ABSTRACT
The human cortex contains inhibitory interneurons derived from the medial ganglionic eminence (MGE), a germinal zone in the embryonic ventral forebrain. How this germinal zone generates sufficient interneurons for the human brain remains unclear. We found that the human MGE (hMGE) contains nests of proliferative neuroblasts with ultrastructural and transcriptomic features that distinguish them from other progenitors in the hMGE. When dissociated hMGE cells are transplanted into the neonatal mouse brain, they reform into nests containing proliferating neuroblasts that generate young neurons that migrate extensively into the mouse forebrain and mature into different subtypes of functional interneurons. Together, these results indicate that the nest organization and sustained proliferation of neuroblasts in the hMGE provide a mechanism for the extended production of interneurons for the human forebrain.
Subject(s)
Interneurons/physiology , Median Eminence/embryology , Neural Stem Cells/physiology , Neurogenesis , Prosencephalon/cytology , Animals , Animals, Newborn , Cell Movement , Cell Proliferation , Cerebral Cortex/cytology , Cerebral Cortex/embryology , Cerebral Cortex/growth & development , GABAergic Neurons/cytology , GABAergic Neurons/physiology , Gene Expression Profiling , Gestational Age , Humans , Interneurons/cytology , Median Eminence/cytology , Median Eminence/growth & development , Mice , Neural Stem Cells/transplantation , Prosencephalon/embryology , Prosencephalon/growth & development , Transplantation, HeterologousABSTRACT
BACKGROUND: Changes in patient-reported seizure frequencies are the gold standard used to test efficacy of new treatments in randomized controlled trials (RCTs). Recent analyses of patient seizure diary data suggest that the placebo response may be attributable to natural fluctuations in seizure frequency, though the evidence is incomplete. Here we develop a data-driven statistical model and assess the impact of the model on interpretation of placebo response. METHODS: A synthetic seizure diary generator matching statistical properties seen across multiple epilepsy diary datasets was constructed. The model was used to simulate the placebo arm of 5000 RCTs. A meta-analysis of 23 historical RCTs was compared to the simulations. RESULTS: The placebo 50 %-responder rate (RR50) was 27.3 ± 3.6 % (simulated) and 21.1 ± 10.0 % (historical). The placebo median percent change (MPC) was 22.0 ± 6.0 % (simulated) and 16.7 ± 10.3 % (historical). CONCLUSIONS: A statistical model of daily seizure count generation which incorporates quantities related to the natural fluctuations of seizure count data produces a placebo response comparable to those seen in historical RCTs. This model may be useful in better understanding the seizure count fluctuations seen in patients in other clinical settings.
