搜索结果：Journal of neurophysiology

During explicit sequence learning (ESL), micro-offline gains (MOGS) occur during brief rest periods. MOGS are calculated as the difference in sequence speed between the first correct sequence of one trial and the last sequence of the preceding trial. To date, all studies evaluating MOGS have calculated sequence speed from the execution time that occurs between keypresses, but this approach ignores potential contributions from motor preparation that occur before the first keypress. Given that ESL relies on both premovement motor planning and subsequent motor execution, we hypothesized that ignoring motor preparation time neglects a critical component of skill acquisition, potentially misrepresenting the true magnitude of MOGS. To test this, we calculated MOGS with and without preparation time in 30 adults who performed an ESL task. The dataset used for this analysis was obtained as part of a larger study to evaluate the effects of pretrial temporal predictability on ESL performance and learning by controlling the predictability of trial onset. Our results show that including preparation time flipped MOGS from positive to negative and significantly increased the positive correlation between early learning and a gold-standard ESL metric: the number of correct sequences performed. Our results suggest that preparation time should be incorporated into MOGS calculations and that excluding it overestimates micro-offline learning.NEW & NOTEWORTHY Current standards quantify micro-offline gains in terms of execution speed, entirely ignoring motor preparation time. If these gains reflect true learning, they should persist when accounting for premotor planning. Our results demonstrate a striking reversal: integrating motor preparation time completely flips micro-offline gains to micro-offline losses. Furthermore, by correcting this methodological artifact, our study provides a behaviorally validated, necessary framework for future studies investigating micro-offline gains.

Functional calcium imaging with genetically encoded calcium indicators (GECIs) has become a cornerstone of preclinical in vivo circuit analysis. Yet, due to light scattering, two-photon (2P) functional calcium imaging has been largely confined to superficial cortical layers in rodent models. Three-photon (3P) excitation offers deeper penetration due to reduced scattering of longer excitation wavelengths, but lower repetition rates of 3P laser systems impose a significant limitation on temporal resolution. Therefore, 3P calcium imaging of cortical microcircuits is still in its infancy. In this study, we performed a back-to-back comparison of 2P and 3P functional calcium imaging in the visual cortex of awake, head-fixed mice. We assessed the efficacy of 3P imaging to capture the local functional microcircuit dynamics in the visual cortex. 3P imaging not only revealed neuronal somata and neuropil in layers V/VI with robust morphological SNR but also generated label-free contrast of the blood vessels via third harmonic generation. Functionally, in superficial layers, a comparable functional architecture was assessed with both methods; while 3P detected lower firing frequencies, the underlying circuit dynamics, such as functional connectivity, remained consistent with 2P recordings. Notably in layers V/VI, while 2P failed to resolve the functional circuit state, with 3P a functional readout of neuronal circuits became achievable. These results demonstrate that, despite its current temporal limitations, 3P calcium imaging can reliably capture the functional architecture across all cortical layers, providing unmatched depth penetration and vascular contrast.NEW & NOTEWORTHY This study explores the capability of three-photon functional imaging to resolve functional cortical architecture in mice. By a quantitative, back-to-back comparison in awake head-fixed mice, we demonstrate that three-photon imaging is equally capable compared to two-photon imaging at superficial layers (II/III) and allows functional assessment of deep cortical layers (V/VI), beyond the reach of conventional two-photon microscopy.

Polytherapy in epilepsy is associated with a higher risk of adverse events, poorer adherence, and impaired quality of life. Thus, reducing concomitant antiseizure medications (ASMs) and/or using a newly added ASM such as cenobamate with only 1 other ASM (i.e., bitherapy) may improve tolerability. This post hoc analysis evaluated the impact of the number and type of concomitant ASMs on treatment-emergent adverse events (TEAEs) that occurred in the cenobamate C021 open-label clinical trial. Adjunctive cenobamate was initiated in adults (aged 18-70 years) with uncontrolled focal seizures who were taking 1 to 3 ASMs. The number and type of concomitant ASMs and the frequency, severity, and time to resolution of TEAEs were assessed. The most frequently reported (≥ 10%) TEAEs in the overall population (n = 1340) were somnolence, dizziness, fatigue, and headache. The percentage of patients with dizziness, somnolence, and fatigue increased with increasing numbers of concomitant ASMs, especially when combined with benzodiazepines, chiefly clobazam, and in patients taking ≥ 2 sodium channel blockers. Median time to resolution of frequently reported TEAEs was shorter in patients taking fewer concomitant ASMs, with the exception of fatigue. The proportion of patients experiencing more severe TEAEs (except for headache) also increased with increasing numbers of concomitant ASMs. Patients taking fewer concomitant ASMs reported better tolerability as evidenced by fewer and less severe AEs and faster time to resolution. These findings emphasize the importance of optimizing concomitant ASM regimens through dose adjustments, ASM substitution, and treatment simplification to improve tolerability.

