REVIEWTHE CONTRIBUTION OF FUNCTIONAL NEUROIMAGING
TO RECOVERY AFTER BRAIN DAMAGE: A REVIEW
Luigi Pizzamiglio1,2, Gaspare Galati1,2 and Giorgia Committeri1,2
(1Laboratory of Neuropsychology, Fondazione Santa Lucia, Roma, Italy; 2Department ofPsychology, Università “La Sapienza”, Roma, Italy)
ABSTRACT
The introduction of functional neuroimaging techniques has contributed to understandingthe neural correlates of recovery of motor, sensory and cognitive functions after braindamage. In this paper, we review the literature of the past twenty years, with particularemphasis on quantitative studies of cerebral blood flow and metabolism. Studies arepresented that examine recovery from hemiparesis, aphasia, spatial hemineglect and sensorydisorders. The contribution of this research is critically discussed in a methodologicalperspective. A basic distinction is made between cerebral plasticity and recovery offunctions. It is also argued that the most frequently used experimental designs do not permitdirectly relating changes in brain activity to functional recovery. The importance of accuratebehavioural measures is underlined. Alternative experimental designs are proposed, basedon correlations between behavioural performance and brain activations.
Key words: single photon emission tomography, positron emission tomography,functional magnetic resonance imaging, motor impairment, aphasia, neglect, sensoryimpairment
INTRODUCTION
Most people who survive a stroke experience some recovery of motor,sensory and/or cognitive functions in the following months. It is commonlybelieved that this functional recovery is the effect of some form of functionalreorganisation of the central nervous system that occurs after brain damage.Until a few years ago little was known about these reorganisation phenomena.The introduction of functional neuroimaging techniques that permit measurementof regional cerebral blood flow (CBF), metabolism or other physiological indicesof brain activity in vivo in stroke patients has provided new insights about thecerebral mechanisms of functional recovery. In this paper, we will review thework of the past twenty years, with particular emphasis on quantitativefunctional neuroimaging techniques, such as single photon emission tomography(SPECT), positron emission tomography (PET) and functional magneticresonance imaging (fMRI).
Several studies were devoted to recovery from hemiparesis and aphasia,probably because these are the deficits most commonly encountered after stroke.Less attention has been given to the recovery of sensory and spatial functions.These fields will be reviewed in separate sections. Clinical data and methodsused in the reviewed studies will be summarised in tables. In the discussion, we
Cortex, (2001) 37, 11-31
will critically examine the methodological limits of the experimental designsmost frequently used in neuroimaging studies, and will outline themethodological requirements that must be met if changes in brain activity are tobe related to functional recovery.
RECOVERY OF MOTOR FUNCTIONS
The studies dealing with the recovery of motor abilities can be divided intotwo subgroups according to the issues they address. The former (Table IA) ismainly concerned with the contribution neuroimaging techniques can make inpredicting the outcome of motor disorders in stroke patients, both with corticaland subcortical lesions. The latter (Table IB) is mainly concerned with theunderstanding of which neural structures, either ipsilateral or contralateral to thelesion, are recruited to underpin the functional reorganisation of the motorsystem. Less recent papers deal almost exclusively with completely recoveredpatients with subcortical infarcts (striato-capsular lesions). Instead, a tendency toconsider patients with cortical lesions is evident in the most recent studies.
Prediction of Motor Recovery
Di Piero, Chollet, Lenzi et al. (1992) measured the brain metabolism at restbefore and after recovery. Recovery of motor functions was not correlated withthe intensity of the initial motor deficit, the location of the lesion or the level ofoxygen consumption at rest. A positive correlation was observed between motorrecovery and the mean relative increase of metabolism in cerebral regionsinvolved in motor functions (primary motor cortex, premotor cortex,supplementary motor area, basal ganglia, and thalamus), particularly in the ipsi-and contralesional primary motor cortex. Good recovery was associated withincreased metabolism of contralesional areas, but the best motor improvementwas observed when metabolic activity increased bilaterally. This study stressesthe role of both hemispheres, suggesting the possible importance of directipsilateral projections in motor recovery.
Binkofski, Seitz, Arnold et al. (1996) studied a larger population of strokepatients and also found no correlation in the whole group between motorrecovery and either the size of the lesion or the remote depression of glucosemetabolism. However, a strong depression of glucose metabolism in theipsilateral thalamus emerged in the subgroup of patients showing poor recovery.These subjects also presented more severe damage of the pyramidal tract,according to the structural MRI, and a greater reduction in the amplitude of themagnetic evoked motor potentials. The preservation of the thalamus and part ofthe pyramidal tract were indeed the major factors predicting the motor outcome.
The role of the thalamus is also supported by the poor prognosis of motorrecovery when capsular lesions are associated with thalamic lesions (Fries,Danek, Scheidtmann et al., 1993). This very relevant structural neuroimagingstudy, performed by computerised tomography (CT), also showed that selectivelesions of either the anterior or posterior limb of the internal capsule initially
12 Luigi Pizzamiglio and Others
produce severe motor impairment, followed by good recovery. The authorsargued that different cortical areas, such as the supplementary motor area(SMA), the premotor and the primary motor cortex, project their outputs throughdifferent parts of the internal capsule, and these different motor systems areorganised in a parallel fashion, such that the impairment of one of them can becompensated for by the preserved action of the others.
Other prognostic studies yielded partially contrasting results. Iglesias,Marchal, Rioux et al. (1996) found no correlation between oxygen consumptionand severity of motor deficits in the acute stage, or between changes in oxygenconsumption and motor improvements in the first weeks after stroke. Heiss,Edmunds and Herholz (1993) found a significant correlation between degree ofrehabilitation at the final outcome and global ipsi- and contralesional glucosemetabolism tested in the acute stage, but only in the subgroup of patientscharacterised by hypertension. In the subgroup with no hypertension, youngerage was the best predictor of the final outcome.
A correlation between stroke severity and brain perfusion in the acute stagewas found in a very large population by Alexandrov, Black, Ehlrich et al.(1996). Short-term functional improvement was very good when brain perfusionwas within the normal range in the first few days after the stroke, and wasworse when perfusion was decreased or absent. In a multiple regression analysis,stroke severity appeared to have the highest predictive value, but the metabolicmeasures could significantly increase the prediction, particularly if performedwithin the first 72 hours after stroke.
A more specific hypothesis was suggested by a longitudinal study (Furlan,Marchal, Viader et al., 1996) that documented that recovery was positivelyrelated with the volume of the surviving “ischemic penumbra”, i.e., initiallyfunctionally impaired tissue at risk for infarction, exhibiting reduced cerebralblood flow but preserved structural integrity.
Taken together, the above studies propose neuroimaging techniques as usefultools in predicting motor recovery after stroke. They essentially suggest apositive outcome when the thalamus is preserved and in the presence of earlyregression of cortico-spinal tract damage and of oxygen depletion.
