Brain Research

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.

Background. Pain influences motor function and has been proposed to reduce corticospinal and intracortical excitability. At the same time, performance can be maintained during pain, at the cost of increased perceived effort, a centrally generated signal reflecting resource engagement. Here, we tested whether contralateral thermal heat pain-related changes in corticospinal and intracortical excitability contribute to increased effort perception. Methods. In this preregistered transcranial magnetic stimulation (TMS) study, twenty-one healthy participants received single and paired pulse TMS at rest and during submaximal isometric right wrist flexions performed at 20% maximal peak force. Trials were conducted under a control condition or during contralateral thermal stimulation (painful or non-painful warm) applied to the left forearm. After each contraction, participants rated the intensity of their perceived effort. Corticospinal and intracortical excitability of the right wrist flexor was assessed at rest and during submaximal contractions. Results. Contralateral heat pain significantly increased perceived effort compared with the control and warm conditions. Contralateral heat pain did not reduce corticospinal or intracortical excitability. Conversely, contralateral heat pain increased corticospinal excitability, reflected primarily in decreased cortical silent period duration. Perceived effort was associated with the subjective experience of pain rather than with TMS-derived variables. Conclusions. These findings suggest that increased effort during contralateral heat pain cannot be attributed to inhibition of the primary motor cortex or the corticospinal pathway. The higher perceived effort in the presence of contralateral heat pain likely reflects the cognitive cost of pain rather than alterations in the transmission of the motor command.

Fast periodic visual stimulation (FPVS) has recently demonstrated an ability to index multiple cognitive domains such as facial expression processing, working memory, and more recently, semantic categorization in just a few minutes of recording time. The present work investigates the effects of low semantic distance and how this modulates semantic categorization responses. Twenty-seven healthy young adults completed an FPVS oddball paradigm in order to determine whether comparing fruits and vegetables of the same color would elicit semantic categorization responses. Strong oddball responses were observed up to the 10th frequency harmonic, and responses showed statistically significant right occipito-temporal lateralization that was not present in a low-level color change condition completed by participants and is opposite the pattern observed in recent word-based semantic categorization FPVS studies. The findings suggest that image-based FPVS paradigms should be investigated further as candidate tools to study conditions that affect semantic categorization such as Alzheimers disease.

Neural stem cell (NSC) transplantation is a promising strategy for repairing the injured spinal cord, but transplanted cells typically require immunosuppressive therapy to prevent rejection, even for induced pluripotent stem cell (iPSC)-derived autologous grafts. However, the effects of immunosuppressive drugs on neurite outgrowth and axonal regeneration, processes critical for neural circuit reconstruction, have not been fully characterized. In this study, we tested nine clinically relevant immunosuppressants on human iPSC-derived neurons and primary human spinal cord NSCs in vitro at concentrations approximating clinical exposure levels. The drug panel included FK-506 (tacrolimus), cyclosporine A (CsA), rapamycin, belatacept (Nulojix), etanercept (Enbrel), mycophenolate mofetil (CellCept), cyclophosphamide (Cytoxan), prednisone, and azathioprine (Imuran). Neurite outgrowth was quantified via automated high-content imaging. Multiple agents, including CsA, Imuran, Nulojix, and CellCept, induced significant reductions in neurite outgrowth in a cell type- and dose-dependent manner, with CsA producing the most robust and consistent inhibition across both cell lines. In contrast, FK-506 showed no significant effect on neurite extension at clinically relevant concentrations. Consistent with the in vitro results, human neural progenitor cell grafts in a rodent spinal cord injury model exhibited significantly reduced graft-derived axon extension in the host spinal cord when hosts were treated with CsA rather than FK-506. These findings demonstrate that immunosuppressant choice can profoundly influence neural graft integration and axonal regeneration. Our study underscores the importance of preclinical evaluation of immunosuppressive regimens and suggests that selecting agents such as FK-506 over CsA may improve outcomes in future stem cell-based therapeutic trials for spinal cord injury and related disorders of the central nervous system.

