Meth addiction diagnostics using EEG

PSYN-09834; No of Pages 7
Psychiatry Research: Neuroimaging xxx (2012) xxx–xxx

Contents lists available at ScienceDirect

Psychiatry Research: Neuroimaging
j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / p s yc h r e s n s

Decreased cortical complexity in methamphetamine abusers
Kyongsik Yun a, 1, Hee-Kwon Park b, 1, Do-Hoon Kwon c, Yang-Tae Kim c, Sung-Nam Cho c, Hyun-Jin Cho c,
Bradley S. Peterson d, Jaeseung Jeong a, d,⁎
a
Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Republic of Korea
b
Department of Neurology, Seoul National University Hospital, Seoul 110-744, Republic of Korea
c
Department of Psychiatry, Bugok National Hospital, Gyeongnam 635-890, Republic of Korea
d
Department of Psychiatry, Columbia University, College of Physicians and Surgeons, New York, NY 10032 USA

a r t i c l e i n f o a b s t r a c t

Article history: This study aimed to investigate if methamphetamine (MA) abusers exhibit alterations in complexity of the
Received 24 November 2010 electroencephalogram (EEG) and to determine if these possible alterations are associated with their abuse
Received in revised form 18 May 2011 patterns. EEGs were recorded from 48 former MA-dependent males and 20 age- and sex-matched healthy
Accepted 11 July 2011
subjects. Approximate Entropy (ApEn), an information-theoretical measure of irregularity, of the EEGs was
Available online xxxx
estimated to quantify the degree of cortical complexity. The ApEn values in MA abusers were significantly
Keywords:
lower than those of healthy subjects in most of the cortical regions, indicating decreased cortical complexity of
Methamphetamine MA abusers, which may be associated with impairment in specialization and integration of cortical activities
EEG owing to MA abuse. Moreover, ApEn values exhibited significant correlations with the clinical factors
Cortical dynamics including abuse patterns, symptoms of psychoses, and their concurrent drinking and smoking habits. These
Approximate Entropy findings provide insights into abnormal information processing in MA abusers and suggest that ApEn of EEG
recordings may be used as a potential supplementary tool for quantitative diagnosis of MA abuse. This is the
first investigation to assess the “severity-dependent dynamical complexity” of EEG patterns in former MA
abusers and their associations with the subjects' abuse patterns and other clinical measures.
© 2012 Published by Elsevier Ireland Ltd.

1. Introduction Methamphetamine (MA) is a potent neurotoxin causing long-term
damage to the central nervous system. Animal studies suggest that
The abuse of methamphetamine (“speed”) and its pure crystalline continuous administration of MA produces long-lasting reductions in
form (“crystal meth”, “ice”, or “glass”) has reached epidemic pro- striatal dopamine (DA) concentrations, DA transporter levels, and rate-
portions. The estimated lifetime prevalence of methamphetamine limiting synthetic enzymes, as well as autophagocytosis of the neuritis
abuse is 5.3% in the United States, and 33 states exhibited a 100% and apoptosis of the DA neurons in the striatum (Ricaurte et al., 1980;
increase in the numbers of people admitted to treatment centers for Wagner et al., 1980; Villemagne et al., 1998). In vivo studies on acute
methamphetamine abuse between the years of 1992 and 2001 (Office neurobiological effects of MA in humans have documented marked
of Applied Studies, 2005). On the other side of the world, the United alterations to the DA neurotransmitter systems and rates of neural
Nations reported that approximately 33.4 million people use meth- metabolism in the cerebrum and the basal ganglia. Recent neuroimaging
amphetamine in Asia, particularly in eastern and southeast Asian studies have shown that long-term use of MA decreases the density of
countries such as Japan and South Korea, where its abuse is one of the DA transporters in reward circuits (McCann et al., 1998; Sekine et al.,
most pressing social concerns (Farrell et al., 2002; Chung et al., 2004; 2001; Volkow et al., 2001a,b; Sekine et al., 2003) and the density of
Kulsudjarit, 2004). These behaviors frequently lead to profoundly serotonin transporters in cortical regions (Sekine et al., 2006). In
harmful social and public health consequences (Seivewright, 2000; particular, long-term MA abuse is associated with glucose hypometa-
London et al., 2004; Sekine et al., 2006). Despite the high prevalence bolism in the frontal regions (Kim et al., 2005b), low activity in the
and destructive effects of methamphetamine abuse, the long-term dorsolateral and ventromedial prefrontal cortices (Paulus, 2002), and
effects of methamphetamine on the neurodynamics of the cortical cortical structural abnormalities of the medial temporal lobe and the
network are poorly understood. cingulate-limbic cortex (Thompson et al., 2004; Kim et al., 2005a). These
studies suggest that MA intoxication is not limited to the subcortical
structures, but also extends to cortical regions.
Only a few studies have investigated patterns of the electroenceph-
⁎ Corresponding author at: Department of Bio and Brain Engineering, KAIST, Daejeon
305-701, Republic of Korea. Tel.: + 82 42 350 4319; fax: + 82 42 350 4310.
alogram (EEG) that characterize MA abusers to detect electrophysio-
E-mail address: jsjeong@kaist.ac.kr (J. Jeong). logical abnormalities of their cortical networks and their associations
1
Indicating authors of equal contribution. with behavioral factors, including reduced working memory

