Modeling spinal locomotor circuits for movements in developing zebrafish.

Many spinal circuits dedicated to locomotor control have been identified in the developing zebrafish. How these circuits operate together to generate the various swimming movements during development remains to be clarified. In this study, we iteratively built models of developing zebrafish spinal circuits coupled to simplified musculoskeletal models that reproduce coiling and swimming movements. The neurons of the models were based upon morphologically or genetically identified populations in the developing zebrafish spinal cord. We simulated intact spinal circuits as well as circuits with silenced neurons or altered synaptic transmission to better understand the role of specific spinal neurons. Analysis of firing patterns and phase relationships helped to identify possible mechanisms underlying the locomotor movements of developing zebrafish. Notably, our simulations demonstrated how the site and the operation of rhythm generation could transition between coiling and swimming. The simulations also underlined the importance of contralateral excitation to multiple tail beats. They allowed us to estimate the sensitivity of spinal locomotor networks to motor command amplitude, synaptic weights, length of ascending and descending axons, and firing behavior. These models will serve as valuable tools to test and further understand the operation of spinal circuits for locomotion.

The spinal cord is a column of nerve tissue that connects the brain to the rest of the body in vertebrate animals. Nerve cells in the spinal cord, called neurons, help to control and coordinate the body's movements. As the spinal cord develops, new neurons are born and new connections are made between neurons and muscles, resulting in more coordinated and skillful movements as time goes on. Zebrafish, for example, display body-bending maneuvers called coils within 24 hours of the egg being fertilized. Next, bursts of swimming movements emerge, which are driven by sporadic tail beats. These tail maneuvers become more consistent as the fish develops, and eventually result in smooth movements called beat-and-glide swimming. The groups of spinal cord neurons that appear at each stage of zebrafish development have been characterized, but it remains unclear how newly formed circuits (groups of neurons recently connected to each other) work together to produce swimming maneuvers. To answer this question, Roussel et al. simulated changes in the spinal cord that help zebrafish acquire new swimming movements as they grow. The computer models encoded neural circuits based on cell populations identified in experimental studies, and replicated swimming behaviors that emerge during the first few days of zebrafish development. Simulations tested how specific neural circuits generate the characteristic swimming movements that represent key developmental milestones in zebrafish. The results showed that adding new neurons and more cell-to-cell connections led to increasingly sophisticated swimming maneuvers. As the zebrafish spinal cord matured, the fish were better able to control the pace and duration of their swimming movements. Roussel et al. also identified specific patterns of neural activity linked to particular maneuvers. For example, tail beats switch direction when neurons on one side of the spinal cord excite neurons on the opposite side. This activity, which becomes more rhythmic, also needs to be exquisitely timed to produce and coordinate the right motion. Roussel et al.'s modelling of developmental milestones in growing zebrafish provides insights into how neural networks control movement. The computer models are among the first to accurately reproduce swimming behaviors in developing zebrafish. More experimental data could be added to the models to capture the full range of early zebrafish movements, and to further investigate how maturing spinal cord circuits control swimming. Since zebrafish and mammals have many spinal neurons in common, further research may aid our understanding of movement disorders in humans.

Spatiotemporal Transition in the Role of Synaptic Inhibition to the Tail Beat Rhythm of Developing Larval Zebrafish.

Significant maturation of swimming in zebrafish (Danio rerio) occurs within the first few days of life when fish transition from coiling movements to burst swimming and then to beat-and-glide swimming. This maturation occurs against a backdrop of numerous developmental changes - neurogenesis, a transition from predominantly electrical to chemical-based neurotransmission, and refinement of intrinsic properties. There is evidence that spinal locomotor circuits undergo fundamental changes as the zebrafish transitions from burst to beat-and-glide swimming. Our electrophysiological recordings confirm that the operation of spinal locomotor circuits becomes increasingly reliant on glycinergic neurotransmission for rhythmogenesis governing the rhythm of tail beats. This transition occurred at the same time that we observed a change in rhythmicity of synaptic inhibition to spinal motoneurons (MNs). When we examined whether the transition from weakly to strongly glycinergic dependent rhythmogenesis occurred at a uniform pace across the length of the spinal cord, we found that this transition occurred earlier at caudal segments than at rostral segments of the spinal cord. Furthermore, while this rhythmogenic transition occurred when fish transition from burst swimming to beat-and-glide swimming, these two transitions were not interdependent. These results suggest that there is a developmental transition in the operation of spinal locomotor circuits that is gradually set in place in the spinal cord in a caudo-rostral temporal sequence.

An Analysis of Informed Consent Form Readability of Oncology Research Protocols.

Twenty-two percent of adults in the United States have only basic health literacy skills. We used a multiple linear regression model to identify associations between readability of informed consent documents with study sponsor, study phase, and approval year using a sample of 143 oncology studies at Ochsner Medical Center. The M ± SD Flesh-Kincaid Reading Grade Level (RGL) was 10.33 ± 0.85 and Flesh Reading Ease (FRE) was 52.89 ± 5.49. National Cancer Institute studies had a significantly lower mean RGL and FRE as compared with other sponsors (RGL 9.85 ± 0.66 vs. 10.72 ± 0.79; p value < .0001). Mean RGL did not differ by study phase. Future research should include assessment and improvement of the readability of informed consent documents.

Do N-of-1 Trials Need IRB Review?

There is no standard policy regarding the regulatory or institutional approval of N-of-1 trials in the United States. The objective of this study was to examine whether institutional review boards (IRBs) accredited by the Association for the Accreditation of Human Research Protection Programs (AAHRPP) consider N-of-1 trials as meeting the definition of human subjects research (45CFR46.102) and requiring IRB approval. A questionnaire was distributed via email to 170 AAHRPP-accredited IRBs in the United States. Responses were analyzed using statistical and qualitative methods. Nineteen of 59 respondents reported viewing N-of-1 trials as research. Twelve respondents reported having a policy regarding N-of-1 trials, and in all cases, such policies did not consider N-of-1 trials as meeting the definition of research. This topic deserves wider examination in the IRB literature and community to inform policies and guidance as N-of-1 trials become more common in the pursuit of personalized, precision medicine.