Abstract
Traumatic brain injury (TBI) is the leading cause of death and disability among children in the United States. Affected children will often suffer from emotional, cognitive and neurological impairments throughout life. In the controlled cortical impact (CCI) animal model of pediatric TBI (postnatal day 16–17) it was demonstrated that injury results in abnormal neuronal hypoactivity in the non-injured primary somatosensory cortex (S1). It materializes that reshaping the abnormal post-injury neuronal activity may provide a suitable strategy to augment rehabilitation. We tested whether high-frequency, non-invasive transcranial magnetic stimulation (TMS) delivered twice a week over a four-week period can rescue the neuronal activity and improve the long-term functional neurophysiological and behavioral outcome in the pediatric CCI model. The results show that TBI rats subjected to TMS therapy showed significant increases in the evoked-fMRI cortical responses (189%), evoked synaptic activity (46%), evoked neuronal firing (200%) and increases expression of cellular markers of neuroplasticity in the non-injured S1 compared to TBI rats that did not receive therapy. Notably, these rats showed less hyperactivity in behavioral tests. These results implicate TMS as a promising approach for reversing the adverse neuronal mechanisms activated post-TBI. Importantly, this intervention could readily be translated to human studies.
Highlights
Cellular level: Neuronal loss and white matter disruptions throughout the brain are often observed in human and animal models of TBI9–11; Abnormal neuronal plasticity that is manifested in increased seizure vulnerability[12,13,14], inappropriate neuronal rewiring[15], and atypical neuronal responses[11,16] are common post-injury occurrences
The latter was manifested by decreases in evoked neuronal responses that were measured with multi-unit activity (MUA), local field potential (LFP), and functional magnetic resonance imaging in neurons located in the contralateral, non-injured cortex
transcranial magnetic stimulation (TMS) has been proposed as a possible treatment for adult TBI26–28
Summary
Cellular level: Neuronal loss and white matter disruptions throughout the brain are often observed in human and animal models of TBI9–11; Abnormal neuronal plasticity that is manifested in increased seizure vulnerability[12,13,14], inappropriate neuronal rewiring[15], and atypical neuronal responses[11,16] are common post-injury occurrences. We have recently demonstrated in a rodent model of pediatric TBI, that injury results in long-term impaired plasticity in remote, non-injured cortical areas[11] This was exhibited by a significant decrease in the ability to induce long-term potentiation (LTP) which is one of the major cellular mechanisms of plasticity, as well as in neuronal hypoactivity. Acute and chronic neuronal hypoactivity following TBI was previously implicated as a contributing factor to post-traumatic epileptogenesis in rodent models[17,18,19] and may delay and prohibit normal circuit maturation and recovery during development[20], contributing to the neurological and cognitive deficits that TBI victims suffer Capitalizing on these studies, reshaping the abnormal post-injury neuronal activity materializes as a suitable strategy to augment rehabilitation. Biomarkers for neuronal activity in the form of expression of plasticity markers and electrophysiological and fMRI responses as well as behavioral testing were evaluated in the weeks after the therapy ended to assess the long-term functional outcome
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