Clinical trial NCT05929274: Safety and Efficacy of tDCS in Pediatric DoC
Official title: Safety and Efficacy of Transcranial Direct Current Stimulation in Pediatric Disorders of Consciousness
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: NA
Conditions: Disorder of Consciousness
Keywords: Pediatric population
tDCS
disorder of consciousness
Lead sponsor: Fondazione Don Carlo Gnocchi Onlus
Sponsor class: OTHER
First posted: 2023-07-03
Enrollment: 0
Sex: ALL
Minimum age (years): 4
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Using a sham-controlled randomized double-blind design, 10 patients were randomly assigned to group A or B.
Primary purpose: TREATMENT

Brief summary: Background: Despite established evidence supporting the use of tDCS in the adult patient with disorders of consciousness, its use in paediatric patients with brain injury is still limited. Regarding the use of tDCS in paediatric patients with DoC, the scientific evidence still appears to be preliminary about the safety profile and requires further data before investigating efficacy on a broad scale. In fact, although the method has been shown to be safe in other clinical conditions, efficacy and tolerability in children with DoC may vary significantly depending on differences in activation threshold and the presence of underlying pathological electrical activity The implementation of clinical trials investigating the safety and tolerability of tDCS in paediatric patients with DoC now represents an essential first step for a future determination of the efficacy of this method in a population for which therapeutic options are currently extremely limited Objective: The study aim to verify the safety of tDCS treatment and to evaluate the effectiveness of stimulation of the left dorsolateral prefrontal cortex by tDCS in promoting improvement in the level of consciousness in paediatric patients with Disorders of Consciousness.

Method: in this mono-center, randomised, double blind cross-over controlled pilot study, real or sham tDCS were applied to the left dorsolateral prefrontal (DLPF) cortex of paediatric patients with disorders of consciousness for two weeks, followed by two weeks of washout, then real or sham tDCS were applied to the left dorsolateral prefrontal (DLPF) cortex for other two weeks, followed by another two weeks of washout.

Detailed description: Introduction Following a severe acquired brain injury of traumatic, hypoxic-anoxic, or vascular origin, conditions of very severe cognitive and motor impairment can occur, named as Disorders of Consciousness (DoC), which include the Vegetative State (VS), characterized by the presence of vegetative functions 'in absence of self-awareness and awareness of the environment, and the Minimal Consciousness State (MCS), in which minimal, inconstant, but repeated behavioral responses to visual, verbal or nociceptive stimuli are recognizable, clearly distinguishable from reflex responses.

Differential diagnosis can be complex, and one of the first (and most frequent) sign of transition from VS to MCS is the appearance of visual tracking of salient stimuli .The natural evolution of DoC is influenced by the etiology, being anoxic forms less favorable to recover than other forms. It has been proven that patients with MCS have more favorable prognoses than patients with VS, especially when the condition of MCS occurs within a few months from the acute event.

Despite significant improvement in the understanding of the neural correlates of DoC, the treatment options currently available for these patients are still very limited. Recent findings, however, suggest a broad spectrum of therapeutic possibilities. In the last decade, in fact, several studies have reported signs of spontaneous improvement of consciousness a few years after the acute event in some patients diagnosed with VS .Furthermore, studies on treatments that enhance cognitive abilities in patients with DoC have shown that deep brain stimulation (DBS) in the intralaminar nuclei of the thalamus and some drugs such as amantadine , intrathecal baclofen and zolpidem can improve sign of consciousness behavior in a large cohort of acute and sub-acute patients with DoC of traumatic origin in sham-controlled studies.

In pediatric population with DoC, the exact incidence of VS and MCS is not entirely clear; however, it appears that MCS is more frequent condition than VS compared to adult patients After the acute phase, the pediatric DoC patient starts a specific rehabilitation pathway; its primary goal is the maximum possible recovery of consciousness. During intensive rehabilitation, about 2/3 of pediatric and young adult patients emerges to a state of consciousness within 7 months after the acute event. The rehabilitation program includes a neuropsychological approach dedicated to the recovery of consciousness; from a pharmacological point of view, the literature suggests the use of the following drugs for pediatric DoC: carbidopa-levodopa, amantadine, zolpidem, and methylphenidate.

Efficacy During the last 20 years, intervention studies with innovative non-invasive brain stimulation techniques, such as transcranial direct current stimulation (tDCS), have shown that cycles of low-intensity electrical stimulation delivered via electrodes applied to the scalp in specific areas can promote the processes of neuronal plasticity, i.e. the ability of the central nervous system to modify its structure and functioning in response to new information and experiences. These effects appear to be particularly interesting in the treatment of various neurological and psychiatric disorders such as Parkinson's Disease, post-stroke aphasia or the neuropsychological outcomes of Multiple Sclerosis. More recently, tDCS has been shown to be a safe, inexpensive, and simple technique that can be easily integrated into rehabilitation programs. In particular, stimulation with tDCS has been shown to be effective in aiding the recovery of the state of consciousness in the adult population in the acute, subacute and chronic phase, predominantly in the MCS condition, considering traumatic and non-traumatic etiology. This occurs especially in the anodic stimulation mode of the left dorsolateral prefrontal cortex. In a study in which tDCS was applied for five consecutive days on the motor cortex and left prefrontal cortex in 10 chronic DoC patients, the effect of stimulation was evaluated up to 12 months after its ending, showing that even chronic DoC patients show signs of improvement and that this effect can be maintained up to 12 months after tDCS treatment. From a neurophysiological point of view, tDCS acts by increasing neuronal excitability and facilitating the action potential by modifying the excitability of N-methyl-D-aspartate (NMDA) receptors. In addition, tDCS can enhance active synaptic connections. The effect of a single tDCS session lasts approximately 60 to 90 minutes; when stimulation is repeated 10 times up to 20 sessions it has been found that the effects last up to 3 months after the ending of the stimulation sessions.

