Escolar Documentos
Profissional Documentos
Cultura Documentos
www.elsevier.com/locate/ijpsycho
Department of Psychiatry and Psychotherapy, General Medical Faculty, Semmelweis University, Budapest, Hungary
b
Institute of Psychology, Hungarian Academy of Sciences, Budapest, Szondi u. 83-85. Hungary
Received 27 October 2006; received in revised form 2 March 2007; accepted 3 May 2007
Available online 13 May 2007
Abstract
Electroencephalographic measures combined with cognitive tasks are widely used for the assessment of cognitive and pathophysiological
changes in Alzheimer's disease (AD). Instead of the analysis of EEG data obtained during the performance of the task, in this study data recorded
in the immediate after-task period were analyzed. It was expected that this period would correspond to the electrophysiological consequences of
the cognitive effort. Data of 14 patients with AD (MMS score: 1624) were compared to that of 10 healthy control subjects. Reverse counting of a
fix duration was used as a cognitive task. Changes of relative frequency spectra, and those of inter-and intrahemispheric coherence were analyzed.
Relative theta power was significantly higher in AD patients compared to the controls both before and after the task. The performance of the task
resulted in an increase of the relative alpha2 band in the AD group, whereas it slightly decreased in the control group.
The most prominent coherence differences between AD and controls were found in the alpha1 band, especially for long-range coherence
values. Coherence in this frequency band increased in the control group following the task, not seen in the AD group. We conclude that EEG
parameters calculated from epochs following the completion of a cognitive task clearly differentiates patients with AD from normal controls. The
electrophysiological changes found in AD may correspond to the decrease of functional connectivity of cortical areas and to the malfunctioning of
the networks engaged in the cognitive task investigated.
2007 Elsevier B.V. All rights reserved.
Keywords: Alzheimer's disease; EEG frequency spectra; EEG coherence; Cognitive task; Mental arithmetic
1. Introduction
Detection of functional brain abnormalities, including the
impairment of cognitive processes in the early stages of
Alzheimer's disease (AD) and mild cognitive impairment
(MCI) is an important aspect for the diagnosis and effective
treatment of the disease. The EEG appears to be a particularly
sensitive method to detect and track functional changes in the
brain including those caused by deterioration of neuronal
connectivity and remains one of the best techniques in the
diagnosis (Claus et al., 1999), staging (Kowalski et al., 2001)
and prediction of the progress of AD Jonkman (1997).
According to the rather widely held view the development of
Corresponding author. Tel.: +36 1 3542 290; fax: +36 1 3542 416.
E-mail address: molnar@cogpsyphy.hu (M. Molnr).
0167-8760/$ - see front matter 2007 Elsevier B.V. All rights reserved.
doi:10.1016/j.ijpsycho.2007.05.002
253
254
to those observed in control subjects and as such, can quantitatively be presented. Thus, it was assumed that 1) the state of
the subject as reflected by the electrophysiological activity
recorded immediately after the performance of a cognitive task
reflects the consequences of the effort required by the task and
2) that the fixed duration and level of difficulty of the task
represented an approximately equal load for all subjects within
the groups making the interindividual comparison of the effect
of the task possible.
Our primary hypothesis was that differences observed in the
electrophysiological parameters (spectral parameters and
changes of coherence in the present study) between the before-task, and after-task conditions will be markedly different in
AD patients compared to those seen in controls. We expected to
find less prominent changes in the AD patients than those seen
in normal controls since the available cognitive capacity is
presumably decreased in AD. In addition, the neural circuitry
involved in the cooperative activity of interactive neuronal
systems during cognitive processes is presumably impaired in
AD depending upon the stage of the disease.
2. Materials and methods
2.1. Patients and subjects
The study was approved by the Medical Ethical Committee
of the Semmelweis University, Budapest. Participants signed an
informed consent after being given complete explanation about
the protocol and the purpose of the study.
The group of AD patients consisted of 8 women and 6 men.
