Annals of Biomedical Engineering, Vol. 36, No. 1, January 2008 (
2007) pp.
141–152
DOI: 10.1007/s10439-007-9402-y
Regional Analysis of Spontaneous MEG Rhythms in Patients
with Alzheimer’s Disease Using Spectral Entropies
JESÚS POZA,1 ROBERTO HORNERO,1 JAVIER ESCUDERO,1 ALBERTO FERNÁNDEZ,2 and CLARA I. SÁNCHEZ1
1
Biomedical Engineering Group, Department T.S.C.I.T., E.T.S. Ingenieros de Telecomunicación, University of Valladolid,
Camino del Cementerio s/n, 47011 Valladolid, Spain; and 2Centro de Magnetoencefalografı́a Dr. Pérez-Modrego, Complutense
University of Madrid, Madrid, Spain
(Received 3 July 2007; accepted 30 October 2007; published online 10 November 2007)
Abstract—Alzheimer’s disease (AD) is the most common
form of dementia. Ageing is the greatest known risk factor
for this disorder. Therefore, the prevalence of AD is expected
to increase in western countries due to the rise in life
expectancy. Nowadays, a low diagnosis accuracy is reached,
but an early and accurate identification of AD should be
attempted. In this sense, only a few studies have focused on
the magnetoencephalographic (MEG) AD patterns. This
work represents a new effort to explore the ability of three
entropies from information theory to discriminate between
spontaneous MEG rhythms from 20 AD patients and 21
controls. The Shannon (SSE), Tsallis (TSE), and Rényi
(RSE) spectral entropies were calculated from the time-
frequency distribution of the power spectral density (PSD).
The entropies provided statistically significant lower values
for AD patients than for controls in all brain regions
(p < 0.0005). This fact suggests a significant loss of irregu-
larity in AD patients’ MEG activity. Maximal accuracy of
87.8% was achieved by both the TSE and RSE (90.0%,
sensitivity; 85.7%, specificity). The statistically significant
results obtained by both the extensive (SSE and RSE) and
non-extensive (TSE) spectral entropies suggest that AD
could disturb long and short-range interactions causing an
abnormal brain function.
Keywords—Magnetoencephalogram, Time-frequency distri-
bution, Shannon spectral entropy, Tsallis spectral entropy,
Rényi spectral entropy.
INTRODUCTION
Alzheimer’s disease (AD) is a progressive neurode-
generative disorder of unknown etiology. It is the
leading form of dementia representing about 50–60%
of all cases.7 Several risk factors have been identified.7
However, the greatest known risk factor for AD is
ageing, which is especially important in western
Address correspondence to Jesús Poza, Biomedical Engineering
Group, Department T.S.C.I.T., E.T.S. Ingenieros de Telecom-
unicación, University of Valladolid, Camino del Cementerio s/n,
47011 Valladolid, Spain. Electronic mail: jespoz@tel.uva.es
141
countries where an increase in life expectancy is
expected.7 Early symptoms of AD include memory loss
and concentration problems, while as the dementia
progresses AD patients may suffer aphasia, apraxia,
and agnosia, accompanied with general cognitive
symptoms such as confusion, personality and behavior
changes, impaired judgment, and disorientation.6
Brain changes in AD are related to the appearance
of two characteristic lesions: senile or neuritic plaques
and neurofibrillary tangles. They both are formed by
clusters of proteins accumulated in two specific brain
regions: the hippocampus and the cerebral cortex.
Whereas the small clumps of beta-amyloid may induce
a degeneration of synapses, the neurofibrillary tangles
destroy a vital cell transport system made of proteins.11
Several potential biomarkers for AD have been
proposed. Among them, the levels Ab1-42 and isoforms
of tau protein in cerebrospinal fluid (CSF) have been
extensively reported in the literature.7 Many other fluid
biomarkers have been analyzed in both serum and
CSF, including isoprostanes and glycation, inflamma-
tion and oxidative stress markers.44 Various plasma
markers are also being investigated, including amyloid
peptide proteins and similar molecules to those ana-
lyzed in CSF.44 Structural neuroimaging studies offer
complementary advantages to the biological markers.
