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Regional changes in the contralateral healthy Э hemisphere after ischemic lesions evaluated by quantitative T2 parametric maps.

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THE ANATOMICAL RECORD 266:118 –122 (2002)
DOI 10.1002/ar.010044
Regional Changes in the
Contralateral “Healthy” Hemisphere
After Ischemic Lesions Evaluated by
Quantitative T2 Parametric Maps
Department of Morphological and Biomedical Sciences, Section of Anatomy and
Histology, University of Verona, Verona, Italy
GlaxoSmithKline S.p.A., Research Laboratories, Verona, Italy
Modifications in the contralateral “healthy” hemisphere in a population
of rats bearing cortical infarction were studied in vivo by magnetic resonance imaging (MRI) with the aim to investigate whether cerebral areas not
directly involved in the lesion react at the presence of an ischemic lesion.
The study was performed in rats in which a transtemporal approach was
adopted to occlude the right middle cerebral artery (MCA). For MRI, the
animals were examined at 4.7 Tesla and quantitative T2 parametric images
were obtained by a multiecho sequence. Healthy rats and sham-operated
animals were used as control groups. The quantitative T2 parametric images showed that in the first week after the ischemia a significant increase
in the mean T2 was seen in the lesioned parietal cortex, compared to the
corresponding region of healthy rats (106 msec vs. 68 msec, P ⬍ 0.001). The
contralateral “healthy” hemisphere showed T2 mean values not significantly different from the corresponding hemisphere of healthy rats (71 msec
vs. 70 msec). However, a statistically significant increase in the T2 values
was evident in the hypothalamic region (74 msec vs. 66 msec, P ⬍ 0.001). In
rats examined 1 month after the ischemia, the T2 values of the hypothalamus were lower than those observed one week after ischemia (69 msec) but
remained higher than in controls. The present study demonstrates that
after a cerebral ischemia areas of secondary involvement distant from the
lesion are present and can be studied in vivo by quantitative MRI. Anat Rec
266:118 –122, 2002. © 2002 Wiley-Liss, Inc.
Key words: MRI; rat; hypothalamus; stroke
The cellular events taking place around a focus of cerebral ischemia are complex (Garcia et al., 1993; Fisher,
1997). In many animal models, cerebral ischemic lesions
can be evidenced by magnetic resonance imaging (MRI)
after a few minutes and they enlarge progressively until
24 hr (Rother et al., 1996). The lesion is usually surrounded by an area of penumbra (or salvageable ischemic
tissue) in which vasogenic and cytotoxic edema spread and
delayed neuronal death may be visible. In addition, secondary changes may gradually develop in ipsilateral areas
outside the ischemic region in laboratory animals and in
men (Kataoka et al., 1989; Tamura et al., 1990; Nakane et
al., 1992). We have recently demonstrated that modifications may also be induced in cerebral areas of the con©
tralateral hemisphere and that they can be evidenced with
histochemical, immunohistochemical, and ultrastructural
methods (Peng et al., 1996; Sbarbati et al., 1996). These
modifications seem to be due, at least in part, to the
*Correspondence to: Prof. Andrea Sbarbati, Dept. of Morphological and Biomedical Sciences, Section of Anatomy and Histology, University of Verona, Medical Faculty, Strada Le Grazie 8,
37134 Verona, Italy. Fax: ⫹39-45-8027163.
Received 7 May 2001; Accepted 12 October 2001
development of a collateral circulation. In the days after
the development of an ischemic lesion, scanning electron
microscopy observations of vascular cast show a modification of preexisting blood vessels (Coyle and Jokelainen,
1982; Coyle, 1984; Coyle and Heistad, 1987), which allows
the development of collateral circles between the two
hemispheres (Sbarbati et al., 1996). This involvement of
the contralateral hemisphere seems to be protracted for
several days, since 1 week after a cerebral lesion increased
expression of nitric oxide synthase, an enzyme involved in
the production of nitric oxide (Peng et al., 1996), could be
immunocytochemically demonstrated in specific regions of
the contralateral hemisphere.
