Neuroscience Letters

Muscle fatigue potentially interferes with proprioceptive afference from peripheral "movement sensors"-- the proprioceptors, which may hinder the crucial sensorimotor integration and thus locomotor performance. However, little is known about how muscle fatigue affects cortical processing of proprioceptive afference. Twenty-four healthy volunteers (30.7 {+/-} 6.5 yrs, 13 females) participated in the experiment, which included magnetoencephalography (MEG) recordings during ankle proprioceptive stimulation (2-Hz passive movements), and fatigue tasks comprised of isometric ankle plantar flexion. Corticokinematic coherence (CKC) between foot acceleration and MEG signals was examined before (PRE) and [~]3 min after (POST) the fatigue tasks to quantify the cortical proprioceptive processing. CKC peaked in the gradiometer pairs above the foot region of the primary sensorimotor (SM1) cortex in each participant. CKC strength did not show significant difference between PRE and POST at 2 Hz (0.30 {+/-} 0.12 vs. 0.30 {+/-} 0.14, p = 0.981) or its first harmonic at 4 Hz (0.38 {+/-} 0.14 vs. 0.37 {+/-} 0.13, p = 0.724). However, 4-Hz MEG power was [~]30% lower in POST than in PRE. Surprisingly, fatigue-induced bilateral increase of alpha and beta power was observed in SM1 hand regions during the movement stimulation. Our results indicated that the early processing of proprioceptive afference from the ankle joint was negligibly affected by muscle fatigue, or it recovered rapidly. The effects of muscle fatigue on the proprioceptive processing appear to extend beyond the primary somatotopic regions to bilateral SM1 neuronal networks. This cortical adaptation to muscle fatigue potentially preserves proprioceptive processing by modulating SM1 inhibitory neurons, offering a novel perspective for future research on proprioception.

Facial color is associated with the perceptual evaluation of emotions, and compared with faces with original facial or greenish color, reddish angry faces are often judged as having higher emotion intensity. Although perceptual modulation by the relationship between anger and red has also been reported from the perspective of electroencephalography (EEG), how variations in perceived emotion intensity are reflected in brain activity remains unclear. This study investigated whether EEG activity associated with face and facial expression processing is modulated as a function of the interaction between facial color and perceived emotion intensity. In the experiment, we recorded EEGs while participants evaluated emotion intensity using facial stimuli created by combining morph continua from neutral to angry expressions with three types of facial color conditions (original, red, and green). The results revealed that, in the red facial color condition, the early posterior negativity (EPN) amplitude significantly increased as a function of emotion intensity compared with those in the original and green facial color conditions. These findings suggest that the early, automatic affective processing of facial expressions, reflected in the EPN, is modulated by the combination of facial color and emotion intensity. Our findings provide new evidence that early, automatic affective processing of facial expressions, as indexed by the EPN, is modulated by the congruency between high anger intensity and a reddish facial color. HighlightO_LIReddish angry faces increase the ERP component associated with emotion evaluation. C_LIO_LIThe relationship between anger and red is evident in the left hemisphere. C_LIO_LIThe interaction between facial expression and color occurs at a later cognitive processing stage than facial expression or facial color processing alone. C_LI

