Isabelle Loubinoux

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.

Fluoxetine modulates motor performance and cerebral activation of patients recovering from stroke

In order to determine the influence of a single dose of fluoxetine on the cerebral motor activation of lacunar stroke patients in the early phase of recovery, we conducted a prospective, double‐blind, crossover, placebo‐controlled study on 8 patients with pure motor hemiparesia. Each patient underwent two functional magnetic resonance imaging (fMRI) examinations: one under fluoxetine and one under placebo. The first was performed 2 weeks after stroke onset and the second a week later. During the two fMRI examinations, patients performed an active controlled motor task with the affected hand and a passive one conducted by the examiner with the same hand. Motor performance was evaluated by motor tests under placebo and under fluoxetine immediately before the examinations to investigate the effect of fluoxetine on motor function. Under fluoxetine, during the active motor task, hyperactivation in the ipsilesional primary motor cortex was found. Moreover, fluoxetine significantly improved motor skills of the affected side. We found that a single dose of fluoxetine was enough to modulate cerebral sensory‐motor activation in patients. This redistribution of activation toward the motor cortex output activation was associated with an enhancement of motor performance.

A longitudinal fMRI study: in recovering and then in clinically stable sub-cortical stroke patients

The aim of this 1-year longitudinal fMRI study was to compare hand motor activation patterns between cerebrovascular paretic patients with a subcortical infarction and healthy elderly subjects and to evaluate the changes between the subacute phase and the chronic phase of recovery. We studied eight right-handed patients with pure motor hemiparesis due to a single ischemic infarct of the corticospinal tract. Each patient underwent a first fMRI (E1) 20 +/- 9 days after stroke, a second (E2) after 4 months and a third (E3) 12 months after stroke. During each fMRI session, the patients performed an active motor task consisting of audio-paced (1 Hz) finger flexion-extension of the paretic hand and underwent a passive motor task consisting of flexion-extension of the paretic hand performed by an examiner. Data were analyzed with SPM99 (random effect analyses). Patients had recovered at E2, were stable between E2 and E3, but still experienced a hand weakness. Displacement of activation maxima coordinates in patients compared to healthy subjects suggested an early reorganization within the SMA and a secondary reorganization within the ipsilesional S1M1 at E2. The main differences between patients and healthy subjects were (1) recruitment of the posterior part of the cingulate cortex and SMA, (2) a general hyperactivation (except in the deefferented primary motor cortex) and (3) an evolution in the S1M1 activation from an early (20 days after stroke) contralesional hyperactivation to a later (4 months after stroke) ipsilesional hyperactivation concomitant to recovery. Changes in activation were confirmed by the passive task that involved no effort and little attention. Despite clinical stability, changes in brain processing seemed to occur between E2 and E3 corresponding to a normalization of ipsilesional S1M1 activation, a decrease of bilateral cerebellar activation, and a progressive increase in SII-BA 40 activity suggesting evolving compensatory networks to sustain recovery.

Correlation between cerebral reorganization and motor recovery after subcortical infarcts.

Our objective was to investigate correlations between clinical motor scores and cerebral sensorimotor activation to demonstrate that this reorganization is the neural substratum of motor recovery. Correlation analyses identified reorganization processes shared by all patients. Nine patients with first-time corticospinal tract lacuna were clinically evaluated using the NIH stroke scale, the motricity index, and the Barthel index. Patients were strictly selected for pure motor deficits. They underwent a first fMRI session (E1) 11 days after stroke, and then a second (E2) 4 weeks later. The task used was a calibrated repetitive passive flexion/extension of the paretic wrist. The control task was rest. Six healthy subjects followed the same protocol. Patients were also clinically evaluated 4 and 12 months after stroke. All patients improved significantly between E1 and E2. For E1 and E2, the ipsilesional primary sensorimotor and premotor cortex, supplementary motor area (SMA), and bilateral Broadmann area (BA) 40 were activated. Activation intensity was greater at the second examination except in the ipsilesional superior BA 40. Magnitude of activation was lower than that of controls except for well-recovered patients. E1 clinical hand motor score and E1 cerebral activation correlated in the SMA proper and inferior ipsilesional BA 40. Thus, we demonstrated early functionality of the sensorimotor system. The whole sensorimotor network activation correlated with motor status at E2, indicating a recovery of its function when activated. Moreover, the activation pattern in the acute phase (E1) had a predictive value: early recruitment and high activation of the SMA and inferior BA 40 were correlated with a faster or better motor recovery. On the contrary, activation of the contralesional hemisphere (prefrontal cortex and BA 39-40) and of the posterior cingulate/precuneus (BA 7-31) predicted a slower recovery.

