Current Research in Neurobiology

Cortico-thalamo-cortical circuits entail extensive trans-thalamic connectivity between cortical areas, yet their structural organization and function remain poorly understood. Here, the thalamocortical projections of several higher-order thalamic nuclei were characterized by retrograde tracing from two cortical areas, the primary somatosensory (S1) and motor (M1) cortices. Cholera toxin B conjugated with different fluorophores allowed for simultaneous detection of projection neurons targeting S1 and M1. A cell detection pipeline based on neural networks was developed to allow semi-automated analysis of large thalamic imaging volumes to quantitatively infer the spatial distribution of projection neurons in the posterior complex (PO) and the adjacent ethmoid nucleus (Eth), nucleus centrolateralis (CL), nucleus paracentralis (PCN), and the nucleus parafascicularis (PF). The arrangement of neurons projecting to both, primary somatosensory and motor cortices, occurs at different connection strengths and was topographically organized in all nuclei studied. Co-injections into both cortical areas revealed projection neurons with axons branching into both S1 and M1 cortices. Our work introduces a pipeline for semi-automated quantitative analysis of thalamic projection patterns that could be useful for connectivity analyses in general. This approach revealed repetitive anatomical patterns in different thalamic nuclei with regard to projection strength, spatial organization and fraction of projection neurons targeting two cortical areas simultaneously.

Multisensory integration is a fundamental feature of cortical processing, yet the functional pathways that deliver visual signals to the auditory cortex remain poorly understood. While anatomical studies reveal multiple candidate projection routes, demonstrating their causal contribution requires targeted manipulation of neural activity. Here, we used cortical cooling to reversibly inactivate the posteromedial lateral suprasylvian cortex (PMLS) and the adjacent area 21 to determine the functional role of higher-order visual areas in generating visual responses within the auditory cortex of the ferret. Units responsive to sound, light, or combined audiovisual stimuli were found across all sampled auditory fields and cortical depths, with visual responses most prominent within the infragranular layers and the non-tonotopic secondary auditory cortex of the Anterior Ectosylvian Gyrus (AEG). Cortical cooling induced robust, bi-directional, and stimulus-specific modulations of firing rates in AC. Approximately 50% of visually responsive units exhibited a significant decrease or complete elimination of visual activity during cooling, confirming a functional role for visual input from PLMS/area 21 to AC. Surprisingly, cooling also revealed circuit-level complexities: a subset ([~]5%) of units showed enhanced or newly emergent visual responses during inactivation, suggesting that PMLS/area 21 normally exerts a gating influence over alternative visual pathways. Furthermore, contrary to feedforward anatomical predictions, neurons in the AEG--the region most heavily innervated by the cooled visual areas --were less frequently impacted by cooling than those in PEG. Together, these findings demonstrate that higher visual areas causally shape cross-modal processing in the auditory cortex through a complex mixture of direct excitation and network-level modulation.

The human larynx, compared to those of closely related primates, lies deeper in the throat and lacks vocal membranes and air sacs. These shifts are usually analyzed regarding their acoustic effects on vowel-like vocalizations, since the evolution of speech was long thought to require an expansion of vocal range driven by vocal tract modifications. However, vowels are just one type of phoneme, and speech is just one class of human utterance. To understand the evolutionary underpinnings of known shifts in human vocal morphology, a broader bioacoustic comparison is needed. Specifically, the range of sounds used in human speech must be compared to that employed in other human vocalizations and in the repertoires of extant close primate relatives. Here, we measure the acoustic-feature space occupied by human speech, non-linguistic, and musical vocalizations along with the calls of chimpanzees, bonobos, and chacma baboons. We use Mel-frequency cepstral coefficients to create an acoustic space depicting the spectro-temporal features of over 750,000 brief vocal segments sourced from published databases and other verified sources. Speech and song occupied significantly less volume in this acoustic space than human non-linguistic vocalizations. In addition, the acoustic-feature volumes of speech and song were not statistically distinct from those of non-human primates. These results suggest that speech was not enabled by an expansion of human vocal acoustic space. Anatomical shifts unique to humans may have led to an elaboration of non-linguistic utterances, but learned vocalizations use a surprisingly small fraction of this space. Our understanding of human vocal evolution will be further informed by additional systematic comparisons of the function and homology of non-speech vocalizations, along with the collection and incorporation of more complete non-human primate vocal datasets, especially from Gorilla and Orangutan.

