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Human behavior depends on a collection of cognitive capacities that are expressed with complexity in humans. Although animal models have been essential for identifying fundamental neural mechanisms, many aspects of human cognition require direct investigation in the human brain. Studies of social decision-making, communication, and spatial navigation increasingly rely on intracranial electrophysiology to probe the neural basis. Related to these topics, reward processing warrants emphasis. It is not uniquely human, but it provides a central organizing signal linking motivation, learning, emotion, and choice across many human behaviors. Disruptions of reward circuits are a hallmark of numerous neurological and psychiatric conditions, giving this domain specific relevance for patient care. Fifteen studies published between 2009 and 2024 used human intracranial recordings to examine reward-related processes, nearly all in patients undergoing invasive monitoring for drug-resistant epilepsy. These studies investigated 17 neocortical and subcortical regions, most frequently the orbitofrontal cortex, using intracranial EEG, deep brain stimulation, and single-unit recordings. Recent work increasingly incorporates social interactions and computational models of learning. The purpose of this narrative review is to provide an overview of human reward processing, emphasizing how intracranial recordings have clarified the neural circuits that underlie a range of human cognitive capacities. Beyond advancing basic neuroscience, intracranial electrophysiology can inform circuit-guided interventions for neurological and psychiatric disorders.
Human behavior depends on a collection of cognitive capacities that are expressed with complexity in humans. Although animal models have been essential for identifying fundamental neural mechanisms, many aspects of human cognition require direct investigation in the human brain. Studies of social decision-making, communication, and spatial navigation increasingly rely on intracranial electrophysiology to probe the neural basis. Related to these topics, reward processing warrants emphasis. It is not uniquely human, but it provides a central organizing signal linking motivation, learning, emotion, and choice across many human behaviors. Disruptions of reward circuits are a hallmark of numerous neurological and psychiatric conditions, giving this domain specific relevance for patient care. Fifteen studies published between 2009 and 2024 used human intracranial recordings to examine reward-related processes, nearly all in patients undergoing invasive monitoring for drug-resistant epilepsy. These studies investigated 17 neocortical and subcortical regions, most frequently the orbitofrontal cortex, using intracranial EEG, deep brain stimulation, and single-unit recordings. Recent work increasingly incorporates social interactions and computational models of learning. The purpose of this narrative review is to provide an overview of human reward processing, emphasizing how intracranial recordings have clarified the neural circuits that underlie a range of human cognitive capacities. Beyond advancing basic neuroscience, intracranial electrophysiology can inform circuit-guided interventions for neurological and psychiatric disorders.
DOI: https://doi.org/10.37349/en.2026.1006131
This article belongs to the special issue Advances in Epilepsy Research
Malignant tumors of the nervous system, such as gliomas, medulloblastomas, and neuroblastomas, pose a greater clinical challenge due to their aggressive and invasive nature and their resistance to current treatment options. The blood-brain barrier (BBB) impairs the delivery of therapeutic agents, which is associated with poor prognosis. The natural flavonoid fisetin has demonstrated potential for cancer treatment by regulating major cancer-related signaling pathways, including PI3K/Akt/mTOR, NF-κB, and MAPK. Preclinical studies suggest that fisetin induces apoptosis, suppresses tumor invasion, and reduces malignancy in glioma, medulloblastoma, and neuroblastoma models. However, evidence for fisetin’s effectiveness remains preclinical and in vitro, with no clinical trials in humans to date. One solution to this challenge is to use nanotechnology-based delivery systems to increase fisetin’s stability and solubility and facilitate its crossing of the BBB, thereby enhancing its therapeutic efficacy. Such advancements have made fisetin a promising option for neuro-oncology treatment. Further clinical trials are needed to assess the safety, efficacy, and effectiveness of fisetin in combination therapies. When conjugated with nanotechnology-based delivery, fisetin may enable a digital transformation in treatment outcomes for patients with malignant nervous system tumors.
Malignant tumors of the nervous system, such as gliomas, medulloblastomas, and neuroblastomas, pose a greater clinical challenge due to their aggressive and invasive nature and their resistance to current treatment options. The blood-brain barrier (BBB) impairs the delivery of therapeutic agents, which is associated with poor prognosis. The natural flavonoid fisetin has demonstrated potential for cancer treatment by regulating major cancer-related signaling pathways, including PI3K/Akt/mTOR, NF-κB, and MAPK. Preclinical studies suggest that fisetin induces apoptosis, suppresses tumor invasion, and reduces malignancy in glioma, medulloblastoma, and neuroblastoma models. However, evidence for fisetin’s effectiveness remains preclinical and in vitro, with no clinical trials in humans to date. One solution to this challenge is to use nanotechnology-based delivery systems to increase fisetin’s stability and solubility and facilitate its crossing of the BBB, thereby enhancing its therapeutic efficacy. Such advancements have made fisetin a promising option for neuro-oncology treatment. Further clinical trials are needed to assess the safety, efficacy, and effectiveness of fisetin in combination therapies. When conjugated with nanotechnology-based delivery, fisetin may enable a digital transformation in treatment outcomes for patients with malignant nervous system tumors.
DOI: https://doi.org/10.37349/en.2026.1006130
This article belongs to the special issue Current Approaches to Malignant Tumors of the Nervous System
Chronic pain, defined as pain persisting beyond 12 weeks, is known to be challenging to manage. Despite increasing opioid prescribing, pain is still an issue for many patients. Patient education has emerged as a key element in supporting self-management and improving pain-related outcomes. This narrative review explores the impact of patient education alongside pain management interventions, with a focus on pain intensity, pain-related beliefs, and pain-related disability. A structured search using PubMed, Medline, EBSCOhost, and UCL Explore identified ten studies (six RCTs, two systematic reviews, two cohort studies) and three national guidelines meeting the inclusion criteria. Inclusion criteria focused on adult patients with chronic non-malignant pain who received some form of education alongside or prior to pain interventions. Pain education was associated with 29% reduction in opioid use, with 7% patients discontinuing opioids entirely in the usual group. Improvements in emotional functioning (41%), pain understanding (75%), and overall functioning (38%) were observed across various trials. Existing research shows promising results; however, the clarity of the type of education needed needs to be established. Short, focused education sessions, especially those incorporating pain neuroscience education (PNE) or cognitive behavioural therapy (CBT) elements, were as effective as longer programs. Further research is required to identify how education improves the outcome of pain management interventions. Integrating targeted patient education into the chronic pain care pathway can significantly reduce disability, improve quality of life, and decrease opioid reliance. These findings support implementing structured education sessions as part of routine pain management services to enhance long-term patient outcomes.