Spreading of Vasogenic Edema and Cytotoxic Edema Assessed by Quantitative Diffusion and T2 Magnetic Resonance Imaging

BACKGROUND AND PURPOSE The apparent diffusion coefficient (ADC) of water should be sensitive to the cytotoxic edema triggered by energy failure during ischemia. Elevated values of T2. the nuclear MR transverse relaxation time of water, seen on T2 nuclear MR images detect vasogenic edema and infarcted areas. The temporal and spatial changes in ADC and T2 abnormalities after occlusion of the middle cerebral artery (MCAO) were therefore estimated by these two quantitative techniques. METHODS Permanent MCAO was performed on rats. Quantitative ADC and T2 maps of brain water were obtained, from which the ischemic volumes were calculated at various times up to 48 hours after MCAO. RESULTS The areas of decreased ADC represented 36 +/- 7% of the final infarct volume (24 hours) at 0.5 hours and 64 +/- 4% at 5 hours after MCAO, suggesting that there is recruitment of peripheral areas with disturbed energy metabolism and cytotoxic edema. The ADC and T2 contours closely matched at 3.5, 24, and 48 hours after MCAO. CONCLUSIONS T2 imaging can assess ischemic insults as well as ADC imaging, but only 3.5 hours after the onset of ischemia. Assessment of edematous swelling (approximately 24.5% of total infarcted volume) demonstrates that ADC and therefore T2 imaging detect all the tissue that will become infarcted approximately 7 hours after occlusion. The spread of ADC and T2 abnormalities would therefore stop at approximately 7 hours, and any further increase in volume observed on the images would be mainly due to edematous swelling.

Within-session and between-session reproducibility of cerebral sensorimotor activation: a test--retest effect evidenced with functional magnetic resonance imaging.

The aim of the current study was to assess the reproducibility of functional magnetic resonance imaging (fMRI) brain activation signals in a sensorimotor task in healthy subjects. Because random or systematic changes are likely to happen when movements are repeated over time, the authors searched for time-dependent changes in the fMRI signal intensity and the extent of activation within and between sessions. Reproducibility was studied on a sensorimotor task called “the active task” that includes a motor output and a sensory feedback, and also on a sensory stimulation called “the passive task” that assessed the sensory input alone. The active task consisted of flexion and extension of the right hand. The subjects had performed it several times before fMRI scanning so that it was well learned. The passive task consisted of a calibrated passive flexion and extension of the right wrist. Tasks were 1 Hz-paced. The control state was rest. Subjects naïve to the MRI environment and non–MRI-naïve subjects were studied. Twelve MRI-naïve subjects underwent 3 fMRI sessions separated by 5 hours and 49 days, respectively. During MRI scanning, they performed the active task. Six MRI-naïve subjects underwent 2 fMRI sessions with the passive task 1 month apart. Three non–MRI-naïve subjects performed twice an active 2-Hz self-paced task. The data were analyzed with SPM96 software. For within-session comparison, for active or passive tasks, good reproducibility of fMRI signal activation was found within a session (intra-and interrun reproducibility) whether it was the first, second, or third session. Therefore, no within-session habituation was found with a passive or a well-learned active task. For between-session comparison, for MRI-naïve or non–MRI-naïve subjects, and with the active or the passive task, activation was increased in the contralateral premotor cortex and in ispsilateral anterior cerebellar cortex but was decreased in the primary sensorimotor cortex, parietal cortex, and posterior supplementary motor area at the second session. The lower cortical signal was characterized by reduced activated areas with no change in maximum peak intensity in most cases. Changes were partially reversed at the third session. Part of the test–retest effect may come from habituation of the MRI experiment context. Less attention and stress at the second and third sessions may be components of the inhibition of cortical activity. Because the changes became reversed, the authors suggest that, beyond the habituation process, a learning process occurred that had nothing to do with procedural learning, because the tasks were well learned or passive. A long-term memory representation of the sensorimotor task, not only with its characteristics (for example, amplitude, frequency) but also with its context (fMRI), can become integrated into the motor system along the sessions. Furthermore, the pattern observed in the fMRI signal changes might evoke a consolidation process.