Their mean age was 67.4 years (range 5879), and their average
MMS score was 20.21 (range: 1624). The group of control
participants consisted of 6 women and 4 men. Their mean age
was 67.2 years (range: 5578), average MMS score was 29.8
(range: 2930).
Inclusion criteria for the AD group were based on those
defined by NINCDS-ADRDA, score on mini mental state
(MMS) between 15 and 24 (inclusive), age 50 years or older,
and stable medication history for one month prior to the beginning of the study. Exclusion criteria were the following: possible causes of dementia other than AD, evidence of mass lesions
(except atrophy) on computer tomography (CT) or magnetic
resonance imaging (MRI), signs of probable vascular dementia,
marked depression (Hamilton Depression Rating Scale N 15).
No subject received psychotropic medication, for at least three
weeks before the beginning of the study. Inclusion criteria for
the healthy control group were: ageN 50 years, absence of any
neurological and psychiatric diseases and no treatment with
drugs of psychotropic effect.
Fig. 1. Changes of the relative theta power in the two groups before and after the
completion of the counting task. Group differences were significant in both
conditions. (AD: AD patients, C: controls).
255
Table 1
Significant group differences of coherence in the different conditions and
frequency bands
Type of
coherence
alpha1
Before
Interhemispheric
Intrahemispheric
short-range
Intrahemispheric
long-range
Fig. 2. Changes of the relative beta1 band in the two groups before and after the
completion of the reverse counting task. (AD: AD patients, C: controls).
T3T4
T4T6
C4P4
P3O1
P4O2
F3T3
F4T4
F3T5
F3P3
F4P4
F4O2
T4P4
T3O1
alpha2
After
Before
beta2
After
Before
After
4.47
6.19
5.26
6.20
9.01
5.24
8.69
8.80
4.81
4.85
12.82
8.16
5.65
7.58
5.60
4.34
4.47
4.73
8.88
5.10
5.42
5.03
9.25
5.47
The numbers shown are F-values. The critical F-values for df(1,22) are 4.3 and 7.95
for p b 0.05 and p b 0.01, respectively. The F-values where coherence was lower in
AD patients compared to controls are shown in italics. For all other F-values,
coherence was higher in AD patients than in controls.
given frequency bands. Power spectra and alpha peak frequencies were measured separately at the O1 and O2 electrodes.
Group statistics were computed based on these averages.
Two-way Multivariate Analyses of Variance (MANOVAs) were
calculated in Group (AD vs. Control) Condition (Before vs.
After task) design for the relative power and coherence values
on each and every frequency band in both conditions. Following
MANOVAs ANOVAs were also calculated in the same twoway and one-way between groups (AD vs. Control) designs to
reveal between group differences for each variable.
3. Results
Fig. 3. Changes of the relative frequency spectra of the delta, alpha2, beta1
bands before and after task in AD patients (AD) and in the controls (C).
AD
Control
Before
After
Difference
Difference
Before
After
0.093
0.161
0.201
0.732
0.326
0.109
0.443
0.137
0.652
0.664
0.637
0.473
0.08
0.155
0.194
0.705
0.302
0.113
0.424
0.138
0.645
0.679
0.662
0.496
0.013
0.006
0.007
0.027
0.024
0.004
0.019
0.001
0.007
0.015
0.025
0.023
0.034
0.042
0.079
0.017
0.066
0.048
0.06
0.055
0.03
0.055
0.025
0.085
0.112
0.257
0.225
0.706
0.337
0.149
0.44
0.197
0.659
0.62
0.577
0.421
0.146
0.299
0.304
0.723
0.403
0.197
0.5
0.252
0.689
0.675
0.602
0.506
256
theta power was found to increase as a result of theta-synchronization, while alpha band power to decrease as a result of alphadesynchronization with increased task difficulty (Klimesch,
1999a; Smith et al., 1999). Increase of delta power and generalized decrease of alpha power, associated with the decrease of
beta power was observed in a study evaluating the effects of
different components of mental calculation on the EEG in healthy
volunteers (Fernandez et al., 1995). Our results in the control
group, although not reaching the level of significance show the
same type of changes, that can be due to the fact that we analysed
the episode following and not during the task.
