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Choosing whether to exert effort to obtain rewards is fundamental to human motivated behavior. However, the neural dynamics underlying the evaluation of reward and effort in humans is poorly understood. Here, we report an exploratory investigation into this with chronic intracranial recordings from the prefrontal cortex (PFC) and basal ganglia (BG; subthalamic nuclei and globus pallidus) in people with Parkinsons disease performing a decision-making task with offers that varied in levels of reward and physical effort required. This revealed dissociable neural signatures of reward and effort, with BG beta (12 to 20 Hz) oscillations tracking effort on a single-trial basis and PFC theta (4 to 7 Hz) signaling previous trial reward, with no effects of net subjective value. Stimulation of PFC increased overall acceptance of offers and sensitivity to reward while decreasing the impact of effort on choices. This work uncovers oscillatory mechanisms that guide fundamental decisions to exert effort for reward across BG and PFC, supports a causal role of PFC for such choices, and seeds hypotheses for future studies.

Background and aimsThe precise roles of screen media activity (SMA) and sleep problems in relation to child/adolescent psychopathology remain ambiguous. We investigated temporal relationships among sleep problems, SMA, and psychopathology and potential involvement of thalamus-prefrontal-cortex (PFC)-brainstem structural covariation.MethodsThis study utilized data from the Adolescent Brain Cognitive Development study (n = 4,641 ages 9-12) at baseline, Year1, and Year2 follow-up. Cross-Lagged Panel Models (CLPMs) investigated reciprocal predictive relationships between sleep duration/problems, SMA, and psychopathology symptoms. A potential mediating role of baseline Thalamus-PFC-brainstem covariation on SMA-externalizing relationships was examined.ResultsParticipants were divided into discovery (n = 2,359, 1,054 girls) and replication (n = 2,282, 997 girls) sets. CLPMs showed 1) bidirectional associations between sleep duration and SMA in late childhood, with higher frequency SMA predicting shorter sleep duration (β = -0.10 [95%CI: -0.16, -0.03], p = 0.004) and vice versa (β = -0.11 [95%CI: -0.18, -0.05], p < 0.001); 2) externalizing symptoms at age 10-11 predicting sleep problems (β = 0.11 [95%CI: 0.04, 0.19], p = 0.002), SMA (β = 0.07 [95%CI: 0.01, 0.13], p = 0.014), and internalizing symptoms (β = 0.09 [95%CI: 0.05, 0.13], p < 0.001) at age 11-12; and 3) externalizing behavior at age 10-11 partially mediating the relationship between baseline thalamus-PFC-brainstem covariation and SMA at age 11-12 (indirect effect = 0.032 [95%CI: 0.003, 0.067], p-value = 0.030). Findings were replicable.ConclusionWe found bi-directional SMA-sleep-duration associations in late childhood. Externalizing symptoms preceded future SMA and sleep disturbances and partially mediated relationships between structural brain covariation and SMA. The findings emphasize the need for understanding individual differences and developing and implementing integrated strategies addressing both sleep concerns and screen time to mitigate potential impacts on psychopathology.

Single administration of low-dose ketamine has both acute and sustained anti-depressant effects. Sustained effect is associated with restoration of glutamatergic synapses in medial prefrontal cortic (mFPC) neurons. Ketamine induced profound changes in a number of molecular pathways in a mouse model for chronic stress. Cell-cell communication analyses predicted that planar-cell-polarity (PCP) signaling was decreased after chronic administration of corticosterone but increased following ketamine administration in most of the excitatory neurons. Similar decrease of PCP signaling in excitatory neurons was predicted in dorsolateral prefrontal cortical (dl-PFC) neurons of patients with major depressive disorder (MDD). We showed that the basolateral amygdala (BLA)-projecting infralimbic prefrontal cortex (IL PFC) neurons regulate immobility time in the tail suspension test and food consumption. Conditionally knocking out Celsr2 and Celsr3 or Prickle2 in the BLA-projecting IL PFC neurons abolished ketamine-induced synapse restoration and behavioral remission. Therefore, PCP proteins in IL PFC-BLA neurons mediate synapse restoration induced by of low-dose ketamine.

Single-cell genomics is a powerful tool for studying heterogeneous tissues such as the brain. Yet little is understood about how genetic variants influence cell-level gene expression. Addressing this, we uniformly processed single-nuclei, multiomics datasets into a resource comprising >2.8 million nuclei from the prefrontal cortex across 388 individuals. For 28 cell types, we assessed population-level variation in expression and chromatin across gene families and drug targets. We identified >550,000 cell type-specific regulatory elements and >1.4 million single-cell expression quantitative trait loci, which we used to build cell-type regulatory and cell-to-cell communication networks. These networks manifest cellular changes in aging and neuropsychiatric disorders. We further constructed an integrative model accurately imputing single-cell expression and simulating perturbations; the model prioritized ~250 disease-risk genes and drug targets with associated cell types.

The ability to respond to emotional events in a context-sensitive and goal-oriented manner is essential for adaptive functioning. In models of behavioral and emotion regulation, the lateral prefrontal cortex (LPFC) is postulated to maintain goal-relevant representations that promote cognitive control, an idea rarely tested with causal inference. Here, we altered mid-LPFC function in healthy individuals using a putatively inhibitory brain stimulation protocol (continuous theta burst; cTBS), followed by fMRI scanning. Participants performed the Affective Go/No-Go task, which requires goal-oriented action during affective processing. We targeted mid-LPFC (vs. a Control site) based on the individualized location of action-goal representations observed during the task. cTBS to mid-LPFC reduced action-goal representations in mid-LPFC and impaired goal-oriented action, particularly during processing of negative emotional cues. During negative-cue processing, cTBS to mid-LPFC reduced functional coupling between mid-LPFC and nodes of the default mode network, including frontopolar cortex-a region thought to modulate LPFC control signals according to internal states. Collectively, these results indicate that mid-LPFC goal-relevant representations play a causal role in governing context-sensitive cognitive control during emotional processing.

BACKGROUND: Alzheimers disease (AD) is a devastating neurodegenerative disorder affecting 44 million people worldwide, leading to cognitive decline, memory loss, and significant impairment in daily functioning. The recent single-cell sequencing technology has revolutionized genetic and genomic resolution by enabling scientists to explore the diversity of gene expression patterns at the finest resolution. Most existing studies have solely focused on molecular perturbations within each cell, but cells live in microenvironments rather than in isolated entities. Here, we leveraged the large-scale and publicly available single-nucleus RNA sequencing in the human prefrontal cortex to investigate cell-to-cell communication in healthy brains and their perturbations in AD. We uniformly processed the snRNA-seq with strict QCs and labeled canonical cell types consistent with the definitions from the BRAIN Initiative Cell Census Network. From ligand and receptor gene expression, we built a high-confidence cell-to-cell communication network to investigate signaling differences between AD and healthy brains. RESULTS: Specifically, we first performed broad communication pattern analyses to highlight that biologically related cell types in normal brains rely on largely overlapping signaling networks and that the AD brain exhibits the irregular inter-mixing of cell types and signaling pathways. Secondly, we performed a more focused cell-type-centric analysis and found that excitatory neurons in AD have significantly increased their communications to inhibitory neurons, while inhibitory neurons and other non-neuronal cells globally decreased theirs to all cells. Then, we delved deeper with a signaling-centric view, showing that canonical signaling pathways CSF, TGFβ, and CX3C are significantly dysregulated in their signaling to the cell type microglia/PVM and from endothelial to neuronal cells for the WNT pathway. Finally, after extracting 23 known AD risk genes, our intracellular communication analysis revealed a strong connection of extracellular ligand genes APP, APOE, and PSEN1 to intracellular AD risk genes TREM2, ABCA1, and APP in the communication from astrocytes and microglia to neurons. CONCLUSIONS: In summary, with the novel advances in single-cell sequencing technologies, we show that cellular signaling is regulated in a cell-type-specific manner and that improper regulation of extracellular signaling genes is linked to intracellular risk genes, giving the mechanistic intra- and inter-cellular picture of AD.

Subjects are often willing to pay a cost for information. In a procedure that promotes paradoxical choices, animals choose between a richer option followed by a cue that is rewarded 50% of the time (No Info) vs. a leaner option followed by one of two cues that signal certain outcomes: one always rewarded (100%) and the other never rewarded, 0% (Info). Since decisions involve comparing the subjective value of options after integrating all their features, preference for information may rely on cortico-amygdalar circuitry. To test this, male and female rats were prepared with bilateral inhibitory Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) in the anterior cingulate cortex, orbitofrontal cortex, basolateral amygdala, or null virus (control). We inhibited these regions after stable preference was acquired. We found that inhibition of the anterior cingulate cortex destabilized choice preference in female rats without affecting latency to choose or response rate to cues. A logistic regression fit revealed that previous choice predicted current choice in all conditions, however previously rewarded Info trials strongly predicted preference in all conditions except in female rats following anterior cingulate cortex inhibition. The results reveal a causal, sex-dependent role for the anterior cingulate cortex in decisions involving information.

