J Neural Transm (1997) 104:483-495

_Journal of_ Neural Transmission 9 Springer-Verlag 1997 Printed in Austria

E E G - m i c r o s t a t e s in mild m e m o r y impairment and A l z h e i m e r ' s disease: possible association with disturbed information processing T. Dierks 1, V. Jelic 2, P. Julin 2, K. Maurer ~, L. O. Wahlund 2, O. Almkvist 2, W. K. Strik 3, and B. Winblad 2 1Department of Clinical Neurophysiology, Psychiatric Hospital, University of Frankfurt/Main, Federal Republic of Germany 2Alzheimer Research Center, Department of Clinical Neuroscience, Karolinska Institute, Huddinge, Sweden 3Department of Psychiatry, University of Wfirzburg, Federal Republic of Germany Accepted March 12, 1997

Summary. The only available functional neuroimaging methods reaching the time resolution of human information processing are E E G and MEG. Since spectral analysis implies analysis of longer time epochs, the high temporal resolution of E E G is partly lost. By dividing the E E G in the time-domain into segments of similar spatial distribution on the scalp (microstates) it has been possible to assess patterns of neuronal activity representing the information process currently performed by the brain. In the present study alterations of E E G microstates in subjective (n = 31) and objective (n = 38) memory impairment as well as in probable Alzheimer disease (DAT: n = 64) compared to healthy controls (n = 21) were investigated. The main findings were reduced segment durations and a more anterior center of gravity of the microstate topography in DAT. With more pronounced cognitive dysfunction larger window sizes were found. Shorter microstates and larger windows reflect more rapidly changing spatial activation patterns, and are interpreted as an impaired capability to establish stable brain states necessary for normal brain function. The anteriorization of the microstates is consistent with results in the frequency domain and may reflect neuropathological changes in DAT. Keywords: EEG, microstates, segmentation, cognitive dysfunction, dementia of Alzheimer type, information processing.

Introduction Dementia of Alzheimer type (DAT) is an organic disorder of the brain that is characterized by deterioration of various cognitive functions. Patients suffering from the disease become progressively more disoriented and out of touch with reality. Furthermore, pronounced deficits in working memory are

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present, with both verbal and spatial memory being impaired. Primary reason for these functional deficits are neuronal degeneration of pyramid cells in neocortical areas, predominantly in association cortices. The neuronal degeneration with its consecutive functional deficits can be assessed by various structural and functional neuroimaging methods. Brain volume, especially of the temporal and parietal lobe, is reduced (Wahlund et al., 1993; Murphy et al., 1993), and cerebral blood flow and glucose metabolism in these areas are also decreased (Duara et al., 1986; Nordberg, 1993). These methods do not reflect short-term brain processes since brain function is averaged over longer time. Higher human brain function like conscious information processing, however, are performed in the sub second range. It has been demonstrated that it is possible for the human brain to make 2 to 3 correct decisions per second, and the human reaction time is around 150ms (Debecker and Desmedt, 1970). In this time range the only available imaging method of higher cerebral functions is the acquisition of the electric or magnetic brain activity. Digitized E E G reaches time resolutions below the millisecond range. Fast imaging methods with high spatial resolution like functional MRI and ~502 PET have not reached such a high time resolution. The most common method for quantitative analysis of brain electrical activity is spectral analysis transforming EEG-data into the frequency domain. Since spectral analysis e.g. by Fourier transformation (FFT) usually is based on time-epochs around 2 sec which commonly are averaged over longer time duration, the high temporal resolution of E E G is partly lost. Furthermore, most quantitative E E G methods are based on data which is dependent on the choice of the recording reference (Lehmann and Skrandies, 1980). Therefore, reference independent methods are preferable since data prune to change with the arbitrary choice of reference are not well suited for physiological interpretations. Several attempts have been undertaken to identify homogenous EEGepochs to achieve a segmentation of the ongoing E E G (e.g. Praetorius et al., 1977; Barlow, 1985), in epilepsy (Grochulski and Penczek, 1986) and sleep (Gath and Bar On, 1983). Since most of these methods were applied in the frequency domain they were, as mentioned before, affected with methodological problems. Considering the spatial distribution of brain electrical fields which is reference independent in the time-domain, Lehmann (1984) noticed that stable topographical configurations of variable duration were separated by rapid transitions, and that a gradual transformation from one configuration to another was not a common feature in EEG. It must be assumed that at one point in time there is simultaneous activity present in several cortical areas. This is part of hypothesis of information processing such as the "Parallel Distributed Processing" (PDP; McClelland et al., 1986; Mesulam, 1990) where mental activity is described as the activity of a distributed neuronal network. Within this network, several cortical centers communicate simultaneously giving raise to a pattern of neuronal activity which represents the information process currently performed by the brain. These neuronal activation patterns are supposed to be reflected on the scalp by the electrical field distribution (Gevins et al., 1983; Lehmann, 1992). It has