Thus, positron emission tomography (PET) imaging of
glucose metabolism and magnetic resonance imaging
(MRI) volumetry of medial temporal lobe have shown
promising results as diagnostic screening in clinical
trials.26 Nevertheless, their routinely use is not rec-
ommended in any consensus guidelines for diagnosis of
the disease.7
Clinical diagnosis of AD is based on a complete
medical history together with physical, psychiatric, and
neurological examinations.25,34 Additionally, labora-
tory studies, such as thyroid-function tests and
assessment of vitamin B12 deficiency, are recom-
mended to identify other forms of dementia and
0090-6964/08/0100-0141/0
2007 Biomedical Engineering Society
142 POZA et al.
coexisting disorders associated with ageing.25 Struc-
tural neuroimaging techniques such as computer
tomography (CT) or MRI are also appropriate to
exclude other causes of dementia.25 Nevertheless, the
diagnosis accuracy is low, with sensitivity of around
81% and specificity of 70%.25 Hence, a definite con-
firmation of AD can be only made by post-mortem
examination of brain tissue.7,34
In spite of the relatively low diagnosis accuracy, an
early and accurate identification of AD should be
attempted. Current therapies are more effective if the
medication is administered in the initial stages of the
disease.11 Additionally, an early diagnosis enables to
develop strategies for coping with the disease. Elec-
troencephalographic (EEG) brain activity has been
extensively analyzed to obtain early markers of AD,
while only a few studies have focused on the magne-
toencephalographic (MEG) disease patterns.23,37 Al-
though EEG and MEG recordings are generated by
synchronous oscillations of pyramidal neurons, they
reflect slightly different characteristics.20 The EEG
measures the electric fields induced by all primary
currents, whereas the MEG is sensitive only to current
flows oriented parallel to the scalp.20,21 Furthermore,
the EEG is strongly influenced by a wide variety of
factors such as head structures (e.g., skull and extra-
cerebral tissues) or several technical and methodolog-
ical issues (e.g., electrode placement, reference point or
even adhesive compound of the electrode to the skin).
MEG recordings are less distorted than EEG signals
on the scalp due to the insensitivity of magnetic fields
to inhomogeneities in the head.21 In addition, MEG
signals are reference-free recordings and offer higher
spatial resolution than conventional EEG.20
A few studies have found several abnormalities in
spontaneous MEG recordings of AD patients when
they were compared to those from healthy controls.
MEG studies using relative power have shown in-
creased slow rhythms and reduced fast activity in
AD.4,14,28 This issue has been also observed by means
of spectral quantifiers such as mean frequency,13,31
individual alpha peak28,29,31 and transition fre-
quency.31 Some authors have found a global decrease
in irregularity31 and complexity19 in AD patients’
MEG recordings at rest. However, the loss of com-
plexity has been only described in the high frequencies
when a detailed spectral analysis in several frequency
bands was performed.8 From another point of view,
other approaches have focused on analyzing functional
connections rather than local abnormalities in AD.
Their findings showed both a decrease of coherence
values in the alpha band18 and a general decrease of
coherence in all frequency bands.4 A reduced level of
synchronization has also been reported in the upper
alpha, beta, and gamma bands of AD patients in
comparison with controls suggesting a loss of func-
tional connectivity.38 In a recent study analyzing
MEG recordings at rest, it has been shown that
functional connectivity in AD is characterized by
specific changes of long and short distance interac-
tions in several frequency bands.39 Decreased levels of
functional connectivity indicate that AD is related to
an abnormal function of the large scale brain net-
works. Nevertheless, further studies should confirm
this hypothesis.
We conclude that MEG signals stem from a com-
plex system where both short and long-range (for in-
terneural distances) phenomena are simultaneously
present. Information measures have recently demon-
strated to be appropriate to characterize complex
recordings. Previous studies have successfully applied
several quantifiers based on extensive (e.g., Shannon
and Rényi entropies) and non-extensive (e.g., Tsallis
entropy) information measures to analyze EEG sig-
nals.2,5,9,24,33,40,41 While extensive quantifiers, such as
Shannon and Rényi entropies, have proved successful
in describing systems with short-range interactions,
non-extensive measures, such as Tsallis entropy, are
able to describe a system where the effective interac-
tions are of long-range.5,40 In addition, MEG record-
ings, like EEG signals, are non-stationary and their
characteristics may change over time. Non-stationary
analysis techniques, such as time-frequency distribu-
tions, are appropriate to accurately describe their
properties. Previous efforts have exploited the analogy
between power spectral densities and probability den-
sities to apply several entropic forms to time-frequency
distributions.2,3
The present study is a new approach to explore the
ability of several measures derived from information
theory to characterize MEG rhythms in AD. This
work has been developed on the basis of the results
obtained in a pilot study where we tested several
entropies using the averaged relative power over all
sensors as a probability distribution.30 Our findings
suggested both a slowing of MEG rhythms and a loss
of irregularity in AD. Further work should be devel-
oped to obtain a temporal evolution of the quantifiers,
to assess the influence of the entropic index and to
perform a spatial analysis. The parameters used in the
present study are extensive and non-extensive entropies
based on the time-frequency distribution, which mea-
sure the irregularity or disorder of MEG recordings.
Initially, the Fourier transform (FT) was used to
compute the power spectral density (PSD) into non-
overlapping temporal windows for each MEG
recording from AD patients and controls. Shannon
(SSE), Tsallis (TSE), and Rényi (RSE) spectral
entropies were then calculated to explore the irregu-
larity of the MEG signals. Additionally, both the RSE
 Entropy Analysis of MEG Rhythms in Alzheimer’s Disease
extensive and the TSE non-extensive entropies were
parameterized by the entropic index q, which was
modified to emphasize particular characteristics of the
associated dynamics.
In ‘‘Experimental setup’’ section, the demographic
and neuropsychological data of the study population
are presented, together with the characteristics of the
MEG recordings. Section ‘‘Methods’’ briefly summa-
rizes the definitions of Shannon, Tsallis, and Rényi
entropies and their application on time-frequency
plane. Results are presented in ‘‘Results’’ section,
where the role of the parameter q is analyzed and
regional entropy analyses are performed. In ‘‘Discus-
sion’’ section the relevant results are discussed, while
‘‘Conclusions’’ section summarizes the major contri-
butions of the paper.
