Spreading depolarization drives distant connectivity changes in the focally injured cortex

Cortical spreading depolarization (SD), a slow-propagating wave of transient cellular depolarization, reliably occurs after acute brain injury but usually remains undetected. Focal brain injury is known to produce a network-level dysfunction that changes the strength and direction of connectivity far beyond lesion site (connectional diaschisis) that can underlie post-injury neurological dysfunction. We suggested that injury-induced SD could contribute to connectional diaschisis and studied the effects of SD on functional and effective connectivity in neural networks supporting cognitive and sensory functions. Electrographic recordings of cortical activity were obtained in freely behaving rats immediately after focal micro-injury of the frontal cortex. The injury-induced SD propagated over the cortex of the ipsilesional hemisphere but never invaded the contralesional cortex. Strength and direction of connectivity were estimated using non-directional (mutual information function) and directional (transfer entropy) measures calculated for recordings from the retrosplenial (a key hub of the default-mode network) and somatosensory cortex. Mutual information analysis showed initial hypercoupling within the injured hemisphere (during SD) followed by longer interhemispheric decoupling (after SD termination). During post-SD hypoconnectivity, influence of the uninjured cortex on the injured one increased in both cortical regions. The retrosplenial cortex, component of the default-mode network, showed strong interhemispheric coupling during the baseline period and complex changes in connectivity after SD. Therefore, SD arising in the injured cortex disturbs long-range connectivity in distant cortical regions and causes widespread network alterations involving the default-mode network. Given the key role of the network in cognition, connectivity changes produced by injury-induced SD could contribute to the mechanisms of cognitive deficit after brain injury.