Self-agency is the awareness of being the agent of ones own thoughts and actions. Self-agency is essential for interacting with the outside world (reality-monitoring). The medial prefrontal cortex (mPFC) is thought to be one neural correlate of self-agency. We investigated whether mPFC activity can causally modulate self-agency on two different tasks of speech-monitoring and reality-monitoring. The experience of self-agency is thought to result from making reliable predictions about the expected outcomes of ones own actions. This self-prediction ability is necessary for the encoding and memory retrieval of ones own thoughts during reality-monitoring to enable accurate judgments of self-agency. This self-prediction ability is also necessary for speech-monitoring where speakers consistently compare auditory feedback (what we hear ourselves say) with what we expect to hear while speaking. In this study, 30 healthy participants are assigned to either 10 Hz repetitive transcranial magnetic stimulation (rTMS) to enhance mPFC excitability (N = 15) or 10 Hz rTMS targeting a distal temporoparietal site (N = 15). High-frequency rTMS to mPFC enhanced self-predictions during speech-monitoring that predicted improved self-agency judgments during reality-monitoring. This is the first study to provide robust evidence for mPFC underlying a causal role in self-agency, that results from the fundamental ability of improving self-predictions across two different tasks.

This study examined whether a 3-month mild-exercise intervention could improve executive function in healthy middle-aged and older adults in a randomized control trial. Ultimately, a total of 81 middle-aged and older adults were randomly assigned to either an exercise group or a control group. The exercise group received 3 months of mild cycle exercise intervention (3 sessions/week, 30-50 min/session). The control group was asked to behave as usual for the intervention period. Before and after the intervention, participants did color-word matching Stroop tasks (CWST), and Stroop interference (SI)-related reaction time (RT) was assessed as an indicator of executive function. During the CWST, prefrontal activation was monitored using functional near-infrared spectroscopy (fNIRS). SI-related oxy-Hb changes and SI-related neural efficiency (NE) scores were assessed to examine the underlying neural mechanism of the exercise intervention. Although the mild-exercise intervention significantly decreased SI-related RT, there were no significant effects of exercise intervention on SI-related oxy-Hb changes or SI-related NE scores in prefrontal subregions. Lastly, changes in the effects of mild exercise on NE with advancing age were examined. The 81 participants were divided into two subgroups (younger-aged subgroup [YA], older-aged subgroup [OA], based on median age [68 years.]). Interestingly, SI-related RT significantly decreased, and SI-related NE scores in all ROIs of the prefrontal cortex significantly increased only in the OA subgroup. These results reveal that a long-term intervention of very light-intensity exercise has a positive effect on executive function especially in older adults, possibly by increasing neural efficiency in the prefrontal cortex.

Sevoflurane, the predominant pediatric anesthetic, has been linked to neurotoxicity in young mice, although the underlying mechanisms remain unclear. This study focuses on investigating the impact of neonatal sevoflurane exposure on cell-type-specific alterations in the prefrontal cortex (PFC) of young mice. Neonatal mice were subjected to either control treatment (60% oxygen balanced with nitrogen) or sevoflurane anesthesia (3% sevoflurane in 60% oxygen balanced with nitrogen) for 2 hours on postnatal days (PNDs) 6, 8, and 10. Behavioral tests and single-nucleus RNA sequencing (snRNA-seq) of the PFC were conducted from PNDs 31 to 37. Mechanistic exploration included clustering analysis, identification of differentially expressed genes (DEGs), enrichment analyses, single-cell trajectory analysis, and genome-wide association studies (GWAS). Sevoflurane anesthesia resulted in sociability and cognition impairments in mice. Novel specific marker genes identified 8 distinct cell types in the PFC. Most DEGs between the control and sevoflurane groups were unique to specific cell types. Re-defining 15 glutamatergic neuron subclusters based on layer identity revealed their altered expression profiles. Notably, sevoflurane disrupted the trajectory from oligodendrocyte precursor cells (OPCs) to oligodendrocytes (OLs). Validation of disease-relevant candidate genes across the main cell types demonstrated their association with social dysfunction and working memory impairment. Behavioral results and snRNA-seq collectively elucidated the cellular atlas in the PFC of young male mice, providing a foundation for further mechanistic studies on developmental neurotoxicity induced by anesthesia.

Reversal learning measures the ability to form flexible associations between choice outcomes with stimuli and actions that precede them. This type of learning is thought to rely on several cortical and subcortical areas, including the highly interconnected orbitofrontal cortex (OFC) and basolateral amygdala (BLA), and is often impaired in various neuropsychiatric and substance use disorders. However, the unique contributions of these regions to stimulus- and action-based reversal learning have not been systematically compared using a chemogenetic approach particularly before and after the first reversal that introduces new uncertainty. Here, we examined the roles of ventrolateral OFC (vlOFC) and BLA during reversal learning. Male and female rats were prepared with inhibitory designer receptors exclusively activated by designer drugs targeting projection neurons in these regions and tested on a series of deterministic and probabilistic reversals during which they learned about stimulus identity or side (left or right) associated with different reward probabilities. Using a counterbalanced within-subject design, we inhibited these regions prior to reversal sessions. We assessed initial and pre-/post-reversal changes in performance to measure learning and adjustments to reversals, respectively. We found that inhibition of the ventrolateral orbitofrontal cortex (vlOFC), but not BLA, eliminated adjustments to stimulus-based reversals. Inhibition of BLA, but not vlOFC, selectively impaired action-based probabilistic reversal learning, leaving deterministic reversal learning intact. vlOFC exhibited a sex-dependent role in early adjustment to action-based reversals, but not in overall learning. These results reveal dissociable roles for BLA and vlOFC in flexible learning and highlight a more crucial role for BLA in learning meaningful changes in the reward environment.

Receiving a favor from another person may induce a negative feeling of indebtedness for the beneficiary. In this study, we explore these hidden costs by developing and validating a conceptual model of indebtedness across three studies that combine a large-scale online questionnaire, an interpersonal game, computational modeling, and neuroimaging. Our model captures how individuals perceive the altruistic and strategic intentions of the benefactor. These inferences produce distinct feelings of guilt and obligation that together comprise indebtedness and motivate reciprocity. Perceived altruistic intentions convey care and communal concern and are associated with activity in insula, ventromedial prefrontal cortex and dorsolateral prefrontal cortex, while inferred strategic intentions convey expectations of future reciprocity and are associated with activation in temporal parietal junction and dorsomedial prefrontal cortex. We further develop a neural utility model of indebtedness using multivariate patterns of brain activity that captures the tradeoff between these feelings and reliably predicts reciprocity behavior.

Animals, including humans, rely on contextual information to interpret ambiguous stimuli. Impaired context processing is a hallmark of several neuropsychiatric disorders, including schizophrenia, autism spectrum disorders, post-traumatic stress disorder, and addiction. While sex differences in the prevalence and manifestations of these disorders are well established, potential sex differences in context processing remain uncertain. Here, we examined sex differences in the contextual control over cue-evoked reward seeking and its neural correlates, in rats. Male and female rats were trained in a bidirectional occasion-setting preparation in which the validity of two auditory reward-predictive cues was informed by the presence, or absence, of a visual contextual feature (LIGHT: X+/DARK: X-/LIGHT: Y-/DARK: Y+). Females were significantly slower to acquire contextual control over cue-evoked reward seeking. However, once established, the contextual control over behavior was more robust in female rats; it showed less within-session variability (less influence of prior reward) and greater resistance to acute stress. This superior contextual control achieved by females was accompanied by an increased activation of the orbitofrontal cortex (OFC) compared to males. Critically, these behavioral and neural sex differences were specific to the contextual modulation process and not observed in simple, context-independent, reward prediction tasks. These results indicate a sex-biased trade-off between the speed of acquisition and the robustness of performance in the contextual modulation of cued reward seeking. The different distribution of sexes along the fast learning ↔ steady performance continuum might reflect different levels of engagement of the OFC, and might have implications for our understanding of sex differences in psychiatric disorders.

Sensory over-responsivity (SOR) is a prevalent cross-diagnostic condition that is often associated with anxiety. The biological mechanisms underlying the co-occurrence of SOR and anxiety symptoms are not well understood, despite having important implications for targeted intervention. We therefore investigated the unique associations of SOR and anxiety symptoms with physiological and neural responses to sensory stimulation for youth with anxiety disorders (ANX), autism spectrum disorder (ASD), or typical development (TD). Age/IQ-matched youth aged 8-18 years (22 ANX; 30 ASD; 22 TD) experienced mildly aversive tactile and auditory stimuli during functional magnetic resonance imaging and then during skin conductance response (SCR) and heart rate (HR) measurements. Caregivers reported on participants' SOR and anxiety symptoms. ASD/ANX youth had elevated SOR and anxiety symptoms compared to TD. ASD/ANX youth showed similar, heightened brain responses to sensory stimulation compared to TD youth, but brain responses were more highly related to SOR symptoms in ASD youth and to anxiety symptoms in ANX youth. Across ASD/ANX youth, anxiety symptoms uniquely related to greater SCR whereas SOR uniquely related to greater HR responses to sensory stimulation. Behavioral and neurobiological over-responsivity to sensory stimulation was shared across diagnostic groups. However, findings support SOR and anxiety as distinct symptoms with unique biological mechanisms, and with different relationships to neural over-reactivity dependent on diagnostic group. Results indicate a need for targeted treatment approaches.