Spinal cord injury (SCI) results in dysfunction of both motor and sensory systems, which can be characterized by neuropathic pain, hypersensitivity, muscular spasticity and rigidity. Most SCIs result from incidents such as vehicle accidents or falls, resulting in polytraumatic SCI that includes peripheral injuries in addition to direct CNS damage. Recent findings suggest that spinal cord synaptic plasticity plays a crucial role in neuropathic pain pathophysiology, specifically in association with spinal sensitization and the consequent onset of AMPA-related maladaptive plasticity. Further findings have demonstrated that nociceptive peripheral stimulation in the acute phase of SCI results in maladaptive spinal synaptic plasticity by overdriving GluA2-lacking calcium-permeable AMPARs (CP-AMPARs). Here, we investigated the effect of a spared nerve injury (SNI) in conjunction with SCI to determine the effect of polytraumatic SCI on maladaptive plasticity in the spinal cord. Near-IR quantitative Western blot analysis demonstrated that SCI+SNI increases spinal GluA1 expression, but not GluA2. Patch-clamp confirmed that AMPAR currents in spinal motorneurons increase after SCI with SNI, and decrease after the administration of NASPM, a CP-AMPAR antagonist. Data-driven analysis using non-linear principal components analysis (NL-PCA) also demonstrated that SCI with SNI produces a multivariate signature of AMPAR plasticity that is observed in other forms of nociceptive peripheral input, indicating a general mechanism for maladaptive plasticity in spinal motor systems in response to polytraumatic SCI.

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.

Abstract Objectives To evaluate and compare the neuro-behavioural safety profiles of piroxicam and nitroglycerine by investigating their differential effects on cognitive function, spatial and recognition memory, and hippocampal neurochemistry in a di-oestrous female Wistar rat model. Methods Female Wistar rats at di-oestrous were randomly assigned to receive distilled water, piroxicam, or nitroglycerine orally for four consecutive days. Following treatment, spatial and recognition memory were evaluated using standard behavioural paradigms. Hippocampal tissues were analysed for acetylcholinesterase and glutamate activity, oxidative stress markers, and neuroinflammatory indices. Results Piroxicam improved recognition memory and was associated with increased glutamatergic activity and a compensatory rise in superoxide dismutase. However, it also elicited elevated nitric oxide signaling, lipid peroxidation, and localized neuroinflammatory markers in the hippocampus. In contrast, nitroglycerine impaired non-spatial memory during di-oestrous. Although both treatments preserved working memory, they produced distinct effects on object recognition, memory discrimination, oxidative stress parameters, and neuroinflammatory mediators. Conclusions Piroxicam and nitroglycerine exert differential effects on cognition and hippocampal neurochemistry during di-oestrous. Piroxicam improved recognition memory and produced distinct hippocampal neurochemical alterations, whereas nitroglycerine impaired recognition memory. These findings highlight the influence of menstrual pain therapeutics on cognitive function and hippocampal physiology under hormonally sensitive conditions. Keywords: cognitive function; cognitive impairment; cyclooxygenase inhibitors; neuroinflammation; neurochemistry

IntroductionThe proteasome is a critical cellular degradative machinery impaired in late-stage Alzheimers disease (AD). However, the status and activity of the proteasome in early-stage sporadic AD (sAD) is unknown. MethodsA cellular model of human early-stage sAD was generated from sAD patient iPSC-derived cortical neurons by dual-SMAD inhibition. The iPSCs, neuroprogenitors, and cortical neurons were validated by the expressions of key markers. The level of total intraneuronal A{beta} was measured by ELISA. Composition and native proteolytic activities of the proteasome in control and sAD cortical neurons were measured using complementary fluorogenic probes. ResultsControl and sAD patients iPSCs expressed pluripotent markers OCT4, NANOG, and SSEA4 which induced into neuroprogenitors expressing NESTIN and PAX6. The neuroprogenitors terminally differentiated into cortical neurons expressing neuronal markers MAP2 and TUJ1, and cortical layer marker TBR1. The level of intraneuronal A{beta} in the sAD cortical neurons was significantly higher compared to control. Control and sAD cortical neurons expressed native 30S, 26S, and 20S proteasome assemblies with the sAD cortical neurons displaying higher 20S assemblies. Increased active 20S assemblies was associated with higher {beta}1, {beta}2, and {beta}5 proteolytic sites activities. DiscussionThe significant elevation in the proteolytic activities of the {beta}1, {beta}2, and {beta}5 subunits of 20S proteasome in sAD cortical neurons suggests that this may be a possible compensatory response to elevated intraneuronal A{beta}. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=120 SRC="FIGDIR/small/734021v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@1d8c382org.highwire.dtl.DTLVardef@b92e8org.highwire.dtl.DTLVardef@1d9c699org.highwire.dtl.DTLVardef@7d826d_HPS_FORMAT_FIGEXP M_FIG C_FIG