These data suggest that secondary effects, which may
be relevant in the recovery of functional activity, are
present in the hemisphere contralateral to an ischemic
lesion. The histological analysis is unfit to put in evidence
these events; on the contrary, their transient and functional nature is better studied by MRI examination, which
has been demonstrated to represent a valid tool to evaluate in vivo areas of secondary changes (see Nakane et al.,
1997). Using this technique, several works described the
in vivo characteristics of ischemic lesions; however, data
about modifications in specific areas of the brain distant
from the main lesion and, for this reason, not directly
involved in the ischemic process are still scarce and restricted to the ipsilateral hemisphere (Nakane et al., 1992,
1997). In addition, quantitative MRI (see Hoehn-Berlage
et al., 1995; Loubinoux et al., 1997), which provides more
detailed information than standard T2-weighted images,
has never been used to study secondary lesions, necessitating further studies on this topic.
In the present work we adopted MRI to study in vivo the
presence of modifications in the contralateral “healthy”
hemisphere throughout a population of animals bearing
cortical infarction. We have used quantitative T2 imaging
as a suitable noninvasive method of evaluating vasogenic
edema in the brain. The aim of the work was to investigate
whether areas of secondary involvement are restricted to
the ipsilateral hemisphere or whether they may also be
located contralaterally.
Male Sprague-Dawley rats, weighing 250 –275 g, were
anaesthetized with 400 mg/kg i.p. of chloral hydrate and
permanent occlusion of the left middle cerebral artery
(MCA) was induced according to the method of Tamura et
al. (1981) (slightly modified). Briefly, the rats were anaesthetized with chloral hydrate (Fluka, 300 mg/kg i.p.) and
maintained normothermically by means of a homeothermic heating system (IMS “K-temp” control unit) coupled to
a rectal thermistor probe. The rats were placed under an
operating microscope in the lateral position, and a curved
2-cm skin incision was made in the midpoint between the
orbit and the external auditory canal. An incision was
made around the superior and posterior margins of the
temporalis muscle that was scraped from the lateral aspect of the skull and reflected forwards. A craniotomy was
performed by a 018 round burr (Ash) at the junction between the medial wall and the roof of the infratemporal
fossa. The position of the skull opening was about 3 mm
anterior and 1 mm lateral to the foramen ovale. At this
point the dura was opened through a cruciate incision by
means of a fine needle. The exposed MCA was coagulated
by bipolar diathermy and then the hole was filled with
absorbable bone sealant (Absele, Ethicon, Somerville, NJ).
The scalp incision was sutured and the animal was placed
under a lamp to facilitate recovery from anaesthesia and
avoid hypothermia. No signs of hyperthermia were observed during the surgery or MRI procedures. A group of
seven healthy male Sprague-Dawley rats, with the same
weight, and a further group composed of sham-operated
rats (n ⫽ 3) were used as controls.
For MRI examination, the rats underwent gas anaesthesia (O2 containing 0.5%–1% halothane) and were positioned,
within an 8-cm-diameter saddle coil, in a SIS 200/330 imager
spectrometer (SIS Co., Freemont, CA) equipped with a 4.7Tesla horizontal magnet (Oxford Ltd., Oxford, UK) and
33-cm bore. Part of the MRI experiments were carried out
using a Biospec System (Bruker, Karlsruhe, Germany)
equipped with the same magnet and a SMIS (Surrey Medical Imaging Systems, Ltd., Surrey, UK) gradient insert. A
72-mm-i.d. transmitter/receiver birdcage coil was used. Proton MRI (at 200 MHz) was performed. In each animal, a
multislice scout spin-echo sequence was performed with the
following parameters: orientation ⫽ sagittal, thickness ⫽ 2
mm, time of repetition (TR) ⫽ 600 msec, time of echo (TE) ⫽
18 msec, number of experiments (NEX) ⫽ 1, field of view
(FOV) ⫽ 10 cm, and matrix size ⫽ 256 ⫻ 192. Then rapidacquisition relaxation-enhanced (RARE) (orientation ⫽ axial, thickness ⫽ 2 mm, TR ⫽ 5,000 msec, TE ⫽ 85 msec,
NEX ⫽ 1, FOV ⫽ 10 cm, and matrix size ⫽ 256 ⫻ 256) and
diffusion-weighted (orientation ⫽ axial, thickness ⫽ 2 mm,
FOV ⫽ 6 cm, NEX ⫽ 1, and matrix size ⫽ 128 ⫻ 128) images
were acquired. Quantitative T2 parametric images were obtained by a multiecho sequence (orientation ⫽ axial, TR ⫽
1,200 msec, TE ⫽ 20 msec, number of echoes ⫽ 6, slice
thickness ⫽ 2 mm, FOV ⫽ 8 cm, acquisition time ⫽ 150 sec,
and matrix size ⫽ 128 ⫻ 128). Such T2 maps were calculated
pixel-by-pixel by fitting the logarithms of the expression S ⫽
S0 exp(–nTE/T2), obtained with the different values n ⫽ 1– 6
from the multiecho sequence. Likewise, T1 maps were produced from spin-echo sequences with different values of TR.