One important aspect of improving cochlear implant performance is a good, quantitative understanding of electrically stimulated nerve fibers and the effects of deafness on their behavior. The main principles of a nerve fiber's responses are well understood. The measures describing the responses, such as the refractory period or facilitation, and the effects of deafness on them, have been investigated in different publications and nerve fiber populations. However, a comprehensive analysis of many measures based on a single dataset is still lacking. Using a fiber-specific model-based analysis, we show that it is possible to extract multiple measures from existing pulse train recordings of 118 guinea-pig nerve fibers. This not only included eight basic measures, such as refractory period and facilitation, but also four spike-train-derived measures (spike rate, dip duration, interspike interval, and vector strength). Using these, we started two lines of investigation. In the first one, we investigated the response differences between fibers from acutely and chronically deafened animals. The results showed that, on average, the chronically deaf groups had a shorter refractory period and a higher discharge rate. In the second line, we investigated the relationship between the basic measures and the spike-train measures using fiber-specific modeling. This showed, e.g., an inverse relationship between the spike rate and the refractory period, confirming our previous findings. Overall, this paper provides a detailed characterization of both acutely and chronically deafened nerve fibers, and an analysis of the interaction between basic measures and spike-train responses.NEW & NOTEWORTHY Quantitative descriptions of electrically evoked auditory nerve responses are essential for improving cochlear implants. Using fiber-specific modeling, this study extracts a comprehensive set of response measures from pulse-train recordings of 118 auditory nerve fibers. Comparing fibers from acutely and chronically deafened animals reveals differences, e.g., in refractory properties and response rate. An investigation into the relationship between the measures revealed a dependency of the rate on the refractory properties and additionally on the dynamic range.

In the first half of the 20th century, Sir Henry Dale played a major role in the development of modern pharmacology. Working with several newly identified biologically active substances and simple bioassays, Dale and his colleagues deduced the existence of specific transmitter and hormone receptors. They developed concepts of agonist and antagonist actions, many years before the receptor proteins responsible for the actions of neurotransmitters were purified and characterized. Dale observed that acetylcholine and epinephrine could evoke either excitatory or inhibitory actions on different target tissues and postulated that these same substances were released in the central nervous system. This was turned by other scientists into the first instantiation of Dale's law, which stated that a given neuron only releases one neurotransmitter. In the second half of the 20th century, it became clear that many neurons synthesize and release many cotransmitters that could elicit postsynaptic actions of variable signs and durations, and that the same neuron could be excitatory at some of its targets and inhibitory at others. Today, the theory community often uses the term "Dale's Law" as a short hand for models in which all of the postsynaptic actions of a modeled neuron are exclusively excitatory or inhibitory. Although much can be learned from these models, this constraint should not be considered as a prerequisite for biologically realistic models. Doing so risks overlooking the open questions that have emerged through modern updates to Dale's work.

