In paediatric neurological disorders, the ever-evolving landscape of scientific research and technological advancement has been seen to be a promising new era of hope for the remedy of these disorders. Neuromodulation intervention has been seen to be the evolving premier to alleviate the oppressive load of neurological disorders in children. However, the predominant use of neuromodulation techniques has mainly been reported so far in a few psychiatric disorders like attention deficit hyperactive syndrome (ADHD) and autism spectrum disorder (ASD) [1]. Neuromodulation is a fast-growing field that uses invasive and non-invasive approaches for therapeutic and diagnostic approaches to neurological disorders. As the name suggests, neuromodulation devices use electromagnetic and chemical methods to influence the neural activity of the nervous system [2]. Neuromodulation techniques (Figure 1) and devices like transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS) and transauricular vagus nerve stimulation (taVNS) are seen to show improvements in neurological symptoms in affected children.

Especially for non-invasive brain stimulation (NIBS) technologies, there has been significant research in adults over the past twenty years; studies involving children are notably scarce. Of over 16,000 human studies on NIBS, only 675 (4%) have focused on paediatric populations. This lack of research in a population with distinct neurobiology and health conditions underscores the importance of investigating the applicability of NIBS in children. Scientists, clinicians, ethics boards, and concerned parents are increasingly seeking evidence on the potential of applying NIBS in youth. The absence of such evidence likely hinders progress in addressing various brain and mental health disorders in children, where the global burden of disease is significant. This Contemporary review is focused on unravelling the intricate workings of various NIBS techniques, delving into the neurologic disorders in children.

Figure 1: Illustration of Neuromodulation intervention in paediatric neurology. (a) Transcranial magnetic stimulation device works on the principle of electromagnetic induction. As soon as the TMS coil is placed over the desired area of intervention for cerebral palsy (M1 area) and stimulated. The magnetic field that is generated causes the neurons to produce postsynaptic potential. Repetitive TMS can induce long-lasting cerebral plasticity associated with therapeutic intervention. (b) Cathodal transcranial direct current stimulation device uses cathode and anode electrodes where the cathodal electrode is placed on the epileptogenic region to inhibit the area associated with epilepsy (Fp2- frontal lobe epilepsy; T3- temporal lobe epilepsy), causing hyperpolarization of epileptic zones and control of seizure. Created with BioRender.com.

A literature review using EBSCO, Google Scholar, and PubMed databases focused on neuromodulation studies targeting paediatric neurologic diseases. The search included keywords such as "transcranial magnetic stimulation," "transcranial direct current stimulation," “vagus nerve stimulation”, and "brain stimulation," along with specific conditions like Cerebral palsy, Epilepsy, Autism, motor speech and attention deficit hyperactive disorder and Parkinson’s disease. Additionally, relevant articles cited in the references of selected papers were also considered. The analysis primarily examined methods related to brain stimulation, patient characteristics, presence or absence of neurological symptoms, study design, experimental protocols, quantification of stimulation parameters, and available brain imaging data. Studies involving only healthy subjects or conducted on non-human animals were excluded. Given the innovative nature of this clinical research field, the review also encompassed well-conducted small-scale studies, recognising their significance in the current body of literature despite the limited number of large randomised controlled clinical trials available to assess efficacy.

Figure 2: The PRISMA flow chart of the studies included in the review.

Figure 1 shows the Prisma flowchart of the studies reviewed and included in the study. After the systematic procedure, 157 out of 250 studies were eligible for analysis. Two and one case reports were excluded due to unclear data reporting and patient characteristics, respectively.

Scopes of Using NIBS Techniques in Paediatric Neurology

Neurological disorders in children are predominantly characterised by dysfunction occurring within various regions of the nervous system related to genetic causes, anoxic conditions, pathogenic infections, and traumas [3]. Many articles on paediatric neurological disorders show that cerebral palsy and seizures are the most common neurological conditions, which show a gender bias towards males [4]. Although neuromodulation treatments have been found to improve the quality of life for those suffering from neurological disorders [5], transcranial magnetic stimulation (TMS) is a non-invasive technique that can be used both for diagnosis and treatment. TMS uses different magnetic fields outside the skull to stimulate brain currents within the brain tissue, enabling the assessment of cortical excitability [6].

Neuromodulation technology is being refined, and neurologists with access to these techniques can understand the diagnosis and therapeutics of this intervention method. The disease management effect can also be one of the primary goals of the devices [7]. For example, motor-categorized disability caused by stroke in children with rTMS studies shows favourable outcomes with almost no significant adverse reactions to the modulation [8]. In addition to improving the quality of life for the juvenile population, neuromodulation techniques can also be used in diagnosing paediatric neurological illnesses and have great potential for clinical applications in rehabilitation [9].

With an emphasis on treating neurological problems by modifying neurocircuitry, the discipline of paediatric neuromodulation is expanding quickly. Minimally invasive approaches, including transcranial magnetic and direct current, aim to rebalance circuit activity by targeting specific nodes within malfunctioning neural circuits. While using experimental methods that were first designed for adults should be done cautiously, this field offers an exciting new treatment option for illnesses that would otherwise be resistant [10]. Although treating neuropsychiatric diseases in children and adolescents has inherent obstacles, increasing evidence indicates that brain stimulation may provide practical and alternative treatments for early-onset neuropsychiatric disorders [11]. It is critical to evaluate and maximise the safety and moral use of neuromodulation techniques as their use increases in paediatric populations [12]. Regardless of the favourable outcomes of using the neuromodulation method in adults, there is very scanty information for use in children and young adults [13]. Many recent reviews warrant that contemporary literature should evoke excitement and scepticism [12,14-16]. Ensuring dependable methods with extensive, well-characterized samples will require carefully balancing ethical considerations and study design. One of the main challenges researchers face in designing a well-controlled study design investigating the efficacy of NIBS on the paediatric population is to involve healthy children. It is essential for scientific purposes but may only sometimes be practical, given that control subjects are unlikely to derive direct benefits from the procedure.