0925-4927/$ – see front matter © 2012 Published by Elsevier Ireland Ltd.
doi:10.1016/j.pscychresns.2011.07.009

Please cite this article as: Yun, K., et al., Decreased cortical complexity in methamphetamine abusers, Psychiatry Research: Neuroimaging
(2012), doi:10.1016/j.pscychresns.2011.07.009

2 K. Yun et al. / Psychiatry Research: Neuroimaging xxx (2012) xxx–xxx

performance (Newton et al., 2004). Power spectrum analysis revealed (N = 20, average age = 34.5± 7.7 years, range= 23–48 years, all males)
an apparent EEG slowing in MA abusers (Newton et al., 2003, 2004), but were recruited from Bugok National Hospital in South Korea. The MA
correlations with abuse patterns and social factors were not examined. abusers were hospitalized patients who met the Diagnostic and
While pre-clinical and clinical investigations have shown that Statistical Manual of Mental Disorders, 4th edition (DSM-IV) (Spitzer
methamphetamine (MA) causes long-term damage to the DA reward et al., 1994) criteria for lifetime MA abuse (N = 31) or dependence
circuits resulting in motor and cognitive deficits (Volkow et al., 2001b; (N = 17). There were no significant correlations between abused and
Johanson et al., 2006; McCann et al., 2008), but little is known about dependent patients in the period of MA use (p = 0.970), the age of first
dynamical disturbance of cortical network in MA abusers. The aim of the abuse (p = 0.437), and the cumulative amount of MA (p = 0.820). All
present study was to determine whether abstinent MA abusers exhibit subjects were men only because of extensive prior evidence that MA-
alterations in complexity of the EEG. Tononi et al.(1998) suggested that induced neurotoxicity is sex-specific, particularly greater in men than in
optimal brain functioning requires the dynamic interplay between local women (Wagner et al., 1980; Dluzen et al., 2002; D'Astous et al., 2005;
specialization and global integration of brain activity. They proposed Kim et al., 2005b). They showed no signs of neurological abnormalities
that this optimal state produces complex activity and that a neural such as seizure, dyskinesia, or coma. MA abusers were excluded if they
complexity measure is capable of estimating the optimal balance had a past or present history of a comorbid psychiatric illness except
between localization and integration of neural networks (Tononi et al., substance abuse (DSM-IV axis I or II diagnosis). After complete
1998; Tononi and Edelman, 1998; Sporns et al., 2000). Indeed, reduced description of the study, written informed consent was obtained from
complexity of EEG patterns has been reported in patients with all subjects prior to participation, in compliance with the procedures of
Alzheimer's disease (Jeong et al., 1998; Abasolo et al., 2005), the Ethics Committee of the Bugok National Hospital.
schizophrenia (Roschke et al., 1994; Breakspear et al., 2003; Paulus For the accuracy of patient profiles, detailed clinical information on
and Braff, 2003; Keshavan et al., 2004; Micheloyannis et al., 2006), and MA use patterns was obtained through interviews with the abuser and
depression (Roschke et al., 1994; Thomasson et al., 2002; Bob et al., his family members as well as by referral to patient medical records
2006; Fingelkurts et al., 2007), many of whom are hypothesized to suffer using the Structured Clinical Interview for DSM-IV (SCID). The clinical
from reduced functional connectivity between cortical regions. A information includes the period of MA use, the age of first abuse, and
previous study also found that EEG complexity is reduced as sleep other substance abuse such as nalbuphine, nicotine, alcohol, and
goes deeper and increased during REM sleep (Burioka et al., 2005b). inhalant solvents. A heavy drinker was defined as consuming on
Thus, in this study, we examined the interplay between the functional average more than four drinks daily, and a heavy smoker was defined as
integration and segregation of cortical networks and consequently the smoking two or more packs per day. We also obtained the clinical
efficiency of information processing the cortex through quantification of information about sexual exploitation and criminal records. In the MA
the complexity in EEG patterns in MA abusers. binge abuse cycle, during the initial response of the rush, the MA
To estimate complexity of EEG patterns in MA abusers, we used abuser's heartbeat races and metabolism, blood pressure, and pulse
Approximate Entropy (ApEn), an information-theoretic measure of increase. During this "high," they partake in a wide range of risky
irregularity. ApEn can stably quantify the complexity of a noisy and behaviors that include having an increased level of sexual behavior
short time series as in physiological recordings (Pincus, 1991; Pincus, (sexual exploitation) and that incorporate unsafe behaviors, driving, or
1995). Several studies have reported that ApEn can be used to discern committing crimes.
various neuropsychiatric conditions such as Alzheimer's disease, These evaluations were performed within 3 days of the EEG
coma (Abasolo et al., 2005; Lin et al., 2005), and epilepsy examination by a trained research psychiatrist blind to the EEG data.
(Radhakrishnan and Gangadhar, 1998; Hornero et al., 1999; Burioka All MA abusers had taken MA intravenously for at least least 2 years,
et al., 2005a). A previous study also reported that ApEn analysis of and each subject had been abstinent for more than 6 days at the time
heart rate in cocaine abusers showed reduced complexity, suggesting of the EEG examination. The drug was only to be taken intravenously
that impaired function, isolation and network diminution are since this is the most common method of use in South Korea (Chung
manifest across multiple axes (Newlin et al., 2000). et al., 2004). Urine tests were performed just prior to EEG recording
MA is known to induce a variety of symptomatic behaviors during for the proof of negative current intoxication.
intoxication or withdrawal that include irritability, anxiety, excitement, The controls were recruited from the local community in Bugok
hallucinations, paranoia (both delusional and psychotic), and aggressive and Busan, South Korea. They were group-matched with the MA
behavior. Social abnormalities such as criminal misconduct or sexual abusers by age, sex, and socioeconomic status (income: b$25,000;
intercourse are also observed in MA abusers during MA intoxication. education: college or high school graduates). They had no history of
Psychotic behaviors of MA users are correlated with their ages, possibly MA use or abuse of other substances. None had a personal or familial
associated with disturbance of neurotransmitters in cortical–subcortical history of psychiatric illness based on an unstructured interview
circuits during the aging process (Chen et al., 2003). Another conducted by a trained psychiatrist. No subjects could be taking
commonality found among MA abusers is the consumption of other medication at the time of the study, and all had negative urine toxin
substances such as alcohol and nicotine during MA intoxication. These screens to ensure the absence of psychoactive drug use. Controls were
multifaceted factors result in the difficulties in treating MA dependen- excluded if they reported drinking alcohol more than once per day or
cies in abusers. Despite the prominent and detrimental effects of MA on N40 g per week or reported smoking more than 10 cigarettes per day.
the nervous systems and social behavior, few neuroimaging or After evaluation of the EEG, IQ was measured for all subjects as the
electrophysiological studies have been performed to investigate the psychometric index of intellectual functioning (Sattler, 2001) using
relationship between cortical alterations and critical factors including the Korean–Wechsler Adult Intelligence Scale (K-WAIS)-Short form
abuse patterns and social behaviors. Therefore, we aimed to determine (Yeom et al., 1992). The four sections of this shortened test required
the association between the complexity of EEG patterns in MA abusers the subjects to answer questions about the information that was
and their drug abuse patterns. provided, picture completion, arithmetic, and block designs. It was
revised and given in Korean. The estimated IQ score was normalized
2. Methods according to the respondent's age.

