reconnecting the dots after stroke

2
3. Yuki N, Kuwabara S. Axonal Guillain-Barre ´ syndrome: carbo- hydrate mimicry and pathophysiology. J Peripher Nerv Syst 2007;12:238 –249. 4. Lonigro A, Devaux JJ. Disruption of neurofascin and gliomedin at nodes of Ranvier precedes demyelination in experimental al- lergic neuritis. Brain 2009;132:260 –273. 5. Willison HJ. The immunobiology of Guillain-Barre ´ syndromes. J Peripher Nerv Syst 2005;10:94 –112. 6. Raphae ¨l JC, Chevret S, Hughes RAC, Annane D. Plasma ex- change for Guillain-Barre ´ syndrome. Cochrane Database Syst Rev 2002;(2):CD001798. 7. Hughes RAC, Raphae ¨l JC, Swan AV, van Doorn PA. Intrave- nous immunoglobulin for Guillain-Barre ´ syndrome. Cochrane Database Syst Rev 2006;(1):CD002063. 8. Hughes RAC, Swan AV, van Koningsveld R, van Doorn PA. Corticosteroids for Guillain-Barre ´ syndrome. Cochrane Data- base Syst Rev 2006;(2):CD001446. 9. Kleyweg RP, van der Meche ´ FG. Treatment related fluctuations in Guillain–Barre ´ syndrome after high-dose immunoglobulins or plasma exchange. J Neurol Neurosurg Psychiatry 1991;54: 957–960. 10. Farcas P, Avnun L, Frisher S, et al. Efficacy of repeated intra- venous immunoglobulin in severe unresponsive Guillain-Barre ´ syndrome. Lancet 1997;350:1747. 11. Kuitwaard K, de Gelder J, Tio-Gillen A, et al. Pharmacokinet- ics of IV immunoglobulin and outcome in Guillain-Barre ´ syn- drome. Ann Neurol (in press). 12. van der Meche ´ FG, Schmitz PI, Dutch Guillain-Barre ´ Study Group. A randomized trial comparing intravenous immune globulin and plasma exchange in Guillain-Barre ´ syndrome. N Engl J Med 1992;326:1123–1129. 13. Eftimov F, Winer JB, Vermeulen M, et al. Intravenous immu- noglobulin for chronic inflammatory demyelinating polyradiculo- neuropathy. Cochrane Database Syst Rev 2009;(1);CD001797. 14. van Schaik IN, van den Berg LH, de Haan R, Vermeulen M. Intravenous immunoglobulin for multifocal motor neuropathy. Cochrane Database Syst Rev 2005;(2):CD004429. DOI: 10.1002/ana.21816 Reconnecting the Dots After Stroke After stroke, the large majority of survivors experience recovery of function. Nevertheless, many patients expe- rience 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, rehabil- itation, and neuroscience. This question has moti- vated 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- phy, diffusion/perfusion) 1 or neurophysiological tech- niques (eg, transcranial magnetic stimulation, electro- encephalography, 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 ap- proach, as it can reveal modifications in the neural net- work 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 exe- cuted movements and motor imagery tasks. 3 Sharma and colleagues compare connectivity between areas of activation seen in stroke survivors with recovered mo- tor performance to the connectivity patterns of healthy individuals engaged in the same tasks. The findings of Sharma and colleagues reveal mecha- nisms of recovery in humans that are similar to those found in animal models of stroke. Lesions in the pri- mary 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 connections 5 indicates that 1 of the pro- cesses 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) ac- tivation of corticomotor regions during performance of motor imagery and executed movements was similar be- tween 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 rel- ative 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 differ- ences in brain connectivity. These findings underline the importance of understanding what happens to the rela- tionship between normal sites of activation in spared brain tissue to compensate for the damaged tissue and to restore function. In other words, to comprehend recov- ery, it is necessary to look at connectivity between re- gions 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 find- ings. 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 570 Annals of Neurology Vol 66 No 5 November 2009

Upload: pablo-celnik

Post on 06-Jun-2016

213 views

Category:

Documents


0 download

TRANSCRIPT

Page 1: Reconnecting the dots after stroke

3. Yuki N, Kuwabara S. Axonal Guillain-Barre syndrome: carbo-hydrate mimicry and pathophysiology. J Peripher Nerv Syst2007;12:238–249.

4. Lonigro A, Devaux JJ. Disruption of neurofascin and gliomedinat nodes of Ranvier precedes demyelination in experimental al-lergic neuritis. Brain 2009;132:260–273.

5. Willison HJ. The immunobiology of Guillain-Barre syndromes.J Peripher Nerv Syst 2005;10:94–112.

6. Raphael JC, Chevret S, Hughes RAC, Annane D. Plasma ex-change for Guillain-Barre syndrome. Cochrane Database SystRev 2002;(2):CD001798.

7. Hughes RAC, Raphael JC, Swan AV, van Doorn PA. Intrave-nous immunoglobulin for Guillain-Barre syndrome. CochraneDatabase Syst Rev 2006;(1):CD002063.

