The Contribution of Functional Neuroimaging to Recovery After Brain Damage: A Review

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


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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.


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).


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


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



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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.


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


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


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.



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


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


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,


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)


The Contribution of Functional Neuroimaging to Recovery After Brain Damage: A Review

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