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.

ObjectiveLateral spinal cord stimulation (LSCS) is a promising approach for restoring somatosensory feedback in lower-limb amputees, but its spatial selectivity remains limited. Percepts often spread to unintended regions of the residual limb, and reducing electrode contact size may not improve focality. This study investigated whether the anatomical organization of lumbar dorsal rootlets (DR) imposes fundamental constraints on LSCS selectivity. ApproachAcute neurophysiology experiments were performed in six adult cats. Both LSCS and individual DR stimulation were conducted in the same animals. For DR stimulation, bipolar hook electrodes were used to stimulate individual DR, while antidromic compound action potentials (CAPs) were recorded from femoral and sciatic nerve branches instrumented with nerve cuffs. For LSCS, custom 32-contact epidural paddle electrodes were placed over the lateral surface of the spinal cord at corresponding vertebral levels. Recruitment thresholds, dynamic ranges, and response patterns were analyzed across spinal levels, and DR recruitment patterns were directly compared to those evoked by LSCS within the same animals. Main resultsA clear rostrocaudal organization was observed across spinal levels during stimulation of individual DR, with femoral branches predominantly recruited at L4-L5 and sciatic branches at L6-L7. However, no somatotopic organization was found across DR within each spinal level; individual DR frequently co-activated multiple branches within the same group, and selective recruitment could only be maintained over a narrow dynamic range (median [~]10 {micro}A). LSCS exhibited even a narrower dynamic range ([~]5 {micro}A) but closely mirrored DR recruitment patterns, indicating that LSCS activates sensory afferents in a manner determined by the organizational structure of the DR. SignificanceThese findings demonstrate that the limited spatial selectivity of LSCS can largely be attributed to the coarse organization of DR within each root level rather than due to limitations of epidural electrode design. Moving electrodes intradurally or reducing contact size further is unlikely to substantially improve focality. Instead, improving paddle stability to ensure consistent placement over the appropriate spinal levels may be a more effective strategy for enhancing percept localization.

Background: Chronic and non-healing wounds remain a major clinical challenge with limited therapeutic options. Angiogenesis and inflammation are central to tissue repair, and mesenchymal stem cells (MSC) contribute to these processes through their trophic and immunomodulatory secretome. Cannabidiol (CBD) exhibits antioxidant and immunomodulatory properties. However, whether CBD-rich Cannabis sativa extract stimulate MSC toward a pro-angiogenic secretome remains unclear. Purpose: This study aims to determine whether purified CBD or a phytochemically CBD-rich full spectrum extract stimulate umbilical cord-derived human MSC (UC-hMSC) to secrete pro-angiogenic factors and enhance endothelial responses relevant to wound healing. Methods: UC-hMSC were preconditioned with either purified CBD or a CBD-rich full-spectrum extract. Transcriptional changes were assessed by qPCR. The functional impact of the resulting secretome was evaluated in vitro using HUVEC-based proliferation and tube formation assays, and in vivo through the chick chorioallantoic membrane assay. To explore underlying mechanisms, we examined HIF-1 stabilization and VEGFA release in UC-hMSC, and VEGFR-2/ERK signaling in HUVEC. Results: Purified CBD and full-spectrum CBD extract preconditioned UC-hMSC secretomes, increased HUVEC proliferation, tube formation, and enhanced vascular branching in the CAM assay. Mechanistic analyses indicated activation of the HIF-1/VEGF axis in UC-hMSC, and ERK1/2 activation in HUVEC that was sensitive to VEGFR-2 blockade. Conclusion: Purified CBD and CBD-rich full-spectrum extract prime UC-hMSC toward a pro-angiogenic secretome that promotes endothelial activation and neovascularization. These findings suggest that cannabinoid-based preconditioning of UC-hMSC involves the HIF-1/VEGF axis and VEGFR-2/ERK signaling pathways in endothelial cells, supporting further investigation of this approach in wound healing and regenerative therapies.

