Neuroscience

Axonal action potential propagation critically depends on tightly regulated intra and extracellular electrolyte concentrations and acid base homeostasis. Experimental studies have demonstrated that changes in extracellular sodium, potassium, and calcium concentrations alter axonal excitability and conduction properties. However, it remains unknown whether small variations in electrolyte concentrations within the physiological range are associated with measurable changes in nerve conduction velocity in humans. In this study, data from neurologically healthy children who underwent both nerve conduction studies and blood gas analysis were analyzed to investigate the relationship between electrolyte concentrations and median motor nerve conduction velocity. Nerve conduction velocity was significantly negatively correlated with ionized calcium concentration and positively correlated with sodium concentration, whereas no significant correlation was observed for potassium. In an a priori defined multiple linear regression model, ionized calcium, sodium, and bicarbonate remained significantly associated with nerve conduction velocity after correction for multiple testing. These findings indicate that even small variations in electrolyte concentrations within the physiological range are associated with measurable differences in peripheral nerve conduction velocity and suggest an additional contribution of acid base status to nerve conduction.

Amacrine cells (ACs) are the most diverse neuron in the retina, with more than sixty different subtypes, each contributing to the detection of specific visual features. Despite their importance in visual feature detection, the genetic basis for this diversity is still not well understood. Recent single-cell transcriptomic datasets have identified several potential genes that may regulate cellular diversity, but the underlying mechanisms have not been investigated. For example, the transcription factor Meis2 is selectively expressed in the GABAergic subclass of ACs. In this study, we focused on how Meis2 regulates the development of GABAergic ACs. We hypothesized that Meis2 is required for specification and survival of GABAergic ACs. To test this, we used the Meis2 conditional knockout mouse (Meis2-CKO) where Meis2 was deleted from either the entire retina or specifically from AC precursor cells. The deletion of Meis2 led to a ~60% reduction in total GABAergic ACs in the retina. This loss of GABAergic ACs occurred only after postnatal day 5 (P5), suggesting Meis2 is not required for early specification but may be required for survival. To further investigate cell death and survival, we quantified cleaved caspase-3 positive cells in the retina at several developmental timepoints. In Meis2-CKO mice, we found an increase in cleaved caspase-3 immunolabeling at P5 and P6 timepoints coinciding with the reduction of GABAergic ACs. Further analysis of GABAergic AC subtypes demonstrated a subtype-specific cell death in Meis2-CKO retinas. For example, the total number of dopaminergic (TH) ACs were significantly reduced, whereas starburst (ChAT) ACs remained unchanged. These findings suggest that Meis2 is important for the survival of a subset of GABAergic AC subtypes in the mammalian retina. In addition, Meis2 may control the expression of specific survival factors that prevent apoptosis during developmental cell death in the retina.

Axonal projections and precise synapse formation are essential for the establishment of functional neural circuits, and their dysregulation contributes to various psychiatric and neurodegenerative disorders. Although numerous extracellular cues secreted from surrounding tissues regulate axon guidance and synapse formation, the mechanisms by which neurons locally regulate terminal patterning within their projection fields remain poorly understood. Bone morphogenetic protein 4 (BMP4) is a classical morphogen that is involved in early neural tube patterning during development. However, its postnatal function remains unclear. Previous in vitro studies using hippocampal glutamatergic neurons demonstrated that BMP4 can act locally on axons to suppress synapse formation, raising the possibility that BMP4 regulates terminal differentiation after target innervation. Here, we investigated the role of BMP4 in postnatal cholinergic circuit development using cholinergic neuron-specific Bmp4 conditional knockout (Bmp4 cKO) mice, with adult analyses performed in males. Basal forebrain cholinergic neurons project extensively throughout the neocortex and are essential for higher brain functions, including arousal and attention. Bmp4 cKO mice exhibited increased cholinergic axon terminals in the neocortex, hippocampus, and amygdala, as well as increased axonal ramification in the neocortex without affecting cytoarchitectonic organization or cholinergic neuron numbers in the basal forebrain. These findings demonstrate that BMP4 functions as a negative regulator of cholinergic terminal formation and axonal arborization, suggesting that BMP4 may act locally to restrict cholinergic axonal expansion during neural circuit maturation.

