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The aim of the study was to investigate the effect of chronic administration of paroxetine (selective serotonin reuptake inhibitor: SSRI) on motor cortex excitability in healthy subjects by means of transcranial magnetic stimulation (TMS), functional magnetic resonance imaging (fMRI) and behavioral motor tests. In a randomized, double-blind, crossover study, twenty-one right-handed subjects received 20 mg daily of either paroxetine or a placebo over a period of 30 days separated by a period of 3 months wash-out. The TMS study is presented here correlated with some results of the motor behavior study (finger tapping test) and the fMRI study (primary sensorimotor cortex (S1M1) volume of activation). TMS was used to test motor threshold (MT), motor evoked potential recruitment curve (RC), cortical silent period (CSP) and paired-pulse intracortical inhibition and facilitation (ICI, ICF). Chronic administration of paroxetine did not modulate ICI or CSP but induced a significant enhancement of mean ICF (ANOVA P=0.04), which significantly correlated with increase of speed in a finger tapping test (P=0.02). This suggests a modulation of cortical interneuronal excitatory pathways without changes in the excitability of cortical inhibitory GABAergic interneurons. A decrease of RC (ANOVA P=0.05) was also observed after 30 days intake of paroxetine in comparison with placebo and was associated with changes of fMRI activation intensity (left S1M1 hypoactivation, ), without changes of S1M1 activation volume. Finally, the different modulation of RC and ICF after chronic administration of paroxetine compared to single dose (opposite effects) emphasizes the different pharmacological action of the drug at cortical level depending on its acute or long-term administration.

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.

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.

It is suggested that resting state networks reflecting correlated neural regional activities participate significantly in brain functioning. A fundamental issue is to understand how these networks interact and how their activities change during behavioral transitions. Our aim was to understand better with functional MRI connectivity how the brain switched from a “resting” to a movement-related state by exploring the transitory readiness state for an intended movement of the right hand. Our study does not address movement preparation occurring in a time scale of milliseconds before movement which has been widely studied but movement-readiness which can last longer. At rest, in the absence of overt goal-directed behavior, a “default-mode” network, whose main areas are the posterior cingulate cortex and precuneus (PCC/Pcu), shows high activity interpreted as day dreaming, free association, stream of consciousness, and inner rehearsal. We found that, during rest, the “default-mode” network and the sensorimotor network were not functionally correlated. During movement-readiness, the two networks were functionally correlated through an interaction between the PCC/Pcu and the medial superior parietal cortex in the upper precuneus. The complex PCC/Pcu has been shown to be involved in retrieval and/or setting up spatial attributes for motor imagery, and thus, would be a key region in the movement-readiness phase. It might functionally connect to the medial superior parietal cortex to initiate the movement programming through retrieval of suited movement parameters. The anterior cingulum, functionally correlated to the primary sensorimotor cortex during movement-readiness would have a motivational role or could generate predictions about the movement.

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.