• Cumulative unpredictable mild stress (CUMS) induced depressive phenotype and memory deficit. • Depressed rats showed downregulation of the serotoninergic system. • Deep brain stimulation (DBS) of medial forebrain bundle alleviated depressive-like symptoms. • DBS upregulated serotoninergic innervation of the medial prefrontal cortex. • Stimulation of serotoninergic pathway in medial forebrain bundle may reverse depressive-like phenotype. The aim of the study is to understand the rationale behind the application of deep brain stimulation (DBS) in the treatment of depression. Male Wistar rats, rendered depressive with chronic unpredictable mild stress (CUMS) were implanted with electrode in the lateral hypothalamus-medial forebrain bundle (LH-MFB) and subjected to deep brain stimulation (DBS) for 4 h each day for 14 days. DBS rats, as well as controls, were screened for a range of parameters indicative of depressive state. Symptomatic features noticed in CUMS rats like the memory deficit, anhedonia, reduction in body weight and 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) levels in mPFC and elevated plasma corticosterone were reversed in rats subjected to DBS. DBS arrested CUMS induced degeneration of 5-HT cells in interfascicular region of dorsal raphe nucleus (DRif) and fibers in LH-MFB and induced dendritic proliferation in mPFC neurons. MFB is known to serve as a major conduit for the DRif-mPFC serotoninergic pathway. While the density of serotonin fibers in the LH-MFB circuit was reduced in CUMS, it was upregulated in DBS-treated rats. Furthermore, microinjection of 5-HT1A receptor antagonist, WAY100635 into mPFC countered the positive effects of DBS like the antidepressant and memory-enhancing action. In this background, we suggest that DBS at LH-MFB may exercise positive effect in depressive rats via upregulation of the serotoninergic system. While these data drawn from the experiments on rat provide meaningful clues, we suggest that further studies aimed at understanding the usefulness of DBS at LH-MFB in humans may be rewarding. [ABSTRACT FROM AUTHOR]

Post-traumatic stress disorder (PTSD) and major depressive disorder (MDD) are psychiatric disorders that can present with overlapping symptoms and shared risk factors. However, the extent to which these disorders share common underlying neuropathological mechanisms remains unclear. To investigate the similarities and differences in task-evoked brain activation patterns between patients with PTSD and MDD. A coordinate-based meta-analysis was conducted across 35 PTSD studies (564 patients and 543 healthy controls) and 125 MDD studies (4049 patients and 4170 healthy controls) using anisotropic effect-size signed differential mapping software. Both PTSD and MDD patients exhibited increased neural activation in the bilateral inferior frontal gyrus. However, PTSD patients showed increased neural activation in the right insula, left supplementary motor area extending to median cingulate gyrus and superior frontal gyrus (SFG), and left fusiform gyrus, and decreased neural activation in the right posterior cingulate gyrus, right middle temporal gyrus, right paracentral lobule, and right inferior parietal gyrus relative to MDD patients. Our meta-analysis suggests that PTSD and MDD share some similar patterns of brain activation, but also have distinct neural signatures. These findings contribute to our understanding of the potential neuropathology underlying these disorders and may inform the development of more targeted and effective treatment and intervention strategies. Moreover, these results may provide useful neuroimaging targets for the differential diagnosis of MDD and PTSD. • A first meta-analysis to investigate the common and distinct neural activation patterns of patients with MDD and PTSD • Common and distinct neural activation patterns in patients with MDD and PTSD were found. • Potential neuroimaging targets for the diagnosis and differentiation of PTSD and MDD were found. [ABSTRACT FROM AUTHOR]

To investigate the effect of 20/4 Hz transcutaneous auricular vagus nerve stimulation (taVNS) on anxiety symptoms in Parkinson's disease (PD) and the potential neural mechanism. In the current randomized, double-blind, sham-controlled trial, 30 PD patients with anxiety (PD-A), 30 PD patients without anxiety (PD-nA), and 30 healthy controls (HCs) were enrolled. PD-A patients were randomly (1:1) allotted to real taVNS stimulation group (RS) or sham stimulation group (SS) to explore the efficacy of a two-week treatment of taVNS to promote anxiety recovery. Simultaneously, all participants were measured activation in the bilateral prefrontal cortex during verbal fluency task (VFT) using functional near-infrared spectroscopy. PD-A patients showed significantly decreased oxyhemoglobin in the left triangle part of the inferior frontal gyrus (IFG) during VFT, which was negatively related to the severity of anxiety symptoms. After two-week treatment of taVNS, the interaction of group and time had significant effect on HAMA scores (F = 18.476, p < 0.001, η2 = 0.398). In RS group, compared with baseline, HAMA scores decreased significantly in the post-treatment and follow-up condition (both p < 0.001). Meanwhile, in RS group, HAMA scores were lower than those in SS group in the post-treatment and follow-up condition (p = 0.006, <0.001, respectively). Furthermore, the 20/4 Hz taVNS remarkably ameliorated anxiety symptoms in PD patients, directly correlated with the increased activation of the left triangle part of the IFG during VFT in RS group. Our results depicted that taVNS could ameliorate the anxiety symptoms of PD-A patients and regulated the function of the left triangle part of the IFG. • taVNS could effectively ameliorate the anxiety of PD patients and modify their brain function. • taVNS might improve the anxiety symptoms of PD patients by modulating the function of left triangle part of the IFG. • taVNS may be a potentially effective neuromodulation tool for PD patients with anxiety. [ABSTRACT FROM AUTHOR]

While self-construal and posttraumatic stress disorder (PTSD) are independently associated with altered self-referential processes and underlying default mode network (DMN) functioning, no study has examined how self-construal affects DMN connectivity in PTSD. A final sample of 93 refugee participants (48 with DSM-5 PTSD or sub-syndromal PTSD and 45 matched trauma-exposed controls) completed a 5-minute resting state fMRI scan to enable the observation of connectivity in the DMN and other core networks. A self-construal index was calculated by substracting scores on the collectivistic and individualistic sub-scales of the Self Construal Scale. Independent components analysis identified 9 active networks-of-interest, and functional network connectivity was determined. A significant interaction effect between PTSD and self-construal index was observed in the anterior ventromedial DMN, with spatial maps localizing this to the left ventromedial prefrontal cortex (vmPFC), extending to the ventral anterior cingulate cortex. This effect revealed that connectivity in the vMPFC showed greater reductions in those with PTSD with higher levels of collectivistic self-construal. This is an observational study and causality cannot be assumed. The specialized sample of refugees means that the findings may not generalize to other trauma-exposed populations. Such a finding indicates that self-construal may shape the core neural architecture of PTSD, given that functional disruptions to the vmPFC underpin the core mechanisms of extinction learning, emotion dysregulation and self-referential processing in PTSD. Results have important implications for understanding the universality of neural disturbances in PTSD, and suggest that self-construal could be an important consideration in the assessment and treatment of post-traumatic stress reactions. • Studies that consider cultural influences on PTSD brain mechanisms are rare. • PTSD interacted with self-construal to affect default mode network connectivity. • The ventromedial prefrontal cortex was the site of interaction. • Findings suggest cultural variables shape the neural substrates of PTSD. [ABSTRACT FROM AUTHOR]

Background and Purpose: Cytoplasmic fragile X messenger ribonucleoprotein 1 (FMR1)‐interacting protein 2 (CYFIP2), as a component of the Wiskott–Aldrich syndrome protein family verprolin‐homologous protein (WAVE) regulatory complex, is involved in actin polymerization, contributing to neuronal development and structural plasticity. Mutating serine‐968 to phenylalanine (S968F) in CYFIP2 causes an altered cocaine response in mice. The neuronal mechanisms underlying this response remain unknown. Experimental Approach: We performed cocaine reward‐related behavioural tests and examined changes in synaptic protein phenotypes and neuronal morphology in the nucleus accumbens (NAc), using CYFIP2 S968F knock‐in mice to investigate the role of CYFIP2 in regulating cocaine reward. Key Results: CYFIP2 S968F mutation attenuated cocaine‐induced behavioural sensitization and conditioned place preference. Cocaine‐induced c‐Fos was not observed in the NAc of CYFIP2 S968F knock‐in mice. However, c‐Fos induction was still evident in the medial prefrontal cortex (mPFC). CYFIP2 S968F mutation altered cocaine‐associated CYFIP2 signalling, glutamatergic protein expression and synaptic density in the NAc following cocaine exposure. To further determine the role of CYFIP2 in NAc neuronal activity and the mPFC projecting to the NAc activity‐mediating reward response, we used optogenetic tools to stimulate the NAc or mPFC‐NAc pathway and observed that optogenetic activation of the NAc or mPFC‐NAc pathway induced reward‐related behaviours. This effect was not observed in the S968F mutation in CYFIP2. Conclusion and Implications: These results suggest that CYFIP2 plays a role in controlling cocaine‐mediated neuronal function and structural plasticity in the NAc, and that CYFIP2 could serve as a target for regulating cocaine reward. [ABSTRACT FROM AUTHOR]