Background. In the era of successful antiretroviral therapy (ART), mood disturbance remains highly prevalent in people with HIV (PWH). In the present study, we investigated the long-term legacy effects of long delay in ART initiation and low nadir CD4 count on mood symptoms in adults with HIV. The impacts of demographic and other HIV clinical factors were also examined. Methods. A total of 109 PWH (disease duration: 24.6{+/-}9.3 years) and 42 demographically matched healthy participants (people without HIV, or PWoH) participated in a cross-sectional study (41-70 years old (55.6{+/-}6.8), 62.9% African Americans, 27.2% female, 14.3{+/-}2.9 years of education). Mood symptoms were assessed with the Beck Depression Inventory-II (BDI-II) and the Profile of Mood States (POMS). A comprehensive neuropsychological test battery was administered to assess neurocognitive function. Results. Despite largely comparable neurocognitive performance between PWH and PWoH , PWH had worse mood symptoms than PWoH, including higher total BDI-II (p<.001) and total POMS scores (p=.002), as well as higher score in all POMS sub-scores (p<.007), except Vigor (p=.724). Within the PWH group, longer delays in ART initiation, lower nadir CD4 count, and lower educational attainment were associated with worse mood symptoms. By contrast, current plasma CD4+ cell count, plasma detectable viral load, and HIV disease duration were not associated with either BDI-II or POMS score. Conclusion. Mood disturbance is highly prevalent in PWH on ART. The long-term legacy effects of delay in ART initiation and low nadir CD4 count on mood management reinforce the necessity of early ART initiation in clinical practice.

Animals and humans often forgo sleep in response to other physiological needs. Prolonged wakefulness leads to a compensatory homeostatic sleep response involving enhanced amounts of sleep and electroencephalographic delta (0.5-4 Hz) power, yet how the type of preceding wakefulness and brain activity affects this response is poorly understood. Here we compared the pattern of brain activity and the homeostatic sleep response following sustained wakefulness induced by either gentle handling (GH), a widely used form of sleep deprivation in rodents; or optogenetic stimulation of neurons involved in avoidance/defensive responses, basal forebrain (BF) vesicular glutamatergic transporter type 2 (vGluT2) neurons. Local infusion of ionotropic glutamate receptor antagonists partially attenuated the wake-inducing effect of vGluT2-stimulation, but not that of GH, suggesting mediation by other non-glutamatergic BF subtypes. These antagonists also tended to produce more NREM sleep and a shorter NREM latency in the recovery period following vGluT2-stimulation. Both manipulations increased high theta (7-9 Hz) during wakefulness, an effect partially blocked by local infusion of the glutamate antagonist cocktail. Enhanced NREM sleep time and NREM delta power in the recovery period were more pronounced following GH than following vGluT2 stimulation. Whole-brain cFos immunohistochemistry revealed stronger neuronal activity in brain regions involved in stress and avoidance/defensive behaviors with vGluT2 stimulation, compared to GH. Our results demonstrate that activation of a brain system involved in defensive behavior (BF vGluT2) elicits a distinct and diminished homeostatic sleep response compared to GH, potentially an evolutionary sleep adaptation which would maintain vigilance in the face of an ongoing threat.