During the acquisition the temperature of the animals was
not controlled; however, clinical examination performed at
the end of the experiment in the present and in a previous
study (Sbarbati et al., 2000) revealed that in none of the rats
was hypothermia induced by gas anaesthesia.
Quantitative parametric T2 maps were obtained in ischemic rats 1 week (7–9 days) and 1 month (28 –31 days)
after the MCA occlusion (MCAO), while the rats of control
(nonoperated or sham-operated) were observed once. In
sham-operated rats, parametric maps were obtained 7
days after MCAO.
Quantitative T2 data were obtained by region of interest
(ROI) analysis of parametric images (axial sections). Operator-defined ROIs were manually traced on cerebral areas
identified according to Paxinos and Watson (1986) approximately at the following coordinates: interaural 7.2 mm/
bregma –1.8 mm. For each rat, 12 areas were evaluated and
the mean value was calculated. The number of pixels involved in the ROIs was optimized over the shape of the
corresponding structure and ranged from 3– 6. The intraROI variability, evaluated as the semidispersion, was about
5%. Two operators performed the measures: one of them was
blinded to the disease or control group. The variability between operators (interrater) was less than 0.4%, while that
of the same operator (intrarater) was less than 0.1%.
Periventricular areas were excluded from calculation to
avoid partial volume effects. For statistical analysis, single-
demonstrated regional differences with respect to the true
normal cerebral hemisphere of control animals (Peng et
al., 1996; Sbarbati et al., 1996). This secondary postischemic involvement has not been studied in vivo by quantitative MRI, probably because previous MRI studies have
mainly focused on the delimitation of the lesion and its
penumbra (Roberts et al., 1993; Kohno et al., 1995; Busch
et al., 1996; Dreher et al., 1998; Rordorf et al., 1998).
Study Limitations
Fig. 1. a: RARE axial image of an ischemic rat brain. b: T2 map
obtained from the same animal.
factor one-way analysis of variance (ANOVA) was used to
compare the mean values of the groups. Bonferroni correction was used for multiple comparisons and differences at a
P value of ⬍0.001; both vs. healthy rats and vs. the sham
group were considered significant.
In the first week after the MCAO, in vivo MRI examination showed in all studied animals a hyperintense area
in the right fronto-parietal cortex, which was visible, both
in the T2- and diffusion-weighted pulse sequences. Figure
1 shows a RARE axial image of an ischemic rat brain and
the T2 map obtained from the same animal. Figure 2
depicts the evolution of the ischemic lesion in another
subject. One month after the ischemia the lesion is reduced in size but still visible.
The quantitative T2 parametric images show (Table 1) a
significant increase in T2 in the ischemic region the first
week after MCAO, in comparison with the corresponding
region (parietal cortex) of healthy or sham rats (106.1
msec vs. 67.5 msec healthy, vs. 69.0 msec sham; P ⬍
0.001). The contralateral, “healthy” hemisphere of the
ischemic rats showed a global mean value of T2 not significantly different from the corresponding hemisphere of
healthy rats (70.7 msec vs. 69.5 msec). However, when
different areas of the contralateral hemisphere were examined, a statistically significant increase in the T2 values in the hypothalamic region (73.7 msec vs. 66.3 msec
healthy, vs. 69.4 msec sham; P ⬍ 0.001) was evident. The
sampled hypothalamic region is evidenced in Figure 3.
The T2 values of this region of the ischemic rats ranged
from 71–78 msec and an increase was visible in all examined rats, compared to the controls.
