Advances in Clinical Neurophysiology (Supplements to Clinical Neurophysiology Vol.

)4)
Editors: R.C. Reisin, M.R. Nuwer, M. Hallett. C. Medina
(i'j 2002 Elsevier Science B,y' All rights reserved.

248

Chapter 37

Neural correlates of cerebral plasticity after brain infarction

Rudiger 1. Seitz", Cathrin M. Butefisch" and Volker Homberg"

'Department ofNeurology, Heinrich-Heine-University Dusseldorf, D-40225 Dusseldorf (Germany)
b Neurological Therapy Center, Heinrich-Heine-University Dusseldorf, D-40591 Dusseldorf (Germany)

Introduction plasticity can be maladaptive and may give rise to

Brain diseases such as ischemic brain infarction
impair brain function by direct interference with
key node areas in functional brain networks but
allow for deficit compensation by brain plasticity.
Plasticity is the process ofuse-dependent enhance-
ment of synaptic efficacy and shaping of connec-
tivity underlying the physiological development,
learning, and post-lesional recovery. Great progress
in understanding the mechanisms of functional
recovery has been achieved by animal research. In
animal experiments, lesions ofthe brain, spinal cord
or peripheral nerves have been shown to affect brain
function and induce adaptive changes in the cerebral
cortex (Kaas and Florence 1997). Functional neu-
roimaging methods, such as positron emission tom-
ography (PET) and functional magnetic resonance
imaging (fMRl), provide the means to study these
mechanisms of reorganization in the living human
brain (Chollet and Weiller 2000). These methods
revealed that not only the infantile brain but also
the brains of adults and even aged people can re-
organize in response to imposed demands. While
* Correspondence to: Dr. R.I. Seitz, Department ofNeu-
rology Center, Heinrich-Heine-University Dusseldorf,
Moorenstrasse 5, D-40225 Dusseldorf, Germany. Fax: +49-
2 11-81-18485.
E-mail: Seitz@n.~urologie.uni-duesseldorf.de
neurological disorders such as dystonia, epilepsy
and pain, it is usually beneficial occurring in rela-
tion to memory and learning and to deficit com-
pensation in neurological diseases such as stroke.
In acute stroke a number of processes that become
sequentially operative determine post-ischemic re-
covery. The events include rapid reperfusion due
to acute therapeutic interventions, spontaneous re-
gression of per i1esionaI and remote dysfunction in
the subacute phase after infarction, and reorgani-
zation of large-scale networks in both cerebral
hemispheres extending into the chronic stage of
the disease (Herholz and Heiss 2000).
Systems level
It appears from Fig. I that most patients recover
well and early. Three different patient groups with
respect to different degrees of post-ischemic im-
pairment and recovery can be differentiated (Bin-
kofski et a1. 200 1a). One group that was severely
impaired recovered, while other patients with a
similar impairment did not recover at all. It is likely
that the decisive distinctive feature is the absence
of residual function and consequently of somato-
sensory feedback of the affected limb over a criti-
cal time span in the non-recovering patients. This
hypothesis is supported by evidence from com-

