Non-technical summary It is not well understood how all of the connections among neurons required for the brain to process information are established during development. It has recently become apparent that waves of spontaneous electrical activity spread across large groups of neurons during early brain development and that these waves of activity are crucial for correct development of brain circuitry. In this paper, we show that waves of spontaneous electrical activity propagate across the mouse cerebral cortex, beginning on the day before birth and continuing through the first 12 postnatal days. These waves are initiated at specific locations in the cortex, which do not change during the period of wave generation. Identity of the neurons that initiate the waves, however, does change during this time. This work indicates that even though spontaneous electrical activity occurs during a short contiguous period of development, the mechanisms underlying that activity change.Abstract Waves of spontaneous electrical activity propagate across many regions of the central nervous system during specific stages of early development. The patterns of wave propagation are critical in the activation of many activity-dependent developmental programs. It is not known how the mechanisms that initiate and propagate spontaneous waves operate during periods in which major changes in neuronal structure and function are taking place. We have recently reported that spontaneous waves of activity propagate across the neonatal mouse cerebral cortex and that these waves are initiated at pacemaker sites in the septal nucleus and ventral cortex. Here we show that spontaneous waves occur between embryonic day 18 (E18) and postnatal day 12 (P12), and that during that period they undergo major changes in transmitter dependence and propagation patterns. At early stages, spontaneous waves are largely GABA dependent and are mostly confined to the septum and ventral cortex. As development proceeds, wave initiation depends increasingly on AMPA-type glutamate receptors, and an ever increasing fraction of waves propagate into the dorsal cortex. The initiation sites and restricted propagation of waves at early stages are highly correlated with the position of GABAergic neurons in the cortex. The later switch to a glutamate-based mechanism allows propagation of waves into the dorsal cortex, and appears to be a compensatory mechanism that ensures continued wave generation even as GABA transmission becomes inhibitory. Abbreviations E, embryonic day; P, postnatal day; PFA, paraformaldehyde.

Spontaneous waves of activity that propagate across large structures during specific developmental stages play central roles in CNS development. To understand the genesis and functions of these waves, it is critical to understand the spatial and temporal patterns of their propagation. We recently reported that spontaneous waves in the neonatal cerebral cortex originate from a ventrolateral pacemaker region. We have now analyzed a large number of spontaneous waves using calcium imaging over the entire area of coronal slices from E18-P1 mouse brains. In all waves, the first cortical region active is this ventrolateral pacemaker. In half of the waves, however, the cortical pacemaker activity is itself triggered by preceding activity in the septal nuclei. Most waves are restricted to the septum and/or ventral cortex, with only some invading the dorsal cortex or the contralateral hemisphere. Waves fail to propagate at very stereotyped locations at the boundary between ventral and dorsal cortex and at the dorsal midline. Waves that cross these boundaries pause at these same locations. Waves at these stages are blocked by both picrotoxin and CNQX, indicating that both GABA(A) and AMPA receptors are involved in spontaneous activity.

Background The majority of patients with Crohn’s disease (CD) will not achieve endoscopic remission on current therapy. Addition of tofacitinib to biologics may improve remission rates. Methods We retrospectively assessed safety and clinical and endoscopic effectiveness of off-label tofacitinib and biologics for CD. Results We identified 19 patients treated with tofacitinib and a biologic for refractory CD between 2017 and 2019. Tofacitinib was added for luminal disease on colonoscopy (n = 13), luminal disease on capsule (n = 3), and pyoderma gangrenosum (n = 3). The mean age was 41.2 years (28–62), mean disease was duration 16.9 years (6–36), and prior exposure to biologics was a median of 4 (1–6). Mean treatment duration was 9.6 months (SD, 3.3). Adverse events (AEs) were reported in 36.8% of patients, most commonly minor infection or CD flare, and no patients had a serious AE; 80.0% (n = 8) achieved clinical response, and 60.0% (n = 6) achieved clinical remission based on Harvey-Bradshaw Index. Endoscopic improvement occurred in 54.5% (n = 6), endoscopic remission in 18.2% (n = 2), and endoscopic healing in 18.2% (n = 2) of patients. Mean Simple Endoscopic Score in CD significantly improved from 13.6 ± 5.2 to 6.5 ± 4.0 after treatment (P < .01). Conclusions In patients treated with tofacitinib in combination with a biologic, no new safety signals were observed. Combination tofacitinib and a biologic was effective in achieving clinical and endoscopic improvement in some patients with severe, refractory CD, although a larger sample size is needed to further assess the efficacy and long-term safety of this treatment strategy.

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