Journal of Sleep Disorders: Treatment and CareISSN: 2325-9639

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Research Article, J Sleep Disor Treat Care Vol: 4 Issue: 1

EEG Morphology and Spectral Analysis in Attention Deficit/ Hyperactivity Disorder. Effect of Methylphenidate Treatment

Angel Molina-Leon1 and Angel Nuñez2*
1Clinical Neurophysiology Department, Complejo Hospitalario de Santa Lucía, Cartagena (Murcia), Spain
2Anatomy, Histology and Neuroscience Department and Research Institute, La Paz University Hospital (IDIPAZ), School of Medicine, Universidad Autonoma de Madrid (Madrid), Spain
Corresponding author :Angel Nuñez, Ph.D
Dept. Anatomia, Histología y Neurociencia. Fac. Medicina., Universidad Autonoma de Madrid, c/ Arzobispo Morcillo 4, 28029 Madrid, Spain
Tel: 34-91-207 3755; Fax: 34-91-397 5338
E-mail: [email protected]
Received: July 27, 2014 Accepted: November 12, 2014 Published: November 14, 2014
Citation: Molina-Leon A, Nuñez A (2015) EEG Morphology and Spectral Analysis in Attention Deficit/Hyperactivity Disorder. Effect of Methylphenidate Treatment. J Sleep Disor: Treat Care 4:1. doi:10.4172/2325-9639.1000148

Abstract

EEG Morphology and Spectral Analysis in Attention Deficit/ Hyperactivity Disorder. Effect of Methylphenidate Treatment

Introduction: Attention deficit/hyperactivity disorder (ADHD) is the most commonly diagnosed disorder in childhood. It has been described structural and functional abnormalities in the brain of these patients. However, the etiology of this disorder is still unknown. The aim of this study is to investigate cortical activity alterations in patients with attention Deficit Hyperactivity disorder (ADHD), that could help diagnose this pathology and monitor electrophysiological prognosis after medical treatment in order to improve the management of this disorder.

Keywords:

Keywords

ADHD; methylphenidate; Power spectra; Diagnostic; Treatment effect; Minimal cortical dysfunction

Introduction

Attention deficit/hyperactivity disorder (ADHD) is the most commonly diagnosed neurodevelopmental disorder in childhood (for recent reviews see [1,2], reaching 3-7% of Spanish childhood. The core symptoms of ADHD are inappropriate levels of inattention, impulsiveness, and hyperactivity [3]. In addition, children with ADHD often have comorbid motor coordination problems [4,5]. However, the etiology of this highly inhomogeneous disorder is still unknown. Structural and functional abnormalities in some brain regions might cause the inattention and hyperactivity of the patients with ADHD. Further analysis on their correlation with the clinical symptoms is still needed [6].
Structural magnetic resonance imaging (MRI) studies have detected approximately 4–5% overall cerebral and cerebellar volumetric reductions in children and adolescents with ADHD, compared to that of typically developing controls [7,8]. Also, white matter is reduced in the brainstem as well as a volumetric reduction of the pons, caudate nucleus and globus pallidus, which contain a high density of dopaminergic and noradrenergic neurons [9,10]. Moreover, functional magnetic resonance imaging (fMRI) studies have shown that ADHD patients reveal a reduction of frontal lobe activity, especially at the left medial frontal cortex during working memory tasks [11]. These results suggest that these patients have structural alteration of cortical neuronal networks.
The cingulo-fronto-parietal cognitive/attention network, including the frontostriatal and frontoparietal pathways, is thought to be the primary substrate for most attention and executive functions [2,12-14]. Accordingly, evoked potential studies have shown a positive wave peaking between 300 and 600 ms latency (P300) in frontal recordings that became maximal after novel stimuli in healthy subjects [15].
Although the use of stimulant medication is widespread, only about 70% of children with ADHD respond to pharmacological treatment [16]. Methylphenidate hydrochloride is commonly used in the treatment of patients with ADHD, and acts by increasing catecholamine levels, which in turn affect the reticular activating system, the limbic system and the prefrontal cortex, all of which are associated with attentional and inhibitory information processing [17-20].
The goal of this study is to investigate cortical activity alterations in patients with ADHD, that could help diagnose this pathology and monitor electrophysiological prognosis after medical treatment in order to improve the management of this disorder.

