Abstract
Attention Deficit Hyperactivity Disorder (ADHD) is a neurodevelopment disorder which causes inattention, hyperactivity, or impulsivity, that directly leads to the learning disability. The conventional ADHD assessment method such as behavioural rating scale requires long term behavior observation and subjective interpretation which may lead to misleading result. Over the past decades, there have been exponential growth in the research in biomedical engineering perspective such as Electroencephalograph (EEG), Magnetic Resonance Imaging (MRI) and electrodermal responding to identify accurate and objective measurements in ADHD assessment. Nevertheless, a clear definitive picture which link neuropsychological, behavioral, and neurophysiological research has yet to develop. The purpose of this study is to investigate ADHD in children aged from 7 to 14 years old at primary schools in Malaysia using Electro Interstitial Scan (EIS) technology which based on chronoamperometry technique. There are total of 182 children data have been collected, which consist of 58 ADHD children (study group) and 124 healthy children (control group). All subjects will undergo EIS measurement and the SPSS statistical analysis was conducted on the primary and secondary EIS parameters to identify significant level in differentiating ADHD and non-ADHD children. The statistical analysis result shows that EIS system reflects significant difference between control group and study group for both primary parameters (EIS channels 1, 2, 3, 4, 9, 10, 15, 16, 17 and 18) and secondary parameters (brain and neurotransmitter related parameters) (p < 0.05). This study concludes that EIS system has good potential in providing a new measurable marker to complement the conventional assessment of ADHD as confirmatory decision support system.
Abstract
Attention deficit hyperactivity disorder (ADHD), chronoamperometry, electro interstitial scan (EIS), electrosomatograph (ESG), neurodevelopment disorders.

3.5 million children are on ADHD medication. The ratio of male to female with ADHD is approximately 2:1 [1] . There is also an increasing amount of literature supporting that ADHD is a chronic health problem due to the persistence of impairment into adulthood that will increase the risk of long-term morbidity if undertreated [4] , [5] . It has been reported that about 30-50% who is diagnosed with ADHD in childhood will not have decline of symptoms and found to persist into adulthood which could contribute to social issue in public community, directly or indirectly [4] , [6] . As a result, a precise, appropriate and early screening or assessment of ADHD is extremely important to avoid the late diagnosis and to enable early effective treatments and therapies after onset of serious symptoms.

Conventional approaches to the assessment of neurodevelopmental disorders such as behavioral rating scales or biomedical instruments present certain limitations and challenges in assessing ADHD accurately [7] [8] [9] [10] . For instance, behavioral rating scales are lack of published psychometric properties [10] and absence of age and gender specific normative [11] [12] [13] . Biomedical engineering approaches such as magnetic resonance imaging (MRI), computed tomography (CT) scan and electroencephalograph (EEG) are still lacking in replicated findings that prove their accuracy as biomarkers for assessing ADHD in clinical settings due to the existence of heterogeneity in ADHD [14] . There is still discrepancy between the advanced biomedical engineering approaches with the psychiatric assessments to diagnose ADHD [11] [12] [13] [14] [15] [16] [17] [18] . As a result, there are continuous efforts by researchers in refining the accuracy of ADHD assessment in order to implement a novel system for objective and quantitative ADHD measurement [15] [16] [17] .

The Electro Interstitial Scan system is a non-invasive assessment tool based on chronoamperometry method which measure and interprets electrical potential membrane activity and the ionic concentration of intercellular liquid (interstitial fluid) locally in the body by applying a harmless low voltage direct current (DC) from electrodes. This paper presents the feasibility study of using EIS system in assessing ADHD in children aged from 7-14 years old. It is aimed to discover a novel ADHD assessment method based on objective and quantitative biomarker as a complementary decision support system of conventional subjective psychiatric test. This study is conducted based on the following hypothesis:

1. Among the 22 channels that generated by the three EIS electrode pairs for voltage transverse, the channel that related with head electrode which voltage transverse through the brain area, such as channel 1, 2, 3, 4, 9, 10, 15, 16, 17 and 18 shall show the significant difference between control group (healthy children) and study group (ADHD children) (p < 0.05). 2. As the ADHD is closely related with the alteration in certain regions of the brain, hence the EIS measurement shall display significance difference in one or more of those secondary EIS brain parameters, in terms of temporal lobe, amydgala, limbic zone (hippocampus), hypophyseal, intracranial vessels, frontal lobe of the cortex and hypothalamic area, between control group (healthy children) and study group (ADHD children) (p < 0.05). 3. As one the significant symptom of the ADHD is hyperactive, the secondary parameter of interstitial dopamine and serotonin of EIS neurotransmitter analysis shall show the significant difference between control group (normal healthy children) and study group (ADHD children) (p < 0.05).
