This review explores ketamine’s expanding role in managing both chronic pain and mental health conditions, focusing on its pharmacologic mechanisms, clinical applications, and therapeutic potential. We assess its analgesic properties, FDA-approved application in the form of Spravato (esketamine) for depression, and off-label use for analgesia and psychiatric disorders.
A systematic search of PubMed, Cochrane Library, and Scopus databases identified studies on ketamine’s efficacy and safety in chronic pain and psychiatric disorders. The analysis included randomized controlled trials (RCTs), observational studies, and systematic reviews.
Ketamine has demonstrated significant efficacy in managing chronic pain in neuropathic pain, fibromyalgia, and complex regional pain syndrome (CRPS), especially in treatment-resistant cases. Mental health comorbidities are common in chronic pain populations, with up to 50% experiencing depression or anxiety. Ketamine’s N-methyl-D-aspartate (NMDA) receptor antagonism not only underlies its analgesic effects but also contributes to rapid antidepressant responses in treatment-resistant depression (TRD) and acute suicidal ideation, as evidenced by its FDA-approved formulation, Spravato (esketamine). Beyond depression, emerging evidence supports ketamine’s potential use in anxiety disorders, obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD), and certain substance use disorders. However, its psychomimetic effects, safety concerns, and unclear long-term impact warrant careful clinical oversight.
Ketamine presents a versatile therapeutic strategy for managing chronic pain and a wide range of mental health disorders, signifying its potential to bridge the gap in treatment-resistant cases. Ongoing research is needed to optimize dosing strategies, assess long-term safety, and integrate ketamine into multidisciplinary care models. This approach emphasizes personalized patient care and comprehensive monitoring to navigate the complexities of coexisting chronic pain and mental health challenges.
Neuroinflammation, meaning an inflammatory process primarily occurring within the central nervous system (CNS), is thought to be associated with the pathogenesis of psychiatric disorders including schizophrenia (SC), although existing evidence is sometimes contradictory. This review critically summarizes the existing data on neuroinflammation and possible neuroinflammatory mechanisms in the pathogenesis of SC. Despite heterogeneity and inconsistency, the existing evidence indicates dysregulation of inflammatory genes and infiltration of the CNS parenchyma by immune cells, disturbances in the blood–cerebrospinal fluid barrier and blood–brain barrier, and activation of microglia and astroglia. Widely documented increases in levels of peripheral inflammatory biomarkers also reflect activation of inflammatory processes in the CNS. Nevertheless, patients differ in the degree of activation of neuroinflammatory processes, indicating the existence of immunophenotypes of SC with and without neuroinflammation. Neuroinflammation may be associated with dysregulation of synaptic pruning, impaired neuroplasticity, glymphatic-clearance dysfunction, and white-matter pathology, all of which may ultimately lead to functional brain dysconnectivity and disease manifestation. Dysregulation of the hypothalamic–pituitary–adrenal axis and gut–brain axis and disturbances in the kynurenine pathway are the main molecular mechanisms linking peripheral and central inflammation. However, neuroinflammation may not only be associated with negative consequences but also indicate activation of adaptive and reparative processes. Thus, neuroinflammation may be entwined in the pathogenetic mechanisms of SC; therefore, anti-inflammatory therapeutic strategies may improve patient care.
Cognitive training offers a potential approach for the prevention of cognitive decline in later life. Repetition of targeted exercises may improve, or at least preserve, both specific domain and general cognitive abilities by strengthening neural connections and promoting neuroprotective processes within brain networks. Importantly, middle-aged adults have been omitted from the cognitive training literature. In this experiment, we investigated short-term training (1 session) on a perceptual-cognitive-motor task in middle-aged adults. Furthermore, we examined the functional and structural neural correlates of this training.
