A Preliminary DTI Tractography Study of Developmental Neuroplasticity 5–15 Years After Early Childhood Traumatic Brain Injury

Plasticity is often implicated as a reparative mechanism when addressing structural and functional brain development in young children following traumatic brain injury (TBI); however, conventional imaging methods may not capture the complexities of post-trauma development. The present study examined the cingulum bundles and perforant pathways using diffusion tensor imaging (DTI) in 21 children and adolescents (ages 10–18 years) 5–15 years after sustaining early childhood TBI in comparison with 19 demographically-matched typically-developing children. Verbal memory and executive functioning were also evaluated and analyzed in relation to DTI metrics. Beyond the expected direction of quantitative DTI metrics in the TBI group, we also found qualitative differences in the streamline density of both pathways generated from DTI tractography in over half of those with early TBI. These children exhibited hypertrophic cingulum bundles relative to the comparison group, and the number of tract streamlines negatively correlated with age at injury, particularly in the late-developing anterior regions of the cingulum; however, streamline density did not relate to executive functioning. Although streamline density of the perforant pathway was not related to age at injury, streamline density of the left perforant pathway was significantly and positively related to verbal memory scores in those with TBI, and a moderate effect size was found in the right hemisphere. DTI tractography may provide insight into developmental plasticity in children post-injury. While traditional DTI metrics demonstrate expected relations to cognitive performance in group-based analyses, altered growth is reflected in the white matter structures themselves in some children several years post-injury. Whether this plasticity is adaptive or maladaptive, and whether the alterations are structure-specific, warrants further investigation.

The cholinergic system modulates negative BOLD responses in the prefrontal cortex once electrical perforant pathway stimulation triggers neuronal afterdischarges in the hippocampus

Repeated high-frequency pulse-burst stimulations of the rat perforant pathway elicited positive BOLD responses in the right hippocampus, septum and prefrontal cortex. However, when the first stimulation period also triggered neuronal afterdischarges in the hippocampus, then a delayed negative BOLD response in the prefrontal cortex was generated. While neuronal activity and cerebral blood volume (CBV) increased in the hippocampus during the period of hippocampal neuronal afterdischarges (h-nAD), CBV decreased in the prefrontal cortex, although neuronal activity did not decrease. Only after termination of h-nAD did CBV in the prefrontal cortex increase again. Thus, h-nAD triggered neuronal activity in the prefrontal cortex that counteracted the usual neuronal activity-related functional hyperemia. This process was significantly enhanced by pilocarpine, a mACh receptor agonist, and completely blocked when pilocarpine was co-administered with scopolamine, a mACh receptor antagonist. Scopolamine did not prevent the formation of the negative BOLD response, thus mACh receptors modulate the strength of the negative BOLD response.

Transcriptomic analysis of dorsal and ventral subiculum after induction of acute seizures by electric stimulation of the perforant pathway in rats

Preconditioning is a mechanism in which injuries induced by non-lethal hypoxia or seizures trigger cellular resistance to subsequent events. Norwood et al., in a 2010 study, showed that an 8-hour-long period of electrical stimulation of the perforant pathway in rats is required for the induction of hippocampal sclerosis. However, in order to avoid generalized seizures, status epilepticus (SE), and death, a state of resistance to seizures must be induced in the hippocampus by a preconditioning paradigm consisting of 2 daily 30-minute stimulation periods. Due to the importance of the subiculum in the hippocampal formation, this study aims to investigate differential gene expression patterns in the dorsal and ventral subiculum using RNA-sequencing, after induction of a preconditioning protocol by electrical stimulation of the perforant pathway. The dorsal (dSub) and ventral (vSub) subiculum regions were collected by laser-microdissection 24 hours after preconditioning protocol induction in rats. RNA sequencing was performed in a Hiseq 4000 platform, reads were aligned using the STAR and DESEq2 statistics package was used to estimate gene expression. We identified 1176 differentially expressed genes comparing control to preconditioned subiculum regions, 204 genes were differentially expressed in dSub and 972 in vSub. The gene ontology enrichment analysis showed that the most significant common enrichment pathway considering up-regulated genes in dSub and vSub was Cholesterol Biosynthesis. In contrast, the most significant enrichment pathway considering down-regulated genes in vSub was Axon guidance. Our results indicate that preconditioning induces synaptic reorganization, increased cholesterol metabolism, and astrogliosis in both dSub and vSub. Both regions also presented a decrease in glutamatergic transmission, an increase in complement system activation, and increased in GABAergic transmission. The down-regulation of proapoptotic and axon guidance genes in the ventral subiculum suggests that preconditioning induces a neuroprotective environment in this region.