A Case Study on EEG Analysis: Embedding Entropy Estimations Indicate the Decreased Neuro-Cortical Complexity Levels Mediated by Methylphenidate Treatment in Children With ADHD
CLINICAL EEG AND NEUROSCIENCE, cilt.53, sa.5, ss.406-417, 2022 (SCI-Expanded)
- Yayın Türü: Makale / Tam Makale
- Cilt numarası: 53 Sayı: 5
- Basım Tarihi: 2022
- Doi Numarası: 10.1177/15500594211064008
- Dergi Adı: CLINICAL EEG AND NEUROSCIENCE
- Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED)
- Sayfa Sayıları: ss.406-417
- Anahtar Kelimeler: attention deficit hyperactivity disorder, entropy, complexity, methylphenidate, qEEG, ATTENTION-DEFICIT/HYPERACTIVITY DISORDER, UNDERACTIVATION, METAANALYSIS, BOYS
- Açık Arşiv Koleksiyonu: AVESİS Açık Erişim Koleksiyonu
- Hacettepe Üniversitesi Adresli: Evet
Özet
https://pubmed.ncbi.nlm.nih.gov/34923863/
ABSTRACT
Objective: Complexity analysis is a method employed to understand the
activity of the brain. The effect of methylphenidate (MPH) treatment on
neuro-cortical complexity changes is still unknown. This study aimed to reveal
how MPH treatment affects the brain complexity of children with attention
deficit hyperactivity disorder (ADHD) using entropy-based quantitative EEG
analysis.
Method: Three embedding entropy approaches were applied to short segments
of both pre- and post- medication EEG series. EEG signals were recorded for 25
boys with combined type ADHD prior to the administration of MPH and at the end
of the first month of the treatment.
Results: In comparison to Approximate Entropy (ApEn) and Sample Entropy
(SampEn), Permutation Entropy (PermEn) provided the most sensitive estimations
in investigating the impact of MPH treatment. In detail, the considerable
decrease in EEG complexity levels were observed at six cortical regions (F3,
F4, P4, T3, T6, O2) with statistically significant level (p < .05). As well,
PermEn provided the most meaningful associations at central lobes as follows:
1) The largeness of EEG complexity levels was moderately related to the
severity of ADHD symptom detected at pre-treatment stage. 2) The percentage change
in the severity of opposition as the symptom cluster was moderately reduced by
the change in entropy.
Conclusion: A significant decrease in entropy levels in the frontal region
was detected in boys with combined type ADHD undergoing 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.
DISCUSSION
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.