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NeuroImage 28 (2005) 72 – 83

Rhythmic brain activity at rest from rolandic areas in acute

mono-hemispheric stroke: A magnetoencephalographic study

Franca Tecchio,a,b,* Filippo Zappasodi,a Patrizio Pasqualetti,b Mario Tombini,c Carlo Salustri,a

Antonio Oliviero,d Vittorio Pizzella,e Fabrizio Vernieri,b,c and Paolo Maria Rossinib,c,f

aIstituto di Scienze e Tecnologie della Cognizione (ISTC), CNR, Rome, ItalybAFaR, Dipartimento di Neuroscienze, Ospedale ‘‘Fatebenefratelli’’, Isola Tiberina, Rome, ItalycNeurologia Clinica, Universita Campus Biomedico, Rome, ItalydUnidad de Neurologıa Funcional, Hospital Nacional de Paraplejicos, SESCAM, Toledo, SpaineDip. Scienze Cliniche e Bioimmagini ed ITAB, Universita ‘‘G. D’Annunzio’’, Chieti, ItalyfIRCCS ‘‘S. Giovanni di Dio-Fatebenefratelli’’, Brescia, Italy

Received 8 November 2004; revised 10 May 2005; accepted 20 May 2005

Available online 14 July 2005

In order to deepen our knowledge of the brain’s ability to react to a

cerebral insult, it is fundamental to obtain a ‘‘snapshot’’ of the acute

phase, both for understanding the neural condition immediately after

the insult and as a starting point for follow-up and clinical outcome

prognosis.

The characteristics of the brain’s spontaneous neuronal activity in

perirolandic cortical areas were investigated in 32 patients who had a

stroke in the middle cerebral artery (MCA) territory of one hemisphere

in the previous 10 days.Magnetic fields from both left and right rolandic

areas were recorded at rest with open eyes. Total and band power pro-

perties, the individual alpha frequency (IAF) and the spectral entropy

were analyzed and compared with a sex-age matched control group.

In agreement with electroencephalographic literature, low fre-

quency absolute powers were higher and high frequency were lower in

the affected (AH) than in the unaffected hemisphere (UH), and also

their values in both hemispheres differed from control values. An IAF

reduction was found in AH with respect to UH. As new findings, the

total power was higher in AH than in UH, after excluding 4 right-

damaged patients with cortico-subcortical lesions, who showed a

completely disorganized spectral pattern. Spectral entropy was lower

in AH than in UH.

Clinical severity correlated with the AH decrease of gamma band

power, IAF and spectral entropy. Larger lesions were associated to

worse clinical pictures and MEG alterations.

A lesion affecting the MCA territory of one hemisphere induces a

perilesional increase of the low-frequency rhythms’ spectral power

within the AH rolandic areas; the same effect was present also in the

UH, indicating interhemispheric diaschisis. In the AH, results showed

an increase of the total power and a reduction of the spectral entropy,

suggesting a higher synchrony of local neuronal activity, a reduction of

the intra-cortical inhibitory networks efficiency and an increase of

1053-8119/$ - see front matter D 2005 Published by Elsevier Inc.

doi:10.1016/j.neuroimage.2005.05.051

* Corresponding author. ISTC-CNR, Unita MEG, Dipartimento di

Neuroscienze, Ospedale ‘‘Fatebenefratelli’’ Isola Tiberina, Rome, Italy.

E-mail address: franca.tecchio@istc.cnr.it (F. Tecchio).

Available online on ScienceDirect (www.sciencedirect.com).

neuronal excitability. Direct correlation linked gamma band activity

preservation and less severe clinical status. Dependence of the clinical

picture, and associated spectral alterations, on the lesion volume and

not on the lesion level, suggests a diffuse neuronal impairment, rather

than a selective structures damage, contributing to neurological status

in the acute phase of stroke.

D 2005 Published by Elsevier Inc.

Keywords: Sensorimotor cortex; Hand representation; Spontaneous activity;

Neural plasticity; Magnetoencephalography (MEG)

Introduction

Changes and adjustments of neuronal output to a stable amount

of input, involving molecular, cellular and network remodeling, are

generally referred to as ‘‘neuronal plasticity’’. Plastic cerebral

phenomena are very diverse, depending on the actual conditions of

the system to which the involved cells belong; most dramatically,

they depend on whether the system is in a healthy or pathological

condition (Rossini et al., 2004), and, in the latter case, on whether

the pathogenic process is in the acute or stabilized stage (Gloor et

al., 1977; Cramer and Bastings, 2000; Dijkhuizen et al., 2003;

Giaquinto et al., 1994).

In this study, the patterns of spontaneous rhythmic neuronal

activity within the rolandic cortical areas in patients who had

suffered an infarction in the middle cerebral artery (MCA) territory

within the previous 10 days were investigated via magnetoence-

phalographic (MEG) recordings. In order to highlight the processes

taking place not only in the affected hemisphere but also in the

unaffected one, monohemispheric stroke patients were enrolled. The

neuronal ‘‘resting state’’ characteristics are of primary importance for

determining the brain’s processing capabilities. If – for instance –

we consider regions involved in functions showing hemispheric

F. Tecchio et al. / NeuroImage 28 (2005) 72–83 73

dominance, the dominant areas are known to have better processing

abilities, i.e., finer event-related activation properties (Triggs et al.,

1999; Volkmann et al., 1998; Soros et al., 1999). These same areas

also show rest-state differences, as shown for example for alpha

activity asymmetries between the dominant and the non-dominant

hemisphere (Cobb, 1963; Kiloh, 1970; Wieneke et al., 1980; Pereda

et al., 1999). Rest properties cannot be used to predict activation

characteristics, since different – or partly different – neuronal

populations contribute to the recorded signal in the two conditions.