Hypoxia impairs cognitive function, yet its effects on navigation and intrinsic brain activity remain poorly understood. This study investigated whether a continuous exposure to hypoxia (CH) or an intermittent exposure to hypoxia (IH) differentially influence navigation performance and resting-state electroencephalography (EEG) in healthy young adults. Seventy-two participants completed sham (FiO2 = .209) and hypoxia (FiO2 = .13) sessions during either a one hour of CH or IH intervention. Navigation was assessed using the Spatial Performance Assessment for Cognitive Evaluation (SPACE), while resting-state EEG was recorded before and after the intervention in a subset of participants (n = 40). EEG spectra were parameterised into periodic (alpha and beta power and central frequency) and aperiodic (exponent and offset) components. Aligned rank transform (ART) analyses of variance examined effects of hypoxia and intervention group, while linear regression determined whether reductions in peripheral oxygen saturation (SpO2) predicted changes in navigation or EEG. Hypoxia impaired multiple components of navigation, increasing path integration distance error and egocentric pointing angle error irrespective of intervention group, while mapping accuracy was preferentially impaired following IH and perspective taking performance following CH. Hypoxia also reduced alpha and beta power, beta central frequency, and aperiodic exponent, while aperiodic offset and alpha central frequency remained stable. The reduction in aperiodic exponent was primarily evident following IH, suggesting that the temporal pattern of oxygen delivery may influence specific neurophysiological responses. Contrary to our hypothesis, SpO2 reduction did not predict individual differences in navigation performance or EEG activity. These findings demonstrate that brief, moderate hypoxic exposure can disrupt allocentric and egocentric components of spatial navigation while selectively altering periodic and aperiodic features of intrinsic brain activity.

Introduction: Observation of a partner in pain elicits empathy-related cortical responses and social support can modulate pain. Objective: The aim of this study was to investigate empathy and the cortical response during observation of a romantic partner in pain with and without consoling touch. Methods: A total of 40 participants (20 couples) completed validated measures of handedness, pain and empathy. Each member of the couple was randomly assigned to be either the recipient of cold pressor pain or the consoling partner undergoing EEG. EEG activity was recorded from the consoling partner during baseline and pain conditions (with and without consoling touch) to investigate how observation of a partner in pain could alter mu rhythms. Results: Observing a romantic partner in pain significantly enhanced mu at electrodes C4 and Cz, yet addition of consoling touch did not significantly change mu rhythms. Personal Distress was positively associated with mu rhythm enhancement at electrode C4 during pain without consoling touch (r = .576, p = .008). Conclusion: Viewing a romantic partner in pain significantly increased mu rhythms, that was not further changed by offering consoling touch. The association between increases in mu rhythms and Personal Distress in the current study suggests that self-oriented distress may be especially relevant to sensorimotor cortex responses when witnessing a partner in pain, particularly when consoling touch is not possible. Keywords: pain; empathy, EEG, mu rhythms, cold pressor

Abstract The importance of hypothalamic kisspeptin (Kiss1) neurons in controlling the reproductive axis is well established, while a population of extra-hypothalamic Kiss1 neurons is found in the medial amygdala (MeA) of both males and females in rodents and is less well understood. The MeA is connected with the olfactory bulbs, the hypothalamus and cortical areas. MeA Kiss1 neurons have been implicated in sexual behaviour and modulation of the reproductive axis; however, little is known about their action potential firing properties, which would influence kisspeptin release in target brain regions, nor whether their physiological properties are sex- or estrous cycle-dependent. In this study, whole-cell patch-clamp recordings were made from Kiss1 neurons in brain slices containing the MeA of adult female (estrous and diestrous) and male mice. MeA Kiss1 (Kiss1MeA) neurons were sexually dimorphic, with greater numbers in male compared to female mice and a slower change in excitability in estrous females compared with males. However, combining a range of electrophysiological parameters using principal component analysis did not reveal a distinct sex- or estrous cycle-linked phenotype, suggesting that the properties of Kiss1MeA neurons- and therefore kisspeptin release- are broadly similar. Interestingly, Kiss1MeA neurons had unique electrophysiological properties compared with anteroventral periventricular (AVPV) hypothalamic Kiss1 (Kiss1AVPV) neurons in female mice; with their reduced excitability, achieving action potential firing frequencies greater than 10Hz required a larger current input, indicating that Kiss1MeA neurons require stronger synaptic input to achieve firing frequencies that drive kisspeptin release. These findings provide new information about the physiological properties of Kiss1MeA neurons, showing subtle sex differences and profound regional differences between the MeA and AVPV.