Twenty-one healthy middle-aged adults between the age of 40 and 50 years underwent one scanning session during which they learned and performed the perceptual-cognitive-motor task. We compared performance and functional imaging on the Early and Late Learning phases of the task. We used diffusion Magnetic Resonance Imaging (MRI) to examine baseline microstructural variation in the brain in relation to training outcome. The diffusion indices included fractional anisotropy (FA), mean diffusivity (MD), neurite density index (NDI), and orientation dispersion index (ODI).
We found a significant improvement in performance following training on the task. The improvement correlated with gaming experience, but not with impulsivity. There were also significant training-induced changes in functional activity in cerebellar, cortical and subcortical brain regions. Furthermore, significant correlations were found between the diffusion indices of FA, MD, and ODI and training outcome.
These results suggest fast reorganisation of functional activity in the middle-aged brain, and that individual variation in brain microstructure correlates with fast visuo-motor task performance gains.
Aging is a multifaceted biological process characterized by numerous physiological and molecular alterations that profoundly impact health and susceptibility to disease. Among the genetic determinants influencing aging, the apolipoprotein E (APOE) gene cluster has emerged as a critical focus of research. This study explored the diverse roles of APOE in both normal and pathological aging, with particular emphasis on its involvement in Alzheimer’s disease (AD). We first examined the “physiological” aspects of aging, highlighting cellular and systemic adaptations that support organismal homeostasis. This was followed by an analysis of the pathophysiological deviations underlying neurodegenerative disorders, with AD as a key example. The role of APOE in normative aging was then discussed, including its contributions to lipid metabolism, synaptic plasticity, and neuroprotection—functions essential for maintaining both cerebral and systemic health. However, the pathological implications of APOE genetic variants, particularly the ε4 allele, were considered in relation to the increased risk of AD and other age-related diseases. Additionally, the APOE gene cluster, which includes adjacent regulatory and interactive genes, was examined for its potential to modulate APOE expression and function, thereby influencing the aging process. This synthesis underscores the pivotal role of the APOE gene cluster in elucidating the genetic and molecular mechanisms underlying aging and age-related diseases, providing a foundation for the development of targeted therapeutic interventions.
Accidental hypoxia has detrimental effects on the brain, particularly on the hippocampal subfields (HS), which are highly sensitive to oxygen deprivation and play a crucial role in episodic memory. This raises the question: could freediving training induce anatomical changes in the HS and lead to significant memory deficits? This study aimed to investigate the impact of a season of freediving training on HS anatomy and episodic memory performance, as freedivers represent a unique natural model for studying the effects of repeated voluntary hypoxic exposure on brain function in healthy individuals. Extending previous research, this study assessed these effects over a prolonged training period.
Seventeen male freedivers were evaluated before and after 7 months of training and compared with a control group of 20 non-freediver athletes. HS anatomical volumes were measured using MRI segmentation and episodic memory performance was evaluated using a pattern separation (PS) task. This task specifically targeted HS-related memory processes by distinguishing between three types of items: (i) identical, (ii) similar, and (iii) new.
No significant differences were observed between freedivers and controls in HS volumes or memory performance, either before or after the 7 month training period. A two-way repeated measures ANOVA revealed that freedivers exhibited the same memory pattern as the control group in the PS task. Specifically, both groups performed better with (i) identical items compared with (ii) similar items (p < 0.001) and were less accurate with (ii) similar items compared with (iii) new items (p < 0.001). This aligns with expectations, as distinguishing similar items from previously presented ones is more cognitively demanding than recognizing new items.
These findings suggest that repeated voluntary hypoxic exposure during freediving training does not impair episodic memory function. Freedivers’ memory performance remained comparable with that of the control group, with no detectable adverse effects on hippocampal anatomy.