The subiculum (SUB) is a major hippocampal output hub that routes information to cortical and subcortical targets, and its long-range projections are considered excitatory. Using enhancer-driven adeno-associated viral vectors to selectively label {gamma}-aminobutyric acid (GABA)-releasing neurons across species, here we show that the dorsal SUB also sends an inhibitory projection to the dorsal part of the medial entorhinal cortex (MEC) in mice and rats. Anterograde tracing in mice revealed that the dorsal SUB contains GABAergic neurons that project sparsely to all layers of the dorsal MEC with enrichment in superficial layers, in contrast to the glutamatergic SUB axons targeting MEC layer V. Slice electrophysiology demonstrated that these GABAergic axons form inhibitory synapses in the MEC. A subset of projecting neurons expressed parvalbumin (PV), whereas somatostatin-positive neurons were rare. Consistently, PV neuron-specific anterograde tracing recapitulated the SUB-to-MEC projection. In rats, subicular GABAergic axons were enriched in MEC layer II, and SynaptoTAG2-labeled presynaptic boutons were positive for the vesicular GABA transporter, supporting inhibitory synapse formation. Anterograde tracing of PV neurons similarly recapitulated the laminar axonal distribution in the MEC. These results identify a conserved PV-associated inhibitory SUB-to-MEC projection with species-specific laminar organization, extending the canonical excitatory view of subicular output.

CLN3 disease, or juvenile Batten disease, is a neurodegenerative lysosomal storage disorder in which visual impairment is typically the earliest clinical manifestation. Although retinal pathology has been extensively studied, functional alterations within central visual pathways remain poorly understood. Here, we used functional ultrasound (fUS) imaging to characterize visually evoked activity across central visual circuits in young Cln3 knockout (Cln3-/-) mice before the onset of severe retinal degeneration. Visually evoked hemodynamic responses were quantified in regions spanning the geniculostriate and extrageniculate visual pathways, including cortical, thalamic, and midbrain regions. To assess regional pathological burden, accumulation of subunit c of mitochondrial ATP synthase (SCMAS), a pathological marker of CLN3 disease, was examined using immunohistochemistry. We found that Cln3-/- mice exhibited pathway-specific alterations in visually evoked activity. Regions along the extrageniculate pathway, including the midbrain, posterior thalamus, and anterior secondary visual cortex, showed enhanced activation relative to wild-type controls. In contrast, activation within the geniculostriate pathway was reduced in the anterior thalamus and remained unchanged in the primary and posterior secondary visual cortex. SCMAS accumulation was elevated across all examined visual regions in Cln3-/- mice relative to wild-type controls, with greater accumulation observed in geniculostriate regions than in extrageniculate regions. These findings demonstrate early pathway-specific functional and pathological alterations in the visual system of Cln3-/- mice, suggesting pathway-level reorganization of central visual processing. This study advances understanding of central visual dysfunction in CLN3 disease and highlights fUS imaging as a sensitive approach for detecting early functional abnormalities in neurodegenerative disorders.

The feline auditory cortex is understood to consist of 13 distinct subregions with unique anatomical and functional properties. Differential patterns of SMI-32 immunoreactivity are commonly used to identify the borders between these subregions; however, the detailed description of areal differences that is commonly cited did not include descriptions of the patterns observed along the posterior ectosylvian gyrus. Thus, the current manuscript aims to provide a more complete data set that can used to delineate the dorsal, intermediate, and ventral divisions of the posterior ectosylvian gyrus (auditory cortical regions dPE, iPE, and vPE, respectively) based on SMI-32 reactivity using the same methods and measures. Taken together, the current data and those published previously allow for a standardized approach to identifying all 13 auditory cortical subregions in this essential model of auditory cortical structure and function.