Nonetheless, the spontaneous rolandic 10–20 Hz oscillations which

are inhibited by sensorimotor tasks of the contralateral limbs (mu

rhythm), are predominantly generated in the hand area (Tiihonen et

al., 1989; Narici et al., 1990; Salmelin and Hari, 1994; Hari et al.,

1998) and come from cortical regions overlapping those activated by

a somatosensory hand stimulation (Tiihonen et al., 1989). Direct

relation between the intensity of such cortical sources and the power

of the prestimulus mu-rhythm was demonstrated (Nikouline et al.,

2000).

Spontaneous brain activity in our patients was studied between

the 2nd and the 10th day after the symptom onset: for this reason,

neither the first hours after stroke phenomena, nor effects of

therapeutic procedures in this early phase were considered in the

present study.

Evidences from both electroencephalographic studies in

humans (Nagata et al., 1982; Sainio et al., 1983; Ahmed, 1988;

Makela et al., 1998; Jackel and Harner, 1989; Murri et al., 1998;

Niedermeyer, 1997), and intra-cerebral recordings in animals

(Gloor et al., 1977; Carmichael and Chesselet, 2002) suggest that

high-voltage perilesional slow-wave rhythmic foci, topographical

distribution asymmetries of alpha activity and high-voltage Fspiky_activities are all functional signs of a cerebral lesion. MEG is a

non-invasive technique, which detects neuromagnetic fields at the

cranial surface and can spatially identify synchronous postsynaptic

currents in firing neurons related to spontaneous cerebral activity

or in response to an external stimulus (Del Gratta et al., 2001). The

use of MEG in poststroke studies is encouraged by the fact that the

presence of morbid tissue near the cerebral generators has minimal

effects on the scalp distribution of the magnetic fields (Huang et

al., 1990; Orrison and Lewine, 1993). Nevertheless, so far, no

MEG studies have been specifically dedicated to spectral character-

istics of the brain rest magnetic activity in the early poststroke

period, unless one paper devoted to slow-band activity sources in

patients in different phases after a stroke (Butz et al., 2004). In the

present study, the focus of attention is devoted to the spectral

properties of homologous affected and non-affected regions in a

quite large group of acute stroke patients, accepting the limitation

of not to assess the generator positions. In fact, the updated ability

in reconstructing cerebral sources generating oscillatory rest

activity is still under development. The studies devoted to

localization of slow band activity in stroke patients (Fernandez-

Bouzas et al., 1997; Vieth, 1990; Butz et al., 2004), report the

generators in the perilesional region, in complete agreement with

the long-lasting experience based on visual EEG inspection (Van

der Drift and Kok, 1972; Nagata et al., 1982; Sainio et al., 1983;

Pfurtscheller, 1986; Ahmed, 1988; Makela et al., 1998; Jackel and

Harner, 1989; Niedermeyer, 1997; Murri et al., 1998, Fernandez-

Bouzas et al., 2000). Moreover, no consistent relationship between

perilesional activity and clinical symptoms was observed through

this kind of analysis (Butz et al., 2004), suggesting that the

modelling suitability is low when vast areas are involved

generating the signal, fluctuating in space during time.

The aim of the present work was to assess in poststroke acute

state any relationship between spontaneous neuronal activity

within the rolandic areas, the clinical status and neuroradiological

findings.

Materials and methods

Patients

Thirty-two patients between 30 and 86 years of age (mean 68 T12 years, 15 females, 17 males) were enrolled in the study after a

first-ever acute ischemic stroke, diagnosed on the basis of clinical

history and examination and confirmed by brain magnetic

resonance imaging (MRI) at our Neuroscience Department. The

criteria for inclusion in the study were: clinical evidence of a motor

and/or a sensory deficit of the upper limb and a neuroradiological

diagnosis of ischemic brain damage. Exclusion criteria were: brain

hemorrhage, a previous stroke, neuroradiological evidence of

cerebral atrophy or multifocal hypoxic– ischemic encephalophaty,

neuroradiological evidence of involvement of both hemispheres,

peripheral neuropathies that would cause sensory testing and

nerves stimulation to be ineffective, dementia, severe aphasia and/

or other conditions mitigating compliance. None of the enrolled

patients underwent intravenous or intra-arterial thrombolysis with

rtPA. The best clinical management of medical problems (cardiac

and respiratory care, fluid and metabolic maintenance) and of

physiologic variables after stroke, particularly blood pressure,

glucose and body temperature was provided for all patients,

according to ad hoc guidelines (Adams et al., 2003). Anticoagulant

therapy, if indicated (i.e., cardioembolism), or platelet antiaggre-

gant treatment was administered as well. The experimental

protocol was approved by the ‘‘S. Giovanni Calibita’’-Fatebene-

fratelli Hospital’s Ethical Committee and all patients signed a

written informed consent.

MEG recordings and clinical scores were collected between 2

and 10 days (mean 5.2 T 2.6 days) after the stroke. All patients,

except 4 (with insufficient compliance), completed the MEG

examination without problems. The National Institute of Health

stroke scale score (NIHSS) and the Barthel Index (BI) were used

for neurological assessment of stroke severity and the evaluation of

personal self-sufficiency in everyday activities. Hand motor scores

were obtained according to the Canadian Neurological Scale, while

a similar arbitrary four-degree scale (0–1.5; 1.5 being normal)

evaluated the sensory impairment.

Features of the neuronal activity evoked by bilateral median

nerves stimulation in the same patient sample have been previously

reported (Oliviero et al., 2004).

Control group

Fourteen subjects with age and sex comparable to our patients

(pts: 68 T 12, ctrl: 66 T 18 years, P = 0.688; pts: 14f/18m, ctrl: 7f/

7m, P = 0.695) were enrolled as control group.

