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17 papers

The Human Dorsolateral Prefrontal Cortex in Pain and Pain Modulation: A Review and Activation-Likelihood Estimation Approach.

Crawford LS et al. · Jul 1, 2026

Background The dorsolateral prefrontal cortex (dlPFC) has become a cornerstone of pain neuroscience, believed critically involved in processing acute and chronic pain, as well as in pain modulation. The dlPFC is thought to balance sensory perception with the cognitive appraisal of noxious stimuli. In humans however, the dlPFC spans several cortical nodes, and little attention has been given to precisely which subareas are tethered to these delineable processes. The primary goal of this review and co-ordinate based meta-analysis was to precisely map dlPFC areas engaged under varied effects on overall pain perception. Methods Here, we combined a stringent meta-analytic approach of neuroimaging studies reporting dlPFC activation as a core finding (i.e., within title, abstract, or keywords of each manuscript), with activation likelihood estimation to determine dlPFC engagement across experimental acute pain (combined n = 814), chronic pain (combined n = 2467), and the pain modulatory phenomenon of placebo analgesia (combined n = 791), conditioned pain modulation (combined n = 184), and offset analgesia (combined n = 47). Through activation likelihood estimate and foci analysis, we produced schema of the similar and disparate locations of dlPFC activity within and between pain perceptual and modulatory effects. Results During both acute and chronic pain and in placebo analgesia, we identified remarkably similar activation patterns predominantly within Brodmann areas 8, 9, and 46-with no clear laterality effect and the left and right cortical hemispheres engaged regardless of the site of experimentally applied or conditionally-present pain. Offset analgesia and conditioned pain modulation appeared to preferentially engage Brodmann areas 8 and 45, and 9 and 46, respectively. Conclusions Despite the dlPFC large cortical surface area, these findings suggest that both the percept and inhibition of pain by placebo engage a similar focussed area of this region. Better understanding of exactly which cortical components of the extensive cortical pain system are involved in pain perception and modulation is critical for refining novel treatments such as non-invasive brain stimulation which seek to target and modulate specific sites of cortical processing to alleviate pain. Significance statement This meta-analysis precisely maps the dorsolateral prefrontal cortex (dlPFC) subregions engaged across acute pain, chronic pain and major endogenous pain-modulation paradigms. By integrating data from more than 4000 participants, it provides the most anatomically resolved evidence to date that dlPFC engagement is a shared feature of pain perception and modulation. These findings refine the cortical targets most relevant for therapeutic neuromodulation and strengthen the rationale for dlPFC-focused interventions in pain treatment.

Neuroscience

The role of moral identity in ideological obsession and violent extremism.

Bélanger JJ et al. · Jul 1, 2026

This research examines how ideological passion shapes moral identity and support for political violence, drawing on the Dualistic Model of Passion to distinguish between obsessive (OP) and harmonious passion (HP). Across six studies with diverse ideological groups, OP consistently predicted the adoption of a villainous moral identity, whereas HP predicted a heroic identity. Studies 1A (N = 202; Democrats) and 1B (N = 232; Republicans) showed that OP was associated with villain identity, which mediated support for political violence. Study 2 (N = 315; environmentalists) experimentally manipulated passion, demonstrating that an OP mindset increased villain identification and violent endorsement. Study 3 (N = 179; Black Lives Matter supporters) manipulated moral identity directly, revealing that adopting a villain role amplified support for political violence. Studies 4 (N = 277; U.S. Muslims) and 5 (N = 294; Republicans, preregistered) examined mechanisms of appeal, showing that OP individuals perceived villains as warm, which reinforced villain identification. Finally, Study 6 (N = 236; environmentalists) showed that villain identity was tied to a coherent pattern of moral inversion-villains recast as justified and not harmful, heroes as harmful-which in turn predicted support for political violence.

Neuroscience

A Non-Channel Function of CFTR: Attenuating Mitochondrial Oxidative Stress and Cardiomyocyte Senescence via Stabilization by USP45.