Germany's longstanding separation of healthcare sectors - most prominently between outpatient and inpatient care - creates risks of fragmented service delivery, disrupted information flows, and ultimately suboptimal outcomes for patients. This position paper examines how cross-sectoral and integrated strategies can effectively mitigate or overcome this fragmentation. During a Berlin Forum of the Association of the Scientific Medical Societies in Germany (AWMF) (6 December 2024), experts presented best-practice models and discussed legal, structural, financial, and regional dimensions of integrated care. The insights from these discussions were synthesized into AWMF's recommendations. Integrated care represents a critical lever for improving the efficiency and quality of the German healthcare system. Promising examples exist across surgical, medical, psychiatric, and regionalized care settings. Key recommendations address the following topics: harmonized financing and remuneration system, regional population-based healthcare networks, interoperable information exchange across healthcare sectors, shared decision-making on care options. Health services research - and especially implementation research - plays an indispensable role in guiding and evaluating these reforms. The AWMF further emphasizes the need for integrated education and postgraduate training, particularly within structured residency networks, and offers AWMF as an important interdisciplinary and interprofessional platform for promoting cross-sectoral care. Broad implementation of integrated care, combined with robust and evidence-based monitoring of implementation, is essential for meeting the challenges posed by demographic change and increasing demands on healthcare delivery. Die bisherige Trennung der Versorgungssektoren in Deutschland – insbesondere zwischen ambulanter und stationärer Versorgung – birgt die Gefahr von unzureichend effizienten Behandlungsabläufen, Informationsverlusten und folglich einer suboptimalen Patientenversorgung. Dieses Positionspapier evaluiert, wie sektorenübergreifende Ansätze diese Fragmentierung verbessern und überwinden können. Im Rahmen eines Berliner Forums der Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften (AWMF) (6. Dezember 2024) wurden Beispiele guter Praxis sowie rechtliche, strukturelle und regionale Aspekte der sektorenübergreifenden Versorgung durch Expertinnen und Experten vorgestellt und diskutiert. Die Ergebnisse flossen in ein Positionspapier ein, das Empfehlungen der AWMF formuliert. Die sektorenübergreifende Versorgung ist ein zentraler Ansatzpunkt zur Verbesserung der Effizienz und Qualität des deutschen Gesundheitssystems. Beispiele guter Praxis sind ermutigend. Die Empfehlungen der AWMF betreffen die folgenden Themenbereiche: Harmonisierung der Finanzierungs- und Vergütungssysteme, Etablierung regionaler Gesundheitsnetzwerke, interoperabler Informationsaustausch über alle Sektoren, partizipative Entscheidungsfindung zu Behandlungsalternativen. Die Versorgungsforschung spielt dabei eine zentrale Rolle. Die AWMF empfiehlt zudem eine sektorenübergreifende Aus- und Weiterbildung z.B. in Weiterbildungsverbünden und bietet die Nutzung der AWMF als strategische Plattform für interdisziplinäre und interprofessionelle Weiterentwicklung sektorenübergreifender Versorgung an. Eine Ausweitung der sektorenübergreifenden Versorgung mit evidenzbasiertem Monitoring der Implementierungsschritte ist essenziell, um den Herausforderungen des demografischen Wandels und den steigenden Anforderungen an die Gesundheitsversorgung zu begegnen.

A muscarinic acetylcholine receptor (MAchR) mechanism at the hypoglossal motor nucleus (HMN) can suppress tongue motor activity, and anti MAchR agents are a component of pharmacotherapy for obstructive sleep apnea. However, the source and operation of cholinergic modulation of HMN activity are unknown in-vivo. Here we identify tongue motor responses to optical stimulation of cholinergic neurons at the HMN and intermediate reticular nucleus (IRt) in isoflurane-anesthetized transgenic mice (ChAT-ChR2(H134R)-EYFP) with and without pharmacological manipulation of the HMN. The IRt constitutes a major source of cholinergic input to the HMN and relay station for transmission of respiratory drive. In response to 2 sec pulsed (10ms at 10Hz, 0-20mW, n=15) or tonic ('square-wave', 0-20mW, n=9) optical stimulation of the HMN or IRt, there was a power-dependent increase in tongue motor responses with lesser responses from the IRt (all P<0.05). During tonic IRt stimulation we identified that MAchR antagonism at the HMN (scopolamine, 2mM, n=7) increased endogenous respiratory tongue motor activity at higher stimulation intensities (20mW, P=0.030) whereas addition of nicotinic (N) AchR antagonism (mecamylamine, 200&#xb5;M) decreased respiratory tongue activity at lower stimulation intensities (5mW, P=0.012). These data identify opposing inhibitory and excitatory MAchR- and NAchR-dependent modulation of respiratory hypoglossal motor output. In contrast, MAchR antagonism alone or combined with NAchR antagonism at the HMN decreased evoked tonic motor activity (10 and 20mW, P<0.034), identifying reduction of a tonic excitatory effect. Together, these data identify cholinergic modulation of IRt-evoked HMN activity that shapes tonic and respiratory hypoglossal motor outputs in-vivo.