In other areas of the contralateral hemisphere, nonstatistically significant alterations of the T2 values were evident
(Table 1). In rats examined 1 month after ischemia, T2
values of the hypothalamus were lower than those recorded
1 week after ischemia (68.7 msec) but remained higher than
those in healthy controls (66.3 msec). The T2 values obtained
from the contralateral hypothalamic region or whole contralateral hemisphere in each rat are reported in Figure 4.
These data reveal a significant increase in hypothalamic T2
values 1 week after MCAO.
Secondary Postischemic Involvement
The cerebral hemisphere contralateral to an ischemic
lesion is widely considered “normal” at MRI, and it is free
of systemic effects on T2 values originating from the lesion
(Hoehn-Berlage et al., 1995). However, other techniques
In vivo paradigms provide anatomical information that
is not available by traditional histological methods. Major
limitations are the partial volume effect and the inaccurate sampling of the hypothalamic ROI. In fact, a single
hypothalamic nucleus of a rat cannot be visualized with
MRI. However, the technique of ROI definition is widely
used and turned out to be a sound method for our measurements: the interrater variability is scarce and the
intrarater variability is quite negligible, allowing statistically significant differences between the groups in particular areas to be obtained. Another drawback of analyzing
in vivo data pertains to a certain degree of variability
between anatomical regions and groups. This variability
in SDs found by other groups (Loubinoux et al., 1997) is
confirmed in the present work, suggesting that it does not
originate from the sampling method but is intrinsically
linked to in vivo MRI evaluations.
Effect of Ischemia on T2 Values
In the first week after a permanent ischemic lesion, T2
increases on the whole contralateral hemisphere, but this
change is not statistically significant. This finding seems to
be in accordance with results obtained by Schuier and Hossmann (1980), who demonstrated in cats that massive edema
is absent in the contralateral hemisphere of animals with
cerebral ischemia. However, analysis of the different regions
demonstrated that significant differences with the homotopic regions of nonischemic animals can be observed by
quantitative MRI. In control regions our quantitative evaluations are generally in accordance with those calculated by
Loubinoux et al. (1997), who found that the T2 values are
65.9 msec for the cortex, 63.7 msec for the striatum, 66.0
msec for the hypothalamus, and 55.8 msec for the thalamus.
Data of previous studies (Loubinoux et al., 1997) and
the present findings demonstrate that the cortex and the
hypothalamus have more or less similar values in normal
conditions. In the week after an ischemic lesion, the hypothalamus in the contralateral “normal” hemisphere was
found to have a significantly higher T2 than the cortex.
The high T2 values in the hypothalamus are difficult to
explain because in our experimental model this region is
not primarily involved in the ischemic process (Tamura et
al., 1981). A long-range interaction with the contralateral
hemisphere has been described in other types of lesions,
such as lesions induced by kainic acid injection (Zaczek et
al., 1980). In our opinion, the T2 increase detected in the
contralateral hemisphere is not a direct indicator of local
lesion, since the values observed are clearly lower than
those of the ischemic zone. A high relaxation time T2 is
linked to changes in the physical state of the tissutal free
water and is generally considered to result from the presence of excessive amounts of extracellular liquid (vasogenic edema). However, alterations in the activity status
of the tissue, influencing the cerebral blood volume, could
Fig. 2. Evolution of an ischemic lesion in a rat brain. RARE image of the brain 2 days after MCAO (a), 9
days after MCAO (b), and 30 days after MCAO (c).