MEG investigation

Brain magnetic fields were recorded by means of a 28-channel

system (Tecchio et al., 1997) covering a scalp area of about 180

cm2, located inside a magnetically shielded room (Vacuum-

schmelze GMBH). Cerebral activity was recorded (band-pass

F. Tecchio et al. / NeuroImage 28 (2005) 72–8374

F. Tecchio et al. / NeuroImage 28 (2005) 72–83 75

filtering 0.48–250 Hz, sampling rate 1000 Hz) from the

perirolandic region of each hemisphere centered approximately in

C3 and C4 of the International 10–20 electroencephalographic

system. The exact position of the sensors with respect to the subject

head was detected by using 6 current fed coils, whose positions

were digitized together with 5 anatomical landmarks (nasion, the

two preauricular points, vertex and inion). The subjects were

comfortably lying on a non-magnetic hospital bed, with their eyes

open to reduce the effects of the occipital spontaneous activity in

the rolandic region.

Spontaneous activity was recorded for 3 min in each hemi-

sphere. The 28-channel system does not allow simultaneous

recording of spontaneous activity from both hemispheres, but this

limitation does not hamper spectral characteristics estimate. In fact,

in the literature, the test–retest reliability of rest activity spectral

characteristics has been reported, showing that evaluations based

on more than 1 min of non-artifactual tracts are quite stable

(Salinsky et al., 1991; Kondacs and Szabo, 1999, EEG data), and

also agrees with our experience on healthy subjects spontaneous

activity recorded in different sessions (3–5 times) changing the

order of left– right recordings.

After data visual inspection and the application of an ad hoc

developed artifact rejection procedures (Samonas et al., 1997;

Barbati et al., 2004), the Power Spectral Density (PSD) was

estimated for each MEG channel via the Welch procedure (2048

ms duration, Hanning window, 60% overlap, about 180 artifact

free trials used). The total PSD was calculated as the mean of the

PSDs obtained by the 16 inner gradiometer channels which

covered a circular area of about 12 cm diameter. Total signal

power was obtained by integrating the PSD value in the 2–44 Hz

frequency interval. Spectral properties were investigated in the

classical frequency bands (IFSECN, 1974), instead of being settled

on the basis of individual spectral characteristics (Klimesch, 1999),

as spectral properties are known to be affected by stroke. The

investigated frequency bands were: 2–3.5 Hz (delta), 4–7.5 Hz

(theta), 8–12.5 Hz (alpha), 13–23 Hz (beta1), 23.5–33 Hz

(beta2), 33.5–44 Hz (gamma). Relative power spectral density

(rPSD) was obtained as the ratio of PSD to total power in the 2–44

Hz frequency range. The relative band powers were calculated by

integrating in the frequency intervals indicated above. All absolute

values were log transformed in order to better fit normal

distribution for statistical analysis.

Entropy is a quantity introduced in the second half of the

XIX century: when referred to a multiparticles system (i.e.,

made of a very high number of elements, with proportional

number of degrees of freedom), entropy is a state function

describing the number of microscopic states with which a

certain macro-state can be realized. Accordingly, it has been

later introduced in information theory as the expected value

(i.e., the average amount) of the information of a probability

distribution (Shannon, 1948). The definition was also extended

to the EEG relative PSD (spectral entropy, Inouye et al., 1991).

In the present case, the Frichness_ of the frequency content, i.e.,

Fig. 1. Four main classes appeared when considering the right minus left band pow

group with respect to controls. Grey area represents normative range and the white

symmetry line (dashed black line). Left-damaged patients are indicated by white

normative area indicate higher AH values than UH in left-damaged patients and lo

above normative area. In the left column, the band alterations defining each sp

numbers in bold indicate the representative subject whose PSD is presented in th

the spectral shape, is a main feature of the rest activity. For this

reason, we computed the spectral entropy in the 2–44 Hz

frequency interval:

�X44

f ¼ 2

rPSD fð Þlog2rPSD fð Þ

The spectral entropy quantifies the Frichness_ of the spectrum; it

gives a measure of how much a rPSD is fragmented (minimal

entropy) or flat (maximal entropy), independently of the total

power. In fact, a sinusoid, for example, is characterized by only

one spectral component and has minimal entropy; on the opposite

extreme, white noise, whose PSD is constant in the whole band,

i.e., contains all the frequencies with the same weight, has

maximal entropy. Since our frequency resolution was 0.49 Hz in a

total range [2, 44] Hz, the total number of points is 86 (=42/0.49),

resulting in a maximal entropy value of 6.476 (flat spectrum); for

the lower limit, we considered one peak whose amplitude was

99% above the basal level, resulting in entropy value of 4.037

(peaked spectrum).

We also defined a hemispheric individual alpha frequency

(IAF) as the frequency with maximal PSD in the [6, 13] Hz band in

each hemisphere (Klimesch, 1999).

Statistical analysis

In summary, the following parameters were considered: total

power, band powers, relative band powers, spectral entropy and

individual alpha frequency. Due to the relatively small size of

the control group, no attempt to define normative ranges was

done. Therefore, for each parameter, control subjects’ values

were entered in the statistical design. For such a purpose,

analysis of variance (ANOVA) was applied, with lesion (no

lesion, right hemispheric lesion, left hemispheric lesion) as

between-subjects factor. In order to take into account eventual

interhemispheric differences in controls, hemisphere (right

hemisphere = RH, left hemisphere = LH) was added as

within-subjects factor, instead of contrasting the affected hemi-

sphere (AH) vs. the unaffected hemisphere (UH). However,

when no interhemispheric ‘‘physiological’’ differences were

evidenced in control values, it was considered not necessary

to discriminate left and right hemispheres and the comparisons

were AH vs. UH (for control subjects, we arbitrarily aligned

AH with RH and UH with LH, but the opposite matching was

also verified). Whenever the Mauchly’s test indicated a

significant departure from the sphericity assumption, Green-

house–Geisser correction of degrees of freedom was applied.

Moreover, to describe individual spectral properties, we

observed that it is very important to get rid of the intersubject total

and band power variability, by considering the band interhemi-

spheric difference (IHSD). A IHSD normative range (mean T1.645*SD, covering about 90% of the healthy population) was

er differences (interhemispheric spectral differences = IHSD) in the patient

line the mean of IHSD in controls. Note that the control mean is above the 0

circles and right-damaged by black squares. Note that regions below the

wer AH values than UH in right-damaged; the opposite was true for regions

ectral class are indicated, and the belonging subjects listed. Identification

e right column (AH in bold line and UH in fine line).

