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Reconnecting the dots after stroke.

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DOI: 10.1002/ana.21816
Reconnecting the Dots
After Stroke
After stroke, the large majority of survivors experience
recovery of function. Nevertheless, many patients experience excessive fatigue after routine activities and do not
return completely to normal. Understanding why some
patients recover and others do not is currently 1 of the
biggest conundrums in the fields of neurology, rehabilitation, and neuroscience. This question has motivated numerous studies of the complex mechanisms
underlying stroke recovery. Many longitudinal or
cross-sectional investigations have used imaging (eg,
functional magnetic resonance imaging [fMRI],
diffusion-tensor imaging, positron emission tomogra-
Annals of Neurology
Vol 66
No 5
November 2009
phy, diffusion/perfusion)1 or neurophysiological techniques (eg, transcranial magnetic stimulation, electroencephalography, magnetoencephalography)2 to study
recovery in patients with motor deficits after stroke;
however, few have focused on understanding how the
brain regions normally involved in motor function are
reconnected in a novel way to support motor functions
in well-recovered patients. This is an interesting approach, as it can reveal modifications in the neural network underlying motor functions that support restored
performance. In this issue of the Annals of Neurology,
Sharma and colleagues take this approach using fMRI
and structural equation modeling to analyze changes in
connectivity when well-recovered stroke patients executed movements and motor imagery tasks.3 Sharma
and colleagues compare connectivity between areas of
activation seen in stroke survivors with recovered motor performance to the connectivity patterns of healthy
individuals engaged in the same tasks.
The findings of Sharma and colleagues reveal mechanisms of recovery in humans that are similar to those
found in animal models of stroke. Lesions in the primary motor cortex (M1) of squirrel monkeys result in
changes in distant upstream motor areas associated with
motor recovery.4 Development of new local and distant
corticocortical connections5 indicates that 1 of the processes by which animals recover is by establishing new
connections between motor areas distant to the lesion.
The study by Sharma and colleagues confirms that this
mechanism also occurs in stroke patients. Although the
magnitude of blood oxygen level dependent (BOLD) activation of corticomotor regions during performance of
motor imagery and executed movements was similar between stroke and healthy controls, effective connectivity
analysis found different coupling of prefrontal cortex,
supplementary motor area, premotor cortex, and M1
during motor imagery in the recovered stroke group relative to healthy older individuals. These connectivity
changes were correlated with concurrent motor abilities.
Importantly, as these patients were well recovered, with
similar levels of performance to healthy individuals, only
the more complex tasks (motor imagery) revealed differences in brain connectivity. These findings underline the
importance of understanding what happens to the relationship between normal sites of activation in spared
brain tissue to compensate for the damaged tissue and to
restore function. In other words, to comprehend recovery, it is necessary to look at connectivity between regions of activation in the entire brain rather than focus
solely on the locations or magnitude of neural activation.
There are several important implications of these findings. To begin, the stroke patients enrolled in this study
all had recovered good motor function with low scores
on the National Institutes of Health Stroke Scale and
high scores in the Action Research Arm Test and
Motricity Index, and they showed similar levels of task
performance as healthy controls. Despite a high level of
recovery and performance, and normal sites of brain activation after stroke, the connections between activated
areas are different than in healthy individuals. This may
be 1 of the underlying reasons for fatigue, a frequent
and disabling symptom even in well-recovered stroke patients6; the neural network underlying the task might be
sufficient for performance but less efficient than the normal network, thereby resulting in fatigue. The difference
in connectivity in the neural network supporting motor
function might also account for the report that even
stroke survivors with normal physical and neurological
examinations experience limitations in activities of daily
living, social participation, and accomplishment of more
complex motor tasks.7 There are 2 aspects to this problem that deserve further investigation. First, some stroke
survivors are able to perform with competence similar to
that of healthy individuals, apparently by establishing
new cortical connections as suggested by Sharma and
colleagues; however, these new connections may be task
specific, an issue that cannot be determined from the
current study. If so, when patients are exposed to a different task, or the same task in a different context, they
might perform poorly because the new connections
might not be activated by the unfamiliar task or context.