The current model of the action inhibition network includes the prefrontal cortex and the subthalamic nucleus (STN) connected via the prefrontal hyperdirect pathway. Proactive inhibition refers to preparatory mechanisms that facilitate action inhibition (i.e. enables a person to act with restraint), while reactive inhibition is a sudden stopping triggered by an external stimulus. Most research has focused on the reactive paradigm, with more limited investigation of proactive inhibition. We studied electrophysiologic activity in multiple cortical and STN regions in 17 patients with Parkinsons disease using high-resolution intracranial electrodes. Subjects performed a Go/NoGo task and a simpler Go task. Proactive inhibition was assessed by contrasting Go trials in the context of two tasks. In the rostral middle frontal gyrus, we found increased beta oscillations during movement preparation in Go trials of the Go/NoGo task compared to the Go task. A similar but weaker, preparatory beta modulation was observed in dorsal STN, while central STN was associated with significant modulation in theta power prior to movement. We interpret this activity as a reflection of the role of these regions in proactively restraining anticipated responses. Conversely, inferior frontal gyrus and ventral STN were primarily engaged during rapid post-cue action control. Specifically, withholding of action after the NoGo signal was accompanied by increased theta activity in these regions. Beta modulation within the STN mirrored those of sensorimotor cortex during successful inhibition and movement execution. In both regions, beta activity decreased during movement and was higher when movement was withheld. We conclude that communication within the hypothesized motor control network is frequency dependent, with key nodes promoting specific functions.

Over the last decade, pre-clinical research has witnessed the advancement of human induced pluripotent stem-cell derived 3D brain organoid models and their differentiation into specific brain regions. In the realm of Parkinsons disease research, development of midbrain-specific organoids has enabled studies of this neurodegenerative disorder in patient derived 3D organoid models that attempt to recapitulate the human brain complexity. Within this line of research, neural functionality of the organoid models is established through electrophysiology. As a novel methodological approach, this study aimed to establish whether clustering of electrophysiological activity originating from midbrain organoids would aid in identifying different types of action-potential waveforms exhibited by neurons within the organoid model. Long-term extracellular electrophysiological recordings were conducted by use of a multi-electrode array device. The local field potential signal was spike-sorted, and the extracted putative neuron units were clustered into groups of spike waveform profiles. After establishing this methodological analysis pipeline, the clusters of waveform types were further analyzed in terms of electrophysiology. Results revealed that the clustering approach was successful at identifying three types of spike waveforms categories. Furthermore, it was proposed that one spike waveform profile potentially originated from dopaminergic neurons, which were one on the neural cells populating the organoid models. Overall, this study has successfully established a new methodological clustering approach to analyze electrophysiological data recoded from 3D organoid models in the context of Parkinsons disease modelling and organoid model development research.

ObjectiveCisplatin, a life-saving chemotherapeutic drug, causes ototoxicity. Although sodium thiosulfate is used to prevent ototoxicity in pediatric patients, no other intervention has been approved for clinical use against cisplatin-induced hearing loss. Hence, there is an urgent need to identify drugs that prevent cisplatin ototoxicity. MethodsCBA/J mice were treated with cisplatin (3 mg/kg, i.p., daily for 5 days), and MnTBAP (10 mg/kg, i.p., daily for 8 days) was used to inhibit cisplatin-induced ototoxicity. Auditory brainstem responses (ABRs) and distortion product otoacoustic emissions (DPOAEs) were recorded before and after treatment to assess hearing loss, while immunohistochemistry was performed to examine hair cells and spiral ganglion neuron (SGN) loss. ResultsCisplatin treatment elevated the nitrotyrosine levels in hair cells and SGNs and increased the loss of these cells in the middle and basal cochlear regions. A negative correlation was observed between cisplatin-induced changes in the hair cell count or SGN density and nitrotyrosine levels. Cisplatin elevated the hearing thresholds and lowered the DPOAE amplitudes. However, MnTBAP cotreatment prevented the cisplatin-induced changes in the hearing sensitivity and reversed the morphological changes. ConclusionThe otoprotection observed with MnTBAP cotreatment indicates its potential as a therapeutic drug against cisplatin-induced ototoxicity.