Chronic pain, defined as pain persisting beyond 12 weeks, is known to be challenging to manage. Despite increasing opioid prescribing, pain is still an issue for many patients. Patient education has emerged as a key element in supporting self-management and improving pain-related outcomes. This narrative review explores the impact of patient education alongside pain management interventions, with a focus on pain intensity, pain-related beliefs, and pain-related disability. A structured search using PubMed, Medline, EBSCOhost, and UCL Explore identified ten studies (six RCTs, two systematic reviews, two cohort studies) and three national guidelines meeting the inclusion criteria. Inclusion criteria focused on adult patients with chronic non-malignant pain who received some form of education alongside or prior to pain interventions. Pain education was associated with 29% reduction in opioid use, with 7% patients discontinuing opioids entirely in the usual group. Improvements in emotional functioning (41%), pain understanding (75%), and overall functioning (38%) were observed across various trials. Existing research shows promising results; however, the clarity of the type of education needed needs to be established. Short, focused education sessions, especially those incorporating pain neuroscience education (PNE) or cognitive behavioural therapy (CBT) elements, were as effective as longer programs. Further research is required to identify how education improves the outcome of pain management interventions. Integrating targeted patient education into the chronic pain care pathway can significantly reduce disability, improve quality of life, and decrease opioid reliance. These findings support implementing structured education sessions as part of routine pain management services to enhance long-term patient outcomes.
DOI: https://doi.org/10.37349/en.2026.1006129
Adult human hippocampal neurogenesis has been debated for decades, with methodological differences producing conflicting reports. Radiocarbon birth-dating provided population-level evidence of sustained dentate gyrus neuron turnover, while immunohistochemical studies produced variable results depending on fixation protocols. Optimized post-mortem handling has reported higher detectability of immature-neuron markers across adulthood, whereas longer post-mortem delays and prolonged fixation can reduce signal and contribute to apparent null findings; however, marker-based interpretations remain debated and require cautious, multi-marker validation. Recent single-nucleus and spatial transcriptomics further support persistent neurogenesis, identifying immature granule-cell signatures and niche programs into late life. This article critically appraises evidence from radiocarbon dating, immunohistochemistry, and transcriptomics, highlighting sources of discrepancy and convergence. Practical standards for human tissue handling, antigen retrieval, and multimarker panels are proposed to minimize methodological artefacts. Collectively, convergent evidence favors low-level, lifelong neurogenesis with potential contributions to memory precision and affective regulation, albeit at lower rates than rodents. It is concluded that integrating radiocarbon baselining, optimized immunohistochemistry, and transcriptomic validation provides a robust framework for resolving the controversy and advancing translational relevance in cognition, aging, and psychiatry.
Adult human hippocampal neurogenesis has been debated for decades, with methodological differences producing conflicting reports. Radiocarbon birth-dating provided population-level evidence of sustained dentate gyrus neuron turnover, while immunohistochemical studies produced variable results depending on fixation protocols. Optimized post-mortem handling has reported higher detectability of immature-neuron markers across adulthood, whereas longer post-mortem delays and prolonged fixation can reduce signal and contribute to apparent null findings; however, marker-based interpretations remain debated and require cautious, multi-marker validation. Recent single-nucleus and spatial transcriptomics further support persistent neurogenesis, identifying immature granule-cell signatures and niche programs into late life. This article critically appraises evidence from radiocarbon dating, immunohistochemistry, and transcriptomics, highlighting sources of discrepancy and convergence. Practical standards for human tissue handling, antigen retrieval, and multimarker panels are proposed to minimize methodological artefacts. Collectively, convergent evidence favors low-level, lifelong neurogenesis with potential contributions to memory precision and affective regulation, albeit at lower rates than rodents. It is concluded that integrating radiocarbon baselining, optimized immunohistochemistry, and transcriptomic validation provides a robust framework for resolving the controversy and advancing translational relevance in cognition, aging, and psychiatry.
DOI: https://doi.org/10.37349/en.2026.1006128
The circadian clock orchestrates cellular physiology by synchronizing transcriptional, metabolic, and signaling networks with the environmental light-dark cycle. Basic helix-loop-helix ARNT-like protein 1 (BMAL1), a core transcriptional regulator of circadian timing, contributes to rhythmic gene expression and is implicated in cellular responses to stress and energy demand. Emerging evidence suggests an interplay between BMAL1 and the phosphatidylinositol 3-kinase (PI3K)/AKT pathway, a central hub controlling cell survival, metabolism, and angiogenesis. In ischemic conditions, BMAL1 is associated with increased PI3K/AKT activity and downstream mTOR signaling, which may help preserve mitochondrial integrity, limit oxidative stress, and support neuronal and vascular recovery. Conversely, BMAL1 deficiency is linked to impaired AKT phosphorylation and redox imbalance, exacerbating ischemic injury. Proteomic and functional studies further suggest that BMAL1 may contribute to metabolic reprogramming through PI3K/AKT-dependent regulation of oxidative phosphorylation and antioxidant defenses. This review is based on a focused narrative evaluation of experimental and translational studies retrieved from PubMed, emphasizing circadian regulation of PI3K/AKT signaling in ischemic and vascular contexts. Collectively, these findings support the concept that BMAL1 functions as a temporal modulator of PI3K/AKT signaling, integrating circadian and metabolic cues to promote cellular resilience. Understanding this regulatory axis may offer novel therapeutic perspectives for ischemic and neurovascular disorders associated with circadian misalignment.
The circadian clock orchestrates cellular physiology by synchronizing transcriptional, metabolic, and signaling networks with the environmental light-dark cycle. Basic helix-loop-helix ARNT-like protein 1 (BMAL1), a core transcriptional regulator of circadian timing, contributes to rhythmic gene expression and is implicated in cellular responses to stress and energy demand. Emerging evidence suggests an interplay between BMAL1 and the phosphatidylinositol 3-kinase (PI3K)/AKT pathway, a central hub controlling cell survival, metabolism, and angiogenesis. In ischemic conditions, BMAL1 is associated with increased PI3K/AKT activity and downstream mTOR signaling, which may help preserve mitochondrial integrity, limit oxidative stress, and support neuronal and vascular recovery. Conversely, BMAL1 deficiency is linked to impaired AKT phosphorylation and redox imbalance, exacerbating ischemic injury. Proteomic and functional studies further suggest that BMAL1 may contribute to metabolic reprogramming through PI3K/AKT-dependent regulation of oxidative phosphorylation and antioxidant defenses. This review is based on a focused narrative evaluation of experimental and translational studies retrieved from PubMed, emphasizing circadian regulation of PI3K/AKT signaling in ischemic and vascular contexts. Collectively, these findings support the concept that BMAL1 functions as a temporal modulator of PI3K/AKT signaling, integrating circadian and metabolic cues to promote cellular resilience. Understanding this regulatory axis may offer novel therapeutic perspectives for ischemic and neurovascular disorders associated with circadian misalignment.
