Effect of Precision-based HD-tDCS Over Conventional HD-tDCS in Young-onset Mania: Protocol for an Active Comparison fMRI and TMS Study

Abstract

Background:

As more accurate neuromodulation systems combining high-resolution electroencephalogram (EEG) and anatomical biomarkers develop, it is prudent to evaluate how refined and effective precision neuromodulation is compared to conventional techniques. Considering the growing incidence and the lack of studies outlining an optimal treatment approach, which often leads to a poorer prognosis, young-onset mania presents an ideal challenge for such a comparison.

Novelty:

This study aims to be the first to directly compare precision and conventional neuromodulation in child and adolescent populations. It also seeks to study and compare, for the first time, changes in neuroimaging parameters caused by precision and conventional techniques. By correlating perturbation-induced changes in cortical inhibition paradigms and functional connectivity of cerebral circuits, we aim to introduce a more objective measure of therapeutic efficacy and response, as opposed to relying solely on subjective clinical scales. Furthermore, we aim to study, for the first time, task-based differential activation of brain areas in young-onset mania.

Methods:

Participants would be randomly allocated to the intervention group 1 (G1) or the active control treatment group 2 (G2). Baseline assessments of both groups will include evaluations using clinical scales (Clinical Global Impression [CGI], Brief Psychiatric Rating Scale-Child [BPRS], Young Mania Rating Scale [YMRS], Barratt’s Impulsivity Scale [BIS], and Affectivity Reactivity Index [ARI]), task-based and resting-state functional magnetic resonance imaging (rs-fMRI), and transcranial magnetic stimulation (TMS)-based cortical inhibition paradigms (cortical silent period [CSP], short interval intracortical inhibition [SICI], and long interval intracortical inhibition [LICI]).

 G1 would receive precision-based high-definition transcranial direct current stimulation (HD-tDCS) over the right ventromedial prefrontal cortex (VMPFC) daily for 10 days with 2 sessions spaced 4 h apart. G2 would receive conventional HD-tDCS over the right VMPFC daily for 10 days with sessions spaced 4 h apart.

 Participants would undergo reassessment at 2 weeks following the completion of 20 sessions, using scales, task-based and rs-fMRI, and cortical inhibition paradigms, as well as at 6 weeks. Data would be analyzed using the Statistical Package for the Social Sciences (SPSS) for outcome variables as defined for the study. The primary outcome variable would be the improvement in the severity of young-onset mania, as measured by YMRS and CGI scale scores, using precision over conventional HD-tDCS. The secondary outcome would be an improvement in functional connectivity, as measured by neuroimaging, and enhancement of cortical inhibition, as measured by cortical inhibition paradigms, in young-onset mania after receiving adjunctive precision over conventional HD-tDCS.

Conclusions:

This study protocol aims to explore the effect of novel precision-based HD-tDCS in young-onset mania compared to conventional HD-tDCS, thereby allowing for the examination of precision neuromodulation in young-onset mania.

Key Message:

Pioneer of comparison between conventional and precision neuromodulation in young-onset mania using neuroimaging and cortical biomarkers to refine precision psychiatry.

According to the National Mental Health Survey 2015–2016, more than 14% of childhood and adolescent age groups experience mental health conditions, resulting in a disproportionately high risk of mental illness. Young-onset mania is one such growing problem, with approximately 1 in every 100 youths currently being affected. ¹ There has been an increase in the incidence of mania among the adolescent population from 79.21 per 100,000 in 1990 to 84.97 per 100,000 in 2019. ²

The onset of bipolar disorder has a peak during the adolescent age group, attributed to neural changes occurring during the maturation of the nervous system. Younger age of onset of symptoms is associated with a greater risk of recurrence even when under medication. ³ Younger-onset bipolar disorder is often misdiagnosed, leading to inappropriate treatment and contributing to treatment resistance in later life. ⁴ Even with the presence of approved pharmacological options in adult bipolar disorder, children suffer from partial effectiveness and higher levels of resistance and side effects on these medications, culminating in an increased burden and over-reliance on medications. ⁴ These challenges highlight the rationale for exploring effective and adjunctive treatment options.