Neural Substrate for the Effects of Passive Training on Sensorimotor Cortical Representation: A Study with Functional Magnetic Resonance Imaging in Healthy Subjects

Repetitive passive movements are part of most rehabilitation procedures, especially in patients with stroke and motor deficit. However, little is known about the consequences of repeated proprioceptive stimulations on the intracerebral sensorimotor network in humans. Twelve healthy subjects were enrolled, and all underwent two functional magnetic resonance imaging (fMRI) sessions separated by a 1-month interval. Passive daily movement training was performed in six subjects during the time between the two fMRI sessions. The other six subjects had no training and were considered as the control group. The task used during fMRI was calibrated repetitive passive flexion-extension of the wrist similar to those performed during training. The control task was rest. The data were analyzed with SPM96 software. Images were realigned, smoothed, and put into Talairachs neuroanatomical space. The time effect from the repetition of the task was assessed in the control group by comparing activation versus rest in the second session with activation versus rest in the first session. This time effect then was used as null hypothesis to assess the training effect alone in our trained group. Passive movements compared with rest showed activation of most of the cortical areas involved in motor control (i.e., contralateral primary sensorimotor cortex, supplementary motor area [SMA], cingulum, Brodmann area 40, ipsilateral cerebellum). Time effect comparison showed a decreased activity of the primary sensorimotor cortex and SMA and an increased activity of ipsilateral cerebellar hemisphere, compatible with a habituation effect. Training brought about an increased activity of contralateral primary sensorimotor cortex and SMA. A redistribution of SMA activity was observed. The authors demonstrated that passive training with repeated proprioceptive stimulation induces a reorganization of sensorimotor representation in healthy subjects. These changes take place in cortical areas involved in motor preparation and motor execution and represent the neural basis of proprioceptive training, which might benefit patients undergoing rehabilitative procedures.

Engineering of adult human neural stem cells differentiation through surface micropatterning

Interaction between differentiating neural stem cells and the extracellular environment guides the establishment of cell polarity during nervous system development. Developing neurons read the physical properties of the local substrate in a contact-dependent manner and retrieve essential guidance cues. To restore damage brain area by tissue engineering, the biomaterial scaffold has to mimic this microenvironment to allow organized tissue regeneration. To establish the validity of using microgrooved surfaces in order to simultaneously provide to primary adult human neural stem cells a permissive growth environment and a guide for neurite outgrowth in a pre-established direction, we have studied the long-term culture of adult human neural stem cells from patient biopsies on microgrooved polymers. By exploiting polymer moulding techniques, we engineered non-cytotoxic deep microstructured surfaces of polydimethylsiloxane (PDMS) exhibiting microchannels of various widths. Our results demonstrate that precoated micropatterned PDMS surfaces can serve as effective neurite guidance surfaces for human neural stem cells. Immunocytochemistry analysis show that channel width can impact strongly development and differentiation. In particular we found an optimal microchannel width, that conciliates a high differentiation rate with a pronounced alignment of neurites along the edges of the microchannels. The impact of the microstructures on neurite orientation turned out to be strongly influenced by cell density, attesting that cell/surface interactions at the origin of the alignment effect, are in competition with cell/cell interactions tending to promote interconnected networks of cells. Considering all these effects, we have been able to design appropriate structures allowing to obtain neuron development and differentiation rate comparable to a plane unpatterned surface, with an efficient neurite guidance and a long-term cell viability.

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.

Post-stroke depression: mechanisms, translation and therapy.

The interaction between depression and stroke is highly complex. Post‐stroke depression (PSD) is among the most frequent neuropsychiatric consequences of stroke. Depression also negatively impacts stroke outcome with increased morbidity, mortality and poorer functional recovery. Antidepressants such as the commonly prescribed selective serotonin reuptake inhibitors improve stroke outcome, an effect that may extend far beyond depression, e.g., to motor recovery. The main biological theory of PSD is the amine hypothesis. Conceivably, ischaemic lesions interrupt the projections ascending from midbrain and brainstem, leading to a decreased bioavailability of the biogenic amines – serotonin (5HT), dopamine (DA) and norepinephrine (NE). Acetylcholine would also be involved. So far, preclinical and translational research on PSD is largely lacking. The implementation and characterization of suitable animal models is clearly a major prerequisite for deeper insights into the biological basis of post‐stroke mood disturbances. Equally importantly, experimental models may also pave the way for the discovery of novel therapeutic targets. If we cannot prevent stroke, we shall try to limit its long‐term consequences. This review therefore presents animal models of PSD and summarizes potential underlying mechanisms including genomic signatures, neurotransmitter and neurotrophin signalling, hippocampal neurogenesis, cellular plasticity in the ischaemic lesion, secondary degenerative changes, activation of the hypothalamo‐pituitary‐adrenal (HPA) axis and neuroinflammation. As stroke is a disease of the elderly, great clinical benefit may especially accrue from deciphering and targeting basic mechanisms underlying PSD in aged animals.