2.1. Subjects 2.2. EEG recording

Currently abstinent MA abusers (N = 48, average age = 36.7 ± EEGs were recorded from 16 channels using EEG amplifier (Model 9
5.8 years; range= 26–49 years, all males) and 20 control subjects EEG Grass Instrument Co.) in the morning (10:30–11:30 AM) to


K. Yun et al. / Psychiatry Research: Neuroimaging xxx (2012) xxx–xxx 3

minimize the circadian and homeostatic modulation of wakefulness Table 1
(Taillard et al., 2003). Subjects were instructed to lie with their eyes Demographic profile of the study samples.

closed, think of nothing in particular, and not fall asleep in a sound- MA group (n = 48) Control group (n = 20)
attenuated room. Ag-AgCl electrodes were placed according to the
Age (years) 37.0 (5.8) 34.5 (7.7)
international 10–20 System. Data were collected using a Cz referential IQ (points) 97.8 (6.1) 116.5 (5.3)⁎
montage and were digitized at 200 EEG samplings per second which Duration of MA use (years) 11.8 (6.5) N/A
were obtained by the QUINGY, MASS system (bandpass filtered 0.3– Abstinence period (days) 30.5 (27.2) N/A
Total amount in a previous year (g) 1.125 (1.095) N/A
70 Hz). At least 20 min of EEG activity was recorded and a minimum of
30 s of artifact-free EEG was selected by visual inspection and then was Means are presented with standard deviations in parentheses.
⁎ p b 0.05.
analyzed. To obtain maximally long stationary EEG data, the first 2 min
of data were discarded. Three epochs of 10-s of EEG recordings were
randomly selected to estimate the ApEn values and their means were between the groups. Thus, we employed ‘Levene's Test for Equality of
used. An additional three epochs of 10 s of EEG recordings were Variances’ to select a proper statistic. Levene's Test with p b 0.05
randomly selected. We found that the ApEn values were robust to epoch indicated that variance was not homogeneous. If Levene's Test indicated
selection and the results were consistent in that MA abusers exhibited that variances were homogeneous between groups, then Student's t-
decreased ApEn values compared with those of the healthy subjects in test was used. Otherwise, Welch's t-test was used. Welch's t-test is a
all 15 channels (p b 0.001) except F4 (p N 0.05). There was no effect of variation of Student's t-test intended for use with two samples having
epoch selection (p N 0.3). Using stationary EEG data and random epoch unequal variances.
selection might help to control the possibly variable cognitive processes
involved in the resting state. Moreover, robustness of the ApEn results to 3. Results
epoch selection might indicate that a rather consistent cognitive state
was maintained in our resting supine condition. 3.1. Decreased cortical complexity of MA abusers