Table 1

Clinical and neuroradiological data

# Age Sex Days after

stroke

NIHSS BI Motor

score

Sensory

score

Main lesion site

identified on MRI scan

AH Lesion

volume

Lesion

site

1 63 M 2 5 100 1.5 1 PC, FC, IC, BG L 2 CS

2* 75 F 4 6 70 1 0.5 FC R 2 CS

3 64 M 2 2 100 1.5 1.5 BG L 1 S

4 66 M 7 5 75 1 1 PC R 3 C

5 52 M 4 6 80 1 0.5 FC L 1 C

6 58 F 4 2 100 1.5 1.5 PC L 3 CS

7* 75 F 5 4 80 1 1 PC, FC, BG R 3 CS

8* 75 M 8 14 40 0.5 0.5 FC, BG, IC R 3 CS

9 85 F 3 14 40 0.5 1 PC, FC R 3 CS

10 72 M 4 14 60 0.5 1 IC, BG R 3 S

11 72 M 3 6 90 1.5 1 PC, FC, IC R 3 CS

12* 76 M 8 6 60 1.5 1 IC L 3 S

13 70 M 6 11 70 1 0.5 PC, FC L 3 CS

14 86 F 2 4 100 1.5 0.5 PC, FC, IC, BG R 3 CS

15 57 F 10 9 70 1 1 PC, FC, Th, BG R 3 CS

16 67 M 10 7 70 1 1.5 PC R 3 CS

17 65 M 10 5 60 0.5 1.5 BG L 1 S

18 79 F 4 5 100 1.5 1 FC, BG R 3 CS

19 76 F 2 7 70 1 1.5 PC L 2 CS

20 58 M 10 4 100 1.5 1 IC L 1 S

21 67 M 4 11 70 0.5 0.5 FC, IC L 3 CS

22 85 F 4 4 80 1 1.5 FC L 3 C

23 83 F 5 6 90 1.5 1 PC, IC, Th, BG L 3 CS

24 78 F 6 5 75 1 1 PC, BG L 2 CS

25 70 M 3 4 100 1.5 1.5 PC L 1 C

26 57 M 3 4 100 1 1.5 BG L 2 S

27 52 M 3 6 80 1.5 1 BG R 1 S

28 80 F 5 6 80 1 1.5 FC R 1 C

29 30 F 10 8 70 1 0.5 PC, FC, BG R 3 CS

30 75 M 7 6 90 1 1 PC, FC, Th R 3 CS

31 57 F 4 6 90 0.5 1 PC, FC, BG L 2 CS

32 80 F 4 14 40 0 0.5 PC, FC L 3 C

Mean 68.9 5.2 6.8 78.1 1.0 1.0

SE 2.1 0.5 0.6 3.2 0.1 0.1

NIH = NIH severity stroke scale; BI = Barthel Index; AH = affected hemisphere; R = right; L = left; C = cortical; S = subcortical; CS = cortico-subcortical;

PC = parietal cortex; FC = frontal cortex; IC = internal capsule; BG = basal ganglia; Th = thalamus; Volume of lesion: 1 = small; 2 = medium; 3 = large.

Patient’s identification numbers coincide with the ones in a previous paper of our group’s (Oliviero et al., 2004). Patients marked with asterisks had missing

data due to insufficient compliance. In the last two rows, mean values and their standard errors are indicated.

F. Tecchio et al. / NeuroImage 28 (2005) 72–8376

obtained on the basis of our control subjects (grey area in Fig. 1).

This allowed to recognize different groups of spectral alterations.

MRI investigation

Brain MRI was taken at 1.5 T, using Turbo Spin-Echo (TSE) and

Spin-Echo (SE) T1 and T2weighted sequences. T1weighted images

were also taken after intravenous administration of Gadolinium-

DTPA. All sequences provided contiguous 5 mm thick slices in

sagittal, coronal and axial planes. These images allowed an estimate

of the ischemic lesion volume, which was classified according to a

three-degree scale: 1 for small (�5 cm3), 2 for medium (<30 cm3), 3

for large (>30 cm3). A lesion was further classified as ‘‘cortical’’ (C)

when mainly cortical areas were involved or the lesion extended to

subcortical white matter excluding basal ganglia through internal

capsule; it was classified ‘‘subcortical’’ (S) when there was no visible

cortical involvement and basal ganglia, thalamus, caudate nucleus,

nucleus lenticularis or internal capsule were affected (Dromerick

and Reding, 1995); finally it was classified ‘‘cortico-subcortical’’

(SC) when both cortical and subcortical structures were involved.

Results

Clinical and neuroradiological features

Clinical and neuroradiological data are summarized in Table 1.

All patients showed mild-to-medium levels of neurological

impairment (mean NIHSS = 6.8 T 3.4) and of upper limb

sensorimotor deficit (mean motor and sensory scores 1.0 T 0.4).

Fifteen patients were affected by a right and 17 by a left

hemispheric stroke. Six patients were affected by a cortical lesion,

7 by a subcortical, 19 by a cortico-subcortical lesion.

Significant worse clinical status was associated to larger lesions

(Pearson rho = 0.370, P = 0.037). No significant differences were

found among the patients in clinical global status and hand

functionality related to the lesion side, although right-damaged

patients presented slightly more severe clinical scores than left-

damaged ones (mean NIHSS = 7.6 T 3.6 vs. 6.0 T 3.2,

respectively); no differences in clinical global status were found

in dependence on the lesion level (mean NIHSS = 6.5 T 3.8 in C,

5.8 T 4.2 in S and 3.3 in CS).

F. Tecchio et al. / NeuroImage 28 (2005) 72–83 77

Lesion volume resulted larger in right-damaged patients than

in left-damaged (2.60 T vs. 2.06 T, P = 0.052), and in CS with

respect to both C and S (both LSD P = 0.021, mean 2.7 T 0.5 vs.