DOI: https://doi.org/10.37349/en.2026.1006127
Hydrocephalus is a complex neurological disease characterized by abnormal cerebrospinal fluid (CSF) accumulation, ventricular enlargement, and progressive neurologic dysfunction. Existing therapies are predominantly surgical, with high complication rates, with high complication rates, prompting ongoing efforts to develop alternative modalities. This review integrates developments across mechanistic platforms and integrated disease models—including genetic and induced animals, patient-derived organoids, and organ-on-a-chip systems—to evaluate their ability to recapitulate CSF kinetics and subventricular zone (SVZ) biology. New therapies, including surgical enhancements, drugs, stem cell-based repair, and gene-targeted therapies, are discussed for translation potential. Ethics and regulatory frameworks, 3Rs, and validation and scalability issues are discussed critically. Finally, computational modeling and AI are introduced as ways to integrate multi-scale data and enable precision medicine. Each of these perspectives outlines a roadmap in which bioengineering, precision medicine, and ethical rigor converge to accelerate discovery and improve outcomes for patients with hydrocephalus.
Hydrocephalus is a complex neurological disease characterized by abnormal cerebrospinal fluid (CSF) accumulation, ventricular enlargement, and progressive neurologic dysfunction. Existing therapies are predominantly surgical, with high complication rates, with high complication rates, prompting ongoing efforts to develop alternative modalities. This review integrates developments across mechanistic platforms and integrated disease models—including genetic and induced animals, patient-derived organoids, and organ-on-a-chip systems—to evaluate their ability to recapitulate CSF kinetics and subventricular zone (SVZ) biology. New therapies, including surgical enhancements, drugs, stem cell-based repair, and gene-targeted therapies, are discussed for translation potential. Ethics and regulatory frameworks, 3Rs, and validation and scalability issues are discussed critically. Finally, computational modeling and AI are introduced as ways to integrate multi-scale data and enable precision medicine. Each of these perspectives outlines a roadmap in which bioengineering, precision medicine, and ethical rigor converge to accelerate discovery and improve outcomes for patients with hydrocephalus.
DOI: https://doi.org/10.37349/en.2026.1006126
DOI: https://doi.org/10.37349/en.2026.1006125
Aim:
Tissue transglutaminase [transglutaminase 2 (TG2)] is implicated in central neuronal apoptosis and is expressed in the peripheral nervous system; however, its role in sensory neuron survival and neuropathic pain after nerve injury remains poorly defined. This study examined whether TG2 knockout (KO) affects dorsal root ganglion (DRG) neuron survival and pain-related behaviors following sciatic nerve injury.
Methods:
TG2 KO mice and wild-type (WT) controls underwent complete sciatic nerve transection (axotomy). Pain-related behavior was evaluated using detailed autotomy scoring over 14 days. DRG neuron survival was assessed using unbiased stereological counts.
Results:
TG2 KO resulted in a distinct, previously unreported “atypical autotomy” pattern, with lesions localized mainly to the midplantar paw region. In contrast, WT mice exhibited typical autotomy directed primarily at the toes. Despite this clear difference in pain phenotype, stereological analysis revealed that TG2 KO did not alter neuronal counts in intact or axotomized DRGs, with both groups showing comparable, significant neuronal loss after injury.
Conclusions:
These findings indicate that TG2 functions as an important modulator of neuropathic pain but is not required for neuronal survival in the adult DRG following nerve injury.
Aim:
Tissue transglutaminase [transglutaminase 2 (TG2)] is implicated in central neuronal apoptosis and is expressed in the peripheral nervous system; however, its role in sensory neuron survival and neuropathic pain after nerve injury remains poorly defined. This study examined whether TG2 knockout (KO) affects dorsal root ganglion (DRG) neuron survival and pain-related behaviors following sciatic nerve injury.
Methods:
TG2 KO mice and wild-type (WT) controls underwent complete sciatic nerve transection (axotomy). Pain-related behavior was evaluated using detailed autotomy scoring over 14 days. DRG neuron survival was assessed using unbiased stereological counts.
Results:
TG2 KO resulted in a distinct, previously unreported “atypical autotomy” pattern, with lesions localized mainly to the midplantar paw region. In contrast, WT mice exhibited typical autotomy directed primarily at the toes. Despite this clear difference in pain phenotype, stereological analysis revealed that TG2 KO did not alter neuronal counts in intact or axotomized DRGs, with both groups showing comparable, significant neuronal loss after injury.
Conclusions:
These findings indicate that TG2 functions as an important modulator of neuropathic pain but is not required for neuronal survival in the adult DRG following nerve injury.
DOI: https://doi.org/10.37349/en.2026.1006124
Aim:
Male infertility resulting from neurological disorders, oxidative stress, and hormonal imbalance is a growing health concern. This study, therefore, investigated the effects of Aframomum melegueta and Aframomum danielli-supplemented diets on sperm quality and testicular oxidative damage in a scopolamine-induced rat model.
Methods:
Adult male rats were randomly allocated into seven groups: normal group; scopolamine-induced group; donepezil-treated scopolamine group and four treatment groups receiving 4% or 8% dietary supplementation of Aframomum melegueta or Aframomum danielli, respectively. Sperm motility, count, and morphology were evaluated. In addition, serum testosterone and follicle stimulating hormone levels, testicular oxidative stress markers, inflammatory cytokines, and antioxidant activities were assessed to determine reproductive and biochemical responses. High performance liquid chromatography (HPLC) profiling was also conducted to identify the major phenolic compounds in both seeds.
Results:
Scopolamine administration impaired sperm quality, decreased hormonal levels, promoted oxidative stress, and altered inflammatory responses. These alterations were, however, reversed by diets supplemented with Aframomum melegueta and Aframomum danielli in a dose-dependent manner. The 8% supplementation produced better outcomes than 4% supplementation and donepezil treatment in most parameters, indicating protective effects on sperm quality and other reproduction-related indices. HPLC profiling revealed bioactive compounds that may collectively account for the observed restorative effects of the seeds.