Postoperative cognitive dysfunction (POCD) is a central nervous system (CNS) complication seen in elderly patients, characterized by a decline in memory, comprehension, and attention in patients after surgery and general anesthesia. The pathophysiologic mechanisms of postoperative cognitive dysfunction are not well understood and effective means of prevention and treatment are currently lacking. Basic and clinical research, including the use of pre-clinical animal models of POCD, is advancing rapidly. In this paper, we review and summarize various factors that contribute to the development of POCD, including oxidative stress, autophagy, impaired synaptic function, and neuroinflammation, and describe the construction of animal models of POCD. By analyzing the gap between clinical and basic research, we propose recommendations for clinically relevant animal model development and the conducting of clinical studies to better understand the mechanisms and etiology associated with POCD. We aim to enhance understanding of the occurrence of POCD and to provide a more comprehensive perspective on the prevention and treatment of POCD.
The brain’s valuation network, including the ventral striatum and ventromedial prefrontal cortex (VMPFC), represents the value of rewards and punishments and underpins decision behavior. These neural signals are not fully characterized in individuals recovering from prescription opioid use disorder (POUD).
We tested the hypothesis that neural responses to monetary gain and loss differ in individuals recovering from POUD relative to individuals without prior substance use.
Twenty-three individuals in an early stage of recovery from POUD (abstinent 2–3 weeks after admission to an inpatient treatment facility, no other substance use disorder), and 21 neurotypical controls group individuals without prior history of substance use completed a card guessing task during functional magnetic resonance imaging (fMRI), gaining or losing small monetary amounts after each guess. Whole-brain and valuation network regions of interest (ROI) analyses compared POUD and control group fMRI signal responses to monetary gain and loss outcomes.
Ventral striatum signal change following gain and loss outcomes differed between the POUD and control groups. Specifically, time series analysis suggested that left ventral striatum responses following monetary losses remained elevated for a longer duration in POUD compared with control group participants.
This exploratory, small sample study suggests brain responses to non-drug incentives may differ in POUD compared with neurotypical controls, which has implications for understanding affective responses in individuals recovering from POUD.
Thalamic hemorrhage pain (THP), a subtype of central post-stroke pain (CPSP), commonly develops following ischemic or hemorrhagic injury to the thalamus. Current therapeutic options remain inadequate due to the absence of well-defined molecular targets. This study aimed to elucidate critical genes implicated in THP pathogenesis through an integrated multi-omics approach.
A mouse model of THP was established and mice were divided into THP and control groups. Comprehensive multi-omics profiling involving transcriptomics, proteomics, metabolomics, ribosome profiling (Ribo-seq), and single-cell RNA sequencing (scRNA-seq) was conducted. Differentially expressed genes (DEGs), differentially expressed proteins (DEPs), ribosome footprint-associated DEGs (RF-DEGs), and differentially expressed metabolites (DEMs) were identified via comparative expression analyses. Hub genes were extracted from the DEGs and subsequently intersected with scRNA-seq DEGs, DEPs, and RF-DEGs to define key gene candidates. These genes underwent gene set enrichment analysis (GSEA), disease association mapping, and drug prediction. Expression levels of key genes were used to delineate critical cell populations, followed by analyses of intercellular communication and pseudotemporal differentiation trajectories. Orthogonal partial least squares discriminant analysis was used to validate the model.
The THP mouse model was successfully validated. Multi-omics analyses yielded distinct profiles of DEGs, single-cell DEGs, DEPs, RF-DEGs, and DEMs, which were functionally annotated through enrichment strategies. Notably, 12 hub genes were prioritized, of which eight key genes (ferritin light chain 1 (Ftl1), tropomyosin 4 (Tpm4), C-C motif chemokine ligand 3 (Ccl3), C-C motif chemokine ligand 4 (Ccl4), C-C motif chemokine receptor 2 (Ccr2), interleukin 33 (Il33), C-X-C motif chemokine ligand 2 (Cxcl2), and Lymphocyte antigen 6 complex, locus C2 (Ly6c2) were identified. These genes were predominantly associated with oxidative phosphorylation and ribosomal pathways. Further analyses revealed strong associations with necrotic and inflammatory processes, and compounds such as alprostadil and anisomycin were identified as potential therapeutic agents. Single-cell analyses highlighted six pivotal cell types, including endothelial cells and macrophages. Intercellular communication networks and lineage progression patterns of these cells were systematically characterized, alongside spatial and temporal expression profiles of key genes.