Valproic acid (VPA) is a widely used antiepileptic drug that also increases the risk of neurodevelopmental disorders in the offspring of exposed mothers. Prenatal exposure to VPA is a widely used rodent model of autism spectrum disorder (ASD). Anatomical, functional and molecular alterations in the retinas of various ASD model animals have been described in the literature, but the impact on the neural composition of the retina remains unclear. We examined whether and how the density and spatial regularity of selected retinal neurons are altered in the VPA induced model of ASD. Whole-mount retinas of 2-month-old VPA-treated and control animals were immunolabeled for S-cones, horizontal cells, AII amacrine cells, and parvalbumin-positive wide-field amacrines (PV-wfACs), and the positions of labelled cells mapped in various regions of interest (n = 39 for treated, n = 32 for control animals) across the retinas. Multivariate analysis of variance revealed a significant overall effect of VPA on cell densities (p = 6.1x10-7, 2 = 0.43), driven mainly by reduced AII amacrine density, while horizontal cells showed a modest reduction and S-cones were unaffected. After adjusting for retinal location, analysis of covariance indicated a 7% decrease in AII cells and a 15% increase in PV-wfACs. Regularity indices calculated from nearest neighbor distances or Voronoi-domain areas of cell mosaics were largely unchanged. These findings suggest that prenatal VPA exposure selectively alters inhibitory inner retinal circuitry in the rat ASD model at the time of cell differentiation, but self-organizing mechanisms responsible for spatial order are not affected. Lay SummaryValproic acid (VPA) is a medicine for epilepsy, but it can also raise the risk of autism in children when taken during pregnancy. In rats exposed to VPA before birth, we found changes in certain nerve cells of the retina: one type of cell important for night vision was reduced, while another type increased slightly, while most other cells stayed the same. This suggests that the changes in development that lead to autism may also be reflected in the structure and function of the eye.

Tinnitus is commonly associated with psychosocial stress. However, it is unclear whether stress alone is sufficient to induce neural alterations resulting in tinnitus. In this study, we investigated the causal role of stress in tinnitus generation by experimentally isolating stress exposure as the sole independent variable in a well-established Mongolian gerbil model. Animals were subjected to repeated, inescapable electric foot shocks over three weeks to create a chronic, repeated stress paradigm. Behavioural, endocrine and histological measures were combined to assess tinnitus perception, stress system activation and cochlear synaptopathy. Repeated stress exposure reliably activated the endocrine stress response, as indicated by transient increases in serum cortisol following specific stress sessions. Basal cortisol levels returned to baseline values after the stress period. Behavioural assessment using gap-prepulse inhibition of the acoustic startle reflex revealed only isolated cases of behavioural signs of tinnitus, which occurred at a frequency consistent with false-positive detection and were evenly distributed between stress-exposed and control animals. Histological analyses revealed that ribbon synapse counts were preserved across the cochlea, with no evidence of stress-induced synaptopathy. No systematic relationships were observed between endocrine activation, behavioural outcomes and the number of inner hair cell ribbon synapses. Taken together, these findings suggest that, in the absence of acoustic trauma, repeated chronic stress is not sufficient to induce tinnitus or inner hair cell synaptopathy. These results argue against a primary causal role of stress alone in tinnitus generation and instead support models in which stress modulates symptom expression or perceptual salience in the context of pre-existing auditory dysfunction.

When we produce sounds ourselves, the brain modulates the auditory neural response through an efference copy mechanism, allowing us to distinguish between self-initiated and externally generated auditory inputs. However, the precise level of the auditory pathway at which this attenuation occurs remains unclear. While evidence from animal models suggests that early auditory processing of self-generated sounds may be modulated by corticofugal signaling, localized cortical modulation would preserve the high-fidelity subcortical sound encoding while allowing flexible, context-dependent processing at higher levels. To probe potential motor influences in the early auditory system, we collected scalp-recorded frequency following responses (FFRs) from 33 normal-hearing adults during active (self-initiated) and passive (externally presented) listening conditions using a 170 ms speech stimulus. Data were collected with a vertical montage that emphasizes subcortical generators of the FFR. We observed no significant differences in the FFR between active and passive conditions in spectral power, response amplitude, pitch tracking, onset latency, or phase consistency. In contrast, cortical event-related potentials showed motor-induced suppression (MIS): reduced early peak amplitudes in the active condition after correcting for motor signals, increased phase consistency prior to auditory feedback, and more precise phase consistency at sound offset. In addition to indicating FFRs can be collected during a wider range of behavioral tasks without substantial motor contamination, our observation of the canonical MIS in cortical signals but not in FFRs suggests that MIS of self-initiated sounds primarily affects later stages of auditory processing rather than the early encoding reflected in the FFR.