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been proposed that the E E G segments with stable spatial configurations, microstates, reflect basic units of human cognition ("atoms of thought" L e h m a n n et al., 1987). A n important methodological issue is how to recognize or separate different spatial patterns. First proposals have been published by L e h m a n n et al. (1987) and W a c k e r m a n n et al. (1993). Strik and L e h m a n n (1993) published a data-driven m e t h o d to find an optimal window size for the space-oriented segmentation procedure. Previous studies, using this methodology in a clinical setting showed that there are shorter segments and increased topographical variability but no topographical differences of the microstates in depressive patients compared to controls (Strik et al., 1995). Abnormal topographical configurations of microstates have been reported in schizophrenic patients (Strik et al., 1994) and in patients with Gilles de la Tourette syndrome (Stevens et al., 1996). Since cognitive impairments are the leading symptoms in dementia of Alzheimer type, the objective of the present study was to investigate to which degree the spatial electrical activity patterns in subjects with subjective and objective m e m o r y disturbances as well as in patients with manifest D A T are altered. Furthermore, to find out whether the time epochs of stable spatial configurations are altered in duration, reflecting a temporal disarrangement of the neuronal networks responsible for information processing. Since most quantitative E E G studies in D A T patients demonstrated a slowing of E E G (Soininen et al., 1991; Dierks et al., 1991; Duffy et al., 1995) it was hypothesized in the present study that patients with cognitive dysfunction would show longer duration of the microstates if these reflected the properties of the E E G in the frequency domain. Methods

Subjects We studied in total 154 subjects. Twenty-one were healthy control subjects, 31 subjects complained of subjective memory impairment, 38 subjects showed objective memory impairment and 64 patients were diagnosed as suffering from dementia of Alzheimer type (DAT). In the DAT-group, 46 patients were classified as mildly impaired and 18 as moderately impaired (for further demographic data see Table 1 and for definition of groups see below). All subjects and patients were screened to exclude subjects with concomitant neurological or psychiatric disorders (besides DAT), as well as epilepsy, head injury, alcohol or drug dependency and use of psychopharmacologically active medication. Control subjects were recruited from ongoing projects at the Dept. of Clin. Neuroscience at the Karolinska Institute (Jelic et al., 1996) and were tested by the MiniMental-Status-Examination (MMSE; Folstein et al., 1975) to exclude any cognitive impairment (MMSE: 26-30). None of the control subjects complained about subjective memory impairment. All patients and subjects with subjective or objective memory impairment participated in a project on dementia and aging from the in- and out-patient Geriatric Department, Huddinge University Hospital. Subjects complaining about memory impairment who did not show significant decline of functional status or any difficulties in everyday life activities and did not fulfill the established criteria (DSM IV, American Psychiatric Association, 1994) for dementia were devided into two groups according to their performance on neuropsychological tests. Subjects who performed less than one standard

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Table 1. Demographic data of the investigated population

(MMSE Mini-Mental-Status-

Examination; Folstein et al., 1975)