Most of what we know about neural mechanisms of incremental learning through feedback comes from descriptive, univariate analyses. Here, we go one step further, seeking brain activity that is not just statistically reliable (potentially small but significant) but can track such learning at the item level, taking a classifier-based approach to narrow in on basic neural encoding processes. Participants ( N = 45 ) learned 48 word-value mappings through trial-and-error. First, we checked whether established EEG markers of feedback processing, the feedback-related negativity (FRN) and frontal midline theta activity (FMT), are in fact predictive of trial-to-trial learning of the current item-and they were (above chance, but not by much), validating the behavioural relevance of those features. Next, we asked whether there might be considerably more information about encoding on single trials beyond these statistically robust, regular signals. Indeed, multivariate classifiers (LDA and SVM), incorporating signal-features beyond the FRN and FMT, predicted learning more substantially and exceeded previous performance on episodic recognition using the same basic approach (Chakravarty et al., Journal of Neurophysiology, 124(6), 2060-2075, 2020). Time-frequency spectral features produced better classifications (AUC &#x223c; 0.7) than time-domain features. Finally, a possible shortcut due to accuracy varying systematically with trial number could not explain away classification success. In sum, FRN and FMT are not just descriptive of feedback-driven learning but also a bit predictive-but are the tip of the iceberg (subject-specific, spatiotemporal features) uncovered by the multivariate classifiers. This extends current classifier-based approaches to brain activity from episodic memory to incremental, feedback-driven learning.

Clawed frogs communicate acoustically to coordinate reproduction, with males producing species-specific advertisement calls to attract females. In Xenopus laevis, males generate fast trills composed of clicks repeated at 60 Hz, a feature absent in Silurana tropicalis males and X. laevis females, whose calls consist of slower click rates (30 Hz and 7 Hz, respectively). In male X. laevis, fast trills are generated by premotor neurons in the parabrachial nucleus (PBN), known as fast trill neurons (FTNs). We hypothesized that FTNs are unique in male X. laevis and absent or distinct in clawed frogs lacking fast trills. To test this, we used constellation pharmacology to profile receptor and ion channel expression in PBN neurons by measuring intracellular Ca2+ responses to pharmacological agents in male X. laevis, male S. tropicalis, and female X. laevis. Surprisingly, we found putative FTNs (pFTNs) in all three groups. Furthermore, a similar proportion of pFTNs across groups expressed fast-kinetic voltage-gated potassium channels known to support rapid firing, indicating the presence of these channels does not correlate with producing fast trills. Instead, some of these channels were more prevalent in males of both species than in female X. laevis, suggesting a sex-specific, nonvocal function. These results suggest FTNs may have an unrecognized function conserved across species but were repurposed for fast trills during X. laevis speciation; alternatively, they may differ in unresolved molecular or electrophysiological properties, or represent latent ancestral circuitry persisting in slow-trilling species. These findings provide new insight into neural circuit evolution across species and sexes.NEW & NOTEWORTHY Premotor vocal neurons share molecular profiles across clawed frogs, despite differences in calls, revealing unexpected conservation and functional divergence of homologous neurons underlying the evolution of vocal behavior.

