Stroke is the leading cause of disability in the US, with an annual incidence of 780,000 and over 5.8 million survivors. Most stroke survivors experience a limited degree of spontaneous recovery in the first weeks to months following injury, but this recovery is often incomplete. For decades animal models have implicated cellular and molecular events including synaptogenesis, dendritic and axonal sprouting, as being important for recovery. While it was believed that these cellular programs are involved in the formation of new connections important for recovery, more recent systems-level analysis have revealed how brain-network plasticity may be involved in recovery. Focal ischemia results in the acute loss of function to modalities mapped onto infarcted brain tissue. Interestingly, behavioral recovery occurs as lost modalities remap onto the peri-infarct cortex suggesting remapping may be critical for behavioral recovery. In addition to examining local peri-lesional changes, more recent work has examined alterations in global brain networks following stroke. By examining patterns of neural synchronization in the resting state brain, termed functional connectivity (fc, it is clear that global patterns of functional connectivity are altered following focal ischemia. Immediately following ischemic stroke, weak interhemispheric homotopic fc (which is robust in healthy individuals) predicted poor motor and attentional performance in humans. In a rat focal ischemia recovery model, interhemspheric homotopic fc decreased following injury and recovered in parallel with sensorimotor behavioral performance. These studies suggest that remapping may involve long range network changes. Indeed, molecular profiling has revealed synaptogenesis and neuroplasticity occurring in the contralesional cortex after injury. However, the role the contralesional influence on remapping and recovery is not well defined. There is some evidence that homotopic interhemispheric fc may reflect the excitatory/inhibitory balance between homoptic cortical regions and that this balance is important for normal unilateral functionality 15. Ischemic injury is thought to disrupt network architecture and result in increase inhibitory tone in the perilesional cortex that exacerbates deficits and limits recovery. This coul explain the potential efficacy of repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) to restore interhemispheric balance and improve sensorimotor function. However, there are conflicting reports in humans and animal models regarding the impact of contralateral homotopic influence on functional recovery, and it is unclear if interhemispheric communication benefits or inhibits recovery. Animal models may enable a better understanding of contralesional cortex physiology after ischemia allowing better targeting of therapies for stroke patients. In this grant, I will test the hypothesis that interhemispheric functional connectivity directly influences cortical remapping and behavioral recovery after focal ischemia. To visualize cortical maps and fc in a mouse focal ischemia model, I will utilize imaging modalitiy, fc optical intrinsic signal (fcOIS) to address the followig aims:
Aim 1 : To determine the relationship between interhemispehric fc, cortical remapping, and behavioral recovery following focal ischemia in mice.
Aim 2 : To determine the influence of transcallosal interhemispheric connectivity on cortical remapping and behavioral recovery following focal ischemia.
Spontaneous recovery following focal ischemia is poorly understood. There has been recent interest in global brain influences on local repair. Perilesional topographic remapping of lost modalities occurs following infarction, and more recent work has shown that the neuronal signaling from the contralesional cortex may influence this remapping. However, it is unclear if the contralesional cortex aids or impairs remapping and recovery. Taking advantage of novel functional imaging capability in mice, this research project will advance our understanding of interhemispheric communication in cortical remapping and behavioral recovery following focal ischemia. This work may lead to novel neurorehabilitiation therapies directed at the contralesional hemisphere in patients suffering disability after stroke.
| Mitra, Anish; Kraft, Andrew; Wright, Patrick et al. (2018) Spontaneous Infra-slow Brain Activity Has Unique Spatiotemporal Dynamics and Laminar Structure. Neuron 98:297-305.e6 |
| Kraft, Andrew W; Mitra, Anish; Bauer, Adam Q et al. (2017) Visual experience sculpts whole-cortex spontaneous infraslow activity patterns through an Arc-dependent mechanism. Proc Natl Acad Sci U S A 114:E9952-E9961 |
| Yan, Ping; Zhu, Alec; Liao, Fan et al. (2015) Minocycline reduces spontaneous hemorrhage in mouse models of cerebral amyloid angiopathy. Stroke 46:1633-1640 |
