Quantitative Electroencephalography and Low Resolution Electromagnetic Tomography Imaging of Alzheimer’S Disease

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0ORIGINAL ARTICLE0 Psychiatry Investig 2007;4:31-37 ISSN 1738-3684

Quantitative Electroencephalography and Low Resolution Electromagnetic Tomography Imaging of Alzheimer’s Disease

Hyung-Tae Jung, MD, ObjectiveㅋThe EEG abnormalities of Alzheimer’s disease (AD) patients are characterized by Seung-Hwan Lee, MD, PhD, increased slow wave activities and reduced asymmetry between the two hemispheres. We attempted to find the specific spatio-temporal EEG pattern of AD through quantitative EEG Jong-Nam Kim, PhD, (qEEG) and the source localization of specific frequency bands. Kang-Joon Lee, MD, PhD, MethodsㅋThe AD group consisted of 22 patients who fulfilled the DSM-IV criteria of AD with Young-Cho Chung, MD, PhD no space occupying lesions confirmed by brain CT or MRI. The normal control (NC) group Department of Psychiatry, consisted of 27 subjects with no personal history of psychiatric or neurological abnormalities. Inje University College of Medicine, We performed qEEG, compared the hemispheric asymmetry between the AD and NC groups, Ilsan Paik Hospital, Goyang, Korea and tried to obtain source imaging of each frequency band using low resolution electromagnetic tomography (LORETA). ResultsㅋCompared with the NC group, the AD patients had significantly increased slow wave activities of the theta (4-7 Hz) and delta waves (1-3 Hz) over all of the electrodes. There was no statistically significant asymmetric difference between the AD and NC groups. The slow waves of the AD patients were dominant in the right hemisphere compared to the NC subjects. Increased theta wave activity was observed, especially in Brodmann area 40 (inferior parietal lobule) in the AD patients compared with the NC subjects. Increased delta wave activity was observed especially in Brodmann area 7 (postcentral gyrus) in the AD patients compared with the NC subjects. The MMSE score had a significant negative correlation with the theta waves and a positive correlation with the alpha waves in the AD patients. There was a positive correlation between the duration of illness and the theta waves in the AD patients. ConclusionsㅋOur results showed that AD patients had increased theta and delta wave activity in the right parietal areas, which reflect their decreased brain function in these regions. Our results suggest that qEEG and LORETA imaging are useful tools for detecting and evaluating AD.

KEY WORDS: Quantitative electroencephalography, Brain mapping, Low-resolution brain electromagnetic tomography, Alzheimer’s disease.

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Introduction

Correspondence Alzheimer’s disease (AD) represents the most frequent cause of senile dementia. Seung-Hwan Lee, MD, PhD This disease has a slow onset and gradual progression, so its diagnosis is very im- Department of Psychiatry, portant. Over the past few years, considerable importance has been attributed to the Inje University College of Medicine, Ilsan Paik Hospital, diagnostic techniques of brain imaging, which are able to provide morphological and 2240 Daehwa-dong, Ilsan-seo-gu, functional images. EEG mapping is one of the most widely used methods. In this Goyang 411-706, Korea study, we used qEEG and LORETA1-3 to perform EEG mapping. Tel +82-31-910-7262 qEEG can compare the statistical values of the voltage and frequency that quali- Fax +82-31-910-7268 E-mail [email protected] tative EEG cannot. Therefore, it can draw a topographic map representing focal brain E-mail [email protected] function. LORETA can make a three dimensional and functional brain map by calcu-