II. RELATED WORK
A broad spectrum of biomedical engineering approaches and psychiatric assessment such as EEG, MRI and CT scan, as well as psychiatric assessments such as Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V) and International Classification of Diseases 10th Revision (ICD-10) have been researched to diagnose and assess ADHD in a more objective manner than previously adopted. Several studies have revealed that ADHD is characterized by an elevated theta/beta ratio (TBR) which is an inattentiveness index in ADHD evaluation, that appears to be a significant biomarker for the EEG-based diagnosis of ADHD, though this finding remains controversial [18] , [19] . It is due to the reason that EEG is a complex and chaotic signal, which does not produce reliable results to facilitate the diagnosis of ADHD. There is still a dearth of robust evidence to prove its accuracy in clinical settings due to existence of heterogeneity in ADHD. In July 2013, the Food and Drug Administration (FDA) approved an EEG Neuropsychiatric EEG-Based Assessment Aid (NEBA) system based on the TBR as an assessment aid to integrate with conventional ADHD evaluations. It serves as the confirmatory support, by means of improving the accuracy of ADHD diagnosis, though this system should not be used as a stand-alone assessment tool of ADHD evaluation [20] .
II. RELATED WORK
ADHD potentially has a close relationship with the volumetric brain measurements obtained via MRI scan. Several MRI neuroimaging studies show a trend toward structural alterations, primarily in the accumbens, amygdala, caudate, hippocampus, putamen and intracranial volume [15] , whereas no changes have been observed in the thalamus, pallidum [16] , and globus pallidus [21] . These structural brain differences seem to become less significant as children with ADHD growth and mature into adults [16] , [17] . However, this approach remains underdeveloped, and is currently characterized by a few non-replicated studies. In addition to that, MRI neuroimaging is also considered as a cost expensive assessment compared to other assessment like EEG and psychiatric test.
II. RELATED WORK
The DSM-V serves as a psychiatric classification and diagnostic tool which widely been used by universal authority. The DSM-V findings provide instructions, scoring information, and interpretation guidelines that later been used to enhance clinical decision-making and not as the sole basis for making a clinical ADHD diagnosis [2] . DSM-V assessment in ADHD children is complicated, time consuming and no definitive method [22] . Thus over-diagnose or underdiagnose may happen, which eventually leading mistreated especially among the young age children and even college students [12] , [14] .
II. RELATED WORK
Despite the positive and negative findings thus far, biomedical engineering approaches have made notable progress pertaining to the assessment of ADHD over the past few decades. With respect to future studies regarding the application of biomedical engineering methods to ADHD diagnosis, the brain regions of interest shall include the frontoparietal network which supports goal-oriented executive functions, the subcortical regions which regulate emotions, and the ventral attention network which aids in sustaining attention. The synergistic effects of conventional ADHD psychiatric assessment and biomedical engineering approaches can help to better explain the heterogeneity present in ADHD.
II. RELATED WORK
The working principle of electrodermal activity scan is measuring the resistance of the skin towards electrical stimulant, it is known as electrical potential of the eccrine sweat gland. It has been widely used in prediction of diagnosis and prompt treatment response and provides an opportunity for improving efficiency of intervention. The examples of electrodermal activity scan are such as electrodermal responding (EDR) and eletro interstitial scan (EIS). For EIS system, aside from being non-invasive and cost-effective, it is also simple to operate. In comparison with conventional ADHD children assessment method, EIS system has the advantage of providing more immediate and quantitative output. Previous work done by Caudal et al. has concluded that the conductivity measurements of the forehead pathway achieved 98% specificity and 80% sensitivity to differentiate ADHD from control group using EIS system [14] . There is another study conducted by Hau et al. using EIS system has observed that ADHD subjects tend to have significant variation between left and right frontal lobe comparing to normal healthy subjects. These literatures prove that the EIS system is useful in screening ADHD as confirmatory decision support system.