Traumatic brain injury (TBI) is a characteristic feature of neurodegenerative diseases such as Alzheimers disease and chronic traumatic encephalopathy. Small animal models have been used to establish clinically relevant biomarkers of neuropathology, however, they show significant anatomical differences from humans and are affected by artificial experimental manipulations, making them often unsuitable for longitudinal study of repetitive mild TBI. Building on a previous study of neuropathology in headbutting bovids in the wild, this pilot study investigated whether freely headbutting domestic goats, which naturally engage in low-intensity, high-frequency head impacts, accumulate measurable biomarkers of neurodegeneration in cerebrospinal fluid (CSF) and brain tissue. Over a six-month period, three male goats (Capra hircus) were allowed to freely headbutt under continuous video surveillance. Monthly CSF samples were collected, and concentrations of key neurodegeneration biomarkers were measured via multiplex immunoassays, including amyloid {beta} ; peptides (A {beta} 40, A {beta} 42), total and phosphorylated tau (tTau and pTau), glial fibrillary acidic protein (GFAP), S100 calcium-binding protein B (S100B), and neurofilament M (NF-M). Postmortem immunohistochemistry was conducted on prefrontal cortical tissues using antibodies targeting pTau, GFAP, and S100B. Head impact kinematics were quantified using horn-mounted accelerometer and inclinometer sensors that recorded linear acceleration, rotational velocity, and head orientation during naturally occurring headbutting events. Several notable trends were observed. Phosphorylated tau as well as reactive astrocytes were detected in the brain tissue, mirrored by elevated GFAP detected in the CSF. PET TSPO was unsuccessful, however, FDG PET revealed frontal-dominant activity in all goats, and one with asymmetrical activation. Overall, the goats sustained 5,000-7,000 head impacts each over six months, with forces up to 388 N and peak acceleration up to 16.5 g. This multi-modal observational study is the first to characterize neurodegeneration biomarkers and kinematics in headbutting goats. Even at one year old, the combination of pTau and gliosis in both the brain tissue and CSF indicates that the goat s repetitive head impacts begin to show neurodegenerative consequences early in life. Likely, the severity of these consequences increases with headbutts and age, eventually resulting in chronic neurodegeneration. This system shows promise as a large-animal model for the longitudinal study of the onset and progression of neurodegenerative disease.

Acquiring reading proficiency, unlike spoken language, requires the brain to engage several specialized neural systems to map visual symbols (letters) to their corresponding phonological sounds (audiovisual integration), laying the foundation for fluent reading. This study investigates the neural and behavioral trajectory of developing audiovisual (AV) integration during the first year of learning to read. Thirty-two healthy Hebrew-speaking first-grade children were assessed at 3 time points across the school year: beginning, middle, and end of first grade. Participants underwent behavioral testing and brain fMRI scans while performing a block-design fMRI task involving AV matching or non-matching letters and sounds. Together with improvement in behavioral test scores related to general abilities, working memory, cognitive flexibility, and phonemic abilities, a Drift Diffusion Modeling (DDM) analysis of the accuracy and reaction time across sessions suggested faster and more efficient responses as the year progressed. fMRI results showed a significant increase in activation, from the beginning to the end of the first grade, in the left superior temporal gyrus (STG), frontal cortices and parietotemporal cortices, with a shift towards left-lateralization in the fusiform gyrus at the end of the year. These findings point towards the second half of the first grade as the time window for neural specialization and lateralization to phonological and orthographic information. A significant positive correlation between the fusiform gyrus activation and naming objects and colors scores across all sessions links this neural specialization to cognitive flexibility behavioral skills. Key pointsO_LISignificant increase, predominantly between the middle and end of the first grade, in activation in fusiform, left superior temporal, frontal, and parietotemporal cortices across the first grade. C_LIO_LISignificant left lateralization in the fusiform gyrus at the end of first grade. C_LIO_LIPositive correlation between naming skills and a bilateral fusiform gyrus activation throughout the first grade. C_LI

