clinicaltrials.gov Identifier: NCT01829581.

Changes of neuronal excitability and gamma-aminobutyric acid (GABAA)-receptor expression were studied in the surround of photothrombotic infarcts, which were produced in the sensorimotor cortex of the rat by using the rose bengal technique. In a first series of experiments, multiunit recordings were performed on anesthetized animals 2-3 mm lateral from the lesion. Mean discharge frequency was considerably higher in recordings from lesioned animals (> 100 Hz in the first postlesional week) compared with control animals (mean, 15 Hz). These alterations were already present after 1 day but were most pronounced 3 to 7 days after lesion induction. Thereafter the hyperexcitability declined again, although it remained visible up to 4 months. In a second series of experiments, the GABAA-receptor expression was studied autoradiographically. This revealed a reduction of GABAA receptors in widespread brain areas ipsilateral to the lesion. The reduction was most pronounced in the first days after lesion induction and declined with longer intervals. It is concluded that cortical infarction due to photothrombosis leads to a long-lasting and widespread reduction of GABAA-receptor expression in the surround of the lesion, which is associated with an increased neuronal excitability. Such alterations may be responsible for epileptic seizures that can be observed in some patients after stroke and may contribute to neurologic deficits after stroke.

Transient and permanent focal cerebral ischemia results in a series of typical pathophysiologic events. These consequences evolve in time and space and are not limited to the lesion itself, but they can be observed in perilesional (penumbra) and widespread ipsi- and sometimes contralateral remote areas (diaschisis). The extent of these areas is variable depending on factors such as the type of ischemia, the model, and the functional modality investigated. This review describes some typical alterations attributable to focal cerebral ischemia using the following classification scheme to separate different lesioned and perilesional areas: (1) The lesion core is the brain area with irreversible ischemic damage. (2) The penumbra is a brain region that suffers from ischemia, but in which the ischemic damage is potentially, or at least partially, reversible. (3) Remote brain areas are brain areas that are not directly affected by ischemia. With respect to the etiology, several broad categories of remote changes may be differentiated: (3a) remote changes caused by brain edema; (3b) remote changes caused by waves of spreading depression; (3c) remote changes in projection areas; and (3d) remote changes because of reactive plasticity and systemic effects. The various perilesional areas are not necessarily homogeneous; but a broad differentiation of separate topographic perilesional areas according to their functional state and sequelae allows segregation into several signaling cascades, and may help to understand the functional consequences and adaptive processes after focal brain ischemia.

Our results suggest that a neocortical infarction leads to hyperexcitability not only in its direct vicinity but also in the contralateral hemisphere. Such hyperexcitability may contribute to increased activation of contralateral brain areas and to functional reorganization after stroke.

Functional recovery after stroke is partly due to cortical reorganization on a structural as well as a functional level. Recent investigations have shown that the excitability of brain areas surrounding cortical ischemic lesions is increased, probably due to a down-regulation of gamma-aminobutyric acid-receptor activity. There is some evidence that these changes might increase the susceptibility of the lesioned brain for adaptive changes and recovery. Here, we investigated the propensity for the induction of long-term potentiation (LTP) in the surround of experimentally induced focal cortical infarcts in rat somatosensory cortex in vitro. By using standard paradigms, LTP induction was found to be facilitated ipsilaterally in slices of lesioned animals 1 week after lesion induction. In homotopic contralateral areas, LTP was not different from control values. As LTP is commonly associated with plasticity and learning, the results provide further evidence for the lesion-induced amplification of network plasticity, as it is required for the reshaping of cortical circuits by timely training procedures.