1.8 T 1.0 and 1.8 T 1.3).

Inter-hemispheric spectral differences (IHSD)

As mentioned above, we carefully analyzed each patient’s

IHSD qualitatively and quantitatively, comparing it with the IHSD

normative range defined in the Materials and methods section. As

shown in Fig. 1, the IHSD of each patient was drawn with respect

to such range. This allowed a classification of the patients in four

classes: three classes (A, B, C) included 16 patients showing

alterations of the spectral properties, i.e., band powers interhemi-

spheric differences exceeding IHSD normative range. In particular

(Fig. 1): class A grouped 3 patients with alpha to gamma frequency

band powers higher in AH than in UH; class B included 8 patients

with delta or theta bands higher in AH than UH; class C by 4

patients with alpha and high frequencies lower in AH than UH. A

single patient (Fig. 1, class e) showed anomalous activity around

40 Hz in both hemispheres, with higher power and slower gamma

peak in AH (41 Hz) than in UH (43 Hz). Class D included the 12

patients with spectral asymmetry between AH and UH within

normative range. Of note, class A was constituted by only left-

damaged patients, whereas class C by only right-damaged patients.

No relationship could be appreciated between spectral classes

and the clinical scores (consistently, Kruskal–Wallis test provided

P > 0.20 for NIHSS, BI, motor and sensory scores).

Total power

To study the behavior of total power in the AH with respect to

the UH, taking into account the interhemispheric ‘‘physiological’’

difference in controls, we used ANOVAwith hemisphere (LH, RH)

as within-subjects factor and lesion side (no lesion, right lesion, left

lesion) as between-subjects factor. However, in order to obtain

clearer and more reliable findings, we previously analyzed the

effect of belonging to a one of the 4 specific spectral class in both

right- and left-damaged patients (8 groups). Since, as noted above,

Fig. 2. Upper row: Mean values of total power (log-transformed), entropy and IAF

AH and UH of patients, separated on the base of the lesion side. Lower row: Mean

power (log-transformed), entropy and IAF; empty circles indicate single subjects

no right-damaged patient fell in class A and no left-damaged patient

fell in class C, 6 groups could be defined. ANOVA indicated that in

all these groups the power was consistently higher in AH than in

UH, with the exception of right-damaged patients belonging to class

C. This finding was corroborated by the hemisphere * group

significant interaction [F(5, 21) = 4.328, P = 0.007], which

disappeared after the exclusion of this group [F(4, 18) = 1.614,

P = 0.214], disclosing a strong main effect of hemisphere [F

changed from F(1,21) = 2.382, P = 0.138 to F(1, 18) = 9.605, P =

0.006]. The anomalous class C was constituted by 4 right-damaged

subjects with subcortical involvement and large lesion volume, who

completely lose physiological activity and showed only activity in

delta and theta bands (Fig. 1, class C). For this reason they were

separately treated in further total power analysis.

ANOVA with hemisphere (RH, LH) as within-subjects factor

and lesion side (no lesion, right lesion, left lesion) and lesion level

(pure cortical, subcortical involvement) as between-subjects

factors indicated that the strongest significant effect was the

interaction hemisphere * lesion side [F(1,31) = 12.803; P =

0.001]. As shown in Fig. 2, the ‘‘physiological’’ higher power

found in the right hemisphere of the majority of control subjects

was amplified in patients with right lesion and inverted in those

with left lesion. For a more precise evaluation of such a behavior,

the interhemispheric differences were computed and also repre-

sented in Fig. 2. As confirmed by Tukey’s post hoc comparisons,

left-damaged patients presented an opposite interhemispheric

asymmetry with respect to controls and right-damaged patients

(respectively, P = 0.040 and P = 0.002), while no statistical

evidence separated right-damaged patients and controls, although

one-sample t tests showed that the distance from the 0 symmetry

line provided a P value of 0.070 in controls and of <0.001 in

right-damaged patients (Fig. 2).

Band power

ANOVA of the absolute band powers was performed with band

(delta, theta, alpha, beta1, beta2, gamma) and hemisphere (AH,

UH) as within-subjects factors, lesion side (no lesion, right

hemispheric lesion, left hemispheric lesion) and lesion level (pure

in the left and right hemispheres of healthy subjects (no lesion) and in the

and standard deviations of interhemispheric asymmetries (right-left) of total

values.

F. Tecchio et al. / NeuroImage 28 (2005) 72–8378

cortical, subcortical involvement) as between-subjects factors. No

effect involving lesion level was found, thus this item was removed

from further analysis. The main result was the triple interaction

band * hemisphere * lesion side [F(4.28, 81.28) = 4.645, P =

0.002], indicating different band behavior in controls and in

patients with a left or a right lesion. For this reason, band powers

were separately analyzed in detail, by performing ANOVA with

group (no-lesion, lesion) as a between-subjects factor (Fig. 3).

Delta band

Delta band activity absolute power was significantly higher in

the AH than in UH [F(1, 23) = 13.662, P = 0.001]. To evaluate

eventual differences induced by a lesion in the left or in the right

hemisphere, ANOVA with delta (AH, UH) as within-subjects

factor and lesion side (no lesion, right lesion, left lesion) as

between-subjects factor was performed. The significant delta *

lesion side effect indicated different behaviors of AH minus UH

difference in left- with respect to right-damaged patients. In fact,

only in right-damaged patients the AH increase was significant

(P = 0.003 and P = 0.379, respectively for right- and left-

damaged patients).

If delta absolute power in the two hemispheres was compared

to control values, not only AH were significantly increased

(univariate ANOVA, group factor [F(1, 39) = 11.643, P = 0.002]

but also UH [F(1, 39) = 4.609, P = 0.038] (Fig. 3). If again the

effect of the lesion side was considered, AH delta powers were

above controls clearly in right- and left-damaged patients (P <

0.001 and P = 0.025, respectively LSD correction), whereas UH

delta only reached significant levels in right-damaged (P = 0.012

and P = 0.331).