The auditory system decomposes sounds into different frequencies, but does not represent them equally: in the human cochlea, lower frequencies occupy a larger spatial extent than higher frequencies, creating a quasi-logarithmic frequency map with finer low-frequency resolution. It remains unclear whether the primary auditory cortex preserves this quasi-logarithmic frequency mapping, or further magnifies behaviourally relevant frequencies, analogous to the foveal over-magnification in primary visual cortex that is thought to underpin visual hyperacuity phenomena such as Vernier acuity. Here, we used ultra-high field functional magnetic resonance imaging to quantify frequency magnification in the primary auditory cortex of 20 human listeners. We compared cortical frequency magnification to predictions based on published estimates of either cochlear frequency resolution or behavioural frequency discrimination performance, a form of perceptual frequency hyperacuity. Cortical frequency magnification was better predicted by frequency discrimination performance than by cochlear frequency resolution, with an additional unexpected over-representation of frequencies around 1 kHz. These findings suggest that frequency discrimination is constrained by cortical processes rather than by frequency information available at the cochlea, consistent with similar observations in the visual and tactile systems.

Understanding speech in noisy environments relies strongly on binaural cues such as interaural time differences (ITDs) and interaural level differences (ILDs), which support spatial hearing and the segregation of competing sound sources. When these cues are degraded, listeners experience substantial difficulty in complex acoustic environments. Behavioural measures of binaural benefit, such as binaural masking level differences (BMLDs), binaural intelligibility level differences (BILDs), and spatial release from masking (SRM), are well established in normal-hearing (NH) listeners, but they require an active behavioural response. Neural speech tracking using electroencephalography (EEG) has emerged as a promising approach for quantifying neural processing of continuous speech, yet its sensitivity to spatial hearing cues remains insufficiently characterised. In this study, we investigated the neural correlates of spatial release from masking in NH listeners using EEG-based neural speech tracking. Nineteen participants listened to continuous Dutch speech stories presented with masking noise under two spatial configurations, collocated (S0N0) and spatially separated (S0N90), across multiple signal-to-noise ratios (SNRs). Neural tracking of the speech envelope was quantified using both envelope reconstruction and temporal response function (TRF) analyses. Spatial separation enhanced neural tracking of the target speech envelope, particularly at challenging SNRs where behavioural SRM was also observed. TRF analysis further revealed condition-dependent morphologies, including increased amplitudes and decreased latencies of late cortical components consistent with spatial unmasking effects. These neural differences were most pronounced at low SNRs, where spatial cues provide the greatest perceptual benefit. Together, these findings demonstrate that neural speech tracking captures cortical signatures of spatial unmasking and closely reflects behavioural improvements in speech understanding. Establishing these relationships in NH listeners supports the development of objective neural measures for evaluating binaural benefit in difficult-to-test populations.

A critical step in visual cortical maturation is refinement of receptive field (RF) size, producing higher acuity vision. This was previously studied using species with well-developed vision (e.g., carnivores, primates), in which visual experience was necessary for refinement but not maintenance of RFs in visual cortex. In contrast, in Syrian hamsters, a crepuscular species with low visual acuity, dark rearing had no effect on RF refinement in juveniles, but RFs re-enlarged in adulthood, resulting in reduced acuity. These inter-species differences raise the question of whether the need for visual experience is primarily related to the phylogenetic position of the species or to its ecological niche. Here we report that dark rearing had no effect on development or maintenance of RF properties of visual cortical neurons in nocturnal mice. Mice with lifelong visual deprivation refined and maintained their RF size over time. Furthermore, the development of stimulus direction tuning was unaffected by dark rearing. In contrast, surround suppression, orientation tuning and the sharpness of direction tuning were abnormal in dark reared mice. These and our previous results from hamsters show that species living in an ecological niche with minimal daylight exposure require little to no visual experience to develop and maintain refined RFs. This study is an important step in developing a better understanding of the role of visual experience in the development of visual processing circuitry and suggests that diurnal mammals may be a better model for human visual cortical development than mice.