Motor imagery and overt action are proposed to share common planning mechanisms while relying on distinct processes during movement performance. To investigate how repetition affects physical and imagined movements, participants physically or mentally drew paths while avoiding barriers. The barrier orientations were either repeated or different across consecutive trials, and the modality (execution or imagery) of the trials either changed or remained the same for two consecutive trials. Reaction time and movement time were analysed as measures of movement planning and task performance, respectively. Imagined movements produced longer reaction times and movement times than physical movements. Repetition of orientation reduced reaction times in both physical and imagined trials, indicating that trajectory repetition facilitated movement preparation. In contrast, previous trial type influenced reaction times only for physical movements, which were only initiated faster when preceded by another physical trial. Different effects emerged for movement time. Physical movements were faster when the same trajectory was repeated no matter the previous trial type, whereas imagined movements were unaffected by orientation and instead showed shorter durations when preceded by another imagined trial. The findings indicate that physical and imagined movements rely on more similar trajectory representations during the planning stage, but diverge during task performance. While physical movements appear to benefit from the persistence of previously generated movement trajectories, imagined trials seems more influenced by modality-specific cognitive processes. These results provide behavioural support for the Motor-Cognitive model and contribute to understanding how movement repetition influences overt and imagined actions.

Humans exhibit head movements synchronized with musical rhythms, frequently observed during instrument playing or dancing (e.g., hip hop). We conjectured that vestibular input from head movements could aid motor execution anticipatory of musical rhythms, known as sensorimotor synchronization (SMS). To examine this, we applied subthreshold galvanic vestibular stimulation (GVS) simultaneously with musical beats while healthy adults performed SMS to those beats. We designed a GVS waveform where the current rose steeply before each beat onset, which was expected to trigger intense vestibular afferent firing before the beats (as actual head movements would). Participants flexed their index finger in synchrony with the beats of syncopated auditory rhythms. In GVS trials, the SMS timing variability was significantly lower than in trials without GVS, suggesting that vestibular input stabilizes SMS to musical beats. Additionally, a control experiment using a waveform with a gradually increasing current revealed no significant difference in SMS variability between trials with and without GVS. This study provides causal evidence that the vestibular system is involved in synchronized movement to music. In addition, the results suggest that a specific parameter of the GVS waveform could influence predictive motor execution anticipatory of upcoming auditory events.

The vestibular system consists of peripheral end organs that provide the brain with temporally precise information about head position in space required for motor coordination and postural stability. Irregular vestibular afferents of the inner ear are particularly sensitive to rapid changes in acceleration, or jerk, which is necessary for making quick, corrective movements and postural adjustments. Vestibular short-latency evoked potentials (VsEPs) are waveforms that provide a measure of synchronous irregular afferent activity originating from peripheral (early peaks) and central (later peaks) vestibular pathways. These VsEPs are elicited by head jerk stimuli, commonly used preclinically. Previous studies have shown that early VsEP waves are dependent upon jerks of an adequate intensity, number, and duration. However, less is known about jerk characteristics necessary for generation of reliable VsEP signals centrally (later peaks). The present study examines the precise temporal dynamics of peripheral and central vestibular centers across a broad range of mechanical vestibular load in rats. We found differential changes in synchrony and timing driven by jerk repetition, intensity, and duration between early and late VsEP waves representing distinct anatomical components of the vestibular circuit. Our results suggest that central components are uniquely sensitive to jerk duration, intensity, and repetition, indicating a disconnect between peripheral and central neuronal recruitment, adaptive plasticity, and time-frequency dynamics. This work provides a foundation for using VsEP to assess jerk-induced physiological vestibular dysfunction and to understand how central relays differentially adapt to variations of mechanical vestibular stress compared with the precise, high-fidelity transmission observed in the periphery.

