Search Results (2,745)

Background: Glioblastoma (used to be called glioblastoma multiforme—GBM) is the most common and aggressive brain tumor, having the lowest overall survival rate. Initial focal neurological deficits are primarily attributable to surrounding edema; however, as tumor invasion progresses, these deficits become more pronounced and permanent. The standard treatment for newly diagnosed glioblastoma is represented by cytoreductive neurosurgery followed by the Stupp Protocol. Postoperative recovery of the patient with glioblastoma is a long-term process that should include, for overall more acceptable outcomes, neurorehabilitation. This review aims to bring together evidence from neuro-oncology, neurosurgery, and neurorehabilitation in order to better understand the factors associated with recovery, functional status, and quality of life (QoL) after glioblastoma surgery. Our work also aimed to update the related knowledge base and to attempt to optimize the related protocols in patients with operated cerebral glioblastoma. Methods: For these purposes, we conducted a systematic literature review to assess the current state of research referring to the above-mentioned topic. We have used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA—widely recognized internationally) methodology. We used, in this respect, specific keyword combinations/“syntaxes” for searching literature in the domain, in four international databases. Results: Following PRISMA screening, 14 studies met the predefined eligibility criteria. Additional manual reference screening and complementary searches identified further relevant publications, resulting in a total of 22 included articles. Together, the reviewed work addressed a diverse range of topics relevant to postoperative glioblastoma management, including the potential role of multidisciplinary rehabilitation, cognitive interventions, neuromodulation approaches, and functional assessment strategies in improving postoperative outcomes and QoL in glioblastoma patients, while emphasizing that this interdisciplinary domain warrants more extended approaches. Discussion and Conclusions: Despite the relatively limited and largely exploratory available information, neurorehabilitation may contribute to improved functional outcomes and QoL in patients with glioblastoma. Full article

Current pitchside concussion assessments are limited by low sensitivity, reliance on player self-report, and the need for on-site healthcare professionals. Impairments in cognitive function and motor control are a key predictor of concussive injury. The Circle Sequencing Task (CST) is a newly developed concussion assessment tool to assess both cognitive function and motor control in one test. Here, we seek to assess the CST’s ability to differentiate between healthy and recently concussed individuals relative to existing cognitive tests. Concussed (n = 13; mean age 26 ± 7 yrs) and healthy (n = 13; mean age 28 ± 9 yrs) participants completed the CST, the Trail Making Test, a Go/No-Go task, the Digit Span Test and a simple reaction time task online via a link. Concussed individuals showed significant deficits in inhibitory control (p = 0.01) and memory (p = 0.04) components of the CST compared to healthy controls, with these components showing a larger effect size (d = 1.05 and d = 0.78, respectively) than metrics derived from the existing cognitive tests of Go/No-Go (d = 0.37) and the Digit Span Test (d = 0.52). The findings provide preliminary evidence that CST-derived inhibitory control and memory metrics may differ between recently concussed individuals and healthy controls and warrant further validation in larger clinically controlled studies. Full article

Background/Objectives: Persistent cognitive impairments are prevalent in methamphetamine (meth) use disorder and contribute to maladaptive decision-making and increased relapse vulnerability. There are currently no effective treatments for meth-associative cognitive deficits, and their neurobiological underpinnings remain incompletely understood. This study investigated the effects of chronic meth self-administration on episodic-like recognition memory and evaluated whether pharmacological potentiation of metabotropic glutamate receptor subtype 2 (mGlu2) could rescue these deficits. Methods: Adult male Long–Evans rats underwent 7 days of limited- (1 h/day) followed by 14 days of extended-access (6 h/day) meth self-administration, followed by 30 days of abstinence. Recognition memory was assessed using the object-in-place (OIP) task. A positive allosteric modulator of mGlu2 receptors, LY-487379 (25 mg/kg, s.c.), was administered prior to the memory test. In parallel, changes in total and surface mGlu2/3 protein levels in the prelimbic and perirhinal cortices were evaluated. Results: Rats with extended access to meth self-administration exhibited escalated drug intake and persistent deficits in OIP memory. Administration of LY-487379 acutely rescued this deficit. Total mGlu2/3 protein levels were unaltered; however, meth exposure was associated with a significant increase in surface mGlu2/3 receptor expression in both cortical regions examined. Conclusions: These results demonstrate that chronic meth produces persistent cognitive dysfunction that can be rescued by mGlu2 receptor potentiation. The observed increase in surface mGlu2/3 expression may represent a compensatory response to chronic glutamatergic dysregulation, but it appears to be insufficient to restore cognitive function alone, without pharmacological enhancement. The current data encourage further exploration of mGlu2’s role in stimulant-associated cognitive dysfunction. Full article

Mulberroside A (MsA) possesses neuroprotective effects, but whether it alleviates Alzheimer’s disease (AD)-like cognitive impairment through the microbiota–gut–brain axis remains unclear. Using a scopolamine-induced mouse model of acute cognitive impairment (male ICR mice, n = 10/group), we demonstrated that daily administration of MsA (10, 20, and 30 mg/kg/day) for 5 weeks significantly ameliorated cognitive performance in novel object recognition and Morris water maze tests. At the optimal dose (30 mg/kg/day), MsA suppressed hippocampal microglial activation, reduced pro-inflammatory cytokines (IL-6, IL-1β, TNF-α), and attenuated oxidative stress by decreasing malondialdehyde (MDA) while restoring superoxide dismutase (SOD) and glutathione (GSH) levels. MsA also strengthened intestinal barrier integrity (ZO-1, occludin) and significantly altered the gut microbiota, notably increasing the beneficial genus Dubosiella. Brain metabolomics indicated that MsA reversed scopolamine-induced metabolic disturbances, mainly restoring phospholipid balance. Correlation analysis demonstrated a strong gut–brain connection, with Dubosiella abundance positively associated with neuroprotective phospholipids and negatively with stress markers. Furthermore, fecal microbiota transplantation from MsA-treated donors successfully replicated these behavioral improvements in recipient mice, underscoring the functional involvement of the reshaped microbiome rather than a simple autonomous recovery. These results suggest that MsA alleviates AD-like cognitive impairment by reducing neuroinflammation and oxidative stress through microbiota remodeling, enhancing the intestinal barrier, and modulating the Dubosiella-associated gut–metabolite–brain axis, making MsA a promising multi-target nutraceutical for ameliorating AD-like cognitive deficits. Full article

