Brain reorganization after experimental stroke: functional and structural MRI correlates

Ischemic stroke is a major cause of death and long-term disability in the Western society. The disease leads to debilitating effects like neuronal death, loss of anatomical connections between neurons and subsequent loss of function. Although such ischemic stroke damage can be devastating, many patients survive the insult and undergo a certain degree of recovery in the following weeks and months. An increasing number of animal and human stroke studies has attributed this spontaneous functional recovery at later stages to the brain’s capability to reorganize and remodel the affected bilateral neuronal networks. Yet, the underlying mechanisms of functional and structural plasticity processes and their relationship with improved behavioral outcome remain incompletely understood. Evidently, elucidation of the neuronal substrates and the spatiotemporal characteristics of brain reorganization associated with improved function may guide the development of new therapeutic strategies at later time points after cerebral ischemia. This thesis deals with the spatiotemporal characterization of changes in functional and structural organization of the bilateral sensorimotor network in relation to behavioral recovery after stroke in rats, using different magnetic resonance imaging (MRI) methods. Furthermore, the mutual link between functional and structural modifications of neuronal circuitry was investigated. Therefore, a relatively new technique, resting-state functional MRI (rs-fMRI), in combination with MRI of structural connectivity (i.e., manganese-enhanced MRI (MEMRI) and diffusion tensor imaging (DTI)) was applied to allow non-invasive and serial measurements of changes in organization of functional networks after unilateral stroke in rats. Our data have revealed that rapid and mainly perilesional remodeling with transient disturbance of functional network organization is related to almost complete functional recovery after subcortical stroke, whereas prolonged and extensive bilateral reorganization including increased contralesional connectivity is correlated with partial restoration of function after large stroke involving cortical areas. Independent of stroke severity, intact interhemispheric synchronization of neuronal activity (i.e., interhemispheric functional connectivity) seems to be crucial for improved behavioral outcome, which for its part may also reciprocally stabilize and strengthen new functional connections. Next to a strong direct correlation between functional and structural connectivity changes, an indirect and probably reciprocal relationship exists between the reinstatement of interhemispheric signal synchronization and recovery of the structural integrity in the ipsilesional corticospinal tract. Moreover, despite strong correlations between recovery and MRI measures of functional reorganization, preserved structural integrity of the unilateral ipsilesional corticospinal tract appears to be the most essential basis for good functional outcome after unilateral stroke in rats. This may indicate that regained balance of somatosensory input and motor output signals between bilateral corticospinal tracts is essential for recovery of interhemispheric functional connectivity and subsequent sensorimotor function. The MRI findings discussed in this thesis corroborate the concept that a network perspective is fundamental to improve our understanding of underlying neuronal mechanisms of spontaneous functional recovery, and for developing novel therapeutic or rehabilitative strategies in stroke subjects. Moreover, the unique information about the specific pattern of functional reorganization, as obtained with rs-fMRI, could be used to tailor therapeutic interventions (e.g., brain stimulation) to the individual situation of the stroke patient.