Controls Subjective MI Objective MI Mild DAT Moderate DAT

n

Age (years)

Women/ men

MMSE

MMSE range

Education (years)

21 31 38 46 18

63.4 58.3 61.2 62.4 60.6

8/13 17/14 21/17

29.0 28.8 27.2 23.2 15.3

26-30 26-30 22-30 20-29 10-19

10.3 10.6 11.0 10.4 10.2

+_ 10.9 _+ 6.6 + 7.6 • 7.0 • 6.0

25/21 10/8

• 1.1 • 1.3 + 2.1 _+ 2.5 _+ 3.0

+ + • • +

3.0 3.6 3.5 3.4 3.1

deviation below the average of their age reference group in neuropsychological subtests representing one or more areas of cognition were classified as "subjects with subjective memory impairment" and subjected performing between 1 and 2 standard deviations below average as "subjects with objective memory impairment" (Rediess and Caine, 1996). Details concerning neuropsychological test battery and differences in neuropsychological performance between subgroups are described elsewhere (Jelic et al., 1996). All DAT patients fulfilled established criteria for probable DAT (McKhann et al., 1994). They were hospitalized for a period of 2 to 3 weeks for diagnostic evaluation, which included medical history, physical and neurological examination and routine laboratory tests. All patients were investigated with a battery of neuropsychological tests assessing cognitive function, language, apraxia, agnosia, visuospatial abilities, mood and behavioral changes. The stage of mental impairment was assessed by the MMSE. DAT patients were split into a group called "DAT patients with a mild degree of dementia" (MMSE = 2029) and a group of patients called "DAT patients with a moderate degree of dementia" (MMSE = 10-19).

Data acquisition Silver-silver chloride cup electrodes were applied at 20 sites to the scalp according to the international 10-20 system (Fpl, Fp2, F7, F3, Fz, F4, F8, T3, C3, Cz C4, T4, T5, P3, Pz, P4, T6, O1, Oz, and 02). The EEG were recorded referred to linked mastoids. Prior to the recording, the impedances were measured and low and similar values were ensured in all channels. The subjects were sitting comfortably in a reclining chair with their eyes closed. Data were recorded with a 20 channel Bio-Logic Brain Atlas. The EEG was sampled at a rate of 128 Hz per channel and stored onto magnetic disks for further analysis off-line. Before AD-conversion, the EEG was filtered analogous with a band pass of 1.0-30.0Hz. Overall amplification was 20.000 times. For data analysis the first fifteen successive artefact free 2 sec epochs were selected off-line from the stored spontaneous EEG. The epochs were chosen as early as possible (range: 3 to 11 sec) after starting the digital EEG recording. Subjects and patients were continuos monitored by the technical assistant to ensure a constant high vigilance level.

Segmentation procedure The spatial distribution of the EEG-signal was quantified by means of the centroids of the positive and of the negative area of the map representing the electrical activity using common average reference. At time points with optimal spatial signal to noise ratio which correspond to the peaks of the spatial variance (Global Field Power; GFP, Lehmann and Skrandies, 1980), a spatial adaptive window was placed around each of the two topographical map descriptors - the centroids. When the centroids at the next GFP peak is located outside this window a new segment is initiated, whereas in the case of similar

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configurations (centroids within the window) the segment continues at least until the next GFP peak. Obviously, larger windows yield fewer and longer segments, whereas smaller windows produce more and shorter segments. The applied procedure to optimize the window size based on meaningful data-driven criteria is described in detail in Strik and Lehmann (1993). For each EEG-epoch, the optimal window was determined individually (individual window size). After the segmentation procedure, the obtained segments, so called microstates, were quantified by their duration and location. Since topographically stable EEG-epochs with small excursions of the centroids lead to smaller optimal windows than EEG-epochs with highly variable topography, the optimal window size which is an expression of the spatial variability of the EEG-epoch was extracted as a further parameter.