Reorganisation of Motor Functional Circuits
Broadly speaking, two classes of processes have been suggested to underliefunctional recovery from hemiparetic stroke: reorganisation of ipsilesional motorregions and changes in the homologous regions of the unaffected hemisphere.When the ipsilesional primary motor cortex is spared, it probably mediates therecovery (Weiller, 1998). However, the exclusive role of the ipsilesionalstructures alone has been suggested by few studies. For example, a recent singlesubject study (Rossini, Caltagirone, Castriota-Scanderbeg et al., 1998),conducted with refined techniques such as transcranial magnetic stimulationmapping, functional magnetic resonance imaging and magnetoencephalography,found an enlargement and a posterior shift of the sensorimotor areas in theaffected hemisphere after excellent motor recovery.
Emphasis on the participation in recovery of the healthy contralesional
Neuroimaging contribution to functional recovery 13
14 Luigi Pizzamiglio and Others
TA
BLE
IA
Clin
ica
l Da
ta a
nd
Me
tho
ds
of
Stu
die
s o
f M
oto
r R
eco
very
: S
tud
ies
Co
nce
rne
d w
ith P
red
ictio
n o
f th
e O
utc
om
e o
f M
oto
r F
un
ctio
ns
Mon
ths
afte
rst
roke
(m
ean
or r
ange
)a
Ass
essm
ent
ofA
ctiv
atio
nA
utho
rsM
etho
dsP
atie
nts
Lesi
onP
reP
ost
mot
or f
unct
ions
Con
trol
sta
skb
Mai
n re
sults
Di P
iero
et
al.,
1992
PE
T10
Cor
tical
and
0.2
3B
arth
el S
cale
-N
one
Met
abol
ic in
crea
se in
su
bcor
tical
mot
or r
egio
ns a
fter
reco
very
Bin
kofs
ki e
t al
., 19
96P
ET
, M
EPc
23C
ortic
al a
nd
0.1d
0.8
Mul
tifac
toria
l sco
reN
one
Tha
lam
ic m
etab
olis
m
subc
ortic
alas
soci
ated
with
rec
over
yIg
lesi
as e
t al
., 19
96P
ET
19M
CA
e<
0.1
0.5-
1O
rgog
ozo
Sca
le-
Non
eN
o co
rrel
atio
n be
twee
n ox
ygen
con
sum
ptio
n an
d re
cove
ryH
eiss
et
al.,
1993
PE
T76
Cor
tical
and
<
0.5
-B
arth
el S
cale
-N
one
Con
tral
ater
al
subc
ortic
alm
etab
olis
m p
redi
cts
reco
very
Ale
xand
rov
et a
l., 1
996
SP
EC
T45
8C
ortic
al a
nd
< 0
.5-
Can
adia
n -
Non
eP
erfu
sion
pre
dict
s su
bcor
tical
Neu
rolo
gica
l Sca
lere
cove
ryF
urla
n et
al.,
199
6P
ET
11M
CA
e<
0.1
-M
athe
w a
nd
-N
one
Pen
umbr
a as
soci
ated
O
rgog
ozo
Sca
les
with
rec
over
y
a T
he t
ime
whe
n th
e ne
uroi
mag
ing
expe
rimen
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ere
cond
ucte
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ind
icat
ed i
n tw
o se
para
te c
olum
ns,
for
expe
rimen
ts c
ondu
cted
bef
ore
and
afte
r be
havi
oura
l re
cove
ry r
espe
ctiv
ely.
bN
o ac
tivat
ion
task
mea
ns t
hat
neur
oim
agin
g sc
ans
wer
e co
llect
ed i
n a
“res
t” s
tate
(st
eady
-sta
te t
echn
ique
).
cM
EP
= m
otor
evo
ked
pote
ntia
ls.
dO
nly
ME
Ps
wer
e ob
tain
ed b
efor
ere
cove
ry. e
MC
A =
mid
dle
cere
bral
art
ery.
Neuroimaging contribution to functional recovery 15
TA
BLE
IB
Clin
ica
l Da
ta a
nd
Me
tho
ds
of
Stu
die
s o
f M
oto
r R
eco
very
: S
tud
ies
Co
nce
rne
d w
ith t
he
Re
org
an
isa
tion
of
the
Mo
tor
Sys
tem
aft
er
Str
oke
Mon
ths
afte
rst
roke
(m
ean
or r
ange
)a
Ass
essm
ent
ofA
ctiv
atio
nA
utho
rsM
etho
dsP
atie
nts
Lesi
onP
reP
ost
mot
or f
unct
ions
Con
trol
sta
skb
Mai
n re
sults
Ros
sini
et
al.,
1998
TM
Sc ,
fM
RI,
1M
CA
e-
12C
linic
al e
valu
atio
n-
Fin
ger
Shi
ft of
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sorim
otor
M
EG
dst
imul
atio
nha
nd r
epre
sent
atio
nT
FO
f
Cho
llet
et a
l., 1
991
PE
T6
Mai
nly
->
2C
linic
al e
valu
atio
n-
TF
Of
Bila
tera
l act
ivat
ion
of
subc
ortic
alm
otor
are
asW
eille
r et
al.,
199
2P
ET
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tria
to-c
apsu
lar
->
3C
linic
al e
valu
atio
n10
TF
Of
Bila
tera
l act
ivat
ion
of
mot
or a
reas
and
oth
er
area
sW
eille
r et
al.,
199
3P
ET
8C
apsu
lar
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72C
linic
al e
valu
atio
n10
TF
Of
Indi
vidu
ally
diff
eren
t pa
ttern
s of
re
orga
nisa
tion
Cra
mer
et
al.,
1997
fMR
I10
Cor
tical
and
-
0.4-
14M
edic
al R
esea
rch
9T
appi
ngIp
sila
tera
l act
ivat
ion
subc
ortic
alC
ounc
il S
cale
of m
otor
are
asC
ao e
t al
., 19
98fM
RI
8M
ainl
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NIH
Str
oke
Sca
le8
TF
Of
Ipsi
late
ral o
r bi
late
ral
activ
atio
n of
mot
or a
reas
Sab
atin
i et
al.,
1994
SP
EC
T1
Cor
tical
and
-
228
Clin
ical
eva
luat
ion
-T
FO
fIp
sila
tera
l act
ivat
ion
of
subc
ortic
alm
otor
are
asS
ilves
trin
i et
al.,
1993
Tra
nscr
ania
l 12
Sub
cort
ical
-5-
13M
otric
ity I
ndex
12T
FO
fB
ilate
ral a
ctiv
atio
n of
D
oppl
erm
otor
are
asP
anta
no e
t al
., 19
96S
PE
CT
37C
ortic
al a
nd
-2-
7A
dam
s’ S
cale
-N
one
CB
F in
con
tral
esio
nal
subc
ortic
alsu
bcor
tical
str
uctu
res
asso
ciat
ed w
ith r
ecov
ery
Sei
tz e
t al
., 19
99P
ET
7M
CA
e-
6M
ultif
acto
rial s
core
7T
FO
fR
ecov
ery-
rela
ted
netw
ork
of n
on-m
otor
ar
eas
Det
tmer
s et
al.,
199
7P
ET
6M
CA
e-
2-72
Clin
ical
eva
luat
ion
6F
orce
exe
rtio
nDiff
eren
t re
latio
nshi
p be
twee
n fo
rce
and
activ
atio
n in
pat
ient
s
a, b
See
Tab
le I
A. c
TM
S =
tra
nscr
ania
l mag
netic
stim
ulat
ion.