Conclusions:
These findings demonstrate that Aframomum melegueta and Aframomum danielli seeds effectively reversed the adverse reproductive alterations caused by scopolamine-induced neurotoxicity. Both species significantly improved sperm quality and testicular function, which may suggest their possible development as plant-based nutraceuticals for protecting male reproductive health in future studies. Their phytochemical abundance further supports their potential as plant-based nutraceuticals.
Aim:
Male infertility resulting from neurological disorders, oxidative stress, and hormonal imbalance is a growing health concern. This study, therefore, investigated the effects of Aframomum melegueta and Aframomum danielli-supplemented diets on sperm quality and testicular oxidative damage in a scopolamine-induced rat model.
Methods:
Adult male rats were randomly allocated into seven groups: normal group; scopolamine-induced group; donepezil-treated scopolamine group and four treatment groups receiving 4% or 8% dietary supplementation of Aframomum melegueta or Aframomum danielli, respectively. Sperm motility, count, and morphology were evaluated. In addition, serum testosterone and follicle stimulating hormone levels, testicular oxidative stress markers, inflammatory cytokines, and antioxidant activities were assessed to determine reproductive and biochemical responses. High performance liquid chromatography (HPLC) profiling was also conducted to identify the major phenolic compounds in both seeds.
Results:
Scopolamine administration impaired sperm quality, decreased hormonal levels, promoted oxidative stress, and altered inflammatory responses. These alterations were, however, reversed by diets supplemented with Aframomum melegueta and Aframomum danielli in a dose-dependent manner. The 8% supplementation produced better outcomes than 4% supplementation and donepezil treatment in most parameters, indicating protective effects on sperm quality and other reproduction-related indices. HPLC profiling revealed bioactive compounds that may collectively account for the observed restorative effects of the seeds.
Conclusions:
These findings demonstrate that Aframomum melegueta and Aframomum danielli seeds effectively reversed the adverse reproductive alterations caused by scopolamine-induced neurotoxicity. Both species significantly improved sperm quality and testicular function, which may suggest their possible development as plant-based nutraceuticals for protecting male reproductive health in future studies. Their phytochemical abundance further supports their potential as plant-based nutraceuticals.
DOI: https://doi.org/10.37349/en.2026.1006123
This article belongs to the special issue Medicinal Plants and Bioactive Phytochemicals in Neuroprotection (Vol II)
Flavonoids are a large class of natural polyphenolic substances ubiquitously synthesized in the plant kingdom. When entering the human body, these compounds can exert a wide range of biological activities, including immunomodulatory, antiinflammatory, and anticancer effects. Over the recent years, the mechanisms underlying these actions have become increasingly clear, also indicating the important involvement of G protein-coupled receptors (GPCRs), such as adenosine receptors, in signal transduction networks. In this perspective article, the potential role of flavonoids as adenosine receptor antagonists on the development, progression, and spread of glioblastoma is discussed, blocking the tumor-promoting and immunosuppressive actions of elevated levels of endogenous adenosine. Therefore, flavonoids can be considered as structural leads for developing novel antiglioblastoma agents, applied either alone or as boosters of chemo- or immunotherapy to improve the quality of life and outcome of patients. The importance of these studies is, in turn, emphasized by the current lack of effective treatment strategies for this highly aggressive and fast-growing brain tumor, associated with poor prognosis.
Flavonoids are a large class of natural polyphenolic substances ubiquitously synthesized in the plant kingdom. When entering the human body, these compounds can exert a wide range of biological activities, including immunomodulatory, antiinflammatory, and anticancer effects. Over the recent years, the mechanisms underlying these actions have become increasingly clear, also indicating the important involvement of G protein-coupled receptors (GPCRs), such as adenosine receptors, in signal transduction networks. In this perspective article, the potential role of flavonoids as adenosine receptor antagonists on the development, progression, and spread of glioblastoma is discussed, blocking the tumor-promoting and immunosuppressive actions of elevated levels of endogenous adenosine. Therefore, flavonoids can be considered as structural leads for developing novel antiglioblastoma agents, applied either alone or as boosters of chemo- or immunotherapy to improve the quality of life and outcome of patients. The importance of these studies is, in turn, emphasized by the current lack of effective treatment strategies for this highly aggressive and fast-growing brain tumor, associated with poor prognosis.
DOI: https://doi.org/10.37349/en.2026.1006122
This article belongs to the special issue Current Approaches to Malignant Tumors of the Nervous System
Cerebral amyloid angiopathy (CAA), characterized by amyloid β deposition in cerebral vasculature, is increasingly recognized as a major contributor to both cognitive decline and lobar intracerebral hemorrhage (ICH) in older adults and often coexists with Alzheimer’s disease (AD). Understanding CAA is a crucial step for improving health outcomes and the development of effective therapies. However, significant gaps remain in our understanding of CAA’s pathophysiology, diagnostic approaches, biomarker development, and clinical management. A comprehensive review is therefore essential to synthesize existing knowledge and highlight key directions for future research. This review goes beyond prior summaries by critically synthesizing recent evidence on diagnostic innovations—including the Boston criteria v2.0 and emerging plasma biomarkers—and addressing pressing clinical dilemmas such as anticoagulation management in patients with coexisting atrial fibrillation and CAA. It also highlights ongoing research into multimodal diagnostic frameworks and precision treatment strategies aimed at bridging current diagnostic and therapeutic gaps. Together, these updates underscore how advancing biomarker validation, individualized risk stratification, and amyloid-targeted approaches may shape future CAA management and prevention.
Cerebral amyloid angiopathy (CAA), characterized by amyloid β deposition in cerebral vasculature, is increasingly recognized as a major contributor to both cognitive decline and lobar intracerebral hemorrhage (ICH) in older adults and often coexists with Alzheimer’s disease (AD). Understanding CAA is a crucial step for improving health outcomes and the development of effective therapies. However, significant gaps remain in our understanding of CAA’s pathophysiology, diagnostic approaches, biomarker development, and clinical management. A comprehensive review is therefore essential to synthesize existing knowledge and highlight key directions for future research. This review goes beyond prior summaries by critically synthesizing recent evidence on diagnostic innovations—including the Boston criteria v2.0 and emerging plasma biomarkers—and addressing pressing clinical dilemmas such as anticoagulation management in patients with coexisting atrial fibrillation and CAA. It also highlights ongoing research into multimodal diagnostic frameworks and precision treatment strategies aimed at bridging current diagnostic and therapeutic gaps. Together, these updates underscore how advancing biomarker validation, individualized risk stratification, and amyloid-targeted approaches may shape future CAA management and prevention.