Chen C et al. · Jul 1, 2026

Cardiomyocyte senescence drives cardiovascular disease, underscoring the need to define its molecular mechanisms. The role of cystic fibrosis transmembrane conductance regulator (CFTR) ion channel in this process remains unclear, particularly regarding its expression and function. Atrial tissues were collected from patients with sinus rhythm or atrial fibrillation (AF) of varying durations. CFTR was downregulated in AF patients and negatively correlated with p16, p21, and p53. Myocardial aging models were established using D-galactose (D-gal) in both mice and neonatal mouse cardiomyocytes (CMs). In both animal and cellular models, D-gal increased SA-β-gal positivity and senescence markers while decreasing CFTR. Overexpressing CFTR reduced D-gal-induced elevations in p16, p21, p53, and malondialdehyde (MDA), and restored superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) activities. Mechanistically, CFTR alleviates mitochondrial oxidative stress damage by enhancing plasma membrane Ca 2+ ATPase (PMCA) activity to reduce cytoplasmic Ca 2+ levels. Furthermore, we identified USP45 as a direct binding partner of CFTR, which deubiquitinates CFTR by specifically targeting K48-linked chains and the K688 residue. CFTR knockdown exacerbated D-gal-induced senescence and mitochondrial oxidative stress, which was rescued by USP45 overexpression. In conclusion, this study reveals a novel mechanism in which USP45-mediated deubiquitination of CFTR mitigates cardiomyocyte senescence and mitochondrial oxidative stress, offering a targeted intervention against age-related cardiovascular diseases.

Neuroscience

Boundary Vector Cells Encode a Future-Biased Spectrum of Positions in the Rat.

Newman EL et al. · Jul 1, 2026

Spatial tuning is a hallmark property of neural firing in the hippocampal formation. Yet, that tuning is often less well correlated with the instantaneous current position of an animal than it is with an integrated version of the past or future state of the animal. Whether that encoding is biased toward past or future states and the extent to which it shows fixed versus multi-scale encoding varies across circuits and cell types. The temporal encoding properties of boundary vector cells of the subiculum are not well established. To address this here, we re-analyzed recordings of boundary vector cells (BVCs) described previously by Lever et al. (2009) with multiple approaches. In the first, we asked if adding a temporal offset between the rat position and the spiking of a BVC increased the apparent spatial tuning in the firing rate map. We found that aligning BVC spiking with future states maximized the rate map spatial tuning. These results were mirrored in a second analysis that, instead of optimizing rate map spatial tuning, optimized how well the firing rate map predicted the BVC spiking. The second analysis also allowed us to ask whether that encoding is focused on a particular temporal horizon or whether the encoding captures behavior at multiple scales. To this end, for a given recording, we asked "How much time-integration of the behavioral state is the observed spiking most consistent with?" We observed a wide spectrum of time-constants of integration across cells, indicating that BVCs form a multiscale encoding of future states. The distribution of both offsets and integration rates observed across BVCs did not differ significantly from other, non-BVC, subiculum neurons. Taken together, these findings indicate that BVCs, along with other subiculum neurons, form a multi-scale encoding of future states.

Neuroscience

Comparative Cochlear-Vestibular Aging Reveals Age-Aligned Mitochondrial Ultrastructural Burden, Mitophagy-Autophagy Remodeling, Synaptic Uncoupling, and Sensory Functional Decline.