Cav1.2 is an L-type voltage-gated Ca2+ channel (VGCC) that supports Ca2+ influx in response to membrane depolarization. Ca2+ entering via Cav1.2 alters gene expression, activates Ca2+-dependent enzymes and has been implicated in synaptic plasticity. ORL-1 is a Gi/o-coupled G protein-coupled receptor (GPCR) that is expressed in the peripheral and central nervous systems. Both Cav1.2 and ORL-1 are expressed in the hippocampus, where they have been implicated in learning and memory. It is well-documented that ORL-1 interacts with another VGCC, Cav2.2. However, less is known about potential interactions between Cav1.2 and ORL-1. Here, we examine the interplay between Cav1.2 (Cav1c, Cav2{delta}-1, Cav{beta}1) and ORL-1 co-expressed in tsA-201 cells by using biochemical, electrophysiological and confocal imaging analysis. Co-immunoprecipitations revealed that ORL-1 independently interacts with Cav1c and Cav2{delta}-1 subunits of the Cav1.2 channel complex. Electrophysiological recordings revealed that co-expression with ORL-1 reduced Cav1.2 peak current density without altering its biophysical properties. Acute perfusion with the ORL-1 receptor agonist nociceptin (1 M) did not alter Cav1.2 current density. Confocal imaging experiments revealed that ORL-1 significantly decreases Cav1.2 plasma membrane expression by disrupting forward trafficking. Interestingly, ORL-1 did not affect Cav1.2 endocytosis. Overall, our results demonstrate a previously unrecognized interaction between ORL-1 and Cav1.2 that alters Cav1.2 membrane expression without affecting biophysical properties.

Background. Balance training in older adults can lead to reduced centre of mass accelerations and reduced angular momenta after perturbations of unipedal stance, reflecting an enhanced ability to recover balance. It has been suggested that the co-occurring changes in muscle synergies indicated strategy-specific adaptations in feedback control. Methods. We investigated the cortical involvement in such adaptations by focusing on the interaction between muscle synergies and cortical activity after perturbations. Twenty older adults (>65 years) underwent short-term and three-week long-term balance training, and we assessed their recovery from unpredictable mediolateral perturbations during unipedal stance. We measured high-density EEG and activation of leg and trunk muscles. The representations of the balance-related muscle synergies were localised in the cortex using coherence-based beamformers in the {beta}-frequency band. Results. Balance performance was accompanied by task-specific {beta}-band activation in the somatotopic representation of the lower extremities in the primary motor cortex. The {beta}-power significantly dropped during the response to perturbations, while the coherence with the activation of muscle synergies significantly increased, especially for synergies active in the early stage of balance recovery. The task-related changes in cortico-synergy coherence, especially during the later phase of balance recovery, were significantly affected by short-term training. Conclusion. Refinements of feedback control seem to underlie balance improvements in older adults. The significant changes in the cortico-synergy interaction after balance training suggest cortical involvement in these refinements.

Objective: Aftereffects of 1 Hz repetitive transcranial magnetic stimulation (rTMS) often differ within and between subjects and thus show low reliability. In this study we investigated the mean and individual aftereffects of 1 Hz rTMS using two opposing current directions, their reliability and potential influences of current direction, participants' sex and state on cortical excitability modulations. Methods: Thirteen healthy, right-handed participants underwent four experimental sessions separated by at least 7 days receiving 2000 pulses of suprathreshold 1 Hz rTMS over the primary motor cortex per session. Two sessions were conducted with an induced current direction of anterior-posterior - posterior-anterior (AP-PA) and two sessions with a PA-AP current direction. Before and after rTMS, 100 single TMS pulses were administered with the respective current direction and electromyography was recorded from the first dorsal interosseous. Questionnaires on demographic data and subjective ratings were completed during the experiment. Results: Linear mixed effect model analysis revealed that 1 Hz rTMS induced an excitatory aftereffect when applied with the PA-AP current direction, and no aftereffect with AP-PA. There was a substantial interindividual variability with only three subjects showing an inhibition to 1 Hz rTMS overall. Also, current direction was the only predictor of rTMS aftereffect. Reliability values of these aftereffects were in the poor to moderate range. Conclusions: Current direction plays a crucial role in determining 1 Hz rTMS aftereffects. Reliability was found to be moderate at best. Additional to current direction, more factors need to be considered to tailor the 1 Hz rTMS aftereffects individually.