Various studies have concluded that derangements in structural and functional connectivity between different brain areas during the formative years lead to the onset of mania.^5,6 Amongst cortical structures, the ventral prefrontal cortex is of specific interest for its role in regulating emotion. Circuits connecting the left amygdala to the right ventromedial prefrontal cortex (VMPFC) are characteristically affected in patients with mania, making this circuit a probable location for neuromodulation. ⁷ Enhancing VMPFC activity through neuromodulation techniques such as transcranial direct current stimulation (tDCS) has been shown to reduce aggressiveness and emotional dysregulation, highlighting its role in mania. ⁸

Non-invasive neuromodulation alters the connectivity of such circuits through plasticity, thereby attenuating mania. Neuromodulation allows differential modulation of both hyperactive and hypoactive locations of the brain in mania. In comparison to invasive brain stimulation, non-invasive neuromodulation offers a better safety profile, making it feasible for younger age groups. Several neuromodulation techniques have thus been used in the treatment of mania. Two of them, namely, transcranial magnetic stimulation (TMS) and tDCS, are undergoing the most active investigation. Both techniques share a capacity to modulate regional cortical excitability and are well-tolerated by the young age group. ⁹ tDCS has shown potential to mitigate manic symptoms effectively. However, these findings are preliminary and are based on the adult population. Studies such as those conducted by Schestatsky et al. reported a mean improvement in Young Mania Rating Scale (YMRS) scores by using a bifrontal montage, reinforcing the therapeutic promise of tDCS in mania. ¹⁰ tDCS has also been proposed to engage pre-fronto-cerebellar circuits implicated in mood regulation by targeting sleep abnormalities. This approach has been found effective in reducing the risk of relapse, mitigating treatment resistance, and thereby improving long-term outcomes. ¹¹ Though lowering relapse risk is not directly related to efficacy in acute mania, the review shows a range of existing benefits of tDCS on mania, and further provides a proof-of-concept for the intervention. Also, tDCS neuromodulation is driven by a favorable safety profile, lower operation cost, and fairly reproducible effects on the cortex. ¹² However, its major limitation is relatively poor spatial precision. High-definition tDCS (HD-tDCS) addresses this limitation by employing a compact, circumscribed ring electrode system that enhances focality. This improved focality enables more precise and safer stimulation with low current, thereby enhancing the safety of the procedure. ¹² It would thereby be easier to access and modulate deeper areas of the brain, such as MPFC, with greater precision via HD-tDCS. ¹³ HD-tDCS has been safely used in a wide range of psychiatric conditions with promising results in terms of safety. In post-traumatic stress disorder (PTSD), cathodal HD-tDCS targeted at the right lateral temporal cortex has been shown to improve PTSD symptoms significantly. ¹⁴ Similarly, in late-life depression, HD-tDCS led to a marked reduction of Hamilton Rating Scale for Depression (HAM-D) scores and baseline apathy. ¹⁵ Also, in patients with obsessive-compulsive disorder co-morbid with mood symptoms, HD-tDCS led to substantial symptom reduction without inducing affective destabilization during early treatment phases. ¹⁶

The role of inhibitory deficits linked to impaired activity of gamma-aminobutyric acid cortical interneurons in mania is well documented. ¹⁷ With this pathology being evident, it would be prudent to explore cortical inhibition to quantify the severity of inhibition deficits and also the severity of the manic episode. However, there is a lack of studies that explore such objective parameters. This study will, for the first time, explore the role of long interval intracortical inhibition (LICI), short interval intracortical inhibition (SICI), and cortical silent period (CSP) in predicting the course, severity, and response of mania to intervention.

The course of mania and its clinical severity are suggestive of the fact that the origin of this disorder lies in the derangement of functional connectivity. Studies have detected regional brain activation abnormalities via task-based functional magnetic resonance imaging (fMRI), which have normalized with the treatment of mania in adults.^18,19 Resting-state fMRI (rs-fMRI) studies performed in young-onset mania observed derangement in functional connectivity in the default mode network, a major neuronal network consisting of various components of the prefrontal cortex, mainly the VMPFC. ²⁰ However, there is a lack of task-based neuroimaging studies in young-onset mania, which is otherwise a better biomarker for quantifying the severity of mania.

Rationale and Novelty for the Study

Apart from the poorer natural course of the disease, several gaps exist in research regarding the condition. Considering longer duration of illness, higher severity profile, and modestly growing incidence of young-onset mania, there is an urgent need for exploring safer and effective augmenting options such as neuromodulation to conventional pharmacological management.^21,22

Even though precision in neuromodulation is being achieved, no studies are comparing the efficacy of precision over conventional neuromodulation, especially in young-onset severe mental illness. The primary rationale for this study is to address this research gap by comparing the effect of precision neuromodulation with conventional neuromodulation.

