This study aimed to reveal how OROS-MPH treatment affects the brain complexity of children with ADHD using entropy-based QEEG analysis. The present study was the first to detect a significant decrease in the entropy level in the F4 region in boys with combined type ADHD undergoing OROS-MPH treatment using all three entropy analyses (ApEn, SampEn, and Perm En) at resting-state mode. In addition, a significant decrease in entropy level was found in the F3, P4, T3, T6, and O2 regions using the PermEn method. Considering the clinical implications of the reduction in resting entropy resulting from OROS-MPH treatment, two significant associations in the C3 and C4 regions were observed. First, the degree of decrease in entropy was moderately related to the overall severity of ADHD symptoms pre-treatment as well as to pre-treatment conduct disorder symptom cluster severity. The second clinical manifestation observed was that the percentage change in the severity of opposition as the symptom cluster was moderately reduced by the change in entropy.

Currently, MPH is the primary medication used in the pharmacological treatment of ADHD 2. Studies on MPH treatment in children with ADHD, supported by structural and functional imaging techniques, have shown that it normalizes the brain 27. One study reported that in untreated children with ADHD, cortical thickness, especially in the right motor cortex, inferior gyrus, and parieto-occipital regions, decreased compared to typically-developing children during the brain maturation process. A similar study showed that children with ADHD receiving MPH treatment underwent a “normalization” of grey matter volume, including putamen, insula, and cerebellum compared to control subjects with ADHD who were not treated 28. These studies can be divided into those investigating resting-state brain activation and those investigating task-related brain activation. Studies on the latter have identified specific areas of activation with MPH treatment in the parietal regions during tasks involving attention, error monitoring, and interference inhibition 29, in the inferior frontal cortex during selective attention and response inhibition 30, and in the striatum during tasks involving reward and response inhibition 31. Studies evaluating cognitive control in children with ADHD have shown that MPH improves the ability to inhibit inappropriate responses in favor of more appropriate ones by increasing activation in frontostriatal circuits, ultimately normalizing brain activation patterns and executive functions during the assessed tasks 29,32,33. Resting-state studies have focused on the default mode network (DMN), discovered in 2001 when certain brain regions were observed to deactivate during the performance of cognitive tasks and reactivate when tasks were not being performed 34. The default mode network is composed of the medial prefrontal cortex, posterior cingulate cortex, precuneus, and inferior temporal and parietal regions, which are activated during rest 34. DMN, which functions to expand cognitive capacity by deactivating during cognitive loading, is associated with thought processes independent of stimuli such as self-referencing, imagining the future, mentalizing, and reflecting on the past 27,34. The most consistent finding reported in studies on DMN in children with ADHD is the inadequacy of DMN deactivation during the performance of cognitive tasks 27,34–36. There is sufficient evidence to suggest that if the mind-wandering function of DMN is insufficiently deactivated during cognitive tasks, distractibility and impulsivity may result in children with ADHD and that increasing DMN deactivation may play a role in clinical improvements observed with MPH treatment 27,35,37. In light of all these data, treatment with MPH is revealed to impart a clear protective and normalizing effect on the brain. Positive structural and functional changes observed following MPH treatment, especially in the prefrontal cortex, as well as improvement in DMN deactivation during cognitive loading may be considered evidence of its normalizing effect. In the present study, the decrease in entropy observed in resting state activity, particularly in the frontal regions, in children with ADHD undergoing MPH treatment represents a novel contribution to the existing literature indicating that MPH normalizes the brain. To this end, elaboration of the concept of “entropy” will be necessary.

Entropy refers to the complexity, randomness, and disorder in a given system 38. Because the human brain is a complex non-linear system, neurophysiological signals obtained using EEG exhibit complex fluctuations both spatially and temporally, reflecting a non-linear dynamic process 39. Adapting the concept of entropy to EEG data by evaluating the chaos and uncertainty in EEG recordings using non-linear analysis therefore presents a number of potential benefits 9. Higher entropy levels indicate greater uncertainty and more chaotic signals; in this context, the region with higher entropy represents the more active region 7,14. Methods employing entropy analysis have been successfully applied in numerous areas, including assessment of consciousness and depth under anesthesia 40, predicting the likelihood of seizures 41, and evaluating the etiology, pathophysiology, treatment, and prognosis of psychopathologies 10. Although a literature review revealed few studies on children with ADHD employing non-linear analysis, their findings are intriguing. A study investigating the diagnostic value of functional near-infrared spectroscopy (fNIRS) using PermEn in drug-naive children with ADHD found that the PermEn values for the right dorsolateral prefrontal cortex were significantly higher in children with ADHD than in normal control subjects. The researchers interpreted this result as suggesting that conducting a complexity analysis of fNIRS signals could be a promising tool for diagnosing ADHD 13. Another study employing ApEn to identify a more successful method than classical linear analysis for separating ADHD patients and healthy control subjects found a significant decrease in entropy in regions indicated by the Fp1 and Fp2 channels. These low entropy levels detected in the prefrontal regions could explain the inadequate response to cognitive demands observed in children with ADHD 15. In a study investigating the diagnostic value of ApEn in children with ADHD, ApEn-related feature descriptors revealed higher rates for average true positive (0.846), average true negative (0.814), and average accuracy (0.817) compared with TBR-related feature descriptors 14. ApEn was thus more successful and promising in predicting ADHD than TBR, given that the latter is only approximately 50% accurate in predicting ADHD 42. A study conducted using the continuous performance test (CPT) found that the average ApEn of ADHD patients in the right frontal regions (Fp2 and F8) was significantly lower than in healthy control subjects 43. Based on the aforementioned findings, we may conclude that if an EEG signal is obtained during the performance of a cognitive task, the increase in entropy, which indicates activation, will be lower in children with ADHD than in control subjects. Similarly, if the EEG signal is obtained at resting-state mode, we may expect increased entropy compared to the controls, indicating increased DMN activity. In the present study, the decrease in entropy, especially in the frontal regions, detected under resting-state conditions in patients receiving MPH treatment, can be interpreted as reflecting MPH having normalized the increased DMN activity in children with ADHD compared to control subjects. Our finding that entropy changes were correlated with both pre-treatment general ADHD symptom severity and conduct disorder symptom cluster severity was also consistent with data reported in previous studies indicating that inadequate DMN deactivation in children with ADHD may be related to impulsivity.

The present study had several limitations. First, children with ADHD combined-type without comorbidities other than ODD might not accurately reflect the general population since ADHD is known to have a high comorbidity rate, thus restricting the generalization of our results. Another important limitation is the absence of a control group, which may lead to a deficiency in determining whether OROS-MPH treatment actually had a significant effect on the case group. Other limitations included a small sample size and the lack of blinding procedures for the clinicians. However, these limitations are balanced by the naturalistic prospective observational design and the use of semi-structured interviews with the clinical approval of two different experts in the diagnostic process, both of which may be considered strengths.

To the best knowledge of our knowledge, this is the first study employing entropy-based qEEG analysis to investigate how OROS-MPH treatment affects the brain complexity of children with ADHD. A significant decrease in entropy levels in the frontal region was detected in boys with combined type ADHD undergoing OROS-MPH treatment at resting-state mode. The changes in entropy correlated with pre-treatment general symptom severity of ADHD and conduct disorder symptom cluster severity.