During social interactions, people continuously align their movements and rhythms, a process known as interpersonal synchrony that supports rapport, mutual understanding, and smooth communication. In autism spectrum disorder (ASD), previous studies have often reported atypical or reduced synchrony, but most have relied on aggregate or session-averaged measures that may miss how coordination develops over time. It therefore remains unclear whether interactional differences in autism reflect a general reduction in synchrony or altered temporal dynamics of interpersonal coordination. We examined the temporal dynamics of head-movement synchrony during a structured face-to-face communication task, comparing non-autistic dyads (two typically developing [TD] partners) with mixed-neurotype dyads (one TD speaker paired with one autistic listener), using gyroscope-based tracking and time-resolved trajectory modelling. Phase-based synchrony, indexed by the phase-locking value (PLV), was lower overall in mixed-neurotype dyads. Critically, time-resolved analyses revealed a marked group difference in synchrony trajectories: non-autistic dyads showed progressive, adaptive growth in synchrony over the interaction, whereas mixed-neurotype dyads showed a significantly attenuated, flatter pattern. These findings suggest that autism may involve altered temporal organization of social coordination rather than simply reduced synchrony overall. Lay AbstractWhen we talk with someone, we often naturally match their body language and rhythms without even realizing it. This physical "syncing up" helps us feel connected, builds trust and shared understanding, and makes communication flow easily. Research shows that autistic people might sync their movements differently during conversations compared to non-autistic people. However, past studies usually just measured an overall average of this syncing across a whole interaction. This approach misses how human interactions actually unfold over time. We wanted to know: do autistic people just sync less overall, or does their syncing change differently as the conversation goes on? To find out, we used small motion sensors to track the head movements of adults having structured face-to-face conversations and compared two types of pairs: non-autistic pairs, where both people were non-autistic, and mixed-neurotype pairs, where one non-autistic speaker talked to one autistic listener. We found a notable difference in how the two groups interacted over time. For the non-autistic pairs, the physical syncing grew progressively stronger as the conversation progressed; they progressively "tuned in" to each other. In contrast, mixed-neurotype pairs showed a flatter pattern--their level of syncing stayed relatively constant from start to finish without that same gradual build-up. These findings are important because they suggest that differences in autistic communication are not simply a "lack" or "deficit" in social coordination. Instead, autistic individuals have a distinct style of interacting--one that maintains social engagement without relying on the progressive build-up of physical syncing that non-autistic people use. Taken together, our results highlight the importance of examining how interactions evolve over time to better understand the different ways autistic and non-autistic people communicate.

The amplitude of motor-evoked potentials (MEPs) elicited using transcranial magnetic stimulation (TMS) has been shown to decrease in the short interval prior to response initiation. The cause of this premovement MEP suppression is currently unclear and has been attributed to various processes such as preparation-related inhibition preventing the premature release of planned action or increasing signal-to-noise ratio to facilitate rapid response initiation. The present study explored whether the decrease in MEP amplitude is affected by the task requirements, using reaction time (RT) paradigms that differ in the timeline of preparation and initiation of a motor response. Participants completed simple RT (SRT), choice RT (CRT), and go/no-go (GNG) tasks, while TMS was applied at various times between the warning signal and go-signal. It was hypothesized that if MEP suppression relates to preparation level, the greatest suppression would be observed during the SRT and GNG tasks, as these paradigms encourage advance preparation and response inhibition. Conversely, if the reduction in corticospinal excitability is associated with facilitating response initiation processes, then suppression would be expected for all tasks, including the CRT paradigm in which preparation does not occur until presentation of the go-signal. Results showed MEP amplitudes decreased for all tasks as the go-signal approached; however, both the SRT and GNG had significantly greater MEP suppression 50 ms prior to, and coincident with the go-signal. These results indicate that the nature and origin of the suppression is likely multifactorial and relates to both preparatory and initiation-related processes, with the timeline and magnitude of suppression dependent on the nature of the task being executed. Impact StatementTranscranial magnetic stimulation was used to elicit motor-evoked potentials to examine the timeline of corticospinal activation during the instructed delay period for choice, simple and go/no-go reaction time tasks. For all tasks, corticospinal excitability was initially elevated compared to baseline, followed by a similar magnitude of early suppression. However, just prior to the go-signal, those tasks that allowed advance preparation showed additional suppression, providing novel information linking pre-movement corticospinal suppression to preparatory and inhibition processes.

