Prescription trends in anti-seizure medications for adult patients with epilepsy in Japan: A retrospective cohort study using the database of health insurance claims between 2015 and 2019.

OBJECTIVE: To investigate whether newer anti-seizure medications (ASMs) are widely prescribed for a range of adult patients in Japan, including patients with previously and newly diagnosed epilepsy, or with focal and generalized epilepsies. METHODS: A retrospective cohort study was conducted using the Japanese insurance claims database including 8.4 million people to identify adults (≥16 years of age) with epilepsy diagnosis code identified between January 2015 and December 2018. Patients were included in the prevalent population if epilepsy was already diagnosed at baseline, and in the incident population if prior baseline data for at least 12 months included no epilepsy diagnosis code or ASM prescription. Patients were followed up from the month when the initial oral ASM was prescribed for up to 4 years until the end of 2019 as long as at least one ASM was prescribed. Proportions of prescribed oral ASMs were analyzed by population with epilepsy (prevalent vs. incident) and classification (focal vs. generalized). Anti-seizure medications were classified into older vs. newer ASMs according to the date of approval before and after 1990, respectively. RESULTS: A total of 24,691 patients fulfilled the eligibility criteria for the analysis. Of these, 21,046 and 3,645 were included in the prevalent and incident populations, respectively. The proportion of older ASMs significantly decreased, whereas the proportion of newer ASMs significantly increased (p < 0.0001) during the study period. This trend was more apparent in the population with incident epilepsy than in that with prevalent epilepsy, and was also apparent in the subgroup of focal epilepsy, but not in that of generalized epilepsy. Levetiracetam was the most frequently prescribed of the newer ASMs. CONCLUSION: Newer ASMs became more widely prescribed throughout the study period in populations with both prevalent and incident epilepsies, as well as the subpopulation with focal epilepsy. The advantages of newer ASMs such as better safety profiles may have led to the increasing proportions of prescriptions and newer ASMs may increase the treatment options for patients.

Similarity in Neuronal Firing Regimes across Mammalian Species.

UNLABELLED: The architectonic subdivisions of the brain are believed to be functional modules, each processing parts of global functions. Previously, we showed that neurons in different regions operate in different firing regimes in monkeys. It is possible that firing regimes reflect differences in underlying information processing, and consequently the firing regimes in homologous regions across animal species might be similar. We analyzed neuronal spike trains recorded from behaving mice, rats, cats, and monkeys. The firing regularity differed systematically, with differences across regions in one species being greater than the differences in similar areas across species. Neuronal firing was consistently most regular in motor areas, nearly random in visual and prefrontal/medial prefrontal cortical areas, and bursting in the hippocampus in all animals examined. This suggests that firing regularity (or irregularity) plays a key role in neural computation in each functional subdivision, depending on the types of information being carried. SIGNIFICANCE STATEMENT: By analyzing neuronal spike trains recorded from mice, rats, cats, and monkeys, we found that different brain regions have intrinsically different firing regimes that are more similar in homologous areas across species than across areas in one species. Because different regions in the brain are specialized for different functions, the present finding suggests that the different activity regimes of neurons are important for supporting different functions, so that appropriate neuronal codes can be used for different modalities.

Stepwise synaptic plasticity events drive the early phase of memory consolidation.

Memories are initially encoded in the hippocampus but subsequently consolidated to the cortex. Although synaptic plasticity is key to these processes, its precise spatiotemporal profile remains poorly understood. Using optogenetics to selectively erase long-term potentiation (LTP) within a defined temporal window, we found that distinct phases of synaptic plasticity play differential roles. The first wave acts locally in the hippocampus to confer context specificity. The second wave, during sleep on the same day, organizes these neurons into synchronously firing assemblies. Finally, LTP in the anterior cingulate cortex during sleep on the second day is required for further stabilization of the memory. This demonstrates the precise localization, timing, and characteristic contributions of the plasticity events that underlie the early phase of memory consolidation.

The Cellular and Mechanical Basis for Response Characteristics of Identified Primary Afferents in the Rat Vibrissal System.

