François Chollet

Fluoxetine for motor recovery after acute ischaemic stroke (FLAME): a randomised placebo-controlled trial

BACKGROUND Hemiplegia and hemiparesis are the most common deficits caused by stroke. A few small clinical trials suggest that fluoxetine enhances motor recovery but its clinical efficacy is unknown. We therefore aimed to investigate whether fluoxetine would enhance motor recovery if given soon after an ischaemic stroke to patients who have motor deficits. METHODS In this double-blind, placebo-controlled trial, patients from nine stroke centres in France who had ischaemic stroke and hemiplegia or hemiparesis, had Fugl-Meyer motor scale (FMMS) scores of 55 or less, and were aged between 18 years and 85 years were eligible for inclusion. Patients were randomly assigned, using a computer random-number generator, in a 1:1 ratio to fluoxetine (20 mg once per day, orally) or placebo for 3 months starting 5-10 days after the onset of stroke. All patients had physiotherapy. The primary outcome measure was the change on the FMMS between day 0 and day 90 after the start of the study drug. Participants, carers, and physicians assessing the outcome were masked to group assignment. Analysis was of all patients for whom data were available (full analysis set). This trial is registered with ClinicalTrials.gov, number NCT00657163. FINDINGS 118 patients were randomly assigned to fluoxetine (n=59) or placebo (n=59), and 113 were included in the analysis (57 in the fluoxetine group and 56 in the placebo group). Two patients died before day 90 and three withdrew from the study. FMMS improvement at day 90 was significantly greater in the fluoxetine group (adjusted mean 34·0 points [95% CI 29·7-38·4]) than in the placebo group (24·3 points [19·9-28·7]; p=0·003). The main adverse events in the fluoxetine and placebo groups were hyponatraemia (two [4%] vs two [4%]), transient digestive disorders including nausea, diarrhoea, and abdominal pain (14 [25%] vs six [11%]), hepatic enzyme disorders (five [9%] vs ten [18%]), psychiatric disorders (three [5%] vs four [7%]), insomnia (19 [33%] vs 20 [36%]), and partial seizure (one [<1%] vs 0). INTERPRETATION In patients with ischaemic stroke and moderate to severe motor deficit, the early prescription of fluoxetine with physiotherapy enhanced motor recovery after 3 months. Modulation of spontaneous brain plasticity by drugs is a promising pathway for treatment of patients with ischaemic stroke and moderate to severe motor deficit. FUNDING Public French National Programme for Clinical Research.

Neuroimaging in Stroke Recovery: A Position Paper from the First International Workshop on Neuroimaging and Stroke Recovery

Baron, Jean-Claude*Black, Sandra E.Butler, Andrew J.Carey, JamesChollet, FrancoisCohen, Leonardo G.*Corbetta, MaurizioCramer, Steven C.*Dobkin, Bruce H.*Frackowiak, RichardHeiss, W.D.Johansen-Berg, Heidi*Krakauer, John W.Lazar, Ronald M.Lennihan, Laura L.Loubinoux, Isabelle*Marshall, Randolph S.*Matthews, PaulMohr, J.P.Nelles, GereonPascual-Leone, AlvaroPomeroy, ValerieRijntjes, MichelRossini, Paolo MariaRothwell, John C.Seitz, Rudiger J.Small, Steven L.Sunderland, AlanWard, N.S.*Weiller, CorneliusWise, Richard J.S.IntroductionThe First International Workshop on Neuroimagingand Stroke Recovery was convened in February, 2004 inNew York City. The purpose of the workshop was to de-scribe the state of the field with regard to technical andanalytical methods, to discuss the use of complementaryimaging modalities, and to assess the current potential toapply functional neuroimaging to the development of ratio-nal treatment strategies for enhanced stroke recovery.Presented herein is a summary statement of topics dis-cussed at the workshop. These included (i) the clinical rel-evance of functional imaging changes after stroke for themotor and language systems; (ii) the technical challengesfaced in moving towards establishing functional neuro-imaging as a clinically useful tool; (iii) the contributions ofneurophysiological probes such as transcranial magnet-ic stimulation (TMS) to improve understanding of themechanisms underlying brain reorganization after stroke;and (iv) the potential role of neuroimaging in the assess-ment and development of rational pharmacological andbehavioral therapies.Clinical RelevanceFunctional recovery commonly occurs in survivingstroke patients in the weeks and months following theinjury. There is evidence from animal models that cere-bral reorganization underlies at least some of this recov-ery and it is hoped that an understanding of the neuro-physiological processes underlying this reorganization inthe human brain will lead to a rational approach to thetreatment of impairment. In animal models, focal braindamage triggers a number of changes at the molecular, cel-lular, and systems level, some of which alter the potentialfor cerebral reorganization and consequent functionalrecovery. Although the same techniques are not availableto study the working human brain, functional brain imag-ing has provided insights into how the human brainresponds to focal injury.