Background and Purpose: Sevoflurane, a commonly used inhaled anaesthetic known for its favourable safety profile and rapid onset and offset, has not been thoroughly investigated as a potential treatment for depression. In this study, we reveal the mechanism through which sevoflurane delivers enduring antidepressant effects. Experimental Approach: To assess the antidepressant effects of sevoflurane, behavioural tests were conducted, along with in vitro and ex vivo whole‐cell patch‐clamp recordings, to examine the effects on GluN1–GluN2 incorporated N‐methyl‐d‐aspartate (NMDA) receptors (NMDARs) and neuronal circuitry in the medial prefrontal cortex (mPFC). Multiple‐channel electrophysiology in freely moving mice was performed to evaluate sevoflurane's effects on neuronal activity, and GluN2D knockout (grin2d−/−) mice were used to confirm the requirement of GluN2D for the antidepressant effects. Key Results: Repeated exposure to subanaesthetic doses of sevoflurane produced sustained antidepressant effects lasting up to 2 weeks. Sevoflurane preferentially inhibited GluN2C‐ and GluN2D‐containing NMDARs, causing a reduction in interneuron activity. In contrast, sevoflurane increased action potentials (AP) firing and decreased spontaneous inhibitory postsynaptic current (sIPSC) in mPFC pyramidal neurons, demonstrating a disinhibitory effect. These effects were absent in grin2d−/− mice, and both pharmacological blockade and genetic knockout of GluN2D abolished sevoflurane's antidepressant actions, suggesting that GluN2D is essential for its antidepressant effect. Conclusion and Implications: Sevoflurane directly targets GluN2D, leading to a specific decrease in interneuron activity and subsequent disinhibition of pyramidal neurons, which may underpin its antidepressant effects. Targeting the GluN2D subunit could hold promise as a potential therapeutic strategy for treating depression. [ABSTRACT FROM AUTHOR]

• Drinking and sleep deficiency are comorbid and associated with cognitive deficits. • Sleep deficit reduced left PCG activation during semantic processing in women. • Alcohol misuse reduced right MFG activation during semantic processing in women. • Path model inter-related sleep deficit, alcohol misuse, and the neural markers. Both alcohol misuse and sleep deficiency are associated with deficits in semantic processing. However, alcohol misuse and sleep deficiency are frequently comorbid and their inter-related effects on semantic processing as well as the underlying neural mechanisms remain to be investigated. We curated the Human Connectome Project data of 973 young adults (508 women) to examine the neural correlates of semantic processing in link with the severity of alcohol use and sleep deficiency. The latter were each evaluated using the first principal component (PC1) of principal component analysis of all drinking metrics and the Pittsburgh Sleep Quality Index (PSQI). We employed path modeling to elucidate the interplay among clinical, behavioral, and neural variables. Among women, we observed a significant negative correlation between the left precentral gyrus (PCG) and PSQI scores. Mediation analysis revealed that the left PCG activity fully mediated the relationship between PSQI scores and word comprehension in language tasks. In women alone also, the right middle frontal gyrus (MFG) exhibited a significant negative correlation with PC1. The best path model illustrated the associations among PC1, PSQI scores, PCG activity, and MFG activation during semantic processing in women. Alcohol misuse may lead to reduced MFG activation while sleep deficiency hinder semantic processing by suppressing PCG activity in women. The pathway model underscores the influence of sleep quality and alcohol consumption severity on semantic processing in women, suggesting that sex differences in these effects need to be further investigated. [ABSTRACT FROM AUTHOR]

[Display omitted] • There is a learning cost when an attentional set must shift to new cues. • An attentional shift to cues experienced as redundantly predictive still has a cost. • mPFC inactivation increases the cost of an attentional set shift. • mPFC inactivation enhances subsequent learning about previously redundant cues. • A reduction in learned inattention can account for both effects. Without a functioning prefrontal cortex, humans and other animals are impaired in measures of cognitive control and behavioral flexibility, including attentional set-shifting. However, the reason for this is unclear with evidence suggesting both impaired and enhanced attentional shifting. We inhibited the medial prefrontal cortex (mPFC) of rats while they performed a modified version of an attentional set-shifting task to explore the nature of this apparent contradiction. Twelve adult male Lister hooded rats received AAV5-CaMKIIa-hM4D(Gi)-mCherry viral vector bilaterally into mPFC to express inhibitory 'Designer Receptors Exclusively Activated by Designer Drugs' (iDREADDs). The receptors were activated by systemic clozapine N -oxide (CNO) to inhibit mPFC function. The rats were tested in the standard attentional set-shifting task four times: twice after i.p. administration and twice after oral administration of vehicle or CNO (10 mg/kg). They were then tested twice in a modified task, with or without oral CNO. The modified task had an extra stage before the extradimensional shift, in which the relevant exemplars remained relevant and new exemplars that were fully predictive but redundant replaced the previous irrelevant exemplars. These exemplars then became relevant at the subsequent ED stage. In the standard task, mPFC inactivation impaired attentional set-shifting, consistent with previous findings. However, in the modified task, mPFC inactivation abolished ED shift-costs. The results support the suggestion that the mPFC is needed for the downregulation of attention that prevents learning about redundant and irrelevant stimuli. With mPFC inactivated, the rat learns more rapidly when previously redundant exemplars become the only relevant information. [ABSTRACT FROM AUTHOR]

[Display omitted] • Social behavior is altered by nanoplastic (NPx) administration. • NPx-induced alteration of social behavior is partly dependent on neurodevelopment. • NPx administration affects the neural circuit where the dopamine system innervates. • NPx-induced alteration of neural activity depends on neurodevelopment. • Therefore, NPx induces different effects at different developmental stages. Exposure to environmental microplastics has been demonstrated to impact health. However, its effect on development remains unclear. This study investigated whether consumption of nanoplastics (NPx) during development affects social and cognitive functions in rodents. In this study, we utilized male Institute of Cancer Research mice; they were divided into five subgroups based on the duration of NPx administration. NPx (100 nm) was orally administered via gavage for 6 days from gestational day (GTD) 7, representing the mid-gestation period, and for 5–6 days from GTD13 to birth, representing the late-gestation period; the male offspring were used for experiments. NPx was orally administered for 15 days starting at postnatal day (PND) 21 as the juvenile, PND38 as the adolescent, and PND56 as adulthood. On PND77, offspring were assessed for locomotion, social behavior, and nest-building tests. We observed that NPx administration altered dopamine system responses in GTD13 and PND56 groups. Social behavior was similarly affected by NPx treatment, with GTD13 and PND56 groups displaying decreased familiarity. Additionally, NPx treatment enhanced local field potentials in the prefrontal cortex, nucleus accumbens, and amygdala of GTD7 group and in the striatum of GTD13 group, while amphetamine treatment induced changes of local field potentials compared to saline treatment in the prefrontal cortex and the ventral tegmental area of CTR, GTD7, PND21, and PND56 groups. Taken together, these results showed that NPx treatment induced changes in social behavior partly depending on developmental stage, and these changes are associated with neural circuits innervated by the dopamine system. [ABSTRACT FROM AUTHOR]

[Display omitted] • mGluR5 PAM pre-treatment prevents MK-801 induced increased extracellular glutamate. • mGluR5 PAM does not affect mPFC extracellular glutamate when given alone. • mGluR5 PAM may restore cognitive function by regulating mPFC glutamate. • Targeting mGluR5 with PAMs may treat neuropsychiatric disorder impairments. Potentiation of metabotropic glutamate receptor subtype 5 (mGluR5) function produces antipsychotic-like and pro-cognitive effects in animal models of schizophrenia and can reverse cognitive deficits induced by N-methyl-D-aspartate type glutamate receptor (NMDAR) antagonists. However, it is currently unknown if mGluR5 positive allosteric modulators (PAMs) can modulate NMDAR antagonist-induced alterations in extracellular glutamate levels in regions underlying these cognitive and behavioral effects, such as the medial prefrontal cortex (mPFC). We therefore assessed the ability of the mGluR5 PAM, 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl) benzamide (CDPPB), to reduce elevated extracellular glutamate levels induced by the NMDAR antagonist, dizocilpine (MK-801), in the mPFC. Male Sprague-Dawley rats were implanted with a guide cannula aimed at the mPFC and treated for ten consecutive days with MK-801 and CDPPB or their corresponding vehicles. CDPPB or vehicle was administered thirty minutes before MK-801 or vehicle each day. On the final day of treatment, in vivo microdialysis was performed, and samples were collected every thirty minutes to analyze extracellular glutamate levels. Compared to animals receiving only vehicle, administration of MK-801 alone significantly increased extracellular levels of glutamate in the mPFC. This effect was not observed in animals administered CDPPB before MK-801, nor in those administered CDPPB alone, indicating that CDPPB decreased extracellular glutamate release stimulated by MK-801. Results indicate that CDPPB attenuates MK-801 induced elevations in extracellular glutamate in the mPFC. This effect of CDPPB may underlie neurochemical adaptations associated with the pro-cognitive effects of mGluR5 PAMs in rodent models of schizophrenia. [ABSTRACT FROM AUTHOR]