qEEG and LORETA Imaging of Alzheimer’s Disease lating the brain waves of the scalp surface. Although this and functional brain imaging of AD through qEEG and method has a low resolution power, it can give us im- LORETA.1-3 Also, we analyzed the relations between the portant information about brain functioning. mini mental status exam (MMSE) score and the power The EEG patterns of AD patients have consistency. of each frequency value. They are characterized by a slowed mean frequency and reduced asymmetry between the two hemispheres.4 qEEG Methods has also shown that there is a decrease in the mean frequency along with an increase in the delta and theta power Subjects and a parallel decrease in the alpha and beta power in AD The AD group consisted of 22 patients (19 female and patients compared with the corresponding results for nor- 3 male) who fulfilled the DSM-IV criteria of dementia mal elderly subjects.5-11 It is generally thought that the of Alzheimer’s type. Their mean age was 73.8±7.6 years earliest changes are an increase in the theta activity and with a mean duration of AD 22.4±19 months. Patients a decrease in the beta activity, which are followed later with other medical conditions known to cause dementia by a decrease in the alpha activity. The delta activity in- were excluded by means of neurological, serological and creases at a later period of the disease course. Patients imagery tests, including computed tomographic imaging with severe dementia exhibit a decrease in alpha and an scan (CT-scan) and magnetic resonance imaging (MRI). increase in delta activity.12-16 The symptom severity of AD was assessed by MMSE. There have been many equivocal reports about the to- The mean MMSE score was 19.2±3.6. The control group pographic findings in AD patients. However, Go et al.17 consisted of 27 subjects (13 female and 14 male) with no reported there was a pathophysiologic location especi- personal history of psychiatric or neurological abnorma- ally in the left parietotemporal areas in AD patients com- lities. Their mean age was 66.5±4.7 years and their mean pared to the NC group. Moreover, they reported that these MMSE score was 27.37±1.1 (Table 1). findings were comparable with the PET or SPECT findings.18,19 Duffy et al.20 reported that the areas of maxi- EEG Recording and analysis mal group differences in slow waves between the senile The 18 EEG channels of the international 10-20 cri- AD patient group and their controls involved the mid- teria were used. The right ear was used as a reference frontal and anterior frontal lobes, bilaterally. Elmstahl et electrode. The measurements were performed with the al.21 reported that the delta wave activity was most mar- subjects laying down in a resting position. Their brain ked over the posterior regions of the brain in AD patients. waves were recorded about 15 minutes using a Nicolete Prichep et al.22 reported that there was no localized or system (Nicolete biomedical, Madison, WI, WSA) with a lateralized findings, but only diffuse increased theta waves sampling rate of 250 Hz/channel, a sensitivity of 7μV, a over all brain regions. Schreiter-Gasser et al.23 reported lower filter of 1 Hz, a higher filter of 70 Hz, and a time that there were increased slow waves in the total brain constant of 0.3. Five epochs (eye closed state) were taken area, but there were localized decreased fast waves in per subject over the whole record. The length of an epoch the left parietotemporal area. was 4.5 seconds, and eye movement and blinking and arti- Generally, the asymmetry of the cerebrum is a rather fact data were visually screened and rejected. In the analy- natural phenomenon. However, the asymmetry of the EEG sis of the qEEG, the delta range was 1-3 Hz, the theta pattern of AD patients is more significant than that of NC range 4-7 Hz, the alpha range 8-12 Hz, and the beta ran- subjects.17 Celsis et al.24 reported that there were lateral ge 13-25 Hz. asymmetries of the cognitive functions, SPECT and EEG findings in AD patients, but not in controls. Montplaisir Statistical analysis et al.25 reported that the degrees of interhemispheric asy- The independent t-test and bivariate correlation were mmetry calculated by both qEEG and single photon emis- TABLE 1. Demographic data of AD and NC subjects sion computerized tomography (SPECT) were concordant AD NC p-value 26 for the parieto-occipital region. Breslau et al. reported Numbers of patients 22 27 that AD patients were characterized by a marked delta Sex Male 03 14 asymmetry in the temporal regions, which was not seen Female 19 13 in the NC groups. Age (year) 073.8±07.6 66.50±04.7 <0.001 Thus, the measurement of qEEG or asymmetry of brain Symptom duration (month) 22.4±19. waves may be a useful device for the early detection of MMSE 019.2±03.6 27.37±01.1 <0.001 AD. Therefore, in this study, we attempted to find the Values are mean±standard deviation. MMSE: mini mental sta- specific EEG pattern, hemispheric asymmetry findings tus exam, AD: Alzheimer’s disease, NC: normal control