32
26
20
~
~'- 14
.eo
:E 8 and highly timed electrical median nerve stimula-
2 (MEPs) recorded from the abductorpollicis brevis
3 7 14 21 28 35 42 49 56
Days after stroke
Fig. I. Recovery of motor functions after hemiparetic brain
infarction. Patients with a slight impairment, as indicated by
a mean motor score of8, recover rapidly within 30 days. For
comparison, patients with severe hemiplegia (mean motor
score greater than 20) show a more protracted recovery course
of many weeks. Note that patients with such a severe acute
deficit may not recover at all. For details of the motor score
and the relation of recovery to brain lesion volume see
Binkofski et al. 2001a.
bined clinical and electrophysiological studies sug-
gesting that in addition to the degree of motor im-
pairment the presence of somatosensory evoked
potentials indicated good recovery (Feys et al.
2000). Likewise, deafferented monkeys who were
not using the affected limb many weeks after in-
jury failed to recover (Taub et al. 1999). Con-
versely, animal experiments show an enlargement
of the somatosensory representations during skill
recovery after focal lesions of the primary soma-
tosensory cortex (Xerri et al. 1998). From these
observations the concept was derived that the ani-
mals learned not to use the affected limb because
of discomfort, stress and frustration when doing
so, but used the intact arm instead. This concept of
'learned non-use' laid the ground for subsequent
therapy studies in severely impaired chronic human
stroke victims. There is good evidence to support
the view that reafferent somatosensory informa-
249
tion from the partly compromised limb is critically
required for tuning the remaining network into
function as may be evident from passive move-
ments (Nelles et al. 1999). These data are corrobo-
rated further by the observation that there is a
posterior shift of the sensorimotor area in patients
with sensorimotor strokes (Rossini et al. 1998).
Such changes of cortical representations may in-
volve long-term potentiation (LTP) or enhanced
synaptic efficiency. Using paired associated stimu-
lation of trans cranial magnetic stimulation (TMS)
tion it was shown that motor evoked potentials
muscle are significantly increased compared to the
recording before the interventional paired stimu-
lation (Stefan et al. 2000). Preliminary data of a
collaborative study suggest that an increased acti-
vation area as measured with fMRI during individual
thumb abductions is the neuroimaging correlate of
this fast occurring cortical plasticity.
Temporal evolution
In acute brain infarction, the location and extent
of impaired brain tissue perfusion and of changes
of tissue diffusion are of paramount importance
for functional recovery, since they determine the
development ofthe manifest stroke lesion and, thus,
to what degree the different mechanisms of cer-
ebral reorganization may come into play subse-
quently (Seitz and Freund 1997).
In the subacute stage after brain infarction the
mechanisms of cerebral plasticity include regres-
sion of perilesional dysfunction and recruitment
ofdistributed systems in both cerebral hemispheres.
These infarct induced changes can be monitored
by neuroimaging and electrophysiological meas-
ures and correspond to the concept of diaschisis
(Witte et al. 2000). Functionally related pathways
in either brain hemisphere have been shown to
contribute to recovery and to be recruited by re-learn-
ing. Increasing evidence suggests that the human
brain employs multiple, interconnected brain areas
for information processing and control of behavior.
Brain diseases are expected to affect these networks
250
directly by interference and indirectly as a conse-
quence of deficit compensation. Covariance analy-
ses applied to functional brain imaging data open
the opportunity to study neural networks and their
disease related changes in the human brain (Seitz et
al. 2001). A hypothesis driven, multivariate analy-
sis of resting regional cerebral metabolic data in
patients with infarctions ofthe motor cortex showed
that motor recovery from hemiparesis was associ-
ated with a relative enhancement of interregional
interactions in a cerebello-thalamocortical network.
Most important for recovery was the functional
coupling between the ipsilesional thalamus and the
contralesional cerebellum. Support for these data
comes from categorical comparisons studying the
decrease ofoxygen metabolism in frontomesial cor-
tex and of glucose metabolism in the thalamus in
hemiparesis with poor recovery (Seitz and Freund
1997; Iglesias et a1. 2000). In the chronic stage af-
ter stroke cross-modal recruitment of alternative
strategies mostly involving the contralesional hemi-
sphere have been shown to engage preferentially
the visual cortex during sensorimotor activity as
demonstrated in congenital blind subjects and in
patients after stroke (Sadato et a1. 1998; Seitz et
a1. 2001).
Recovery mechanisms
These types of large-scale reorganization appear
to involve facilitatory and compensatory engage-
ment of pre-existing, hitherto latent pathways. Evi-
dence for this hypothesis comes from neuroreceptor
studies and studies with TMS by which functional
systems of the human brain can be probed (Witte
et a1. 2000). We wished to address the question
whether the activity of excitatory and inhibitory in-
terneurons in the motor cortex contralateral to the
affected hemisphere is disturbed in stroke patients.
Paired pulse TMS technique at short interstimulus
intervals allows the measurement of intracortical
inhibition which probably is mediated by GABA-
ergic interneurons. In 12 stroke patients, we stud-
ied the motor cortex of the non-affected side using
paired pulse TMS technique with an interstimulus
interval of 2 ms. This was compared to results of
MEP-ratio
2
1,5
0,5
o
-0,5 - t - - - - - - - , , - - - - - - - r - - - - - - ,
20 40 60
-1
% of stimulator's output
Fig. 2. Altered excitability after brain infarction in the contra-
lesional motor cortex. Shown is the intracortical inhibition and
excitation as tested by paired pulse TMS at interstimulus in-
terval of2 ms for different intensities of the subthreshold CS
in patients (triangle) and healthy volunteers (square). The CS
intensity is expressed as percentage of the stimulator's out-
put; the amplitude ofMEP elicited by the succeeding, condi-
tioned suprathreshold magnetic stimulation are expressed as
ratio of the mean MEP amplitude evoked by five single test
pulses. Different modulation of the MEPs between patients
and controls (2-way factorial ANOYA; CS intensity p < 0.005;
group x CS intensity p < 0.01).
left hemispheric stimulation in 9 healthy right
handed volunteers. As illustrated in Fig. 2, the size
of the test MEP was significantly influenced by
the intensity of the conditioning pulse (CS) and
modulated differently in patients and normal vol-
unteers. At small intensities of CS (25-30% of
maximal stimulator output), a reduction in the
conditioned test MEP amplitude was seen in both
groups. In contrast, at higher stimulus intensities,
patients and normal volunteers showed a different
pattern: the conditioned test MEP amplitudes in-
creased at a steeper rate in patients and exceeded
the size of the MEP amplitude evoked by the single
test pulse. This facilitatory effect was not seen in
the healthy subjects. These first results support the
hypothesis that in the motor cortex the threshold for
activation of inhibitory interneurons is lower than
for excitatory interneurons (Ziemann et a1. 1996;
Chen et a1. 1998) and that changes in the excitabil-
ity of brain areas remote from a stroke lesion occur.
Interestingly, stroke patients may engage an al-
ternative strategy for coping with a post-ischemic
neurological deficit. Similar observations were