Cannabidiol (CBD) is a non-psychoactive component of cannabis that has been studied as a potential therapy for chronic pain. CBD attenuates behavioral hypersensitivities in models of neuropathic pain, and promotes production of bioactive lipids (e.g., anandamide), altering lipid signaling. However, a lack of understanding of the mechanisms underlying the therapeutic effects of CBD has hindered development and application of CBD to mechanism-based therapies for pain in people. We asked whether the analgesics effects of CBD were dependent upon the enzyme NAPE-PLD. We used a mouse model of chemotherapy-induced peripheral neuropathy (CIPN) to evaluate the acute and chronic antinociceptive effects of CBD and investigate its mechanisms. Pharmacological specificity was tested with antagonists targeting CB1, CB2, PPAR{gamma}, and PPAR receptors. Mechanisms were further examined using NAPE-PLD and GPR55 knockout mice. We also assessed repeated CBD dosing during both the development and maintenance of paclitaxel-induced CIPN in wild-type, GPR55 KO, and NAPE-PLD KO mice. CBD suppressed paclitaxel-induced behavioral hypersensitivities; these effects were attenuated by a PPAR and PPAR{gamma} antagonists, but not CB1 or CB2 antagonists. CBD reduced both the development and maintenance of neuropathic nociception in a model CIPN in wild-type mice, but these effects were absent in NAPE-PLD KO mice. By contrast, anti-allodynic efficacy of CBD was fully preserved in GPR55 KO mice. Pharmacological blockade of the PPAR receptor and genetic deletion of NAPE-PLD abolished the antinociceptive effects of CBD in a model of CIPN, suggesting a pivotal role for NAPE-PLD and PPAR receptors in CBD-mediated analgesia in chemotherapy-induced neuropathic pain.

Multipotent mesenchymal stem cells (MSCs) including bone marrow stromal cells (BMSCs) have shown analgesic efficacy in recent years. Studies suggested that the therapeutic effect of MSCs was mediated by their secreted small extracellular vesicles (sEVs) mainly exosomes. The present study evaluated the antihyperalgesic effect of BMSC-related sEVs in a mouse model of neuropathic pain involving chronic constriction injury of the infraorbital nerve (CCI-ION). Our separation protocol generated EV particles mostly sized in the range of exosomes (30-170 nm) and express exosome marker proteins CD9, CD81, and Tsg101, suggesting their endosome origin. We show that intravenous injection of BMSC-related sEVs attenuated pain hypersensitivity induced by CCI-ION as indicated by decreased mechanical hypersensitivity (von Frey test) and reduced aversion to noxious stimulation (conditioned place avoidance test). The antihyperalgesic effect of sEVs was observed in both female and male animals, and the effect was dose-dependent. sEVs from NAIVE serum-treated BMSC cultures produced short-lasting antihyperalgesia in male but not female mice, suggesting a subtle sex difference. The antihyperalgesia of sEVs from BMSC culture was blocked by the pretreatment of the culture with GM4869, the antagonist of exosome secretion, suggesting that the effect was not related to other co-isolated soluble mediators but mediated by MSC-derived exosomes. Interestingly, the prior injury condition in which sEVs were isolated favors the pain-relieving effect of sEVs. sEVs isolated from the serum of BMSC-treated animals receiving tendon ligation (TL) injury attenuated hyperalgesia for 24 h, while sEVs from the serum of BMSC-treated NAIVE animals only attenuated hyperalgesia at 3 h after injection. sEVs from the BMSC culture treated with the serum of TL rats were antihyperalgesic, but sEVs from the BMSC culture treated with the serum of naive animals were ineffective. Our results indicate that BMSC-related sEVs produced antihyperalgesia similar to that produced by BMSCs. The results suggest that the interactions between BMSCs and injury conditions are crucially important for producing efficacious sEVs/exosomes and support that the effect of sEVs could be optimized by priming BMSCs with injury-related conditions.

