Transient loss of interhemispheric functional connectivity following unilateral cortical spreading depression in awake rats

Abstract

Objective Growing evidence shows a critical role of network disturbances in the pathogenesis of migraine. Unilateral pattern of neurological symptoms of aura suggests disruption of interhemispheric interactions during the early phase of a migraine attack. Using local field potentials data from the visual and motor cortices, this study explored effects of unilateral cortical spreading depression, the likely pathophysiological mechanism of migraine aura, on interhemispheric functional connectivity in freely behaving rats. Methods Temporal evolution of the functional connectivity was evaluated using mutual information and phase synchronization measures applied to local field potentials recordings obtained in homotopic points of the motor and visual cortices of the two hemispheres in freely behaving rats after induction of a single unilateral cortical spreading depression in the somatosensory S1 cortex and sham cortical stimulation. Results Cortical spreading depression was followed by a dramatic broadband loss of interhemispheric functional connectivity in the visual and motor regions of the cortex. The hemispheric disconnection started after the end of the depolarization phase of cortical spreading depression, progressed gradually, and terminated by 5 min after initiation of cortical spreading depression. The network impairment had region- and frequency-specific characteristics and was more pronounced in the visual cortex than in the motor cortex. The period of impaired neural synchrony coincided with post-cortical spreading depression electrographic aberrant activation of the ipsilateral cortex and abnormal behavior. Conclusion The study provides the first evidence that unilateral cortical spreading depression induces a reversible loss of functional hemispheric connectivity in the cortex of awake animals. Given a critical role of long-distance cortical synchronization in sensory processing and sensorimotor integration, the post-cortical spreading depression breakdown of functional connectivity may contribute to neuropathological mechanisms of aura generation.