TABLE 1. Quantitative T2 data obtained by ROI analysis of parametric images
Hypothalamus (ipsilateral)
Parietal cortex (ipsilateral)
Cingulate cortex (ipsilateral)
Pyriform cortex (ipsilateral)
Basal ganglia (ipsilateral)
Ipsilateral hemisphere
Hypothalamus (contralateral)
Parietal cortex (contralateral)
Cingulate cortex (contralateral)
Pyriform cortex (contralateral)
Basal ganglia (contralateral)
Contralateral hemisphere
(n ⫽ 7)
(n ⫽ 3)
One week after MCAO
(n ⫽ 8)
67.0 ⫾ 1.4
67.5 ⫾ 1.0
66.7 ⫾ 1.0
78.3 ⫾ 1.0
64.3 ⫾ 1.4
69.2 ⫾ 0.3
66.3 ⫾ 0.7
66.4 ⫾ 0.4
67.4 ⫾ 1.2
75.3 ⫾ 1.9
62.2 ⫾ 0.6
69.5 ⫾ 0.4
69.0 ⫾ 2.0
69.0 ⫾ 1.7
67.0 ⫾ 2.6
82.7 ⫾ 2.5
67.0 ⫾ 2.6
71.3 ⫾ 1.0
69.4 ⫾ 0.7
70.1 ⫾ 1.7
67.5 ⫾ 1.0
77.9 ⫾ 1.9
67.4 ⫾ 3.2
72.7 ⫾ 1.1
73.4 ⫾ 1.8
106.1 ⫾ 12.6
67.5 ⫾ 1.5
80.1 ⫾ 2.4
65.4 ⫾ 1.5
79.5 ⫾ 4.7
73.7 ⫾ 2.1
68.9 ⫾ 1.4
69.8 ⫾ 1.5
77.7 ⫾ 2
65.8 ⫾ 0.9
70.7 ⫾ 1.3
One month after MCAO
(n ⫽ 8)
68.7 ⫾ 3.6
70.1 ⫾ 4.9
67.1 ⫾ 1.9
77.9 ⫾ 3.0
64.3 ⫾ 1.4
74.7 ⫾ 6.1
68.7 ⫾ 1.1
67.8 ⫾ 0.7
65.3 ⫾ 1.4
77.6 ⫾ 1.5
63.4 ⫾ 1.0
70.1 ⫾ 1.6
Values of T2 are expressed in milliseconds (mean ⫾ SD). The measurements of the experimental groups with significant
difference vs. both healthy and sham groups are indicated (P ⬍ 0.001, one-way single-factor ANOVA).
also cause bigger changes in the T2 values (Cohen and
Bookheimer, 1994). The high signal intensity observed in
nonquantitative T2-weighted images was found in areas
of secondary involvement (substantia nigra) ipsilateral to
an ischemic lesion (Nakane et al., 1997). These secondary
changes have been suggested to be due to a transsynaptic,
neurotransmitter-mediated disinhibition as a result of
loss of GABAergic input resulting in a reversible edema
(Nakane et al., 1997).
Therefore, our results seem to indicate that even if not
directly involved in the cerebral ischemia areas of the
contralateral hemisphere can be secondarily involved.
This involvement could be due to vasogenic edema or to an
alteration of the functional activity of the tissue. Both
aspects are difficult to be demonstrated by conventional
histological methods. It has been proved that MRI is a
more suitable tool to estimate edema than histology,
which might explain why hypothalamic involvement has
not been detected in postmortem examination. Also the
transient nature of this event, which is reduced 1 month
after the MCAO, may have hampered postmortem demonstration. A further hypothesis is that the contralateral
involvement could be related to the increased permeability of the cerebral blood vessels described in the days after
an ischemia (Brightman et al., 1970; Preston et al., 1993).
The hypothalamus could be particularly sensitive to this
vascular condition due to the absence of the blood-brain
barrier in the area of the median eminence (Brightman et
al., 1970; Sage and Wilson, 1994).
In conclusion, the present study demonstrates that in
brain ischemia involvement of hypothalamic areas out of
Fig. 3. MRI image (left) and anatomical map (right) showing the
hypothalamic region and the ROI used for MRI evaluations: 1, paraventricular nucleus hypothalamus; 2, anterior hypothalamic nucleus; 3, ventromedial nucleus hypothalamus.
the lesion can be present and studied in vivo by quantitative MRI. This finding confirms the hypothesis that, in
addition to the primarily involved areas (the lesion and its
penumbra), areas of secondary, transient involvement
Fig. 4. Comparison of T2 values in MCAO-operated, sham-operated,
and healthy control rats. a: Contralateral hypothalamic region. b: Contralateral “healthy” hemisphere.
may occur after a cerebral ischemia. These areas also
develop at a distance from the lesion and may be located in
the contralateral hemisphere. In our opinion, the presence
of secondary involvement areas deserves further study
since they might play an important role in the recovery
process following an ischemic lesion and as such could be
the target of pharmacological treatments.
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