III. ELECTRO INTERSTITIAL SCAN BASED ON CHRONOAMPEROMETRY TECHNIQUE
The EIS device is a non-invasive investigation tool for the entire human body functions by measuring electrochemical skin conductance through the eccrine sweat ducts based on chronoamperometry analysis. Chronoamperometry is an electrochemical technique in which the potential of the working electrode is stepped and the resulting current from faradaic processes occurring at the electrode is monitored as a function of time. Eccrine sweat ducts are tubular glands which rich in supply of blood vessels and sympathetic cholinergic nerve fibres. The distribution of eccrine glands covers a density of 500-600cm 2 over the palms of the hands and soles of the feet and 180/cm 2 on the forehead [23] . Figure 1 shows the steps of the direct current transfer from active electrode to passive electrode. Steps of the current transfer from anode to cathode and then from cathode to anode for each pathway.
Steps 1 and 2 (Entrance of the Current From the Active Electrodes):
A low-voltage current 1.28v is applied at the active electrodes through the eccrine sweat ducts, which represents the physiological pathway of the interstitial fluid, i.e. the source of the eccrine sweat. This will attract chloride ions from the sweat ducts which are highly concentrated on the palms and feet. At voltages less than 10V, the stratum corneum is electrically insulating and the voltage is not able to penetrate through, only sweat-gland ducts are conductive.
Steps 1 and 2 (Entrance of the Current From the Active Electrodes):
Step 3 (Pathway Into the Human Body Between the two Electrodes): According to Fricke's circuit, the plasma membrane will act as an insulator and DC is not be able to penetrate the cell alternatively it will pass through the interstitial fluid space whereas AC is able to penetrate the cell membrane. With external electrical stimulation, free ions will conduct a current in the interstitial fluid because the biological tissue is considered as an ionic conductor. The total ionic conductance of a solution is relying on the concentration, activity, charge, and mobility of all free ions in the solution. The ionic concentration is proportional to the ratio of intensity and voltage, as the ionic concentration increases, more intensity and less voltage are observed.
Steps 1 and 2 (Entrance of the Current From the Active Electrodes):
Steps 4, 5, and 6 (Process of the Exit of the Current to the Passive Electrodes): The electrical stimulation from the electrodes causes released of sweat response. The mechanical response initiated by shear stress causes a phosphorylation cascade that removes phosphate groups from proteins and kinases, and activate endothelial Nitric Oxide (NO) synthase. Production of NO facilitates the release of cyclic guanosine monophosphate, and a change in potassium permeability.
Steps 1 and 2 (Entrance of the Current From the Active Electrodes):
In a subject with normal sweat function, healthy sweat glands possess high amount of innervation and microvascularate. Activation of these small nerve fibres cause chloride ions to be secreted by sweat glands and released on the surface of the skin. The DC current created an electrochemical reaction extract chloride ion from the sweat ducts. At this low voltage, the stratum corneum acts as a capacitor and only allow the transmission of ions from the sweat ducts.
Steps 1 and 2 (Entrance of the Current From the Active Electrodes):
Step 7: (Electrochemical reactions on the passive electrode (electrolysis)): In the interstitial fluid of human body, Na + represents 96% of the positive ions, while Cl − and HCO 3 − represent 96% of the negative free ions. The interstitial fluid VOLUME 7, 2019 acts as an electrolytic solution of Na + and Cl − however HCO 3 − and Na + ions may not be discharged and they do not work on the DC current transfer. The in vitro electrochemical model described below is applicable for the Cl − ions at the anode only.
Steps 1 and 2 (Entrance of the Current From the Active Electrodes):
A. AT THE CATHODE Na + ions are not discharged at the cathode as sodium is less electropositive hence it requires more energy and a large negative voltage on the cathode to impose electrons on Na + ions. At lower voltage, dissolved oxygen is reduced and water molecules are decomposed. When the voltage supply is adjusted (>1V), oxygen reduction is performed. The water electrochemical reaction (reduction) at the cathode is
B. AT THE ANODE
The current at the anode is due to the discharge of Cl − ions. Chloride possesses strong electropositive property, thus less energy is required for taking electrons from the chloride ions than from water molecules. The water electrochemical reaction (oxidation) at the anode is 2H 2 
B. AT THE ANODE
EIS measures the electrical potential membrane activity and the ionic concentration of the intercellular liquid (interstitial fluid) that located outside the membrane of the cell and not influenced by different chemical buffers such as blood as shown in Figure 2 . The ionic battery potential differences of relative inner negativity compared to outer positivity are created by the total electrochemical ionic equilibrium. The signal received from the electrodes analyse by the software to provide estimated parameters in interstitial fluid space which is sodium ion related to the Na+/K+ATPase pump activity.