2.3. Approximate Entropy analysis Table 1 summarizes the demographic characteristics displaying the
similarities between the former MA abuser and control groups. The two
The recorded EEG data were reformatted offline to compute the groups did not differ significantly in age, but there was a difference in
power spectrum (see supplementary material for power spectrum their IQ levels (p b 0.05). To assess the possible presence of abnormal
analysis and results) and ApEn values. First introduced by Pincus, the complexity of cortical activity in MA abusers, we estimated the ApEn
ApEn is an index that quantifies the irregularity or complexity of a values of EEG patterns in 48 MA abusers and compared them with those
dynamical system (Pincus, 1991). It is particularly efficient to use with of 20 control subjects. We found that MA abusers exhibited decreased
short and noisy time-series data such as physiological data. The ApEn ApEn values compared with those of the healthy subjects in all 16
measures the logarithm frequency with which neighborhoods of channels (Student's t-test; p b 0.00001) (Fig. 1). We also calculated a
temporal patterns of length m that are within a certain distance (r) in multivariate general linear model (dependent variables: ApEn values of
phase space remain close together (br) for patterns that are augmented 16 channels, fixed factor: MA abusers/controls, covariate: IQ, smoking
by one point of time (i.e., for patterns of length m + 1) (see amount). Including IQ and smoking amount as a covariate decreased the
supplementary material for detailed algorithm). Thus, smaller values statistical difference between MA and control groups. However, most
of the ApEn imply stronger regularity or persistence in a time series. channels were still significantly different between groups (Fp1, T6, O1,
Conversely, larger values of the ApEn signify the presence of greater O2, p b 0.0001; T5, p b 0.001; Fp2, P3, P4, F7, F8, T3, p b 0.01; F3, C3,C4, T4,
fluctuations, or irregularity, in a time series. ApEn values of EEG are p b 0.05).
possibly determined by the balance between the functional segrega- To investigate the effects of severity of MA abuse on the ApEn values
tions and integrations of cortical regions. of EEGs, we classified the MA group into two separate subgroups based
on the period of MA abuse and recent intake amount: a moderate and
2.4. Statistical analysis a severe MA abuse group. The “severe MA abusers” (average age was
37.7± 5.52 years; age range: 29–49 years; the average cumulative
Group comparisons of the demographic variables were conducted amount of MA was 14.3 ± 15.2 g) consisted of subjects who used MA
using t-tests. The average values of the ApEn of the EEG in the MA- for at least 6 years or more than 0.75 g of MA injection in the most recent
dependent group and the control group are presented as “mean ± year, compared with ‘moderate MA abusers’ (average age 30.6 ±
standard error” across all subjects. The one-way analysis of variance 3.31 years; age range 26–35 years; average MA cumulative amount
(ANOVA) procedure was used to compare the severe and moderate MA 0.92 ± 0.52 g). ANOVA analysis revealed that severe and moderate MA
abusers and the control group. If the results from the ANOVA achieved abuser groups and the control group exhibited significant differences in
statistical significance (pb 0.05), multiple comparisons were performed ApEn values in all channels (p b 0.0001), indicating the significant
afterwards (LSD test). The effects of abuse patterns, clinical/social
measures, and comorbidity on the cortical complexities of MA abusers
were evaluated separately using t-tests. Pearson's correlation coefficient
was used for the linear correlation analysis, while a statistical software
package (SPSS 11.0.1, SPSS Inc., Chicago, IL, USA) was used. Statistical
significance was defined to have an alpha level of 0.05. Adjacent
electrodes were grouped for pair-wise correction for multiple compar-
isons (Fp1–F3, Fp2–F4, F7–T3, F8–T4, C3–P3, C4–P4, T5–O1, T6–O2).
For normality test of the data, we used the ‘Kolmogorov–Smirnov
test’ before ApEn analysis and did not use outliers to maintain the
normality of the data. Outliers were detected through visual examina-
tion of the scattergrams and normal probability distribution plots. Fewer
than three channels out of the total electrodes for each subject were Fig. 1. Topographic map of average ApEn values in (a) healthy subjects and (b) MA
removed from the study through the normality test. In comparisons of abusers. MA abusers exhibited reduced ApEn values compared with healthy subjects in
two samples (t-test), the variances of some EEG data are not equal all channels (Student's t-test; p b 0.00001).