Introduction to Paediatric Neurological Disorders

Neurological conditions significantly contribute to disability during childhood, with a disproportionate impact on children in developing regions of the world [17]. The children who incubate neurological impairment have constantly been seen to advance to an overall poor quality of life. Recent advancements in methodologies indicate that among neurological disorders, children with conditions such as cerebral palsy, Autism, ADHD, epilepsy, and psychiatric issues are prominently represented in current studies disorders [18].

Makila published a paper known as the Five to Fifteen (FTF) parental survey, which was utilised to assess parents viewpoints on the developmental progress of children born preterm and between the ages of five and eight. Significant differences were identified in the scores of gross motor abilities, language, and executive function between extremely preterm and term-born children on various evaluated activities. It is advisable to use the FTF as a screening tool for the early detection of preterm children susceptible to neurodevelopmental challenges [19]. The following section discusses various neuropsychiatric disorders and how the NIBS technology can be used to remediate these conditions.

Cerebral Palsy (CP)

CP is a non-progressive neurological condition that impairs coordination and motor function and causes function to deteriorate. Pathological alterations in the brain resulting from cerebral palsy (CP) are identified by irregular brain development, brain injury from oxygen deprivation, and bleeding within the skull [20,21]. CP manifests as delayed motor responses and challenges in movement execution due to factors like dystonia, muscle weakness, and lack of muscle coordination [22]. These movement difficulties increase energy expenditure, hindering normal muscle growth and resulting in secondary muscle and tissue tightness and skeletal deformities [23] consequently, children with CP experience functional limitations in daily activities such as self-care and mobility [24]. The unilateral form of CP is the most prevalent kind [22]. According to a recent comprehensive review, the worldwide incidence of cerebral palsy (CP) is reported to be 1.6 per 1000 births [24]. Arabic-speaking countries, such as Saudi Arabia, Egypt, and Jordan, reported a slightly elevated prevalence rate of 1.8 per 1000 live births [24]. The primary aim for children with CP is achieving independence in self-care and mobility.

The predominant cause of CP is damage to the brain's white matter, which, if untreated, can exacerbate clinical symptoms due to abnormal central nervous system development [25]. Effective therapeutic interventions must influence brain neuroplasticity over the long term to yield lasting benefits [26]. Current paediatric neurology research explores the efficacy of non-invasive brain stimulation (NIBS) for treating various paediatric neurological disorders [27]. NIBS involves applying electrical currents to brain tissue to modulate motor cortex excitability [28], making it a promising non-drug treatment option for paediatric movement disorders [29]. Among NIBS techniques, repetitive transcranial magnetic stimulation (rTMS) stands out for its non-invasive and painless nature [29,30]. By employing electromagnetic principles to target specific brain regions, rTMS can adjust neuronal excitability [31] and has shown significant therapeutic effects in neurological conditions [14]. Thus, rTMS is increasingly utilised in managing CP [14], with reported benefits including improved motor function [32], spasm relief [33] and speech restoration [34]. Furthermore, rTMS can induce changes in brain function by influencing developmental plasticity [35]. However, studies evaluating rTMS in CP treatment vary in sample size and outcomes, highlighting the need for more high-quality, evidence-based research. Table 1 provides a brief overview of the studies employing TMS in cerebral palsy.

Table 1: Overviewing studies of TMS in Cerebral Palsy (CP).

The table lists studies overviewing Transcranial Magnetic Stimulation intervention in Cerebral Palsy (CP). M1, primary motor cortex; rTMS, repetitive transcranial magnetic stimulation.

A recent meta-analysis encompassed 29 studies [33], with only four [44,45,33,38] rated as excellent quality according to the PEDro scale, while ten were deemed low quality [46,36,33, 39,47,48]. The limitations included difficulties in controlling allocation concealment and blinding, biased heterogeneity possibly due to differences in intervention factors, and small sample sizes. Regarding study characteristics, most focused on comparing conventional rehabilitation with rehabilitation combined with rTMS, with only four exploring the efficacy of sham versus real TMS [32,44,45,38]. These studies showed rTMS effectiveness in improving motor function and language ability in CP patients. Examined parameters included stimulation site, duration, number of sessions, and frequencies ranging from 0.2 to 30 Hz [40,45]. Limited evidence exists on the efficacy of rTMS at different frequencies for CP treatment. High-frequency rTMS (>1 Hz) has shown excitatory effects [49,50], while low-frequency rTMS (≤1 Hz) depresses excitability [51,32,52], as seen in stroke patients. However, the applicability and generalisability of these findings to CP patients remain uncertain because of smaller effect sizes and inconsistency in findings. Studies by Valle [38] and Gupta [40] demonstrated significant reductions in spasticity and motor function improvement, respectively, with varying stimulation frequencies and intensities. Valle proposed that enhancing motor cortex function with cortical stimulation will increase the inhibitory impact on spinal excitability via the corticospinal tract, diminishing the hyperactivity of alpha and beta neurons and enhancing spasticity [38]. Parvin suggest that rTMS, in conjunction with occupational therapy can effectively and persistently improve neuromuscular deficits in children with spastic cerebral palsy [37]. Thus, rTMS efficacy in CP treatment depends on stimulation frequency, intensity, duration, and pulse sequence, which needs further investigation and validation.

