Naohisa Miyakawa

Area TE is required for normal learning of visual categories based on perceptual similarity. To evaluate whether category learning changes neural activity in area TE, we trained two monkeys (both male) implanted with multielectrode arrays to categorize natural images of cats and dogs. Neural activity during a passive viewing task was compared pre- and post-training. After the category training, the accuracy of abstract category decoding improved. Single units became more category selective, the proportion of single units with category selectivity increased, and units sustained their category-specific responses for longer. Visual category learning thus appears to enhance category separability in area TE by driving changes in the stimulus selectivity of individual neurons and by recruiting more units to the active network.

Objectives: We evaluated the medication selection and clinical characteristics of rheumatoid arthritis (RA) patients who started treatment with/without methotrexate (using biologic disease-modifying antirheumatic drugs or Janus kinase inhibitors [JAKi] instead) in Japan. Methods: Using a Japanese hospital-based administrative claims database, RA patients who received treatment (abatacept, interleukin-6 receptor inhibitor [IL-6Ri], tumor necrosis factor inhibitor, or JAKi) between 1/January/2015 and 31/December/2019 were enrolled. Results: In total 19,301 patients were included (10,530 receiving methotrexate; 8,771 not receiving methotrexate within 60 days of the first treatment). Mean ages at diagnosis were 60.7 and 65.9 years in the methotrexate and non-methotrexate groups (p p Conclusions: Methotrexate is used less frequently among older Japanese RA patients or those with comorbidities. Abatacept is the most frequently used drug, followed by IL-6Ri, in patients not using methotrexate at the treatment start.

Epilepsy is a disorder in which abnormal neuronal hyperexcitation causes several types of seizures. Because pharmacological and surgical treatments occasionally interfere with normal brain function, a more focused and on-demand approach is desirable. Here we examined the efficacy of a chemogenetic tool—designer receptors exclusively activated by designer drugs (DREADDs)—for treating focal seizure in a nonhuman primate model. Acute infusion of the GABA_A receptor antagonist bicuculline into the forelimb region of unilateral primary motor cortex caused paroxysmal discharges with twitching and stiffening of the contralateral arm, followed by recurrent cortical discharges with hemi- and whole-body clonic seizures in two male macaque monkeys. Expression of an inhibitory DREADD (hM4Di) throughout the seizure focus, and subsequent on-demand administration of a DREADD-selective agonist, rapidly suppressed the wide-spread seizures. These results demonstrate the efficacy of DREADDs for attenuating cortical seizure in a nonhuman primate model.

Imaging-guided selective silencing of the prefronto-caudate/thalamus pathways reveals their distinct roles in cognitive functions.

The chemogenetic technology designer receptors exclusively activated by designer drugs (DREADDs) afford remotely reversible control of cellular signaling, neuronal activity and behavior. Although the combination of muscarinic-based DREADDs with clozapine-N-oxide (CNO) has been widely used, sluggish kinetics, metabolic liabilities and potential off-target effects of CNO represent areas for improvement. Here, we provide a new high-affinity and selective agonist deschloroclozapine (DCZ) for muscarinic-based DREADDs. Positron emission tomography revealed that DCZ selectively bound to and occupied DREADDs in both mice and monkeys. Systemic delivery of low doses of DCZ (1 or 3 μg per kg) enhanced neuronal activity via hM3Dq within minutes in mice and monkeys. Intramuscular injections of DCZ (100 μg per kg) reversibly induced spatial working memory deficits in monkeys expressing hM4Di in the prefrontal cortex. DCZ represents a potent, selective, metabolically stable and fast-acting DREADD agonist with utility in both mice and nonhuman primates for a variety of applications.

The chemogenetic technology Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) affords remotely reversible control of cellular signaling, neuronal activity and behavior. Although the combination of muscarinic-based DREADDs with clozapine-N-oxide (CNO) has been widely used, sluggish kinetics, metabolic liabilities, and potential off-target effects of CNO represent areas for improvement. Here we provide a new high affinity and selective agonist deschloroclozapine (DCZ) for muscarinic-based DREADDs. Positron emission tomography revealed that DCZ selectively bound to and occupied DREADDs in both mice and monkeys. Systemic delivery of low doses of DCZ (1 or 3 μg/kg) enhanced neuronal activity via hM₃Dq within minutes in mice and monkeys. Intramuscular injections of DCZ (100 μg/kg) reversibly induced spatial working memory deficits in monkeys expressing hM₄Di in the prefrontal cortex. DCZ represents the most potent, selective, metabolically stable and fast-acting DREADD agonist reported with utility in both mice and non-human primates for a variety of applications.

Natural sound is composed of various frequencies. Although the core region of the primate auditory cortex has functionally defined sound frequency preference maps, how the map is organized in the auditory areas of the belt and parabelt regions is not well known. In this study, we investigated the functional organizations of the core, belt, and parabelt regions encompassed by the lateral sulcus and the superior temporal sulcus in the common marmoset (Callithrix jacchus). Using optical intrinsic signal imaging, we obtained evoked responses to band-pass noise stimuli in a range of sound frequencies (0.5–16 kHz) in anesthetized adult animals and visualized the preferred sound frequency map on the cortical surface. We characterized the functionally defined organization using histologically defined brain areas in the same animals. We found tonotopic representation of a set of sound frequencies (low to high) within the primary (A1), rostral (R), and rostrotemporal (RT) areas of the core region. In the belt region, the tonotopic representation existed only in the mediolateral (ML) area. This representation was symmetric with that found in A1 along the border between areas A1 and ML. The functional structure was not very clear in the anterolateral (AL) area. Low frequencies were mainly preferred in the rostrotemplatal (RTL) area, while high frequencies were preferred in the caudolateral (CL) area. There was a portion of the parabelt region that strongly responded to higher sound frequencies (>5.8 kHz) along the border between the rostral parabelt (RPB) and caudal parabelt (CPB) regions.

The inferior temporal cortex (ITC) contains neurons selective to multiple levels of visual categories. However, the mechanisms by which these neurons collectively construct hierarchical category percepts remain unclear. By comparing decoding accuracy with simultaneously acquired electrocorticogram (ECoG), local field potentials (LFPs), and multi-unit activity in the macaque ITC, we show that low-frequency LFPs/ECoG in the early evoked visual response phase contain sufficient coarse category (e.g., face) information, which is homogeneous and enhanced by spatial summation of up to several millimeters. Late-induced high-frequency LFPs additionally carry spike-coupled finer category (e.g., species, view, and identity of the face) information, which is heterogeneous and reduced by spatial summation. Face-encoding neural activity forms a cluster in similar cortical locations regardless of whether it is defined by early evoked low-frequency signals or late-induced high-gamma signals. By contrast, facial subcategory-encoding activity is distributed, not confined to the face cluster, and dynamically increases its heterogeneity from the early evoked to late-induced phases. These findings support a view that, in contrast to the homogeneous and static coarse category-encoding neural cluster, finer category-encoding clusters are heterogeneously distributed even outside their parent category cluster and dynamically increase heterogeneity along with the local cortical processing in the ITC.