Background The ischemic penumbra, a metabolically compromised yet potentially salvageable region surrounding the ischemic core, is a prime target for acute stroke intervention. Yet an objective molecular definition of the penumbra, particularly during the earliest stages of ischemia, remains lacking. Methods and Results We applied principal component analysis (PCA) followed by k-means clustering to high-resolution mass spectrometry imaging data covering multiple metabolic pathways to identify a metabolically defined penumbra in a mouse model of hyperacute stroke (45 min middle cerebral artery occlusion, MCAO). Targeted spatial metabolomic profiling by matrix-assisted laser desorption/ionization (MALDI) and desorption electrospray ionization (DESI) reveals a distinct penumbral metabolic profile, marked by relative preservation of high-energy phosphates, comparable lactate accumulation, and reduced succinate accumulation relative to the core. Spatial transcriptomics revealed selective induction of immediate-early genes, including Npas4, Fos and Junb, within the penumbra. Consistently, imaging mass cytometry shows enrichment of phospho-histone H3 (pHH3) within the penumbra, suggesting a chromatin-associated response potentially linked to immediate-early gene activation. Conclusion Together, these findings provide a multimodal molecular atlas of the hyperacute metabolically defined penumbra and reveal molecular features that facilitates its identification and inform future therapeutic strategies.

Atrial fibrillation (AF) is associated with an increased risk of neurological morbidity, yet its impact on cerebral perfusion and neuro-cardiorespiratory regulation remains incompletely understood. We used arterial spin labeling, blood oxygenation level-dependent functional MRI (BOLD-fMRI), and a breath-hold challenge to characterize alterations in 14 AF patients compared with 14 age-matched healthy controls. We also examined the changes after catheter ablation with pulmonary vein isolation (PVI) in a subset of patients. Compared with controls, AF patients exhibited widespread reductions in basal cerebral perfusion, including in brainstem regions involved in cardiorespiratory regulation, and a higher prevalence of periodic breathing during wakeful rest. During breath-hold challenge, the coupling between heart rate and BOLD signal changes ({Delta}BOLD) was smaller in AF, whereas {Delta}BOLD coupling with breath-by-breath O2-CO2 exchange ratio was greater at rest within pontine respiratory centers, indicating altered cardiac and respiratory contributions to cerebral hemodynamic regulation. Follow-up MRI scans 1-6 months after PVI demonstrated that restoration of sinus rhythm was associated with stronger heart rate-{Delta}BOLD coupling during breath-hold challenge, whereas basal cerebral perfusion showed no significant change. This dissociation suggests distinct temporal responses of neuro-cardiorespiratory coupling and cerebral perfusion after sinus rhythm restoration, while the timing of cerebral perfusion recovery remains unresolved.

Serotonin 5-HT4 receptors (5-HT4Rs) have emerged as potential therapeutic targets in neuropsychiatric and neurodegenerative disorders by modulating circuits that shape mood, cognition, and motor function. Ligands for 5-HT4Rs can modify dopamine (DA) and acetylcholine (ACh) transmission but mechanisms and circuits have not been fully resolved. Some 5-HT4R agonists have been suggested to have effects that include inhibition of acetylcholinesterase (AChE), raising speculation that 5-HT4R ligands might modulate ACh and/or DA through this action. Here, we investigated the impact of RS67333, a partial 5-HT4R agonist, on DA and ACh release dynamics in the striatum detected ex vivo in mouse brain slices using fast-scan cyclic voltammetry and genetically encoded ACh sensor GRABACh3.0 respectively. We found that RS67333 significantly modulated electrically evoked DA release in dorsolateral striatum and nucleus accumbens core, effects that were abolished by a nicotinic receptor (nAChR) antagonist. In parallel, RS67333 altered evoked ACh signals by extending extracellular ACh lifetime, and correspondingly, RS67333 was found to inhibit striatal AChE enzymatic activity. By contrast, BIMU8, an alternative 5-HT4R ligand that did not inhibit striatal AChE, had no effect on evoked striatal ACh or DA release. These findings indicate that RS67333 modulates striatal ACh transmission, which shapes downstream regulation of DA release by nAChRs, not through 5-HT4Rs but through AChE inhibition. These findings emphasize the caution due in attributing functions to 5-HT4Rs, but also highlight an alternative pharmacological profile of some purported 5-HT4R ligands as AChE inhibitors of potential utility for treating ACh/DA disorders.