Motoneuron subtypes exhibit distinct firing properties that are critical for the graded control of muscle force. A key determinant of these differences is the medium afterhyperpolarization (mAHP), which shapes discharge rate and firing gain. Although subtype-specific variation in mAHP properties has traditionally been attributed to differences in small-conductance calcium-activated potassium (SK) channel expression, emerging evidence suggests that additional conductances may contribute. Here, we investigated the role of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in regulating the mAHP and excitability of mouse spinal motoneurons during postnatal development. Using whole cell patch-clamp recordings obtained from lumbar motoneurons of 2- to 3-wk-old mice, we show that mAHP amplitude is negatively correlated with the magnitude of the h current (Ih) in fast motoneurons, where Ih is active at resting potential. Pharmacological blockade of HCN channels with ZD7288 increased mAHP amplitude in fast but not slow motoneurons, without affecting mAHP duration, indicating a subtype-specific contribution to mAHP amplitude. In line with the mAHP regulating firing gain, ZD7288 also reduced firing gain in fast but not in slow motoneurons. These findings support a contribution of HCN channel activity to the regulation of mAHP amplitude and firing gain in fast motoneurons, highlighting a potential interaction between Ih and SK channel-dependent mechanisms in shaping motoneuron excitability.NEW & NOTEWORTHY Fast and slow motoneurons differ in firing properties critical for force control, yet mechanisms underlying subtype-specific regulation of the medium afterhyperpolarization (mAHP) remain unclear. We show that hyperpolarization-activated cyclic nucleotide-gated (HCN) channel activity selectively constrains mAHP amplitude and firing gain in fast alpha motoneurons in mice, revealing Ih as an important contributor to subtype-specific excitability, providing a complementary mechanism to traditional small-conductance calcium-activated potassium (SK) channel regulation of the mAHP.

Late-onset unexplained epilepsy (LOUE) represents a substantial proportion of epilepsies with onset after 50 years and often manifests as temporal lobe epilepsy (LO-TLE). Although a link with Alzheimer disease (AD) has been suggested, only a subset of LO-TLE shows AD-related biomarkers, indicating biological heterogeneity. This study aims to characterize the cognitive and CSF phenotype of LO-TLE and compare it with healthy controls (HCs) and patients with mild cognitive impairment due to AD (MCI-AD). This Italian cross-sectional cohort study included LO-TLE patients with normal CSF &#x3b2;-amyloid (A&#x3b2;) biomarkers, MCI-AD, and age-matched and sex-matched HC. Participants underwent structural MRI, neuropsychological assessment, and CSF biomarkers assay, including neurofilament light chain (NfL) and the phosphorylated-to-total tau ratio (p/t-tau). Cortical thickness and subcortical volumes were quantified from structural MRI. Cognitive performance was summarized using principal component analyses. Group differences in imaging, cognition, and CSF biomarkers were assessed, and associations between CSF markers and cognition were examined within groups. The study included 18 LO-TLE, 24 MCI-AD, and 17 HC. LO-TLE showed preserved cortical thickness and subcortical volumes comparable with HC, whereas MCI-AD exhibited widespread cortical thinning and medial temporal atrophy. Despite normal imaging, LO-TLE showed lower performance compared with HC in episodic memory (t(53) = -7.79, pFDR < 0.001), short-term memory (t(53) = -2.94, pFDR = 0.007), language (t(53) = 4.12, pFDR < 0.001), and executive functions (t(53) = -3.76, pFDR < 0.001), while attention was preserved. Global cognitive performance further distinguished LO-TLE from MCI-AD, with the former group performing better (t(53) = 4.21, pFDR < 0.001). LO-TLE CSF profiles were characterized by low NfL levels and a p/t-tau ratio below the proposed cutoff of 0.17, whereas MCI-AD showed pathologic A&#x3b2; and tau alterations, elevated NfL, and p/t-tau ratio above 0.17. In LO-TLE, a higher p/t-tau ratio was associated with better performance on global cognition (rs = 0.585, pFDR = 0.032) and short-term memory (rs = 0.588, pFDR = 0.032), whereas no associations emerged in MCI-AD. LO-TLE with normal CSF AD biomarkers is characterized by distinct cognitive and biological features compared with MCI-AD, suggesting a disease process independent of AD. The low p/t-tau ratio may reflect alternative pathophysiologic mechanisms and warrants further investigation in larger longitudinal studies to clarify the underlying pathology and clinical trajectories.