The task applied in our study was a combination of a mental
calculation and a working memory task. Mental calculation
itself is thought to represent a complex process, involving the
interaction of different cognitive mechanisms (Caramazza and
McCloskey, 1987). Mental arithmetic is also thought to include
activation of working memory (Hitch, 1978). According to our
data the effect of the task was the opposite in AD patients than
those seen in the controls in the delta, alpha2 and beta1 frequencies, possibly showing different responses of neural networks involved in task performance. Spectral analysis revealed
a connection between different kinds of mental calculation
processes and topographical changes of EEG activity in healthy
subjects (Harmony et al., 1999). According to this study an
increase of the 3.9 Hz activity within Broca's and left parietotemporal cortices corresponds to processes related to internal
speech, storage and rehearsal of working memory. The
increased activity of the 5.64 Hz frequency within the right
dorsolateral prefrontal cortex was suggested to be related to
sustained attention, while the decrease at the 12.46 Hz within
the left parietal cortex was interpreted as the sign of retrieval of
arithmetic facts from long term memory. In a study using
functional MRI in evaluating the effect of mental calculation
found induced activity in a cerebral network including the
supplementary motor area, the posterior parietal cortices
bilaterally, the Broca's area, the dorso-lateral prefrontal cortices
bilaterally, the cerebellum bilaterally and premotor cortices
bilaterally were found in healthy subjects. In AD patients the
inferior parietal and lateral prefrontal activations were significantly reduced compared to normal controls (Rmy et al.,
2004). Activation of the right ventral prefrontal cortex caused
by the emotional stress related to the performance of mental
arithmetic task (serial subtraction) was observed using perfusion MRI in healthy subjects (Wang et al., 2005).
Decreases of EEG power in the delta frequency range also
observed in our patient group as a result of performing mental
arithmetic during manual-motor tasks and music perception in
AD patients were described (Gnther et al., 1993). The
significant differences between the two groups of subjects
regarding before-and after-task conditions according to our
results was found in the alpha2 band, where the increase of the
relative power in the AD group might be a correlate of a
rebound effect, which was more pronounced than that seen in
the control group. The higher amount of relative alpha2 band
seen in AD patients following the task may correspond to a
long-lasting effect of the increased effort invested in the
execution of the task. This effect may represent some kind of
257
258
259
Hitch, G.J., 1978. The role of short-term working memory in mental arithmetic.
Cogn. Psychol. 10, 302323.
Hogan, M.J., SwanWick, G.R.J., Kaiser, J., Rowan, M., Lawlor, B., 2003.
Memory-related EEG power and coherence reductions in mild Alzheimer's
disease. Int. J. Psychophysiol. 49, 147163.
Jelic, V., Shigeta, M., Julin, P., Almkvist, O., Winblad, B., Wahlund, L.O., 1996.
Quantitative electroencephalography power and coherence in Alzheimer's
disease and mild cognitive impairment. Dementia 7 (6), 314323.
Jonkman, E.J., 1997. The role of the electroencephalogram in the diagnosis of
dementia of the Alzheimer type: an attempt at technology assessment. Clin.
Neurophysiol. 27, 211219.
Karrasch, M., Laine, M., Rinne, J.O., Rapinoja, P., Sinerva, E., Krause, C.M., 2006.
Brain oscillatory responses to an auditory-verbal working memory task in mild
cognitive impairment and Alzheimer's disease. Int. J. Psychophysiol. 59,
168178.
Klimesch, W., 1999a. Event-related band power changes and memory performance.
In: Pfurtscheller, G., da Silva, L. (Eds.), Event-related desynchonization Handbook of Electroencephalography and Clinical Neurophysiology. Elsevier,
Amsterdam, pp. 161178.
Klimesch, W., 1999b. EEG alpha and theta oscillations reflect cognitive and
memory performance: a review and analysis. Brain Res. Rev. 29, 169195.
