Non-Invasive Brain Stimulation to Improve Language in Down Syndrome.

Floriana Costanzo

Status and phase: Enrolling; Phase 2

Conditions: Down Syndrome

Treatments: Device: Sham Group; Device: Active Group (Active Anodal tDCS to the left IFG or Cathodal tDCS to the left IFG)

Study type: Interventional

Funder types: Other

Identifiers

NCT07044804

Jérôme Lejeune Foundation (Other Grant/Funding Number)

3406_OPBG_2024

Details and patient eligibility

About

Down syndrome (DS) is associated with cognitive deficits, caused by alterations in neuroplasticity and synaptic transmission. Non-invasive brain stimulation techniques, such as transcranial direct current stimulation (tDCS), can modulate the brain's plasticity mechanisms and neurotransmitter balance. Anodal tDCS increases cortical excitability by depolarizing neurons, while cathodal tDCS decreases it through hyperpolarization. When combined with cognitive training, tDCS may produce faster and longer-lasting therapeutic effects. Although most of the neurorehabilitation studied have applied anodal excitatory stimulation, recent evidence suggest the potential of the cathodal inhibitory stimulation in neurodevelopmental disorders with alteration of synaptic transmission, as people with Autism Spectrum Disorders. Potentially both anodal and cathodal stimulation protocols could lead to positive clinical effects in DS.

This proof-of-concept study is a double-blind, placebo-controlled, clinical trial aiming at evaluating the efficacy of tDCS, combined with speech and language training, to improve language skills in adolescents and young adults with DS. The study also aims at identifying the most effective parameters of tDCS treatment, for customization in adolescents and young adults with DS. Thirty-six participants, aged 12 to 21 years, will be randomly assigned to three groups receiving anodal, cathodal, or sham (placebo) tDCS. Each participant will undergo 10 sessions of tDCS at 1 mA for 20 minutes, alongside speech and language training five times per week for two weeks.

Neuropsychological, behavioral, biomarker (including brain-derived neurotrophic factor [BDNF] and neurofilament light chain [NfL]), and electroencephalogram assessments will be performed at baseline, post-treatment, and three months after treatment completion.

The study hypothesizes that tDCS will enhance language abilities, particularly expressive vocabulary, and modulate biomarkers of brain plasticity in DS participants. The primary objective is to compare the efficacy of two active tDCS protocols (anodal and cathodal) targeting the left inferior frontal gyrus (IFG) versus sham stimulation. Secondary objectives include evaluating the combined effects on cognitive and behavioral functions.

Given that tDCS effects may persist beyond treatment, the study will assess whether improvements are maintained at three months follow-up.

If effective, this combined tDCS and speech training approach could pave the way for new DS rehabilitation strategies and future larger trials.

Full description

Down Syndrome (DS), caused by trisomy 21, is the leading genetic cause of Intellectual Disability. This chronic and complex condition disrupts normal brain development and function, resulting in deficits in cognition and adaptive behavior. A hallmark of DS is cognitive impairment, characterized by low IQ and difficulties in learning, language processing, and executive functioning-largely associated with atypical neural organization.

In recent years, substantial progress has been made in uncovering the pathogenetic mechanisms responsible for these deficits. Research has identified specific neuroanatomical and neurochemical abnormalities, including alterations in the glutamatergic and GABAergic systems, as well as dysregulation of neuromodulators such as noradrenaline, dopamine, and acetylcholine. Individuals with DS also exhibit compromised synaptic plasticity, reduced neurogenesis, and diminished neural remodeling capacity-all contributing to their unique cognitive profile.

These neurobiological insights have spurred interest in developing therapeutic interventions aimed at improving cognitive function. Although some pharmacological strategies have shown promise in preclinical and limited clinical trials, their clinical translation has often yielded limited success, underscoring the need for alternative approaches. Among these, non-invasive brain stimulation (NiBS), particularly Transcranial Direct Current Stimulation (tDCS), is emerging as a promising method to enhance cognitive and language abilities.

The primary goal of this project is to build a robust scientific basis for novel brain-targeted rehabilitation strategies, specifically to address language deficits in adolescents and young adults with DS. Given the limited research on NiBS in this population, this proof-of-concept study aims to evaluate the feasibility and efficacy of two active tDCS protocols-anodal and cathodal stimulation-targeting the left inferior frontal gyrus (IFG), both compared to a placebo (sham) stimulation condition.

This is a proof-of-concept, non-profit, single-center, prospective, randomized, double-blind, placebo-controlled trial. Both participants and outcome assessors will be blinded to treatment allocation. Thirty-six participants with DS, aged 12 to 21 years, will be randomly assigned to three groups receiving anodal, cathodal, or sham (placebo) tDCS combined with speech and language training. The intervention comprises ten sessions of either anodal tDCS, cathodal tDCS, or sham (placebo) stimulation, delivered over two consecutive weeks (five sessions per week), in conjunction with a tailored speech and language training protocol. The stimulation intensity will be set at 1 mA for 20 minutes per session, each speech and language treatment session, administered by a trained speech therapist, will last 20 minutes structured in 10 minutes of motor planning/programming and 10 minutes addressing lexical, morphosyntactic, and functional language domains.

A neuropsychological, linguistic, behavioural and functional communication assessment will be will be carried prior to (baseline - T0), following the end of the treatments after two weeks (T1) and at 3 months after the end of treatment (T2), to evaluate potential long-lasting benefits. In addition to behavioral and cognitive measures, the study will explore biological markers of treatment response, specifically plasma levels of Brain-Derived Neurotrophic Factor (BDNF) and Neurofilament Light Chain (NfL), as well as EEG recordings, to evaluate neuronal plasticity changes after treatment.