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HT Jung et al. used to analyze the EEG relative values, including the the alpha waves in the AD patients. There was a posi- spectral power and asymmetry. tive correlation between the duration of illness and theta To analyze the asymmetry, we used the lateral asymme- waves in the AD patients (Table 5). try index (LAI).27 The LAI was determined by comparing the corresponding frequency band percentages for the left TABLE 2. Mean transformed relative power of electrodes for theta frequency band (4-7 Hz) in the resting EEG of AD patients and right hemispheres. The LAI was computed by divi- and NC subjects ding the differences between the two hemispheres by their Location AD (N=22) NC (N=27) t p sum, A=(Pleft-Pright)/(Pleft+Pright), where Pleft and Fp1 0.088 0.067 2.785 0.006† Pright are the relative powers of the corresponding fre- Fp2 0.096 0.078 2.140 0.033* quency band in the appropriate brain region. The resulting F3 0.125 0.096 2.489 0.014* values potentially ranged from 1, when the right hemis- F4 0.013 0.107 1.922 0.056* phere had zero activity, to -1, when the left hemisphere F7 0.102 0.078 2.918 0.004† had zero activity. An index of 0 indicated equivalent ac- F8 0.100 0.085 1.894 0.060* tivity in the two hemispheres. A positive LAI points to T1 0.098 0.084 2.148 0.033* dominant brain activity in the left hemisphere, while a T2 0.102 0.087 2.175 0.031* negative LAI indicates dominant brain activity in the T3 0.105 0.081 3.217 0.002† right hemisphere. T4 0.118 0.081 4.844 0.000† We made functional source images using the LORETA- † 1-3 T5 0.113 0.087 3.208 0.002 key package. The maximum t-statistics of LORETA is † a kind of non-parametric analysis. Thus, it compares each T6 0.110 0.078 3.596 0.000 † group in 5,000 randomized comparisons. The voxel-by- C3 0.113 0.088 2.872 0.005 † voxel independent t-test of each group was conducted. C4 0.122 0.083 4.479 0.000 We obtained LORETA images that were increased in each P3 0.103 0.086 2.034 0.043* † frequency band in each brain region. P4 0.115 0.085 3.002 0.003 O1 0.097 0.083 1.731 0.085* Results O2 0.095 0.081 1.570 0.118* *p<0.05 student t-test,†p<0.01 student t-test. EEG: electroencephalography, AD: Alzheimer’s disease, NC: normal control We compared the relative value of the spectral powers in each frequency between the AD and NC groups, and TABLE 3. Mean transformed relative power of electrodes for del- found prominent increases in the theta and delta power ta frequency band (1-3 Hz) in the resting EEG of AD patients spectra in the AD patients compared to the NC subjects. and NC subjects In the theta frequency spectrum, there were significant Location AD (N=22) NC (N=27) t p statistical differences in almost all electrodes in the AD Fp1 0.117 0.109 0.823 0.411 patients compared to the NC subjects. In addition, the AD Fp2 0.120 0.110 1.009 0.314 patients showed maximal differences in the T4, T6, and F3 0.095 0.091 0.436 0.663 C4 electrodes (p<0.001) compared to the NC subjects. F4 0.093 0.088 0.680 0.497 In the delta frequency spectrum, the AD patients showed F7 0.122 0.111 1.328 0.186 statistically significant differences in the T2 electrodes F8 0.124 0.111 1.388 0.167 (p<0.01). However, in the alpha and beta frequency bands, T1 0.148 0.134 1.503 0.134 there were no statistically significant differences between T2 0.152 0.127 2.638 0.009† the AD and NC subjects (Table 2 and 3). T3 0.111 0.095 1.983 *0.049* There was no significant statistical difference in the T4 0.112 0.097 1.877 0.062 LAI between the AD and NC groups (Table 4). T5 0.088 0.081 0.914 0.362 In the LORETA source imaging, increased theta wave T6 0.091 0.075 1.669 0.097 activity was observed, especially in Brodmann areas 40, C3 0.088 0.079 1.183 0.238 2, 1, 3 and 5 (inferior parietal lobule, post central gyrus) C4 0.092 0.086 0.823 0.411 in the AD patients compared to the NC subjects. Increased P3 0.101 0.085 1.980 *0.049* delta wave activity was observed especially in Brodmann P4 0.112 0.097 1.477 0.141 ( ) areas 7, 5, 4, 3 and 40 post central gyrus in the AD pa- O1 0.093 0.086 0.652 0.515 ( ) tients compared to the NC subjects Figures 1 and 2 . O2 0.091 0.077 1.616 0.108 The MMSE score had a significant negative correla- *p<0.05 student t-test,†p<0.01 student t-test. EEG: electroence- tion with the theta waves and a positive correlation with phalography, AD: Alzheimer’s disease, NC: normal control