B. AT THE ANODE
Theoretically, if direct current is applied, it will primarily pass through the interstitial fluid as shown in Figure 3 . On the other hand, if alternating current (AC) is injected, it will penetrate the cell membrane. Likewise, the EIS device introduces the low intensity nsmith@example.com DC of electrical signal that pass through the human body via 6 electrodes to assess human body function. Studies of AC bioimpedance analysis systems operating at 50 KHz or higher have revealed that these frequency AC electric currents flow non-selectively through both intracellular and extra cellular spaces and thus provide relatively non-specific information regarding the physical properties and chemical composition of body compartments. An approximately 16% of total body water consists of interstitial fluid. The interstitial space is the main pathway for the body substances include oxygen, carbon dioxide, glucose, as well as thousands of other compounds to pass through between the cells and the blood stream. The chemical composition of the interstitial fluid may reflect the physiology of nearby cells with delay no longer than 5 to 10 minutes. Since DC current will pass through the interstitial space during EIS measurement, any abnormality in the chemical composition of the interstitial fluid could be discovered. Figure 4 shows the Electro Interstitial Scan (EIS) system which is a non-invasive investigation tool for the entire human body that applied in this study. It comprises of an USB hardware, an interface box, 2 pieces of disposable electrodes, 4 pieces of reusable plates, and cables, with an acquisition and analysis software installed on a computer. A subject under study will be connected to the EIS system via 6 electrodes. The six electrodes are placed on the skin with two in contact on the forehead, two on the palms, and two in contact on the feet, with red electrode on t he left side of body and black electrode on the right side of body, respectively. The electrodes for the palms and feet are 250cm 2 and made of stainless steel. While the single-use electrodes of forehead are at the size of 15.75 cm 2 and made of Ag/AgCl.
B. AT THE ANODE
The Electro Interstitial Scan (EIS) system applies a low and harmless 1.28V DC alternately between 6 electrodes on the left and right of forehead, palms and feet symmetrically throughout the body to assess organ functional state, as shown in Table I . The full cycle of EIS scan comprises of 22 conductance measurements through the 11 pathways alternating in the polarity of anode and cathode (in 1 second) and in the polarity of cathode and anode (in 1 second)reflecting some aspect of the physical and chemical properties of the interstitial fluid space. For instance, channel 1 is measures the conductivity from left forehead electrode to left palm electrode whereas channel 2 measures the conductivity from left palm electrode to left forehead electrode. The full cycle of EIS scan completes in 3 to 4 minutes to complete measurement of total 22 channels as shown in Table I .
B. AT THE ANODE
The EIS system indexed the measured conductivity, millivolt (mV) correspond to absolute value −100 to +100. The conductivity is transmitted in numeric form for each pathway to a computer program which transforms the value into conductivity entered on a graph. This graph of 22 pathways is called an electrosomatogram (ESG) [14] , [24] . The EIS system will generate comprehensive results which demonstrate in primary parameters and secondary parameters with its proprietary algorithm. The primary parameters are defined as 22 channels of Normal parameters (C1 to C22 Na) and another 22 channels of Automatic parameters (C1 to C22 Aa). Na is an empirically-derived coefficient determined according relatively to age, gender, weight and height which have been registered during preliminary process. It corresponds to functional norms of optimal concentration of the interstitial space. Aa is calculated according to individual's metabolism relative to the mean electrical resistance of cell membranes or their permeability. This will demonstrate the relationship between electrical membrane conductivity and ionic concentration of the interstitial space [25] .
B. AT THE ANODE
The secondary parameters are derived from the primary parameter based on proprietary algorithm and they are useful to assess overall body risks, overall body function, brain, heart, bone, dermatomes, neurotransmitter analysis, dental and lymph nodes chain. In this study, only brain and neurotransmitter parameter will be the main focus to determine its significance in differentiating ADHD and healthy children. The brain parameters include frontal lobes, temporal lobes, limbic systems, amygdala, intracanial vessels, hypophyseal and hypothalamic. The neurotransmitter parameters include serotonin and dopamine.
IV. METHODOLOGY
In order to conduct data collection using the EIS device at primary schools in Malaysia, it is compulsory to obtain ethical approvals from (15)) to conduct data acquisition at all primary schools in Malaysia.