Compared to our understanding of the response properties of receptors in the auditory and visual systems, we have only a limited understanding of the mechanoreceptor responses that underlie tactile sensation. Here, we exploit the stereotyped morphology of the rat vibrissal (whisker) array to investigate coding and transduction properties of identified primary tactile afferents. We performed in vivo intra-axonal recording and labeling experiments to quantify response characteristics of four different types of identified mechanoreceptors in the vibrissal follicle: ring-sinus Merkel; lanceolate; clublike; and rete-ridge collar Merkel. Of these types, only ring-sinus Merkel endings exhibited slowly adapting properties. A weak inverse relationship between response magnitude and onset response latency was found across all types. All afferents exhibited strong "angular tuning," i.e., their response magnitude and latency depended on the whisker's deflection angle. Although previous studies suggested that this tuning should be aligned with the angular location of the mechanoreceptor in the follicle, such alignment was observed only for Merkel afferents; angular tuning of the other afferent types showed no clear alignment with mechanoreceptor location. Biomechanical modeling suggested that this tuning difference might be explained by mechanoreceptors' differential sensitivity to the force directed along the whisker length. Electron microscopic investigations of Merkel endings and lanceolate endings at the level of the ring sinus revealed unique anatomical features that may promote these differential sensitivities. The present study systematically integrates biomechanical principles with the anatomical and morphological characterization of primary afferent endings to describe the physical and cellular processing that shapes the neural representation of touch.

Shaping somatosensory responses in awake rats: cortical modulation of thalamic neurons.

Massive corticothalamic afferents originating from layer 6a of primary sensory cortical areas modulate sensory responsiveness of thalamocortical neurons and are pivotal for shifting neuronal firing between burst and tonic modes. The influence of the corticothalamic pathways on the firing mode and sensory gain of thalamic neurons has only been extensively examined in anesthetized animals, but has yet to be established in the awake state. We made lesions of the rat barrel cortex and on the following day recorded responses of single thalamocortical and thalamic reticular neurons to a single vibrissal deflection in the somatosensory system during wakefulness. Our results showed that the cortical lesions shifted the response of thalamic neurons towards bursting, elevated the response probability and the gain of thalamocortical neurons, predominantly of recurring responses. In addition, after the lesions, the spontaneous activities of the vibrissa-responsive thalamic neurons, but not those of vibrissa-unresponsive cells, were typified by waxing-and-waning spindle-like rhythmic spiking with frequent bursting. In awake rats with intact cortex, identified layer 6a corticothalamic neurons responded to a single vibrissal deflection with short latencies that matched those of layer 4 neurons, strongly suggesting the existence of an immediate corticothalamic feedback. The present results show the importance of corticothalamic neurons in shaping thalamic activities during wakefulness.

The Roles of Cortical Slow Waves in Synaptic Plasticity and Memory Consolidation.

Sleep plays important roles in sensory and motor memory consolidation. Sleep oscillations, reflecting neural population activity, involve the reactivation of learning-related neurons and regulate synaptic strength and, thereby affect memory consolidation. Among sleep oscillations, slow waves (0.5-4 Hz) are closely associated with memory consolidation. For example, slow-wave power is regulated in an experience-dependent manner and correlates with acquired memory. Furthermore, manipulating slow waves can enhance or impair memory consolidation. During slow wave sleep, inter-areal interactions between the cortex and hippocampus (HC) have been proposed to consolidate declarative memory; however, interactions for non-declarative (HC-independent) memory remain largely uninvestigated. We recently showed that the directional influence in a slow-wave range through a top-down cortical long-range circuit is involved in the consolidation of non-declarative memory. At the synaptic level, the average cortical synaptic strength is known to be potentiated during wakefulness and depressed during sleep. Moreover, learning causes plasticity in a subset of synapses, allocating memory to them. Sleep may help to differentiate synaptic strength between allocated and non-allocated synapses (i.e., improving the signal-to-noise ratio, which may facilitate memory consolidation). Herein, we offer perspectives on inter-areal interactions and synaptic plasticity for memory consolidation during sleep.

Context-dependent representation of reinforcement in monkey amygdala.

It has been reported that neurons in the amygdala respond to visual cues that predict reward and aversive outcomes. However, it remains unclear whether the representation of reinforcement in the amygdala depends on the relative preference for an outcome compared with another simultaneously available outcome. In this study, we introduced three reinforcements (juice, water, and electrical stimulus) and used two of them in one experimental block. Of 52 neurons that showed cue responses reflecting the outcome information, 23% of amygdala neurons coded preferred outcomes, whereas only one neuron coded nonpreferred outcomes. These proportions of amygdala were significantly different from those of the orbitofrontal cortex, which had both types of neurons.