SPECT study of cerebral blood flow reactivity after acetazolamide in patients with transient ischemic attacks

We investigated 15 patients with one or more transient ischemic attacks (TIAs) in the internal carotid artery territory within the month following the most recent TIA. Cerebral blood flow (CBF) was measured by single-photon emission computed tomography, using intravenous xenon-133 before and after injection of 1 g acetazolamide. Six patients had severe carotid stenosis or occlusion; the other nine patients had no significant carotid lesions. Twenty age-matched volunteers free of neurologic symptoms or history were used as controls. Mean CBF in the sylvian region was not significantly different between patients and controls. Seven patients exhibited a focal hypoperfusion at rest in the symptomatic hemisphere, and their hypoperfused areas were hyporeactive after administration of acetazolamide. Seven other patients exhibited hyporeactive areas after acetazolamide administration while their CBF tomograms at rest were normal. Thus, CBF abnormalities were detected in 14 of the 15 patients. Our findings suggest that CBF measured early after acetazolamide administration could be useful to confirm the clinical diagnosis of TIA. In the nine patients with no significant lesion of the internal carotid artery, the areas of hypoperfusion were small and were probably related to the focal ischemic event. In the six patients with severe lesions of the internal carotid artery, abnormalities were of variable size and intensity but were often large and pronounced. The discrepancy between these two subgroups of patients could be ascribed to the hemodynamic influence of the internal carotid artery lesions. Moreover, our findings may provide some insight into the pathophysiology of TIAs.

Posterior cerebral hypoperfusion in migraine without aura

In cerebral blood flow studies, migraine aura is characterized by a posterior cortical hypoperfusion. In contrast, only rare and mild changes in brain perfusion have been demonstrated in migraine without aura, suggesting two different haemodynamic patterns in migraine with and without aura. Our aim was to study hypoperfusion with positron emission tomography (PET) as early as possible during spontaneous migraine without aura attacks. We used H2 15O PET to investigate seven patients (six female, one male) with migraine without aura (International Classification of Headache Diseases-II code 1.1) in three situations: during the headache phase, after headache relief following sumatriptan injection, and during an attack-free interval. Statistical analysis was performed with SPM2. Within 4 h after the attack onset, significant relative bilateral posterior cortical hypoperfusion was found and persisted after headache relief following sumatriptan injection. A posterior cortical hypoperfusion demonstrated in migraine without aura could suggest a common pathogenesis in migraine with and without aura. The significance of relative posterior hypoperfusion in migraine without aura is discussed according to the current knowledge of migraine pathogenesis.

Motor recovery after acute ischaemic stroke: a metabolic study.