DOI: https://doi.org/10.37349/en.2026.1006121
Neurogenetic disorders remain genetically uncharacterized in many populations, including Libya. We report three Libyan patients from two consanguineous families with pathogenic variants in sodium channel genes. Two adult sisters (Patients 1 & 2) presented with global developmental delay and progressive spastic paraparesis without epilepsy. Whole exome sequencing identified the same heterozygous SCN8A variant (c.142G>A; p.Asp48Asn) in both sisters, classified as a variant of uncertain significance (VUS). Its occurrence in two affected siblings with a consistent phenotype and the absence of other explanatory variants provide supporting evidence for its potential pathogenicity. These cases represent the first documented instances of a suspected SCN8A-related disorder in Libya. A third, unrelated 10-year-old boy (Patient 3) with a phenotype consistent with Dravet syndrome, including refractory seizures and neurodevelopmental regression, was found to harbor a likely pathogenic heterozygous SCN1A variant (c.2113del; p.Glu705Lysfs*10). This report expands the genetic and phenotypic spectrum of neurological disorders in Libya and underscores the critical role of genetic testing, while also highlighting the need for segregation studies to achieve a definitive molecular diagnosis.
Neurogenetic disorders remain genetically uncharacterized in many populations, including Libya. We report three Libyan patients from two consanguineous families with pathogenic variants in sodium channel genes. Two adult sisters (Patients 1 & 2) presented with global developmental delay and progressive spastic paraparesis without epilepsy. Whole exome sequencing identified the same heterozygous SCN8A variant (c.142G>A; p.Asp48Asn) in both sisters, classified as a variant of uncertain significance (VUS). Its occurrence in two affected siblings with a consistent phenotype and the absence of other explanatory variants provide supporting evidence for its potential pathogenicity. These cases represent the first documented instances of a suspected SCN8A-related disorder in Libya. A third, unrelated 10-year-old boy (Patient 3) with a phenotype consistent with Dravet syndrome, including refractory seizures and neurodevelopmental regression, was found to harbor a likely pathogenic heterozygous SCN1A variant (c.2113del; p.Glu705Lysfs*10). This report expands the genetic and phenotypic spectrum of neurological disorders in Libya and underscores the critical role of genetic testing, while also highlighting the need for segregation studies to achieve a definitive molecular diagnosis.
DOI: https://doi.org/10.37349/en.2025.1006120
This article belongs to the special issue Advances in Epilepsy Research
Although addiction is a complex and contextually embedded disorder that extends beyond individual pathology and neurobiological dysfunction, prevailing computational and clinical models often reduce addiction to a chronic brain disease. While such frameworks have shaped dominant approaches to treatment and theory, they remain poorly aligned with the lived experience and behavioral phenomena of addiction, ignoring its psychological, social, and systemic dimensions. This paper examines the limitations of various disease and compulsion models both critically and in-depth, highlighting their empirical and conceptual shortcomings. In doing so, it argues for the development of context-sensitive and psychologically grounded computational models, ones capable of capturing the nuanced realities of addiction and informing more effective, personalized interventions.
Although addiction is a complex and contextually embedded disorder that extends beyond individual pathology and neurobiological dysfunction, prevailing computational and clinical models often reduce addiction to a chronic brain disease. While such frameworks have shaped dominant approaches to treatment and theory, they remain poorly aligned with the lived experience and behavioral phenomena of addiction, ignoring its psychological, social, and systemic dimensions. This paper examines the limitations of various disease and compulsion models both critically and in-depth, highlighting their empirical and conceptual shortcomings. In doing so, it argues for the development of context-sensitive and psychologically grounded computational models, ones capable of capturing the nuanced realities of addiction and informing more effective, personalized interventions.
DOI: https://doi.org/10.37349/en.2025.1006119
Primary central nervous system lymphoma is a rare form of extranodal non-Hodgkin lymphoma that is confined to the brain, spinal cord, leptomeninges, or eyes, representing less than one percent of all non-Hodgkin lymphomas and approximately four percent of primary brain tumors. When the disease is truly isolated to the central nervous system, with no evidence of systemic spread, it poses unique diagnostic and therapeutic challenges, particularly in immunocompetent patients. We reviewed nine recently published cases from 2021 to 2024 that described isolated primary central nervous system lymphoma without extracranial involvement. Patients ranged in age from forty-four to eighty-five years, with both immunocompetent and immunosuppressed individuals represented. Presenting symptoms include focal neurological deficits, seizures, progressive confusion, cranial neuropathies, and neurolymphomatosis. Magnetic resonance imaging findings were diverse, including intra-axial masses, leptomeningeal and cranial nerve enhancement, and mass effect. Cerebrospinal fluid analysis was variably positive for lymphoma cells. Histopathological analysis confirmed diffuse large B-cell lymphoma in all cases, although initial biopsies were sometimes inconclusive, underscoring the importance of repeat tissue sampling and expert pathology review. Treatment strategies most often included high-dose methotrexate-based chemotherapy, monoclonal antibody therapy, and radiotherapy, with some patients undergoing surgical decompression or diagnostic craniotomy. Follow-up data revealed variable survival outcomes, with a subset of patients achieving disease-free survival beyond one year. These cases highlight the wide clinical spectrum and diagnostic complexity of isolated primary central nervous system lymphoma and reinforce the need for a high index of suspicion, timely advanced imaging, multidisciplinary discussion, and appropriate tissue diagnosis to guide individualized management.
Primary central nervous system lymphoma is a rare form of extranodal non-Hodgkin lymphoma that is confined to the brain, spinal cord, leptomeninges, or eyes, representing less than one percent of all non-Hodgkin lymphomas and approximately four percent of primary brain tumors. When the disease is truly isolated to the central nervous system, with no evidence of systemic spread, it poses unique diagnostic and therapeutic challenges, particularly in immunocompetent patients. We reviewed nine recently published cases from 2021 to 2024 that described isolated primary central nervous system lymphoma without extracranial involvement. Patients ranged in age from forty-four to eighty-five years, with both immunocompetent and immunosuppressed individuals represented. Presenting symptoms include focal neurological deficits, seizures, progressive confusion, cranial neuropathies, and neurolymphomatosis. Magnetic resonance imaging findings were diverse, including intra-axial masses, leptomeningeal and cranial nerve enhancement, and mass effect. Cerebrospinal fluid analysis was variably positive for lymphoma cells. Histopathological analysis confirmed diffuse large B-cell lymphoma in all cases, although initial biopsies were sometimes inconclusive, underscoring the importance of repeat tissue sampling and expert pathology review. Treatment strategies most often included high-dose methotrexate-based chemotherapy, monoclonal antibody therapy, and radiotherapy, with some patients undergoing surgical decompression or diagnostic craniotomy. Follow-up data revealed variable survival outcomes, with a subset of patients achieving disease-free survival beyond one year. These cases highlight the wide clinical spectrum and diagnostic complexity of isolated primary central nervous system lymphoma and reinforce the need for a high index of suspicion, timely advanced imaging, multidisciplinary discussion, and appropriate tissue diagnosis to guide individualized management.