In Alzheimer's disease (AD), reports on the association between false recognition and brain structure have been inconsistent. In dementia with Lewy bodies (DLB), no such association has been reported. This study aimed to identify brain regions associated with false recognition in AD and DLB by analyzing regional gray matter volume (rGMV). We included 184 patients with AD and 60 patients with DLB. The number of false recognitions was assessed using the Alzheimer's Disease Assessment Scale' word recognition task. Brain regions associated with the number of false recognitions were examined by voxel-based morphometry analysis. The number of false recognitions significantly negatively correlated with rGMV in the bilateral hippocampus, left parahippocampal gyrus, bilateral amygdala, and bilateral entorhinal cortex in patients with AD (p < 0.05, family-wise error [FEW] corrected) and in the bilateral hippocampus, left parahippocampal gyrus, right inferior frontal gyrus, right middle frontal gyrus, right basal forebrain, right insula, left medial and lateral orbital gyri, and left fusiform in those with DLB (p < 0.05, FWE corrected). Bilateral hippocampus and left parahippocampal gyrus were associated with false recognition in both diseases. However, we found there were regions where the association between false recognition and rGMV differed from disease to disease. [ABSTRACT FROM AUTHOR]

For better decisions in social interactions, humans often must understand the thinking of others and predict their actions. Since such predictions are uncertain, multiple predictions may be necessary for better decision-making. However, the neural processes and computations underlying such social decision-making remain unclear. We investigated this issue by developing a behavioral paradigm and performing functional magnetic resonance imaging and computational modeling. In our task, female and male participants were required to predict others' choices in order to make their own value-based decisions, as the outcome depended on others' choices. Results showed, to make choices, the participants mostly relied on a value difference (primary) generated from the case where others would make a likely choice, but sometimes they additionally used another value difference (secondary) from the opposite case where others make an unlikely choice. We found that the activations in the posterior cingulate cortex (PCC) correlated with the primary difference while the activations in the right dorsolateral prefrontal cortex (rdlPFC) correlated with the secondary difference. Analysis of neural coupling and temporal dynamics suggested a three-step processing network, beginning with the left amygdala signals for predictions of others' choices. Modulated by these signals, the PCC and rdlPFC reflect the respective value differences for self-decisions. Finally, the medial prefrontal cortex integrated these decision signals for a final decision. Our findings elucidate the neural process of constructing value-based decisions by predicting others and illuminate their key variables with social modulations, providing insight into the differential functional roles of these brain regions in this process. [ABSTRACT FROM AUTHOR]

Although the locus ceruleus (LC) is recognized as a crucial modulator for attention and perception by releasing norepinephrine into various cortical regions, the impact of LC-noradrenergic (LC-NE) modulation on auditory discrimination behavior remains elusive. In this study, we firstly recorded local field potential and single-unit activity in multiple cortical regions associated with auditory- motor processing, including the auditory cortex, posterior parietal cortex, secondary motor cortex, anterior cingulate cortex, prefrontal cortex, and orbitofrontal cortex (OFC), in response to optogenetic activation (40 Hz and 0.5 s) of the LC-NE neurons in awake mice (male). We found that phasic LC stimulation induced a persistent high gamma oscillation (50-80 Hz) in the OFC. Phasic activation of LC-NE neurons also resulted in a corresponding increase in norepinephrine levels in the OFC, accompanied by a pupillary dilation response. Furthermore, when mice were performing a go/no-go auditory discrimination task, we optogeneticaly activated the neural projections from LC to OFC and revealed a shortened latency in behavioral responses to sound stimuli and an increased false alarm rate. These impulsive behavioral responses may be associated with the gamma neural activity in the OFC. These findings have broadened our understanding of the neural mechanisms involved in the role of LC in auditory-motor processing. [ABSTRACT FROM AUTHOR]

AbstractBackgroundAimsStudy designMethodologyResultsConclusionPre-frontal cortex operates a combination of emotional, cognitive and behavioural functions. Understanding the symptoms of pre-frontal cortex lesions serves as paramount for accurate diagnosis and management.This review aims to determine an association between the causes of prefrontal cortex lesions and the resulting symptoms, as well as the ideal form of treatment.A systematic review through utilisation of 3 databases was done using the keywords “Prefrontal cortex lesions,” “dysfunction,” “symptoms,” &” treatment”RCTs, observational studies, and systematic reviews were searched using Cochrane/EMBASE, PubMed/Medline, and Pedro between 1948 and2024. Studies published in English only were included, and two reviewers were involved in the data extraction processResults showed a notable correlation between right-handed individuals and prefrontal cortex lesions with cognition impairment, particularly executive dysfunction, being the most prevalent symptom. Emotional instability followed as the second most common issue, while aphasia remained the primary language deficit. Noninvasive brain stimulation emerged as an effective treatment option for various prefrontal cortex-related disordersFurther investigation is needed to understand the mechanism linking handedness to lesion occurrence. Noninvasive brain stimulation should be prioritised for treating prefrontal injuries [ABSTRACT FROM AUTHOR]

To survive in nature, it is crucial for animals to promptly and appropriately respond to visual information, specifically to animacy cues that pose a threat. The subcortical visual pathway is thought to be implicated in the processing of visual information necessary for these responses. In primates, this pathway consists of retina-superior colliculus-pulvinar-amygdala, functioning as a visual pathway that bypasses the geniculo-striate system (retina-lateral geniculate nucleus-primary visual cortex). In this mini review, we summarize recent neurophysiological studies that have revealed neural responses to threatening animacy cues, namely snake images, in different parts of the subcortical visual pathway and closely related brain regions in primates. The results of these studies provide new insights on (1) the role of the subcortical visual pathway in innate cognitivemechanisms for predator recognition that are evolutionarily conserved, and (2) the possible role of the medial prefrontal cortex (mPFC) and anterior cingulate cortex (ACC) in the development of fear conditioning to cues that should be instinctively avoided based on signals from the subcortical visual pathway, as well as their function in excessive aversive responses to animacy cues observed in conditions such as ophidiophobia (snake phobia). [ABSTRACT FROM AUTHOR]

Social exclusion stands as a source of social discord and holds substantial research value. Prior investigations on social exclusion have overlooked the interactive relationship between the excluded individuals and the observers. Hence, this study comparatively explores the neural mechanisms underlying the psychological responses of two distinct roles within the same social exclusion context. A total of 35 pairs (19 pairs of females) participated in the experiment. Within each pair, one individual assumed the role of a socially excluded participant (target), while the other acted as a social exclusion observer. Targets engaged in an online ball-passing game where controlled ball allocations to the participants created an exclusion scenario. Meanwhile, observers spectated the targets playing the game. Throughout the ball-passing activity, functional near-infrared spectroscopy (fNIRS) recorded the blood oxygen data in the prefrontal cortex (PFC) and temporoparietal junction (TPJ) of both participants. Our findings revealed varied levels of rejection sensitivity elicited by direct or observed social exclusion experiences. Additionally, distinct patterns of neural activation were observed: targets displayed conditional differences in the medial prefrontal cortex (mPFC), while male observers exhibited conditional activation differences in the mPFC, and female observers showed conditional activation differences in the right dorsolateral prefrontal cortex (dlPFC). This study juxtaposes the behavioral and neural activation variances between targets and observers within the same social context, offering a novel perspective on investigating the neural mechanisms of social exclusion. [ABSTRACT FROM AUTHOR]

The ability to switch between rules associating stimuli and responses depend on a circuit including the dorsomedial prefrontal cortex (dmPFC) and the subthalamic nucleus (STN). However, the precise neural implementations of switching remain unclear. To address this issue, we recorded local field potentials from the STN and from the dmPFC of neuropsychiatric patients during behavioral switching. Drift-diffusion modeling revealed that switching is associated with a shift in the starting point of evidence accumulation. Theta activity increases in dmPFC and STN during successful switch trials, while temporally delayed and excessive levels of theta lead to premature switch errors. This seemingly opposing impact of increased theta in successful and unsuccessful switching is explained by a negative correlation between theta activity and the starting point. Together, these results shed a new light on the neural mechanisms underlying the rapid reconfiguration of stimulus-response associations, revealing a Goldilocks' effect of theta activity on switching behavior. Direct electrophysiological recordings in the human prefronto-subthalamic circuit show that behavioral switching requires an optimal level of theta activity to be successful, which is well accounted for by a negative modulation of a drift-diffusion model starting point. [ABSTRACT FROM AUTHOR]