Furthermore, the data suggest that the neurological examination is a rather limited assessment of recovery; despite normal physical findings, the lesioned brain is performing differently than the healthy brain. Neurologists
may need to identify new ways to evaluate recovered
stroke patients in making decisions regarding capacity
for return to work and other activities.
Another important implication, briefly discussed by
Sharma and colleagues, is the need to carefully consider
the site of stimulation when performing investigations
using noninvasive stimulation techniques to enhance
motor function in stroke patients. In recent years, many
studies have raised the enthusiasm for the potential use
of transcranial magnetic stimulation or transcranial direct current stimulation (tDCS) as neurorehabilitation
strategies.8 –11 These studies have targeted, for the most
part, either the ipsilesional or contralesional M1 areas
with modest motor improvement. However, the present
results by Sharma and colleagues suggest that it is possible that rather than directly enhancing M1, it may be
more appropriate to target regions upstream to M1 such
as prefrontal cortex. Another important implication is
that brain stimulation studies using tDCS will have to
reconsider the common belief that the reference electrode, considered not active, placed over frontal regions
may in fact be affecting part of the new network that
supports motor function in these investigations.8,10
A vast number of stroke patients experience recovery
after stroke. However, recovery is often incomplete and
does not bring full return of function. The study by
Sharma and colleagues is an important contribution to
our understanding of the complex mechanisms of motor
recovery after stroke. Future studies will need to investigate whether changes in cortical coupling are dependent
on specific tasks or mediate overall recovery (ie, as a
“jump start” to achieve normal performance levels on a
variety of tasks). It seems that the ability to recover motor function after stroke might depend on the capacity
of the individual’s brain to “reconnect the dots”—to
connect normal areas of activation in a novel way after
perturbation of the system by a lesion.
Pablo Celnik, MD
Argye E. Hillis, MD
Department of Physical Medicine and Rehabilitation
Department of Neurology
Johns Hopkins University School of Medicine
Baltimore, MD
Potential conflict of interest: Nothing to report.
1. Calautti C, Baron J-C. Functional neuroimaging studies of motor recovery after stroke in adults: a review. Stroke 2003;34:
2. Butefisch CM, Kleiser R, Seitz RJ. Post-lesional cerebral
reorganisation: evidence from functional neuroimaging and transcranial magnetic stimulation. J Physiol Paris 2006;99:437– 454.
3. Sharma N, Baron JC, Rowe JB. Motor imagery after stroke:
relating outcome to motor network connectivity. Ann Neurol
2009;66:604 – 616.
4. Frost SB, Barbay S, Friel KM, et al. Reorganization of remote
cortical regions after ischemic brain injury: a potential substrate
for stroke recovery. J Neurophysiol 2003;89:3205–3214.
5. Dancause N, Barbay S, Frost SB, et al. Extensive cortical rewiring after brain injury. J Neurosci 2005;25:10167–10179.
6. Dobkin BH. Fatigue versus activity-dependent fatigability in
patients with central or peripheral motor impairments. Neurorehabil Neural Repair 2008;22:105–110.
7. Krakauer JK, Bagesteiro LB, Mazzoni PL, Sainburg RL. Deficits
in skill learning and in control of arm inertia after recovery
from pure motor hemiparesis. Neural Control of Movement
Conference, 2005. 15th Annual Meeting, April 12–17, 2005.
Key Biscayne, FL.
8. Boggio PS, Nunes A, Rigonatti SP, et al. Repeated sessions of
noninvasive brain DC stimulation is associated with motor
function improvement in stroke patients. Restor Neurol Neurosci 2007;25:123–129.
9. Celnik P, Paik NJ, Vandermeeren Y, et al. Effects of combined
peripheral nerve stimulation and brain polarization on performance of a motor sequence task after chronic stroke. Stroke
2009;40:1764 –1771.
10. Hummel F, Celnik P, Giraux P, et al. Effects of non-invasive
cortical stimulation on skilled motor function in chronic stroke.
Brain 2005;128:490 – 499.
11. Khedr EM, Ahmed MA, Fathy N, Rothwell JC. Therapeutic
trial of repetitive transcranial magnetic stimulation after acute
ischemic stroke. Neurology 2005;65:466 – 468.
DOI: 10.1002/ana.21811
Rodriguez: Autoimmune Demyelinating Disease
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