made recently in monkeys with focal lesions of
motor cortex (Friel and Nudo 1998). Such an al-
ternative strategy is likely to activate the premotor
cortex, since premotor cortex plays a critical role
for coding motor acts (Rizzolatti et al. 1998). In
particular, patients who have recovered from hemi-
paretic brain infarction were shown to engage pre-
motor cortex, both after subcortical as well as
cortical brain infarctions (Chollet and Weiller
2000; Seitz et a1. 2000). In addition, an enhanced
activation of prefrontal cortex was observed cor-
responding to an enhanced cognitive load related
to enhanced difficulty of task performance (Seitz
et al, 2000). Two aspects are challenging in this
context and deserve further studies. First, there is
good evidence that lesions of the parietal cortex
induce persistent deficits of well defined delicate
motor functions such as the shaping of the hand
for prehension of objects, tactile object explora-
tion, mirror transformation (Binkofski et a1. 1998,
1999, 2001 b). No comparable deficits were ob-
served in frontal brain lesions, although highly
organized parietal-premotor circuits have been iden-
tified and ascribed to different subfunctions of sen-
sorimotor activity. Apparently, parietal functions
have a highly specialized modular organization and,
therefore, are lateralized precluding substitution by
the contralesional homologue area whereas the pre-
motor cortex has, a more bilateral organization pat-
tern. The latter seems to be supported by the imaging
data both in healthy volunteers and in patients who
recovered from brain lesions such as brain infarc-
tion (Chollet and Weiller 2000). A further surpris-
ing observation is the preponderance of dorsal
premotor cortical activations in motor activity in
stroke victims while the inferior parts of the pre-
motor cortex was not active. This part of the pre-
motor cortex is very much involved in movement
ideation and movement observation probably cor-
responding to the premotor cortical sub-area F5
which was shown in primates to accommodate so-
called mirror neurons (Parsons et al. 1995; Binkofski
et a1. 2000; Gerardin et a1. 2001). These neurons are
active both during observation and actual perform-
ance of movements thus being candidate structures
for movement imitation. We are now testing the hy-
pothesis that imaginative-cognitive learning strat-
251
egies may improve recovery after brain infarction
by tasks known to activate this structure.
References
Binkofski, F., Dohle, C., Posse, S., Stephan, K.M., Hefter, H., Seitz,
R.J. and Freund, H.-J. Human anterior intraparietal area sub-
serves prehension. A combined lesion and functional MRI acti-
vation study. Neurology, 1998, 50: 1253-1259.
Binkofski, F.. Buccino, G., Dohle, C., Seitz, RJ., Freund, H.-J.
Mirror agnosia and mirror ataxia constitute different parietal lobe
disorders. Ann. Neurol., 1999,46: 51--61.
Binkofski, F., Amunts, K., Stephan, K.M., Posse, S., Schorrnann,
T., Zilles, K. and Seitz, RJ. Broca's area subserves imagery of
motion: a combined cytoarchitectonic and MRI study. Hum.
Brain Mapp., 2000, 11: 273-285.
Binkofski, F.. Seitz, R.J., Hacklander, T., Pawelec, D., Mau, J. and
Freund, H.-J. The recovery of motor functions following hemi-
paretic stroke: a clinical and MR-morphometric study. Cerebra-
vase. Dis., 2001a, I]: 273-281.
Binkofski, F" Seitz, R.J., Kunesch, E., Dohlc, e. and Freund, H.-J.
Tactile apraxia. Unimodal apractic disorder of tactile object ex-
ploration associated with parietal lobe lesions. Brain, 200 Ib,
124: 132--144.
Chen, R., Tam, A., Butefisch, e.M., Corwell, B., Ziemann, U.,
Rothwell, J. and Cohen, L.G. Intracortical inhibition and facili-
tation in different representations of the human motor cortex. J
Neurophysiol., 1998,80: 2870-2881.
Chollet, F. and Weiller, e. Recovery of neurological function. In:
J.C. Mazziotta, A.W. Toga and RS.1. Frackowiak (Eds.), Brain
Mapping. The Disorders. Academic Press, San Diego, CA, 2000:
588-597.
Feys, H., Van Hees, 1., Bruyninckx, E, Mercelis, R. and De Weerdt,
W. Value of somatosensory and motor evoked potentials in pre-
dicting arm recovery after a stroke. J Neural. Neurosurg. Psy-
chiatry, 2000, 68: 323-331.
Friel, K.M. and Nudo, R.J. Recovery of motor function after focal
cortical injury in primates: compensatory movement patterns
used during rehabilitative training. Somatosens Mot. Res., 1998,
153: 173-189.
Gerardin, E, Sirigu, A., Lehericy, S., Poline, J.B., Gaymard, B.,
Marsault, e., Agid, Y. and Le Bihan, D. Partially overlapping
neural networks for real and imagined hand movements. Cereb.
Cortex, 2000,10: 1093-1104.
Herholz, K. and Heiss, W.-D. Functional imaging correlates of re-
covery after stroke in humans. J Cereb. Blood Flow Metab.,
2000,12: 1619-1631.
Iglesias, S., Marchal, G., Viader, F. and Baron, J.e. Delayed intra-
hemispheric remote hypometabolism. Correlations with early
recovery after stroke. Cerebrovase. Dis. 2000,10: 391-402.
Kaas, J.H. and Florence, S.L. Mechanisms of reorganization in sen-
sory systems of primates after peripheral nerve injury. In: H.-J.
Freund, B.A. Sabel and O.w. Witte (Eds.), Brain Plasticity.
Lippincott-Raven, Philadelphia, PA, 1997: 147-158.
Nelles, G., Spiekermann, G., Jueptner, M., Leonhardt, G., Muller,
S., Gerhard, H. and Diener, H.e. Evolution of functional reor-
ganization in hemiplegic stroke: a serial positron emission to-
mographic activation study. Ann. Neurol., 1999,46: 901-909.
252
Parsons, L.M., Fox, P.T., Downs, J.H., Glass, T., Hirsch, T.B., Mar-
tin, e.e., Jerabek, P.A. and Lancaster, J.L. Use of implicit mo-
tor imagery for visual shape discrimination as revealed by PET.
Nature, 1995, 375: 54-58.
Rizzolatti, G., Luppino, G. and Matelli, M. The organization of the
cortical motor system: new concepts. Electroencephalogr. Clin.
Neurophysiol., 1998, 106: 283-296.
Rossini, P.M., Tecchic, F., Pizzella, V., Lupoi, D., Cassetta, E. and
Pasqualetti, P. On the reorganization of sensory hand areas after
mono-hemispheric lesion: a functional (MEG)/anatomical (MRI)
integrative study. Brain Res., 1998,782: 153-166.
Sadato, N., Pascual-Leone, A., Grafman, J., Deiber, M.P., Ibanez,
V and Hallett, M. Neural networks for Braille reading by the
blind. Brain, 1998,121: 1213-1229.
Seitz, R.J. and Freund, H.-J. Plasticity of the human motor cortex.
In: H.-J. Freund, B.A. Sabel and D.W. Witte (Eds.), Brain Plas-
ticity. Adv. Neurol., 1997,73: 321-333.
Seitz, R.J., Stephan, K.M. and Binkofski, F. Control of action as
mediated by the human fronta/lobe. Exp. Brain Res., 2000, /33:
71-80.
Seitz, R.J., Knorr, D., Azari, N.P. and Weder, B. Cerebral networks
in sensorimotor disturbances. Brain Res. Bull., 2001, 54: 299-
305.
Stefan, K., Kunesch, E., Cohen, L.G., Benecke, R. and Classen, J.
Induction of plasticity in the human motor cortex by paired as-
sociative stimulation. Brain, 2000,123: 572-584.
Taub, E., Uswatte, G. and Pidikiti, R. Constraint-induced move-
ment therapy: a new family of techniques with broad applica-
tion to physical rehabilitation - a clinical review. 1. Rehabil.
Res, Dev., 1999,36: 237-251.
Xerri, e., Merzenich, M.M., Peterson, B.E. and Jenkins, W. Plastic-
ity of primary somatosensory cortex paralleling sensorimotor
skill recovery from stroke in adult monkeys. 1. Neurophysial.,
1998,79:2119-2148.
Witte, D.W., Bidmon, H.-J., Schiene, K., Redecker, e. and Hage-
mann, G. Functional differentiation of multiple perilesional zones
after focal cerebral ischemia. 1. Cereb. Blood Flow Metab., 2000,
20: 1149-1165.
Ziemann, U., Lonnecker, S., Steinhoff, B.J. and Paulus, W. Effects
of different antiepileptic drugs on motor cortex excitability in
humans: a transcranial magnetic stimulation study. Ann, Neurol.,
1996,40: 367-378.