Data analysis The following segment categories were analyzed: 1) the longest segment in each analyzed epoch, 2) all segments, 3) segments that include only one global field power peak (single peak segments) and 4) all segments excluding the segments that include only one global field power peak (multiple-peak-segment). The following parameters were extracted for each segment category and for each subject over all epochs: a) mean segment duration, b) mean amplitude of the electrical brain activity during the segment (measured at the global field power peaks), c) size of the optimal window, d) direction of the electrical field orientation during the segment (angle), and e) localization of the center of gravity of the electrical field on the scalp during the segment (in two dimensions: anterior-posterior and left-right; Dierks and Maurer, 1990).

Statistics A normal distribution of all parameters was achieved by logarithmical transformation (natural logarithm) which was tested by the Kolmogorov-Smirnov test for normality For all statistical evaluation logarithmical values were used. With the intention to keep transparency of the results, raw non-logarhithmical transformed data are presented in tables and figures. For each segment category and parameter an one-way A N O V A was performed (df = 4, 149) and, when a statistical significant result was achieved, the Scheffe-test was performed post-hoc to investigate group differences. For the parameter window size only one A N O V A was performed since the window size is independent of segment category. After a correction for multiple testing in-between the segment categories, the results regarding the topography of segments retained significancy. However, the study was performed with an exploratory intention to investigate which parameters would be sensible to separate various groups of cognitive impairment. Thus, all results are presented without any correction for multiple testing. Results

Overall statistical effects T h e o n e - w a y A N O V A s h o w e d significant overall effects for the d u r a t i o n of t h e l o n g e s t s e g m e n t a n d the s e g m e n t s with m u l t i p l e global field p o w e r p e a k s ( T a b l e 2). F u r t h e r m o r e , an overall significant effect was o b s e r v e d for t h e a m p l i t u d e , w i n d o w size a n d localization of the c e n t e r p o i n t in t h e anteriorp o s t e r i o r d i r e c t i o n of all s e g m e n t c a t e g o r i e s ( T a b l e 2). T h e r e was an overall significant d i f f e r e n c e in w i n d o w size b e t w e e n t h e g r o u p s (F[df = 4, 149] = 3, 16; p = 0.016). T h e w i n d o w size was smallest in t h e h e a l t h y c o n t r o l g r o u p a n d t e n d e d to get larger in t h e g r o u p s of subjects with subjective a n d objective

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Table 2. Result of the ANOVA (df = 4, 149) comparison between disease groups for each segment category and each segment parameter [duration = duration of segments (Fig. 2); amplitude = mean amplitude of GFP peaks in segments (Fig. 3); angle of the direction of the electrical field; ant.-post. = localization of the center of gravity of the electrical field distribution in anterior-posterior direction (Fig. 4), left-right = localization of the center of gravity of the electrical field distribution in left-right direction]. Significant p values are typed in bold characters

ANOVA Longest All Single Multi

Duration

Amplitude

Angle

F 4.81 2.01 0.37 3.19

F 3.50 2.82 2.49 2.98

F 1.18 0.96 0.569 0.095

p 0.001 0.100 0.828 0.015

p 0.009 0.027 0.046 0.021

p 0.324 0.433 0.689 0.434

Ant.-post.

Left-right

F 11.83 11.32 10.01 11.66

F 0.67 0.89 0.89 0.85

p 0.000 0.000 0.000 0.000

p 0.612 0.471 0.470 0.492

Fig. 1. Mean window size [+_standard deviation] leading to the optimal segmentation procedure for the 5 different groups of subjects respectively patients (a control, b subjective memory impairment, c objective memory impairment, d mild and e moderate dementia of Alzheimer type)

m e m o r y i m p a i r m e n t and was largest in b o t h groups with D A T patients (Fig. 1).