IV. METHODOLOGY
According to regulation of MOH, it is required to prepare Participant Information Sheet (PIS) and Informed Consent Form (ICF) for the subjects to consent to participate in data collection. Participant Information Sheet (PIS) is a document that provides detailed information of the research mainly to enlighten the parents/guardian or teacher on the process and risks of this study. PIS will include the purpose of this study, procedures of data collection, potential risks and side effects and data protection property with this study. The parents/guardian or teacher are obliged to fully understand this study prior to enrolment to avoid any unwanted consequences. Agreement to participate in this study must follow by completing the Informed Consent Form (ICF). ICF is required to fill in and consented by parents/guardian or teacher.
IV. METHODOLOGY
The subjects are divided to two groups, which are control group and study group. The control group is healthy children aged between 7 to 12 years old recruited from normal stream primary school children in Malaysia with no history of mental disorder and preferably excellent in academic performance. The study group is children aged between 7 to 14 years old who have been diagnosed with ADHD by health care practitioners prior to this study recruited from school who offered special education in Malaysia. Children were excluded if, in the opinion of the investigator, a child was clinically not suitable as a candidate for the study; or if there were contraindications in the use of the EIS system. The contraindications included but not limited to pre-existing dermatological issues (skin allergy or lesions), metallic pins or prostheses in digits or joints, absence of a limb, inability to sit still for 4 minutes, in the presence of defibrillators, implanted with electronic device or connected to electronic life support devices.
IV. METHODOLOGY
Both groups of children are required to undergo EIS measurement as detail procedure described below:
IV. METHODOLOGY
1. Subject registration. The investigator will register the personal information of the subject into the EIS system, e.g. gender, date of birth, weight, and height. 2. The subject is requested to be barefooted. Any metal object or crystal ornament which is in contact with the body must be removed. 3. The EIS hand and foot electrode metal plates will be disinfected with alcohol swabs and left to dry up. 4. Any cream or makeup on the forehead are removed with alcohol swab before placing the electrodes on the forehead. The feet and palms are cleaned with alcohol wipes, and then air-dried. 5. The measurement is measured with the patient in a seated position as shown in Figure 4 . Put the feet and hands flat on the metal plates without excessive pressure. The EIS measurement takes 3 to 4 minutes to complete. 6. In case the ADHD subject is having features of fidgeting, moving around or poor attention which causing the EIS measurement failed, then the subject will be retested when the condition is stable, up to maximum of 3 measurements. If the test is failed after 3 attempts, the subjects will be replaced with a new participant. 7. The subject should not move excessively, especially do not detach the feet and hands with the metal plates, as well as pull off the head electrode while taking the EIS measurement.
IV. METHODOLOGY
Upon completion of data collection, SPSS statistical analysis was conducted to determine the significance level of chosen EIS primary and secondary parameter in differentiating ADHD or non-ADHD children. The entire datasets were tested on Shapiro-Wilk normality test. Independent t-test was selected if both compared parameters were in normal distribution, whereas Mann-Whitney U-test was preferred if either one of the compared parameters was not normally distributed. The EIS datasets were analyzed thoroughly to observe if there is any significant difference between study and control group, and hence determine the significant parameter.
V. RESULTS

After the data collection, the composition of the two groups was:
Study Group: 58 ADHD children (mean age: 10 years old; 11 females and 48 males).
After the data collection, the composition of the two groups was:
Control Group: 124 non-ADHD children (mean age: 10.2 years old; 69 females and 55 males). Table II illustrates the analysis results of the primary parameters of 22 channels between the study and control groups. It shows the normality test results, the means and the significance level of the test (P value). The findings in Table II indicates the mean of channels 1, 2, 3, 4, 9, 10, 11, 15, 16, 17 and 18 show significant difference in both Na and Aa parameters (p < 0.05). The main interests in this study are channels 9 and 10, which are the conductivity measurements of two pathways between the forehead electrodes (from left forehead to right forehead, and vice versa) that show significant differences between control and study group (p < 0.05). A Mann-Whitney U Test indicated that parameter A Mann-Whitney U Test indicated that parameter C15Aa between control group (M = 39.04) and study group (M = 15.74) show significant differences (Mann-Whitney U = 2614.50, p = 0.003 (<0.05)); C15Na between control group Table III illustrates the analysis results of the secondary parameters such as brain and neurotransmitters parameters between the study and control groups. It shows the normality test results, the means and the significance level of the test (P value). The key observation in secondary parameters such as frontal lobe, temporal lobe and limbic system show significant differences between control and study group (p < 0.05). A Mann-Whitney U Test indicated that the right frontal The region which is commonly corresponds to channel 1, 2, 3, 4, 9, 10, 15, 16, 17 and 18 is the limbic system in the brain. The primary structures within the limbic system include hypothalamus, thalamus, amygdala, basal ganglia (caudate, putamen, and globus pallidus) and hippocampus [26] . The application of EIS in limbic system parameters able to differentiate significantly between ADHD and non-ADHD subjects of as concluded by several findings in this study. This finding is justified by Mann-Whitney U Test which indicated that the right limbic system between control group (M = −7.31) and study group (M = −26.02) show significant differences (Mann-Whitney U = 2539.50, p = 0.001 (<0.05)); and the left limbic between control group (M = −9.37) and study group (M = −23.33) also show significant differences (Mann-Whitney U = 2790.50, p = 0.015 (<0.05)). To prove this further, the left and right amygdala findings also show significant differences in assessing control and study group. A Mann-Whitney U Test which indicated that the right amygdala for control group (M = 7.10) and study group (M = 26.02) show significant differences (Mann-Whitney U = 2526.50, p = 0.001 (<0.05)); as well as left amygdala for control group (M = 9.30) and study group (M = 23.33) show significant differences (Mann-Whitney U = 2789.50, p = 0.015 (<0.05)).