Similarly, motor dysfunction is a common issue in cerebral palsy (CP), leading to various studies exploring this aspect. Studies by Marzbani [25], Dadashi [51], Gupta Eyre [40,41] indicated positive effects of rTMS on motor function and balance control in children with CP. However, more extensive studies with well-designed randomised controlled trials are needed to confirm this. Spasticity is a significant contributor to motor disability in CP, with long-term effects on musculoskeletal health and quality of life [42]. Studies showed a significant reduction in muscle spasms with rTMS, particularly when combined with conventional therapy [33]. In contrast, Valle [38] suggested high-frequency stimulation as more effective in reducing spasticity, albeit with limited evidence. Language development disorders are prevalent in CP and significantly impact communication and quality of life [53]. Children diagnosed with hemiplegic cerebral palsy have demonstrated significant improvements in upper limb motor abilities as well as the development of delicate motor abilities after receiving repetitive transcranial magnetic stimulation in conjunction with induction of therapy treatment [33]. Meta-analysis revealed that rTMS could improve various aspects of language ability, significantly enhancing expression and comprehension quotients compared to controls [33]. Vry mentioned that Patients with diplegic cerebral palsy and PVL had shorter silent periods, which is indicative of lower cortical GABAergic inhibition, which was confirmed by the use of the TMS method [42]. Children with hemiplegic CP showed several distinct patterns of sensorimotor representation; hence, individualised customized therapy would be a more effective form of rehabilitation for CP patients [43]. However, research in this area must be more extensive and warrants further exploration and expansion.

Unlike TMS, tDCS allows for greater flexibility, enabling concurrent therapy sessions and reducing treatment duration. tDCS is a non-invasive technique that utilises low-intensity direct current to modulate cortical activity. It works by placing electrodes on the scalp, affecting neuronal excitability through changes in resting membrane potential [54]. CP children often face motor challenges like abnormal muscle tone, poor hand function, and balance issues [55]. While it's unclear if theories on improving motor function apply to children's developing brains, some suggest an inhibitory imbalance between hemispheres in unilateral CP [44,56]. In tDCS treatment, electrodes are placed to increase excitability on the injured side or decrease it on the non-injured side of the primary motor cortex [57,58].

Reports on tDCS improving upper limb motor function in CP children are limited but promising. Some studies combining tDCS with other interventions have improved muscle strength and spasticity where anodal stimulation on the injured side primary motor cortex (M1) is often used, lasting 20 minutes at an intensity of 1.0 mA [59,61]. There is variability in the optimal stimulation dose. For instance, a study on unilateral hemiplegic CP children used a higher intensity of 1.5 mA for 20 minutes, showing immediate effects on hand flexibility [62]. Other studies used lower intensities like 0.7 mA for exciting the corticospinal tract [58] or 1 mA for 15 minutes over 10 days to improve muscle stiffness and spasticity in the upper limbs [62]. While tDCS shows promise for improving upper limb function ("Cerebellar tDCS during treadmill training for a child with dystonic cerebral palsy: a case report," 2019) [63,64], its effects on lower limb function in CP children have been studied less. Some research suggests potential benefits for gait and balance [64], but the mechanisms remain unclear. Few studies have explored tDCS effects on cognitive and language functions in CP children. However, evidence from case reports and small studies suggests potential benefits for cognitive training and speech function improvement [65-67]. Further research is needed to determine optimal stimulation parameters and regional targeting for enhancing cognitive and language abilities in CP children, drawing insights from tDCS applications in other neurodevelopmental disorders like ADHD and ASD [68-71].

Epilepsy

A seizure is described as a brief episode of symptoms brought on by synchronous, aberrant, or excessive brain neuronal activity accompanied by sudden, involuntary skeletal muscle contractions. To avoid Status Epilepticus (SE), early diagnosis, treatment, and specialised medical support are necessary. Particularly in the paediatric population, there are specific risk factors that are associated with the beginning of seizures, such as a positive family history, fever, infections, neurological comorbidity, and preterm delivery caused by maternal alcohol usage, and smoking during pregnancy. Children without neurological comorbidity have an early death risk that is comparable to that of the general population [72]. The discovery of ongoing or recurring seizures is typically the basis for diagnosis; however, an electroencephalogram (EEG) evaluation may be helpful if a status epilepticus disease is suspected. The primary objective of treatment is to disrupt the pathogenic mechanism that arises in status epileptics before irreversible brain cell loss begins [72].

Children with status epilepticus may experience long-term neurologic and cognitive abnormalities due to neuronal death and network alterations, both of which are life-threatening conditions and medical emergencies. Refractory status epileptics develop when the normal pharmacological treatment fails to control seizures, and super-refractory status epileptics occur if the seizures continue for more than 24 hours, even with anaesthetics. Potential treatment treatments for this condition include vagus nerve stimulation, deep brain stimulation and electroconvulsive treatment clinical neuromodulation approaches for managing super-refractory status epileptics in children [73].