Methods

Participants
This study included 68 participants (21 girls, 31% and 47 boys, 69%) with an age range of 5-16 years and a mean age of 9.4 ± 0.7. All of studied patients had to meet diagnostic criteria for ADHD. Twelve unmedicated patients with ADHD (9.6 ± 0.9 years old; nine boys and three girls) and 56 (9.1 ± 0.5 years old; 41 boys and 15 girls) medicated subjects were recruited from the Department of Pediatrics (Hospital Santa Maria del Rosell, Cartagena, Spain). Participants or their parents gave written informed consents to the study protocol, approved by the Ethics Committee of the Hospital Santa Maria del Rosell. Children with ADHD were clinically assessed by a paediatrician and a psychologist using diagnostic criteria from the Diagnostic and Statistical Manual of Mental Disorders (DSM V; 21) and Assessment of Attention Deficit Hyperactivity Disorder Scale (EDAH; 22). Subjects were followed over time (at least 6 months) with repeated monitoring studies. Previous studies have indicated that ADHD patients are a heterogeneous population that may be classified in hyperactive/impulsive subjects, inattentive subjects or in combined subtype (1). Our subject population corresponded to the combined subtype. The medicated ADHD group took a methylphenidate as treatment for the disorder (mean=26 mg/day; range: 18-54 mg/day). Eight patients took methylphenidate for 3-6 months (mean= 5.6 ± 0.2 months) while 48 patients received methylphenidate for 1-3 years (mean= 2.5 ± 0.2 years). Current comorbidities with lifetime history of psychotic, bipolar or substance abuse disorders were excluded.
Additionally, 12 age-matched and healthy control subjects (mean 10.5 ± 0.8 years old; p=0.325 with respect to ADHD patients) participated in the study (four girls, 33% and eight boys, 67%). They had to meet the same exclusion criteria and did not suffer from ADHD. Participants underwent exploration/examination by clinical psychologists as detailed above.
EEG recording
We recorded the EEG in ADHD children with and without methylphenidate treatment, and compared them with control subjects of the same age range. We analysed EEG signals using a power spectrum analysis. EEG was recorded in an eyes-open or eyes-closed resting condition, with subjects seated on a reclining chair. Electrode placement followed the International 10–20 system, using an electrode cap. A linked mastoid reference was used with all EEG. Impedance was kept below 5 K Ω for all electrodes. The EEG recordings were amplified with a bandpass filter of 0.5–70 Hz, and sampled by an A/D converter with a sampling rate of 200 Hz on a digital polygraph, using EEG Portaview software (Nihon Kohden). Recording periods with eye movement or blink artefacts were excluded from further analysis.
EEG recordings were analysed from 18 scalp positions in a bipolar montage: Fp1-F3, F3-C3, C3-P3, P3-O1, Fp1-F7, F7-T3, T3-T5, T5- O1, Fp2-F4, F4-C4, C4-P4, P4-O2, Fp2-F8, F8-T4, T4-T6, T6-O2, Fz-Cz and Cz-Pz. The absolute power values were obtained through calculation of the fast Fourier transform (FFT) for each EEG channel. To reduce slow wave contamination from eye movement, the EEG derivations from Fp1 or Fp2 were not considered to power spectrum analysis. The power spectrum was calculated from 5 minutes of continuous EEG recording using Spike 2 software (Cambridge Electronic Design, UK) and the mean power of delta (0.5-4 Hz), theta (4-8 Hz), alpha (8-12 Hz) and beta (13-30 Hz) were determined. The percentage of each frequency band was calculated considering the sum of the power of all frequencies between 0.5-30 Hz as 100%.
To compare unmedicated against medicated ADHD subjects, the proportion of the power spectrum of these subjects was calculated with respect to control subjects’ values. The unmedicated (n=12), 3-6 months (n= 8) of medication, and 1-3 years of medication (n= 48) groups were compared. Comparisons were tested by Mann-Whitney test or Chi-square test and a p-value of less than 0.05 was considered as significant. Statistical analyses were performed using GraphPad Prism software.