Post-hoc testing Segment duration (Fig. 2): T h e patients with a m o d e r a t e d e g r e e of D A T s h o w e d a significant s h o r t e r s e g m e n t d u r a t i o n of the longest s e g m e n t c o m p a r e d to h e a l t h y c o n t r o l subjects and to subjects with subjective a n d objective m e m o r y i m p a i r m e n t . Since no overall significant effects w e r e s e e n for t h e categories "all s e g m e n t s " a n d "single p e a k s e g m e n t s " no p o s t - h o c c o m p a r i -

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Fig. 2. Mean [_+standard deviation] segment duration for the 4 segment categories (A longest segment; B all segments; C single GFP peak segments; D multi GFP peak segments) and the 5 different groups of subjects respectively patients (M1 memory impairment; DA T dementia of Alzheimer type)

sons were performed. For the multiple-peak segment category, moderately demented patients exhibited significantly shorter segments compared to subjects with subjective memory impairment, and a tendency to shorter segments compared to healthy controls and to objective memory impaired subjects. Mean amplitude of GFP peaks in segments (Fig. 3): Even though there was a slight decrease of amplitude in the mildly and especially in the moderately demented DAT-patients the main reason for the overall significant effect for all four segment categories was the increase in amplitude in subjects with objective memory impairment. Except for the comparisons with this group of objectively memory impaired subjects no significant differences could be obtained in the post hoc tests for any segment category. Angle oft he direction of electricalfield: Since no overall significant effects were obtained in the ANOVA, further post hoc testing was not performed.

Localization of the center of gravity of the electrical field in the anterior posterior direction (Fig. 4): Moderately as well as mildly demented DATpatients showed a significant more anterior localization compared to healthy control subjects and to subjects with subjective and objective memory impairment. No significant differences were observed neither between healthy subjects and subjects with subjective and objective memory impairment, nor between mildly and moderately demented patients. However, moderately

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Fig. 3. Mean amplitude [+standard deviation] of GFP peaks in segments for the 4 segment categories categories (A longest segment; B all segments; C single GFP peak segments;D multi GFP peak segments) and the 5 different groups of subjects respectively patients (MI memory impairment; DAT dementia of Alzheimer type) demented patients did show a more anterior localization compared to the mildly demented one.

Localization of the center of gravity of the electrical field in left right direction: Since no overall significant effects were obtained in the ANOVA, further post hoc testing was not performed. Discussion

The purpose of the present exploratory study was to characterize alterations of time epochs with similar spatial topographical pattern, microstates, of spontaneous brain electrical activity in patient groups showing different degrees of cognitive dysfunction. Consequently no alpha adjustment was performed with regard to different segment categories. One of the main findings of the investigation was a reduced segment duration in patients suffering from dementia of Alzheimer type. Furthermore, the segments were located more anteriorly in the demented group compared to healthy controls and to the two groups of subjects with subjective and objective memory impairment. The observation of shorter segment duration in demented patients was not expected since the most common described feature of E E G in patients with cognitive deficits is a slowing of the E E G

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Fig. 4. Mean localization [_+standard deviation] of the center of gravity of the electrical field in anterior posterior direction for the 4 segment categories categories (A longest segment; B all segments; C single GFP peak segments; D multi GFP peak segments) and the 5 different groups of subjects respectively patients (MI memory impairment; DA T dementia of Alzheimer type) (Dierks et al., 1991, 1993; Duffy et al., 1995). This slowing of E E G is supposed to reflect the slowing of information processing in dementive diseases (Nebes and Brady, 1992). The finding of shorter segments in demented patients shows that the spatial E E G segmentation in the time domain leads to independent results and, therefore, offers additional information compared to conventional frequency analysis of electrical brain activity. In particular, the differences of the microstate duration can not be explained by changes of the carrier frequency of the E E G since in the investigated patient groups a slowing of E E G has been reported (Jelic et al., 1996). Furthermore, the larger optimal window-size in demented patients can not explain the result of shorter duration in demented patients, since larger windows in the demented group, in principle, allowed longer microstates. In a previously published study, based on a similar methodology, longer segment durations in patients with dementia of Alzherimer type were reported (Ihl et al., 1993). This is, apparently, in contrast to the results of the present investigation. However, the absolute length of the segments in the Ihl et al. study was much shorter than of those of the present investigation, and reached approximately the time between phase reversals of the EEG. The methodology used by Ihl and coworkers detected virtually only segments which we defined as single peak segments, and this is underscored by the fact