Background and objectives: Several studies have reported on the restingstate electroencephalogram (EEG) power in patients with schizophrenia, with a decrease in a (especially a2) and an increase in d and b1 power compared with healthy control; however, reports on at-risk mental states (ARMS) are few. In this study, we measured the resting-state EEG power in ARMS, and investigated its features and the relationship between the power of the frequency bands and their diagnostic outcomes. Methods: Patients with ARMS who were not on any psychotropic medication and met the Comprehensive Assessment of At-Risk Mental State criteria were included. Patients who developed psychotic disorders were labeled as the ARMS-P group, while patients with ARMS who were followed up prospectively for more than 2 years and did not develop psychotic disorders were classified as the ARMS-NP group. EEGs were measured in the resting state, and frequencies were analyzed using standardized low-resolution brain electromagnetic tomography (sLORETA). Seven bands (d, ", a1, a2, b1-3) underwent analysis. The sLORETA values (current source density [CSD]) were compared between the ARMS-P and ARMS-NP groups. Clinical symptoms were assessed at the time of EEG measurements using the Positive and Negative Syndrome Scale (PANSS). Results: Of the 39 patients included (25 males, 14 females, 18.8 ± 4.5 years old), eight developed psychotic disorders (ARMS-P). The ARMS-P group exhibited significantly higher CSD in the b1 power within areas of the left middle frontal gyrus (MFG) compared with the ARMS-NP group (best match: X = 35, Y = 25, Z = 50 [MNI coordinates], Area 8, CSD = 2.33, p < 0.05). There was a significant positive correlation between the b1/a ratio of the CSD at left MFG and the Somatic concern score measured by the PANSS. Discussion: Increased b1 power was observed in the resting EEG before the onset of psychosis and correlated with a symptom. This suggests that resting EEG power may be a useful marker for predicting future conversion to psychosis and clinical symptoms in patients with ARMS. [ABSTRACT FROM AUTHOR]

Episodic memory is essential for forming and retaining personal experiences, representing a fundamental aspect of human cognition. Traditional studies of episodic memory have typically used static analysis methods, viewing the brain as an unchanging entity and overlooking its dynamic properties over time. In this study, we utilized dynamic functional connectivity analysis on fMRI data from healthy adults performing an episodic memory task. We quantified integration and recruitment metrics and examined their correlation with memory performance using Pearson correlation. During encoding, integration across the entire brain, especially within the frontoparietal subnetwork, was significantly correlated with memory performance. During retrieval, recruitment becomes significantly associated with memory performance in visual subnetwork, somatomotor subnetwork, and ventral attention subnetwork. At the nodal level, a significant negative correlation was observed between memory scores and integration of the anterior cingulate gyrus, precentral gyrus, and inferior frontal gyrus within the frontoparietal network during encoding task. During retrieval task, a significant negative correlation was found between memory scores and recruitment in the left progranular cortex and right transverse gyral ventral, whereas positive correlations were seen in the right posterior inferior temporal, left middle temporal, right frontal operculum, and left operculum nodes. Moreover, the dynamic reconfiguration of the functional network was predictive of predict memory performance, as demonstrated by a significant correlation between actual and predicted memory scores. These findings advance our understanding network mechanisms underlying memory processes and developing intervention approaches for memory-related disorders as they shed light on critical factors involved in cognitive processes and provide a deeper understanding of the underlying mechanisms driving cognitive function. [ABSTRACT FROM AUTHOR]

Background and Purpose Methods Results Conclusions Neuropathic pain (NP) is a debilitating condition following spinal cord injury (SCI). The role of periaqueductal gray (PAG) in NP development following SCI remains underexplored. Using resting‐state functional MRI (rsfMRI), our study aimed to demonstrate the alterations in functional connectivity (FC) of PAG in NP following SCI.Ten SCI patients (SCI + NP, n = 7, and SCI − NP, n = 3), alongside 10 healthy controls (HCs), were enrolled. rsfMRI was conducted followed by seed‐to‐voxel analysis using PAG as the seed region and then group‐based analysis comprising three groups (SCI + NP, SCI − NP, and HC). Age and gender were considered as confounding variables.Compared to HCs, SCI + NP demonstrated decreased FC between PAG and right insula, right frontal orbital cortex, right pallidum, dorsal raphe nucleus (DRN), red nuclei (RN), substantia nigra (SN), and ventral posterolateral (VPL) thalamic nuclei. Compared to SCI − NP, SCI + NP demonstrated increased FC between PAG and posterior cingulate cortex (PCC), hippocampus, cerebellar vermis lobules IV and V, and thalamic structures (posterior and lateral pulvinar, the mediodorsal nuclei, and the ventral lateral nuclei). Additionally, decreased FC between the PAG and VPL, geniculate bodies, intralaminar nuclei of thalamus, DRN, RN, SN, and prefrontal cortex was observed in this comparison.Altered FC between PAG and right anterior insula, VPL, DRN, RN, SN, cerebellar vermis lobules IV and V, frontal cortex, and PCC was associated with NP sequelae of SCI. Additionally, SCI was independently associated with decreased FC between PAG and right posterior insula, cerebellar lobules IV and V, and cerebellar vermis lobules III, IV, and V. [ABSTRACT FROM AUTHOR]

From adolescence, women become more likely to experience fear dysregulation. Oral contraceptives (OCs) can modulate the brain regions involved in fear processes. OCs are generally used for years and often initiated during adolescence, a sensitive period where certain brain regions involved in the fear circuitry are still undergoing important reorganization. It remains unknown whether OC use during adolescence may induce long‐lasting changes in the fear circuitry. This study aimed to examine whether age of onset moderated the relationship between duration of use and fear‐related brain structures. We collected structural MRI data in 98 healthy adult women (61 current users, 37 past users) and extracted grey matter volumes (GMV) and cortical thickness (CT) of key regions of the fear circuitry. Non‐linear multiple regressions revealed interaction effects between age of onset and quadratic duration of use on GMV of the right hippocampus and right ventromedial prefrontal cortex (vmPFC). Among women who initiated OCs earlier in adolescence, a short duration of use was associated with smaller hippocampal GMV and thicker vmPFC compared to a longer duration of use. For both GMV and CT of the right vmPFC, women with an early OC onset had more grey matter at a short duration of use than those with a later onset. Our results suggest that OC use earlier in adolescence may induce lasting effects on structural correlates of fear learning and its regulation. These findings support further investigation into the timing of OC use to better comprehend how OCs could disrupt normal brain development processes. [ABSTRACT FROM AUTHOR]

Transcriptome-wide association study (TWAS) tools have been applied to conduct proteome-wide association studies (PWASs) by integrating proteomics data with genome-wide association study (GWAS) summary data. The genetic effects of PWAS-identified significant genes are potentially mediated through genetically regulated protein abundance, thus informing the underlying disease mechanisms better than GWAS loci. However, existing TWAS/PWAS tools are limited by considering only one statistical model. We propose an omnibus PWAS pipeline to account for multiple statistical models and demonstrate improved performance by simulation and application studies of Alzheimer disease (AD) dementia. We employ the Aggregated Cauchy Association Test to derive omnibus PWAS (PWAS-O) p values from PWAS p values obtained by three existing tools assuming complementary statistical models—TIGAR, PrediXcan, and FUSION. Our simulation studies demonstrated improved power, with well-calibrated type I error, for PWAS-O over all three individual tools. We applied PWAS-O to studying AD dementia with reference proteomic data profiled from dorsolateral prefrontal cortex of postmortem brains from individuals of European ancestry. We identified 43 risk genes, including 5 not identified by previous studies, which are interconnected through a protein-protein interaction network that includes the well-known AD risk genes TOMM40 , APOC1 , and APOC2. We also validated causal genetic effects mediated through the proteome for 27 (63%) PWAS-O risk genes, providing insights into the underlying biological mechanisms of AD dementia and highlighting promising targets for therapeutic development. PWAS-O can be easily applied to studying other complex diseases. We present an omnibus proteome-wide association study pipeline (PWAS-O) to identify risk genes with genetic effects potentially mediated through genetically regulated proteome abundance for complex diseases. Application studies identified 43 PWAS risk genes for Alzheimer disease dementia, demonstrating the superior power of PWAS-O by leveraging multiple complementary statistical models. [ABSTRACT FROM AUTHOR]

Parkinson disease (PD) is a neurodegenerative disorder that causes motor and cognitive deficits, presenting complex challenges for therapeutic interventions. Repetitive transcranial magnetic stimulation (rTMS) is a type of neuromodulation that can produce plastic changes in neural activity. rTMS has been trialed as a therapy to treat motor and non-motor symptoms in persons with Parkinson disease (PwP), particularly treatment-refractory postural instability and gait difficulties such as Freezing of Gait (FoG), but clinical outcomes have been variable. We suggest improving rTMS neuromodulation therapy for balance and gait abnormalities in PwP by targeting brain regions in cognitivemotor control networks. rTMS studies in PwP often targeted motor targets such as the primary motor cortex (M1) or supplementary motor area (SMA), overlooking network interactions involved in posture-gait control disorders. We propose a shift in focus toward alternative stimulation targets in basal gangliacortex- cerebellum networks involved in posture-gait control, emphasizing the dorsolateral prefrontal cortex (dlPFC), cerebellum (CB), and posterior parietal cortex (PPC) as potential targets. rTMS might also be more effective if administered during behavioral tasks designed to activate posture-gait control networks during stimulation. Optimizing stimulation parameters such as dosage and frequency as used clinically for the treatment of depression may also be useful. A network-level perspective suggests new directions for exploring optimal rTMS targets and parameters to maximize neural plasticity to treat postural instabilities and gait difficulties in PwP. [ABSTRACT FROM AUTHOR]

