Cortical Reorganization after Experimental Traumatic Brain Injury: A Functional Autoradiography Study

Abstract

Cortical sensorimotor (SM) maps are a useful readout for providing a global view of the underlying status of evoked brain function, as well as a gross overview of ongoing mechanisms of plasticity. Recent evidence in the rat controlled cortical impact (CCI) injury model shows that the ipsilesional (injured) hemisphere is temporarily permissive for axon sprouting. This would predict that size and spatial alterations in cortical maps may occur much earlier than previously tested and that they might be useful as potential markers of the postinjury plasticity period as well as indicators of outcome. We investigated the evolution of changes in brain activation evoked by affected hindlimb electrical stimulation at 4, 7, and 30 days following CCI or sham injury over the hindlimb cortical region of adult rats. [(14)C]-iodoantipyrine autoradiography was used to quantitatively examine the local cerebral blood flow changes in response to hindlimb stimulation as a marker for neuronal activity. The results show that although ipsilesional hindlimb SM activity was persistently depressed from 4 days, additional novel regions of ipsilesional activity appeared concurrently within SM barrel and S2 regions as well as posterior auditory cortex. Simultaneously with this was the appearance of evoked activity within the intact, contralesional cortex that was maximal at 4 and 7 days, compared to stimulated sham-injured rats, where activation was solely unilateral. By 30 days, however, contralesional activation had greatly subsided and existing ipsilesional activity was enhanced within the same novel cortical regions that were identified acutely. These data indicate that significant reorganization of the cortical SM maps occurs after injury that evolves with a particular postinjury time course. We discuss these data in terms of the known mechanisms of plasticity that are likely to underlie these map changes, with particular reference to the differences and similarities that exist between rodent models of stroke and traumatic brain injury.

Disconnection and hyper-connectivity underlie reorganization after TBI: A rodent functional connectomic analysis

“…Therefore in support of the former theory that reduced CPL indicates enhanced local connectivity after injury, increased neuronal correlated activity in the monkey was found to be limited only to regions undergoing reorganization following induction of cortical map plasticity (Dinse et al, 1993). Similar correlated activity changes, albeit at the level of BOLD and not direct neuronal activity was seen in the current data within pericontusional and homotopic cortex, regions that have been shown to undergo significant changes in map plasticity (Harris et al, 2013a,b). These data would therefore concur with a hypothesis that TBI results in increased level of local connectedness primarily within regions undergoing reorganization as a compensatory measure to offset the loss in functional homeostasis.…”

“…In agreement with our initial hypothesis, the deficits in inter-hemispheric and subcortical functional connectivity that we have shown in the present work are thus entirely expected, and generally consistent with the known structural alterations in transcallosal and cortical–thalamic disruptions after CCI injury (Mac Donald et al, 2007; Harris et al, 2009b) and in other rodent models of TBI (Donovan et al, 2014; Stemper et al, 2014; Holschneider et al, 2013). Similarly, the pericontusional deficits in functional connectivity within the ipsilateral sensorimotor regions are also congruent with both the significant alterations in fore- and hind-limb cortical somatotopic map organization (Harris et al, 2013a,b) as well as limb reaching deficits in this model (Harris et al, 2010a). Current research on whether structure and function are necessarily linked in the naïve brain is controversial and ultimately may depend on the model used for correlation (Abdelnour et al, 2014), the methodology used for analysis, or the presence or absence of CNS disease.…”

“…Once again this is not an unexpected finding given the contralateral shift in the affected forelimb cortical map that occurs after injury in this model (Harris et al, 2003). Within the confines of the current data this effect was maximal at 14 days and this temporally corresponds to the development of contralateral hyper-excitability in this model (Verley et al, 2013).…”

“…This is an area that consistently survives within the pericontused region in this model and which is a site for significant spontaneous sprouting after injury (Harris et al, 2010b). The likelihood of a close structural-function relationship, at least within this region is further supported by data in the same model showing that when axonal sprouting is enhanced through manipulation of the extracellular environment after injury, newly spouting axons are functionally active within the previously injured forelimb circuit (Harris et al, 2013a,b). …”

“…Altered functional connectivity has also been shown after TBI, clinically (Nakamura et al, 2009; Kasahara et al, 2010, 2011; Mayer et al, 2011; Stevens et al, 2012; Pandit et al, 2013; Zhou et al, 2013; Han et al, 2014; Hillary et al, 2014) but with few studies in experimental models (Holschneider et al, 2013; Mishra et al, 2014) and no rsfMRI studies in the well-known controlled cortical impact (CCI) injury model of TBI where we have shown some degree of structural reorganization (Harris et al, 2009a) as well as functional reorganization (Harris et al, 2013a,b) that generally coincides with spontaneous recovery in this model.…”