Results

EEG alterations in ADHD patients
This study revealed that 52 (76%) out of all the studied ADHD patients; 12 patients (100%) of the unmediacted and 40 patients (71%) of the medicated ADHD patient showed isolated delta or theta waves of 70 ± 10.8 μV amplitude in the EEG (Figure 1; arrows). They appeared as a single slow wave or more frequently as a train of 2-6 theta waves mainly into the theta (4-8 Hz) frequency band or at slower frequencies. This activity was recorded in fronto-parietotemporal areas. The slow activity appeared both during eyes-closed or eyes-open periods, and in both hemispheres. No significant statistical differences were detected between the medicated group and the unmedicated group regarding age and gender. The remaining 16 children did not show EEG alterations.
Figure 1: The EEG of ADHD patients shows a slow wave activity into the theta frequency band. A representative EEG recording from a 9 years old ADHD child. Slow waves at theta frequency appears spontaneously in P3-O1, P4-O2, T6-O2 and Cz-Pz derivations (arrows).
A power spectrum analysis was performed in ADHD patients (12 unmedicated and 56 medicated patients) and compared with 12 healthy subjects (controls). EEG analysis showed that theta and beta waves were elevated across the scalp (Table 1). Figure 2 shows a statistically significant increase of EEG theta and beta waves in ADHD patients with respect to control subjects (p=< 0.001) when the average of all EEG channels were considered. This increase was accompanied by a reduction of alpha waves (p=< 0.001) while delta waves were not affected (p= 0.407). These changes in the percentage of frequency bands in the power spectrum were evident in the eyesclosed condition and in the eyes-open condition.
Table 1: Comparison of the percentage of the EEG frequency bands in the different ADHD subgroups and the control group (mean ± SEM).
Figure 2: Percentage of EEG frequency bands in control and ADHD patients in eyes-closed and eyes-open conditions. The mean percentage of each frequency band was calculated in all EEG derivations considering the sum of the power of all frequencies between 0.5-30 Hz as 100%. ADHD patients show an increase of theta and beta frequencies and a reduction of alpha frequencies. In this and in the following figures *, p=<0.05; **, p=<0.01; ***, p=<0.001.
The frequency band percentages were calculated in each EEG derivation to establish the cortical areas showing EEG alterations in ADHD patients (n= 68; Figures 3-6). Figure 3 displays the delta frequency band percentage in each recorded derivation. An increase in delta waves was prominent in F7-T3 and F8-T4 derivations during eyes-closed condition in comparison with control subjects, while delta waves decreased in C3-P3, T3-T5, C4-P4, T4-T6 and Cz-Pz derivations. For this reason the mean percentage on the scalp did not change, as shown in Figure 2. During eyes-open condition, increased delta waves in F7-T3 and F8-T4 derivations remained in the EEG of ADHD patients. However, a general increase of theta waves was observed in almost all EEG derivations of ADHD patients during eyes-closed and eyes-open conditions (Figure 4). In contrast, the alpha frequency band decreased mainly in frontal cortical areas in eyes-closed condition and in all cortical derivations and in both eyes-open and eyes-closed conditions (Figure 5). Moreover, cortical activity in the beta frequency range was increased mainly in eyesclosed conditions (Figure 6). This increment in beta activity in ADHD patients with respect to control subjects was larger in frontal cortical derivations than in occipital cortical areas.
Figure 3: The percentage of delta frequency band in control and ADHD subjects. The percentage of delta activity is shown in each EEG derivation during closed-eyes and open-eyes condition. Note that delta activity increases in frontal cortical areas while decrease in more caudal areas i ADHD patients.
Figure 4: Theta frequency band in control and ADHD subjects. The percentage of theta activity is shown during closed-eyes and open-eyes condition. Theta activity is increased in the majority of cortical areas in ADHD patients. No differences are observed between hemispheres.
Figure 5: Alpha frequency band in control and ADHD subjects. The percentage of alpha activity is shown. Alpha activity is decreased in the most of cortical areas in ADHD patients, especially in closed-eyes condition.
Figure 6: Beta frequency band is increased in ADHD subjects. The percentage of beta activity is shown during closed-eyes and open-eyes condition. Beta activity is increased in the majority of cortical areas in ADHD patients during closed-eyes condition. No differences are observed between hemispheres.