Background: Previous studies based on resting-state functional magnetic resonance imaging(rs-fMRI) and voxel-based morphometry (VBM) have demonstrated significant abnormalities in brain structure and resting-state functional brain activity in patients with early-onset schizophrenia (EOS), compared with healthy controls (HCs), and these alterations were closely related to the pathogenesis of EOS. However, previous studies suffer from the limitations of small sample sizes and high heterogeneity of results. Therefore, the present study aimed to effectively integrate previous studies to identify common and specific brain functional and structural abnormalities in patients with EOS. Methods: The PubMed, Web of Science, Embase, Chinese National Knowledge Infrastructure (CNKI), and WanFang databases were systematically searched to identify publications on abnormalities in resting-state regional functional brain activity and gray matter volume (GMV) in patients with EOS. Then, we utilized the Seed-based d Mapping with Permutation of Subject Images (SDM-PSI) software to conduct a whole-brain voxel meta-analysis of VBM and rs-fMRI studies, respectively, and followed by multimodal overlapping on this basis to comprehensively identify brain structural and functional abnormalities in patients with EOS. Results: A total of 27 original studies (28 datasets) were included in the present meta-analysis, including 12 studies (13 datasets) related to resting-state functional brain activity (496 EOS patients, 395 HCs) and 15 studies (15 datasets) related to GMV (458 EOS patients, 531 HCs). Overall, in the functional meta-analysis, patients with EOS showed significantly increased resting-state functional brain activity in the left middle frontal gyrus (extending to the triangular part of the left inferior frontal gyrus) and the right caudate nucleus. On the other hand, in the structural meta-analysis, patients with EOS showed significantly decreased GMV in the right superior temporal gyrus (extending to the right rolandic operculum), the right middle temporal gyrus, and the temporal pole (superior temporal gyrus). Conclusion: This meta-analysis revealed that some regions in the EOS exhibited significant structural or functional abnormalities, such as the temporal gyri, prefrontal cortex, and striatum. These findings may help deepen our understanding of the underlying pathophysiological mechanisms of EOS and provide potential biomarkers for the diagnosis or treatment of EOS. [ABSTRACT FROM AUTHOR]

Introduction: Perturbation walking (PW) has been shown to improve gait, however its effect on the cortical control of gait might provide insights on neural mechanisms underlying falls in adults with osteoarthritis. The objective of this study is to investigate the effect of PW on prefrontal cortical (PFC) activation in older women with (OA) and without osteoarthritis (HOA). We hypothesized that there would be an increase in PFC activation during PW relative to comfortable walking (CW) and higher increase in PFC activation during PW in HOA compared to OA. Methods: Twenty community-dwelling older women (66.7 ± 5.41 years old) walked on an instrumented treadmill that provided perturbations at pseudorandom intervals between 5-25 s using a counterbalanced design. Functional Near Infrared Spectroscopy was used to quantify PFC oxygenated hemoglobin (HbO2) and deoxyhemoglobin (Hb) levels, while standing prior to the task as a baseline. A linear mixed effects model was conducted to investigate the effects of cohort (HOA vs OA), task (PW vs CW), and their interaction on HbO2 (mM) and Hb (mM) levels. Results: HbO2 and Hb levels differed significantly between CW and PW tasks for both cohorts (P < 0.001) and demonstrated significant task by cohort interaction (P < 0.05). In addition, we found changes in walking performance (stride time, stride length, stride width and stance time) during and after PW. Spearman correlation demonstrated a strong association between increased stance time, increased body mass index and decreased PFC activation during PW. No other significant results were found. Discussion: This study found increase in PFC activation during PW and gait adaptation after a short bout of PW in HOA and OA. This increase in PFC activation was higher in HOA compared to OA, particularly during PW tasks, and was consistent with theory of limitations in mobility affecting neural activation in older adults. Further work remains to examine how pain, obesity, and mobility impacts cortical control in older adults with and without osteoarthritis. [ABSTRACT FROM AUTHOR]

The orbitofrontal cortex (OFC) is crucial for tracking various aspects of expected outcomes, thereby helping to guide choices and support learning. Our previous study showed that the effects of reward timing and size on the activity of single units in OFC were dissociable when these attributes were manipulated independently (Roesch et al., 2006). However, in real-life decision-making scenarios, outcome features often change simultaneously, so here we investigated how OFC neurons in male rats integrate information about the timing and identity (flavor) of reward and respond to changes in these features, according to whether they were changed simultaneously or separately. We found that a substantial number of OFC neurons fired differentially to immediate versus delayed reward and to the different reward flavors. However, contrary to the previous study, selectivity for timing was strongly correlated with selectivity for identity. Taken together with the previous research, these results suggest that when reward features are correlated, OFC tends to “pack” them into unitary constructs, whereas when they are independent, OFC tends to “crack” them into separate constructs. Furthermore, we found that when both reward timing and flavor were changed, reward-responsive OFC neurons showed unique activity patterns preceding and during the omission of an expected reward. Interestingly, this OFC activity is similar and slightly preceded the ventral tegmental area dopamine (VTA DA) activity observed in a previous study (Takahashi et al., 2023), consistent with the role of OFC in providing predictive information to VTA DA neurons. [ABSTRACT FROM AUTHOR]

Background Objectives Methods Results Discussion and conclusion Anejaculation represents significant psychological distress and sexual and reproductive challenges among male individuals and couples. Effective fertility management options are available to address the reproductive challenges associated with anejaculation. However, there is a lack of methods to reverse the condition itself.This study aims to assess the effectiveness and safety of repetitive transcranial magnetic stimulation (rTMS) in patients suffering from anejaculation.A total of 94 patients with anejaculation individuals were randomly assigned to receive high‐frequency (HF) stimulation on the left dorsolateral prefrontal cortex (DLPFC), low‐frequency (LF) stimulation on the right DLPFC, and sham stimulation for 4 weeks, with daily sessions of stimulation occurring on five consecutive weekdays each week.After 4 weeks of rTMS treatment, the patients in both the HF and LF groups exhibited a similar reduction in their male sexual health questionnaire for ejaculatory dysfunction bother/satisfaction score, Hamilton Anxiety Scale score, Hamilton Depression Scale score, and Pittsburgh Sleep Quality Inventory score, which were statistically significant compared with sham treatment. Additionally, there were no significant differences observed in erectile function and cognitive function across the three groups. However, there were notable disparities in the cure rates between HF‐ and LF‐group patients (16.1% vs. 54.8%, p = 0.001). Additionally, it is worth noting that only two HF group patients and one LF group patient experienced spontaneously resolving minor adverse effects during the treatment process. At the 8‐week follow‐up, among patients who initially responded to the treatment, only one from the HF group experienced a relapse.The findings of this study demonstrate that rTMS represents a secure and efficacious remedy for anejaculation patients. [ABSTRACT FROM AUTHOR]

The massive use of herbicides, particularly glyphosate‐based herbicides (GBHs), raises several worries, notably their neurotoxic effects. Several studies have explored the consequences of developmental exposure. Our work aims to determine the impact of maternal exposure to GBH on behavioral disorders and memory deficits, as well as the involvement of oxidative stress in the hippocampus and prefrontal cortex. In addition, our study explores the neuroprotective properties of melatonin in male and female offspring. Pregnant Wistar rats were injected with GBH 75 mg/kg during gestation and lactation. After weaning, the offspring were treated with melatonin (4 mg/kg) from postnatal days 30–58. Our results show that GBH increases anxiety‐like behavior levels in offspring, as well as depression‐like behavior. GBH also impairs working memory in progeny. While markers of oxidative stress show a disturbance in lipid peroxidation and catalase activity, with a more pronounced effect in females, on the other hand, melatonin considerably attenuated the neurotoxic impact observed in the offspring, with higher efficacy in females. The oxidative stress results confirm the antioxidant power of melatonin to counteract the damaging effects of exposure to environmental contaminants such as glyphosate‐based pesticides. It will then be interesting to further our work to fully understand the sex‐dependent effect of melatonin. [ABSTRACT FROM AUTHOR]