Table 2 3.2. Correlations of ApEn values with clinical/social measures
Significant differences of ApEn values of EEGs in MA abusers and controls. Group 1
corresponds to a group having lower ApEn values than those of group 2.
To investigate the associations between ApEn values and clinical
Group 1 Group 2 factors, we divided MA abusers into several groups according to their
MA⁎ Control Fp1, Fp2, F3, C3, P3, P4, F7, F8, T3, T4, sexual histories, their drug-related criminal records, and if they
T5, T6, O1 experienced common symptoms of psychosis (such as hallucinations
Severe-MA⁎ Moderate-MA F3, C3, P3, F7, T5, O1 or delusions). We found no significant correlation between the ApEn
No psychosis⁎ Psychosis Fp1, Fp2, F3, F4, C4, P4, F7, F8, T3, T4,
value of the EEG and the age at which a subject first used MA. The MA
T5, T6, O1, O2
No sex acts⁎ Sex acts C3, P3 patients exhibiting delusions or hallucinations (N = 37) had higher
Drug-related No criminal record Fp2, F4, C3, C4, P3, P4, F7, F8, T3, T4, ApEn values in most channels than the abusers without these
Criminal records⁎ T5, T6, O1, O2 symptoms (Fp1, Fp2, F3, F4, C4, P4, F7, F8, T3, T4, T5, T6, O1, O2;
Heavy smoking⁎ Light smoking C4, P4, F8, T4, T5, T6, O1, O2 p b 0.05) (Fig. 3(a)). MA patients who participated in sexual
No nalbuphine⁎ Nalbuphine Fp2, F4, C3, C4, P3, P4, F7, F8, T3, T4,
intercourse during their MA binges (N = 25) had higher ApEn values
T6, O2
in the centro-parietal areas than the other abusers who did other
Severe-MA: 6 or more years of MA abuse or taking at least 0.75 g of MA in the previous
activities (such as driving cars or playing video games) (C3, P3;
year.
Moderate-MA: under 6 years of MA abuse and taking less than 0.75 g of MA in the p b 0.05) (Fig. 3(b)). The MA patients with drug-related criminal
previous year. records (N = 21) had lower ApEn values than the other subjects (all
Heavy smoking: More than or equal to two packs/day. channels, except Fp1 and F3; p b 0.05) (Fig. S2). However, the MA
Light smoking: Less than two packs/day. patients with other types of criminal records had lower ApEn values
⁎ p b 0.05.
that were limited to the centro-parietal areas (C4, P4; p b 0.05). These
results demonstrate that reductions in cortical complexity (measured
by the ApEn values of the EEGs) of MA abusers are associated with the
influence of the duration of MA abuse and the dosage received during the pathological behaviors that occur during MA abuse.
previous year. To control the possible age difference between groups, we
applied an analysis of covariace (ANCOVA). We selected age, IQ, and
smoking amount as covariates. All channels except F4 were still
significantly different between severe and moderate MA abuser and
control groups (Fp1, T6, O1, O2, p b 0.0001; P4, T3, T5, p b 0.001; F3, C3,
P3, F7, F8, p b 0.01; Fp2, C4, T4, p b 0.05). In post-hoc analyses, the
significant differences were found between the moderate and the severe
MA groups in the left cortical areas (LSD test; F3, t(43.999) = 51.638,
p = 0.042; C3, t(44.421) = 65.289, p = 0.031; P3, t(44.793) = 40.909,
p = 0.049; F7, t(42.743) = 30.308, p = 0.043; T5, t(41.146) = 25.373,
p = 0.037; O1, t(44.979) = 23.934, p = 0.030). The severe MA abuse
group had significantly lower ApEn values than the control group in
most channels (Fp1, Fp2, C3, P3, F7, F8, T3, T5, T6, O1, O2, p b 0.005; F3, C4,
P4, T4, p b 0.05). The moderate MA group exhibited significantly
decreased ApEn values of the EEG in Fp1 channel compared with the
values of the control subjects (LSD test; t(43.592) = 24.366, p b 0.0001)
(Table 2). These results indicate the period-dependent, MA-induced
reduction in cortical complexity in the MA group (Fig. 2).

Fig. 2. ApEn values of the EEG in control, moderate MA abuse, and severe MA abuse groups. Fig. 3. ApEn values of the EEG correlated with (a) the presence of psychoses and (b) sexual
Significant differences were found in cortical regions marked with an asterisk (*) between intercourse during MA intoxication. The asterisk (*) indicates significant differences in
the moderate and the severe MA user groups (F3, C3, P3, F7, T5, O1; p b 0.05). ApEn values (p b 0.05).



