills; testing the critical role of neural markers at developmental ages using a closed-loop tRNS to improve learning and cognitive outcomes from the training; investigating the safety and tolerability of tRNS. The investigator's overarching goal is to provide a scientific foundation for devising new rehabilitation strategies in DD.

Official Title
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Improving Math Deficits in Children With Dyscalculia by tRNS: a Randomized, Double-blind Study

Conditions
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Developmental Dyscalculia

Intervention / Treatment
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* Device: Brainstim DLPFC
* Device: Brainstim PPC
* Device: Brainstim Sham
* Behavioral: Cognitive Training


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Children and adolescents with DD (Total Quotient of BDE-2 ≤ 70) IQ ≥ 85 Exclusion Criteria: Having a comorbidity with an important medical conditions; Having neurological diseases; Having Epilepsy o family history of epilepsy; Receiving a treatment for DD in the previous three months before the baseline screening;

Ages Eligible for Study
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Minimum Age: 8 Years
Maximum Age: 14 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Brainstim DLPFC<br>tRNS over bilateral DLPFC + cognitive training | Device: Brainstim DLPFC<br>* The active tRNS will be delivered to bilateral DLPFC for five consecutive days for two weeks for a total of ten days. tRNS will be delivered by a battery driven, random-noise current stimulator through a pair of saline-soaked sponge electrodes kept firm by elastic bands. The electrodes will be placed on the left and right DLPFC, F3 and F4 position according to the 10-20 international EEG system for electrode placement, while participants will receive a usual treatment (cognitive training). Stimulation intensity will be set at 0.75 milliampere (mA) (100-500 Hz), the duration of stimulation will be 20 min.<br>* Other names: tRNS over bilateral DLPFC;Behavioral: Cognitive Training<br>* A cognitive training (Vektor; Nemmi et al., 2016) will be adiministered concomitantly to Brainstim DLPFC, Brainstim PPC, Brainstim Sham for 20 min. The training consisted of math exercises (number line, calculations) and math-related exercises (visuo-spatial working memory, mental rotation).<br>|
| Experimental: Brainstim PPC<br>tRNS over bilateral PPC + cognitive training | Device: Brainstim PPC<br>* The active tRNS will be delivered to bilateral PPC for five consecutive days for two weeks for a total of ten days. tRNS will be delivered by a battery driven, random-noise current stimulator through a pair of saline-soaked sponge electrodes kept firm by elastic bands. The electrodes will be placed on the left and right PPC, P3 and P4 position according to the 10-20 international EEG system for electrode placement, while participants will receive a usual treatment (cognitive training). Stimulation intensity will be set at 0.75mA (100-500 Hz), the duration of stimulation will be 20 min.<br>* Other names: tRNS over bilateral PPC;Behavioral: Cognitive Training<br>* A cognitive training (Vektor; Nemmi et al., 2016) will be adiministered concomitantly to Brainstim DLPFC, Brainstim PPC, Brainstim Sham for 20 min. The training consisted of math exercises (number line, calculations) and math-related exercises (visuo-spatial working memory, mental rotation).<br>|
| Sham Comparator: Brainstim Sham<br>Sham tRNS (bilateral DLPFC/bilateral PPC) + cognitive training | Device: Brainstim Sham<br>* The same electrode placement will be used as in the stimulation conditions (Brainstim DLPFC or Brainstim PPC), but the current will be applied for 30 s and will be ramped down without the participants awareness, and will be held five consecutive days for two weeks for a total of ten days.<br>* Other names: Sham tRNS (bilateral DLPFC/bilateral PPC);Behavioral: Cognitive Training<br>* A cognitive training (Vektor; Nemmi et al., 2016) will be adiministered concomitantly to Brainstim DLPFC, Brainstim PPC, Brainstim Sham for 20 min. The training consisted of math exercises (number line, calculations) and math-related exercises (visuo-spatial working memory, mental rotation).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number Line | The proportion of patients with change of at least 1 SD in the number line task of the Diagnostic battery for Dyscalculia (BDE 2, Biancardi et al., 2016) in Brainstim DLPFC and Brainstim PPC than in Brainstim Sham. | immediately after the intervention, one week and three months after the intervention | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total Quotient | The proportion of patients with change in the Total Quotient of the BDE 2 (Biancardi et al., 2016) in Brainstim DLPFC and Brainstim PPC than in Brainstim Sham. | immediately after the intervention, one week and three months after the intervention | 
| Numerical Quotient | The proportion of patients with change in the Numerical Quotient of the BDE 2 (Biancardi et al., 2016) in Brainstim DLPFC and Brainstim PPC than in Brainstim Sham. | immediately after the intervention, one week and three months after the intervention | 