The metabolic changes occurring after ischaemic stroke were measured to investigate the functional anatomy of clinical motor recovery. Positron emission tomography (PET) and the steady-state 15O technique was used to compare resting relative metabolic distributions at the onset of functional deficit with those following recovery. Ten patients were studied with repeat scans. Motor recovery was associated in some patients with an increase of relative oxygen metabolism in anatomical structures normally involved in motor function in the affected hemisphere, particularly in the cortical motor areas. In those patients without such metabolic changes in the cortex of the diseased hemisphere, relative increases in cortical metabolism in the contralateral hemisphere were associated with better motor recovery than in patients with no relative cortical metabolic increase in either hemisphere. There was no correlation between the degree of improvement in motor function and the severity of motor deficit at onset, the size and site of the lesion and the metabolic changes in the infarcted zone. No particular pattern of global metabolic changes was observed after recovery. Thus different relative patterns of metabolic recovery were seen in patients with different lesions and evidence was found for the participation of contralateral structures in the recovery process in some patients.

Functional MRI and intraoperative brain mapping to evaluate brain plasticity in patients with brain tumours and hemiparesis.

OBJECTIVE To support the hypothesis about the potential compensatory role of ipsilateral corticofugal pathways when the contralateral pathways are impaired by brain tumours. METHODS Retrospective analysis was carried out on the results of functional MRI (fMRI) of a selected group of five paretic patients with Rolandic brain tumours who exhibited an abnormally high ipsilateral/contralateral ratio of activation—that is, movements of the paretic hand activated predominately the ipsilateral cortex. Brain activation was achieved with a flexion extension of the fingers. Statistical parametric activation was obtained using a t test and a threshold of p<0.001. These patients, candidates for tumour resection, also underwent cortical intraoperative stimulation that was correlated to the fMRI spatial data using three dimensional reconstructions of the brain. Three patients also had postoperative control fMRI. RESULTS The absence of fMRI activation of the primary sensorimotor cortex normally innervating the paretic hand for the threshold chosen, was correlated with completely negative cortical responses of the cortical hand area during the operation. The preoperative fMRI activation of these patients predominantly found in the ipsilateral frontal and primary sensorimotor cortices could be related to the residual ipsilateral hand function. Postoperatively, the fMRI activation returned to more classic patterns of activation, reflecting the consequences of therapy. CONCLUSION In paretic patients with brain tumours, ipsilateral control could be implicated in the residual hand function, when the normal primary pathways are impaired. The possibility that functional tissue still remains in the peritumorous sensorimotor cortex even when the preoperative fMRI and the cortical intraoperative stimulations are negative, should be taken into account when planning the tumour resection and during the operation.

Induction of Cortical Plastic Changes in Wrist Muscles by Paired Associative Stimulation in the Recovery Phase of Stroke Patients

Background. Paired associative stimulation (PAS) combining peripheral nerve and transcranial magnetic stimulation (TMS) have been proposed to induce long-term changes in excitability of the cerebral cortex and potentially optimize motor recovery in stroke patients. Objective. This pilot study examined whether short-lasting changes in cortical excitability could be induced by a single session of PAS within the first months after stroke. Methods. Six hemiparetic patients with a subcortical stroke were included. The single session PAS protocol was applied at 1, 5, and 12 months after stroke. During the follow-up, the clinical recovery of wrist function was assessed in parallel to the PAS study by the Fugl-Meyer motor scale and dynamometry of wrist extension. Results. The PAS protocol induced a significant extensor carpi radialis motor evoked potential facilitation (mean +78.5%) on the paretic side 5 months after stroke. The facilitation was still present 12 months after stroke but on average smaller (+30 %). Conclusions. These electrophysiological findings suggest that patients with subcortical infarcts may respond to PAS in an earlier than later period after stroke. If the clinical efficacy of interventions such as PAS is confirmed, it could be proposed early as add-on therapy to optimize training-induced plasticity processes.