Knott, V., Mohr, E., Mahoney, C., Ilivitsky, V., 2000. Electroencephalographic
coherence in Alzheimer's disease: comparisons with a control group and
population norms. J. Geriatr. Psychiatry Neurol. 13, 18.
Kowalski, J.W., Gawel, M., Pfeffer, A., Barcikowska, M., 2001. The diagnostic
value of EEG in Alzheimer Disease: correlation with severity of mental
impariment. J. Clin. Neurophysiol. 18 (6), 570575.
Kwak, Y.T., 2006. Quantitative EEG findings in different stages of Alzheimer's
disease. J. Clin. Neurophysiol. 23, 456461.
Leocani, L., Comi, G., 1999. EEG coherence in pathological conditions. J. Clin.
Neurophysiol. 16 (6), 548555.
Leuchter, A.F., Newton, T.F., Cook, I.A., Walter, D.O., Rosenberg-Thompson,
S., Lachenbruch, P.A., 1992. Changes in brain functional connectivity in
Alzheimer-type and multi-infarct dementia. Brain 115, 15431561.
Locatelli, T., Cursi, M., Liberati, D., Franceschi, M., Comi, G., 1998. EEG coherence
in Alzheimer's disease. Electroencephalogr. Clin. Neurophysiol. 106 (3),
229237.
Mattia, D., Babiloni, F., Romigi, A., Cincotti, F., Bianchi, L., Sperli, F., Placidi, F.,
Bozzao, A., Giacomini, P., Floris, R., Grazia Marciani, M., 2003. Quantitative
EEG and dynamic susceptibility contrast MRI in Alzheimer's disease: a
correlative study. Clin. Neurophysiol. 114 (7), 12101216.
McCloskey, M., Caramazza, A., Basili, A., 1985. Cognitive mechanisms in
number processing and calculation: evidence from dyscalculia. Brain Cogn.
4, 171196.
Missonnier, P., Gold, G., Herrmann, F.R., Fazio-Costa, L., Michel, J.P., Deiber, M.P.,
Michon, A., Giannakopoulos, P., 2006. Decreased theta event-related
synchronization during working memory activation is associated with
progressive mild cognitive impairment. Dement. Geriatr. Cogn. Disord. 22,
250259.
Morrison, J.H., Rogers, J., Scherr, S., Levis, D.A., Campbell, M.J., Bloom, F.E.,
1996. The laminar and regional distribution of neocortical somatostatin and
neuritic plaques: implications for Alzheimers disease as a global neocortical
disconnection syndrome. In: Scheibel, A.B., Wechsler, A.F. (Eds.), The
biological substrates of Alzheimer's disease. Academic Press, Orlando.
Nobili, F., Copello, F., Vitali, P., Prastaro, T., Carozzo, S., Perego, G.,
Rodriguez, G., 1999. Timing of disease progression by quantitative EEG in
Alzheimer's patients. Clin. Neurophysiol. 16 (6), 566.
Osipova, D., Rantanen, K., Ahveninen, J., Ylikoski, R., Happola, O.,
Strandberg, T., Pekkonen, E., 2006. Source estimation of spontaneous
MEG oscillations in mild cognitive impairment. Neurosci. Lett. 405, 5761.
Pogarell, O., Teipel, S.J., Juckel, G., Gootjes, L., Moller, T., Burger, K.,
Leisinger, G., Moller, H.-J., Hegerl, U., Hampel, H., 2005. EEG coherence
reflects regional corpus callosum area in Alzheimer's disease. J. Neurol.
Neurosurg. Psychiatry 76, 109111.
Primavera, A., Novello, P., Finocchi, C., Canaveri, E., Corsello, L., 1990.
Correlation between mini-mental state examination and quantitative
electroencephalography in senile dementia of the Alzheimer type.
Neuropsychobiology 23, 7478.
260
Rajna, P., Csibri, ., Pal, I., Szelenberger, W., 2003. Task related difference EEG
spectrum a new diagnostic method for neuropsychiatric disorders. Med.
Hypotheses 61 (3), 390397.