The application of electric facilitation to influence the CNS to lessen seizure frequency and intensity is known as neurostimulation for epilepsy. There are many different methods, from non-invasive to invasive [74]. Some focus on the specific patient's seizure-onset zone (SOZ), while others target broader areas that are assumed to impact seizure-related neural networks. While some gadgets sense brain activity and administer stimulation in response to identified events, others offer stimulation continuously (Open-Circuit) (Closed-Circuit).

In 1997, the U.S. Food and Drug Administration (FDA) approved the use of vagus nerve stimulation (VNS) in the management of refractory focal epilepsy; patients four years of age and older can now receive this approval. In paediatrics, the neurostimulation modality has been explored the most. The Vagus nerve is wrapped in a cuff and linked to a VNS generator, usually inserted just below the pectoral muscle [74]. The left side Vagus nerve is mainly employed to prevent stimulating the sinoatrial node supplied by the right vagus nerve. Through the augmentation of activity in the nucleus tractus solitarius (NTS) and its subsequent connections to the limbic system and thalamus, vagus nerve stimulation (VNS) is believed to modulate hyperexcitable regions of the brain. Consequently, the NTS extends to the locus coeruleus and the raphe nuclei, and the ventral nerve system promotes the synthesis of norepinephrine [NE, noradrenaline (NA)] and serotonin, both of which demonstrate antiepileptic characteristics [75].

In around 50% of patients, seizures were decreased by 50% or more, according to a meta-analysis of 74 trials, including 3321 individuals following VNS [76]. Comparable efficacy levels in adult and paediatric VNS patients have been reported in other investigations. Over time, the response rate gets better. Of the 440 patients followed up for three years from a clinical trial conducted earlier, 44% were responders. In general, VNS is well tolerated. Coughing, dysphagia, voice changes, and neck pain are typical side symptoms that are not connected to implantation. Side effects are typically associated with output current and, to a lesser degree, duty cycling. These parameters can generally be adjusted to accommodate the patient's tolerance.

A closed-loop system called a responsive neurostimulation (RNS) device is intended to deliver tailored stimulation to the predicted seizure onset zone (SOZ). Unlike other neurostimulation strategies that have been considered, RNS attempts to stop seizure activity. It uses a pre-programmed algorithm to identify seizures and then initiate stimulation to stop seizures or behaviour related to seizures. After the pulse generator is surgically inserted into the patient's cranium, doctors can freely modify the stimulation and detection settings to meet the specific needs of each patient [77]. The discovery that the administration of stimulation might stop after discharges produced during electrical stimulation for functional mapping in patients undergoing intracranial monitoring impacted the design of responsive neurostimulation (RNS) [78]. Responsive stimulation was first thought to prevent seizures, but it may function mainly by changing the plasticity of critical neuronal networks [79]. Kokoszka observed that the utilisation of responsive neurostimulation (RNS) in a 14-year-old with onset of independent hemispheric seizure and a 9-year-old with seizure onset in the eloquent cortex of the left frontal and parietal lobes led to a reduction of over 80% in seizure frequency for both patients [80]. Currently, the only commercially accessible method for long-term electrocorticography is RNS. In terms of clinical practice, this helps monitor the occurrence of seizures throughout the duration and, for instance, figure out the localisation of seizure outset in cases of bilateral mesial temporal engagement. As a result, RNS provides distinctive usefulness and has resulted in helping patients with multifocal epilepsy successfully resect a single seizure centre [81].

Chronic subthreshold cortical stimulation (CSCS), like RNS, aims to stimulate the area where seizures begin. It is, nevertheless, open loop, like DBS and VNS. Constant stimulation is subthreshold, meaning it is applied in a way that maintains cortical function. Intracranial EEG monitoring is used to identify potential candidates [82]. In cases when the beginning of a seizure is multifactorial or involves the eloquent cortex, the current protocol entails utilising the implanted hardware for 1-3 days of trial stimulation. The potential efficacy of various stimulation paradigms is assessed by examining the frequency of interictal epileptiform discharge and seizure occurrence. Permanent leads can be inserted if stimulation seems effective [82]. How exactly constant stimulation reduces the likelihood of seizures is still being determined. Based on earlier research, continuous cortical stimulation is considered safe and may reduce the frequency of seizures in those using CSCS, as documented by Velasco in ten individuals with intractable temporal lobe epilepsy [83]. Three (43%) of the seven paediatric patients, aged 6 to 17, stopped having seizures, and all seven experienced a decrease in the frequency of the onset of seizures in more than 50% of the individuals. A follow-up review about two years later involving these seven paediatric patients (median follow-up of 2.8 years) found that five had not experienced any incapacitating seizures in the previous three months and that the mean reduction in seizure frequency was 85% [83].