EXPERIMENTAL SETUP
Selection of Subjects
We analyzed MEG signals from 41 subjects re-
corded in the ‘‘Centro de Magnetoencefalografı́a
Dr. Pérez-Modrego’’ of the Complutense University
of Madrid (Spain). Twenty subjects (7 men and 13
women, age = 73.05 ± 8.65 years, mean ± standard
deviation SD) were AD patients derived from the
‘‘Asociación de Familiares de Enfermos de Alzheimer’’
(AFAL) and the Geriatric Unit of the ‘‘Hospital Clı́-
nico Universitario San Carlos’’ from Madrid. They
were diagnosed on the basis of exhaustive medical,
physical, neurological, psychiatric, and neuropsycho-
logical examinations, which were complemented with
brain scans to exclude other causes of dementia. All of
them fulfilled the criteria for probable AD according to
the clinical guidelines of the National Institute of
Neurological and Communicative Disorders and
Stroke and the AD and Related Disorders Association
(NINCDS-ADRDA).27 Both the Mini-Mental State
Examination (MMSE)17 and the Functional Assess-
ment Staging (FAST)32 were used to evaluate the
cognitive function. AD patients obtained mean scores
of 17.85 ± 3.91 and 4.00 ± 0.32 on the MMSE and
FAST, respectively. None of the AD patients suffered
from any other significant medical, neurological, and
psychiatric disorder. They were not taking any drug
that could affect the MEG recordings.
Twenty-one healthy subjects (9 men and 12 women,
age = 70.29 ± 7.07 years, mean ± SD) were en-
rolled in the study as control group. They were cog-
nitively normal elderly controls with no history of
neurological or psychiatric disorders. The mean
MMSE and FAST scores were 29.10 ± 1.00 and
1.71 ± 0.46, respectively.
143
We did not obtain significant differences (p > 0.05,
Student’s t-test) when the mean age of AD patients
and controls was compared. In addition, all healthy
volunteers and patients’ caregivers accepted to partic-
ipate in the study and gave written informed consent.
The trial was approved by the study center’s Research
Ethics Committee.
MEG Recording
MEG signals were obtained using a 148-channel
whole-head magnetometer (MAGNES 2500 WH, 4D
Neuroimaging), which was confined in a magnetically
shielded room. During the data acquisition, subjects
were asked to remain relaxed, awake and with eyes
closed in order to minimize the presence of artifacts in
the recordings. Additionally, MEG signals were con-
tinuously monitored to prevent drowsiness. Five min-
utes of spontaneous MEG activity were acquired with
a sample frequency of 678.17 Hz. Initially, both a 0.1–
200 Hz hardware band-pass filter and a 50 Hz notch
filter were applied. Then, each MEG recording was
downsampled by a factor of four to reduce the
data length. Artifact-free epochs of length 10 s
(26.43 ± 5.49 artifact-free epochs per channel and
subject, mean ± SD) were selected for further analy-
sis. Prior to calculate spectral entropies, MEG signals
were processed using a 560th order finite impulse re-
sponse (FIR) filter designed with a Hamming window
and cut-off frequencies at 0.5 and 70 Hz. The selected
frequency range enables to keep the relevant spectral
content and to minimize the presence of oculographic
and myographic artifacts.
METHODS
Definition of Spectral Entropies
The FT is a well-known technique used to analyze
the spectral content of a signal. A common method to
assess the distribution of the power as a function of
frequency is the PSD. In the present work, the PSD
was calculated from the FT of the autocorrelation
function.13,14,31 Then, the spectral content between 0.5
and 70 Hz was selected and the PSD was normalized
to a scale from 0 to 1 leading to the normalized PSD
(PSDn)
PSDðfÞ
PSDn ðfÞ ¼ : ð1Þ
P
70Hz
PSDðfÞ
f¼0:5Hz
After the normalization, it follows that
P70 Hz
f¼0:5 Hz PSD n ðfÞ ¼ 1: The PSDn can be considered
as a probability distribution with N points, whose
144 POZA et al.
definition will be further extended to the time-fre-
quency plane. This representation provides a suitable
tool for analyzing and characterizing the power spec-
trum, since it is possible to apply several entropies
based on a probability density function. Thus, in the
present work three entropies were calculated from the
PSDn: the SSE, TSE, and RSE.