DOI: https://doi.org/10.37349/en.2025.1006117
Neurological disorders constitute a major global health burden with limited effective treatments. Despite advances in molecular neuroscience, critical gaps persist in understanding intercellular communication systems underlying central nervous system homeostasis and neurodegeneration. Extracellular vesicles (EVs), nanoscale to microscale membrane-bound vesicles secreted by virtually all cell types, have emerged as pivotal mediators of intercellular communication in neurological pathologies. This review examines molecular mechanisms governing EV biogenesis, cargo selection, and pathological functions in neurological disorders, emphasizing the emerging role of ubiquitin-like protein 3 (UBL3) as a novel regulator of EV-mediated protein sorting. Neural cell populations produce specialized EV subtypes containing distinct molecular cargo reflecting their physiological states. UBL3, a membrane-anchored post-translational modifier, operates through geranylgeranylation-dependent mechanisms to promote selective protein incorporation into small EVs (sEVs), with knockout studies demonstrating approximately 60% reduction in EV protein content. Proteomic analyses reveal UBL3 interacts with over 1,200 proteins, with ~30% classified as EV cargo proteins. Critically, UBL3-mediated sorting influences disease-associated protein trafficking, including α-synuclein in Parkinson’s disease and mutant huntingtin in Huntington’s disease, suggesting involvement in prion-like spreading mechanisms. EVs’ dual nature as pathological mediators and therapeutic vehicles represents a paradigm shift in neurological medicine. EVs offer advantages as natural drug delivery systems capable of crossing the blood-brain barrier, accessible biomarkers for noninvasive disease monitoring via liquid biopsies (achieving diagnostic accuracies exceeding 0.88 ROC-AUC), and engineered therapeutic platforms for delivering CRISPR-Cas9 systems and neuroprotective factors. However, clinical translation requires addressing challenges, including standardizing isolation protocols, elucidating cell-type-specific cargo sorting mechanisms, and defining optimal administration routes. Understanding UBL3-mediated cargo sorting mechanisms presents promising therapeutic opportunities by selectively modulating pathogenic protein trafficking. EVs, positioned at the intersection of pathogenesis and therapy, represent attractive targets for precision medicine approaches in neurological conditions, with UBL3 emerging as a novel molecular handle for manipulating EV composition and function.
Neurological disorders constitute a major global health burden with limited effective treatments. Despite advances in molecular neuroscience, critical gaps persist in understanding intercellular communication systems underlying central nervous system homeostasis and neurodegeneration. Extracellular vesicles (EVs), nanoscale to microscale membrane-bound vesicles secreted by virtually all cell types, have emerged as pivotal mediators of intercellular communication in neurological pathologies. This review examines molecular mechanisms governing EV biogenesis, cargo selection, and pathological functions in neurological disorders, emphasizing the emerging role of ubiquitin-like protein 3 (UBL3) as a novel regulator of EV-mediated protein sorting. Neural cell populations produce specialized EV subtypes containing distinct molecular cargo reflecting their physiological states. UBL3, a membrane-anchored post-translational modifier, operates through geranylgeranylation-dependent mechanisms to promote selective protein incorporation into small EVs (sEVs), with knockout studies demonstrating approximately 60% reduction in EV protein content. Proteomic analyses reveal UBL3 interacts with over 1,200 proteins, with ~30% classified as EV cargo proteins. Critically, UBL3-mediated sorting influences disease-associated protein trafficking, including α-synuclein in Parkinson’s disease and mutant huntingtin in Huntington’s disease, suggesting involvement in prion-like spreading mechanisms. EVs’ dual nature as pathological mediators and therapeutic vehicles represents a paradigm shift in neurological medicine. EVs offer advantages as natural drug delivery systems capable of crossing the blood-brain barrier, accessible biomarkers for noninvasive disease monitoring via liquid biopsies (achieving diagnostic accuracies exceeding 0.88 ROC-AUC), and engineered therapeutic platforms for delivering CRISPR-Cas9 systems and neuroprotective factors. However, clinical translation requires addressing challenges, including standardizing isolation protocols, elucidating cell-type-specific cargo sorting mechanisms, and defining optimal administration routes. Understanding UBL3-mediated cargo sorting mechanisms presents promising therapeutic opportunities by selectively modulating pathogenic protein trafficking. EVs, positioned at the intersection of pathogenesis and therapy, represent attractive targets for precision medicine approaches in neurological conditions, with UBL3 emerging as a novel molecular handle for manipulating EV composition and function.
DOI: https://doi.org/10.37349/en.2025.1006118
Background:
Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults, with a poor prognosis despite advances in treatment options. T-cell-engager therapies, which have an antibody-based structure connecting immune cells to target cancer cells with high affinity, offer a promising strategy but face four key barriers: antigen heterogeneity, immune escape, the blood-brain barrier (BBB), and the immunosuppressive tumor microenvironment (TME). This systematic review synthesizes preclinical developments in bispecific T-cell engager (BiTE), tri-specific T-cell engager (TriTE), and multi-specific T-cell engagers for GBM over the last 10 years, evaluating their capacity to overcome these barriers.
Methods:
A systematic search was conducted in OVID Medline, Embase, and ClinicalTrials.gov for pre-clinical and clinical studies. A descriptive analysis without meta-analysis was formulated in which data were grouped thematically by the ability of treatments to overcome GBM-specific barriers.
Results:
Among the 14 studies meeting inclusion criteria, all studies were preclinical, with 12/14 (85.7%) utilizing an in vivo mouse model. BiTEs were used in 12/14 (85.7%) studies, while 4/14 (28.6%) studies targeted multiple antigens through either TriTEs or multivalent BiTEs. There was a range of antigen targets with the most common being interleukin 13 receptor alpha 2 (IL13Rα2) as well as epidermal growth factor receptor (EGFR) or EGFR variant III (EGFRvIII) in 7/14 (50.0%) studies. Most studies (85.7%) addressed two or more barriers, with 13/14 (92.9%) showing evidence of affecting the TME.