Also the proportion of different frequency bands (ADHD patients vs. control subjects) is also displayed in Figure 7A. This method allowed to study the evolution of EEG along the medical treatment. Values close to 1 indicated that this frequency band did not change in ADHD patients with respect to control subjects. Values above or below 1 indicated an increase or decrease, respectively, of the frequency band in ADHD patients with respect to control subjects. Since the above results indicated that EEG changes were similar in both hemispheres, frequency band proportions were calculated with the mean EEG activity in both hemispheres and plot in Figure 7A. In unmedicated ADHD patients the greatest difference was observed in the beta frequency range, especially in frontal cortical areas (Figure 7A, unmedicated). Also, the proportion of delta waves in F7/8 and T3/4 EEG derivations was larger than in other cortical areas (Figure 7A, unmedicated), suggesting that these patients may have localized affectations.
Figure 7: The percentage between EEG frequency bands in ADHD subjects vs. control subjects in unmedicated, 3-6 months of methylphenidate medication or 1-3 years of medication. A, plots of percentage s of EEG frequency bands (delta, theta, alpha and beta) in ADHD subjects vs. control subjects show a large increase of beta frequencies in unmedicated ADHD patients. This activity is reduced is reduced during medication. Note that the mean cortical activity in both hemispheres is displayed. B, mean cortical activity in each frequency band in all EEG derivations. Note that delta activity increases with time while a simultaneous reduction of alpha activity occurs. Methylphenidate treatment only reduces beta activity.
The mean proportion for beta EEG frequency in all EEG derivations was 2.7 ± 0.3% (Figure 7B, unmedicated). This increase was accompanied by a reduction in alpha EEG frequencies in all cortical derivations (mean 0.8 ± 0.06). Furthermore, the mean proportion of the delta frequency band was 0.9 ± 0.13 and 1.3 ± 0.03 for the theta frequency band, indicating that these frequencies bands were less affected in ADHD patients (Figure 7B, unmedicated).
Methylphenidate treatment
Methylphenidate was given as a stimulant treatment medicine for the medicated group (56 subjects) at a mean dose of 26 mg/day. The effect of Methylphenidate on the EEG was analysed and compared among the subgroup of patients that received it for 3-6 months (n=8 patients; duration= 5.6 ± 0.2 months), the subgroup of patients that received it for 1-3 years (n= 12 patients; duration= 2.5 ± 0.2 years), the unmedicated patients (n= 12 patients) and the control group (n=12 patients).
The proportion of beta waves in the EEG recordings was significantly lower in both medicated subgroups of patients that received methylphenidate for 3-6 months and 1-3 years respectively when compared to the unmedicated group (P= 0.003, 0.004 respectively). Meanwhile, beta waves means remained significantly higher in both the medicated subgroups with respect to the control group (P= 0.001, 0.007 respectively (Figure 7 and Table 1).
In addition, medication for 3-6 months induced significant reduction of alpha waves (P=<0.001) and also significant increase of theta waves (P=<0.001) in comparison to the control group and no significant differences were detected for both waves when compared to the unmedicated subgroup (P= 0.559, P= 0.439 respectively) (Figure 7 and Table 1). Longer duration of therapy for 1-3 years maintained the same significant changes of both alpha and theta waves when compared to the control group (P=< 0.001) and for alpha waves when compared to the medicated subgroup (P= 0.012). The proportion of theta frequency band in ADHD patients respect to control subjects was higher than 1, indicating that this frequency band had a higher power in the EEG than in control subjects (Figure 7B).
Meanwhile, delta waves did not show significant changes in the medicated subgroup (3-6 months) in comparison to both the control group and the unmedicated subjects (P= 0.852, P= 0.653 respectively). While, 1-3 years of treatment induced a significant increase in delta activity with regard to control subjects (P= 0.036). Delta wave also after 1-3 years of therapy showed a trend of increase with regard to the unmedicated subgroup (P= 0.055). This significant increase in the percentage of delta waves in the 1-3 years medicated subgroup with respect to control subjects (P= 0.036) was balanced by a significant decrease in the alpha frequency band (p<0.001) ( Figure 7B).