Shannon’s entropy is a disorder quantifier whose
original meaning implies uncertainty of information in
terms of disorder, discrepancy and diversity.5 The
definition of Shannon’s entropy is based on a proba-
bility distribution. Previous EEG and MEG studies
have used the PSDn to compute the SSE as a statistical
descriptor of the signal’s irregularity in AD.1,31 The
irregularity is estimated in terms of the flatness of the
PSDn.36 A uniform PSDn with a broad spectral con-
tent (e.g., a highly irregular signal like white noise)
gives a high SSE value. On the contrary, a narrow
PSDn with only a few spectral components (e.g., a
highly predictable signal like a sum of sinusoids) yields
a low SSE value. In the present work, the definition of
the SSE is based on Shannon’s entropy computed over
the PSDn from 0.5 to 70 Hz22 and it is written by
X
70Hz
SSE ¼
PSDn ðfÞ  ln ½PSDn ðfÞ: ð2Þ
f¼0:5Hz
The second entropic form is the Tsallis entropy. It is
a generalized information measure, which extends the
notion of Shannon’s entropy.42 The Tsallis entropy is a
non-logarithmic entropy, which can be useful to ex-
plore the properties of a probability distribution from
a new mathematical framework in relation to Shan-
non’s entropy.42,43 Previous EEG studies have suc-
cessfully used the relative power distribution of wavelet
coefficients to analyze different brain states in epi-
lepsy.9,33 Given the fact that the Tsallis entropy is a
non-extensive measure, it is able to characterize a
system where long-range interactions appear.5 The
degree of non-extensivity is stated by the entropic in-
dex q 2 <.12 The parameter q might be considered as a
zoom lens, which can be focused on long-range inter-
actions (low q values) or on short abrupt changes (high
q values).43 The Tsallis entropy recovers the definition
of the Boltzmann–Gibbs entropy in the limit q fi 1.42
The definition of the discrete version of the TSE is
given by
1 7X
0Hz
TSEðqÞ ¼ fPSDn ðfÞ
½PSDn ðfÞq g; q>0:
q
1 f¼0:5Hz
ð3Þ
Finally, the Rényi entropy is a generalized infor-
mation measure, which also extends the definition of
Shannon’s entropy.35 Similarly to Shannon’s entropy,
it is an additive entropy, which is based on a loga-
rithmic transformation of a given probability distri-
bution. The PSDn represents again the probability
density function, analogously to previous EEG stud-
ies.2,24 Hence, the Rényi entropy can be considered as
an alternative way to estimate the irregularity of time-
frequency distributions.3 This entropic form is
parameterized by an entropic index q 2 <, in order that
the Rényi entropy can be reduced to the Boltzmann–
Gibbs entropy in the limit q fi 1.35 The definition of
the RSE reads
( )
7X
0Hz
1 q
RSEðqÞ ¼ ln ½PSDn ðfÞ ; q>0: ð4Þ
1
q f¼0:5Hz
The previous entropies (SSE, TSE, and RSE) were
normalized in order to take values in the 0–1 interval.
Hence, the aforementioned entropic forms were divided
by their corresponding maximum possible values. They
were ln(N) for both the SSE and the RSE and [1 - N (1-
q)
] for the TSE, where N was the number of frequency
bins and q represented the entropic index.5,33
Time Evolution of Spectral Entropies
The MEG recordings irregularity can be analyzed
indirectly applying several entropy definitions to their
power frequency distributions. In this way, entropy
provides a description of average uncertainty for a
given signal.41 However, MEGs are non-stationary
recordings and their properties can be accurately de-
scribed by using non-stationary signal analysis tech-
niques, such as time-frequency distributions.2,3 In the
present work, an alternative entropic form based on
the sliding temporal window technique was applied to
obtain the entropy evolution.2,3 Each MEG epoch of
10 s (M = 1696 samples) was divided into non-over-
lapping temporal fragments of 0.5 s, whose length is
denoted as L (L = 84 samples) and each time interval
is identified by i (i = 1,..., NT, with NT = M/L). The
PSD is calculated for each temporal window and the
PSDn is computed from the PSD
PSDðiÞ ðfÞ
PSDðniÞ ðfÞ ¼ ; i ¼ 1; . . . ; NT : ð5Þ
P
70Hz
PSDðiÞ ðfÞ
f¼0:5Hz
The evolution of the SSE, TSE, and RSE is com-
ðiÞ
puted from the PSDn ðfÞ and each value is assigned to
the central point of the corresponding interval
7X
0Hz h i
SSEðiÞ ¼
PSDðniÞ ðfÞ  ln PSDðniÞ ðfÞ ; i ¼ 1;. ..;NT
f¼0:5Hz
ð6Þ
 Entropy Analysis of MEG Rhythms in Alzheimer’s Disease 145

X
70 Hz n h iq o measures analyses. Differences were considered statis-
ðiÞ 1
TSE ðqÞ ¼ PSDðniÞ ðfÞ
PSDðniÞ ðfÞ ; tically significant for p < 0.05.
q
1 f¼0:5 Hz The classification performance of each parameter
i ¼ 1; . . . ; NT was evaluated using a linear discriminant analysis
(LDA) with a leave-one-out cross-validation proce-
ð7Þ dure. Classification statistics were shown in terms of
( ) sensitivity (percentage of AD patients with a correct
1 X
70 Hz h iq diagnosis), specificity (proportion of controls properly
ðiÞ ðiÞ
RSE ðqÞ ¼ ln PSDn ðfÞ ;
1
q ð8Þ recognized) and accuracy (total fraction of AD pa-
f¼0:5 Hz
tients and healthy subjects well classified).
i ¼ 1; . . . ; NT : All statistical analyses were performed using SPSS
software (version 14.0; SPSS Inc, Chicago, Ill).
Finally, the previous quantifiers are normalized by
their maximum possible values, which were specified in
the previous section.