While CSCS, RNS and VNS involve internal administration of electrical stimulation, transcranial magnetic stimulation (TMS) externally modifies defined cortical circuits through fluctuations in a magnetic field. The FDA has approved TMS for managing severe Conditions like depression, migraines, and pre-surgical motor mapping and linguistic operations, among many other indications [27]. The quality of the evidence supporting the intervention of TMS to lower the seizure frequency was deemed low in a 2016 Cochrane review [84]. Fregni treated 21 patients diagnosed with refractory epilepsy and developmental cortical abnormality in a randomised clinical trial conducted using operative or sham TMS. Compared to the sham group, the active group saw a statistically significant reduction in seizure frequency, with a 72% drop for an eight-week follow-up period [85]. While rTMS poses a risk of inducing seizures, systematic reviews indicate a low crude per-subject seizure risk of only 2.9% in patients with epilepsy, with most seizures being consistent with the patient's baseline characteristics [86]. Although FDA-approved for major depressive disorder and non-invasive mapping of the language cortex, its use in epilepsy treatment lacks FDA approval but shows some potential benefits. Reviews of case reports and case series reveal transient or sustained seizure cessation in a subset of patients with refractory epilepsy [87-92]. Open-label trials demonstrate reductions in seizure frequency and severity, particularly in patients with extra-temporal lobe epilepsy and frontal cortical dysplasia [93-96]. Controlled clinical trials using sham stimulation protocols have yielded mixed results, with some showing significant reductions in seizure frequency and interictal epileptiform discharges, especially in patients with neocortical epilepsy or cortical developmental malformations [85,97].

Due to its non-invasive nature and safety profile, tDCS has garnered interest as a potential treatment option in paediatric patients (Refer to Table 2). Research, including randomised controlled [85,98] trials (RCTs), has shown promising results. A study conducted by Auvichayapat [99] demonstrated significant reductions in epileptic discharge frequency immediately following tDCS in children with drug-resistant focal epilepsy. Similarly, another RCT by the same group showed a significant decrease in seizure frequency and epileptic discharges in children with Lennox–Gastaut syndrome after multiple sessions of cathodal tDCS [100]. However, some studies, such as the cross-over study by Varga [101], have reported conflicting results. Nevertheless, the most recent pilot study by Kaye [102] showed a significant reduction in seizure frequency during and after tDCS treatment in children with drug-resistant focal epilepsy. Whereas studies conducted by Yook showed that there is control and reduction of seizure attack occurrence after tDCS treatment [103]. Post-intervention of tDCS, a decrease in seizure-related epileptic discharge can be seen [104]. San-Juan [105]. Also showed a reduction in seizure and duration of seizure attacks. Adverse events associated with tDCS in children have been limited, including superficial skin burns under the reference electrode and an increase in seizure frequency in rare cases. A case study by Ekici [106]. Reported that a child had a seizure after a tDCS simulation. Sierawska [107]. Also reported the onset of seizure in a healthy teenage subject post-tDCS stimulation. Further larger-scale trials are needed to validate these findings and explore customised montages for tDCS administration.

The advancement of neuromodulation significantly enhances the range of treatment options for epilepsy. While anti-seizure medications are typically the initial approach, neuromodulation becomes a valuable alternative for children with drug-resistant epilepsy who are not suitable candidates for surgical procedures like resection or laser interstitial thermal therapy. This option becomes particularly important in cases where the patient lacks identifiable lesions, experiences seizure onset in critical brain areas, has multifocal seizure onsets, poorly defined seizure networks, or suffers from generalised epilepsy such as genetic generalised epilepsy or Lennox-Gastaut syndrome.

Table 2: Overviewing studies of tDCS in seizures.

The table lists studies overviewing Transcranial Direct Current Stimulation intervention in Seizures. c-tDCS, Cathodal transcranial direct current stimulation; a-tDCS, Anodal transcranial direct current stimulation; SOA, stimulus onset asynchrony.

Autism Spectrum Disorder

This neurological disease, ASD, is lifelong. Qualitative behavioural problems in communication and reciprocal social contact, together with repetitive, limited, and stereotyped interest and activity patterns, have been identified as hallmarks of autism spectrum disorder. These deficiencies are widespread, enduring, often evident in early life, and likely to result in functional problems in various contexts. According to the National Institute of Health and Clinical Excellence (NICE), the diagnosis is made in about 3% of children, and epidemiological research indicates that at least one in 100 cases of the condition is likely to occur. Genetic variations such as "rare causal" copy number variants and single gene polymorphisms have been found. These changes are substantial or "causal" in around 10% of individuals with ASD diagnoses.

Electroencephalography technology is used to assess and diagnose ASD. Simultaneous transcranial magnetic stimulation (TMS) with electroencephalography (EEG) has been applied to diverse mental health conditions. Individuals with Autism Spectrum Disorder (ASD) exhibit altered excitatory/inhibitory balance in the cerebral cortex, leading to gamma oscillation abnormalities, deficits in executive function, and stimulus-bound behaviours [108]. Transcranial Magnetic Stimulation (TMS) offers a non-invasive therapeutic approach to modulate gamma oscillations and address maladaptive behaviours in ASD [109]. Recent literature reviews support the safety and efficacy of TMS in ASD treatment [110-115]. However, selecting appropriate outcome measures remains crucial, necessitating unbiased electrophysiological assessments alongside subjective methods [116]. Objective measures of quality care, including autonomic measures, can provide insights into functional changes and adverse experiences. Future efforts should focus on large-scale clinical trials with targeted criteria and longitudinal follow-up to address critical questions regarding outcome predictors, benefits duration, and utility of booster sessions.

Regarding clinical impairment, numerous studies have shown that transcranial Direct Current Stimulation (tDCS) has significant positive effects on various aspects of autism spectrum disorder (ASD). These effects include socialisation improvements, repetitive behaviour, sensory and cognitive awareness, health status, and behavioural problems [117]. However, it's noteworthy that only a few studies included gold-standard ASD instruments in their design [118], highlighting the need for more rigorous research methodologies. For instance, one case study successfully treated an 18-year-old patient with ASD using tDCS applied over the right temporo-parietal junction (rTPJ), a brain region crucial for social functioning [119]. Despite promising results, randomised controlled trials and standardised evaluation protocols are necessary to enhance the generalisation of findings and validate the efficacy of tDCS in treating ASD symptoms.