d
ME
G =
mag
neto
ence
phal
ogra
fy.
eM
CA
= m
iddl
e ce
rebr
al a
rter
y.
fT
FO
= t
hum
b fin
ger
oppo
sitio
n ta
sk.
gn.
s. =
not
spec
ified
.
hemisphere or of both hemispheres comes from a series of PET studies thatmeasured brain activity at rest and during an activation task (thumb-fingeropposition), performed either with the affected or the unaffected hand. In a studyon well recovered patients (Chollet, Di Piero, Wise et al., 1991), movements ofthe unaffected hand resulted in the activation of the sensorimotor cortex, thepremotor cortex, the SMA, the striate, the insula, and the inferior parietal cortexin the contralateral hemisphere, and of the ipsilateral cerebellum and sensorimotorcortex. When the affected hand was moved, the activation involved the samecortical and subcortical structures, but was bilateral. Furthermore, it was shownthat the ipsilesional thalamus, although not activated, significantly covaried withthe motor areas bilaterally, while the contralesional thalamus covaried only withstructures on the same side. This study demonstrates the participation ofuncrossed motor pathways in the process of motor recovery, and supports the ideaof a bilateral recruitment of motor regions. Consistent with the studies reported inthe previous section, it also points out the role of the thalamus.
In a subsequent study (Weiller, Chollet, Friston et al., 1992), well recoveredpatients with small lesions restricted to the striato-capsular region also showedactivation of both contra- and ipsilateral cortical and subcortical motor areasduring finger movements of the affected hand. In addition, a higher bilateralactivation of the insula and of the premotor, parietal, and lateral prefrontalcortices was found with respect to normal controls. A greater recruitment ofsomatosensory areas was also demonstrated when movements of the unaffectedhand were compared with those of normal controls. This study confirmed therelevance of both ipsi- and contralateral activations of motor pathways in therecovery of motor functions, and pointed out the relevant role played by non-motor structures. These findings were considered to support the relevance ofattentional and intentional mechanisms in the recovery from motor stroke. Thesame group of researchers confirmed these results in another group of patientswith capsular infarction (Weiller, Ramsay, Wise et al., 1993), also showingindividual differences in the pattern of reorganisation, dependent upon the site ofthe cortical lesion and the somatotopic organisation of the pyramidal tract. Itmust be said, however, that the interpretation of contralesional activations isdifficult, as mirror movements of the unaffected hand were observed during theexecution of the movement task by the affected hand.
Strong support for a compensatory role of pre-existing uncrossed motorneural pathways also comes from fMRI studies. During movement of therecovered hand, Cramer, Nelles, Benson et al. (1997) observed an increasedactivation of ipsilateral motor regions with respect to normal controls. In anotherstudy (Cao, D’Olhaberriague, Vikingstad et al., 1998), half of the patientsshowed a bilateral activation of the primary sensorimotor cortex during paretichand movements, while the other half had only a contralesional activation. Thesedifferent patterns of activation may be due to the use of patients who had notattained the same degree of restitution of motor functions.
The role of the contralesional hemisphere is confirmed by studies usingtechniques with lower spatial resolution. Sabatini, Toni, Pantano et al. (1994)used SPECT to study the motor recovery of a single patient who had suffered adeep left-sided hemiplegia at the age of 12, followed by good motor recovery.
16 Luigi Pizzamiglio and Others
At the age of 31, when the study was performed, he showed increased activationin the left sensorimotor and premotor cortices while performing movements bothwith the left and the right hand. Silvestrini, Caltagirone, Cupini et al. (1993)used transcranial Doppler to show the role of both the healthy and the affectedhemispheres in stroke patients’ motor recovery.
An attempt to correlate CBF values with a quantitative measure of the degreeof motor impairment and of possible functional recovery was made by Pantano,Formisano, Ricci et al. (1996), who studied patients with a persistent, severemotor deficit or poor and delayed recovery. The severity of the motor deficitwas not correlated with the volume, side and location of the infarct, but wasnegatively correlated with CBF values in the ipsilesional parietal andsupplementary motor areas and in the contralesional primary motor cortex. Thedegree of motor improvement was positively correlated with CBF values in thecontralesional thalamus, lentiform and caudate nuclei, and premotor cortex (basalganglia-frontal network).
A different approach, resulting in different findings, was adopted by Seitz,Azari, Knorr et al. (1999), who analysed PET data using a principal componentanalysis. Their study revealed a recovery-related cortico-subcortical network,activated during complex movements of the recovered hand, which, at variancewith previous studies, involved occipital and prefrontal cortices bilaterally, thecontralesional cingulate, the hippocampal formation, the dorsal thalamus, and thebilateral cerebellum, but not the cortical motor areas. The authors considered thereduction of contralesional diaschisis (i.e., a temporary functional impairment instructurally unaffected brain regions) as the major factor subserving recovery inthe chronic phase.
In conclusion, the majority of the reported studies suggest the recruitment ofparallel projecting cortical areas in both hemispheres, but mainly in thecontralesional one, as the neural correlates of motor functional recovery afterstroke. However, the almost exclusive use of recovered patients casts somedoubt on the relation of these results to recovery mechanisms, as they may beinfluenced by undetected residual deficits and aspecific mechanisms of cerebralplasticity. We will consider these and related methodological issues in the finalsection of this paper.
RECOVERY OF LANGUAGE
Partial or complete recovery, either spontaneous or following treatment, oflinguistic functions has long been observed in aphasic patients. Attempts toexplain the neural mechanisms underlying it have mainly focused on the conceptof diaschisis (see Feeney and Baron, 1986), or on the take-over of linguisticfunctions by the contralateral, undamaged hemisphere. Both hypotheses havereceived some support (for a review, see Cappa, 1998; Cappa and Vallar, 1992).
Although several reports of experiments based on cognitive activationparadigms are now available, most studies have used steady-state techniques tostudy abnormalities in brain metabolism or perfusion during a “rest” state, beforeand/or after recovery (Table IIA).