3.3. Correlation of the ApEn values with comorbidity ApEn reflects the dynamic balance between the functional integra-
tion and segregation of neural networks (Pincus and Goldberger, 1994;
We determined the relationship between the ApEn values of the Tononi et al., 1994). ApEn appears to decrease when the functional
EEGs in MA abusers and the presence of comorbidity of other cortical network is isolated or decoupled, and this reduced integration
substance abuse. Although other co-morbid abuse of inhalant solvents leads to hypoactivity, or slow signal transmission in the cortical
(N = 7) did not have an effect on the ApEn values, we found heavy networks (Pincus, 1994). This reduction in cortical complexity,
smoking (N = 5) (more than or equal to two packs/day) decreased the particularly in the temporal and frontal regions, probably stems from
ApEn values in the right frontal and central areas and both sides of the the anatomical and functional disconnections among the regions that
temporal and occipital areas (C4, P4, F8, T4, T5, T6, O1, O2, p b 0.05) are most affected by the long-term toxicity of MA. This speculation may
(Fig. S3). The ApEn values revealed that MA abusers who were heavy be consistent with the decreases in the metabolism rates of frontal white
smokers exhibited greater cortical dysfunctions than those who matter in MA abusers, and it suggests that persisting deficiencies can be
smoked fewer cigarettes or did not smoke at all. The abuse of found in the frontal lobes (Kim et al., 2005b). The frontostriatal circuit
nalbuphine hydrochloride or other similar opioid medications (N = 7) might be affected in MA abusers so the decreased striatal metabolism
increased the ApEn values in the global cortical areas (Fp2, F4, C3, C4, rates cause the lower levels of metabolism in the frontal cortical regions.
P3, P4, F7, F8, T3, T4, T6, O2; p b 0.05) (Fig. 4). This hypo-metabolism found in cortical regions possibly decreases the
integrations of the neural networks. This in turn leads to the isolation or
4. Discussion decoupling of the network.
Alternatively, the reductions in dynamical complexity of EEG
In the present study, we detected significantly reduced ApEn values patterns may reflect the toxicity of MA to several cortical monoam-
of EEG patterns (i.e. cortical complexity) in former MA abusers in the inergic neurotransmitter systems such as dopamine and noradrenalin,
global cortical regions compared with those of healthy subjects. Within and thus reduced local activities of cortical regions. The most
the MA abuser group, severe MA abusers had more disproportionate prominent and toxic effects are on the neurites of dopaminergic
reductions in cortical complexity compared with moderate MA abusers. neurons in the deep brain including the striatum, caudate, and
Although the EEG has a poor spatial resolution and possibly topograph- putamen (Kraemer and Maurer, 2002; Kita et al., 2003). Brain damage
ical implications of these findings must be interpreted with extreme by MA is not limited to deep brain structures, but also extends to
caution, this reduction was more prominent in fronto-temporal and global cortical areas (Ciraulo et al., 2003; Kim et al., 2005a). The
occipital regions. MA patients that suffered from delusions and involvement of dopamine in the process of drug addiction is likely to
hallucinations or those that participated in sexual intercourse during be accompanied by functional and structural changes to the circuits,
MA intoxication exhibited increased levels of cortical complexity including the cortical areas. The vast damage of cortical and
compared with those MA abusers that had not experienced similar subcortical regions to which these monoaminergic systems project
psychotic symptoms or sexual intercourse during MA intoxication. MA as found in previous studies may account for the reductions in global
patients having histories of drug-related criminal activities had the most dynamical complexity observed in the former MA abusers of our
decreased cortical complexity among the MA abusers. The MA abusers study. Regardless of the resulting reductions in dynamical complexity
who smoked heavily had decreases in cortical complexity in the right that might be consequences of MA abuse on a functionally coupled
frontal, central, temporal, and occipital areas. The subjects concurrently neural system or the drug's comparable effects on multiple mono-
using nalbuphine hydrochloride had increases in cortical complexity in amine systems, the estimated duration and amount of MA abuse
most areas among the other MA users. These findings indicate overall correlated strongly with global and dynamical EEG complexity across
reductions in dynamical complexity in the cortical networks of MA all portions of these monoaminergic and functional networks. These
abusers, possibly due to the severe and long-lasting presence of toxins in findings suggest that the duration and amount of exposure to MA
the monoaminergic neurotransmitter systems of the brain in MA accounts for a substantial amount of variance found in the severity of
abusers. To the best of our knowledge, this is the first investigation to its long-term and system-wide neurotoxic effects in people.
assess the “severity-dependent dynamical complexity” of EEG patterns In previous reports, delusions and hallucinations found in MA
in former MA abusers and their associations with the subjects' abuse abusers were associated with abnormalities in the dopamine receptors
patterns and other clinical measures. or transporters of the caudate, putamen, and nucleus accumbens (Wada
and Fukui, 1990; Sekine et al., 2001). The ApEn revealed that MA abusers
exhibiting delusions or hallucinations had more complex cortical
activity than the abusers without these psychotic symptoms. It seems
that psychotic symptoms might not only explain certain dopaminergic
system deficits, but the presence of these symptoms might also be the
reason for the reorganization or partial recoveries of the deficits
(Lautenschlager and Forstl, 2001; Kato et al., 2006) resulting from the
toxicity of the drug and the damage to the cortical and sub-cortical
systems, such as the serotonergic system, stemming from the psychoses
initiated by using MA (Sekine et al., 2006).
Elevated complexity in EEG patterns mainly in the left centro-
parietal areas was found in those MA abusers that participated in sexual
intercourse during their MA binges. Previous reports have suggested
that the parietal regions are associated with erotic, especially visual,
stimuli (Montorsi et al., 2003; Mouras et al., 2003). Our results suggest
that the sexual intercourse that occurs concurrently with MA abuse is, to
some extent, associated with relatively intact brain function, rather than
a simple recreational behavior. Further investigation is required to
examine not only former abusers but also current and potential abusers
to confirm the measure's diagnostic power.
Fig. 4. ApEn values of MA abusers correlated with the presence of nalbuphine abuse. Our findings must be interpreted in light of the limitations of this
The asterisk (*) indicates significant differences in ApEn values (p b 0.05). study. First, the precise mental processes during resting remain



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background activity of epileptic patients. IEEE Engineering in Medicine and Biology
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could be canceled out in between-subjects level statistics. Second, the Alzheimer's disease with optimal embedding dimension. Electroencephalography
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Supporting Online Material

Decreased Cortical Complexity in Methamphetamine abusers

Kyongsik Yun*, Hee-Kwon Park*, Do-Hoon Kwon, Yang-Tae Kim

Sung-Nam Cho, Hyun-Jin Cho, Bradley S. Peterson, Jaeseung Jeong

Materials and methods

Approximate Entropy

EEG can be reconstructed as phase space representation using the method of delays.