ObjectiveAging is associated with changes in cortical excitability and altered responsiveness to benzodiazepines, but the effects of benzodiazepine challenge on motor cortical paired-pulse physiology in older adults remain incompletely understood. We examined whether intravenous midazolam differentially modulates corticospinal excitability and short-interval paired-pulse transcranial magnetic stimulation (TMS) responses in younger and older adults. MethodsFifteen younger adults (18-35 years) and fifteen older adults (50-69 years) underwent single-pulse and paired-pulse TMS of the left primary motor cortex at baseline and during intravenous midazolam administration. Single-pulse motor evoked potential (MEP) amplitude was used to assess corticospinal excitability. Short-interval paired-pulse responses were quantified as the ratio of conditioned to unconditioned MEP amplitude. ResultsAt baseline, younger adults showed greater corticospinal excitability than older adults, reflected by larger single-pulse MEP amplitudes (adjusted p = 0.04). Younger adults demonstrated paired-pulse inhibition at baseline, reflected by a conditioned/unconditioned MEP ratio below 1.0 (ratio = 0.73; adjusted p < 0.01), whereas older adults did not show inhibition and instead had a mean ratio above 1.0 (ratio = 1.25). Midazolam reduced single-pulse MEP amplitudes in both groups. During midazolam administration, paired-pulse inhibition was no longer observed in younger adults, and older adults continued to show no evidence of inhibition. ConclusionsYounger and older adults differed in baseline corticospinal excitability and in short-interval paired-pulse TMS responses. Intravenous midazolam reduced corticospinal excitability and altered paired-pulse response patterns, eliminating baseline paired-pulse inhibition in younger adults while producing little measurable change in older adults. These findings suggest that aging may modify the net motor cortical response to benzodiazepine challenge. The results should be interpreted in relation to the paired-pulse stimulation parameters used and support further studies using complementary approaches to characterize age-related differences in inhibitory and facilitatory motor cortical circuits.

Background: The ability to remember object locations in real life is a fundamental cognitive process that supports goal-directed behavior and is particularly vulnerable to aging and neurodegenerative disease. Despite a growing body of functional magnetic resonance imaging (fMRI) research on object-location memory (OLM), the neural substrates of establishing and retrieving location information are largely unknown. Objective: This systematic review and coordinate-based meta-analysis aimed to identify brain regions consistently activated during OLM in healthy adults, primarily for encoding and - on an exploratory basis - for retrieval, and to characterize age-related differences in OLM-related neural activity. Methods: A systematic search was conducted across three databases (PubMed, PsycInfo, Cochrane Library) up to February 2026. Studies employing task-based fMRI during the encoding and retrieval of object-location associations in healthy adults were eligible. Age-related differences in OLM-related brain activity were examined via narrative synthesis. An activation likelihood estimation (ALE) meta-analysis was performed on studies reporting stereotactic peak coordinates. The review was pre-registered on PROSPERO (CRD420251023695). Results: Twenty-one studies comprising 637 participants were included in the systematic review, with 12 studies being eligible for the encoding ALE meta-analysis. The retrieval ALE meta-analysis was not possible due to the limited number of included studies and reported foci. The systematic review indicated that OLM encoding consistently recruited bilateral fusiform gyri and parahippocampal cortices, with additional engagement of parietal and prefrontal regions across individual studies, whereas OLM retrieval recruited mainly the hippocampus and precuneus. The coordinate-based ALE meta-analysis revealed two significant clusters of activation during OLM encoding: a left-lateralized cluster encompassing the fusiform gyrus, parahippocampal gyrus, and inferior temporal gyrus (peak MNI: -28, -38, -16), and a right-hemisphere cluster spanning the parahippocampal gyrus and fusiform gyrus (peak MNI: 30, -46, -16). Age-related differences, based on a small number of studies with direct age comparison, pointed toward reduced activity in posterior cortical regions coupled with increased activity in prefrontal and midline regions. Additionally, younger adults showed greater hippocampal activation for successful than unsuccessful spatial retrieval, whereas older adults showed the opposite pattern. Conclusion: The systematic review and meta-analysis identify the fusiform gyri and parahippocampal cortices as the most reliably activated regions during OLM encoding, locating OLM formation primarily within the ventral visual-to-medial-temporal processing stream. Retrieval additionally engaged the hippocampus and precuneus, consistent with their established roles in episodic memory. Age-related differences included reduced posterior cortical encoding activity in older adults, a reversal of the hippocampal activation pattern during retrieval, and weaker suppression of midline regions during task performance. The identified encoding pathway may inform targeted network-level interventions such as non-invasive brain stimulation to counteract cognitive decline in aging and neurodegenerative disease.