Neurophysiologists have discovered many mechanisms underlying the production of animal behaviors in specific species; these involve a collection of neuromuscular systems, neuronal membrane and neural network properties, as well as the hormones and neuromodulators known to modify them. However, the mechanistic basis of behavioral evolution is less well studied, and causal links between differences in gene expression, cellular mechanisms, and species-typical behaviors are rare. Vertebrate vocal behaviors are an excellent system for studying the evolution of behaviors because they are ancient, diverse, and readily quantifiable. Xenopus frogs are particularly well suited to the study of vocal evolution because of the temporal diversity of male advertisement calls between closely related species and the well-described vocal pattern-generating circuitry. Here we focus on two species, X. laevis and X. petersii, that diverged 8.5 million years ago and produce advertisement calls with distinct timing. To begin bridging the gap between behavioral and mechanistic diversity in Xenopus vocal behaviors, we performed RNA sequencing of the parabrachial nucleus, a vocal premotor hindbrain area known to encode species-typical temporal patterns in X. laevis and X. petersii. We identified hundreds of differentially expressed genes between the two species, including many genes related to hormone signaling, neuromodulation, neuronal and synaptic functions, ion channels, and neurotransmitter receptors. We explore several testable hypotheses emerging from these results that may explain mechanisms by which candidate genes and gene families contribute to vocal pattern differences between X. laevis and X. petersii.NEW & NOTEWORTHY This study is the first attempt in Xenopus frogs to link gene expression to circuit function to behavior in order to understand the neuronal mechanisms underlying vocal evolution.

Visual response strength in the primate superior colliculus (SC) has recently been shown to inversely correlate with trial-by-trial saccadic reaction time in a much stronger way than visual response strength in the primary visual cortex (V1). However, for any given visual stimulus onset, populations of neurons in each brain area are concurrently activated, leaving open the question of how V1 visual response strength can predict trial-by-trial saccadic reaction time when multiple simultaneously recorded neurons are taken into account. Using a classic visually guided saccade task, here we assessed the quality of predicting trial-by-trial saccadic reaction time from the visual response strengths of 1 to 10 simultaneously recorded neurons in each brain area. For each session, we modeled saccadic reaction time as a weighted linear combination of the visual response strengths of N simultaneously recorded neurons. Consistent with the prior work, the visual response strength of a single SC neuron was better than that of a single V1 neuron at predicting reaction time. By adding more simultaneously recorded neurons, the prediction got much better in the SC, but not in V1. Only for 100% contrast dark stimuli (darker in luminance than the surrounding gray background) did V1 show an increase in prediction quality with more simultaneously recorded neurons. This increase, which was still substantially weaker than in the SC, could reflect the ecological relevance of dark contrasts in scenes. These results suggest that despite qualitative similarities between SC and V1 visual responses, SC visual responses are functionally reformatted from their V1 counterparts.NEW & NOTEWORTHY The superior colliculus (SC) is an important sensory-motor structure for controlling eye movements, and it receives a significant portion of its inputs directly from the primary visual cortex (V1). Despite this, SC visual responses are much better correlated with trial-by-trial variability in saccadic eye movement timing than V1 visual responses, and this effect is strongly amplified when considering simultaneously recorded neurons. Thus, SC and V1 visual responses serve fundamentally different functions from a motor perspective.

The olfactory bulb (OB)-entorhinal cortex (EC) circuit is involved in odor information processing and contextualization, as well as other cognitive processes that require the proper generation of neuronal network activity patterns often synchronized with breathing and affected during rhinitis. Although both the OB and the EC frequently show clear signs of neuroinflammation and neuronal stress in response to a variety of peripheral and central proinflammatory stimuli, the functional state of the OB-EC circuit during experimental rhinitis has not been explored. To fill this gap, we explored the impact of nasal inflammation, induced by the viral mimetic polyinosinic:polycytidylic acid [poly(I:C)], on the circuit composed of the OB and EC by measuring their individual neural network activities and quantifying their functional connectivity in the absence and presence of odors. We also measured the presence of proinflammatory markers in both structures and the animals' olfaction. We found that three daily intranasal poly(I:C) administrations are enough to increase proinflammatory cytokine levels in the OB and EC and to reduce olfactory detection in a novel context. Intranasal poly(I:C)-induced inflammation leads to a reduction in the power of OB and EC neural network activity and diminishes their response to odors. Moreover, poly(I:C)-induced inflammation reduces coupling between the OB and the EC at various frequencies, including those close to the respiratory rhythm. It also reduces the coupling between the EC and breathing, which is not observed in the OB. Taken together, our findings indicate that intranasal viral infection leads to neuroinflammation in the OB-EC circuit, affecting its function and connectivity, as well as its coupling to breathing, which could contribute to the olfactory and cognitive deficits observed in rhinitis.NEW & NOTEWORTHY To understand the olfactory and cognitive deficits observed in viral rhinitis, we described the impact of nasal inflammation, induced by the viral mimetic poly(I:C), on the circuit composed of the olfactory bulb and entorhinal cortex by measuring their individual neural network activities and their functional connectivity in the absence and presence of odors. We also evaluated signs of neuroinflammation in both structures and the animals' olfaction, revealing pathological mechanisms behind neurological manifestations associated with rhinitis.