Novelty

The study will address the need for an objective method of studying the severity and response of mania and other mental illnesses in the young. Changes in neuroimaging parameters are considered superior markers of response in mania as compared to clinical markers. ²³ Since the pathophysiology of mania includes alteration of neural connectivity in the brain, neuroimaging plays an important role in assessing treatment response. Although task-based brain activity has been studied extensively and also proposed as a biomarker of severe mental illness in adults, there is a lack of studies regarding the same in younger age groups.

The study will study electrophysiological markers of cortical inhibition, exploring its role in severity and response in young-onset mania, which in turn are robust objective biomarkers of severe mental illness.

Objectives of the Study

The study has the following objectives.

1. To compare the change in psychopathology in patients with young-onset mania after receiving precision-based HD-tDCS as compared to conventional HD-tDCS.

2. To measure a change in fMRI-based BOLD activation and functional connectivity in patients of young-onset mania after receiving precision-based HD-tDCS as compared to conventional HD-tDCS.

3. To compare the changes in cortical inhibition parameters as measured by TMS paradigms in patients with young-onset mania on receiving precision-based HD-tDCS over conventional HD-tDCS.

4. To assess the association of treatment-emergent changes in patients of young-onset mania receiving precision-based HD-tDCS with changes in biological markers, psychopathological, and clinical variables.

Materials and Methods

Ethical Consideration

The study was approved by the Institutional Ethics Committee before submission, with approval number IEC/CIP/2024-25/56.

Aim

The study aims to assess whether adjunctive precision-based HD-tDCS on the right VMPFC is effective in managing young-onset mania and whether it leads to changes in neuroimaging or cortical inhibition biomarkers.

Study Setting

The study would be conducted at the Cognitive Neuroscience unit of Central Institute of Psychiatry, Ranchi, which is equipped with the facilities of HD-tDCS, TMS, and fMRI.

Study Design

The study would be a prospective, hospital-based, active comparator intervention study.

Study Population and Sample Size

The sample size for the study, as the total sample size calculated by using G*Power version 3.1.9.4 with alpha (α) error being 0.05 and power (1-β) being 0.9, was attained at 36. Considering a 10% standard rate of attrition for the study, a sample size of 40 would be chosen. The total sample would be divided into 2 groups, with 20 participants receiving precision-based HD-tDCS and 20 receiving conventional HD-tDCS stimulation. These participants will receive neuromodulation as an adjunct to their pharmacotherapy. The dosage of psychotropic medications will be kept stable till the reassessment at 2 weeks.

Sampling and Allocation Method

The type of sampling used would be purposive forward sampling with random allocation. All participants meeting the inclusion criteria would be randomly assigned to groups (G1 receiving intervention group, high-resolution precision-based HD-tDCS, and G2 active control group receiving conventional HD-tDCS).

The procedure would involve a series of sealed envelopes, which would be assigned to groups, and the envelopes would be opened only immediately before the commencement of the neuromodulation session. The patients and raters (independent observers) would be blinded to the treatment, but the clinicians administering the tDCS would be aware of the treatment group. To maintain transparency and avoid bias, clinicians administering the intervention will not participate in routine clinical care, academic rounds, and discussions concerning participants enrolled in the study.

Inclusion Criteria for Subjects

1. Diagnosis of bipolar type I disorder (6A60) with current episode manic according to the International Classification of Diseases, 11th Revision (ICD-11). ²⁴

2. The age of onset of mania is less than 18 years of age, belonging to either sex.

3. The patient’s current age is between 10 and 20 years.

4. Written informed assent or consent on behalf of participant, parents, guardians, or caregivers as applicable.

Exclusion Criteria for Subjects

1. Presence of any other co-morbid psychiatric or neurological disorders.

2. History of major medical illness.

3. History of epilepsy, sustained brain damage, or any neurological procedures.

4. Subjects who have received electroconvulsive therapy or repetitive TMS in the past 6 months.

5. Developmental delay or intellectual disability.

6. Any contraindication to undergoing fMRI, TMS, or HD-tDCS.

7. Mixed episodes of depression and mania measured as a score of >6 on HAM-D.

8. Any other co-morbid conditions other than mania as detected on Mini International Neuropsychiatric Interview for Children and Adolescents (MINI-KID version 7.0.2).

Description of Tools for Assessment

Informed Bilingual Consent and Patients’ Instruction Form

Participants will be informed about the entire procedure. They would be given relevant instructions, and informed consent would be taken.

Socio-demographic and Clinical Data Sheet

This datasheet would be used to collect basic social and demographic information about participants via a pre-designed format. It shall include:

Demographic information includes age, gender, marital status, religion, educational status, occupation, socio-economic status, and family type.