Moderate-to-severe traumatic brain injury (msTBI) is recognized as a chronic and evolving neurological condition characterized by progressive structural brain changes and persistent cognitive impairment. While prior studies have demonstrated widespread atrophy following msTBI, less is known regarding the longitudinal trajectory of gray matter (GM) changes during recovery and post-rehabilitation. The current study used longitudinal voxel-based morphometry (VBM) to characterize GM volume changes over a period of 9 months, in individuals with msTBI relative to healthy controls (HC). Associations between regional GM volume and neuropsychological functioning were examined. Twenty-eight participants (14 msTBI, 14 HC) completed MRI and neuropsychological assessments across three timepoints spanning outpatient rehabilitation and follow-up. Longitudinal VBM analyses revealed significant group and time interactions within subcortical and limbic regions. Relative to HC, individuals with msTBI showed lower GM volume in these regions at baseline, with trajectories that converged toward HC values (right hippocampus) or increased relative to HC over the rehabilitation period (bilateral pulvinar), whereas the right amygdala and inferior cerebellar vermis remained persistently reduced. Significant longitudinal improvements in memory and psychomotor speed during the rehabilitation period were demonstrated in msTBI. Greater (preserved) GM volume within the right hippocampus, thalamus, and bilateral pulvinar was associated with better performance across measures of verbal memory, processing speed, executive functioning, and cognitive flexibility. These findings suggest that msTBI is associated with dynamic structural brain changes involving subcortical, limbic, and cerebellar networks, and that the rehabilitation period was accompanied by relative volumetric stabilization in these regions and by meaningful cognitive improvement.

Background: Dopamine (DA) is a neurotransmitter critically involved in food-related reinforcement learning. While mesolimbic DA reward-associated signaling in the nucleus accumbens has been widely investigated, far less is known about DA function in the hippocampus (HPC), a brain region traditionally known for its role in episodic and spatial memory processes that has recently been associated with appetite and food intake control. Methods: Here we investigated dorsal HPC DA signaling dynamics in rats using fiber photometry to detect changes in DA binding (via GRAB-DA sensors) before, during, and after a meal consumption in food-restricted rats. Pharmacological studies targeting HPC dopamine 2 receptors (D2R) assessed the functional role of HPC DA signaling in food intake and meal-related memory processes. Results: HPC DA binding was significantly elevated in the post-meal relative to the pre-meal state following standard chow consumption. This effect was replicated after consuming a high fat diet or liquid sucrose, but not a low-calorie sweetener. These post-meal DA signaling elevations are dependent on nutrient consumption, as HPC DA binding levels were unaffected by intraperitoneal administration of glucose or the satiation hormone, cholecystokinin, in otherwise fasted rats. Direct HPC D2R agonists administration reduced food intake, whereas HPC D2R blockade after a meal reduced the latency to the next meal and impaired spatial memory for meal location without affecting spatial memory for object location. Conclusions: Collective results identify HPC DA-D2R signaling as a candidate neurobiological mechanism through which nutrient consumption promotes meal-related episodic memory formation, and by extension, reduces subsequent food intake.