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that the durations of our single peak segments are similar to the segments reported by Ihl et al. This is of practical importance since single peak segments are dependent of the E E G carrier frequency (Strik, 1995) and, thus, explains why they were longer in the slowed E E G of demented patients. In the present study additional information is attained by parting segments into different categories allowing a more differentiated picture of alterations of brain processing in cognitive dysfunction. In dementia, cognitive performance is reduced and the associated behavioral correlates are delayed, suggesting that information processing is slowed down as a whole. In this context, considering the proposal of microstates being the building blocks of thought, shorter microstates might be interpreted as a sign of reduced maintenance of single units of information processes. In other words, the ability of the brain to structure the flow of information into stable communicating neuronal activation patterns, necessary for adequate and correct brain function, is disturbed. Several clinical apparent cognitive disturbances are manifested already in early stages of dementia of Alzheimer type, one of the more obvious is reduced attentional performance in some cognitive areas (Parasuraman et al., 1992). Alzheimer patients do not just perform slower in cognitive tests requiring attention, but they also produce more errors. In the light of the present study, the loss of ability to focus on the task can be interpreted as an incapability to establish stable states of communicating neuronal networks for time epochs (microstates) long enough to solve the task. This interpretation is supported by the findings of Mohr et al. (1990) who reported an impaired cortical control of attention. The second major finding of a more anteriorly located center of gravity of the microstates is compatible with investigations using conventional frequency analysis, and physiological confirmation come from studies in which the intracerebral generators of brain electrical activity were estimated (Dierks et al., 1993). The anteriorization of brain activity probably reflects the neuropathological alterations in DAT. This degeneration is most pronounced, and starts commonly in temporo-parietal cortical regions (Brun and Gustafson, 1976). Positron emission tomography (PET) and single photon emission computed tomography (SPECT) studies of cerebral blood flow, oxygen consumption and glucose metabolism demonstrate pathological changes in temporo-parietal areas in earlier stages of the disease (Fazekas, 1990). This pattern of histopathological and functional changes indicate that normal neuronal connections within these regions are disrupted, while frontal areas are still intact. It may be speculated that the less impaired frontal neuronal populations are the reason for the more anterior center of gravity of the brain electrical field. The physiological meaning of differences in GFP amplitude is difficult to interpret. Since the differences in large follow the same trend as for localization of the center of gravity of microstates in anterior posterior direction, meaning that more anterior localized microstates exhibit lower amplitude, it could be speculated that the disrupted parieto-temporal neuronal networks in DAT will lead to a reduced strength of neuronal activation compared to the