Medical information such as history of presenting illness, past medical and psychiatric illness, family history of psychiatric illness, and pre-morbid personality.

Significant physical examination findings.

Mental status examination.

Clinical Global Impressions (CGI) Scale ²⁵

The CGI-S is rated on a 7-point scale, with the severity of illness scale using a range of responses from 1 (normal) to 7 (amongst the most severely ill patients). Treatment response ratings should take into account both therapeutic efficacy and treatment-related adverse events and range from 0 (marked improvement and no side effects) to 4 (unchanged or worse, and side effects outweigh the therapeutic effects). Each component of the CGI is rated separately; the instrument does not yield a global score. The CGI is considered a valid and reliable clinical outcome measure suitable for routine use. ²⁶ The CGI has been used to validate several other clinical rating instruments and to establish cut-off values for severity as well as benchmark ranges for change. The CGI is useful in situations where change over time is to be assessed.

Handedness Preference Schedule ²⁷

The Hindi version of this tool would be used to collect information regarding which hand of the participant is dominant. ²⁷ The schedule has 15 activities rated from 1 to 5, where scores will be assigned based on the preference of the side of the hand to perform a task. It is a self-reported questionnaire.

Brief Psychiatric Rating Scale-Child (BPRS) ²⁸

Brief Psychiatric Rating Scale-Child (BPRS) is a scale developed for measuring and rating psychopathology and provides a concise description of a range of child and adolescent psychopathology. ²⁸ It is commonly used in trials, medical practice, and research. It is an indispensable instrument for assessing childhood mental disorders. The scale consists of 21 items, which the interviewer asks the participating child or adolescent and their parents to complete.

Young Mania Rating Scale (YMRS) ²⁹

The YMRS is the most widely used tool for clinically quantifying mania. The scale has a total of 11 items, which are known to be the common clinical symptoms of mania. Four items, namely, disruptive behavior, irritability, speech rate and amount, and thought content, are marked higher with a range from 0 to 8 as compared to others being marked from 0 to 4. The Cronbach’s α coefficient for the scale for all items is 0.89.

Hamilton Depression Rating Scale (HAM-D) ³⁰

The HAM-D Scale is one of the most widely used depression assessment tools developed with an emphasis on melancholia and depression. Currently, the 17-item scale is used instead of the 21-item scale, as the last 4 items in the conventional scale were not considered significant parameters for the severity of depression. The scores on the HAM-D may range from 0 to 54, with 6 being the cut-off for the presence of depression. Scores of 7–17 indicate mild depression, 18–24 indicate moderate depression, and more than 24 is indicative of severe depression. HAM-D has been effectively used to assess, compare results, and track changes in the severity of depression in individuals as young as 13 years. ³¹ Thus, we conclude that even though not ideal for the lower age group, HAM-D is an optimal option for this age range.

MINI-KID Version 7.0.2. ³²

The MINI-KID is a compact, structured diagnostic interview based on the diagnostic criteria provided in the Diagnostic and Statistical Manual of Mental Disorders (DSM) and ICD for children and adolescents. The standard version assesses the 30 most common and clinically relevant diagnoses in the young age group, or disorder subtypes in child and adolescent mental health. This interview will be significant in ruling out any other co-morbid states that are frequently present with ADHD.

Barrat’s Impulsivity Scale (BIS 11) ³³

The Barratt’s Impulsivity Scale (BIS) is a tool to measure the severity of impulsivity. It is a 30-item self-report measure. These 30 items are rated on a Likert scale, which has the range of 1 (rarely/never) to 4 (almost always). The scores of each such item will be summed to obtain the total level of impulsivity. The range of this scale is from 30 to 120, with higher scores indicating greater impulsivity.

Affectivity Reactivity Index (ARI) Scale ³⁴

The Affectivity Reactivity Index (ARI) scale primarily measures and rates the irritability of the respondent over the last 6 months. It thus indicates chronic irritability. The scale consists of 6 symptom items and one impairment item of irritability. The individual items will be scored on a range of 0 to 2, and the impairment item will be measured separately. The scale was designed to examine various aspects of irritability, such as the threshold for anger, frequency of angry behavior, and duration of anger persistence.

Magnetic Resonance Imaging (MRI) Feasibility Checklist

This checklist contains all contraindications for MRI scans, which include implanted orthopedic implants, pacemakers, deep brain stimulation coils, and cochlear devices, among others. This checklist will be provided to all study participants. In the event of any contraindications for MRI, participants will not be recruited for the study.