Discussion:
In the last decade, T-cell engager therapies have evolved in both antigenic targets and delivery vehicles used to overcome the key barriers. An emerging area within T-cell engager therapies is targeting multiple antigens through multi-specific T-cell engager therapies, such as the TriTEs. Studies have explored chimeric antigen receptor T-cells (CAR-Ts) as a potential delivery vehicle for BiTEs. A future clinical trial using multi-specific T-cell engager therapies or a CAR-T-secreting BiTE in adult patients is required to determine the potential clinical utility of T-cell engagers.
Background:
Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults, with a poor prognosis despite advances in treatment options. T-cell-engager therapies, which have an antibody-based structure connecting immune cells to target cancer cells with high affinity, offer a promising strategy but face four key barriers: antigen heterogeneity, immune escape, the blood-brain barrier (BBB), and the immunosuppressive tumor microenvironment (TME). This systematic review synthesizes preclinical developments in bispecific T-cell engager (BiTE), tri-specific T-cell engager (TriTE), and multi-specific T-cell engagers for GBM over the last 10 years, evaluating their capacity to overcome these barriers.
Methods:
A systematic search was conducted in OVID Medline, Embase, and ClinicalTrials.gov for pre-clinical and clinical studies. A descriptive analysis without meta-analysis was formulated in which data were grouped thematically by the ability of treatments to overcome GBM-specific barriers.
Results:
Among the 14 studies meeting inclusion criteria, all studies were preclinical, with 12/14 (85.7%) utilizing an in vivo mouse model. BiTEs were used in 12/14 (85.7%) studies, while 4/14 (28.6%) studies targeted multiple antigens through either TriTEs or multivalent BiTEs. There was a range of antigen targets with the most common being interleukin 13 receptor alpha 2 (IL13Rα2) as well as epidermal growth factor receptor (EGFR) or EGFR variant III (EGFRvIII) in 7/14 (50.0%) studies. Most studies (85.7%) addressed two or more barriers, with 13/14 (92.9%) showing evidence of affecting the TME.
Discussion:
In the last decade, T-cell engager therapies have evolved in both antigenic targets and delivery vehicles used to overcome the key barriers. An emerging area within T-cell engager therapies is targeting multiple antigens through multi-specific T-cell engager therapies, such as the TriTEs. Studies have explored chimeric antigen receptor T-cells (CAR-Ts) as a potential delivery vehicle for BiTEs. A future clinical trial using multi-specific T-cell engager therapies or a CAR-T-secreting BiTE in adult patients is required to determine the potential clinical utility of T-cell engagers.
DOI: https://doi.org/10.37349/en.2025.1006116
This article belongs to the special issue Current Approaches to Malignant Tumors of the Nervous System
Aim:
This study investigated the effect of brain-derived neurotrophic factor (BDNF) Val66Met polymorphism on post-stroke outcomes, including quality of life, physical fitness, cognitive function, depression, and overall disability.
Methods:
The difference between Met carriers and non-Met carriers was analyzed for the entire sample and in pair-matched analysis, using age, sex, time since stroke, and race.
Results:
We evaluated 89 stroke participants (mean age, 57 ± 10 years; 58% male; 54% White, and 49% Hispanic). Twelve participants (13%) had one copy of the BDNF Val66Met (Val/Met heterozygotes) and none had two copies (Met/Met homozygotes). Comparing Met (n = 12) and non-Met carriers (n = 77), no significant differences were observed in demographics or clinical characteristics, including motor or cognitive outcomes. In pair-matched analysis, a significant difference was observed for the Center for Epidemiological Studies Depression (CES-D) scale, where Met carriers had significantly greater CES-D scores than non-Met carriers (24 ± 16 vs. 9 ± 9, p = 0.011). Regardless of the chosen CES-D cut-off scores (≥ 16 vs. ≥ 20), more cases of depressive symptomatology were observed among those with the BDNF Val66Met polymorphism than those without it (p values < 0.05).
Conclusions:
The BDNF Val66Met polymorphism may be associated with post-stroke depression but not motor or cognitive recovery.
Aim:
This study investigated the effect of brain-derived neurotrophic factor (BDNF) Val66Met polymorphism on post-stroke outcomes, including quality of life, physical fitness, cognitive function, depression, and overall disability.
Methods:
The difference between Met carriers and non-Met carriers was analyzed for the entire sample and in pair-matched analysis, using age, sex, time since stroke, and race.
Results:
We evaluated 89 stroke participants (mean age, 57 ± 10 years; 58% male; 54% White, and 49% Hispanic). Twelve participants (13%) had one copy of the BDNF Val66Met (Val/Met heterozygotes) and none had two copies (Met/Met homozygotes). Comparing Met (n = 12) and non-Met carriers (n = 77), no significant differences were observed in demographics or clinical characteristics, including motor or cognitive outcomes. In pair-matched analysis, a significant difference was observed for the Center for Epidemiological Studies Depression (CES-D) scale, where Met carriers had significantly greater CES-D scores than non-Met carriers (24 ± 16 vs. 9 ± 9, p = 0.011). Regardless of the chosen CES-D cut-off scores (≥ 16 vs. ≥ 20), more cases of depressive symptomatology were observed among those with the BDNF Val66Met polymorphism than those without it (p values < 0.05).
Conclusions:
The BDNF Val66Met polymorphism may be associated with post-stroke depression but not motor or cognitive recovery.
DOI: https://doi.org/10.37349/en.2025.1006115
Guillain-Barré Syndrome (GBS) is a rare cause of acute, flaccid paralysis and affects populations around the world, usually in the setting of recent gastrointestinal infection. The myelin sheaths of affected patients are destroyed, and consequently, the disease can manifest variably with the most common complaints including weakness, disturbances in sensation, and pain. Multiple available pharmacotherapies are employed to address disease progression and promote the reversal of symptoms. However, there is no widely accepted guideline detailing tiers of pain management options, despite pain being a significant primary complaint during the acute phase of the disease. To address this, we searched the GBS literature for publications that specifically discussed patient pain, how the pain was managed by the clinician, and how patients responded to various modalities. We discuss the findings of the literature review we conducted, evaluate the expansive list of existing options for treating pain and how they fared in symptom resolution, and draw conclusions based on our observations of which interventions addressed patient pain effectively and which were less successful. While general management of GBS, including treatment and efforts towards symptom reversal, has been robustly discussed in the literature, our work stresses the lack of research towards pain management in GBS and emphasizes the need to fill the gap in patient care for patients with this disease.
