RESUMEN
Background: How the prefrontal cortex (PFC) recovers its functionality following lesions remains a conundrum. Recent work has uncovered the importance of transient low-frequency oscillatory activity (LFO; < 4 Hz) for the recovery of an injured brain. We aimed to determine whether persistent cortical oscillatory dynamics contribute to brain capability to support 'normal life' following injury. Methods: In this 9-year prospective longitudinal study (08/2012-2021), we collected data from the patient E.L., a modern-day Phineas Gage, who suffered from lesions, impacting 11% of his total brain mass, to his right PFC and supplementary motor area after his skull was transfixed by an iron rod. A systematic evaluation of clinical, electrophysiologic, brain imaging, neuropsychological and behavioural testing were used to clarify the clinical significance of relationship between LFO discharge and executive dysfunctions and compare E.L.´s disorders to that attributed to Gage (1848), a landmark in the history of neurology and neuroscience. Findings: Selective recruitment of the non-injured left hemisphere during execution of unimanual right-hand movements resulted in the emergence of robust LFO, an EEG-detected marker for disconnection of brain areas, in the damaged right hemisphere. In contrast, recruitment of the damaged right hemisphere during contralateral hand movement, resulted in the co-activation of the left hemisphere and decreased right hemisphere LFO to levels of controls enabling performance, suggesting a target for neuromodulation. Similarly, transcranial magnetic stimulation (TMS), used to create a temporary virtual-lesion over E.L.'s healthy hemisphere, disrupted the modulation of contralateral LFO, disturbing behaviour and impairing executive function tasks. In contrast to Gage, reasoning, planning, working memory, social, sexual and family behaviours eluded clinical inspection by decreasing LFO in the delta frequency range during motor and executive functioning. Interpretation: Our study suggests that modulation of LFO dynamics is an important mechanism by which PFC accommodates neurological injuries, supporting the reports of Gage´s recovery, and represents an attractive target for therapeutic interventions. Funding: Fundação de Amparo Pesquisa Rio de Janeiro (FAPERJ), Universidade Federal do Rio de Janeiro (intramural), and Fiocruz/Ministery of Health (INOVA Fiocruz).
RESUMEN
OBJECTIVES/HYPOTHESIS: To examine the relationship between hearing and connexin 43, a dominant gap junctional protein in the central nervous system. STUDY DESIGN: Original research. METHODS: Connexin 43 heterozygous mice are used to assess its mutational effect on hearing. Results are compared to controls consisting of connexin 43, wild type and CBA/J mice. Hearing is assessed using auditory brainstem response and distortion product otoacoustic emissions tests. Distribution of connexin 43 in the organ of Corti and the retrocochlear auditory centers (eight nerve, cochlear nucleus, olivary complex, lateral lemniscus, inferior colliculus, respectively) is examined. Fluorescent markers are used to elucidate cell types. RESULTS: Mean click auditory brainstem response threshold for the young connexin 43 heterozygous mice (3-4 months) was 36.7 ± 12.6 dB compared to 25 ± 0 dB for control mice (P < 0.05). Mean threshold difference became more pronounced (68 ± 7.5 dB vs. 31 ± 2.2 dB) at 10 months (P < 0.05). Tonal auditory brainstem response testing showed elevated thresholds (>60 dB) at all frequencies (4-32 kHz) compared to the controls. Distortion product otoacoustic emissions (DPOAE) were present in all the mice, although the older connexin 43 heterozygous mice responded at higher thresholds. The pattern of connexin 43 immunoreactivity was distinctive from connexin 26 and 30, showing minimal presence in the organ of Corti but robustly present in the retrocochlear centers. CONCLUSION: Connexin 43 heterozygous mice demonstrated greater degree of hearing loss compared to age-matched controls. It is abundantly found in the retrocochlear auditory centers. The mechanism of hearing loss in these mice does not appear to be related to hair cell loss.