Gamma oscillations are altered in several conditions such as schizophrenia, Alzheimers Disease, and Mild Cognitive Impairment. Both 40-Hz transcranial alternating current stimulation (tACS) and 40-Hz auditory steady-state stimulation can entrain gamma oscillations and improve cognitive outcomes, but their combined effects remain unclear. This study tested whether preconditioning gamma activity with tACS enhances the auditory steady-state response (ASSR) to 40-Hz auditory stimulation, reflecting a potential synergistic interaction. In a within-subject, sham-controlled design, EEG was recorded before and after 40-Hz tACS delivered over bilateral sensorimotor areas in 34 healthy participants. 40-Hz auditory stimulation was administered before and after tACS to evaluate potential changes in ASSR. Source-level gamma power was analyzed in temporal and sensorimotor regions using linear mixed-effects models. Compared to sham, real tACS increased ASSR-related gamma activity in the superior temporal gyrus, with no effects elsewhere or between hemispheres. These findings support the use of multimodal gamma entrainment to enhance neural oscillations. To conclude, combining 40-Hz tACS with auditory stimulation enhances gamma activity more than either intervention alone, supporting potential clinical applications for neuropsychiatric conditions with disrupted gamma oscillations.

Parkinsons disease (PD) is associated with motor impairment and cortical synaptic dysfunction, which involve altered glutamate receptor trafficking, yet the underlying mechanisms remain incompletely understood. VPS26B, a component of the retromer complex, regulates GluA1 recycling in the trans-entorhinal cortex region. However, its role in the primary motor cortex (M1) under Parkinsonian conditions has not been explored. Here, we show that VPS26B levels are reduced in the M1 of an MPTP-induced PD mouse model, accompanied by decreased surface GluA1 and synaptic protein levels. VPS26B overexpression partially attenuated these alterations. In the accelerating rotarod test, VPS26B-deficient mice exhibited unstable motor performance following MPTP administration, whereas VPS26B overexpression was associated with improved performance in both wild-type and knockout mice. These findings suggest that cortical VPS26B may contribute to maintaining glutamate receptor surface expression and synaptic protein levels, especially under Parkinsonian conditions, with potential implications for motor learning.

The addictive properties of opioids are due in part to these drugs ability to alter ventral tegmental area (VTA) activity via activation of mu opioid receptors (MORs) on local and distal inputs. Prior studies have identified numerous opioid-modulated afferents to the VTA, some of which show differing levels of functional modulation by opioids, but the degree to which this parallels differences in receptor expression is not known. Hence, we used retrograde labeling combined with RNAscope to examine oprm1 mRNA expression in VTA-projecting afferents arising from a variety of distal brain regions. Because opioids are thought to be particularly influential on GABAergic afferents to the VTA, we also examined colocalization of oprm1 with GABAergic markers in VTA-projecting neurons. Interestingly, we found that oprm1 mRNA is present in both GABAergic and non-GABAergic VTA-projecting neurons. However, many (though not all) GABAergic afferents expressed higher levels of oprm1 compared to most non-GABAergic afferents (especially those arising from the cortex). These results complement previous anatomical studies that had examined oprm1 expression in these regions but in a non-quantitative way and without regard to their efferent targets. Our findings encourage future work to examine the functional implications of MOR sensitivity within these afferent pathways.