In this representation, the state at each point in time is represented by a vector generated by

taking successive amplitudes separated by a time lag tau. This reconstruction of the

underlying dynamics is the first step of all techniques of phase space analysis. The

geometrical properties of the trajectories in the phase space can then be expressed

quantitatively using nonlinear measures. Approximate entropy can be represented by

difference between geometrical property of m dimensional phase space trajectory and that of

m+1 dimensional phase space trajectory.

In detail, ApEn is derived from the correlation integral Cim (r ) , which represents the

number of points within a distance r from the ith point when the signal is embedded in an m-

dimensional space:

N - ( m -1)
m -1
C (r ) = ( N - (m - 1))
i å Q(r - Xi - Xj )
j =1
(1)

Where Q(t ) is the Heaviside function (if t ³ 0, Q(t ) = 1 ; if t<0, Q(t ) =0) and Xi and Xj are

vectors constructed from the time series [ x(1), x(2), . . . , x(N)] as

1

Xi = {x(i ), x(i + t ),..., x(i + (m - 1)t )}
Xj = {x( j ), x( j + t ),..., x( j + (m - 1)t )} (2)
(i, j = 1,2,...N - (m - 1)t )

where t is the time lag at which the mutual information between consecutive samples

becomes negligible. The ApEn statistic is defined as follows:

ApEn(m, r ) = Qm (r ) - Qm +1 (r ) (3)

N - ( m -1)
Q m (r ) = ( N - (m - 1)) -1 å ln C i
m
(r ) (4)
i =1

Entropy can be viewed as a measure of disorder, larger values corresponding more disorder,

randomness, or complexity (Williams, 1997). We set the distance, r, to be 0.2 times the SD of

the original data series to produce reasonable statistical validity of ApEn (Pincus, 1991). We

tested embedding dimension from 2 to 6. We used an embedding dimension of 2 (ie, m = 2)

(Peitgen et al., 1992) in which ApEn differences between groups are maximum. The

parameter choices of m = 2 and r = 0.2 SD in the ApEn specification are standard choices and

widely applied in diverse settings. To embed the time series in state space, we used the

concept of time lag. These values were chosen as the time lags that were determined for each

time series as the lag at which the first minimum of the mutual information in the EEG. ApEn

was computed with a software package (MATLAB 7.0; The MathWorks, Inc).

Surrogate data

The surrogate data are a randomized sequence of the original data having the same linear

properties and the significant differences between the ApEn of original EEG data and their

surrogate data indicate that the original EEG sequences have a nonlinear structure within the

patterns. Nonlinear indexes such as the ApEn are computed for several surrogate data series.

Their values are compared with that assumed by the nonlinear index computed for the

2

original data (Theiler et al., 1992).

No statistical difference indicates that the original time series were generated from a

linear process, since random shuffling of the original time series, which is surrogate data,

does not change the linear properties of the original data. On the contrary, the statistically

significant difference in ApEn between the original and surrogate data explains that the

original signal contains the nonlinear properties.

To test for a statistical significance of difference (ie, the s of Theiler et al. (Theiler et al.,

1992)) in ApEn between the original and the surrogate data, 10 surrogate data series were

generated to match each original signal. Let ApEnorig be the ApEn of the original data, and let

ApEnsurr be the ApEn of the 10 surrogate series (i = 1,…,10). The mean and SD of ApEnsurr (i

= 1,…,10) are estimated as ApEnsurr and SDApEn_surr (Theiler et al., 1992) then is computed as

follows:

ApEnorig - < ApEnsurr >
Z= (5)
SDApEn _ surr

This statistic represents the number of SDs ( s ) distant from ApEnorig. It follows a Student t

test distribution with 9 degrees of freedom ( t9[1- a /2]). For a =0.05, the critical value of t

is 2.26. Accordingly, when the s of Theiler et al. (Theiler et al., 1992) is > 2.26, the null

hypothesis is rejected at the 5% probability level, and the original data are considered to

contain nonlinear features.

3

Results

Power spectrum analysis

The reformatted data were than processed using a fast Fourier transform (MATLAB 7.0; The

MathWorks, Inc) to obtain relative power values in 4 standard frequency bands, delta (0.5–4

Hz), theta (4–8 Hz), alpha (8–12 Hz), and beta (12–30 Hz).

Relative power values were obtained across the 4 standard EEG bands. Areas in

prefrontal, frontal, and temporal regions were decreased (Fp1, F8, T5; p<0.05) in MA-

dependent group in delta band. Other EEG bands indicate no significantly different power

values between MA-dependent and control groups.

Surrogate data analysis

The test of Theiler et al. (Theiler et al., 1992) was performed for each data series

separately to test for nonlinearity (FigS1). The mean (± standard error) values of the test of

Theiler et al. (Theiler et al., 1992) were 41.3 ± 5.3 for ApEn of MA-dependent subjects, 44.2

± 6.3 for ApEn of high-dose MA-dependent subjects, 35.5 ± 6.6 for ApEn of low-dose MA-

dependent subjects. The mean values of the control group were 2.33 ± 0.5. The signals of all

channels of MA group show clear evidence for nonlinearity) Whereas signals of 8 channels

of control group (Fp2, C3, C4, F8, T3, T4, T5, T6) failed the test signals of 8 other channels

of control group (Fp1, F3, F4, P3, P4, F7, O1, O2) showed nonlinearity. It shows relatively

significant nonlinear feature in MA-dependent subjects. The signals of all channels of MA

group show clear evidence for nonlinearity although signals for only 8 channels show

significant nonlinear feature in the control group.