Neuroimaging contribution to functional recovery 17
Steady-state studies support the hypothesis that recovery of aphasia is due toregression of functional deactivation (diaschisis) in structurally unaffected brainregions connected to the injured areas. This holds especially in the case oflesions that do not directly affect the cortical language areas of the lefthemisphere. Aphasic patients with exclusively subcortical left lesions show areduction of cortical perfusion in the left hemisphere and the recovery oflanguage functions is associated with a reduction of cortical hypoperfusion andhypometabolism (Baron, D’Antona, Pantano et al., 1986; Vallar, Perani, Cappaet al., 1988).
Studies on aphasic patients with cortical lesions provided partially similarresults. Glucose metabolism in the left hemisphere, measured in the acute stage,was positively correlated with the degree of recovery of language (Heiss et al.,1993) and with performance on language tests two years after stroke (Karbe,Kessler, Herholz et al., 1995). Metter, Jackson, Kempler et al. (1992) found apositive correlation between recovery of language (measured as the change ofscores on neuropsychological tests) and the change of glucose metabolism in thetemporo-parietal cortex, in the right as well as in the left hemisphere.
Similarly to the last study, Cappa, Perani, Grassi et al. (1997) showedhypometabolism in structurally unaffected regions of both hemispheres in theacute phase; glucose metabolism increased in both hemispheres after severalmonths and a good recovery. Moreover, changes in language performance werepositively correlated with changes in metabolic values in several regions of theright hemisphere.
The relative role of the two hemispheres is documented by a study showingclear data in favour of a gradual compensatory function of the right hemisphere(Mimura, Kato, Kato et al., 1998). While the left hemisphere, and particularly itsperilesional regions, played a crucial role in early recovery, the right hemisphere,mainly the homotopic frontal and thalamic regions, participated in long-termrecovery.
All these studies suffer from the limitations of the “steady-state”neuroimaging techniques. Since patients are in a “rest” state during scanning,i.e., they are not actively engaged in linguistic tasks, this methodology provideslittle information about the functional organisation of the neural systemssubserving linguistic functions in brain damaged subjects. Several activationstudies, based on the cognitive subtraction principle, were conducted to clarifythis issue (Table IIB).
Early SPECT and PET studies focused on the contribution of the twohemispheres to recovery. In patients recovered from aphasia, Yamaguchi, Meyer,Sakai et al. (1980) found activation of the homologue of Broca’s area in theright hemisphere during a verbal task. More extensive activation of the righthemisphere in recovered patients with respect to normal subjects was alsoreported by Demeurisse and Capon (1987), but only in the subgroup of patientswith Broca’s aphasia. However, the best predictor of good recovery remainedthe activation of the left hemisphere. In a deep dysphasic patient with a lefttemporo-parietal lesion, activation of the homologue of Wernicke’s area in theright hemisphere was observed (Cardebat, Démonet, Celsis et al., 1994), butonly during semantic tasks (when performance was quite good), not during
18 Luigi Pizzamiglio and Others
phonological tasks (when the error rate was 100%). A more complex pattern wasfound by Knopman, Rubens, Selnes et al. (1984): good recovery of auditorycomprehension was associated with early diffuse activation of the righthemisphere and late left posterior parieto-temporal activation. However, inpatients whose lesion involved Wernicke’s area, recovery was incomplete andactivation could be observed in the right inferior frontal regions.
Weiller, Isensee, Rijntjes et al. (1995) emphasised the role of the righthemisphere as part of a redistribution of activity in a pre-existing bilateralnetwork, rather than as a simple take-over of functions. These authors employedpseudo-word repetition and verb generation tasks with patients recovered fromWernicke’s aphasia caused by small left perisylvian lesions. Normal subjectsshowed robust activation of Broca’s and Wernicke’s areas and weak blood flowincreases in homotopic regions of the right hemisphere. Patients showedpreserved activation of Broca’s area, together with clear right hemisphericactivation in the homologues of Broca’s and Wernicke’s areas. Similar resultswere obtained in aphasic patients who had at least recovered the ability to repeatwords (Ohyama, Senda, Kitamura et al., 1996). In the repetition task, thepatients showed a higher activation than the normal controls in the rightposterior-inferior frontal lobe (including the homologue of Broca’s area), and inthe right posterior-superior temporal lobe (including the homologue ofWernicke’s area). This study also underlines the role of the undamagedposterior-inferior left frontal areas in spontaneous speech in non-fluent patients.
More recently, three studies by Heiss’ group (Heiss, Karbe, Weber-Luxenburger et al., 1997; Heiss, Kessler, Thiel et al., 1999; Karbe, Thiel,Weber-Luxenburger et al., 1998) strongly supported the idea that left temporalareas are necessary for efficient recovery of linguistic abilities, and that righthemispheric areas contribute to the restoration of linguistic functions only whenleft hemispheric regions are permanently impaired. In fact, more than one yearafter stroke onset, there was a negative correlation between right and leftactivations (Karbe et al., 1998). The role of perilesional regions was alsodemonstrated in a study on a single subject with complete recovery ofcomprehension (Zahn, Huber, Erberich et al., 1999) and by a group studyemploying a word retrieval task (Warburton, Price, Swinburn et al., 1999). Innormal controls, the infero-lateral temporal activation was restricted to the leftside and attributed to the retrieval of appropriate words from semantic memory.Patients’ activation involved peri-infarct areas. However, it is worth noting that4 of the 6 patients, but only 2 of the 9 controls, also showed a significantactivation of the right infero-lateral temporal cortex.
These activation studies suggest that the metabolic changes after recoveryfrom aphasia brought out by steady-state techniques do reflect a change in theway language is processed in the brain. When language-related areas of the lefthemisphere are structurally unaffected, behavioural recovery is associated withan increase of their metabolism (Heiss et al., 1997; Heiss et al., 1999; Karbe etal., 1998; Knopman et al., 1984; Ohyama et al., 1996; Warburton et al., 1999;Zahn et al., 1999). When they are injured, recovery is mediated by an increasein metabolism in the homologues of the language areas of the right hemisphere(Calvert, Brammer, Morris et al., 2000; Cardebat et al., 1994; Demeurisse and
Neuroimaging contribution to functional recovery 19
20 Luigi Pizzamiglio and Others
TA
BLE
IIA
Clin
ica
l Da
ta a
nd
Me
tho
ds
of
Stu
die
s o
n L
an
gu
ag
e R
eco
very
. S
tea
dy-
Sta
te S
tud
ies
Mon
ths
afte
rst
roke
(m
ean
or r
ange
)a
Act
ivat
ion
Aut
hors
Met
hods
Pat
ient
sLe
sion
Pre
Pos
tC
ontr
ols
task
bM
ain
resu
lts
Bar
on e
t al
., 19
86P
ET
10T
hala
mic
1-63
5-8.