The anterolateral system (ALS) originates from neurons in various regions of the spinal cord and conveys somatosensory information related to pain, skin temperature and itch to several brain targets. One component of the ALS is the spinotectal tract, which projects to the superior colliculus (SC) and is thought to underlie directed movements of the head towards a painful stimulus. Using anterograde and retrograde tracing, we demonstrate that the input from the spinal enlargements to the SC originates predominantly from neurons in the lateral spinal nucleus (LSN), many of which express calbindin. This input, which mainly targets the caudal and lateral parts of the SC, is somatotopically organised, and is associated with the clusters of Pitx2-expressing neurons that have been identified in previous studies. Since activation of Pitx2 neurons drives directed head movements, input from LSN neurons to the Pitx2 cells is likely to be a critical component of orientation and attention towards a noxious stimuli. We also provide evidence that spinotectal LSN cells receive excitatory synaptic input from neurons in superficial dorsal horn that express substance P or the gastrin-releasing peptide receptor (GRPR). Since GRPR neurons are strongly implicated in itch, our findings raise the possibility that the SC has a role in coordinating movements in response to pruritic stimuli.

Tau is a microtubule-associated protein important for neuronal structure and function, with abnormal phosphorylation associated with neuronal dysfunction and degeneration. While tau pathology has been extensively studied in neurodegenerative diseases and traumatic brain injury, its role in spinal cord injury (SCI) remains unclear. This study investigates changes in the levels of tau isoforms and phosphorylation following a high lateral C2 hemisection (C2Hx) in adult female rats. Western blot analysis was performed on spinal cord tissue collected caudal to the lesion at 4 weeks post-injury. Low-molecular-weight (LMW) tau and high-molecular-weight, Big tau did not differ significantly between injured and control groups. In contrast, phosphorylated tau (p-tau), detected using the AT8 antibody, was significantly elevated after injury, suggesting a shift in tau functional state. Assessment of microtubule stability markers revealed increased acetylated tubulin and decreased tyrosinated tubulin after SCI, indicating a shift toward a more stable cytoskeletal state. Immunohistochemistry was performed on spinal cord sections at 6 weeks post-injury and dorsal root ganglia (DRG) at 8 weeks post-injury. These analyses demonstrated increased p-tau immunoreactivity within the ipsilateral dorsal horn of the injured spinal cord and a higher proportion of p-tau-positive neurons in DRGs from injured animals compared with controls. Together, these findings demonstrate that cervical SCI induces persistent tau phosphorylation without altering total tau levels, and that this modification extends beyond the lesion site into distal spinal regions and beyond the acute phase of injury. These alterations may influence neural plasticity and remodeling in the injured spinal cord.

Objective: Hyperthyroidism and hypothyroidism related to iodine deficiency are major public health concerns in Afghanistan. This study aimed to assess the frequency of thyroid dysfunction among male patients referred for thyroid testing and its association with age, and to examine monthly trends in thyroid dysfunction at Asia Med Laboratory in Herat, Afghanistan, from July 2021 to January 2022. Methods: A retrospective analysis was conducted on 250 male patients aged 0-69 years. We measured Serum TSH, total T4, and total T3 levels, and thyroid status was classified using age specific reference ranges. In addition, the frequency of thyroid dysfunction was analyzed across age groups with monthly trends of thyroid state. Results: Overall, the euthyroid state consisted of 69.2% of participants, 24.8% with overt hypothyroidism, 3.2% with overt hyperthyroidism, and 2.8% with subclinical hyperthyroidism. Thyroid status differed significantly by age (p = 0.0135), with hypothyroidism increasing in older age groups and reaching its highest proportion among men aged 60-69 years (55.6%). Euthyroidism predominated in patients aged 10-39 years, while hyperthyroidism across age groups remained relatively infrequent. After September 2021, a threefold increase was observed in the total number of male patients referred for thyroid testing. During this period, the proportion of hyperthyroidism increased slightly, whereas hypothyroidism cases declined. Conclusion: In conclusion, hypothyroidism was more frequent with older age. The rise in absolute case numbers after September 2021 likely reflects increased patient referrals, underscoring the need for ongoing monitoring of thyroid function. The study may assist in the early management of thyroid disorders and in reducing their complications.