RESULTS
To characterize the entropy evolution by a single
value, the temporal average per parameter and subject Optimization of the Entropic Index q
was calculated for each quantifier
In a first stage, we analyzed the role of the entropic
1 X NT
index q in the parameterized entropies: TSE and RSE.
hSSEi ¼  SSEðiÞ ð9Þ
NT i¼1 The evolution of the TSE and RSE over each of the
10 s MEG segments was computed taking non-over-
lapping temporal windows of 0.5 s. Results were
1 X NT
averaged for each channel and each subject to obtain
hTSEðqÞi ¼  TSEðiÞ ðqÞ ð10Þ
NT i¼1 an entropy evolution per channel and subject. Finally,
temporal averages for the TSE and the RSE were
1 X NT computed to obtain a quantitative measure per subject
hRSEðqÞi ¼  RSEðiÞ ðqÞ: ð11Þ and q value. The dependence of the TSE and RSE on
NT i¼1
the entropic index q was explored modifying its values
All calculations were carried out with the software (q = {0.25, 0.5,...,5}) according to previous EEG
package Matlab (version 7.0; Mathworks, Natick, MA). studies.2,3,9,24,33
The TSE showed a significant main effect of group
(F(1,38) = 27.909; p = 0.000005) and a significant
Statistical Analysis group by q interaction (F(19,722) = 13.792;
p = 0.000514). Figure 1 depicts the evolution of the
Both the Kolmogorov–Smirnov and the Shapiro– p-values from the univariate ANOVAs with contrasts
Wilk tests were used to evaluate the normal distribu- and age as a covariate in function of the entropic index
tion of each variable, while homoscedasticity was q, when the ÆTSEæ averaged over all channels is com-
assessed with Levene’s test. After the descriptive pared between AD patients and controls. As it can be
analysis, log-transformed variables met parametric test seen, the TSE with both low and high q values
assumptions. Firstly, the mean entropy values aver- achieved the greatest p-values. The most significant
aged over all channels were analyzed using two-way
repeated measures ANOVAs (with group as between-
subject factor and parameter q as within-subject fac-
tor) with age as a covariate. Secondly, optimal mean
entropy values at five brain regions (anterior, central,
left lateral, posterior, and right lateral) were compared
between AD patients and controls by means of two-
way repeated measures ANOVAs (with group as be-
tween-subject factor and brain region as within-subject
factor) with age as a covariate. Finally, univariate
ANOVAs with contrasts and age as a covariate were
performed when previous analyses showed significant
interactions. In order to correct possible violations of
FIGURE 1. Evolution of the statistical significance in func-
the sphericity assumption and to reduce type I errors, tion of the entropic index q when the mean TSE over all
Greenhouse-Geisser epsilon was used in all repeated channels is compared between AD patients and controls.
146
FIGURE 2. Evolution of the statistical significance in func-
tion of the entropic index q when the mean RSE over all
channels is compared between AD patients and controls.
differences (p = 0.000001) were obtained by the
TSE(q = 2).
The RSE exhibited a significant main effect of group
(F(1,38) = 34.189; p = 0.000001) and a significant
group by q interaction (F(19,722) = 7.794;
p = 0.006891). Figure 2 illustrates the evolution of the
p-values from the univariate ANOVAs with contrasts
and age as a covariate in function of the entropic index
q, when the ÆRSEæ averaged over all channels is com-
pared between AD patients and controls. The statisti-
cal significance achieved with the RSE augmented as
q increased. It can be observed that this trend is
stable around q = 3. The most significant result
(p < 0.000001) was obtained with RSE(q = 3.5).
Regional Entropy Analysis
In a second step, we explored the regional patterns
of the SSE, as well as the previously optimized
TSE(q = 2) and RSE(q = 3.5). The evolution of the
previous quantifiers over each of the 10 s MEG seg-
ments was computed taking non-overlapping temporal
windows of 0.5 s. According to Fig. 3, five brain areas
(anterior, central, left lateral, posterior, and right lat-
eral) were defined to obtain a regional entropy analy-
sis. Results were averaged in each of the five brain
regions, obtaining an entropy evolution per region
and subject. Additionally, temporal averages for the
entropies were computed to obtain a quantitative
measure per region and subject.
The SSE showed a significant main effect of group
(F(1,38) = 25.986; p = 0.000010), whereas no signifi-
cant group by region interaction was observed
(p = 0.072579). Results of univariate ANOVAs with
contrasts and age as a covariate are shown in Table 1.
Classification analyses using LDA with a leave-one-out
cross-validation procedure are shown in Table 2. AD
patients obtained significantly lower SSE values than
controls in all cerebral regions, which suggests an
irregularity decrease in AD patients’ MEGs, in terms
POZA et al.