Xie J et al. · Jul 1, 2026

Age-related hearing loss and balance decline are prevalent features of organismal aging, yet how the cochlea and vestibular organs converge on shared cellular liabilities remains insufficiently resolved. In particular, whether mitochondrial ultrastructural injury and mitochondrial quality-control programs co-vary with synaptic vulnerability and sensory functional decline across these systems within an age-resolved framework has not been clearly delineated. Here, we compared cochlear and vestibular aging in SAMP8 mice of different ages using integrated functional assays, region-resolved quantification of hair cells and CtBP2/GluA2 synapses, cochlear NF200+ fiber area fraction, transmission electron microscopy, and targeted qPCR of mitophagy/autophagy-lysosome genes. The results show that ABR thresholds rose progressively across 5.6-32 kHz. VsEP exhibited age-dependent threshold shifts and prolonged P-wave latency. Relative to the magnitude of synaptic and functional changes, cochlear hair-cell numbers were broadly preserved, although regional OHC loss was observed in middle-to-basal turns, whereas vestibular macular hair-cell density declined with age. Ultrastructurally, the proportion of pathological mitochondria increased with age, featuring electron-lucent matrix, disrupted cristae organization, and rounded/swollen profiles. What's more, guided by an adult-versus-aged transcriptomic screen nominating the Ca 2+ extrusion gene Atp2b4, we derived z-scored molecular indices, including a flux-burden signature (z(p62)-z(Lc3b)) and a TFEB-lysosome module. Descriptive coupling across age-group means indicated that mitochondrial pathology burden aligned closely with high-frequency ABR loss and basal synaptic uncoupling, and tracked the flux-burden signature more consistently than the TFEB-lysosome module. Together, these findings support age-aligned associations among mitochondrial ultrastructural injury, molecular remodeling, synaptic vulnerability, and progressive sensory decline across cochlear and vestibular systems.

Neuroscience

Maternal serum from 'high-stress' pregnancies demonstrates bioactivity capable of attenuating neurite growth through a TNFα-dependent pathway in SH-SY5Y cells.

Deady C et al. · Jul 1, 2026

Prenatal stress is associated with deleterious neurodevelopmental consequences in affected offspring. Prenatal stress via exposure to high physiological levels of inflammation in utero may induce an inflammatory state in the fetal brain. However, inflammation is not only associated with disease-states but also can be seen in a healthy pregnancy. There is limited research examining the potential that exposure to biological mediators of stress may have on neurodevelopment. We aim to determine whether certain circulating biological markers in maternal serum influence neurite growth in partially differentiated SH-SY5Y cells as a potential mechanism impacting neurodevelopment. Blood was collected at 20-weeks' gestation as part of the SCOPE pregnancy cohort study. These factors, including pro-inflammatory cytokines, markers of tryptophan metabolism, and gut permeability that were previously analysed, were used to stratify women into low (n = 10) and high (n = 10) biological stress groups. Exposure to the serum categorised as 'high-stress' significantly reduced neurite length in comparison to serum categorised as 'low-stress', with tumour necrosis factor-α playing a substantial role in mediating this reduction. The 'high-stress' serum was subsequently found to increase the levels of phospho-Ser536-p65. Phosphorylation of p65 Ser536 has previously been shown to switch NF-κΒ from promoting neuronal growth, to inhibiting it. The reduction in neurite length seen following exposure to the 'high-stress' serum was prevented when NF-κΒ p65 was knocked down. The present study emphasises the potential negative impact that circulating factors may have on neuronal growth, and the mechanism behind it.

Neuroscience

rTMS Over Dorsolateral Prefrontal Cortex Augments Dual-Task Training for Mobility, Balance and Cognition in Sub-Acute Stroke: A Randomized Controlled Trial.

Yang L et al. · Jul 1, 2026

Objective To evaluate the effects of adding repetitive transcranial magnetic stimulation (rTMS) to dorsolateral prefrontal cortex (DLPFC) with dual-task (DT) exercise on DT mobility, balance and cognitive performance in individuals with sub-acute stroke. Methods Thirty sub-acute stroke patients [age, mean (SD) = 59.2 (7.9) years] were randomly assigned to the experimental group (N = 15), or the sham stimulation group (N = 15). 5 Hz rTMS (90% resting motor threshold, 1200 pulses/session) or sham stimulation was applied to the ipsilesional DLPFC, 1 session/day, 5 days/week for 2 weeks, followed by dual-task training. Two mobility tests [10 m walking and timed-up-and-go (TUG) test] and two cognitive tasks (serial 3 subtractions and verbal fluency) were assessed separately [that is, single-task (ST) condition] and concurrently (i.e., DT condition) before and after the intervention. Results The experimental group had greater improvement in TUG time under both ST and DT conditions (p Discussion The 2-week rTMS to DLPFC combined with DT training augments DT walking performance, and improves balance and cognitive function in mild to moderate motor and cognitive impairment individuals with sub-acute stroke. Implications of physiotherapy practice This combined intervention is a feasible, effective strategy to improve real-world mobility in sub-acute stroke rehabilitation. Trial registration Chinese Clinical Trial Registry platform (www.chictr.org.cn), with the registration number ChiCTR2200066237.