Ishihara Color Plates Test ³⁵

The Ishihara color plates or cards will be used to assess color perception disorders, such as deuteranopia and red-green color deficiencies. The test involves viewing several colored plates or cards, known as Ishihara plates. Each of these plates contains many circles of dots, which are randomized in terms of their color or their size. These dots collectively form a shape that is visible to individuals with intact color vision. However, for those with a color vision perception deficiency, these dots may appear invisible or challenging to perceive. In total, the test consists of 38 plates.

Magnetic Resonance Imaging (MRI) (3T INGENIA)

INGENIA, a 3T MRI machine developed by Philips, would be used for the functional neuroimaging aspect of this study.

fMRI is a functional neuroimaging technique that defines activity in the healthy and pathological states of the brain. BOLD fMRI can detect local increases in the relative concentration of oxyhemoglobin in blood. Oxygenation of blood is considered to be a direct consequence of neuronal activity and the action of neurotransmitters. ³⁶ This technique allows localizing brain areas with volumes of the order of a few cubic millimeters with accuracy. ³⁷ Due to the functional localization of a particular brain area, an activation map of the brain may be generated, thereby detecting anatomical correlates of mental disorders. ³⁸

The 2 primary testing designs utilized in fMRI are the block design and event-related design. Block design involves alternating blocks of activity (or a paradigm) with periods of inactivity or alternative activity. Due to its widespread use, it is the predominant study design employed in clinical fMRI. A paradigm refers to a stimulus experienced by the patient, crafted to evoke a particular cortical response. A variety of paradigms, ranging in complexity, have been created. In clinical settings, 4 paradigms are typically utilized, adapted as needed for specific clinical contexts: Visual, motor, speech, and memory paradigms. A block design paradigm generated from the color Stroop task in the task-based fMRI will be used in this study.

Emotional Stroop Task ³⁹

The Stroop Color and Word Test (SCWT), a widely used psychological assessment, serves both experimental and clinical purposes by evaluating the capacity to suppress cognitive interference. Initially introduced by Stroop in 1935, this test requires participants to read 3 distinct tables swiftly. ⁴⁰ Two tables present a “congruous condition,” where participants read color words in black ink (W) and name color patches (C). This setup challenges individuals to perform a less automated task (identifying ink color) while inhibiting interference from a more automated task, exemplifying the Stroop effect. While primarily used to assess inhibition of cognitive interference, its versatility extends to measuring attention, processing speed, cognitive flexibility, and working memory. Thus, the SCWT holds promise for assessing multiple cognitive functions simultaneously. The emotional Stroop effect is a variant of the Stroop task where the viewed carrier words convey specific emotions. There is a longer delay in naming emotional words than neutral words. The emotional carrier words may be chosen to meet a tested pathology.

GTEN 200 Neuromodulation Research System

The Geodesic Transcranial Electrical Neuromodulation System (GTEN) 200 integrates high-definition electroencephalogram (EEG) and neuromodulation capabilities within a single platform. Utilizing a 256-channel HydroCel Geodesic Sensor Net (HCGSN), this device records brain electrical activity while simultaneously modulating it, eliminating the need for additional equipment. Enhanced by high-resolution head modeling, the system ensures more consistent neuromodulation and precise localization of cortical sources. Offering various modalities of tDCS, GTEN leverages the reciprocity theorem, where a source’s scalp voltage projection mirrors the stimulation pattern required for modulation. This principle, combined with GTEN’s advanced MR-based head models, enhances source localization and modulates outcomes by optimizing current targeting accuracy and minimizing off-target activation. GTEN 200 supports both automatic montage selection, employing algorithms to determine the optimal electrode montage for stimulating specific cortical regions, and manual montage selection, providing flexibility for researchers.

HD-tDCS is a technically enhanced version of tDCS, giving more focal stimulation and predictable effects. HD-tDCS is used in a ring-like fashion in a 13-electrode configuration. The 4*1 ring-shaped configuration has been mainly studied. Depending on the type of stimulation, it can be either cathodal, that is, inhibitory, or anodal, that is, excitatory.

HD-tDCS Feasibility Checklist ⁴¹

The feasibility of a participant undergoing HD-tDCS will be assessed by examining various factors, as outlined in the checklist. The checklist would include factors such as the number of treatment sessions previously attended by each participant, dropouts in previous studies, and the participant’s willingness to undergo the intervention. The feasibility is calculated on a rating scale ranging from “not at all willing” (0) to “very willing.” ¹⁰

HD-tDCS Side-effect Checklist ⁴²

Eryilmaz and colleagues developed a checklist comprising 13 side effects, rated categorically based on their occurrence during and after HD-tDCS. ³¹ Ratings range from 0 (none) to 5 (very severe). The listed items include numbness, redness, itching, burning, and pain at the stimulation site, nausea, sleep disturbances, fatigue, inability to concentrate, mood changes, and changes in visual perception.