Objectives: Opioids disrupt sleep, but how repeated exposure reorganizes thalamocortical networks is unknown. We asked whether morphine alters sleep architecture, regional oscillations, and phase synchronization, and how exposure history modifies these effects. Methods: From mice, we analyzed cortical electroencephalogram (EEG), central medial thalamic (CMT) local field potentials (LFP), and electromyography (EMG) for 24h after the first and fourth injections of morphine and in abstinence, and quantified vigilance-state occupancy, spectral power, state-power correlations, and the weighted phase-lag index (wPLI), which minimizes volume conduction. Results: Morphine produced hyperlocomotion, wake promotion persisting with repeated exposure, non-rapid eye movement (NREM) sleep suppression, complete rapid eye movement (REM) sleep loss, and rebound sleep. Cortex and thalamus dissociated: in NREM sleep after the first injection, cortical delta and low-gamma power increased, while CMT delta, theta, alpha, and beta power decreased. NREM occupancy coupled more strongly to CMT delta and theta power after both injections, whereas cortical wake correlations in theta, alpha, and beta fell and reversed during abstinence. Overall synchronization was altered only in theta and alpha: corticocortical alpha synchronization decreased acutely, and repeated exposure reduced thalamocortical theta synchronization in wake and NREM sleep. During abstinence, sleep architecture and synchronization largely normalized while spectral and state-power abnormalities persisted alongside mechanical hypersensitivity. Conclusions: We found that morphine does not merely reduce sleep; it reorganizes it: cortex and CMT move in opposite directions, thalamocortical phase synchronization is redistributed, and the resulting spectral and state-power abnormalities outlast the recovery of sleep architecture itself rather than producing tolerance.

Cannabis is one of the most widely consumed substances in the world. Consumers seek out cannabis cultivars with varying levels of phytocannabinoids, primarily delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). The effects of THC, CBD or the combination of THC:CBD have distinct outcomes on cognitive processes, cellular functions, and phytocannabinoid pharmacokinetics. The majority of research on cannabis effects on the brain has focussed on neurons, and few studies have investigated the impact of different cannabis cultivars on glia. In particular, the impact of varying levels of THC:CBD on oligodendrocyte lineage cells, which play numerous support roles in the brain essential to proper neuronal communication, is relatively unknown. This study set out to examine the acute impact of different cultivars of vaporized cannabis on oligodendrocyte lineage cells in the forceps minor of adult male and female mice. Mice were exposed to vapor from cannabis flower high in THC, high in CBD or balanced in THC:CBD over 15 minutes, and brains were fixed 30 minutes post-cannabis onset. Using immunofluorescence microscopy, we observed significant changes to oligodendrocyte progenitor cell (OPC) morphology in mice exposed to balanced cannabis, and, using correlative light and electron microscopy, we observed alterations to OPC mitochondria. The alterations observed (i.e., enlarged soma and nucleus volume, reduced density and increased area of mitochondria in the soma) in OPCs due to balanced cannabis are reminiscent of the very early changes seen during OPC differentiation. This study highlights the differing effects of cannabis cultivars on OPCs and the rapidity of the OPC response to inhaled phytocannabinoids.

The mouse superior colliculus (SC) regulates critical behaviors such as prey capture and visual threat avoidance, each of which depend on binocular visual processing. In contrast to our previous understanding, recent work has demonstrated widespread and diverse binocular interactions in the mouse SC. The SC receives direct input from contralaterally and ipsilaterally projecting retinal ganglion cells (contra- and ipsi-RGCs), but the ways in which eye-specific information is filtered in the SC remain unclear. Here, we utilized a trans-synaptic, intersectional viral tracing strategy to label SC neurons receiving input monocularly from contra-RGCs (SC-C), monocularly from ipsi-RGCs (SC-I), or binocularly from both (SC-B). We show that a surprising number of SC neurons receive ipsi-RGC input and that the proportions of SC-C, SC-I, and SC-B neurons are consistent throughout the SC. Morphometric analysis revealed few differences between neurons receiving different eye-specific patterns of input. Consistent with this, we show that SC-C, SC-I, and SC-B neurons are comprised of similar proportions of five morphologically distinct subtypes. And, the expression of candidate molecular markers appears similar across innervation patterns. Together, these data suggest that eye-specific information is widespread throughout the SC targeting overlapping populations of neurons.

