Noradrenergic enhancement improves motor network connectivity in stroke patients

Abstract

OBJECTIVE: Both animal and human data suggest that noradrenergic stimulation may enhance motor performance after brain damage. We conducted a placebo-controlled, double-blind and crossover design study to investigate the effects of noradrenergic stimulation on the cortical motor system in hemiparetic stroke patients. METHODS: Stroke patients (n = 11) in the subacute or chronic stage with mild-to-moderate hand paresis received a single oral dose of 6 mg reboxetine (RBX), a selective noradrenaline reuptake inhibitor. We used functional magnetic resonance imaging and dynamic causal modeling to assess changes in neural activity and interregional effective connectivity while patients moved their paretic hand. RESULTS: RBX stimulation significantly increased maximum grip power and index finger-tapping frequency of the paretic hand. Enhanced motor performance was associated with a reduction of cortical 'hyperactivity' toward physiological levels as observed in healthy control subjects, especially in the ipsilesional ventral premotor cortex (vPMC) and supplementary motor area (SMA), but also in the temporoparietal junction and prefrontal cortex. Connectivity analyses revealed that in stroke patients neural coupling with SMA or vPMC was significantly reduced compared with healthy controls. This 'hypoconnectivity' was partially normalized when patients received RBX, especially for the coupling of ipsilesional SMA with primary motor cortex. INTERPRETATION: The data suggest that noradrenergic stimulation by RBX may help to modulate the pathologically altered motor network architecture in stroke patients, resulting in increased coupling of ipsilesional motor areas and thereby improved motor function.