Screening 13-item Questionnaire for TMS Candidates ⁴³

This screening questionnaire for TMS comprises a 13-item standard questionnaire administered to all candidates before undergoing TMS. The updated guidelines address the safety concerns of conventional TMS protocols, as well as the risks associated with emerging TMS interventions.

It is unanimously agreed that an affirmative response to one or more questions in the questionnaire did not disqualify an individual from receiving TMS. Instead, the treating physician should carefully balance the risk-to-benefit ratio for each patient.

The Magstim TMS apparatus with electromyography and CED 1902 amplifier.

The Magstim TMS apparatus would be used to deliver TMS pulses via 70 mm figure-of-8 coils for measuring cortical excitability in our study. TMS works on the principle of inducing magnetic fields within the brain for neuromodulation. Electricity passing through the TMS coil creates a proportional magnetic field around it. The dynamic magnetic field induces low-amplitude electric currents (Eddy currents) in the brain. ⁴⁴ If the magnetic field applied to the brain tissue is of sufficient strength, it leads to the depolarization of neurons within this field. TMS may be used as a non-invasive modality to examine inhibitory circuits of the human cortex with excellent temporal resolution. ⁴⁵ Thus, in the current study, it is being used to detect the pre- and post-inhibitory intracortical paradigms to assess the efficacy of intervention.

Procedure for Data Collection

Recruitment

Individuals diagnosed with Bipolar I Disorder, current episode manic as per the ICD-11 criteria, ²⁴ and with an onset of symptoms before age 18, providing consent and thus meeting inclusion criteria and not meeting exclusion criteria, will undergo initial screening using a socio-demographic datasheet, handedness preference scale, after obtaining informed consent. Participants would be randomly allocated to either the intervention (G1) or active control treatment (G2) group using the envelope technique.

Assessments

Baseline Assessments

Baseline assessments of both groups will include evaluations using clinical scales, task-based and rs-fMRI, and cortical inhibition paradigms such as CSP, SICI, and LICI. The clinical scales would consist of:

Clinical Global Impressions (CGI) scale ²⁵

Brief Psychiatric Rating Scale-Child (BPRS) ²⁸

Young Mania Rating Scale (YMRS) ²⁹

Barrat’s Impulsivity Scale (BIS 11) ³³

Affectivity Reactivity Index (ARI) scale ³⁴

The interventional group (G1) would receive precision-based HD-tDCS daily for a duration of 10 days with sessions spaced approximately 4 h apart. The active control group (G2) would receive conventional HD-tDCS daily for a duration of 10 days, with sessions spaced at least 4 h apart. In case of any adverse effects, the intervention will be discontinued with immediate effect. The in-patient status of the participant would ensure adherence to the intervention.

High-resolution Precision HD-tDCS Procedure (Intervention Group)

The study intervention consists of administering 20 sessions of high-resolution precision HD-tDCS using the GTEN200 neuromodulation system, targeting the right VMPFC. Electrodes from the HCGSN would be used for stimulation based on the equidistant placement system after creating individual head models. Six circular Ag/AgCl PiStim high-definition electrodes (1 cm radius, p cm²) would be used, applied with conductive gel to transmit currents.

In each session, the experimental group would receive an active stimulation with a 2-mA current for 20 min to the right-sided VMPFC. The electrodes would be placed on the surface of the scalp corresponding to the anatomical location of VMPFC. Two sessions would be conducted daily with approximately a 3-h gap between them, over 10 consecutive days. Each session would commence once the patient transitions from routinely administered rescue injectables during admission to primarily oral pharmacotherapy, thereby mitigating any interventional bias.

Conventional HD-tDCS Procedure (Active Comparison Group)

The control group would receive 20 sessions of conventional HD-tDCS, administered to the right VMPFC without using EEG-based localization. Electrodes from the HCGSN would be used for stimulation based on the equidistant placement system after creating individual head models. Six circular Ag/AgCl PiStim high-definition electrodes (1 cm radius, p cm²) would be used, applied with conductive gel to transmit currents. In each session, the control group would receive an active stimulation with a 2-mA current for 20 min to the right-sided VMPFC.

Two sessions would be conducted daily with approximately a 3-h gap between them over 10 consecutive days. Each session would commence once the patient transitions from routinely administered rescue injectables during admission to primarily oral pharmacotherapy, thereby mitigating any interventional bias.