Guillain-Barré Syndrome (GBS) is a rare cause of acute, flaccid paralysis and affects populations around the world, usually in the setting of recent gastrointestinal infection. The myelin sheaths of affected patients are destroyed, and consequently, the disease can manifest variably with the most common complaints including weakness, disturbances in sensation, and pain. Multiple available pharmacotherapies are employed to address disease progression and promote the reversal of symptoms. However, there is no widely accepted guideline detailing tiers of pain management options, despite pain being a significant primary complaint during the acute phase of the disease. To address this, we searched the GBS literature for publications that specifically discussed patient pain, how the pain was managed by the clinician, and how patients responded to various modalities. We discuss the findings of the literature review we conducted, evaluate the expansive list of existing options for treating pain and how they fared in symptom resolution, and draw conclusions based on our observations of which interventions addressed patient pain effectively and which were less successful. While general management of GBS, including treatment and efforts towards symptom reversal, has been robustly discussed in the literature, our work stresses the lack of research towards pain management in GBS and emphasizes the need to fill the gap in patient care for patients with this disease.
DOI: https://doi.org/10.37349/en.2025.1006114
Cyclic vomiting syndrome (CVS) is a rare disorder in which stereotypical periods of intermittent nausea and vomiting last between hours and over a week. The disorder overlaps with migraine, and the current treatment recommendations follow those of migraine management. The current patient had experienced vomiting periods lasting up to a week since the age of two. Prophylactic amitriptyline had led to probably slightly longer intervals between CVS periods, while several medications had proven ineffective. At the age of 17, there was an excellent response to peroral olanzapine, which eventually proved sufficient to abort the vomiting periods in a single dose when taken at the beginning of one. In light of these and previously reported cases, early administration of olanzapine is suggested to treat CVS periods.
Cyclic vomiting syndrome (CVS) is a rare disorder in which stereotypical periods of intermittent nausea and vomiting last between hours and over a week. The disorder overlaps with migraine, and the current treatment recommendations follow those of migraine management. The current patient had experienced vomiting periods lasting up to a week since the age of two. Prophylactic amitriptyline had led to probably slightly longer intervals between CVS periods, while several medications had proven ineffective. At the age of 17, there was an excellent response to peroral olanzapine, which eventually proved sufficient to abort the vomiting periods in a single dose when taken at the beginning of one. In light of these and previously reported cases, early administration of olanzapine is suggested to treat CVS periods.
DOI: https://doi.org/10.37349/en.2025.1006113
Schizophrenia (SZ) is a complex psychiatric disorder characterized by disruptions in cognition, perception, and behavior, contributing significantly to the global burden of psychiatric disorders and necessitating ongoing research into its pathophysiology, diagnosis, and treatment. This narrative review explores recent insights into SZ research, highlighting the genetic, neurochemical, and neurodevelopmental factors that contribute to the disorder. Emerging evidence underscores the dynamic interplay between neurotransmitter imbalances, particularly involving dopamine, glutamate, and gamma-aminobutyric acid (GABA), and neuroinflammation, oxidative stress, and immune dysregulation in the pathophysiology of SZ. Neuroimaging, clinical staging models, and multi-omics technologies have deepened our understanding of structural and functional brain abnormalities, identifying potential biomarkers for early detection and subtyping. This has refined diagnostic frameworks and informed precision psychiatry approaches. Advances in pharmacological treatments, including trace amine-associated receptor 1 agonists, glutamatergic modulators, psychedelics, and anti-inflammatory agents, offer new therapeutic possibilities beyond conventional dopamine antagonists. Novel targets, such as N-methyl-D-aspartate (NMDA) receptor modulation and neuroprotective strategies, are also being explored to address negative and cognitive symptoms. Additionally, non-pharmacological interventions, such as neuromodulation techniques, digital therapeutics, and psychosocial interventions, are promising complementary strategies. Digital phenotyping, machine learning (ML), and artificial intelligence (AI)-driven tools enable real-time symptom tracking, early risk prediction, and personalized care delivery. Despite these advancements, challenges remain in early diagnosis, treatment adherence, and equitable access to mental health care, particularly in low-resource settings. Therefore, addressing these barriers requires interdisciplinary collaboration, public health education, and the integration of scalable, culturally sensitive, and AI-based mental health innovations. Future research should prioritize multi-omics integration, longitudinal and transdiagnostic studies, biomarker validation, and the real-world implementation of personalized interventions to improve outcomes and quality of life for individuals living with SZ.
Schizophrenia (SZ) is a complex psychiatric disorder characterized by disruptions in cognition, perception, and behavior, contributing significantly to the global burden of psychiatric disorders and necessitating ongoing research into its pathophysiology, diagnosis, and treatment. This narrative review explores recent insights into SZ research, highlighting the genetic, neurochemical, and neurodevelopmental factors that contribute to the disorder. Emerging evidence underscores the dynamic interplay between neurotransmitter imbalances, particularly involving dopamine, glutamate, and gamma-aminobutyric acid (GABA), and neuroinflammation, oxidative stress, and immune dysregulation in the pathophysiology of SZ. Neuroimaging, clinical staging models, and multi-omics technologies have deepened our understanding of structural and functional brain abnormalities, identifying potential biomarkers for early detection and subtyping. This has refined diagnostic frameworks and informed precision psychiatry approaches. Advances in pharmacological treatments, including trace amine-associated receptor 1 agonists, glutamatergic modulators, psychedelics, and anti-inflammatory agents, offer new therapeutic possibilities beyond conventional dopamine antagonists. Novel targets, such as N-methyl-D-aspartate (NMDA) receptor modulation and neuroprotective strategies, are also being explored to address negative and cognitive symptoms. Additionally, non-pharmacological interventions, such as neuromodulation techniques, digital therapeutics, and psychosocial interventions, are promising complementary strategies. Digital phenotyping, machine learning (ML), and artificial intelligence (AI)-driven tools enable real-time symptom tracking, early risk prediction, and personalized care delivery. Despite these advancements, challenges remain in early diagnosis, treatment adherence, and equitable access to mental health care, particularly in low-resource settings. Therefore, addressing these barriers requires interdisciplinary collaboration, public health education, and the integration of scalable, culturally sensitive, and AI-based mental health innovations. Future research should prioritize multi-omics integration, longitudinal and transdiagnostic studies, biomarker validation, and the real-world implementation of personalized interventions to improve outcomes and quality of life for individuals living with SZ.
DOI: https://doi.org/10.37349/en.2025.1006112