FIGURE 3. Illustration of sensor grouping into the five brain
regions considered for topographic analyses: anterior, cen-
tral, left lateral, posterior and right lateral.
of the spectrum flatness. It is illustrated in Fig. 4,
where the mean SSE evolution over a 10 s period for
each brain region in both groups is shown. Although
the most significant results were obtained in the right
lateral region (p-value = 0.000004; 80.5%, accuracy;
80.0%, sensitivity; 81.0%, specificity), it is noteworthy
that the statistical analyses showed similar statistical
differences and classification parameters in the left
lateral (p-value = 0.000019; 80.5%, accuracy; 75.0%,
sensitivity; 85.7%, specificity) and anterior areas (p-
value = 0.000053; 82.9%, accuracy; 85.0%, sensitiv-
ity; 81.0%, specificity). In addition, the SSE displayed
a higher variability over the 10 s interval in AD
patients than in healthy subjects.
The TSE(q = 2) exhibited a significant main effect
of group (F(1,38) = 35.269; p = 0.000001) and a
significant group by region interaction (F(4,152) =
4.372; p = 0.013079). Table 1 shows that AD patients
obtained a significantly lower TSE(q = 2) than con-
trols in all brain regions. This result can be seen in
Fig. 5, which depicts the mean TSE(q = 2) evolution
over a 10 s period for each brain region in both groups,
suggesting again a decrease in the irregularity of AD
patients’ MEGs. The inspection of Tables 1 and 2 re-
veals that the most significant differences (p-value =
0.000001) were achieved in the right lateral area, with
an accuracy of 78.0% (75.0%, sensitivity; 81.0%,
specificity). Similar statistical results were obtained in
the left lateral (p-value = 0.000003) and anterior re-
gions (p-value = 0.000003). Nevertheless, in the left
lateral and anterior areas the accuracy reached 80.5%
(75.0%, sensitivity; 85.7%, specificity) and 87.8%
(90.0%, sensitivity; 85.7%, specificity), respectively.
 Entropy Analysis of MEG Rhythms in Alzheimer’s Disease 147

TABLE 1. Mean SSE, TSE(q = 2) and RSE(q = 3.5) values averaged in each brain region for each group and the corresponding
p-values from ANOVA with contrasts and age as a covariate.

Controls AD patients
Region Parameter Mean ± SD Mean ± SD p-value

Anterior hSSE i 0.833 ± 0.003 0.720 ± 0.005 0.000053

hTSEðq ¼ 2Þi 0.969 ± 0.001 0.916 ± 0.003 0.000003
hRSEðq ¼ 3:5Þi 0.714 ± 0.006 0.524 ± 0.007 0.000003
Left lateral hSSE i 0.818 ± 0.003 0.723 ± 0.004 0.000019
hTSEðq ¼ 2Þi 0.969 ± 0.001 0.928 ± 0.002 0.000003
hRSEðq ¼ 3:5Þi 0.698 ± 0.006 0.556 ± 0.005 0.000003
Central hSSE i 0.859 ± 0.001 0.786 ± 0.004 0.000172
hTSEðq ¼ 2Þi 0.979 ± 0.000 0.951 ± 0.002 0.000022
hRSEðq ¼ 3:5Þi 0.760 ± 0.003 0.629 ± 0.006 0.000008
Right lateral hSSE i 0.823 ± 0.003 0.722 ± 0.005 0.000004
hTSEðq ¼ 2Þi 0.969 ± 0.001 0.928 ± 0.003 0.000001
hRSEðq ¼ 3:5Þi 0.702 ± 0.005 0.556 ± 0.007 0.000000
Posterior hSSE i 0.815 ± 0.002 0.735 ± 0.006 0.000137
hTSEðq ¼ 2Þi 0.968 ± 0.001 0.937 ± 0.004 0.000102
hRSEðq ¼ 3:5Þi 0.692 ± 0.005 0.577 ± 0.007 0.000023

SD: Standard deviation; p-value: Statistical significance.

TABLE 2. Diagnostic test results derived from linear were obtained in the right lateral region with an
discriminant analysis with a leave-one-out cross-validation accuracy of 78.0% (75.0%, sensitivity; 81.0%, speci-
procedure for the mean SSE, TSE(q = 2) and RSE(q = 3.5)
averaged in each brain region. ficity). Similar statistical results and higher classifica-
tion parameters were found in the anterior (p-
Sensitivity Specificity Accuracy value = 0.000003; 87.8%, accuracy; 90.0%, sensitiv-
Region Parameter (%) (%) (%)
ity; 85.7%, specificity), left lateral (p-value =
Anterior hSSE i 85.0 81.0 82.9 0.000003; 82.9% accuracy; 80.0%, sensitivity; 85.7%,
hTSEðq ¼ 2Þi 90.0 85.7 87.8 specificity) and central areas (p-value = 0.000008;
hRSEðq ¼ 3:5Þi 90.0 85.7 87.8 82.9%, accuracy; 75.0%, sensitivity; 90.5%, specificity)
Left lateral hSSE i 75.0 85.7 80.5 than in the right lateral region.