Regarding cognitive functioning, tDCS has shown benefits, particularly in improving language processes such as verbal fluency [117]. Studies have observed enhanced verbal fluency tasks with emotional content when stimulating the rTPJ [119,120]. The meta-analysis review conducted by Imburgio and Orr (2018) [121] highlighted the positive impact of transcranial Direct Current Stimulation (tDCS) on executive functions, which was further supported by the findings of Rotharmel (2019) [122]. Specifically, tDCS was found to have beneficial effects on working memory and attention, consistent with the results reported by Van Steenburgh (2017) [123]. Moreover, tDCS applied to the primary motor cortex has been associated with improved motor function, increased gait speed and amplitude [124] and enhanced body balance [125]. Additionally, tDCS has positively affected executive functions, working memory, attention, and motor function, albeit with a small effect size [126]. Notably, tDCS has been associated with changes in EEG activity, indicating increased neural activity following stimulation [127,128]. However, while these findings are promising, more research is needed to thoroughly evaluate the impact of tDCS on neuropsychological functions and neural activity. Future studies should focus on employing standardised outcome measures and exploring individualised intervention approaches. Comparisons between tDCS and Transcranial Magnetic Stimulation (TMS) suggest similar benefits for ASD symptoms. While the mechanisms of action differ between tDCS and TMS, both appear to offer promising results in alleviating ASD-related difficulties. However, more studies are required to investigate and compare the efficacy of these two neuromodulation techniques in ASD populations further, particularly in terms of age-related differences and optimal stimulation protocols.

Vagus nerve stimulation (VNS) is a neuromodulation procedure that stimulates autonomic nervous circuits using an electrode inserted or placed around the left Vagus nerve in the exposed Vagus nerve area [129]. To use VNS as a safe and useful adjunct to cognitive behavioural therapy and other rehabilitative therapies for individuals with ASD, future research on both invasive and non-invasive VNS should focus on determining the ideal stimulation settings. For ASD patients with significant anxiety who also have an implant for depression or epilepsy, VNS may be a desirable adjunct to exposure-based therapy ("Vagus Nerve Stimulation as a Treatment for Fear and Anxiety in Individuals with Autism Spectrum Disorder," 2022). Several studies have demonstrated the safety and low side effects of VNS treatment, which may be administered to adults and children as young as six months of age [130].

Motor Speech Disorders

A problem affecting the control and coordination of the muscles used to produce speech is referred to as a motor speech disorder. The seamless, precise, and prompt execution of the motions required for speech can be impacted by several illnesses. The brain regions involved in organising and carrying out speech motions are frequently affected by neurological injury or malfunction, which can lead to motor speech disorders. Currently, there are four types of speech disorders classified. Children exhibiting imprecise and/or unstable spatiotemporal distortions in constants and vowels, along with inappropriate rhythmic oscillation and voice abnormality, are suspected of either Childhood Apraxia of Speech (CAS) or Childhood Dysarthria (CD). This contrasts individual presenting solely with early and intermittently persistent continuous substitution and deletion errors, characteristic features of Speech Delay (SD) [131].

Accurate mapping of the brain has allowed the motor speech area in the brain to be recognised as the site for motor speech disorders with the help of fMRI and MEG. TMS has been introduced to assess the clinical applicability of functional mapping for young children. In a study involving 36 children, mapping language cortices in the temporal regions was effectively accomplished in 11 cases. The application of TMS allowed for observing typical developmental patterns in motor, speech, and language functions and discernible reorganisation induced by disease in this cohort of young children. To map young children's expressive cortices, TMS provides a secure, dependable, and efficient method [132].

The use of non-invasive brain stimulation has recently been examined in the rehabilitation process as transcranial direct current stimulation (tDCS). This technique modulates cortical excitability, causing excitation and inhibition. It has also been found that tDCS requirements for adults and children are different depending on the current strength, and evidence also suggests a contributing factor to the improvement of motor learning capabilities [44,56]. tDCS stimulation over speech production Broca’s Area in a child with cerebral palsy saw that the subject had Distortions and replacements decreased, and oral performance-particularly tongue mobility-improved. The child's imitation test results indicated that they had acquired many accurate consonants and phonemes, suggesting a clinically significant increase in their speech fluency but with significant inter-individual difference. This also raises questions about some of the adverse effects that the technique can cause on children for which proper clinical trials should be conducted.

Attention Deficit Hyperactivity Disorder

Attention-deficit hyperactivity disorder (ADHD) affects 2% to 7.5% of school-aged children and often persists into adulthood, making it one of the most prevalent neurodevelopmental diseases. The three main symptoms define it are impulsivity, hyperactivity, and inattention. Even after extensive research, the pathogenesis of ADHD is still unknown. The absence of commonly used biomarkers or diagnostic procedures impedes the clinical management of ADHD. Even well-designed neuroimaging studies in ADHD are challenging to interpret because of several potentially confounding variables, including changes in brain maturation and motion artefacts from a group that finds it challenging to comply with extensive MRI testing. Despite these obstacles, research on the brain correlates of ADHD has recently made some progress [133]. Dopamine and norepinephrine are two catecholaminergic neurotransmitters that exhibit aberrant behaviour in the ADHD brain along with structural and functional abnormalities. These abnormalities have contributed to play a crucial role in the pathogenesis of ADHD. Now that we have acknowledged the intricacy of ADHD and the severe gaps in our knowledge of the underlying brain mechanisms let's focus on non-invasive brain stimulation and its possible benefits for treating paediatric ADHD [11].