Neural Correlates of Proprioceptive Integration in the Contralesional Hemisphere of Very Impaired Patients Shortly After a Subcortical Stroke: An fMRI Study

Background. The effects of physiotherapy are difficult to assess in very impaired early stroke patients. Objective. The aim of the study was to characterize the impact of 4 weeks of passive proprioceptive training of the wrist on brain sensorimotor activation after stroke. Methods. Patients with a subcortical ischemic lesion of the pyramidal tract were randomly assigned to a control or a wrist-training group. All patients had a single pure motor hemiplegia with severe motor deficit. The control group (6 patients) underwent standard Bobath rehabilitation. The second, “trained,” group (7 patients) received Bobath rehabilitation plus 4 weeks of proprioceptive training with daily passive calibrated wrist extension. Before and after the training period, patients were examined with validated clinical scales and functional MRI (fMRI) while executing a passive movement versus rest. The effect of standard rehabilitation on sensorimotor activation was assessed in the control group on the wrist, and the effect of standard rehabilitation plus proprioceptive training was assessed in the trained group. The effect of 4-week proprioceptive training alone was statistically evaluated by difference between groups. Results. Standard rehabilitation along with natural recovery mainly led to increases in ipsilesional activation and decreases in contralesional activation. On the contrary, standard rehabilitation and paretic wrist proprioceptive training increased contralesional activation. Proprioceptive training produced change in the supplementary motor area (SMA), prefrontal cortex, and a contralesional network including inferior parietal cortex (lower part of BA 40), secondary sensory cortex, and ventral premotor cortex (PMv). Conclusion. We have demonstrated that purely passive proprioceptive training applied for 4 weeks is able to modify brain sensorimotor activity after a stroke. This training revealed fMRI change in the ventral premotor and parietal cortices of the contralesional hemisphere, which are secondary sensorimotor areas. Recent studies have demonstrated the crucial role of these areas in severely impaired patients. We propose that increased contralesional activity in secondary sensorimotor areas likely facilitates control of recovered motor function by simple proprioceptive integration in those patients with poor recovery.

Impairment and recovery of left motor function in patients with right hemiplegia.

OBJECTIVE: To assess the motor function of the left, supposedly unaffected, limbs of patients with an acute right vascular hemiplegia. METHODS: Fifteen patients with an acute vascular right hemiplegia and 16 matched healthy controls were studied. Motor function of the left limbs of each patient was evaluated on days 20 and 90 after their stroke using four validated tools (hand dynamometer, isokinetic dynamometer, finger tapping, and nine hole peg test). RESULTS: There was a significant impairment of motor function of the left limbs of patients at day 20 compared with controls. The impairment had recovered almost completely at day 90 after the stroke. CONCLUSION: These results show the bilateral cerebral representation of the human motor system and suggest the participation of ipsilateral motor pathways in recovery after a stroke.

Methylphenidate modulates cerebral post-stroke reorganization

OBJECTIVE We hypothesized that a single dose of methylphenidate (MP) would modulate cerebral motor activation and behavior in patients having suffered a subcortical stroke. METHODS Eight men with a single stroke on the corticospinal tract resulting in a pure motor hemiparesia were included in a randomized, cross-over, double-blind, placebo-controlled study. Patients were first evaluated 17 days after stroke onset by validated neurological scales, motor tests and fMRI (flexion/extension of the digits) after 20 mg MP or placebo. Seven days later, the patients underwent the same protocol and received the drug they had not taken at the first evaluation. Each patient was his own control. RESULTS Placebo intake did not change performance. MP compared to placebo elicited a significant improvement in motor performance of the affected hand at the finger tapping test. MP induced: (1) a hyperactivation of the ipsilesional primary sensorimotor cortex including the motor hand and face areas and of the contralesional premotor cortex; (2) a hypoactivation of the ipsilesional anterior cingulum. Hyperactivation in the face motor area correlated positively with the improvement in performance. CONCLUSION We demonstrated that the reorganized network may efficiently be targeted by the drug and that the effect of MP might partly rely on an improvement in attention/effort through cingulum modulation.