Security The safety and tolerability of tDCS have been widely demonstrated in adult patients with consciousness disorders and brain damage. Most authors have found a very good safety profile in patients with DoC, recording adverse effects that are generally transient and mild. Common adverse effects reported during or immediately after tDCS include tingling or numbness in stimulated skin, headache, nausea and fatigue. In addition, there is currently no evidence of long-term adverse or serious adverse effects associated with the use of tDCS in adult DoC patients.

The possibility of subclinical neuronal damage induced by stimulation has been ruled out in studies that assessed serum levels of neuron-specific enolase (NSE, a marker of neuronal damage) before and after stimulation and by studies with EEG or magnetic resonance imaging. Regarding the protocols utilized, this method has to be regarded as safe.

Despite established evidence supporting the use of tDCS in the adult patient, its use in paediatric patients with brain injury is still limited. To date, tDCS is mainly used in paediatric age as a complementary therapy in the rehabilitation of neurodevelopmental disorders such as infantile cerebral palsy, attention deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder. In these patients, tDCS was confirmed to be a safe and well-tolerated technique even in the paediatric population with a small number of reported mild and short-lasting adverse events such as tingling (18%), discomfort (8%) and itching (7%).

Regarding the use of tDCS in paediatric patients with DoC, the scientific evidence still appears to be preliminary about the safety profile and requires further data before investigating efficacy on a broad scale. In fact, although the method has been shown to be safe in other clinical conditions, efficacy and tolerability in children with DoC may vary significantly depending on differences in activation threshold and the presence of underlying pathological electrical activity. The implementation of clinical trials investigating the safety and tolerability of tDCS in paediatric patients with DoC now represents an essential first step for a future determination of the efficacy of this method in a population for which therapeutic options are currently extremely limited. Lastly, several studies have shown that certain quantitative measures of functional connectivity derived from electroencephalographic and evoked-potential analysis (e.g., coherence of the EEG signal, presence of event-related evoked potentials) are capable of faithfully reflecting changes in the state of consciousness in adult DoC patients, contributing to the formulation of prognosis and the identification of patients who are most likely to benefit from treatment. In this sense, the identification of possible paediatric neurophysiological biomarker can help to provide a preliminary quantitative measure of response to treatment, while contributing to the understanding of the effect of tDCS on involved brain networks.

Eligibility criteria: Inclusion Criteria:

* Ages between 4 and 17;
* prolonged condition (\>3 and \<12 months) of MCS and VS by severe brain injury;
* admission to the paediatric rehabilitation department of the Don Carlo Gnocchi Foundation in Florence;
* central nervous system drug therapy stable for at least one week;
* stable DoC (i.e. no change in DoC diagnosis detected by 2 consecutive CRS-Rs performed one week apart);
* Signature of informed consent by the legal representative.

Exclusion Criteria:

* Presence of extensive focal lesions in the left dorsolateral prefrontal cortex (DLPFC);
* radiological evidence of blood collection/liquid collection/other between the DLPFC and the anode placement site;
* seizures in the previous month;
* seizures and/or intermittent epileptiform discharges observed at the extended EEG during the screening phase or at any of the EEG recordings during participation in the study;
* Presence of established pregnancy;
* History of cranial surgery, presence of metallic, cochlear or electronic brain implant in the head or neck area, or ventricular shunt to pacemaker;
* Need for mechanical daytime ventilation;
* Head circumference less than 43 cm;
* bilateral severe or profound hypoacusia;
* Presence of skin lesions in the area to be stimulated;
* Taking sedative drugs and/or Na or Ca channel blockers or NMDA receptor antagonists presence of peritoneal ventricle shunt in the stimulated area (prefrontal cortex);
* serious clinical conditions that may influence the clinical diagnosis (e.g. severe liver failure or kidney).

Primary outcomes:
measure: Evaluating the safety of tDCS treatment assessing the change over time
timeFrame: baseline (1-7 days), post-stimulation (within 30-minutes), follow-up (24 hours, 48 hours, 5 days)
measure: Assessing the change of tolerability of treatment with tDCS
timeFrame: Baseline (1-7 days), pre-during-post stimulation (pre-stimulation: within 30 minutes, during: within 20 minutes, post-stimulation: within 30-minutes)
measure: Assessing the change in the state of consciousness by using tDCS
timeFrame: days 1, 8, 12, 19, 35, 40, 47, 62, 92
Secondary outcomes:
measure: To evaluate the effect of tDCS stimulation on brain electrical activity
timeFrame: days 1, 8, 35, 47, 62, 92
measure: To evaluate the effect of tDCS stimulation on cortical electrical activity
timeFrame: days 1, 8, 35, 47, 62, 92
measure: To evaluate the effect of tDCS stimulation in determining haemodynamic response (HDR) changes quantifiable
timeFrame: days 8, 35, 47, 62, 92
measure: Assess caregiver satisfaction with the treatment
timeFrame: days 19 and 47
Other outcomes:
Locations:
Study officials:
affiliation: IRCCS Fondazione Don Carlo Gnocchi ONLUS
name: Giovanna Cristella, MD
role: PRINCIPAL_INVESTIGATOR
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