Theta band

By the same analysis as for delta band, absolute theta power

showed significant lesion side effect [F(1, 38) = 8.410, P = 0.001],

indicating different values in both the AH and UH of left- and

right-damaged patients with respect to controls. Post hoc compar-

Fig. 3. Mean band powers in the left (white box) and right (gray box) hemispheres

divided on the base of the lesion side. Standard errors are shown.

isons showed higher values in both the hemispheres with respect to

controls (P < 0.001 and.039 respectively for right- and left-

damaged patients); also, mean AH and UH values were different in

right- vs. left-damaged patients (P = 0.033).

Again, the effect of the lesion side was considered, and the

behavior was the same as for delta: significant increase of AH

values both in right- and left-damaged patients (P = 0.001

and.031, respectively) and only in right-damaged in the UH (P =

0.002 and 0.141, respectively).

Alpha Y gamma band

No effect was found in alpha band. In beta1 and beta2 bands,

AH powers were reduced with respect to UH values [hemisphere *

group F(1, 39) = 5.632, P = 0.023; F(1, 39) = 5.162, P = 0.029;

F(1, 39) = 5.632, P = 0.023]. In all high frequency bands (beta1,

beta2 and gamma), AH powers were below control values [group

F(1, 39) = 3.924, P = 0.055; F(1, 39) = 9.818, P = 0.003; F(1, 39) =

5.288, P = 0.027]. UH values were below controls only in beta2

band [F(1, 39) = 4.741, P = 0.036]. If the effect of the lesion side

was considered, beta1 and gamma AH absolute powers were

significantly reduced with respect to controls only in right-damages

patients (P = 0.012, P = 0.002, respectively).

A similar behavior as the one of absolute was observed in the

relative-band powers. Some effects in high frequency bands were

strengthen: in fact, beta2 and gamma relative powers were

reduced with respect to control values also in UH. If the effect of

the lesion side was considered, in beta2 band values in AH and

UH were below controls in both right- and left-damage patients

(AH beta2: P < 0.001 and P = 0.006, respectively; UH beta2: P =

0.005 and P = 0.055; LSD correction). In beta1 band, the same

effect was observed in AH (P < 0.001 and P = 0.014 respectively

in both right- and left-damage patients), whereas UH values were

reduced with respect to controls only in right-damaged patients

(P = 0.020 and P = 0.146, respectively). In gamma band AH, as

for absolute power, values were below control only in right-

damage patients (P = 0.018 and P = 0.430, respectively).

of control subjects and in the UH (white box) and AH (gray box) of patients

F. Tecchio et al. / NeuroImage 28 (2005) 72–83 79

Entropy

ANOVA with hemisphere (LH, RH) as within-subjects factor

and lesion side (no lesion, right lesion, left lesion) and lesion

level (pure cortical, subcortical involvement) as between-subjects

factors documented a strong hemisphere * lesion side interaction

[F(1, 37) = 7.447, P = 0.010, Fig. 2], indicating that the

symmetry of the healthy condition is lost in acute stroke patients,

with a decrease of entropy in AH with respect to UH in both left-

and right-damaged patients. Post hoc comparisons showed

significantly reduced absolute values in AH and UH with respect

to controls only in right-damaged patients (P < 0.001 in right and

P = 0.138 in left-damaged, Fig. 2).

As expected, entropy values in AH were lower in patients with

disorganized spectral pattern: groups B and C identified on the

base IHPD exceeding normative values had significant lower

entropy than patients in classes A and D (5.12 vs. 5.59, P = 0.014).

Patients with a right hemisphere damage showed significantly

lower entropy than patients with a left-damage (5.22 vs. 5.58, P =

0.033, Fig. 4).

Individual alpha frequency

ANOVA with hemisphere (LH, RH) as within-subjects factor

and lesion side (no lesion, right lesion, left lesion) and lesion level

(pure cortical, subcortical involvement) as between-subjects

factors. Strong hemisphere * lesion side interaction [F(1, 34) =

Fig. 4. (a) Power spectral density in the two hemispheres of two subjects representa

line). On the left: patient P22, UH entropy = 5.22; AH entropy = 4.45. On the rig

both cases the AH vs. UH entropy reduction quantifies a more concentrated relativ

quantifies Fthe Fpeakness_ (low value)/Fflatness_ (high value) of the rPSD. In parti

activity concentrated only in delta and theta bands, while the example on the

FphysiologicalF bands. Accordingly, AH entropy was much lower in patient P22

Individual entropy values in AH for the two classes with destructured (groups B a

base of left (open circle) or right lesion (filled circle). Horizontal line indicates m

21.286, P < 0.001, Fig. 2], showed a different behavior in control

and patients, with values in the AH lower than UH both in left- and

right-damaged patients.

In 4 patients (P9, P16, P17, P21), the AH IAF fell in the theta

range.

Clinical and neurophysiological relationship

Total power

With our sample size, no relationship could be appreciated

between total power values and the clinical scores (consistently,

Spearman’ rho provided a P value >0.20 when correlating NIHSS,

BI, motor and sensory scores to total power in AH, UH and their

asymmetries).

Band power

Clinical scores showed a linear correlation with AH spectral

properties only for gamma band absolute power (NIHSS rho =

�0.624, P = 0.001; BI rho = 0.637, P < 0.001; motor score rho =

0.484, P = 0.010), showing a direct correlation, namely higher

gamma values linked with better clinical pictures.

When evaluating the correlation with spectral characteristics in

UH, significant positive correlation appeared between beta1 and

beta2 absolute powers and motor score (rho = 0.384, P = 0.048;

rho = 0.424, P = 0.027, respectively with beta1 and beta2).