This study established a validated THP mouse model and employed a multi-omics integration strategy to identify eight key genes and associated molecular pathways. These findings provide novel mechanistic insights into THP pathogenesis and highlight promising targets for therapeutic intervention.
PANoptosis represents a novel form of programmed cell death regulated and controlled by the PANoptosome. It encompasses the essential features of apoptosis, necroptosis, and pyroptosis and combines elements from each process. PANoptosis contributes to the development of various diseases, including bacterial and viral infections, tumors, inflammatory diseases, and neurodegenerative diseases, which offers insights into the pathological mechanisms of these diseases and potential treatments. Retinal ganglion cells (RGCs) are nerve cells located in the final segment of the retina, which belongs to the central nervous system. The loss of RGCs caused by various diseases cannot be reversed. Consequently, safeguarding RGCs from loss is a crucial goal in the treatment of diseases that cause RGCs death (such as trauma, glaucoma, and diabetic retinopathy). Research on the multiple modes of death of RGCs has made some progress and, recently, PANoptosis has been observed during the death of RGCs in different models. In this article, we first give an overview of PANoptosis and summarize the fundamental mechanisms and crosstalk between apoptosis, necroptosis, and pyroptosis, as well as the characteristics of these three modes of cell death that occur in RGCs. Finally, we discuss the current status of research on PANoptosis in neurons and RGCs to establish a theoretical basis for the mechanism of PANoptosis as a novel target for safeguarding RGCs from loss.
The dorsolateral prefrontal cortex (DLPFC) is a critical node in the working memory (WM) neural circuit, established through neurophysiology, neuropsychology, and neuroimaging studies in humans and nonhuman primates. While most of the neurophysiological evidence for the role of the DLPFC in WM comes from visuospatial WM paradigms, evidence for its role in auditory WM has been suggested by the fact that large lateral prefrontal cortex lesions in nonhuman primates cause auditory discrimination deficits. Moreover, DLPFC neurons demonstrate task-related neuronal responses during auditory WM. In contrast, other studies have proposed that the ventrolateral prefrontal cortex (VLPFC) plays a pivotal role in auditory and audiovisual processing, integration, and mnemonic processing, since VLPFC neurons are responsive to complex acoustic stimuli and are robustly active during auditory WM tasks. Furthermore, inactivation of the VLPFC impairs audiovisual and auditory WM. In these inactivation studies the cortical region that was inactivated by cortical cooling included areas 12/47, 45 and 46 ventral. It is possible that inclusion of area 46 ventral may account for the auditory WM performance deficit previously observed while inactivating VLPFC so further experiments are needed.
In the present study we examined whether transient inactivation of the DLPFC, including areas 46v and 46d, and 9, in rhesus macaques would effect auditory WM. The DLPFC was inactivated by cortical cooling while two rhesus macaques performed an auditory working memory task. This was followed by permanent ibotenic acid lesions and assessment of behavioral performance post-lesion.
Our experiments demonstrated that inactivation of DLPFC by cortical cooling in two macaques did not result in a significant decrease in performance of an auditory WM task. The inactivation resulted in an increase in dropped gaze events during the latter half of the task, in one subject, which could be due to a loss of attention or motivation. The ibotenic acid lesions of the DLPFC did not significantly alter performance on the auditory WM task.
Our results showed that DLPFC transient inactivation with cortical cooling and ibotenic acid lesions did not significantly alter overall auditory working memory performance, which differs from the impairment seen when the VLPFC is inactivated. Our data suggest that the DLPFC and VLPFC may play different roles in auditory working memory.