Dietary iron deficiency in the absence of anemia (IDNA) affects numerous people worldwide, with a wide range of negative effects on brain functioning and cognition. Although studies employing electroencephalography (EEG) have revealed a number of negative effects of IDNA in both the time- and frequency domains, to date there have been no attempts to characterize the effects of IDNA on the temporal dynamics of whole brain interactions. To address this issue, we applied multiscale entropy (MSE) analysis to resting-state EEG data collected from IDNA (n = 21) and iron sufficient (IS, n = 21) women. The MSE analysis on this data revealed that entropy was higher overall for the IS than the IDNA group, with significant differences appearing primarily at longer time scales and under right frontal and left and right parietal electrodes. These results suggest that IDNA may negatively affect long-distance interactions among brain regions and that this could conceivably be a source of diminished cognitive function and neural resilience in IDNA.

Modern cochlear implants (CIs) use pulsatile stimulation to restore hearing for individuals with severe hearing loss. CIs provide robust speech recognition in quiet but poorly represent temporal fine structure (TFS), needed for challenging listening situations. Analog stimulation preserves the acoustic waveform and may better encode TFS, yet it has not been evaluated combined with modern current-focusing strategies. We compared neural responses in the inferior colliculus (IC) evoked by CI stimuli consisting of 100 pulses/s biphasic pulse trains and 100 cycles/s sinusoidal analog stimulation with monopolar, bipolar, and tripolar electrode configurations in urethane-anesthetized guinea pigs. Following cochlear implantation, multiunit activity was recorded from the tonotopic axis of the central nucleus of the IC using 16-channel silicon probes. Detection thresholds, spread of excitation, vector strength, sustained response percentage, and temporal response properties were quantified. Analog stimulation consistently evoked significantly lower activation thresholds than pulsatile stimulation while maintaining comparable or sometimes narrower spatial selectivity across stimulation modes. In contrast, analog stimulation generated lower vector strength, larger tonic response components, and a pronounced level-dependent polarity effect. At low stimulus levels, responses were dominated by the cathodic phase of the sinusoidal waveform, whereas increasing stimulus level responses were elicited by both phases, producing synchronization at twice the stimulus frequency. These findings demonstrate that stimulation waveform strongly influences temporal coding while having relatively little effect on the spatial distribution of neural activation. These results provide a physiological basis for reexamining analog stimulation as an alternative strategy for cochlear implant sound coding.

The medial prefrontal cortex (mPFC) plays a significant role in modulating the threat response, particularly in ambiguous circumstances. The mPFC performs this role through its connectivity with multiple brain regions, including the amygdala, long regarded as the central hub for threat responses. However, the roles of specific prefrontal projections to the amygdala in contextual threat discrimination are not yet fully understood, particularly regarding more complex learning tasks and when disentangling the functionally distinct prelimbic (PL) subunit of the mPFC. Here, we challenged mice with a contextual differential threat conditioning (DTC) learning task in which subjects were repeatedly exposed to one context predictive of a foot shock (CS+) and to a similar yet distinct context that was not (CS-). While control mice showed a similar threat response in both contexts immediately after threat conditioning, within a few days of contextual exposures, controls acquire threat discrimination and freeze less to CS- than to CS+ during late DTC. However, we found that inducing localized hypofunction of neuroplasticity in PL neurons projecting to the basolateral amygdala (BLA) impairs performance on DTC. This finding identifies the specific population of neurons in PL cortices as a critical site for learning to discriminate threat.