No relationship appeared between clinical scores and relative

band powers.

tive of a strong entropy reduction in AH (bold line) with respect to UH (fine

ht: patient P20, UH entropy = 5.62; AH entropy = 5.11. To be noted that in

e power in narrower frequency bands, accordingly with the fact that entropy

cular, the example on the left (P22) shows an AH entropy reduction due to

right (P20) shows a strong concentration of the activity power in the

(destructured spectral pattern) than in P20 (preserved spectral pattern). (b)

nd C) and preserved (groups A and D) spectrum; values are marked on the

ean value in control group.

F. Tecchio et al. / NeuroImage 28 (2005) 72–8380

Entropy

NIHSS was negatively (Spearman’ rho = �0.430, P = 0.028)

and BI positively correlated (rho = 0.375, P = 0.059), indicating

less severe clinical conditions being linked with higher entropy

values; on the other hand, entropy levels in UH were not correlated

to clinical scores (P > 0.50).

IAF

It was negatively correlated with NIHSS (Spearman’ rho =

�0.440, P = 0.031) and positively with BI and motor scores

(rho = 0.434, P = 0.034 and rho = 0.433, P = 0.035,

respectively), indicating that higher IAF values correlated with

less severe clinical conditions. IAF levels in UH did not result

related to clinical scores.

Neuroradiological and neurophysiological relationship

Lesion volume correlated with increase of relative theta power

in AH (Pearson rho = 0.435, P = 0.027). It was also associated to

AH absolute delta power only in right-damaged patients (Pearson

correlation �0.619, P = 0.042). With larger lesions, an AH high

frequency rhythm reduction was found (absolute powers: beta2

rho = �0.451, P = 0.018; gamma �0.510, P = 0.007; relative

powers beta2 rho =� 0.407, P = 0.039; gamma�0.403, P = 0.041).

Moreover, AH entropy and bilateral alpha slowing were associated

to larger lesion dimensions (rho =�0.390, P = 0.049; AH IAF rho =

�0.497, P = 0.014 and UH IAF = �0.481, P = 0.015).

Discussion

An ischemic attack in the middle cerebral artery territory

induces in its acute phase remarkable alteration of the neural

rhythmic activity at rest in the sensorimotor areas adjacent to the

central sulcus of both the affected and unaffected hemispheres.

In agreement with previous EEG studies (Van der Drift and

Kok, 1972; Nagata et al., 1982; Sainio et al., 1983; Pfurtscheller,

1986; Ahmed, 1988; Makela et al., 1998, Jackel and Harner, 1989;

Niedermeyer, 1997; Murri et al., 1998; Fernandez-Bouzas et al.,

2000), delta (2–3.5 Hz) and theta (4–7.5 Hz) band powers resulted

asymmetrically enlarged in the affected hemisphere of patients. It

must be noted, though, that also powers within the unaffected

hemispheres resulted increased in patients with respect to controls.

This could be due to the remote effect of primary ischemic lesion

indicating a transcallosal diaschisis; along this vein, it has been

observed that thermal-ischemic lesion of the sensorimotor cortex in

adult rats, induces axonal sprouting in the striatum of the damaged

hemisphere, under the influence of the contralateral corticostriatal

neurons. This sprouting was strongly correlated with synchronous

neuronal activity below 2 Hz generated in the unaffected hemi-

sphere, suggesting that this activity plays a role in anatomical

reorganization after the brain lesion (Carmichael and Chesselet,

2002). The final functional role of low frequency activity from the

patients’ unaffected hemisphere will be evaluated in follow-up

studies.

As an original observation, an enhancement of the total power

within the rolandic areas of the AH with respect to the UH of our

patients was found, except when the physiological activity above

alpha band was completely lost. Among the factors possibly

contributing to the observed power increase, the main ones could

be at cellular level, a higher number of active neurons and/or a

higher level of their firing synchrony and/or an increase of intrinsic

neuronal cell excitability; at network level, an increased efficiency

of the excitatory circuits and/or a reduced efficiency of inhibitory

networks. Between the effects at cellular level, hypoxic– ischemic

and excitotoxic neuronal cell death rule out the first (Castillo et al.,

1997; Borsello et al., 2003, Skaper, 2003); thus, what is expected is

an increase of intra-regional neuronal firing coherence and an

increase of intrinsic neuronal excitability. An increased synchro-

nization is in agreement with findings in animal models, where

cortical strokes induce, in the acute phase, horizontal intra-cortical

connections by axonal sprouting (Carmichael et al., 2001). This

hypothesis is strengthened in our data by the finding of a lower

entropy in the AH than in UH. In fact, the reduced amount of

neuronal activity spectral components increases the probability of

higher interneuronal coherence. Gap junctions (GJs) are evidenced

as a main factor in generating neuronal synchrony (Perez

Velazquez and Carlen, 2000; Blatow et al., 2003, Hasselblatt et

al., 2003; Hu and Bloomfield, 2003; Traub et al., 2003). A possible

neuroprotective role of modulating GJ intercellular communication

has been investigated in cerebral ischemia (Lin et al., 1998): gap

junction inhibitors, when not limited by toxicity, have been found

to have a significant therapeutic potential in the functional recovery

from acute stroke (Rawanduzy et al., 1997; Cotrina et al., 1998;

Nakase et al., 2003). Consistent with the hypothesis of an increased

intrinsic neuronal excitability, it has been clearly shown that

massive deafferentation and, consequently, a decrease in input

signals, can result in enhanced intrinsic and synaptic excitability of

individual neurons (Turrigiano et al., 1998; Mazevet et al., 2003;

Fujioka et al., 2004). Between the cerebral systemic factors

contributing to the observed AH power increase, evidence from

transcranial magnetic stimulation supports the notion of a reduced

efficiency of inhibitory networks both in acute (Liepert et al.,

2000), subchronic (Cicinelli et al., 2003) and chronic poststroke

stages (Shimizu et al., 2002).