The FoxP family of transcription factors has been linked to neurodevelopmental disorders. FoxP1 and FoxP2 were identified as genes associated with autism spectrum disorders (ASD). FoxP1, FoxP2, and FoxP4 are expressed in many brain regions, including the cerebellum that has been of particular interest in the context of ASD. However, their role in the development of the peripheral nervous system (PNS) has been neglected. In view of the fact that a majority of ASD patients show some signs of sensory perception deficits that could go beyond the central nervous system, we focused on neural circuit formation in the PNS. Our in vivo and in vitro studies revealed a role of all three FoxP transcription factors in neural circuit formation in the hindlimb of the chicken embryo. Silencing of FoxP genes altered motor axon guidance and also impacted neural crest cell migration. This in turn resulted in aberrant formation of dorsal root ganglia and deficits in neural circuits in the PNS. Taken together, our results are in line with the hypothesis that some of the sensory perception deficits in ASD patients, either hyper- or hyposensitivity, are due to aberrant neural circuits in the PNS.

A moving object passes through locations in visual space in a particular order. To distinguish opposite directions of motion, visual circuits must convert this temporal order into different direction selective neuronal responses. This ability emerges and is refined as visual circuits develop. In Xenopus laevis tadpoles, direction selectivity in the optic tectum sharpens over development. Companion work by Zheng et al (2026) shows that direction selectivity sharpens between stage 45 (approximately 6 to 7 days postfertilization), when the retinotectal circuit is undergoing rapid refinement, and stage 48 (approximately 10 to 16 days postfertilization), when the projection has completed one phase of refinement and visual acuity has improved. The same study shows that, over this period, both the excitatory synaptic input received by tectal neurons and the intrinsic properties of those neurons change. How these synaptic and intrinsic changes work together to produce a sharpening of direction selectivity unclear. Here, we combined visually evoked excitatory postsynaptic current trains recorded at each stage with stage-specific single-compartment conductance-based models. These simulations reproduced the developmental increase in direction selectivity and reduction in spiking at stage 48. Changing intrinsic properties produced only modest changes in spike counts, while reassigning amplitudes among the original event times did not eliminate developmental sharpening. Together, these results suggest that the temporal organization of synaptic input carries much of the directional information, while intrinsic maturation lowers overall spike output, making the existing directional bias in the input more pronounced.

Background: Immediate transcranial evoked potentials (iTEPs) are ultra-early electroencephalographic responses elicited by single-pulse transcranial magnetic stimulation (TMS) of the primary motor cortical hand area (M1-HAND). Their characteristic latency, waveform, and sensitivity to short-interval intracortical inhibition suggest a close relationship to the cortical generators of indirect corticospinal volleys (I-waves). Here, we tested the hypothesis that iTEPs constitute a fundamental physiological response of human motor cortex and therefore generalize across motor representations, including the leg representation (M1-LEG). Methods: Single-pulse TMS was delivered over the motor cortical representation of the right tibialis anterior (TA) in 16 healthy volunteers. In a subset of participants (n=10), stimulus-response curves and paired-pulse short-interval intracortical inhibition (SICI) measures were obtained. Results: TMS of M1-LEG elicited reproducible iTEPs consisting of a slow positive deflection with superimposed high-frequency peaks with topographic maxima in electrodes adjacent to the stimulation site. M1-LEG iTEPs emerged close to active motor threshold and increased in prevalence and amplitude with increasing stimulation intensity. Paired-pulse stimulation produced consistent SICI of the second and third iTEP peaks. M1-LEG stimulation also evoked conventional later TEPs with latencies and polarities closely resembling those recorded after M1-HAND stimulation. Conclusions: TMS of the human M1-LEG elicits robust iTEPs that closely resemble those recorded from M1-HAND in their timing, intensity dependence, and sensitivity to intracortical inhibition. These findings indicate that iTEPs are not specific to M1-HAND but reflect a general physiological response of human motor cortex closely linked to corticospinal I-wave generation. This broadens their utility as a non-invasive probe of excitatory and inhibitory circuit dynamics throughout the human motor system.