5c11
Non
eD
ecre
ased
hyp
oper
fusi
on in
the
ipsi
lesi
onal
ar
eas
Val
lar
et a
l., 1
988
SP
EC
T6
Sub
cort
ical
0.5
1-6
9N
one
Dec
reas
ed h
ypop
erfu
sion
in t
he ip
sile
sion
al
area
sH
eiss
et
al.,
1993
PE
T76
Cor
tical
0.5
21-7
751
Non
eIn
crea
sed
met
abol
ism
of
ipsi
lesi
onal
he
mis
pher
eK
arbe
et
al.,
1995
PE
T22
Cor
tical
0.5
––
Non
eIp
sile
sion
al m
etab
olis
m o
f sp
eech
-rel
evan
t ar
eas
pred
icts
rec
over
yM
ette
r et
al.,
199
2P
ET
8C
ortic
al3.
312
.5–
Non
eIn
crea
sed
met
abol
ism
in b
ilate
ral t
empo
ro-
parie
tal c
orte
xC
appa
et
al.,
1997
PE
T8
Cor
tical
0.5
610
Non
eIn
crea
sed
met
abol
ism
in b
ilate
ral c
ortic
al
area
s (m
ainl
y on
the
rig
ht s
ide)
Mim
ura
et a
l., 1
998
SP
EC
T20
MC
Ad
39
–N
one
Incr
ease
d pe
rfus
ion
in le
ft he
mis
pher
e 16
MC
Ad
–84
10N
one
(ear
ly r
ecov
ery)
and
rig
ht h
emis
pher
e (lo
ng-t
erm
rec
over
y)
a, b
See
Tab
le I
A. c
Onl
y fo
ur s
ubje
cts
wer
e te
sted
at
this
sta
ge.
dM
CA
= m
iddl
e ce
rebr
al a
rter
y.
Neuroimaging contribution to functional recovery 21
TA
BLE
IIB
Clin
ica
l Da
ta a
nd
Me
tho
ds
of
Stu
die
s o
n L
an
gu
ag
e R
eco
very
. A
ctiv
atio
n S
tud
ies
Mon
ths
afte
rst
roke
(m
ean
or r
ange
)a
Act
ivat
ion
Aut
hors
Met
hods
Pat
ient
sLe
sion
Pre
Pos
tC
ontr
ols
task
bM
ain
resu
lts
Yam
aguc
hi e
t al
., 19
80 13
3 X
e 3
MC
Ac
–3-
60–
Cou
ntin
g, c
onve
rsin
g,Act
ivat
ion
of r
ight
Bro
ca’s
are
ain
hala
tion
liste
ning
Dem
euris
se e
t al
., 19
8713
3 X
e 41
Cor
tical
0.7
320
Nam
ing
Act
ivat
ion
of le
ft he
mis
pher
ein
hala
tion
Car
deba
t et
al.,
199
4S
PE
CT
1T
empo
ral
–6
–P
hone
mic
and
Act
ivat
ion
of r
ight
Wer
nick
e’s
area
onl
y in
an
d pa
rieta
lse
man
tic m
onito
ring
sem
antic
tas
kK
nopm
an e
t al
., 19
8413
3 X
e 21
Cor
tical
35-
12–
List
enin
gA
ctiv
atio
n of
rig
ht h
emis
pher
e (e
arly
) an
d of
left
inha
latio
nW
erni
cke’
s ar
ea (
late
)W
eille
r et
al.,
199
5P
ET
6P
eris
ylvi
an1
5-11
76
Wor
d re
petit
ion
Bila
tera
l act
ivat
ions
of
Bro
ca’s
and
Wer
nick
e’s
and
gene
ratio
nar
eas
Ohy
ama
et a
l., 1
996
PE
T16
Cor
tical
–1-
506
Wor
d re
petit
ion
Act
ivat
ion
of r
ight
Bro
ca’s
and
Wer
nick
e’s
area
s +
left
Bro
ca’s
are
a (n
on-f
luen
t ap
hasi
cs)
Hei
ss e
t al
., 19
97P
ET
6C
ortic
al a
nd
112
-18
6W
ord
repe
titio
nA
ctiv
atio
n of
left
Wer
nick
e’s
area
subc
ortic
alH
eiss
et
al.,
1999
PE
T23
MC
Ac
0.5
211
Wor
d re
petit
ion
Goo
d re
cove
ry:
activ
atio
n of
left
Wer
nick
e’s
area
.P
oor
reco
very
: ac
tivat
ion
of r
ight
hom
olog
ueK
arbe
et
al.,
1998
PE
T12
MC
Ac
119
d10
Rep
etiti
onG
ood
reco
very
: ac
tivat
ion
of le
ft W
erni
cke’
s ar
ea.
Poo
r re
cove
ry:
activ
atio
n of
rig
ht h
omol
ogue
Zah
n et
al.,
199
9fM
RI
1M
CA
c–
5–
Wor
d re
trie
val
Per
ilesi
onal
act
ivat
ion
War
burt
on e
t al
., 19
99P
ET
6M
CA
c–
6-14
9W
ord
retr
ieva
lP
erile
sion
al a
ctiv
atio
n +
rig
ht t
empo
ral c
orte
xC
alve
rt e
t al
., 20
00fM
RI
1P
eris
ylvi
an–
53
Sem
antic
dis
cuss
ionA
ctiv
atio
n of
bila
tera
l lan
guag
e ar
eas
Mus
so e
t al
., 19
99P
ET
4M
CA
c–
6-18
–R
epet
ition
and
T
est
perf
orm
ance
cor
rela
tes
with
act
ivat
ion
com
preh
ensi
onof
rig
ht W
erni
cke’
s an
d B
roca
’s a
reas
Thu
lbor
n et
al.,
199
9fM
RI
2M
CA
c3
6-9
6R
eadi
ng a
nd
Act
ivat
ion
of r
ight
hom
olog
ues
of la
ngua
ge
com
preh
ensi
onar
eas
Bel
in e
t al
., 19
96P
ET
7M
CA
c–
56–
Hea
ring
and
Impr
oved
per
form
ance
: le
ft pe
riles
iona
l act
ivat
ion
repe
titio
nP
oor
perf
orm
ance
: rig
ht h
emis
pher
e ac
tivat
ion
Cao
et
al.,
1999
fMR
I7
MC
Ac
–5-
144
37P
ictu
re n
amin
g an
d B
ette
r re
cove
ry w
ith b
ilate
ral t
han
right
IC
Ae
Ver
b ge
nera
tion
activ
atio
n
a, b
See
Tab
le I
A. c
MC
A =
mid
dle
cere
bral
art
ery.
d
Onl
y se
ven
subj
ects
wer
e te
sted
at
this
sta
ge.
e IC
A =
Int
erna
l car
otid
art
ery.
Capon, 1987; Heiss et al., 1997; Heiss et al., 1999; Karbe et al., 1998; Weilleret al., 1995; Yamaguchi et al., 1980).