The P300 amplitude reduction, or P3AR, is a decrease in the magnitude of the P300 event-related potential (ERP) waveform, typically measured via EEG during oddball tasks, and widely observed in those diagnosed with Alcohol use Disorder (AUD). Though widely acknowledged as a biological correlate of AUD, most of the extant literature on the P3AR features conventional time-domain measurement approaches, and further, the work has predominantly focused on alcohol use specifically. In order to precisely capture the nature of this association as well as assess generalizability to other substances, the current study utilized advanced time-frequency analyses to compare P3 activity in individuals with AUD, cocaine use disorder, and comorbid alcohol and cocaine use. Time-frequency analyses indexed separable theta and delta activity underlying the conventional time-domain P3. Findings revealed that in the conventional time-domain, we observed P3AR shared across alcohol and cocaine use. These findings replicate literature suggesting P3AR associated with substance use. Within time-frequency analyses, we found broad delta reductions across substances, aligning with literature suggesting that delta is mostly comprised of the P3 ERP. For theta-band activity, we found reductions in. amplitude specific to alcohol users only, with no significant diminutions present for cocaine users. As most previous literature focused on alcohol use, unique theta modulations relative to cocaine users provides theoretical clarity in terms of the association of P3AR to substance use more broadly. The findings of the current study highlight the utility of time-frequency measurement approaches in parsing overlapping activity and indexing separable processes with relevance to substance use otherwise unaccounted for in the time domain.

PurposeParkinsons disease (PD) is a neurodegenerative disease that affects motor control but can also influence sensory perception. Changes in vision and proprioception are well-documented but less is known about how PD alters auditory perception, particularly perception of speech acoustic properties. The current study examined perception of speech rate and intensity in PD and the relationship of auditory perception to disease severity. MethodPeople with PD were compared to age- and hearing-matched controls using perceptual tasks focused on discrimination and learning of speech rate and intensity. For rate discrimination, speech, non-speech, and visual stimuli were included to determine whether performance differences for PD participants and controls were specific to speech. Disease severity was assessed using the MDS-Unified Parkinsons Disease Rating Scale (MDS-UPDRS) and the relationship to performance on perceptual discrimination and learning tasks was evaluated. ResultsPeople with PD performed significantly worse than controls in the rate discrimination task for all types of stimuli. There were no significant group differences for intensity discrimination. However, participants with greater PD disease severity demonstrated significantly poorer intensity discrimination accuracy. Performance on learning tasks utilizing rate and intensity manipulations did not differ between PD and control participants and was unrelated to PD disease severity. ConclusionsPeople with PD had difficulty discriminating rate differences across speech, non-speech, and visual stimuli, indicating that challenges with rate perception are not limited to speech. The relationship between intensity discrimination and disease severity suggests common dopaminergic networks between motor symptoms and auditory perception in PD.

Inflammatory bowel disease (IBD) is characterised by chronic pain, a debilitating symptom for which effective treatments are few and far between. IBD pathogenesis includes the prevalence of a variety of pro-inflammatory cytokines, including the Interleukin-6 (IL-6) family members Il-6 and Oncostatin M (OSM). Previous research has shown disruption of OSM signaling can modulate nociceptor sensitization and activation, however the downstream signalling pathway is unknown. When an in silico analysis of murine colonic sensory neuronal populations was undertaken for receptor expression for OSM and other factors necessary for intracellular signaling, we can find diverse expression indicative of functional signaling. We were able to observe that hyper Il-6 (Il-6 bound to the soluble Il-6 receptor) and OSM can elicit activation of a subset of murine sensory neurons by finding an increase in calcium mobilization following superfusion. This could then be attenuated by the pharmacologic inhibition of all janus kinases or interestingly, TYK2 alone. Furthermore, inhibition of transient receptor potential vanilloid 1 or transient receptor potential ankyrin 1 ion channels, which are known to be sensitized by OSM in other sensory neurons also reduced the proportion of OSM-responsive neurons. This further understanding of OSM signaling in sensory neurons creates avenues for more extensive research into the molecular mechanisms occurring as well as the potential to exploit these therapeutically to induce analgesia in a subset of neurons.