8. Hughes RAC, Swan AV, van Koningsveld R, van Doorn PA.Corticosteroids for Guillain-Barre syndrome. Cochrane Data-base Syst Rev 2006;(2):CD001446.

9. Kleyweg RP, van der Meche FG. Treatment related fluctuations inGuillain–Barre syndrome after high-dose immunoglobulins orplasma exchange. J Neurol Neurosurg Psychiatry 1991;54:957–960.

10. Farcas P, Avnun L, Frisher S, et al. Efficacy of repeated intra-venous immunoglobulin in severe unresponsive Guillain-Barresyndrome. Lancet 1997;350:1747.

11. Kuitwaard K, de Gelder J, Tio-Gillen A, et al. Pharmacokinet-ics of IV immunoglobulin and outcome in Guillain-Barre syn-drome. Ann Neurol (in press).

12. van der Meche FG, Schmitz PI, Dutch Guillain-Barre StudyGroup. A randomized trial comparing intravenous immuneglobulin and plasma exchange in Guillain-Barre syndrome.N Engl J Med 1992;326:1123–1129.

13. Eftimov F, Winer JB, Vermeulen M, et al. Intravenous immu-noglobulin for chronic inflammatory demyelinating polyradiculo-neuropathy. Cochrane Database Syst Rev 2009;(1);CD001797.

14. van Schaik IN, van den Berg LH, de Haan R, Vermeulen M.Intravenous immunoglobulin for multifocal motor neuropathy.Cochrane Database Syst Rev 2005;(2):CD004429.

DOI: 10.1002/ana.21816

Reconnecting the DotsAfter Stroke

After stroke, the large majority of survivors experiencerecovery of function. Nevertheless, many patients expe-rience excessive fatigue after routine activities and do notreturn completely to normal. Understanding why somepatients recover and others do not is currently 1 of thebiggest conundrums in the fields of neurology, rehabil-itation, and neuroscience. This question has moti-vated numerous studies of the complex mechanismsunderlying stroke recovery. Many longitudinal orcross-sectional investigations have used imaging (eg,functional magnetic resonance imaging [fMRI],diffusion-tensor imaging, positron emission tomogra-

phy, diffusion/perfusion)1 or neurophysiological tech-niques (eg, transcranial magnetic stimulation, electro-encephalography, magnetoencephalography)2 to studyrecovery in patients with motor deficits after stroke;however, few have focused on understanding how thebrain regions normally involved in motor function arereconnected in a novel way to support motor functionsin well-recovered patients. This is an interesting ap-proach, as it can reveal modifications in the neural net-work underlying motor functions that support restoredperformance. In this issue of the Annals of Neurology,Sharma and colleagues take this approach using fMRIand structural equation modeling to analyze changes inconnectivity when well-recovered stroke patients exe-cuted movements and motor imagery tasks.3 Sharmaand colleagues compare connectivity between areas ofactivation seen in stroke survivors with recovered mo-tor performance to the connectivity patterns of healthyindividuals engaged in the same tasks.

The findings of Sharma and colleagues reveal mecha-nisms of recovery in humans that are similar to thosefound in animal models of stroke. Lesions in the pri-mary motor cortex (M1) of squirrel monkeys result inchanges in distant upstream motor areas associated withmotor recovery.4 Development of new local and distantcorticocortical connections5 indicates that 1 of the pro-cesses by which animals recover is by establishing newconnections between motor areas distant to the lesion.The study by Sharma and colleagues confirms that thismechanism also occurs in stroke patients. Although themagnitude of blood oxygen level dependent (BOLD) ac-tivation of corticomotor regions during performance ofmotor imagery and executed movements was similar be-tween stroke and healthy controls, effective connectivityanalysis found different coupling of prefrontal cortex,supplementary motor area, premotor cortex, and M1during motor imagery in the recovered stroke group rel-ative to healthy older individuals. These connectivitychanges were correlated with concurrent motor abilities.Importantly, as these patients were well recovered, withsimilar levels of performance to healthy individuals, onlythe more complex tasks (motor imagery) revealed differ-ences in brain connectivity. These findings underline theimportance of understanding what happens to the rela-tionship between normal sites of activation in sparedbrain tissue to compensate for the damaged tissue and torestore function. In other words, to comprehend recov-ery, it is necessary to look at connectivity between re-gions of activation in the entire brain rather than focussolely on the locations or magnitude of neural activation.