Background Cortical processing of the knee-joint proprioception is largely unknown. Magnetoencephalography (MEG) can be used to quantify the cortical processing of the proprioceptive afference, but MEG-compatible and well-controlled stimulation of the knee joint is technically challenging, and thus has received less attention. New method We introduced a novel MEG-compatible stimulator that delivers controlled patellar tendon stretches to activate muscle afferent of the knee extensors. The stimulus intensity is adjustable, allowing graded activation of proprioceptive input and, when required, elicitation of the patellar-tendon reflex. Results The novel stimulator elicited clear muscular and cortical responses in both intensity conditions. Cortical responses demonstrated moderate to excellent intersession reliability for peak evoked field amplitude (ICC: 0.69--0.96), beta suppression (0.89--0.90) and beta rebound (0.96--0.97). Notably, beta suppression peaked more laterally than expected in both hemispheres. Peak EMG amplitudes in VL and VM muscles were reliable for both intensity conditions (ICC: 0.66--0.89), and stimulus kinematics remained consistent throughout measurements. Comparison with existing methods Previous robotic or motor-driven devices have been used to evoke cortical responses to knee-joint proprioceptive stimulation, but mechanical coupling across adjacent joints may limit knee-specific input. The present stimulator provides mechanically simple and MEG-compatible alternative that targets knee extensor afferents more directly, reduces distal joint involvement. Conclusion The novel stimulator is a feasible and repeatable tool to study cortical processing of proprioceptive afference from the knee-joint using MEG. The spatially unexpected beta rhythm suppression suggests that knee-joint proprioceptive afference may involve more unique sensorimotor cortical neuronal network than previously recognized.

Background: Norepinephrine (NE) released from locus coeruleus (LC) projections regulates astrocyte structure and function through adrenergic receptor signaling. We previously showed that increasing noradrenergic tone with the NE reuptake inhibitor desipramine increases astrocyte ramification in the molecular layer of the dentate gyrus. However, whether tonic LC-derived noradrenergic tone is required to maintain astrocyte morphological complexity in vivo, and whether {beta}-adrenergic receptor activation is the effector pathway, remained unclear. Methods: Adult male C57BL/6J mice received DSP-4 (50 mg/kg X 3 days i.p.), a selective LC neurotoxin, with or without concurrent isoproterenol that continued for 21 additional days post cessation of DSP-4 treatment (ISO; 2 mg/kg/day X 24 days), or saline (n = 4 mice per group). Animals were sacrificed 22 days after the final DSP-4 injection. Noradrenergic denervation was confirmed by dopamine {beta}-hydroxylase (DBH) immunostaining. GFAP-immunostained astrocytes in the molecular layer of the dentate gyrus were morphologically characterized using Sholl analysis. Astrocyte density was quantified by SOX9 immunostaining. Results: DSP-4 produced >83% reduction in DBH fiber coverage in the molecular layer. Sholl analysis revealed significant reductions in astrocyte branching complexity in both treatment groups, with the reductions concentrated at distances of 5-15 m from the soma. The maximum number of intersections was also significantly reduced in both groups. Unexpectedly, ISO did not rescue morphological complexity. While DSP-4 alone did not alter astrocyte density, as measured by the number of SOX9-expressing astrocytes, DSP-4+ISO increased SOX9-positive cell density, dissociating the effects of adrenergic signaling on morphology from those on cell numbers. Conclusions: LC-derived noradrenergic tone is required for the maintenance of astrocyte arbour complexity in the dentate gyrus molecular layer. {beta}-adrenergic receptor activation alone is insufficient to restore structural integrity following noradrenergic denervation, yet promotes astrocyte density independently of structural remodeling. These findings have implications for understanding how LC neurodegeneration in Alzheimer's disease and depression may compromise hippocampal astrocyte structure and function.