| Calculation Quotient | The proportion of patients with change in the Calculation Quotient of the BDE 2 (Biancardi et al., 2016) in Brainstim DLPFC and Brainstim PPC than in Brainstim Sham. | immediately after the intervention, one week and three months after the intervention | 
| Number Sense Quotient | The proportion of patients with change in the Number Sense Quotient of the BDE 2 (Biancardi et al., 2016) in Brainstim DLPFC and Brainstim PPC than in Brainstim Sham. | immediately after the intervention, one week and three months after the intervention | 
| Mental multiplications and additions | The proportion of patients with change in the Mental Multiplications and Mental Additions tasks of the Diagnostic battery for Dyscalculia 1 (Biancardi et al., 2004) in Brainstim DLPFC and Brainstim PPC than in Brainstim Sham. | immediately after the intervention, one week and three months after the intervention | 
| Tempo Test Rekenen | The proportion of patients with change in the total scores of the Tempo Test Rekenen (De Vos, 1992) in Brainstim DLPFC and Brainstim PPC than in Brainstim Sham. | immediately after the intervention, one week and three months after the intervention | 
| Geometric Puzzle | The proportion of patients with change in the total scores of the Geometric Puzzle (Nepsy II, Korkman et al., 2011) in Brainstim DLPFC and Brainstim PPC than in Brainstim Sham. | immediately after the intervention, one week and three months after the intervention | 
| Math computerized task | The proportion of patients with change in a math computerized task (Math Proc, PEBL) in Brainstim DLPFC and Brainstim PPC than in Brainstim Sham. | immediately after the intervention, one week and three months after the intervention | 
| Motivation and study strategies Questionnaire | The proportion of patients with change (lower score means better outcome) in the Motivation and study strategies Questionnaire from 8 to 15 ages (AMOS 8-15, Cornoldi et al., 2005) in Brainstim DLPFC and Brainstim PPC than in Brainstim Sham. | immediately after the intervention, one week and three months after the intervention | 
| Math Anxiety Questionnaire | The proportion of patients with change (lower score means better outcome) in the Math Anxiety Questionnaire (MARS, Saccani and Cornoldi, 2005) in Brainstim DLPFC and Brainstim PPC than in Brainstim Sham. | immediately after the intervention, one week and three months after the intervention | 
| Sleep quality | The proportion of patients with change (lower score means better outcome) in the Sleep Disturbance Scale for Children (SDSC, Bruni et al., 1996) in Brainstim DLPFC and Brainstim PPC than in Brainstim Sham. | immediately after the intervention, one week and three months after the intervention | 
| Parental stress | The proportion of patients with change (higher score means better outcome) in the Parent Stress Index (PSI, Guarino et al., 2014) in Brainstim DLPFC and Brainstim PPC than in Brainstim Sham. | immediately after the intervention, one week and three months after the intervention | 
| Emotional/behavioural problems | The proportion of patients with change (lower score means better outcome) in the Cross-symptom assessment scales of the Kiddie-Sads- present and lifetime version-Diagnostic and Statistical Manual of Mental Disorders 5 (K-SADS- DSM-5, Kaufman et al., 2016) in Brainstim DLPFC and Brainstim PPC than in Brainstim Sham. | immediately after the intervention, one week and three months after the intervention | 
| Math improvement at school | The proportion of patients with change in math markers in the transcript (scale from 0 to 10, where 10 is the best level and 0 the worst) in Brainstim DLPFC and Brainstim PPC than in Brainstim Sham. | three months after the intervention | 
| Theta/Beta ratio | The proportion of patients with reduction of theta/beta ratio in Brainstim DLPFC and Brainstim PPC than in Brainstim Sham. | immediately after the intervention, one week and three months after the intervention | 
| Verbal and visuo-spatial working-memory | The proportion of patients with change in the index of verbal and visuo-spatial n-back (more score means better outcome) in Brainstim DLPFC and Brainstim PPC than in Brainstim Sham. | immediately after the intervention, one week and three months after the intervention | 
| Incidence of Treatment-Emergent Adverse Events [Safety and tolerability] | The proportion of patients with change in the questionnaire of safety and tolerability (Questionnaire of adverse effect; Brunoni et al., 2011) in Brainstim DLPFC and Brainstim PPC will be the same than in Brainstim Sham. | immediately after the intervention, one week and three months after the intervention | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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tRNS, EEG, Children, Adolescents, transcranial random noise stimulation, numerical abilities, neurodevelopmental disorders, non-invasive brain stimulation, transcranial electrical stimulation