Although the activation of areas not used by normal subjects is clearly aconsequence of the lesion, the general assumption that it reflects new, emergingfunctional properties responsible for the recovery process is not compelling.Since recovery is rarely complete and residual deficits usually persist, it mightbe argued (Belin, Van Eeckhout, Zilbovicius et al., 1996) that the righthemisphere activation in language tasks reflects a maladaptive process, which isresponsible for the persistence of residual deficits rather than for the degree ofrecovery achieved. What is clearly missing in these studies is a direct correlationbetween brain region activity and patients’ performance in different recoverystages.
Musso, Weiller, Kiebel et al. (1999) developed an experimental designdirectly addressing this problem. They correlated CBF during successiverepetitions of the same comprehension task with scores on a modified version ofthe Token test, performed immediately after each scan. A 2-hour languagecomprehension training, carried out during the inter-scan intervals, resulted in anincrease of correct answers on the Token Test in all patients. Performance onthis test was positively correlated with CBF in the right homologues ofWernicke’s area (2 patients) and of Broca’s area (1 patient). This studyconvincingly demonstrates that activity in the right hemisphere during languagetasks is associated with better performance. However, the question of whetherthe effects on brain functioning of such short-term intense training can beequated with those induced by processes of functional reorganisation takingplace over periods of months or even years, remains open.
A recent longitudinal study (Thulborn, Carpenter and Just, 1999) supportsthis hypothesis: two patients showed a progressive shift of language-relatedactivation to the right hemisphere regions homologous to those affected by thelesion, during the first months after stroke. Unfortunately, although thisactivation change was concomitant with a behavioural improvement, the authorsdo not report any quantitative behavioural data to support this relationship.
A different approach to the same problem was used by Belin et al. (1996),with radically different results. The authors studied aphasics who had undergonerehabilitation training with melodic intonation therapy (MIT). This treatmentinvolves speaking with an exaggerated prosody, characterised by a melodiccomponent (Albert, Sparks and Helm, 1973). Patients were poor in repeatingwords with a natural intonation, but improved when they used an MIT-likeintonation. Repetition with natural intonation activated the right homologue ofWernicke’s area and deactivated Broca’s area in the left hemisphere, while MIT-like repetition yielded opposite results. Thus, the “abnormal” activation of righthemispheric areas was associated with the persistence of deficits during normalrepetition, while the “normal” activation of (left) Broca’s area during MIT-likerepetition and the concomitant deactivation of right hemispheric regions wasassociated with improved performance. The authors argued that the activity ofthe homologues of language regions in the right hemisphere reflected thedisruptive effect of the lesion rather than cortical reorganisation. Note, however,that there was no control group in this study, so it is still possible that the
22 Luigi Pizzamiglio and Others
different involvement of left and right language regions is intrinsically related tothe kind of task rather than to the degree of recovery.
Finally, a correlation between neuropsychological scores in language testsand the lateralization of language-related activation has been reported by Cao,Vikingstad, George et al. (1999): better language recovery was observed inindividuals who had bilateral rather than right hemisphere-predominantactivation.
In conclusion, functional neuroimaging studies carried out on the neuralcorrelates of recovery from aphasia can be summarised as follows. Studies ofbrain metabolism and perfusion in a “rest” state have emphasised regressionfrom diaschisis in the structurally unaffected regions of the left hemisphere (andin some cases even in the right hemisphere) as the main mechanism underlyingrecovery of language. Conversely, activation studies focused on the functionalreorganisation of the language network have underlined the increased role of theright hemispheric regions homotopic to the language regions of the lefthemisphere.
RECOVERY OF SPATIAL DISORDERS
Some studies have been devoted to the recovery of spatial hemineglect inrelation to cerebral perfusion and metabolism (Table IIIA).
Two papers (Baron et al., 1986; Vallar et al., 1988) studied spontaneouslyrecovered hemineglect patients with subcortical lesions. The authors comparedpatients’ behavioural performance with neuroimaging data collected at rest(steady-state technique) in two periods of clinical development. Both studiesfound a positive relationship between hemineglect improvement and decreasedipsilateral hypometabolism, suggesting a recovery from diaschisis, previouslyrelated to damage of the thalamo-cortical connections.
An important role of the contralesional as well as the ipsilesional structuresin the recovery of the hemispatial deficit has been suggested by a subsequentstudy (Perani, Vallar, Paulesu et al., 1993).
More recently, two studies (Pantano, Guariglia, Judica et al., 1992;Pizzamiglio, Perani, Cappa et al., 1998) investigated functional recoveryfollowing rehabilitation (2 months) in hemineglect patients with cortical andsubcortical lesions. They observed changes in brain activation induced by thesame task performed before and after hemineglect recovery. Both studiesadopted a visual search task, with targets appearing in different positions of theextrapersonal space. The former found both a perilesional and a contralateral(left anterior) activation in the second measurement. Correlation betweenbehavioural improvement and CBF increase was particularly high in the anteriorcontralateral area. The authors suggested an explanation based on the possibleuse of voluntary strategies during scanning of external space, mediated by eyemovement control mechanisms located in the left hemisphere. The latter studyused a more complex (factorial) design, and a control group of normal subjectsperforming the same tasks. The pattern of results was in the direction of analmost exclusive ipsilesional activation. Recovery of hemineglect was in fact
Neuroimaging contribution to functional recovery 23
associated with increased activation of spared right cortical structures, whichwere the same as those involved in the same kind of task in the control group.
The reported studies on the recovery of the hemineglect syndrome werecharacterised by a small number of patients (less than 20), with a prevalence(2/3) of subcortical lesions. This prevents generalising the conclusions to thepopulation of brain damaged patients with hemineglect. However, compared toother neuropsychological domains described in this review, many studies used atest-retest paradigm, thus allowing for more convincing claims about therelationship between functional and perfusional-metabolic changes.
As a general trend, the above findings suggest the predominant importance ofthe ipsilesional structures in the mediation of functional recovery. However, thelatter conclusion may be dependent upon the large number of subcortical lesionsincluded in the reviewed papers.
RECOVERY OF SENSORY FUNCTIONS
In the visual domain (Table IIIB), a strong positive relationship was observedbetween good recovery of visual functions and reduced size of the metaboliclesion, with an improved metabolism of the striate cortex (Bosley, Dann, Silveret al., 1987). However, strokes in the primary visual area were not associatedwith either metabolic changes or recovery of functions.
A complete recovery of visual field defects was described in two recent casereports. The former (Ptito, Dalby and Gjedde, 1999) described a patient whosuffered an injury to both occipital lobes at birth. At the age of 24 years, hervision was confined to the rightmost temporal field. A second perimetry,performed ten years later, revealed a restitution of vision in the entire rightvisual field and a residual defect confined to the left field. At that time, the MRIshowed a bilateral occipital lesion and PET revealed a bilateral occipitalhypometabolism. Both were less extensive on the left side. The authorsinterpreted the partial restitution of visual function as a manifestation of acerebral plastic process completed in the left occipital lobe.