Correlation with abstinence period

4

We could not find the correlation between abstinence period and EEG analyses such

as ApEn and power spectrum. Although Kim et al. (Kim et al., 2005) reported that long-term

abstinence could improve prefrontal grey-matter, average duration of long-term abstinence

period was over 30 months in that study. In case of our study, the longest abstinence period

was three months, and the relatively short period of abstinence maybe could not show enough

recovery of electrophysiologic function.

5

Discussion

Brecht and his colleagues (Brecht et al., 2000) examined the possible predictors of

that could indicate how long MA abusers could wait before relapsing back into abusing the

drug. They found that an abuser experienced a shorter time period before relapse if the

individual had started using MA at an older age, and age was found to be a significant

predictor in that experiment. In our study, the ApEn values of the left frontal areas exhibit

negative correlations with the ages of subjects’ first intakes of the drug. This preliminary

finding indicates that MA abusers who were older when first exposed to MA have elevated

levels of susceptibility to reductions in their EEG complexities. It is possible that the

dopamine systems is more severely damaged by MA as individual ages since these

neurotransmitter systems are reported to weaken during the course of the normal aging

process. This might compound the effects of the drug as well (Sheline et al., 2002). The

association of ApEn values with the severity of MA abuse and the age at which a user first

uses the drug suggests that EEG complexity measures should be further investigated.

The ApEn revealed decreases in the global cortical areas in those MA abusers that

had drug-related criminal records. Drug-related criminality is frequently associated with MA

abuse (Keene, 2005; Sindelar & Olmstead, 2006). To investigate certain social aspects, such

as the levels of sociality and aggression in MA abusers, we examined the other criminal

records unrelated to substance abuse of our subjects in the patient group. We found that the

general criminality of MA abusers was associated with decreased complex dynamics in the

left fronto-central and right centro-parietal areas that are known to be associated with

increased hostility (Fallon et al., 2004) and more frequent and intense sexual behaviors

(Mouras, 2006). The serotonin transporter likely changes during an individual’s dependence

on MA, leading to elevated levels of aggression even in currently former abusers (Sekine et

6

al., 2006). However, the ApEn analysis revealed increased complexity in these areas

correlated with sexual activity. Thus, this discrepancy suggests that further investigation is

necessary to identify the specific processes of those centro-parietal areas involved in sexual

activity and criminality.

In regards to our observations that showed heavy drinking and smoking habits in

MA abusers, they were associated with EEG complexity in the left frontal and temporal

regions which was consistent with a previous report that stated smoking increased the

psycho-toxic effect of and sensitivity to MA, particularly in the inhibitions of locomotor

sensitization (Kuribara, 1999). We should also note that co-morbid use of nalbuphine

minimized the ApEn decrease that was induced by MA abuse, or this co-morbid use increased

the ApEn in most cortical areas of abusers compared to the healthy control subjects. This is

consistent with previous studies performed on animals that reported that stimulation of the

opioid receptors plays an inhibitory role in MA-induced and self-injurious behaviors (Mori et

al., 2006). The results implicate that ApEn may be able to detect the outcomes of cortical

dynamics produced by an interplay between nalbuphine and methamphetamine. Alternatively,

nalbuphine may offer some protection against MA-induced reductions in cortical complexity

and can play a potential and therapeutic role in treating MA-inducing pathological changes.

7

Supporting References

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Fallon, J. H., Keator, D. B., Mbogori, J., Turner, J., & Potkin, S. G. 2004. Hostility

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K. H., & Renshaw, P. F. 2005. Prefrontal grey-matter changes in short-term and long-

term abstinent methamphetamine abusers. The International Journal of

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National Academy of Sciences 88, 2297-301.

8

Sekine, Y., Ouchi, Y., Takei, N., Yoshikawa, E., Nakamura, K., Futatsubashi, M., Okada, H.,

Minabe, Y., Suzuki, K., Iwata, Y., Tsuchiya, K. J., Tsukada, H., Iyo, M., & Mori, N.

2006. Brain serotonin transporter density and aggression in abstinent

methamphetamine abusers. Archives of General Psychiatry 63, 90-100.

Sheline, Y. I., Mintun, M. A., Moerlein, S. M., & Snyder, A. Z. 2002. Greater loss of 5-

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9

Supporting Figures

FigS1. Surrogate data analysis. A global test of nonlinearity was carried out by a Wilcoxon

matched-pairs signed rank test comparing ApEn values computed on the original data paired

with the corresponding average ApEn values from the matching surrogate data series. Larger

sigma values indicate higher nonlinearity.

10

FigS2. Correlation with criminal records. The ApEn values of the EEG correlated with

drug-related criminal records. Asterisk (*) indicates significant difference in the ApEn values.

11

FigS3. Correlation with smoking. The ApEn values of MA abusers correlated with

heavy/light smoking. Heavy smoking is defined as more than or equal to 2 packs/day.

Asterisk (*) indicates significant difference in the ApEn values.

12

Meth addiction diagnostics using EEG

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Meth addiction diagnostics using EEG