The motor cortex's neurophysiological equivalents to behavioural assessments of hyperactivity in ADHD patients may be investigated using single- and paired-pulse transcranial magnetic stimulation methods. These findings point to a reciprocal link between hyperactivity and short interval intracortical inhibition; more precisely, increased hyperactivity is associated with decreased intracortical inhibition. This implies that intracortical inhibition with short intervals could function as a biomarker for the severity of symptoms [134].

Deficient inhibitory systems are hypothesised to underlie ADHD and may be a target for targeted cortical stimulation (tDCS). L-DLPFC stimulation has been shown to improve inhibitory control in children in multiple trials. Administering anodal transcranial direct current stimulation (tDCS) over the left dorsolateral prefrontal cortex (L-DLPFC) enhanced response accuracy in a Go-No-Go task. At the same time, cathodal tDCS improved the accuracy of No-Go responses, suggesting enhanced inhibitory control, as demonstrated in a randomized crossover study (n = 5–20) [69]. Further investigations explored the impact of slow oscillating tDCS on modulating cortical activity during non-rapid eye movement during sleep phase 2. After slow oscillating tDCS, participants' reaction times and memory functions improved [135]. Recent meta-analyses show that tDCS shows promise as a method for improving ADHD deficits [136], further systematic investigation is necessary to understand its clinical utility fully. Several factors need to be considered in future research to determine the efficacy of tDCS in ADHD. First, Identifying the specific cortical regions involved in ADHD pathophysiology and targeting them with tDCS may enhance its efficacy. Research should focus on elucidating the neural circuits implicated in ADHD symptoms and determining the optimal stimulation sites. Second, parameters such as intensity, duration, polarity, and electrode size play crucial roles in determining the effects of tDCS. Systematic exploration of these parameters is needed to optimise tDCS protocols for ADHD treatment. Third, ADHD is a heterogeneous disorder with diverse symptom presentations. Tailoring tDCS interventions to target specific symptoms or deficits, such as inattention, impulsivity, or hyperactivity, may lead to more effective outcomes. Fourth, considering the developmental aspects of tDCS in childhood ADHD is essential. The effects of tDCS on the developing brain may differ from those in adults, necessitating careful adjustment of stimulation parameters and safety considerations.

This review discusses the clinical application of neuromodulation in treating paediatric neurological disorders, noting its promising yet variable results. Therapeutic outcomes and differences in application techniques, whether invasive or non-invasive, are key factors in therapy selection. Due to the wide variation in application methods, favouring one over the other is impractical. Recommendations for using neuromodulation in paediatric neurology treatment should balance potential benefits and risks, requiring individualised decisions in consultation with the patient's physician.

A significant limitation in neuromodulation research is the small number of participants, particularly those with neurological disorders in the paediatric population, and the need for properly designed randomised, double-blind trials. More clinical trials are needed to establish evidence on efficacy and safety, with larger sample sizes to minimise bias. While patient recruitment poses challenges, smaller trials across multiple centres can enhance available evidence. Another limitation is the lack of long-term follow-up trials essential for understanding response persistence, potential side effects, and optimal stimulation parameters. Studies must account for micro-lesions during implantation and hippocampal sclerosis, which can impact therapy response. Variability in reported outcome measures is also a challenge. While seizure frequency is commonly reported, inter-ictal discharges, neuropsychological tests, and quality-of-life assessments are equally crucial, especially considering neurological disorders’ cognitive implications. Addressing these limitations can enhance the quality and reliability of neuromodulation studies in treating paediatric neurological disorders.

Paediatric neuromodulation is an emerging field that has made great promise for improving the treatment of neurological diseases in children. However, like with many new and creative clinical advances, obstacles in healthcare supply and research's more significant social and political framework may limit its potential. Therefore, researchers and clinicians working in paediatric neuromodulation must be aware of these difficulties and work together to develop accountable procedures for addressing those [137].

Challenges and Future Directions

Below are the discussed specific challenges and future directions required for the application of TMS, tDCS, and taVNS in the paediatric population:

Application of TMS in Paediatric Neurology

The risk of seizures is a significant concern associated with clinically approved technique TMS, particularly in paediatric populations. Several factors contribute to this risk:

• Higher Motor Thresholds in Children: Little children typically have higher motor thresholds, which may necessitate higher stimulus intensities than adults. This increases the chance of negative consequences, including seizures, particularly in younger children whose motor thresholds have not yet reached adult levels.
• Vulnerability of the Developing Brain: The developing brain, especially in babies and young children, is particularly vulnerable to seizures due to insufficient GABA-mediated regulation, decreased glutamate clearance, and elevated sensitivity. These factors make young children more susceptible to the excitatory activity induced by brain stimulation techniques like TMS.
• Differences in Skull Size and Composition: Variations in the size and composition of the skull can lead to differences in the amount of current that reaches the cortex during brain stimulation. This can pose safety issues and complicate the standardisation of stimulation protocols.
• Acoustic Harm during TMS: Young children have smaller external auditory canals, leading to higher resonance frequencies. This increases the risk of acoustic harm during TMS pulse delivery, further complicating safety considerations in paediatric populations.