Rmy, F., Mirrashed, F., Campbell, B., Richter, W., 2004. Mental calculation
impairment in Alzheimer's disease: a functional magnetic resonance
imaging study. Neurosci. Lett. 358, 2528.
Rodriguez, G., Copello, F., Vitali, P., Perego, G., Nobili, F., 1999. EEG spectral
profile to stage Alzheimer's disease. Clin. Neurophysiol. 110 (10), 18311837.
Roselli, M., Ardila, A., 1989. Calculation deficit in patients with right and left
hemisphere damage. Neuropsychologia 27, 607617.
Sauseng, P., Klimesch, W., Schabus, M., Doppelmayr, M., 2005. Fronto-parietal
EEG coherence in theta and upper alpha reflect executive functions of
working memory. Int. J. Psychophysiol. 57, 97103.
Schreiter-Gasser, U., Gasser, T., Ziegler, P., 1994. Quantitative EEG analysis in early
onset Alzhimer's disease: correlations with severity, clinical characteristics, visual
EEG and CT. Electroencephalogr. Clin. Neurophysiol. 90, 267272.
Smith, M.E., McEvoy, L.K., Gevins, A., 1999. Neurophysiological indices of
strategy development and skill acquisition. Cogn. Brain Res. 7, 389404.
Smit, A.S., Eling, P.A.T.M., Coenen, A.M.L., 2004. Mental effort affects vigilance
enduringly: after-effects inn EEG and behaviour. Int. J. Psychophysiol. 53,
239243.
Sneddon, R., Shankle, W.R., Hara, J., Rodriquez, A., Hoffmann, D., Saha, U.,
2005. EEG detection of early Akzheimer's disease using psychophysical
tests. Clin. EEG. Neurosci. 36, 141150.
Stam, C.J., van der Made, Y., Pijnenburg, Y.A., Scheltens, P., 2003. EEG
sychronization in mild cognitive impairment and Alzheimer's disease. Acta
Neurol. Scand. 108 (2), 9096.
Stam, C.J., Montez, T., Jones, B.F., Rombout, S.A.R.B., van der Made, Y.,
Pijnenburg, Y.A.L., Scheltens, P., 2005. Disturbed fluctuations of resting state
EEG synchronization in Alzheimer's disease. Clin. Neurophysiol. 116, 708715.
Stam, C.J., Jones, B.F., Manshanden, I., van Cappellen van Walsum, A.M.,
Montez, T., Verbunt, J.P.A., de Munck, J.C., van Dijk, B.W., Berendse, H.W.,
Scheltens, P., 2006. Magnetoencephalographic evaluation of resting-state
functional connectivity in Alzheimer's disease. NeuroImage 32, 13351344.
Stevens, A., Kircher, T., Nickola, M., Bartels, M., Rosellen, N., Wormstall, H.,
2001. Dynamic regulation of EEG power and coherence is lost early ang
globally in probable DAT. Eur. Arch. Psychiatry Clin. Neurosci. 251, 199204.
Thatcher, R.W., Krause, P.J., Hrybyk, M., 1986. Cortico-cortical associations
and EEG coherence: A two compartmental model. Electroencephalogr. Clin.
Neurophysiol. 64, 123143.
van der Hiele, K., Vein, A.A., Kramer, C.G.S., Reijntjes, R.H.A.M., van Buchem, M.A.,
Westendorp, R.G.J., Bollen, E.L.E.M., van Dijk, J.G., Middelkoop, H.A.M., 2007.
Memory activation enhances EEG abnormality in mild cognitive impairment.
Neurobiol. Aging 28, 8590.
Wang, J., Rao, H., Wetmore, G.S., Furlan, P.M., Korczykowski, M., Dinges, D.F.,
Detre, J.A., 2005. Perfusion functional MRI reveals cerebral blood flow
pattern under psychological stress. Proc. Natl. Acad. Sci. USA/PNAS 102 (49),
1780417809.
Warrington, E.K., 1982. The fractionation of arithmetical skills: a single case
study. Quart. J. Exp. Psychol. 34A, 3151.