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qEEG and LORETA Imaging of Alzheimer’s Disease

Discussion sion of long cortico-cortical association fibers. The neurons are markedly deficient in the basal forebrain nuclei, We found that the AD patients had significantly inc- and this deficiency may account for the severe diminu- reased slow wave activities over all of the electrodes com- tion in the levels of choline acetyltransferase and acetyl- pared with the NC subjects. Moreover, there was a signi- choline in the neocortex and paleocortex. The brain of ficant correlation between the MMSE and slow waves. AD patients exhibits a significant reduction in the mar- These findings suggest that neuronal death in AD can kers of cholinergic transmission. The atrophy of the basal cause increased slow wave activity, which is a pathog- forebrain cholinergic neurons innervating the neocortex nomonic feature of this disease. and hippocampus is also observed in AD. Since several The pathophysiological origin of the slowing of the studies demonstrated that acetylcholine (Ach) and the EEG in AD can be explained by the cholinergic deficit. basal forebrain system maintain desynchronized EEG ac- AD is thought to be a syndrome of neocortical disconnec- tivity, a loss of cholinergic innervation of the neocortex tion, in which profound cognitive losses arise from the might play a critical role in the slowing of the EEG of disrupted structural and functional integrity of the long AD patients.4 cortico-cortical tracts. Senile plaques and neurofibrillary Ricceri et al.28 conducted an animal experiment, in tangles of AD prominently inhibit the signal transmis- which they examined the long-term effects of neonatal lesions of the basal forebrain cholinergic neurons induced TABLE 4. Comparison of the LAI of relative value of EEG theta and delta waves between AD patients and NC subjects by intracerebroventricular injections of an immunotoxin. LAI of AD LAI of NC In the animals lesioned on postnatal day 7 and tested 6

Frequency Channel (N=22) (N=27) p months later, the EEG cortical patterns presented changes Mean SD Mean SD in their alpha, beta and delta activities similar to those Theta F7-F8 -0.015 0.23 -0.038 0.24 0.081 observed in Alzheimer-like dementia. These findings in- (4-7 Hz) Fp1-Fp2 -0.039 0.24 -0.062 0.24 0.448 dicate that neonatal and permanent basal forebrain cho- T3-T4 -0.056 0.20 -0.025 0.21 0.226 linergic hypofunction is sufficient to induce behavioral C3-C4 -0.025 0.23 -0.009 0.22 0.253 and neuropathological abnormalities. T5-T6 -0.048 0.24 -0.060 0.25 0.719 There was no significant statistical difference in the P3-P4 -0.035 0.25 -0.017 0.24 0.099 LAI of the relative spectral power between the AD and O1-O2 -0.026 0.21 -0.031 0.21 0.855 NC groups in our study. However, when we used the ab- Delta F7-F8 -0.004 0.27 -0.001 0.26 0.892 solute spectral power, we could find asymmetry of the (0.5-3 Hz) Fp1-Fp2 -0.022 0.27 -0.006 0.28 0.655 EEG power in the AD patients. Most of our AD patients T3-T4 -0.008 0.24 -0.012 0.21 0.492 were in the early stage of AD. We believe that this is one C3-C4 -0.033 0.24 -0.029 0.27 0.891 of the reasons why there was no asymmetry of the rela- T5-T6 -0.015 0.30 -0.045 0.26 0.412 tive spectral power in our subjects. P3-P4 -0.029 0.27 -0.039 0.25 0.761 In LORETA imaging, maximal different areas of slow O1-O2 -0.036 0.25 -0.021 0.27 0.652 wave activities were observed generally in the right pa- Student t-test. SD: standard deviation, LAI: lateral asymmetry rietotemporal region in the AD patients compared to the index, AD: Alzheimer’s disease, NC: normal control NC subjects. Even though there is some controversy sur-