The primary outcome measure will be expressive vocabulary assessed by the Naming subtests of the BVL: 4-12

Secondary outcome measures will include:

Language and verbal skills:

• Articulation, Naming, Semantic Fluency, and Phonological Fluency subtests of the BVL: 4-12 (Marini et al., 2015).
• Italian 28-word inconsistency task based on DEAP Inconsistency subtest (Scarcella, Michelazzo, and McCabe, 2021).
• Intelligibility in Context Scale (ICS): Italian version (Piazzalunga et al., 2020), a parent-report scale widely validated worldwide, allowing caregivers to rate their child's functional speech intelligibility with different communicative partners.

Adaptive behavior and cognitive function:

-Adaptive Behavior Assessment System - Second Edition (ABAS-II; Oakland, 2008), a questionnaire summarizing information on adaptive behavior and skills.

Verbal Span Task, assessing verbal short-term memory by having the examiner read aloud five sequences of high-frequency disyllabic words at one word per second.

Behavioral assessment:

• Conners' Parent Rating Scales Long Version, Revised, widely used for screening ADHD and related symptoms.
• Child Behavior Checklist 6-18, a 113-item parent-report instrument designed to assess behavior and emotional problems in children.
• Aberrant Behavior Checklist (ABC; Aman, 1995), used to evaluate challenging behaviors.

Sleep disturbances:

-Sleep Disturbance Scale for Children (SDSC; Bruni, 1996), a parent-report questionnaire to collect information on sleep disturbances in children and adolescents.

Quality of life and parental stress:

• Pediatric Quality of Life Inventory (Peds QL; Varni, 1999), a brief measure of health-related quality of life.
• PSI-4 Parenting Stress Index - 4 (Abidin, 2012), exploring parental stress levels in the parent-child relationship.

Adherence to safety protocols will be ensured throughout the study, with side effects systematically monitored using a standardized questionnaire (Brunoni et al., 2011) after each session and during the follow-up period.

Ultimately, this study seeks to generate high-quality evidence on the effectiveness of tDCS-compared to placebo-in enhancing language and cognitive outcomes in DS, while contributing to the identification of biomarkers predictive of individual responsiveness to neuromodulation-based interventions.

Enrollment: 36 estimated patients

Sex: All

Ages: 12 to 21 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

1. Italian speakers participants of both genders with the presence of a free trisomy 21 documented by karyotyping
2. Adolescents and young adults from 12 to 21 years old
3. Mental age ≥ 4 years (as assessed by Leiter-3 at baseline)
4. Scores < 2 SD at the denomination subtest of BVL_4-12
5. Be comprehensible to closest relatives, at least in part, exhibiting consistent speech sounds mesured by Intelligibility in Context Scale (ICS): Italian (McLeod, Harrison, & McCormack, 2012) with a cut-off of 3.5
6. Informed consent/absent from each patient and Informed consent from their caregivers.

Exclusion criteria

1. The presence of any neurosensory deficits, such as hypoacusis or serious visual impairments
2. The presence of epilepsy, familiarity with epilepsy and major psychopathological disorders
3. Scores < 10 points at the denomination subtest of BVL_4-12
4. Ability to verbally imitate less that 7 of 10 words during an imitation screening task
5. Undergoing concomitant speech therapy or psychopharmacological therapy for cognitive or behavioral improvement.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Double Blind

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36 participants in 3 patient groups

Active Anodal tDCS to the left IFG

Active Comparator group

Description:

Anodal- tDCS will be delivered by a battery driven, constant current stimulator through a pair of saline-soaked sponge electrodes kept firm by elastic bands. The device employed will be the BrainStim+ (REF: EMS BSTIM+), a lightweight, battery-operated constant current stimulator.The active electrode will be placed on the left IFG cortex (between F5 and F7 of the extended International 10-20 system for EEG electrode placement) cortex and the reference electrode placed above the contralateral shoulder, as previously applied in DS.Stimulation intensity will be set at 1 mA; the duration of stimulation will be 20 min and will be held five consecutive daily session per week for two weeks for a total of 10 sessions. During the tDCS sessions participant will sit in a comfortable chair and a language training will be administered for 20 minutes.

Treatment:

Device: Active Group (Active Anodal tDCS to the left IFG or Cathodal tDCS to the left IFG)

Active Cathodal tDCS to the left IFG

Active Comparator group

Description:

Cathodal- tDCS the cathode will be placed on the left IFG (between F5 and F7 of the extended International 10-20 system for EEG electrode placement) cortex, while the anode will be placed above the right shoulder. The device employed will be the BrainStim+ (REF: EMS BSTIM+), a lightweight, battery-operated constant current stimulator. Stimulation intensity will be set at 1 mA; the duration of stimulation will be 20 min and will be held five consecutive daily session per week for two weeks for a total of 10 sessions. During the tDCS sessions participant will sit in a comfortable chair and a language training will be administered for 20 minutes.

Treatment:

Device: Active Group (Active Anodal tDCS to the left IFG or Cathodal tDCS to the left IFG)

Sham tDCS to the left IFG

Sham Comparator group

Description:

In the sham condition, participants will undergone electrode placements identical to those used in either the anodal or cathodal tDCS configurations, with equal allocation to each montage. The BrainStim+ device (REF: EMS BSTIM+), a lightweight, battery-operated constant current stimulator, will be used. However, the current will be applied only briefly for 30 seconds before being ramped down in a manner imperceptible to the participant, thereby simulating the initial sensation of stimulation without delivering an active dose. Sham sessions will follow the same schedule as the active conditions-20 minutes per session, five consecutive daily sessions per week over two weeks (total of 10 sessions). During each session, participants will be seated comfortably and engage in concurrent language training.

Treatment:

Device: Sham Group