After the data collection, the composition of the two groups was:
One explanation for the three subtypes of ADHD is that patients have different levels of neurotransmitters, which alter their behaviour. The neurotransmitters related secondary parameters, dopamine and serotonin levels are found varied in ADHD and non-ADHD subjects in this study. A Mann-Whitney U Test which indicated that the serotonin between control group (M = 1.96) and study group (M = −2.5) show significant differences (Mann-Whitney U = 2833.00, p = 0.018 (<0.05)); as well as dopamine between control group (M = −2.82) and study group (M = 4.65) show significant differences (Mann-Whitney U = 2594.00, p = 0.002 (<0.05)) in ADHD and non-ADHD subjects.
VI. DISCUSSIONS
There has been an exponential growth in the literature on various medical imaging and signal processing approaches, such as EEG, MRI, and CT Scan for identifying accurate and objective measurements in the diagnosis of ADHD. A wealth of biomedical engineering evidence exists to support the underlying causes of ADHD are likely to be associated with the alteration in certain regions of the brain [14] , [27] , [28] . The common alteration observed in ADHD subjects are frontal lobe, temporal lobe, limbic system, hypothalamus, hypophyseal and altered dopamine neurotransmission [15] , [17] , [29] .
VI. DISCUSSIONS
In this study, it is concluded that the primary parameters at forehead pathway (channels 9 and 10) which scan through the frontal lobe were significantly dissimilar between study and control group. The variation of C9Aa mean measurement between control (−20.31) and study group (−35.71) was −15.4 and C9Na mean measurement between control (−30.97) and study group (−45.9) was −14.93. While the variation of mean measurement for C10Aa between control (−24.53) and study group (−36.29) was −11.76 and C10Na mean measurement between control (−31.24) and study group (−42.19) was −10.95. Caudal et al. who used the similar EIS approach to assess ADHD subjects reported the conductivity measurements at forehead pathway was higher in ADHD subjects (33.11mS) comparing to control group (2.75mS) [14] .
VI. DISCUSSIONS
In an EEG study by Allahverdy et al., EEG signals were recorded based on the international 10-20 system and unipolar montage. It reported an accuracy of 86% on frontal lobe in differentiate ADHD from control [30] . This is in line with abnormalities observed in a separate fMRI study which measure variation in brain activity, oxygen level concentration, and neuronal connectivity of functional brain regions reported decreased blood flow in fronto-striatal and frontal regions [28] . Left precentral and postcentral cortical in frontal lobes have shown altered distribution of the curvature of vertices whereby curvature reflects density and arrangement of neuronal cells. The alteration of frontal lobe in ADHD subjects is further refined by another voxel-based morphometry studies which reduced grey matter in the motor and premotor cortices has been reported. It is alleged to have correlation with impairment of frontal circuits as concluded in neuropsychological findings [31] . These observations can be further justified with the finding on secondary EIS parameter of this study which demonstrated conductivity differences in the right frontal lobe of the control (M = 4.98) and study group (M = −7.41), and the left frontal lobe of the control (M = 9.68) and study group (M = −5.83).