Neuroscience

Verbal and Visuospatial Working Memory Performance During the CO2 Challenge Model of Anxiety.

Dunger W et al. · Jul 1, 2026

Objective Anxiety influences working memory performance, but the effects on clinical neuropsychological assessments of working memory are not well known. Methods We examined the effect of anxiety, induced using the 7.5% carbon dioxide model of anxiety on standardized clinical neuropsychological tests of working memory and executive function in a single-blind, placebo-controlled, randomized, crossover within-subjects design. Results The CO 2 -challenge reduced spatial working memory performance and verbal working memory performance accuracy when task demands were high. The CO 2 -challenge increased effort and reduced processing efficiency across all verbal and spatial working memory tasks. Conclusions The CO 2 -challenge resulted in significant reductions in working memory performance and processing efficiency. These results encourage the routine assessment of anxiety when administering and interpreting neuropsychological measures of working memory function in clinical practice.

Neuroscience

The Role of Early Visual Experience in Cross-Signal Dependency Detection.

Gupta P et al. · Jul 1, 2026

Temporal co-occurrence of two sensory signals is a powerful indicator of their potential association. Detection of such coincidences is believed to be a key contributor to perceptual organization and a primary objective of cortical computations. Here, we investigate whether the development of this ability requires early sensory experience. We examined the performance of early-blind children who surgically gained sight as adolescents. Our data revealed three key results. First, we found that while not fully reaching the level of normally sighted controls, late-sighted patients examined several years after surgery were able to robustly detect signal dependencies with markedly above-chance accuracy at all but the weakest strengths tested. Second, for both groups, performance levels were comparable for intra- and inter-modal stimuli, revealing significant plasticity for establishing cross-modal linkages late in childhood. Finally, comparison with a separate group of late-sighted patients tracked longitudinally from preoperative to one-month postoperative status suggests that this ability may follow a protracted developmental time course after sight surgery. These results help characterize the development of a foundational process for detecting relationships between environmental entities and point to the resilience of acquiring this important skill to early-onset, prolonged visual deprivation. SUMMARY: We tested the ability of congenitally blind children who gained sight late in childhood to detect repeated temporal co-occurrence of sensory signals. We found that while not reaching the full normally sighted level, late-sighted patients are able to detect signal dependencies with markedly above-chance accuracy. This ability may follow a protracted developmental time course after sight-restoring surgery. The availability of neural plasticity into late childhood has important implications for the rehabilitation prospects of children with congenital blindness.

Neuroscience

Neural and Navigational Features Influencing the Novelty Induced Benefits on Episodic Memory.

Vogelsang DA et al. · Jul 1, 2026

Studies in animals have robustly shown that exposure to novelty can promote memory for information presented in the temporal vicinity. In humans, however, evidence for such novelty-related memory benefits has been mixed. In this EEG study, we investigated the neurobiological mechanisms underlying effects of novelty on memory and whether individual differences in exploration patterns help explain these inconsistencies. We examined the role of theta oscillations in exploring a novel or familiar environment as well as whether spatial exploration behavior can modulate the beneficial effects of novelty on memory. Participants first explored one of two virtual environments and subsequently explored the same (familiar condition) or a new environment (novel condition). After exploring novel and familiar environments, participants performed a word learning task followed by a free recall and recognition memory test. Neurologically, exploration of the familiar rather than novel environment increased theta power, which may reflect environment-related memory processes. However, we did not observe any differences in theta power associated with successful encoding of words after exploring a novel versus familiar environment. Behaviorally, no main effect of novelty on free recall was observed. Crucially, when accounting for variance in spatial exploration patterns, words encoded after exploring a novel environment were recalled better than words encoded after exploring a familiar environment. Furthermore, an interaction effect between the condition and exploratory behavior revealed that increased exploration benefitted free recall specifically in the familiar condition. These findings emphasize the importance of considering the way in which individuals explore a virtual environment when examining novelty effects on memory.

Neuroscience