Introduction: Glyphosate-based herbicides (GBHs) have been shown to have significant neurotoxic effects, affecting both the structure and function of the brain, and potentially contributing to the development of neurodegenerative disorders. Despite the known importance of glycosylation in disease progression, the glycome profile of systems exposed to GBH has not been thoroughly investigated. Methods: In this study, we conducted a comprehensive glycomic profiling using LC-MS/MS, on the hippocampus and prefrontal cortex (PFC) of juvenile rats exposed to GBH orally, aiming to identify glyco-signature aberrations after herbicide exposure. Results: We observed changes in the glycome profile, particularly in fucosylated, high mannose, and sialofucosylated N-glycans, which may be triggered by GBH exposure. Moreover, we found major significant differences in the N-glycan profiles between the GBH-exposed group and the control group when analyzing each gender independently, in contrast to the analysis that included both genders. Notably, gender differences in the behavioral test of object recognition showed a decreased performance in female animals exposed to GBH compared to controls (p < 0.05), while normal behavior was recorded in GBH-exposed male rats (p > 0.05). Conclusion: These findings suggest that glycans may play a role in the neurotoxic effect caused by GBH. The result suggests that gender variation may influence the response to GBH exposure, with potential implications for disease progression and specifically the neurotoxic effects of GBHs. Understanding these gender-specific responses could enhance knowledge of the mechanisms underlying GBH-induced toxicity and its impact on brain health. Overall, our study represents the first detailed analysis of N-glycome profiles in the hippocampus and PFC of rats chronically exposed to GBH. The observed alterations in the expression of N-glycan structures suggest a potential neurotoxic effect associated with chronic GBH exposure, highlighting the importance of further research in this area. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD), the leading cause of dementia, is a multifactorial disease influenced by aging, genetics, and environmental factors. miRNAs are crucial regulators of gene expression and play significant roles in AD onset and progression. This exploratory study analyzed the expression levels of 28 genes and 5 miRNAs (miR-124-3p, miR-125b-5p, miR-21-5p, miR-146a-5p, and miR-155-5p) related to AD pathology and neuroimmune responses using RT-qPCR. Analyses were conducted in the prefrontal cortex (PFC) and the hippocampus (HPC) of the 5xFAD mouse AD model at 6 and 9 months old. Data highlighted upregulated genes encoding for glial fibrillary acidic protein (Gfap), triggering receptor expressed on myeloid cells (Trem2) and cystatin F (Cst7), in the 5xFAD mice at both regions and ages highlighting their roles as critical disease players and potential biomarkers. Overexpression of genes encoding for CCAAT enhancer-binding protein alpha (Cebpa) and myelin proteolipid protein (Plp) in the PFC, as well as for BCL2 apoptosis regulator (Bcl2) and purinergic receptor P2Y12 (P2yr12) in the HPC, together with upregulated microRNA(miR)-146a-5p in the PFC, prevailed in 9-month-old animals. miR-155 positively correlated with miR-146a and miR-21 in the PFC, and miR-125b positively correlated with miR-155, miR-21, while miR-146a in the HPC. Correlations between genes and miRNAs were dynamic, varying by genotype, region, and age, suggesting an intricate, disease-modulated interaction between miRNAs and target pathways. These findings contribute to our understanding of miRNAs as therapeutic targets for AD, given their multifaceted effects on neurons and glial cells. [ABSTRACT FROM AUTHOR]

Epilepsy treatment continues to face significant challenges, including drug resistance and cognitive impairment associated with antiepileptic drugs. 1-Triacontanol cerotate (1TAC), an active component isolated from Marsilea quadrifolia Linn., has emerged as a potential therapeutic avenue for epilepsy. This study investigated the effects of 1TAC on prefrontal cortical neurons and memory retention in chronically epileptic rats, comparing its efficacy to sodium valproate. Our experiment utilized two-month-old adult male Wistar rats, randomly assigned to one of five groups: I - Vehicle Control, II - Rats receiving Pentylenetetrazol (PTZ) at a dosage of 35 mg/kg body weight intraperitoneally every 48 hours, III - Rats given 200 mg/kg body weight of sodium valproate 30 minutes prior to PTZ administration, IV and V - Rats administered 40 and 80 mg/kg body weight of 1-TAC orally 30 minutes before PTZ challenge, respectively. To assess memory performance, we conducted a passive avoidance test. Subsequently, brain specimens were processed for cresyl violet staining to assess cell densities. Results demonstrated that epileptic rats treated with sodium valproate before PTZ administration, and those given 80 mg of 1-Triacontanol cerotate exhibited significantly enhanced memory retention compared to the untreated epileptic group at both 24- and 48-hours postchallenge. Furthermore, 80 mg of 1-Triacontanol cerotate administration showed a protective effect by significantly reducing the loss of pyramidal cells in the medial prefrontal cortex. This intervention effectively minimized the loss of pyramidal neurons in the medial prefrontal cortex and mitigated memory deficits in chronically epileptic rats. [ABSTRACT FROM AUTHOR]

This study aimed to investigate the psychophysiological effects of horticultural activities on the prefrontal cortex (PFC) to understand how horticultural activities can influence mental health and cognitive function. This study involved 39 adults with an average age of 54.6 years (±12.5 years) and was conducted in a laboratory setting at Konkuk University. The impact of five different types of horticultural activities--sowing, transplanting, planting, harvesting, and packaging--on PFC oxyhemoglobin (oxy-HB) concentrations was assessed. Functional near-infrared spectroscopy (fNIRS) was used to measure oxy-HB levels in the PFC while participants engaged in each activity for 90 seconds. The results indicated that the overall PFC oxy-HB concentration was at its lowest during planting and at its highest during sowing (P < 0.001). In the right PFC, oxy-HB was also at its lowest during planting and at its highest during sowing (P < 0.01). In the left PFC, the lowest oxy-HB concentrations were observed during both planting and harvesting, whereas the highest oxy-HB concentrations were observed during transplanting and sowing (P < 0.001). Additionally, sex-based differences were noted, with females showing significantly lower oxy-HB concentrations during sowing (P < 0.05) and transplanting (P < 0.01) than those of males. These findings suggested that psychophysiological responses, as indicated by oxy-HB concentrations, vary depending on the type of horticultural activity and by sex. [ABSTRACT FROM AUTHOR]

The onset of schizophrenia is concurrent with multiple key processes of brain development, such as the maturation of inhibitory networks. Some of these processes are proposed to depend on the development of perineuronal nets (PNNs), a specialized extracellular matrix structure that surrounds preferentially parvalbumin-containing GABAergic interneurons (PVIs). PNNs are fundamental to the postnatal experience-dependent maturation of inhibitory brain circuits. PNN abnormalities have been proposed as a core pathophysiological finding in SCZ, being linked to widespread consequences on circuit disruptions underlying SCZ symptoms. Here, we systematically evaluate PNN density in postmortem brain studies of subjects with SCZ. A systematic search in 3 online databases (PubMed, Embase, and Scopus) and qualitative review analysis of case-control studies reporting on PNN density in the postmortem brain of subjects with SCZ were performed. Results consisted of 7 studies that were included in the final analysis. The specific brain regions investigated in the studies varied, with most attention given to the dorsolateral prefrontal cortex (DLPFC; 3 studies) and amygdala (2 studies). Findings were mostly positive for reduced PNN density in SCZ, with 6 of the 7 studies reporting significant reductions and one reporting a tendency towards reduced PNN density. Overall, tissue processing methodologies were heterogeneous. Despite few studies, PNN density was consistently reduced in SCZ across different brain regions. These findings support evidence that implicates deficits in PNN density in the pathophysiology of SCZ. However, more studies, preferably using similar methodological approaches as well as replication of findings, are needed. [ABSTRACT FROM AUTHOR]

Stress is proposed to be a crucial factor in the onset and presentation of psychosis. The early stage of psychosis provides a window into how stress interacts with the emergence of psychosis. Yet, how people with early psychosis respond to stress remains unclear. The current study examined how stress responses (brain, physiological, self-report) differ in early psychosis. Forty participants (20 early psychosis [EP], 20 healthy controls [HC]) completed a stress task in the scanner that involved viewing stressful and neutral-relaxing images. Physiological responses (cortisol, heart rate) and self-report of stress were also assessed. Region of Interest analyses were conducted with brain regions previously shown to be activated during the stress task (amygdala, hippocampus, striatum, hypothalamus, prefrontal cortex [dorsolateral, ventrolateral, medial orbital]). Linear mixed models were used to test for effects of group (EP, HC) and emotion (stress, neutral-relaxing). HC had higher hippocampus activation to stress versus neutral-relaxing conditions while EP did not show a difference (group x emotion interaction, p = 0.04). There were also significant main effects of group with EP having higher amygdala activation (p = 0.01), ventrolateral prefrontal cortex activation (vlPFC, p = 0.03), self-report of stress (p = 0.01), and heart rate (p < 0.001). Our study found preliminary evidence that people with early psychosis showed heightened response to stressful and non-threatening situations, across multiple levels of stress responses. Our findings suggest a novel perspective on stress alterations in early psychosis and highlight the importance of considering both stressful and non-stressful situations. [ABSTRACT FROM AUTHOR]

Schizophrenia (SZ) is characterized by disconnected cerebral networks. Recent studies have shown that functional connectivity between the cerebellar dorsal dentate nucleus (dDN) and cerebrum is correlated with psychotic symptoms, and processing speed in SZ patients. Dynamic effective connectivity (dEC) is a reliable indicator of brain functional status. However, the dEC between the dDN and cerebrum in patients with SZ remains largely unknown. Resting-state functional MRI data, symptom severity, and cognitive performance were collected from 74 SZ patients and 53 healthy controls (HC). Granger causality analysis and sliding time window methods were used to calculate dDN-based dEC maps for all subjects, and k-means clustering was performed to obtain several dEC states. Finally, between-group differences in dynamic effective connectivity variability (dECV) and clinical correlations were obtained using two-sample t -tests and correlation analysis. We detected four dEC states from the cerebrum to the right dDN (IN states) and three dEC states from the right dDN to the cerebrum (OUT states), with SZ group having fewer transitions in the OUT states. SZ group had increased dECV from the right dDN to the right middle frontal gyrus (MFG) and left lingual gyrus (LG). Correlations were found between the dECV from the right dDN to the right MFG and symptom severity and between the dECV from the right dDN to the left LG and working memory performance. This study reveals a dynamic causal relationship between cerebellar dDN and the cerebrum in SZ and provides new evidence for the involvement of cerebellar neural circuits in neurocognitive functions in SZ. [ABSTRACT FROM AUTHOR]