Parkinsons disease (PD) is characterised by progressive dopaminergic neurodegeneration in the substantia nigra, leading to debilitating motor dysfunction. Current treatments remain largely symptomatic, highlighting the need for disease-modifying therapies. {beta}1 integrin, implicated in neuroinflammation and trophic signalling, represents a candidate therapeutic target. We investigated whether allosteric {beta}1 integrin modulation could attenuate motor asymmetry in the unilateral 6-hydroxydopamine (6-OHDA) mouse model of PD. Adult male C57BL/6 mice received intracerebral 6-OHDA into the substantia nigra. The anti-{beta}1 integrin antibody JB1a (50 {micro}g) was administered prophylactically (3 days pre-lesion) or therapeutically (3 or 7 days post-lesion). Motor asymmetry was assessed through spontaneous circling (5 min) and apomorphine-induced (0.5 mg/kg s.c.) circling (30 min). 6-OHDA induced dose-dependent contralateral circling, confirming nigrostriatal lesion. Pre-treatment with JB1a (3 days before 6-OHDA) reduced apomorphine-induced circling, although this did not reach statistical significance (28.5 {+/-} 12.8, n = 4 versus 38.6 {+/-} 7.5, n = 8; p>0.05). Post-treatment at 3 days post-lesion produced no statistically significant change in either spontaneous or apomorphine-induced circling (p>0.05). Post-treatment at 7 days post-lesion reduced apomorphine-induced circling by approximately 50%, with values returning to those of sham-operated controls (n =8-9; p<0.01). These findings, obtained in a murine 6-OHDA model, indicate that allosteric {beta}1 integrin modulation attenuates lesion-induced motor asymmetry with apparent temporal specificity. As apomorphine-induced rotation reflects post-synaptic dopamine receptor supersensitivity rather than direct neuronal preservation, and as histological confirmation of dopaminergic integrity was not obtainable in this study, the present data should be interpreted as proof-of-concept behavioural evidence requiring further mechanistic and translational validation in models incorporating -synuclein pathology. The findings are not directly generalizable to human Parkinsons disease. The histological confirmation of lesion extent was not available and as such the behavioural findings are correspondingly interpreted as a proof-of-concept observation requiring histological replication.

The behavioural activity of freely moving animals is a confounding factor that affects the recording, analysis, and final results of animal EEG experiments. Along with the lack of standardisation in animal in vivo electrophysiology experiments, this could lead to huge inconsistencies, especially in the analysis of centrally acting drugs. Therefore, the main aim of this paper is to investigate the effects of behavioural activity versus inactivity on the multichannel EEG in freely moving rats. In a large sample (n = 116) of waking recordings from 12 cortical electrodes (ECoG) in Wistar rats, we evaluated behavioural activity-related changes in the power spectrum, current source density, and power-based global functional connectivity (GFC) in a 3D rat brain model, according to the TOHOKU Rat Brain Atlas. The main findings were that behavioural activity induced 1) a robust power increase in 6-8 Hz, peaking at 7 Hz with maximum changes over the parietal and temporal cortex, 2) an increase in gamma power (30-80 Hz) across the whole brain, 3) a decrease in delta (1-4 Hz) and beta (12-30 Hz) power across the whole cortex. Changes were also localised in subcortical regions, particularly in the diencephalon/thalamus. The GFC analysis showed a similar pattern of power changes across the 6-8 Hz, delta, and beta bands; however, GFC in the gamma band decreased. Again, the GFC analysis revealed changes in connectivity within subcortical structures, primarily in the thalamus. None of the measures was affected in the alpha band (8-12 Hz). These findings emphasise behavioural state as a critical factor influencing EEG outcomes, with important implications for the standardisation and translational validity of preclinical neurophysiological studies.