There are several important implications of these find-ings. To begin, the stroke patients enrolled in this studyall had recovered good motor function with low scoreson the National Institutes of Health Stroke Scale andhigh scores in the Action Research Arm Test andMotricity Index, and they showed similar levels of task

570 Annals of Neurology Vol 66 No 5 November 2009

Page 2: Reconnecting the dots after stroke

performance as healthy controls. Despite a high level ofrecovery and performance, and normal sites of brain ac-tivation after stroke, the connections between activatedareas are different than in healthy individuals. This maybe 1 of the underlying reasons for fatigue, a frequentand disabling symptom even in well-recovered stroke pa-tients6; the neural network underlying the task might besufficient for performance but less efficient than the nor-mal network, thereby resulting in fatigue. The differencein connectivity in the neural network supporting motorfunction might also account for the report that evenstroke survivors with normal physical and neurologicalexaminations experience limitations in activities of dailyliving, social participation, and accomplishment of morecomplex motor tasks.7 There are 2 aspects to this prob-lem that deserve further investigation. First, some strokesurvivors are able to perform with competence similar tothat of healthy individuals, apparently by establishingnew cortical connections as suggested by Sharma andcolleagues; however, these new connections may be taskspecific, an issue that cannot be determined from thecurrent study. If so, when patients are exposed to a dif-ferent task, or the same task in a different context, theymight perform poorly because the new connectionsmight not be activated by the unfamiliar task or context.Furthermore, the data suggest that the neurological ex-amination is a rather limited assessment of recovery; de-spite normal physical findings, the lesioned brain is per-forming differently than the healthy brain. Neurologistsmay need to identify new ways to evaluate recoveredstroke patients in making decisions regarding capacityfor return to work and other activities.

Another important implication, briefly discussed bySharma and colleagues, is the need to carefully considerthe site of stimulation when performing investigationsusing noninvasive stimulation techniques to enhancemotor function in stroke patients. In recent years, manystudies have raised the enthusiasm for the potential useof transcranial magnetic stimulation or transcranial di-rect current stimulation (tDCS) as neurorehabilitationstrategies.8–11 These studies have targeted, for the mostpart, either the ipsilesional or contralesional M1 areaswith modest motor improvement. However, the presentresults by Sharma and colleagues suggest that it is pos-sible that rather than directly enhancing M1, it may bemore appropriate to target regions upstream to M1 suchas prefrontal cortex. Another important implication isthat brain stimulation studies using tDCS will have toreconsider the common belief that the reference elec-trode, considered not active, placed over frontal regionsmay in fact be affecting part of the new network thatsupports motor function in these investigations.8,10

A vast number of stroke patients experience recoveryafter stroke. However, recovery is often incomplete anddoes not bring full return of function. The study bySharma and colleagues is an important contribution to

our understanding of the complex mechanisms of motorrecovery after stroke. Future studies will need to investi-gate whether changes in cortical coupling are dependenton specific tasks or mediate overall recovery (ie, as a“jump start” to achieve normal performance levels on avariety of tasks). It seems that the ability to recover mo-tor function after stroke might depend on the capacityof the individual’s brain to “reconnect the dots”—toconnect normal areas of activation in a novel way afterperturbation of the system by a lesion.

Pablo Celnik, MDArgye E. Hillis, MD

Department of Physical Medicine and RehabilitationDepartment of NeurologyJohns Hopkins University School of MedicineBaltimore, MD

Potential conflict of interest: Nothing to report.

References1. Calautti C, Baron J-C. Functional neuroimaging studies of mo-

tor recovery after stroke in adults: a review. Stroke 2003;34:1553–1566.

2. Butefisch CM, Kleiser R, Seitz RJ. Post-lesional cerebralreorganisation: evidence from functional neuroimaging and trans-cranial 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 Neurol2009;66:604–616.

4. Frost SB, Barbay S, Friel KM, et al. Reorganization of remotecortical regions after ischemic brain injury: a potential substratefor stroke recovery. J Neurophysiol 2003;89:3205–3214.

5. Dancause N, Barbay S, Frost SB, et al. Extensive cortical rewir-ing after brain injury. J Neurosci 2005;25:10167–10179.

6. Dobkin BH. Fatigue versus activity-dependent fatigability inpatients with central or peripheral motor impairments. Neuro-rehabil Neural Repair 2008;22:105–110.

7. Krakauer JK, Bagesteiro LB, Mazzoni PL, Sainburg RL. Deficitsin skill learning and in control of arm inertia after recoveryfrom pure motor hemiparesis. Neural Control of MovementConference, 2005. 15th Annual Meeting, April 12–17, 2005.Key Biscayne, FL.

8. Boggio PS, Nunes A, Rigonatti SP, et al. Repeated sessions ofnoninvasive brain DC stimulation is associated with motorfunction improvement in stroke patients. Restor Neurol Neu-rosci 2007;25:123–129.

9. Celnik P, Paik NJ, Vandermeeren Y, et al. Effects of combinedperipheral nerve stimulation and brain polarization on perfor-mance of a motor sequence task after chronic stroke. Stroke2009;40:1764–1771.

10. Hummel F, Celnik P, Giraux P, et al. Effects of non-invasivecortical stimulation on skilled motor function in chronic stroke.Brain 2005;128:490–499.

11. Khedr EM, Ahmed MA, Fathy N, Rothwell JC. Therapeutictrial of repetitive transcranial magnetic stimulation after acuteischemic stroke. Neurology 2005;65:466–468.

DOI: 10.1002/ana.21811

Rodriguez: Autoimmune Demyelinating Disease 571