This study aimed to evaluate spontaneous swallowing frequency (SS-FR) and type of swallowing during awake and sleep states in patients with Parkinson's Disease (PD), using polygraphic recordings to identify possible associations with disease severity. A total of 27 PD patients (19 male, 8 female) and 22 age-matched healthy controls were included. All participants underwent whole-night one-hour polygraphic monitoring, and SS-FR and type of swallowing were analyzed during both wakefulness and sleep stages. Clinical characteristics, disease severity (Hoehn and Yahr staging), and motor symptoms (Unified Parkinson's Disease Rating Scale) were assessed. SS-FR was significantly lower in PD patients compared to controls, both during wakefulness and especially during sleep. In PD patients, SS-FR during wakefulness was positively correlated with Hoehn and Yahr stage and motor symptom scores. The presence of dysphagia was more common in patients with markedly reduced SS-FR, indicating its potential role as a non-invasive marker for swallowing impairment. Salvo swallowing was observed in 4.5% (n&#x2009;=&#x2009;1) of controls and 40.7% (n&#x2009;=&#x2009;11) of patients with PD (p&#x2009;=&#x2009;0.003). SS-FR is significantly altered in PD, with reductions during both awake and sleep states reflecting disease severity. SS-FR measurement through polygraphic recordings may have potential as a non-invasive marker for early detection of swallowing disorders and progression in PD.

Dravet syndrome (DS) is an epileptic encephalopathy most often caused by loss-of-function mutations in the SCN1A gene, leading to haploinsufficiency of the voltage-gated sodium channel NaV1.1. Seizures begin during infancy and wane throughout childhood, but behavioral symptoms, including intellectual disability, motor impairments, and autistic features, remain through adulthood. Seizures primarily stem from inhibitory neuron hypoexcitability in the cortex, hippocampus, and thalamus, but circuit abnormalities underlying persistent behavioral symptoms are poorly understood. Prior work showed synapse dysfunction in thalamocortical neurons in 4-wk-old DS mice, but elucidating the timing and progression of these alterations is necessary to understand the disease stages that synapse dysfunction may contribute to circuit and behavioral phenotypes. We investigated synapse function in the ventral posterolateral (VPL) and ventral posteromedial (VPM) thalamus before seizure onset (P13-P17), after the period of highest seizure burden (P28-P32), and in adulthood (P58-P63). VPL and VPM synaptic activity showed that excitatory input to the VPL was reduced after seizure onset, and this reduction persisted through adulthood, while VPM excitatory input was unaffected. We further showed a selective reduction in the function and number of excitatory sensory synapses in the VPL, with no change to cortical synapses. VPL and VPM neurons both showed inhibitory synapse dysfunction at 4 wk, which persisted in adult DS mice only in VPL neurons. These results revealed persistent input- and cell-type-specific alterations to thalamic synapses that develop after seizure onset and are maintained into adulthood, suggesting synaptic deficits could contribute to ongoing somatosensory thalamocortical circuit dysfunction and behavioral deficits in DS.NEW & NOTEWORTHY This study reveals that synaptic dysfunction in the somatosensory thalamus of Dravet syndrome (DS) mice emerges after seizure onset and persists into adulthood. Using electrophysiology and high-resolution imaging, we demonstrate a selective, persistent reduction of sensory input to VPL neurons, while cortical input remains intact. Inhibitory input to VPL thalamus is similarly impaired after seizure onset and persists in adulthood. These input- and cell-type-specific deficits may contribute to the enduring sensory and sleep impairments characteristic of DS.