Discussion

Results have revealed that patients with ADHD show a characteristic EEG pattern of slow activity (mainly at theta frequencies) in fronto-parieto-temporal cortical areas as well as an increase of beta frequencies in frontal areas. Moreover, power spectrum analyses show that methylphenidate treatment reduces beta EEG activity while slow activities are not affected, indicating that the increase in the beta frequency band is the principal hallmark of these patients and may serve to monitor the effects of medical treatment.
Patients with ADHD perform different tasks more poorly than typically developing controls when assessed for storage and manipulation of information in short-term memory tasks [20,23- 25]. Such attention deficits could be reflected in the EEG recording. In fact, previous studies have reported that the EEG activity of most ADHD patients tend to have increased posterior delta activity [26,27], globally elevated theta activity, most often frontally and reduced alpha activity [28-31]. Results about beta activities are contradictory because a decrease [27,32] or an increase [28] of beta power has been reported in these patients. Also, children with ADHD show higher relative theta activity, reduced relative alpha and relative beta activity, and a larger theta/beta ratio [33-35]. Our EEG results agree with previous studies showing an increase in theta frequencies as well as a decrease of alpha activity, mainly in fronto-temporal-parietal cortical areas [33,34]. Delta activity also increased in fronto-temporal cortical areas but was reduced in more caudal areas. Moreover, current study detected an important increase of beta activities in frontal cortical areas that was very reactive to the methylphenidate medication. The gamma frequency band, although not as extensively researched as the four traditional bands, has been found to be significantly reduced in groups of ADHD children, in both absolute and relative power [29,30,35]. These data suggest that fast EEG activities (beta and gamma frequencies) may be affected in different ways according to the ADHD subtypes.
Previous studies have suggested that there are two different components in the ADHD subjects. The first is a hyperactive/ impulsive component that appears to normalize with increasing age and the second is an inattentive component that does not normalize with age and therefore could be a deviation from normal development [1]. Abnormal EEG (presence of slow wave discharges) has been described in both ADHD components. However, subjects showing a combined component had higher frequency of abnormal EEG findings (73%; [36]). Our subject population corresponded to the combined subtype and also showed a similar percentage of children with abnormal EEG (100% of unmedicated ADHD patients and in 71% of medicated patients). This characteristic EEG pattern could help to diagnose these patients.
Thus, the discrepancy about beta activity may be due to the highly inhomogeneous nature of ADHD disorder. Deficits in vigilance or reduced alerting responses have been reported in these patients while, in other cases, hyperactivity disorders prevail [27]. Beta activity has been found to increase during both physical and mental activity and during periods of cortical information processing [37,38]. However, the increase of beta activity observed in previous [26] and our findings may indicate an overall increased level of cortical alertness that could distort cortical information processing. Stimulant medications appear to produce their therapeutic effect by increasing arousal to more normal levels [33,39,40]. In our study methylphenidate medication reduced beta activity after 3-6 months and after 1-3 years still showing significant difference when compared to control group as shown in Table 1.
In many psychopathologies it is evident that psychological disorders do not come from localized anomalies in discrete brain regions, but rather from impairments in distributed neural networks. Also, partially segregated networks of brain areas may carry out different attentional functions, which include parts of the intraparietal cortex and superior frontal cortex [12-14]. The prevailing theory regarding the neurobiological basis of ADHD identifies the frontostriatal network as a probable substrate of cognitive and behavioural impairments seen in ADHD [41,42]. In agreement with that, the most important EEG alterations observed in our study occurred in the fronto-temporo-parietal cortical areas.
Methylphenidate produces its therapeutic effect by increasing catecholamines in the synaptic cleft [17-19]. Research assessing attentional processes in ADHD reports that, in general, methylphenidate ameliorates deficits in children with ADHD, as indexed by both event-related evoked potential studies and behavioural measures [43,44]. Patients selected to this study with methylphenidate treatment showed significant improvement of their behavioural condition. The findings of this study revealed that the medication resulted in a reduction of beta activity, but this reduction did not represent a normalization of the EEG since slow activities (delta and theta) remained. Consequently, our data suggest that the overall increase in beta cortical activity may be one of the principal events involved in the reduction of attentional processes in ADHD patients and its reduction by methylphenidate treatment is correlated with a reduction of ADHD symptoms.
Our findings and previous results show an “anomalous EEG” in these patients in that slow and fast activities overlap. Deficits in vigilance or reduced alerting responses have been reported, that are correlated with the presence of EEG delta or theta waves. At the same time hyperactivity behaviours seem to be correlated with elevated levels of EEG beta activity. These facts suggest that brain structures involved in EEG generation could be affected in ADHD patients. It has been reported that the thalamus contributes to the generation and synchronization of delta activity as well as fast activity during wakefulness [45-48]. Recently, data from research in high resolution MRI revealed reduced bilateral thalamic volumes as well as regional surface atrophy in the pulvinar nucleus of the left thalamus in ADHD children [49]. These thalamic anatomical alterations could contribute to the anomalous EEG pattern observed in ADHD patients in which slow and fast cortical rhythms coexist. In conclusion, these alterations in ADHD patients induce a characteristic EEG pattern that could be used for diagnosis or to monitor medical treatment.

Acknowledgments

We would like to thank the nurse group in the Clinical Neurophysiology Department and the Pediatric and Psychiatric Departments for their collaboration. This work was supported by grant from Ministerio de Economia y Competitividad (BFU2012-36107). No conflict of interest is reported by the authors.

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