In the latter study (Braus, Hirsch, Hennerici et al., 1999), a 30-year-old patientwith acute encephalomyelitis and right hemianopia was studied longitudinally. Inthe acute stage, the fMRI documented a reduced response to visual stimulation inthe occipital cortex. After 4 weeks, despite a complete recovery of the visual field,large areas of the visual cortex were still not activated. Only after 16 weeks therewas an improvement in cortical functional activation.
The neural correlates of recovery from a different kind of visual deficit havebeen recently described in patients who underwent a single episode of unilateralacute optic neuritis (Werring, Bullmore, Toosy et al., 2000). After theimprovement of visual acuity and colour vision, the pattern of cerebral activitywas studied during photic stimulation. While the stimulation of either eye incontrol subjects activated only the occipital visual cortex, an extensive extra-occipital activation (strongly correlated with latency of the visual evokedpotentials) was observed when the same stimulus was given to the patients’recovered eye.
24 Luigi Pizzamiglio and Others
Neuroimaging contribution to functional recovery 25
TA
BLE
III
Clin
ica
l Da
ta a
nd
Me
tho
ds
of
Stu
die
s o
n R
eco
very
fro
m S
pa
tial (
A),
Vis
ua
l (B
) a
nd
Au
dito
ry (
C)
Dis
ord
ers
.
Mon
ths
afte
rst
roke
a
Act
ivat
ion
Aut
hors
Met
hods
Pat
ient
sLe
sion
Pre
Pos
tC
ontr
ols
task
bM
ain
resu
lts
AB
aron
et
al.,
1986
PE
T2
Tha
lam
ic1-
2.5
7-8.
5–
Non
eD
ecre
ased
ipsi
late
ral h
ypom
etab
olis
mV
alla
r et
al.,
198
8S
PE
CT
2S
ubco
rtic
al0.
53
9N
one
Dec
reas
ed ip
sila
tera
l hyp
omet
abol
ism
Per
ani e
t al
., 19
93P
ET
2C
ortic
al a
nd
0.2
4-8
7N
one
Dec
reas
ed ip
sila
tera
l and
con
tral
ater
al
subc
ortic
alhy
pom
etab
olis
mP
anta
no e
t al
., 19
92S
PE
CT
7C
ortic
al a
nd
4-14
6-16
–V
isua
l sea
rch
Incr
ease
d pe
rfus
ion
in r
ight
pos
terio
r su
bcor
tical
and
left
ante
rior
area
sP
izza
mig
lio e
t al
., 19
98P
ET
3C
ortic
al a
nd
2.5-
114.
5-13
4V
isua
l sea
rch
Incr
ease
d ac
tivat
ion
of r
ight
hem
isph
ere
subc
ortic
al
BB
osle
y et
al.,
198
7P
ET
5C
ortic
al a
nd
0.1-
0.6
1-10
–N
one
Impr
oved
met
abol
ism
of
stria
te c
orte
xsu
bcor
tical
Ptit
o et
al.,
199
9P
ET
1B
ilate
ral
–40
8–
Non
eB
ilate
ral o
ccip
ital h
ypom
etab
olis
m,
less
oc
cipi
tal
exte
nsiv
e on
the
left
side
(re
cove
red
right
hem
ifiel
d)B
raus
et
al.,
1999
fMR
I1
Per
i- n.
s.c1
and
4–
Vis
ual
Incr
ease
d ac
tivat
ion
of v
isua
l cor
tex
vent
ricul
arst
imul
atio
nW
errin
g et
al.,
200
0fM
RI,
VE
Pd
7O
ptic
neu
ritis
–6-
168
7V
isua
l E
xtra
-occ
ipita
l act
ivat
ion
indu
ced
by
stim
ulat
ion
stim
ulat
ion
of r
ecov
ered
eye
CE
ngel
ien
et a
l., 1
995
PE
T1
Bila
tera
l 24
966
Pas
sive
list
enin
g E
xten
sive
bila
tera
l act
ivat
ion
(uni
late
ral
peris
ylvi
anan
d ca
tego
risat
ionin
con
trol
s)of
env
ironm
enta
l so
unds
a, b
See
Tab
le I
A. c
n.s.
= n
ot s
peci
fied.
d
VE
P =
vis
ual e
voke
d po
tent
ials
.
In the auditory domain (Table IIIC), a very well-conducted study byEngelien, Silbersweig, Stern et al. (1995) described the case of a patient withbilateral perisylvian strokes and auditory agnosia, who remained word-deaf butpartially recovered the capacity to recognise environmental sounds. The authorsmeasured the recovered function during the imaging procedure, comparing a taskof categorisation of environmental sounds with passive listening to the samestimuli. The PET activation associated with the recovered ability involved abilaterally distributed network, comprising the prefrontal, middle temporal andinferior parietal cortices, plus the right cerebellum, the right caudate nucleus andthe left anterior cingulate gyrus. Since normal subjects showed the same networkof cortical activation, but only in the left hemisphere, the authors stated that bothperi-infarct regions and contralesional homologous areas contributed to thefunctional reorganisation after injury.
GENERAL DISCUSSION
The basic question that must be addressed when trying to interpret thechanges over time brought out in stroke patients by imaging techniques iswhether they are indeed related to recovery of functions.
First of all, it is essential to stress that functional recovery does not have thesame meaning as cerebral plasticity. The former consists in a return to normal ornear-normal levels of performance, following the initially disruptive effects ofinjury to the nervous system. The latter does not refer only to the structural andfunctional changes of the neuronal organisation which follow an injury, butincludes also the capacity of the nervous system to adapt its structuralorganisation to new situations emerging either from developmental maturationand from interaction with the environment (Macchi, 1985).
The cortical and subcortical changes that follow lesions in the peripheral orcentral nervous systems as well as sensory deprivation and sensory stimulation,are well known in animals and humans (Nudo and Friel, 1999). They may havedifferent meaning. In some cases, spared neuronal populations involved in agiven function undergo reorganisation after the lesion, providing the basis for thefunctional recovery. In other cases, different regions of the brain, which processinformation in a completely different way, are recruited after a lesion tocompensate for a functional loss. The recovery is, therefore, related tosubstitution of function and the plastic changes directly reflect this complexreorganisation. There are, however, other plastic changes following a brainlesion that bear no relationship at all to the recovery of a damaged function (Dasand Gilbert, 1995), or may even have negative consequences on the patient’sfunctional abilities. For instance, there are impressive examples of markedcortical readjustment following limb amputation (Flor, Elbert, Knecht et al.,1995), pointing to an enlargement of the cortical representation of the amputatedlimb in the somatosensory cortex. The increased size is highly correlated withthe intensity of the pain experienced, suggesting that it is related todysfunctional changes rather than to functional recovery.