Basal ganglia-thalamo-cortical circuits are essential for learning complex motor sequences, yet their roles in controlling flexible motor behavior remain poorly understood. The homologous songbird Anterior Forebrain Pathway (AFP) drives song motor learning and was previously thought not to play a role in song performance, as early lesion studies reported no detectable effect. This perspective is now debated, as newer results demonstrate effects in subsets of songbirds. Here, we revisit this question in adult canaries by performing bilateral excitotoxic lesions targeting the lateral and medial subdivisions of the AFP. To quantify behavioral changes across thousands of recorded canary songs, we developed a high-throughput annotation pipeline that extends a self-supervised vision transformer (TweetyBERT) with a supervised classification head, eliminating the memory bottleneck of UMAP-based clustering. This model enables phrase-level analysis across thousands of songs per bird. We find that lesions involving the medial AFP produce a stuttering-like behavior, defined here as a prolonged and variable syllable repetition before transition, resulting in a significant increase in the variability of phrase duration. This effect was strongest in birds with medial+lateral AFP involvement, and was not observed in birds with lateral-only AFP lesions. Phrase duration variability remained elevated across much of the post-lesion recording period and was accompanied by detectable changes in syllable acoustic structure. Our results implicate the medial AFP in the ongoing control of phrase duration in adult canary song, challenging the view that the AFP is dispensable once song is learned. These findings position the medial AFP as a tractable model for understanding how basal ganglia and cortical dynamics jointly maintain complex learned motor sequences.

Nociceptive pain is the most common pain condition, and moderate-to-severe nociceptive pain substantially impacts daily functioning, constituting a significant public health burden. Despite this, most studies investigating the neural mechanisms underlying somatosensory processing and inhibition have focused on other pain conditions (e.g., neuropathic, nociplastic, or mixed pain). Thus, the extent to which neural aberrancies detected in these other populations extend to or differentiate from nociceptive pain conditions remains largely unknown. In this study, 29 individuals with moderate-to-severe nociceptive pain (MSNP) and 47 pain-free (PF) controls underwent magnetoencephalography (MEG) alongside a paired-pulse somatosensory stimulation paradigm to examine somatosensory cortical processing and functional inhibition. Pain status and intensity were determined using validated pain questionnaires, painDETECT and PROMIS-29, respectively. MEG oscillatory responses were source localized via a beamformer to the primary somatosensory cortex (S1) and time series data were extracted from the peak voxel to quantify the dynamics of somatosensory gating (SG; index of cortical inhibitory processing), oscillatory response power, and spontaneous power. We found that adults with MSNP exhibit aberrant theta SG in contralateral S1 compared to PF controls, reflecting reduced functional inhibition of innocuous stimulus processing in this region. Additionally, individuals with MSNP demonstrated exaggerated gamma responses but blunted alpha responses in contralateral S1 to innocuous stimulation. Finally, individuals with MSNP were characterized by weaker spontaneous alpha in contralateral S1 that scaled with self-reported pain intensity. Together, these findings suggest that experiencing MSNP is associated with disrupted somatosensory and cortical inhibitory processing.

How sensory information is processed over time is often conceptualized as a process of temporal integration. Recently, auditory temporal integration has received renewed attention as a potential assay of hidden hearing loss caused by cochlear synaptopathy in rodent and avian studies. How these results relate to human hearing is in question due to a lack of studies in primates, and, more generally, the neural basis of auditory temporal integration is unclear, as most subcortical studies of it have been conducted under anesthesia. We have recently introduced a nonhuman primate (NHP) model which can address translational questions about auditory temporal integration and hidden hearing loss. Thus, in this study, we utilized single-unit recordings and compared derived neurometric measures to psychometric measures of temporal integration in normal hearing NHPs performing a tone-in-noise detection task. We then assessed psychometric measures of temporal integration in NHPs before and after noise exposure. In normal hearing NHPs, cochlear nucleus and inferior colliculus (IC) integration rates were significantly greater than psychometric rates. However, in noise only, [~]25% of IC neurons exhibited similar integration rates to behavior. After noise exposure, psychometric integration was disrupted for brief stimuli presented in quiet, but not in noise. The dynamic range of the psychometric function reliably increased, months after recovery from the noise-induced temporary threshold shift (TTS). Together, these data identify a subcortical neural substrate for temporal integration in noisy environments and suggest that behavioral assays of temporal integration may serve as sensitive indicators of subclinical hearing loss.