Given these risks, guidelines for including children in TMS trials emphasise the importance of strong evidence supporting the use of TMS for refractory cases. Therefore, carefully considering safety protocols and regulatory oversight is essential when employing non-invasive brain stimulation techniques in paediatric populations.

Application of tDCS in the Paediatric Population

When considering the application of transcranial Direct Current Stimulation (tDCS) in neurodevelopmental disorders and paediatric populations, here are some key points to consider:

• Developmental Plasticity: The developing brain in childhood is believed to be more plastic than the adult brain. This heightened plasticity may amplify the effects of plasticity-inducing interventions, especially during sensitive developmental periods.
• Stimulation Intensity and Duration: The smaller head size of children and adolescents may result in a stronger electrical field for the same stimulation intensity than in adults. Therefore, stimulation intensity may need to be adjusted downwards in children to achieve effects similar to those in adults. Higher stimulation intensities also modulate areas beyond the target electrode, potentially leading to unintended impacts on clinical symptoms.
• Polarity-Specific Effects: Cathodal tDCS, which typically has excitability-diminishing effects in adults, may have excitatory effects in children and adolescents. This conversion of after-effects might be beneficial in children, mainly when targeting hypo-active prefrontal regions. However, if an excitability-diminishing effect is undesirable, extracephalic positioning of the return electrode may be advantageous.
• Electrode Size: Smaller electrodes can achieve the desired current density at the brain level with lower current intensity and higher focality. This is particularly relevant in paediatric populations due to the smaller head size compared to adults. The distance between electrodes should be sufficient to minimise current shunting through the skin.
• Ethical and Practical Challenges: There are significant ethical and practical challenges regarding applying tDCS in paediatrics, including the relatively small number of available studies. Additionally, the availability of tDCS and similar devices for purchase online raises concerns about the proper application with necessary regulatory authorisation, which could have severe adverse health consequences. Further systematic investigation is warranted to address these challenges and refine the application of tDCS in paediatric populations.

Application of taVNS in the Paediatric Population

The field of transcutaneous auricular vagus nerve stimulation (taVNS) has seen increasing research interest over the past two decades, particularly in its potential applications for paediatric populations. However, several important considerations and precautions need to be addressed before taVNS can be widely used in paediatric therapeutic interventions:

• Establishment of Reliable Biomarkers: There is a need to establish more reliable biomarkers of taVNS effectiveness, particularly in establishing a causal link between taVNS and increased vagal activity. While some noradrenergic-related activities and parasympathetic functions have been proposed as potential indicators of effective vagus nerve stimulation, inconsistent results have been reported. Further optimisation of stimulation sites and parameters is necessary to enhance treatment efficacy.
• Investigation of Long-Term and Acute Effects: Both the long-term and acute effects of taVNS should be carefully investigated, especially for translational purposes. Understanding potential long-term effects in clinical conditions is essential for optimising individualised treatment approaches.
• Focus on Specific Clinical Conditions: Focusing on specific clinical conditions can benefit treatment procedures and outcome measurements, which may help validate the beneficial effects of taVNS techniques more effectively.
• More Preclinical Evidence: More preclinical evidence is needed on the effects of taVNS, specifically in paediatric populations, as most current studies have been conducted in adult populations.
• Investigation of Side Effects in Paediatric Populations: Randomised clinical trials are needed to investigate the application and potential side effects of taVNS in young children with neurodevelopmental and psychiatric disorders. While some studies have reported no adverse events during treatment, more research is urgently needed.

In summary, early intervention is crucial for improving the quality of life for children with neurodevelopmental or psychiatric disorders. There is considerable evidence supporting the effectiveness of early therapeutic intervention, particularly for neurodevelopmental disorders, given the high capacity for brain plasticity and developmental changes during this stage [138]. Travis shows promise as a non-invasive adjunctive treatment targeting specific behavioural manifestations in paediatric neurodevelopmental and psychiatric disorders [139]. However, standardised stimulation protocols must be established to optimise its effectiveness, including stimulation region and parameters.

The comprehensive exploration of neuromodulation interventions in paediatric neurological disorders reveals a landscape rich with scientific advancements and promising therapeutic possibilities [11]. Over the years, the transition from rudimentary electrical stimulation to contemporary techniques like TMS, tDCS and taVNS reflects the evolving sophistication of neuromodulation approaches [140]. This review highlights the potential of neuromodulation interventions to address these disorders' specific challenges, offering targeted and individualised solutions. Examining efficacy, safety, and long-term outcomes in specific disorders contributes valuable insights for clinicians and researchers, guiding evidence-based practices in paediatric neurological care.

Challenges inherent to neuromodulation, including ethical considerations, demand careful attention. As the field advances, the review underscores the need for personalised approaches, ongoing safety assessments, and a deeper understanding of the ethical implications associated with these interventions, particularly in the vulnerable paediatric population [137,142-147]. The future trajectory of neuromodulation in paediatric neurological care holds promise. The contemplation of potential breakthroughs and evolving paradigms suggests a dynamic landscape with ongoing advancements and refinements. As technology and our understanding of neurobiology progress, the field is poised to contribute novel solutions to the complex challenges posed by paediatric neurological disorders (141,18].

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