Anorexia nervosa is a severe and potentially life-threatening psychiatric disorder characterized by self-starvation, intense fear of weight gain, and a distorted body perception. Treatment remains challenging, and effective interventions for adults are limited. The extrastriate body area (EBA), a cortical region involved in body representation, may contribute to the body perception disturbances. In this double-blind, placebo-controlled, randomized proof-of-concept trial, we investigated the therapeutic potential of targeted theta burst transcranial magnetic stimulation (TMS) of the EBA in patients with anorexia nervosa (n&#x2009;=&#x2009;40). Participants received four weeks of active (n&#x2009;=&#x2009;10) or sham (n&#x2009;=&#x2009;10) TMS combined with body perception training, while a treatment-as-usual group (n&#x2009;=&#x2009;20) and a healthy control group (n&#x2009;=&#x2009;40) served as comparators. Improvements in the primary outcome measure, the Body Shape Questionnaire, differed across groups over time, with active TMS showing faster improvement (after 4 weeks) relative to both control groups, that was sustained at 6 months follow-up. Moreover, active stimulation was associated with changes in EBA responses to self- versus non-self touch, shifting neural activity patterns more closely to those of healthy individuals. These findings provide preliminary evidence that individualized neuromodulation targeting a disorder-relevant neural substrate combined with behavioral training shows potential for effectively recalibrating disturbed body perception. By integrating brain stimulation with behavioral training, this study exemplifies a precision psychiatry approach that links neurobiological mechanisms to personalized therapeutic interventions in anorexia nervosa.

Breathing is an essential motor behavior that originates from the activity of rhythm-generating neurons in the preB&#xf6;tzinger Complex (preB&#xf6;tC). Although the properties of preB&#xf6;tC neurons are sufficient for rhythmogenesis, their activity is continually shaped by long-range inputs that convey homeostatic, emotional, volitional, and behavioral influences. Here, we provide a systematic survey of projections from excitatory (glutamatergic) and inhibitory (GABAergic) neurons across the mouse brain that target the preB&#xf6;tC. Using a dual recombinase-dependent retrograde tracing approach, we compile an atlas of afferent regions, highlighting the breadth of excitatory and inhibitory inputs that converge on this critical brainstem area. This atlas underscores the preB&#xf6;tC as a nexus where multimodal signals are integrated to regulate rhythm generation and patterning. Rather than a self-contained oscillator, the preB&#xf6;tC is a hub whose function is tuned by diverse long-range excitatory and inhibitory influences. By defining the anatomical substrates of this input, we lay a foundation for dissecting the functional roles of higher-order brain regions in shaping breathing across physiological, behavioral, and pathological contexts.

Within the central auditory pathway, the inferior colliculus (IC) is a critical integration center for ascending sound information. While IC neurons have well-characterized receptive fields for individual sound features such as sound frequency, intensity, and location, growing evidence suggests that some neurons also use multiplexing to encode sound feature combinations. Here, we performed in vivo juxtacellular recordings in awake, head-fixed mice to examine how individual IC neurons and neuronal populations encode the speed, direction, and frequency range of frequency-modulated sweeps. To understand the strategies used by neurons to represent different sound features, we trained a support vector machine to decode sound features from different parameters of the spike train, including the firing rate, spike times relative to stimulus onset, distribution of inter-spike intervals, and first spike latency. We found that many IC neurons multiplex features of frequency-modulated (FM) sweeps using distinct temporal coding strategies rather than simple changes in mean firing rate, and that these feature representations are interdependent, yielding a combinatorial encoding of sound features within individual neurons. Accordingly, using static receptive fields for sweep frequency or direction alone yielded poor predictions of neuron responses to vocalizations that contain simple frequency changes. Lastly, we showed that encoding strategies varied across individual neurons, resulting in a highly informative population code for FM sweep parameters. Together, our results suggest that multiplexing is a common mechanism used by IC neurons to represent complex sound features.