hTSEðq ¼ 2Þi 75.0 85.7 80.5
hRSEðq ¼ 3:5Þi 80.0 85.7 82.9
Central hSSE i 70.0 76.2 73.2 DISCUSSION
hTSEðq ¼ 2Þi 65.0 85.7 75.6
hRSEðq ¼ 3:5Þi 75.0 90.5 82.9 We explored the ability of several measures derived
Right lateral hSSE i 80.0 81.0 80.5 from information theory to discriminate between
hTSEðq ¼ 2Þi 75.0 81.0 78.0 spontaneous MEG rhythms of 20 AD patients and 21
hRSEðq ¼ 3:5Þi 75.0 81.0 78.0 control subjects. We calculated extensive (Shannon
Posterior hSSE i 65.0 81.0 73.2 and Rényi) and non-extensive (Tsallis) entropies based
hTSEðq ¼ 2Þi 70.0 76.2 73.2 on the time-frequency plane2,3 to measure the irregu-
hRSEðq ¼ 3:5Þi 75.0 85.7 80.5 larity of MEGs in AD. Initially, we analyzed the
dependence of both the TSE and RSE on the entropic
Analogously to the SSE, the TSE showed a higher index q for discriminating between AD patients and
variability over the 10 s interval in AD patients than in controls. We found q = 2 and q = 3.5 as optimal
healthy subjects. entropic indexes for the TSE and RSE, respectively.
Finally, the RSE(q = 3.5) exhibited a significant Detailed regional analyses were then performed using
main effect of group (F(1,38) = 35.440; p = 0.000001) the SSE, TSE(q = 2) and RSE(q = 3.5) in order to
and a significant group by region interaction explore their spatial and temporal patterns in AD.
(F(4,152) = 4.771; p = 0.006325). Table 1 indicates MEGs from AD patients had significantly lower en-
that AD patients obtained significantly lower tropy values than those from controls in all brain
RSE(q = 3.5) values than controls in all brain regions. regions, which suggests that AD is accompanied by an
The statistically significant decrease in the irregularity overall irregularity decrease.
of AD patients’ MEG recordings is shown in Fig. 6. The dependence analysis of the entropies on the
The most significant differences (p-value < 0.000001) parameter q revealed that the TSE and RSE exhibited
148
FIGURE 4. Grand-average of the SSE evolution over a 10 s period for AD and control groups in each brain region: anterior (A),
central (C), left lateral (L), posterior (P), and right lateral (R).
different behaviors. Similarly, previous EEG studies
have observed that quantifiers based on Rényi
entropy are less sensitive to variations of the parameter
q (q > 1) due to its logarithmic form,33,41 whereas
measures based on the Tsallis statistic showed a strong
dependence on the entropic index.41 This result can
also be observed in the present work. Entropic indexes
greater than 1 produced changes in the significance
level more important with the TSE than with the RSE.
Figures 1 and 2 show that the ability of the TSE to
accurately detect AD is maximal using values of q close
to 2, while the statistical differences between groups
are gradually reduced as q either decreases or increases
with respect to the previous q value. Regarding to the
RSE, the statistical differences between AD patients
and controls gradually increased as q augmented.
Nevertheless, entropic indexes higher than 3.5 did not
offer significant improvement to distinguish between
groups. The ability of q to enhance the accuracy to
identify particular brain states has been previously
discussed. EEG studies detecting epileptic seizures and
characterizing brain function by means of Tsallis and
Rényi entropies have reported a decrease in the
‘‘background EEG-detection-power’’ as the parameter
q (q > 1) increased.5,9,41 We have observed that the
ability to discriminate between AD patients and con-
trols did not improve when the entropic index was
POZA et al.
gradually increased. However, our results indicate that
this trend appears with q values greater than 2 or 3.5
by the TSE and RSE, respectively. Differences may be
due to the fact that we computed both the Tsallis and
Rényi entropies from a time-frequency distribution,
whereas the aforementioned works used an alternative
time-dependent entropy definition based on the sliding
temporal window technique.10
Regional analyses of the entropy patterns showed
significant (p < 0.0005) lower SSE, TSE(q = 2) and
RSE(q = 3.5) values in AD patients’ MEGs than in
controls for all cerebral regions. The SSE decrease in
AD suggests that the disease is accompanied by a loss
of frequency components, which implies a decrease of
irregularity with respect to the flatness of the power
spectrum. The TSE(q = 2) and RSE(q = 3.5) evolu-
tions reveal again that the disorder was reduced in AD
patients compared to controls, supporting the loss of
irregularity in AD. Previous MEG studies have also
reported an overall decrease in both irregularity31 and
complexity19 in AD using the SSE and the Lempel–Ziv
complexity, respectively. On the contrary, van Cap-
pellen van Walsum et al.8 only described a complexity
loss in the high frequencies when a detailed spectral
analysis in several frequency bands was performed
using the neural complexity. An advantage of the
methods used in this work, compared to the previous
 Entropy Analysis of MEG Rhythms in Alzheimer’s Disease
FIGURE 5. Grand-average of the TSE(q = 2) evolution over a 10 s period for AD and control groups in each brain region: anterior
(A), central (C), left lateral (L), posterior (P), and right lateral (R).