With these caveats in mind, it is interesting to discuss the meaning of the
26 Luigi Pizzamiglio and Others
reviewed studies. First, let us consider the limitations of steady-state studies. Asingle measure of cerebral blood flow or metabolism, obtained during the “rest”state after a given interval from the stroke, is scarcely informative about therecovery of specific functions. Even the changes observed in two consecutivemeasures of blood flow are not conclusive. They may be contingent upon avariation of the cognitive performance (e.g., language improvement), but theymight also have depended on physiological plastic changes totally unrelated tothe specific function under scrutiny.
The introduction of activation paradigms certainly increases the possibility torelate the functional improvement to the recruitment of a set of brain structures.The physiological measure, recorded while patients are actively engaged in atask involving the specific sensorimotor or cognitive function being studied, canbe compared to the one obtained in the rest state, or during an appropriatebaseline task (the “cognitive subtraction” principle). However, a number ofmethodological conditions must be met before results can be interpreted inanatomo-clinical terms.
First, most of the studies of motor, language, visual and spatial recoveryreport only one neuroimaging session after a short or long interval from thestroke. The conclusions drawn in these studies are only tentative, since they arebased on the speculation that all the “clinical” improvement in a particularfunction is related to the activation found at a given moment. A moreappropriate design would require measuring the physiological indices of brainactivity during the activation and the baseline tasks, both before and afterfunctional recovery. This is a factorial design, in which the task (activation vs.baseline) by time (before vs. after recovery) interaction is the factor of interest.This kind of design has been increasingly used in the past few years (e.g.Pizzamiglio et al., 1998).
Unfortunately, the neuroimaging studies reviewed so far were much moreprecise and refined in terms of imaging and analysis methods than in terms ofbehavioural measurements and procedures, which were often rather crude. Thebehavioural measurement of recovery of function is not always based on therepetition of the same quantitative techniques at time 1 (i.e., shortly after thestroke) and at time 2 (i.e., weeks or months after the stroke). The semi-quantitative assessment of performance (e.g., Di Piero et al., 1992; Fries et al.,1993) or the limited number of patients studied (often less then 10), underminethe value of the correlation between a certain functional activation andbehavioural changes.
An additional limitation concerns the infrequent use of the same experimentalparadigm in a control group of normal subjects. In its absence, we cannot becertain whether, in performing a given task, recovered patients activate the sameareas as normal subjects. For instance, studies of motor recovery repeatedlyshowed that the finger-thumb opposition movement activates the sensorimotorand premotor structures in control subjects, but additional structures, such as theparietal areas of the contra- and/or ipsilateral hemisphere, in recovered strokepatients. A possible explanation is that recovery is partially based on theactivation of brain areas involved in motor planning, which are not engaged bycontrol subjects when they are performing the same repetitive task. Also, the
Neuroimaging contribution to functional recovery 27
presence of additional (prefrontal and cingulate) activations, probably unrelatedto motor execution, suggests that stroke patients require the intervention ofattentional mechanisms in order to produce an appropriate motor response(Weiller et al., 1992).
Alternatively, the recovery-related activation of regions not normally engagedin a given task may reflect a maladaptive process and be responsible for thepersistence of residual deficits and not for the degree of recovery achieved(Belin et al., 1996). One way to control for this variable would be to contrast theactivation related to fully recovered behaviour with that related to forms ofbehaviour that are still dysfunctional. For example, the use of “single-trial” or“event-related” fMRI paradigms could make it feasible to compare brain activityduring trials in which patients give “correct” and “incorrect” answers.
Additional information can be derived from more refined experimentaldesigns. So far the majority of contributions are based on a categorical analysis,i.e., the comparison between signals measured when the subject is performing acritical task and those observed at rest or when the subject is performing acontrol task. The cognitive subtraction principle assumes that the CBFdifferences identify the areas responsible for the specific changes in theperformance. The cogency of this inference would be heightened if we coulddemonstrate that a change in regional CBF “varies monotonically andsystematically with some parameter of cognitive or sensorimotor processing”(Frith and Friston, 1997). In other words, a linear or non-linear correlationbetween specific activated areas and performance improvements in a particulartask could help identify what circuits specifically support the recovery of a givenfunction. A good example of such a methodological improvement is given in apaper by Dettmers, Stephan, Lemon et al. (1997). The CBF was measured whilesubjects were performing a thumb-finger opposition task at five different levelsof exerted force. Data were submitted to two kinds of analyses, one comparingblood flow during all the active states with that at rest; and another correlatingthe CBF level and the force level. The categorical comparison revealed lessactivation of motor structures, both in the ipsi- and contralateral hemisphere, inpatients than in normal controls. The correlation analysis revealed, in normalsubjects, a logarithmic CBF increase in the contralateral somatosensory cortexwith force increasing; the CBF increase had instead a polynomial trend inpatients’ group. This indicates a qualitative change in the recruitment of motorstructures during task execution. Furthermore, in patients, force level correlatedwith the activation of the ipsilateral ventral posterior supplementary motor areaand parietal areas, which remained silent in normal subjects.
This study also shows a way to control for a potential confound in recoverystudies. Whenever an activation is found in recovered patients that is absent innormal controls, the problem remains unsolved whether it is really due to aprocess of functional reorganisation or is related to the task being more difficultfor patients than for controls. If so, the results could be interpreted as adifferential activation (depending on task difficulty) of a pre-existing cerebralnetwork (e.g., see Engelien et al., 1995). Thus, it is important to match taskdifficulty between patients and controls. In the aforementioned experiment(Dettmers et al., 1997), subjects performed the task at five different force levels,
28 Luigi Pizzamiglio and Others
determined relative to their own maximal voluntary contraction level, that wasmeasured before the experiment.
A final methodological recommendation for cognitive studies on language andspatial deficits is to try to better segregate patients with a defined type ofimpairment. For instance, “comprehension disorders” or “naming disorders”include categories of patients that are too broad to provide useful data forunderstanding the underlying mechanisms of recovery. This caveat particularlyholds when neuroimaging techniques are used to qualify and compare thepotential benefit that neurological and neuropsychological deficits can derive fromdifferent rehabilitative methods (Carlomagno, Van Eeckhout, Blasi et al., 1997).
In conclusion, as we have repeatedly pointed out, brain activations changewhen sensorimotor or cognitive functions improve over time. It is conceivablethat the cerebral readjustment following a brain lesion interacts with the degreeof improvement of a given function. This observation, together with theawareness of large individual variations, points to the need for carefullongitudinal studies, performed on the same patients, to increase knowledgeabout the dynamic aspects of cerebral reorganisation.
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Luigi Pizzamiglio, MD, Laboratorio di Neuropsicologia, Via Ardeatina 306, Roma 00179, Italy. E-mail: [email protected]
(Received 3 March 2000; reviewed 18 April 2000; revised 7 June 2000; accepted 14 June2000)
Neuroimaging contribution to functional recovery 31
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