VI. DISCUSSIONS
The core executive functions are response inhibition, interference control, decision making, motor performance working memory and cognitive flexibility. ADHD characteristics such as deficit in executive functions are closely associated with alteration in frontal lobes. Impairment of response inhibition is the cardinal feature of ADHD wherein it is controlled by the precentral and postcentral cortical areas, prefrontal cortex and caudate nucleus on the frontal lobes [7] , [32] . The dorsal anterior midcingulate cortex (daMCC), dorsolateral prefrontal cortex (DLPFC), parietal cortex, striatum and premotor cortex which are located on the frontal lobes make possible of decision making, selective attention and implementation. The significant difference found in primary parameters, channels C9Na, C9Aa, 10Na and 10Aa and secondary parameter frontal lobe.
VI. DISCUSSIONS
Besides, the conductivity of the temporal lobe expresses significant differences in comparison of study and control group as observed from channel 1, 2, 3, 4, 15, 16, 17, 18. This finding is consistent with alteration of left temporal lobe as noticed in another MRI study by Sun et al. which authors commented a reduction in size of the anterior temporal lobes along with an increased density of grey matter in posterior temporal cortices [7] . Additionally, temporal lobe presented high classification accuracy to distinguish ADHD with control group [33] . The temporal lobes integrate information from lower-order sensory to higher-order perceptual systems used to guide the control of attention and execution/inhibition [7] . It also process both verbal and nonverbal memory [26] . Thus, short attention span and excessive distractibility in ADHD can be correlated with abnormal findings in temporal lobe through chronoamperometry technique using EIS device in this study.
VI. DISCUSSIONS
Another significant finding has been observed in this study is changes in limbic system in ADHD group as demonstrated in channel 1, 2, 3, 4, 15, 16, 17 and 18 and secondary parameters. Limbic system combines higher mental functions and primitive emotion into one system. The primary structures within the limbic system include hypothalamus, thalamus, amygdala, basal ganglia (caudate, putamen, and globus pallidus) and hippocampus [26] .
VI. DISCUSSIONS
The most recent robust cross-sectional mega-analysis with largest dataset to date was conducted by the Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) ADHD Working Group and was intended to investigate brain structural deficiencies in ADHD subjects. The samples comprised 1713 ADHD subjects and 1529 control subjects from 23 sites. Structural T1-weighted MRI brain scans with harmonised protocols were compared between the subjects with and without ADHD. The study observed that participants with ADHD had smaller volumes for several regions of the brain, including the limbic system (amygdala, hippocampus, basal ganglia), accumbens, and intracranial volume, with more profound effects showing in childhood [16] . Another consistent finding for ADHD patients included the presence of reduced volumes in the putamen and caudate [17] , [34] . Several literatures also revealed persistent abnormalities and delayed maturation or degeneration of the subcortical brain volumes in ADHD [17] , [34] , [35] . Dysfunction of the limbic system in the ADHD subjects can be observed in mega-analysis by Hoogman et al. as they presented differences when compare with the non-ADHD subjects. Likewise, the analysis result in this EIS study demonstrated differences in the limbic system between ADHD and control group which could be observed from channels 1, 2, 3, 4, 15, 16, 17 and 18. Referring to literature on the brain, the prominent role of the amygdala is emotional regulation and aggressive behaviors, and thus, dysfunction of the amygdala may lead to difficulties in the recognition of emotional stimuli, high levels of callous and restricted reactions to pleasant stimuli [36] , [37] . A deviation of the amygdala volume may also be associated with the property of hyperactivity. In addition, the functions of the hippocampus are long-term memory and emotional control, which were found to be deficient in ADHD patients from previous literature [38] . Evidence shows that the accumbens and caudate support the reward system of the brain, which could be related to the motivational and emotional dysfunction present in ADHD patients [39] .
VI. DISCUSSIONS
Furthermore, dopamine is a neurohormone that is produced and released by limbic system too [40] . There are studies have showed that lower levels of dopamine are associated with symptoms of ADHD. In ADHD subjects, the neurons in the brain and nervous system have higher concentrations of proteins called dopamine transporters (DAT) in ADHD subjects. These DAT temporarily prevent dopamine from going on to the next cell subsequently lessens the effects of dopamine. Altered dopamine neurotransmission is implicated in ADHD, a condition associated with impaired cognitive control, in turn leading to problems with regulating attention, inhibiting behaviors, achieving specific rewards and forgetting things [41] .