efforts, is to take into account both temporal and
spatial characteristics of the MEG signals. This is due
to the fact that the quantifiers were applied to the time-
frequency plane. We have detected not only lower
entropy values, but also a more irregular entropy
evolution in AD patients than in controls. Addition-
ally, the decreasing entropy values should be inter-
preted from a spectral point of view. We have observed
that AD implies a loss of spectral components, which
can be associated with a reduction of information
content.3 Some authors claimed that the change in
information entropy within the EEG may reflect a real
variation in cortical functional organization.24 Given
the fact that entropy is usually identified with an
indicator of the system’s disorder, it has been
hypothesized that a reduction in entropy may imply
an information processing decrease at the cerebral
cortex.24
Further inspection of the regional entropy analyses
shows that both the TSE(q = 2) and RSE(q = 3.5)
achieved higher significant levels (p < 0.0001) than the
SSE (p < 0.0005) in all brain regions. Moreover, the
generalized entropies reached greater classification
accuracies (between 73% and 87.8%) than the SSE
(between 73.2% and 82.9%). A similar result was
obtained in a previous study (p = 0.00023; 82.93%
accuracy), where the SSE (among other spectral
149
measures) was used to characterize the PSD of MEGs
in AD.31 However, it is noteworthy that the classifi-
cation analyses were performed using a LDA without a
leave-one-out cross-validation procedure. As it was
previously mentioned, the TSE and RSE have been
used in the past to characterize long and short-range
interactions in complex systems, respectively.5,40 Our
findings indicate that both entropic formalisms showed
statistically significant results. Therefore, we can
hypothesize that the brain magnetic activity in AD
may be generated by a system where abnormal long
and short-range interactions appear simultaneously.
This issue has been previously suggested by Stam
et al.,39 who found that the functional connectivity of
spontaneous MEG activity in AD was characterized by
specific changes of both long and short distance
interactions in several frequency bands.
The most significant differences in the entropy
measures were found in the lateral and anterior regions.
However, similar p-values were also obtained in both
central and posterior regions. Berendse et al.4 analyzed
the absolute power of spontaneous MEG recordings of
AD patients and controls. They reported significant
changes in the power patterns over the whole head,
which can be summarized as a significant increase of the
low frequency power over the frontal and central areas
and a significant decrease of the high frequency power
150 POZA et al.

FIGURE 6. Grand-average of the RSE(q = 3.5) evolution over a 10 s period for AD and control groups in each brain region:
anterior (A), central (C), left lateral (L), posterior (P), and right lateral (R).

over the occipital and temporal regions.4 MEG source
analyses have also found differences over the different
brain regions in AD. Fernández et al.15,16 described an
increased dipole density at the delta and theta bands
over the parietal and temporal cortices in AD. On the
other hand, Osipova et al. observed that AD patients
showed an increased activation of higher theta band
sources in the right temporal region,29 together with a
parieto-occipital deficit.28
Finally, some limitations of the study should be
mentioned. It might be possible that the irregularity
decrease in AD could be drug-related. However, none
of the patients were receiving any medication which
could affect spontaneous MEG activity. On the other
hand, the irregularity patterns in other neurodegener-
ative diseases, which have shown alterations in the
spectrum similar to those observed in AD, should be
explored. Further investigation should be attempted to
extend the analyses in mild cognitive impairment,
vascular dementia, Lewy body dementia, major
depression, dementia associated with Parkinson’s dis-
ease, Pick’s disease, Huntington’s chorea and pro-
gressive supranuclear palsy.
Other limitation of the work is related to the small
sample size. Considerations about type I (probability
of a false positive) and type II (probability of a false
negative) errors should be made. The reduced number
of subjects enrolled in the study implies an increase of
beta (probability of making a type II error) and a
decrease of the power of the test (i.e., 1 - beta).
Therefore, it should be appropriate to increase the
number of subjects to both minimize type II errors and
augment the statistical power.
CONCLUSIONS
This study was performed as a new approach to
analyze the ability of information theory methods to
characterize spontaneous MEG activity from AD pa-
tients and controls. Only a few MEG studies have
explored the irregularity and complexity patterns in
AD.8,19,31 The parameters presented in this paper
combine three entropies from information theory with
time-frequency signal processing tools. Our findings
support the notion that AD involves an overall loss of
irregularity in the electromagnetic brain activity. In
addition, the statistically significant results obtained by
both the extensive (SSE and RSE) and non-extensive
(TSE) spectral entropies suggest that AD could disturb
long and short-range interactions leading to an
abnormal brain function.
 Entropy Analysis of MEG Rhythms in Alzheimer’s Disease
Future efforts will be addressed to explore other
measures from information theory to characterize
MEG rhythms in AD. Additionally, further work
should be attempted to increase the sample size and to
extend the results to other dementias.
In summary, our findings suggest that the extensive
(SSE and RSE) and non-extensive (TSE) spectral
entropies may lead to a better understanding of the
underlying brain dynamics in AD. Furthermore, these
new approaches extend the concept of irregularity and
can provide useful descriptors of the spontaneous
MEG rhythms in AD.
ACKNOWLEDGMENTS
This work has been partially supported by the grant
project VA108A06 from ‘‘Consejerı́a de Educación de
Castilla y León’’ and by the ‘‘Ministerio de Educación
y Ciencia’’ and FEDER grant MTM2005-08519-C02-
01. The authors would like to thank the ‘‘Asociación
de Enfermos de Alzheimer’’ (AFAL) for supplying the
patients who have participated in this study.
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