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

NCT ID: NCT07044804

Last Updated: 2025-07-04

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: NA
• Total Enrollment: 36 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2025-01-27
• Study Completion Date: 2026-03-31

Brief Summary

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 studies have applied anodal excitatory stimulation, recent evidence suggests the potential cathodal inhibitory stimulation in neurodevelopmental disorders with alteration of synaptic transmission, as people with DS. 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 to evaluate the efficacy of two active tDCS protocols (anodal and cathodal) targeting the left inferior frontal gyrus (IFG) versus sham stimulation tDCS, combined with speech and language training, to improve language skills in adolescents and young adults with DS. The study also aims to identify 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 tDCS. Each participant will undergo 10 sessions of tDCS at 1 mA for 20 minutes, alongside speech and language training five times for two weeks.

Neuropsychological, behavioral, biomarker (including brain-derived neurotrophic factor and neurofilament light chain), 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 study also hypothesizes that tDCS will enhance other cognitive and behavioral functions. Since tDCS effects may last, the study will check for improvements at the three-month. If effective, this combined approach of tDCS and language training could pave the way for new rehabilitation strategies for DS.

Detailed 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 Battery for the Assessment of Language in Children aged 4 to 12 years (BVL_4-12).

Secondary outcome measures will include:

Language and verbal skills:

• Articulation, Naming, Semantic Fluency, and Phonological Fluency subtests of the Battery for the Assessment of Language in Children aged 4 to 12 years (BVL_4-12)
• Inconsistency Task - 28 Italian words, based on the Inconsistency subtest of the DEAP (Diagnostic Evaluation of Articulation and Phonology).
• Intelligibility in Context Scale (ICS): Italian version, 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), a questionnaire summarizing information on adaptive behavior and skills.

Verbal Span Task (VST), 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, (CPRS-R:L) widely used for screening ADHD and related symptoms.
• Child Behavior Checklist 6-18 (CBCL/6-18), a 113-item parent-report instrument designed to assess behavior and emotional problems in children.
• Aberrant Behavior Checklist (ABC), used to evaluate challenging behaviors.

Sleep disturbances:

-Sleep Disturbance Scale for Children (SDSC), 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 (PedsQL) , a brief measure of health-related quality of life.
• Parenting Stress Index 4 (PSI-4), 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 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.

Conditions

Down Syndrome

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

Active Anodal tDCS to the left IFG

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.

Group Type: ACTIVE_COMPARATOR

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

Intervention Type: DEVICE

Participants in the active tDCS group (Anodal tDCS or Cathodal tDCS) will receive stimulation set at 1 mA (milliampere), with a duration of 20 minutes per session. The stimulation will be administered in five consecutive sessions per day, five days a week, for two weeks, totaling 10 sessions, while participants will also undergo logopedic treatment for 20 minutes. The training protocol will consist of 10 minutes of training in motor planning and programming abilities and 10 minutes of training on the lexical, morphosyntactic, and functional aspects of language and communication.

Active Cathodal tDCS to the left IFG

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.

Group Type: ACTIVE_COMPARATOR

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

Intervention Type: DEVICE

Participants in the active tDCS group (Anodal tDCS or Cathodal tDCS) will receive stimulation set at 1 mA (milliampere), with a duration of 20 minutes per session. The stimulation will be administered in five consecutive sessions per day, five days a week, for two weeks, totaling 10 sessions, while participants will also undergo logopedic treatment for 20 minutes. The training protocol will consist of 10 minutes of training in motor planning and programming abilities and 10 minutes of training on the lexical, morphosyntactic, and functional aspects of language and communication.

Sham tDCS to the left IFG

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.

Group Type: SHAM_COMPARATOR

Sham Group

Intervention Type: DEVICE

For the sham condition, the same electrode placement will be used as in the anodal tDCS condition, but the current will be applied for 30 s and will be ramped down without the participant's awareness. 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

Interventions

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

Participants in the active tDCS group (Anodal tDCS or Cathodal tDCS) will receive stimulation set at 1 mA (milliampere), with a duration of 20 minutes per session. The stimulation will be administered in five consecutive sessions per day, five days a week, for two weeks, totaling 10 sessions, while participants will also undergo logopedic treatment for 20 minutes. The training protocol will consist of 10 minutes of training in motor planning and programming abilities and 10 minutes of training on the lexical, morphosyntactic, and functional aspects of language and communication.

Intervention Type: DEVICE

Sham Group

For the sham condition, the same electrode placement will be used as in the anodal tDCS condition, but the current will be applied for 30 s and will be ramped down without the participant's awareness. 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

Intervention Type: DEVICE

Eligibility Criteria

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.

• Minimum Eligible Age: 12 Years
• Maximum Eligible Age: 21 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Bambino Gesù Children's Hospital IRCCS

OTHER

Sponsor Role: collaborator

Floriana Costanzo

OTHER

Sponsor Role: lead

Responsible Party

Floriana Costanzo

Psychologist, PhD

Responsibility Role: SPONSOR_INVESTIGATOR

Locations

Bambino Gesù Children's Hospital, IRCCS

Rome, Italy, Italy

Site Status: RECRUITING

Countries

Italy

Central Contacts

Floriana Costanzo, PsyD, PhD

Role: CONTACT

floriana.costanzo@opbg.net

+390668597091

Elisa Fucà, PhD

Role: CONTACT

elisa.fucà@opbg.net

+390668597091

Facility Contacts

Floriana Costanzo, PsyD, PhD

Role: primary

floriana.costanzo@opbg.net

0668597091

References

Lopes JBP, Grecco LAC, Moura RCF, Lazzari RD, Duarte NAC, Miziara I, Melo GEL, Dumont AJL, Galli M, Santos Oliveira C. Protocol study for a randomised, controlled, double-blind, clinical trial involving virtual reality and anodal transcranial direct current stimulation for the improvement of upper limb motor function in children with Down syndrome. BMJ Open. 2017 Aug 11;7(8):e016260. doi: 10.1136/bmjopen-2017-016260.

Reference Type: BACKGROUND

PMID: 28801420 (View on PubMed)

Lopes JBP, Miziara IM, Kahani D, Parreira RB, de Almeida Carvalho Duarte N, Lazzari RD, Santos LV, de Mello Monteiro CB, da Silva Cardoso DC, de Oliveira Hassel Mendes J, Dos Santos Alves VL, Silva IO, Oliveira LV, Conway BA, Galli M, Cimolin V, Oliveira CS. Brain activity and upper limb movement analysis in children with Down syndrome undergoing transcranial direct current stimulation combined with virtual reality training: study protocol for a randomized controlled trial. Trials. 2022 Jan 28;23(1):87. doi: 10.1186/s13063-022-06014-4.

Reference Type: BACKGROUND

PMID: 35090554 (View on PubMed)

Faralli A, Fuca E, Lazzaro G, Menghini D, Vicari S, Costanzo F. Transcranial Direct Current Stimulation in neurogenetic syndromes: new treatment perspectives for Down syndrome? Front Cell Neurosci. 2024 Feb 22;18:1328963. doi: 10.3389/fncel.2024.1328963. eCollection 2024.

Reference Type: BACKGROUND

PMID: 38456063 (View on PubMed)

Related Links

https://specchioriflesso.net/media/213835/brochure_informativa_cartacea_versione_1.0_17_06_2024.pdf

Study information brochure approved.

Other Identifiers

Jérôme Lejeune Foundation

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

3406_OPBG_2024

Identifier Type: -

Identifier Source: org_study_id