VI. DISCUSSIONS
In short, the brain and neurotransmitter related primary and secondary parameters in EIS system show convergence of result with the other neuroimaging, neurophysiology, genetics and neurochemistry biomedical engineering approaches in differentiating ADHD and non-ADHD children. This study has further improved from previous work as more in-depth comparison on brain and neurotransmitter related parameters were made to evidence EIS as a useful tool in ADHD assessment.
VII. CONCLUSION
The aim of this study was to identify a novel assessment with objective measurement based on quantitative marker to support the conventional assessment of ADHD in children. This study concluded that the EIS system reflect significant difference between control group (normal healthy children) and study group (ADHD children) in primary as well as secondary brain and neurotransmitter related channels. The statistical significant primary parameters are channels 1, 2, 3, 4, 9, 10, 15, 16, 17 and 18 whereas the secondary parameters are brain (frontal lobe, temporal lobe, limbic system, amygdala, intracanial, hypophyseal and hypothalamic) and neurotransmitter parameters in terms of serotonin and dopamine. One of the characteristics of ADHD is hyperactive, hence the interstitial dopamine level of EIS neurotransmitter analysis also show the significant difference between control group and study group. Hence, this research has further enhanced from previous work as in-depth comparison on brain and neurotransmitter related parameters were made to proof the feasibility of using EIS in ADHD assessment.
VII. CONCLUSION
The proposed method can address the issue of misleading diagnosis of ADHD in behavioral assessment method. With this EIS technology, it helps to diagnose ADHD at early stage hence prompt treatment could be delivered, as childhood development is the most fundamental and essential to lead the children to the correct learning pathway. EIS results has been anticipated to provide adequate cut off and introduce as a new marker as an adjunct to the conventional behavioral assessment of ADHD in future.
VII. CONCLUSION
The limitations of the study include scattered ADHD subjects in various locations due to limited ADHD subjects available for this study in each school hence separate trips had to be made to many different schools to gather sufficient data. A robust longitudinal study is required to further confirm the validity of the EIS system. EIS system is potential to be developed as a new, practical and reliable confirmatory support to conventional method to screen ADHD children.
VII. CONCLUSION
YUAN WEN HAU received the master's and Ph.D. degrees in electrical engineering from Universiti Teknologi Malaysia, in 2005 and 2009, respectively, where she is a Research Fellow and the Head of the cardiac informatics cluster with the IJN-UTM Cardiovascular Engineering Centre. She is also a Senior Lecturer with the School of Biomedical Engineering and Health Sciences, Faculty of Engineering, Universiti Teknologi Malaysia. She has published more than 50 articles in peer-reviewed international journals and conferences. She has also published several book chapters. Her research interest includes the design of multiprocessor systems-on-chip (MPSoC)/networks-on-chip (NoC) from electronic system level (ESL) to register transfer level (RTL) modeling and the implementation of field programmable gate arrays (FPGAs). Her research interests have also spread into the fields of cryptographic and data security applications, and biomedical applications such as arrhythmia classification, medical imaging processing, and attention-deficit/hyperactivity disorder (ADHD)/autism assessment.
VII. CONCLUSION
CHEW MING TIEW is a versatile homeopathic professional in child psychology. He has more than 20 years of clinical experience as well as over 17 years of accomplishments in enduring community service by establishing an organization and providing education to help those in need. He is a pioneer of homeopathic psychology with more than 20 years of experience in treating more than 4 000 children with mental disorders in his own clinic. Furthermore, he serves the community, especially children with mental disabilities by sheltering them in Persatuan Kebajikan Kanak-Kanak Istimewa Insan, which was founded, in 1998. He also established ANS SDN BHD. He is currently the sole lecturer for a course in homeology, which is a new subject that combines the principles of homeopathy and psychology to cultivate students in becoming ANS planners to aid themselves and others.
VII. CONCLUSION
WAN LEONG HAU received the Ph.D. degree in traditional Chinese medicine from the Nanjing University of Traditional Chinese Medicine, in 2013, and the master's degree in traditional Chinese medicine with the Fujian University of Traditional Chinese Medicine, in 1998. He was an Adjunct Professor with the Chinese Medical Institute of Sarawak, Malaysia, as well as INTI International University & Colleges. He has been a renowned professional Traditional Chinese Physician with Pusat Rawatan Homeopati Chen Chin, Johor, Malaysia, since 1995. He has been invited to be a Research Collaborator with the Faculty of Biosciences and Medical Engineering, Universiti Teknologi Malaysia. He is also the Founder of Jing Sen Traditional Chinese Medicine.

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