Our recording system requires serial acquisition of the activity

from the two hemispheres. It can be imagined that when the patient

lies on the paretic side, he/she feels more uncomfortable than when

he/she is on the healthy side, with a greater desire to move. This

could affect the spontaneous activity, by reducing the background

power (Salmelin and Hari, 1994; Schnitzler et al., 1997;

Pfurtscheller and Lopes da Silva, 1999). Our results show higher

total powers in the AH than in the UH; in this respect, the possible

physiological effect of spontaneous activity power reduction when

a subject desires to move, which has to be more evident when the

patient lies on his/her affected side, at the most has reduced the

found asymmetry. If the Fmovement desire-related_ reduction is

considered in the Rolandic mu rhythm range, in alpha band, no

effect was present either between the two hemispheres or with

respect to the corresponding control value, and in beta band, only

right-damaged patients showed a power reduction. Another

methodological point is related to spectral artifact contaminations

when the background activity is under investigation and no simple

average is utilizable to signal to noise ratio increase. In fact, ocular

and cardiac artifacts contamination can be huge, both in controls

and in patients, not only in low-frequency (ocular and cardiac) but

also in alpha and beta bands (cardiac): for this reason, a rejection

procedure (Samonas et al., 1997; Barbati et al., 2004) has been ad

hoc developed and applied.

In our patients, slow frequency band powers did not relate

significantly with the clinical data in acute phase. Previous

electroencephalographic (EEG) reports (Kayser-Gatchalian and

F. Tecchio et al. / NeuroImage 28 (2005) 72–83 81

Neundorfer, 1980; Senant and Samson-Dollfus, 1985) showed a

significant association between acute EEG alterations and the

impairment of consciousness. However, our patient sample did not

include most severe clinical pictures with impaired consciousness.

Moreover, most reports deal with EEG recordings performed

within the first 48–72 h (Herrschaft and Kunze, 1977; Senant and

Samson-Dollfus, 1985), when strongest effects of reduction of

cerebral perfusion involved in the genesis of major EEG

abnormalities are present, which can be ruled out in our

investigation. In agreement with our results, a recent MEG study

in patients with cortical stroke lesions showed no correlation

between the amount of perilesional delta activity and clinical

symptoms (Butz et al., 2004). Moreover, slow frequency band

activity increase did not result clearly associated with the lesion

volume, compatible with our volume estimate, which in acute

phase is blind to the ischemic penumbra.

On the other hand, it is of great interest that the clinical picture

appeared in direct correlation with preserved gamma power in the

AH. Again, a role of the gap junctions (GJs) could be

hypothesized, since interneuron dendrites GJs have been reported

to enhance synchrony of gamma oscillations in distributed

networks (Traub et al., 2001), by virtue of their ability to induce

synchronous firing in principal neurons. Therefore, preserved GJ

function could be hypothesized to have a pivotal role in preserving

the functionality of cortical areas devoted to hand control. Gamma

oscillations are suppressed by blockade of gap junctional trans-

mission, AMPA receptors and GABA-A receptors (Traub et al.,

2001, 2003). In previous studies, both in acute and chronic

poststroke stages enhanced cortical excitability was observed

(Rossini et al., 2001; Oliviero et al., 2004); this was interpreted

as induced by GABA-A inhibitory network activity impairment,

being these neurons more prone to hypoxic ischemic damage than

excitatory ones; these patients showed good hand functionality,

suggesting that GABA function alteration does not directly affect

hand functionality. If – on the base of present results – gamma

activity reduction is taken into account associated to worse hand

functionality, the GJ communication seems to be more involved in

the functional loss, among the factors mediating the gamma band

reduction. Moreover, the gamma band plays a pivotal role in

cognitive motor tasks (Gross and Gotman, 1999; Meador et al.,

2002), as an indicator of selective neural recruitment (Menon et al.,

1996), and as coding feature for functional prevalence in hand

sensory areas (Tecchio et al., 2003, 2004).

A positive relationship was found between higher entropy

levels and better clinical pictures: this suggests that lesions not

affecting neuronal activity frequency richness allow the preserva-

tion of area functionality. A worst clinical picture was also related

to the decrease of AH rolandic areas individual alpha frequency, as

previously reported for parieto-occipital regions (Pfurtscheller,

1986; Giaquinto et al., 1994; Juhasz et al., 1997; Makela et al.,

1998). This suggests that a slowing as well as an unbalancing of

the neural networks generating the main rhythmic activity around

10 Hz (mu-activity in our case, alpha in other studies), with an

increase of slow rather than the fast frequency powers, have a

negative incidence on that neural network functionality.

In conclusion, a lesion affecting the MCA territory of one

hemisphere induces a perilesional increase of the low-frequency

rhythms’ spectral power both in the AH and UH rolandic areas, this

last indicating interhemispheric diaschisis. In the AH, an increase

of the total power and a reduction of the spectral entropy were

found, suggesting a higher synchrony of local neuronal activity, a

reduction of the intra-cortical inhibitory networks efficiency and an

increase of synaptic and intrinsic neuronal excitability. Direct high

correlation was found between preserved gamma band activity and

less severe clinical status. Dependence of the clinical picture, and

associated spectral alterations, on the lesion volume and not on the

lesion level, suggests a diffuse neuronal impairment, rather than a

selective structures damage, contributing to neurological status in

the acute phase of stroke.

It appears clear that a precise assessment of the neuronal brain

function as reflected by spontaneous rhythms at various frequen-

cies in the acute phase constitutes the basis for understanding

modifications during follow-up studies, as well as provides

knowledge about the neuronal reaction to the vascular brain insult.

Acknowledgments

This work has been partially supported by the 2003-prot.

2003060892 of the Italian Department of University and Research

(MIUR) and by the RBNE01AZ92_003, PNR 2001–2003, Fondi

di Investimento per la Ricerca di Base (FIRB) and by the IST/FET

Integrated Project NEUROBOTICS—The fusion of NEURO-

science and roBOTICS, Project no. 001917 under the 6th Frame-

work Programme.

The Authors thank Professor Maurizio Corbetta for scientific

discussions, Professor GianLuca Romani for his continuous

support, Dr. Domenico Lupoi for MR images evaluation and

TNFP Matilde Ercolani for her excellent technical support.

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