SSRIs are postulated to modulate motor behavior. A single dose of selective serotoninergic reuptake inhibitors (SSRIs) like fluoxetine, paroxetine, or fluvoxamine, has been shown to improve motor performance and efficiency of information processing for simple sensorimotor tasks in healthy subjects. At a cortical level, a single dose of SSRI was shown to induce a hyperactivation of the primary sensorimotor cortex (S1M1) involved in the movement (Loubinoux, I., Boulanouar, K., Ranjeva, J. P., Carel, C., Berry, I., Rascol, O., Celsis, P., and Chollet, F., 1999. Cerebral functional magnetic resonance imaging activation modulated by a single dose of the monoamine neurotransmission enhancers fluoxetine and fenozolone during hand sensorimotor tasks. J. Cereb. Blood Flow Metab. 19 1365--1375, Loubinoux, I., Pariente, J., Boulanouar, K., Carel, C., Manelfe, C., Rascol, O., Celsis, P., and Chollet, F., 2002. A Single Dose of Serotonin Neurotransmission Agonist Paroxetine Enhances Motor Output. A double-blind, placebo-controlled, fMRI study in healthy subjects. NeuroImage 15 26--36). Since SSRIs are usually given for several weeks, we assessed the behavioral and cerebral effects of a one-month chronic administration of paroxetine on a larger group. In a double-blind, placebo controlled and crossover study, 19 subjects received daily 20 mg paroxetine or placebo, respectively, over a period of 30 days separated by a wash-out period of 3 months. After each period, the subjects underwent an fMRI (active or passive movement, dexterity task, sensory discrimination task) and a behavioral evaluation. Concurrently, a TMS (transcranial magnetic stimulation) study was conducted (Gerdelat-Mas, A., Loubinoux, I., Tombari, D., Rascol, O., Chollet, F., Simonetta-Moreau, M., 2005. Chronic administration of selective serotonin re-uptake inhibitor (SSRI) paroxetine modulates human motor cortex excitability in healthy subjects. NeuroImage 27,314--322).On the one hand, paroxetine improved motor performances at the finger tapping test (P=0.02) without affecting choice reaction time, strength and dexterity significantly. Subjects were also faster in processing the spatial incongruency between a stimulus and the motor response (P=0.04). In order to differentiate behavioral components, a principal component analysis was performed on all motor tests, and several characteristics were differentiated: strength, speed, skill, attention, and motor response coding. Paroxetine would improve the efficiency of motor response coding (MANOVA on the factors; factor 3, P=0.01). On the other hand, the chronic administration induced a significant hypoactivation of S1M1 whatever the task: motor or sensory, simple or complex (random effect analysis, P0.05). The hypoactivation correlated with the improvement of performances at the finger tapping test (P0.05) suggesting more efficiency in cerebral motor processing.Our results showed a clear modulation of sensory and motor cerebral activation after a chronic paroxetine administration. An improvement in both behavior and cerebral efficiency was suggested. It could be hypothesized that monoamines, by an unspecific effect, may tune the response of pyramidal neurons to optimize performances.

Since serotonin (5-HT) stimulates motor function, pharmacological potentiation of 5-HT neurotransmission may improve motor function in healthy subjects and, possibly, recovery in post-stroke patients. Indeed, fluoxetine, a selective serotonin reuptake inhibitor (SSRI), increased activation in executive motor areas of healthy subjects as fenozolone, a releaser of monoamines (including noradrenaline, dopamine, and serotonin) from intracellular stores. This study is intended to test the hypothesis that paroxetine can likewise modulate brain motor activity in a dose-dependent manner in healthy subjects. In a double-blind counterbalanced study, six subjects underwent functional MRI examinations on three sessions 1 week apart (E1, E2, and E3) at the time of peak plasma concentrations (5 h after drug intake, i.e., either 20 or 60 mg of paroxetine or placebo) with a complex sequential opposition task. Rest and activation alternated in a block design. During activation, subjects performed, with the right hand, a 1-Hz-paced task that alternated two fist closings with a sequential opposition task. Paroxetine elicited effects similar to those reported for fluoxetine; notable changes were hyperactivation in the contralateral S1/M1, and posterior SMA and widespread hypoactivation of basal ganglia and cerebellum. There was an inverse correlation between dose and effect: significantly greater effects were observed with the 20-mg dose compared with 60 mg. Paroxetine dose-dependently modulates activation of the entire motor pathway in a way that favors motor output. Thus, a single dose of the SSRI paroxetine reorganized motor processing.

Using a habituation-recovery paradigm adapted to functional magnetic resonance imaging, we investigated the brain responses to syllables and tones in six right-handed male subjects. We opposed a standard condition (STD) in which the subjects were listening to homogeneous sequences of four identical stimuli, to a deviant condition (DEV) in which the fourth stimulus of the sequence differed in pitch or spectral content for tones and in the initial stop consonant for syllables. The corresponding runs alternated four rest periods with two STD and two DEV conditions. In addition to a marked rightward asymmetry in the primary and secondary auditory cortex for tones and a right inferior frontal activation for the tone condition where the deviant had increased spectral content, the experiment revealed differential activations in the left posterior superior temporal gyrus and in the left supramarginal gyrus. Activations within the left posterior superior temporal gyrus were observed for the DEV condition with tones and for the STD and DEV conditions with syllables. Activation within the inferior part of the left supramarginal gyrus was only observed for the DEV condition with syllables. The analysis of the decreases and increases in the BOLD signal across the STD, DEV, and rest conditions suggests that the left posterior superior temporal gyrus is implicated in the preattentive change detection of acoustic changes in speech as well as nonspeech stimuli, whereas the left supramarginal gyrus is more specifically engaged in the detection of changes in phonological units.