TABLE 5. Correlation between MMSE & duration of illness (DOI) and spectral power of resting EEG of Alzheimer patients Fp1 F3 C3 P3 Fp2 F4 C4 P4 F7 T3 T5 O1 F8 T4 T6 O2 T1 T2 MMSE Alpha ++ ++ ++ ++ ++ ++ ++ ++ ++ ++ ++ ++ + ++ ++ ++ ++ Beta +++ +++ ++++ Theta ------Delta ------DOI Alpha + Beta ------Theta + + +++ ++ Delta - Statistical test was done by bivariate correlation analysis. +,- p<0.05 positive, negative correlation, ++,-- p<0.01 positive, negative correlation. MMSE: mini mental status exam, EEG: electroencephalography

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L A R L S R A S P

LORETA P Top IIBack Left

R A L R SSL P A

P Bottom IFront I Right FIGURE 1. The maximum difference theta wave activity (4-7 Hz) area of LORETA Imaging of the AD patients compared to the NC subjects. The maximum difference theta wave activity area was the right inferior parietal lobule (Brodmann area 40). L: left, R: right, A: anterior, P: posterior, S: superior, I: inferior, LORETA: low resolution electromagnetic tomography, AD: Alzheimer’s disease, NC: normal control.

L A R L S R A S P

LORETA P Top IIBack Left R A L R SSL P A

P Bottom IFront I Right FIGURE 2. The Maximal difference delta wave (1-3 Hz) activity area of LORETA Imaging of the AD patients compared to the NC subjects. The maximal difference delta wave activity area was the right post central gyrus (Brodmann area 7). L: left, R: right, A: anterior, P: posterior, S: superior, I: inferior, LORETA: low resolution electromagnetic tomography, AD: Alzheimer’s disease, NC: normal control. rounding this issue, this finding is in agreement with the MMSE and theta waves, and a significant positive cor- results of a previous study.20 Duffy et al.20 reported that relation between MMSE and alpha waves in the AD the maximal group differences between presenile patients patients. Furthermore, there was a positive correlation bet- and NC subjects are detected in the right posterior tem- ween the duration of illness and theta waves in the AD poral area. Moreover, the right-sided numerical features patients in our study. Correlational analyses between the derived from the topographic maps proved most useful MMSE scores, duration of illness and spectral power of in differentiating the presenile patients and their age-mat- qEEG indicate that increased slowing activity was asso- ched controls. ciated with the state of progression of the disease and the There was a significant negative correlation between severity of AD. These findings imply that EEG can be a

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qEEG and LORETA Imaging of Alzheimer’s Disease useful diagnostic tool for AD. compared with structural brain imaging in patients having organic bra- There are several limitations in our study. The first is in lesion. J Korean Neuropsychiatr Assoc 2006;45:199-207. 4. Jeong J. EEG dynamics in patients with Alzheimer’s disease. Clin the age difference between the AD patients and NC sub- Neurophysiol 2004;115:1490-1505. jects. The age of the AD patients was relative higher than 5. Bennys K, Rondouin G, Vergnes C, Touchon J. Diagnostic value of that of the NC subjects. Even though there were no sig- quantitative EEG in Alzheimer’s disease. Neurophysiol Clin 2001;31: nificant correlations between the age and slow waves ac- 153-160. 6. Brenner RP, Ulrich RF, Spiker DG, Sclabassi RJ, Reynolds CF 3rd, tivities in our subjects, the age is surely an important fac- Marin RS, et al. Computerized EEG spectral analysis in elderly nor- tor influencing EEG activity. Secondly we only used the mal, demented and depressed subjects. Electroencephalogr Clin Neuro- MMSE to evaluate the severity of symptoms of the AD physiol 1986;64:483-492. patients. If we had also used other evaluation scales such 7. Coben LA, Danziger WL, Berg L. Frequency analysis of the resting awake EEG in mild senile dementia of Alzheimer type. Electroen- as the Dementia Rating Scale, Wechsler Intelligence Test, cephalogr Clin Neurophysiol 1983;55:372-380. Wechsler Memory Test, more informative functional corre- 8. Brunovsky M, Matousek M, Edman A, Cervena K, Krajca V. Objec- lations in AD would have been found. Thirdly, we could tive assessment of the degree of dementia by means of EEG. Neurop- not control the effect of psychotropic drugs. There is some sychobiology 2003;48:19-26. 9. Adler G. The EEG as an indicator of cholinergic deficit in Alzhei- controversy about the effect of psychotropic drugs on EEG. mer’s disease. Fortschr Neurol Psychiatr 2000;68:352-356. 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