Anatomical studies have indicated that the brain and the heart are connected through multiple pathways. However, the functional interplay between them is unclear, especially for different task states. This study explored the brain-heart interplay under reflexive and voluntary saccade tasks.
The Synthetic Data Generation model was used to quantify the interplay between the brain and heart.
Bidirectional interplay patterns were found between the brain and heart under different frequency bands for the two types of saccade task. There were significant variations in the interplay coupling across saccade tasks, particularly in the prefrontal and parietal lobes. This phenomenon can be explained by the complexity and cognition load among the saccade tasks.
This study shed light on the dynamic bidirectional interplay mechanisms between the brain and heart, contributing to the understanding of brain-heart interaction.
Sensory feedback from the upper cervical regions is used by the central nervous system to stabilize the occipito-atlantal (C0-C1) joint for leveled vision and to assess head position, which is used in sensorimotor integration (SMI) of neck and upper limb motor control. However, few studies have specifically investigated the impact of C0-C1 dysfunction and/or its rectification on SMI related outcomes. This study sought to determine the impact of restricted C0-C1 mobility and musculoskeletal pain on neck and upper limb motor control, whether these motor control deficits persist without treatment, and whether motor control improves following treatment designed to improve C0-C1 mobility.
Twenty-two participants with restricted C0-C1 mobility attended three data collection sessions (baseline, control (2 to 5 days later), and post-treatment) at a private clinic. The One-to Zero (OTZ) system which treats the C0-C1 first followed by other spinal regions if clinically indicated, was administered twice weekly until participants reached 80% improvement from baseline symptoms. Shoulder range of motion, peak force and electromyography during maximal resisted scapular elevation (upper trapezius) and neck flexion (sternocleidomastoid), peak grip, and quadricep strength were measured before and after treatment. Repeated measures ANOVAs with pre-planned contrasts (e.g., control to baseline, and post-treatment to baseline) were conducted.
Neck and limb control impairments persisted without treatment, with no changes between the double baseline (p > 0.05). Shoulder abduction and extension, and peak force output of the sternocleidomastoid, upper trapezius, and quadriceps improved post-intervention (all p < 0.05).
Selective improvement in neck and limb motor control outcomes post-treatment suggests that increased corticospinal drive/motor neuron excitability from normalized afferent input may impact gross motor output first.
ACTRN12625000627459. https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=389394&isReview=true.
Dyslipidemia during midlife represents a significant risk factor for neuropathological alterations associated with cognitive decline. Given the currently incurable nature of dementia, implementation of preventive strategies and early therapeutic interventions prior to disease progression are paramount. Emerging evidence suggests that hyperbaric oxygen (HBO) therapy exhibits neuroprotective properties in various neurological conditions. However, whether HBO treatment modulates lipid metabolism dysregulation and subsequent neurodegeneration remains unanswered. This investigation aimed to elucidate the therapeutic potential of HBO treatment in ameliorating cerebral dysfunction and metabolic perturbations using apolipoprotein E (ApoE)-deficient (ApoE-/-) mice.
ApoE-/- mice received HBO treatment for 10 consecutive days, and then behavioral assessment tests were performed. Serum and brain tissue were collected to measure oxidative stress levels and inflammatory factors.
Compared with ApoE-/- group, cognitive declines was significantly reversed in mice of the ApoE-/-+HBO mice. The blood lipid profiles of ApoE-/- mice were also improved after HBO treatment, accompanied by a reduction in body weight. Moreover, HBO treatment was found to ameliorates neuronal injury and amyloid-β deposition in the hippocampus of ApoE-/- mice. Further studies have revealed that the benefits of HBO treatment occurred through the reduction of inflammatory factors and attenuation of oxidative stress.
These findings indicate that HBO treatment effectively improves the intracerebral microenvironment of ApoE-/- mice, providing a novel regulatory mechanism of protection against dyslipidemia-associated brain deficits by HBO treatment.