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one in undisrupted neuronal networks. However, since an increased GFP amplitude especially was found in objective memory impaired subjects this explanation is speculative and a final interpretation remains open. Regarding the potential clinical useful ability to separate groups with different degree of cognitive impairment by using segmentation it was a clear difference between subjects with mild cognitive disturbances and patients with a moderate degree of dementia. The localization of the center of gravity in anterior-posterior direction allowed a separation between subjects with objective memory disturbances and patients with a mild degree of dementia of Alzheimer type. Except for this parameter there was, however, no clear cut distinction between non-clinical apparent cognitive disturbances and very mild DAT. This is in line with the opinion that dementia of Alzheimer type is a gradual proceeding pathological process and not one that is abruptly occurring (Braak et al., 1993). In conclusion, the present results indicate that the spatial microstate segmentation is a valuable method for the investigation of rapid spontaneous brain activity. The method is independent from the EEG-parameters in the frequency domain, and is supposed to furnish meaningful information about neuronal activation patterns which are related to cognitive processes. In the present study, shorter microstates were found in demented patients. This novel correlate of disturbed cognitive abilities in dementia is in contrast with the general slowing of cognition and of the EEG frequencies, and is possibly related to impairments of attentional focussing and information processing. Acknowledgement This study was in part supported by the german research counsil (DFG: Di 571/2-1). References American Psychiatric Association (1994) Diagnostic and statistical manual of mental disorder, 4th edn. American Psychiatric Association, Washington DC, pp 1142 Barlow JS (1985) Methods of analysis of nonstationary EEGs, with emphasis on segmentation techniques: a comparative review. J Clin Neurophysiol 2:267-304 Braak H, Braak E, Bohl J (1993) Staging of Alzheimer-related cortical destruction. Eur Neurol 33:403-408 Brun A, Gustafson L (1976) Distribution of cerebral degeneration in Alzheimer's disease. Arch Psychiatr Nervenkr 223:15-33 Debecker J, Desmedt JE (1970) Maximum capacity for sequential one-bit auditory decisions. J Exp Psychol 83:366-372 Dierks T, Maurer K (1990) Reference-free evaluation of auditory evoked potentials P300 in aging and dementia. In: Dostert P, Riederer P, Strolin Benedetti M, Roncucci R (eds) Early markers in Parkinson's and Alzheimer's disease. Springer, Wien New York, pp 197-208 (New Vistas in Drug Research, vol 1) Dierks T, Perisic I, Froelich L, Ihl R, Maurer K (1991) Topography of quantitative E E G in dementia of Alzheimer Type: relation to severity of dementia. Psychiatry Res Neuroimaging 40(3): 181-194 Dierks T, Ihl R, Fr61ich L, Maurer K (1993) Dementia of Alzheimer type (DAT): effects on the spontaneous EEG described by dipole sources. Psychiatry Res Neuroimaging 50:151-162

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Praetorius HM, Bodenstein G, Creutzfeldt OD (1977) Adaptive segmentation of EEG records: a new approach to automatic EEG analysis. Electroencephalogr Clin Neurophysiol 42:84-94 Rediess S, Caine ED (1996) Aging, cognition and DSM-IV. Aging, Neuropsychology and Cognition 3:105-117 Soininen H, Partanen J, Paakonen A, Koivisto E, Riekkinen PJ (1991) Changes in absolute power values of EEG spectra in the follow-up of Alzheimer's disease. Acta Neurol Scand 83:133-136 Stevens A, Gt~nther W, Lutzeberger W, Bartels M, Mfiller N (1996) Abnormal topography of EEG microstates in Gilles de la Tourette syndrome. Clin Neurosci 246: 310316 Strik WK (1995) Short and sustained brain electrical microstates and their relevance for cognitive processes. Riv Pat Nerv Ment 3:17-28 Strik W, Lehmann D (1993) Data-determined window size and space-oriented segmentation of spontaneous EEG map series. Electroencephalogr Clin Neurophysio187: 169174 Strik WK, Dierks T, Lehmann D (1994) Spatial configuration of microstates in the spontaneous EEG of residual schizophrenics. Brain Topogr 6:252 Strik WK, Dierks T, Becker T, Lehmann D (1995) Larger topographical variance and decreased duration of brain electric microstates in depression. J Neural Transm [Gen Sect] 99:213-222 Wackermann J, Lehmann D, Michel CM, Strik WK (1993) Adaptive segmentation of spontaneous EEG map series into spatially defined microstates. Int J Psychophysiol 14:269-283 Wahlund LO, Andersson-Lundman G, Basun H, Almkvist O, BjOrksten KS, Saaf J, Wetterberg L (1993) Cognitive functions and brain structures: a quantitative study of CSF volumes on alzheimer patients and healthy control subjects. Magn Reson Imaging 11:169-174 Authors' address: T. Dierks, M.D., Ph.D., Department of Psychiatry, University of Frankfurt, Heinrich-Hoffmann-Strasse 10, D-60528 Frankfurt, Federal Republic of Germany. Received December 5, 1996