Functional Magnetic Resonance Imaging (fMRI) Procedure

The participants will undergo the following fMRI assessments

Structural Magnetic Resonance Imaging (MRI) Scan

Structural scans would be performed with the parameters of echo time (TE) = 3.4 ms, repetition time, repetition time (TR) = 7.4 ms, FA = 8°, field of view (FOV) = 250 × 250 × 181, matrix = 228 × 228, voxel size = 1.1 × 1.1 × 1.2, scan duration = 4 min 59 s, slice thickness = 0.9 mm). Three-dimensional T1-weighted structural images would thus be acquired to rule out any organic lesions.

Resting-state Functional Magnetic Resonance Imaging (rs-fMRI)

The rs-fMRI would assess the functional connectivity status of different brain regions. A gradient echo planar imaging (EPI) sequence would be used to collect neuroimaging information. The EPI sequence includes specific parameters such as a scan time of 512 s, echo TE of 35 ms, TR of 2025 ms, a flip angle of 90 °, a FOV measuring 220 × 220 × 152 millimeters, a matrix size of 72 × 69, comprising 38 slices with no interslice gap. A total of 250 dynamic scans will be performed. Participants would be instructed to maintain a state of rest but avoid falling asleep during the scanning procedure.

Emotional Stroop Task-based Functional Magnetic Resonance Imaging (fMRI)

A computerized version of the emotional Stroop task would be administered to the participant using E-Prime software. The task would be presented using a block design paradigm, which consists of a total of 9 blocks, each lasting 30 s. Four of these blocks would contain congruent and incongruent color names, while the remaining 5 blocks would serve as rest periods during which the participant would focus on a fixation cross. The active and rest blocks would alternate in sequence.

For the task-based fMRI data acquisition, the following parameters would be utilized: Scan duration of 282 s, TE of 35 ms, repetition time (TR) of 3,000 ms, flip angle of 90 °, FOV dimensions of 231 × 231 × 125 mm, matrix size of 96 × 96, 30 slices with no slice gap. A total of 90 dynamic scans will be acquired.

The emotional Stroop task-based fMRI would be used to study task-based activation of a particular brain area.

Procedure for Measuring Cortical Inhibition Parameters

After connecting the Electromyography (EMG) apparatus to the first dorsal interosseous (FDI) muscle to detect any motor response, such as contraction, the TMS apparatus would be utilized to administer pulses through 70 mm figure-of-8 coils, positioned tangentially over the specific region of the left motor cortex responsible for hand motor activity control. Once identified, this area will be stimulated to induce a resting motor threshold (RMT) and a suprathreshold motor evoked potential (MEP) with an amplitude of 1 mV (SI_1mV).

Measuring the Cortical Silent Period

To measure the CSP, 10 suprathreshold test pulses (SI_1mV) would be consecutively administered at 5-s intervals over the left motor cortex. At the same time, the patient squeezes a softball to maintain an isotonically contracted state in the right FDI. CSP will be defined as the time taken by the cortex to return from the SI_1mV offset period to voluntary motor activity, measured by EMG.

Measuring Short Interval Intracortical Inhibition (SICI)

The SICI paradigm will be assessed by delivering paired pulses via the TMS apparatus. Two pulses, a subthreshold conditioning pulse, with amplitude set at 80% of the RMT, followed by a suprathreshold test pulse (SI_1mV), will be delivered at an interval of 3 ms.

Measuring Long Interval Intracortical Inhibition (LICI)

The LICI paradigm will be assessed by delivering paired pulses via the TMS apparatus. Two pulses, a suprathreshold conditioning pulse (SI_1mV) followed by a suprathreshold test pulse (SI_1mV), would be delivered at an interval of 100 ms. Additionally, a separate recording of MEP with SI_1mV will be obtained, and both SICI and LICI will be expressed as proportions of the test MEP.

Further Assessments

Participants would undergo reassessment at 2 weeks post-baseline, following completion of 20 treatment sessions, using clinical scales, task-based paradigms, rs-fMRI, and cortical inhibition paradigms, as well as at 6 weeks. Figure 1 describes the procedure of data collection. At the end of the 6-week assessment, further treatment for the participants will be decided by the hospital’s treating team.

Figure 1.

Flowchart of the Sequence of Procedure.

Standard Protocol Items: The recommendations for interventional trials (SPIRIT 2013) have been followed for reporting the trial protocol. The checklist is available as “Supplementary Online Material.”

Outcomes

Primary Outcome Variable

Improvement of symptoms and severity of young-onset mania, as measured by YMRS, CGI, BPRS, BIS 11, and ARI scores after receiving adjunctive precision-based HD-tDCS. CGI

Secondary Outcome Variable

Improvement of functional connectivity, as measured by neuroimaging, and enhancement of cortical inhibition as measured by cortical inhibition paradigms in young-onset mania after receiving adjunctive precision-based HD-tDCS.

Magnetic Resonance Imaging (MRI) Analysis

The study involves collecting fMRI rest and Stroop task-based data. The task-based BOLD data would be subjected to quality control checks by denoising the data via pre-existing pipelines. Following this, the data would be processed by using the CONN functional connectivity toolbox, version 22a (CONN v.22a), and Statistical Parametric Mapping (SPM) software. A seed-based Region of Interest (ROI) approach will be adopted. The processed data will be analyzed using the general linear framework (GLM), a framework in SPM that models the relationship between Stroop blocks and observed cortical activation (detected via BOLD) on a voxel-by-voxel basis. GLM will provide 2 activation maps: The beta maps (which show the total magnitude of activation) and the contrast maps (which show the task-specific effects or intervention group-specific effects). After the contrast maps are obtained, a 2-level analysis will be conducted. The first-level analysis will compare activation (via contrast maps) in emotional conditions over neutral conditions. The second will be a group-level analysis. In this, independent sample t-tests will be applied to compare the change in activation between the 2 intervention groups. Furthermore, paired t-tests will be used to compare activation at baseline with that of the second week. Correction for multiple comparisons will be done using false discovery rate corrections.

Statistical Analysis

The obtained results will be collected using an Excel sheet and analyzed using the Statistical Package for the Social Sciences (SPSS) version 29.0 for Windows, with various parametric and nonparametric measures applied where applicable.

Descriptive statistics such as the arithmetic mean, standard deviation, and percentage will be used to describe characteristics of the study sample. Socio-demographic and clinical scale data will be compared using the chi-square test for categorical variables and the independent t-test for continuous data as applicable. Effect size and statistical power will be further assessed by using partial eta squared proportion with a value of more than 0.5 to be categorized as large, 0.2–0.5 as moderate, and less than 0.2 as mild effect sizes, respectively. The α value measured will be crucial in determining the power of the test, and only outcomes with values less than 0.05 will be considered significant and interpreted. The scores of the CGI, BPRS, YMRS, BIS 11, and ARI scales, which will be collected at baseline, 2 weeks, and 6 weeks, will be compared using t-tests. Further scores on the CGI, BPRS, YMRS, BIS 11, and ARI scales obtained in the intervention group and active control group will also be compared using a t-test. Missing data will be managed using the “last observation carried forward” method.

Timeline

Data collection will start in April 2025 and will continue until March 2026.

Discussion

Young-onset mania, apart from the rising incidence, is linked to earlier onset age in mania is linked to more severe, psychotic symptoms, higher risk of rapid cycling, poor treatment adherence, and poorer prognosis. ⁶ The role of neuromodulation in mitigating this severe mental illness is becoming more prominent. With the advent of high-resolution precision-based neuromodulation, more focus and a better safety profile can be achieved compared to conventional methods. This study aims to compare, for the first time, the efficacy of anatomical precision-based neuromodulation (precision HD-tDCS) with that of conventional high-definition neuromodulation (conventional HD-tDCS) in young-onset mania. The purpose of this study is to advance the application of precision and personalized neuromodulation, thereby enhancing the efficacy of novel approaches in addressing therapeutic challenges in mental illnesses. Apart from this, the use of neuroimaging indicators (emotional Stroop task-based fMRI) and cortical inhibition parameters (generated via investigational TMS) will aim to improve the objectivity of classifying severity and identifying response in mania.

The limitations of the protocol, however, are the accessibility of high-end neuromodulatory devices, which hinders the reproducibility of the study, the existence of confounders such as the influence of pubertal hormones and developmental variation in the maturation of fronto-limbic circuits, and the limited sample size, which may lead to overreporting the role of the intervention.

Conclusion

This study protocol aims to explore the effect of novel precision-based HD-tDCS in young-onset mania compared to conventional HD-tDCS, thereby allowing for the examination of precision neuromodulation in young-onset mania. The outcomes of this study will investigate the differences in efficacy between precision neuromodulation and conventional high-definition neuromodulation. It also examines objective electrophysiological and neuroimaging parameters. These parameters have the potential to be considered as a marker for assessing the severity and response of mania to neuromodulation.

Supplemental Material

Supplemental material for this article available online.

Supplemental Material

Supplemental material for this article available online.