Background: Anorexia Nervosa (AN) is a severe eating disorder. Attention Deficit Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD) are two Neurodevelopmental Disorders (NDDs), frequently co-occurring with each other (ADHD+ASD). The present study aimed to clarify cognitive and behavioral profiles, with a specific focus on emotional regulation, executive functions and empathy, in three groups of female adolescents. Methods: A total of 102 female adolescents aged 12–18 years were recruited. Participants were divided into three groups (AN: n = 30, ADHD: n = 47, ADHD+ASD: n = 25). All participants underwent a psychometric and a multidimensional clinical assessment. Group differences were analyzed through ANOVA with Bonferroni corrections. Results: Adolescents with ADHD+ASD scored significantly higher than the ADHD group in verbal comprehension. The AN group performed significantly better than both the ADHD and ADHD+ASD groups in working memory, and significantly better than the ADHD+ASD group in processing speed. Both the AN and ADHD+ASD groups were characterized by significantly greater impairment in global functioning than the ADHD group. No significant differences were found among the three groups on the Attention Switching, Attention to Detail, and Imagination subscales of the Autism Spectrum Quotient. Behaviorally, AN participants exhibited higher internalizing symptoms (anxiety and depression), the ADHD group presented more prominent externalizing behaviors (aggressive, rule-breaking, and attention problems), and the comorbid ADHD+ASD group demonstrated significantly more pronounced social problems. Most measures used to assess emotional dysregulation did not reveal significant differences among the three groups. Both the ADHD and ADHD+ASD groups showed significantly greater impairment in executive functioning than the AN group. Regarding empathic abilities, mixed results emerged. Conclusions: Findings suggest the coexistence of condition-specific features and shared vulnerabilities in female adolescents with AN, ADHD, and ADHD+ASD. These data underscore the importance of investigating the female phenotype from a transdiagnostic perspective to facilitate early detection and tailored interventions. Full article

Objective: To characterize neurodevelopmental disorders in children and adolescents with Tuberous Sclerosis Complex (TSC) and explore associations with epilepsy onset and cortical tuber burden. Methods: This exploratory cross-sectional study included 18 children and adolescents with TSC followed at a tertiary pediatric neurology center in Brazil. Standardized neuropsychological, behavioral, and neuroimaging assessments were performed. Participants were stratified according to epilepsy onset and cortical tuber burden. Results: Epilepsy was present in 94.4% of participants, and pharmacoresistance in 52.9%. Neurodevelopmental disorders were highly prevalent, particularly autism spectrum disorder and attention-deficit/hyperactivity disorder, frequently occurring as comorbidities. Children with earlier epilepsy onset demonstrated exploratory trends toward poorer cognitive outcomes, whereas greater cortical tuber burden showed exploratory trends toward greater behavioral and emotional dysregulation, although these differences did not reach statistical significance. Conclusions: Neurodevelopmental disorders are highly prevalent in pediatric TSC. Exploratory findings suggest that epilepsy characteristics and lesion burden may be related to cognitive and behavioral outcomes. These exploratory findings support systematic multidisciplinary neurodevelopmental monitoring in children with TSC. Full article

Background: Tick-borne encephalitis (TBE) is an endemic neuroinfectious disease prevalent in parts of Europe and is often associated with persistent neurological and cognitive sequelae. The aim of this study was to evaluate the long-term outcomes and predictors of post-encephalitic sequelae in adult patients with TBE in Latvia. Methods: A retrospective cohort with prospective follow-up was used that included 105 adult patients hospitalized with laboratory-confirmed TBE between 2018 and 2024. The patients’ clinical and demographic data were extracted from medical records, and reassessments were performed ≥6 months after discharge using structured clinical and neurological evaluations for neurocognitive, subjective, and neurological sequelae. Disease severity was classified using the Mickienė and Bogovič criteria, and sequelae severity was defined according to the Bohr criteria for post-encephalitic syndrome (PES). Results: Sequelae were observed in 52/105 (49.5%) patients and were more frequent in meningoencephalitis than in meningitis cases (18/25 [72.0%] vs. 33/77 [42.9%]). The most common persistent symptoms were impaired concentration (33/52 [63.5%]), fatigue (29/52 [55.8%]), and sleep disturbances (21/52 [40.4%]). Neurological sequelae included tremor (23/52 [44.2%]), vertigo (11/52 [21.2%]), and hearing impairment (5/52 [9.8%]). According to the Bohr criteria, most of the patients had mild sequelae (42/52 [80.8%]), while 10/52 [19.2%] had moderate sequelae; no severe cases were observed. In the multivariable analysis, increasing age was independently associated with greater sequelae severity (OR = 1.045 per year; 95% CI, 1.015–1.073; p = 0.003). Sex, comorbidities, biphasic disease, and length of hospital stay were not significant predictors. Acute neurological manifestations, particularly paresis (p = 0.002) and tremor (p = 0.019), were associated with worse outcomes. Although the disease severity scores correlated with sequelae in unadjusted analyses, neither the Mickienė nor the Bogovič classification independently predicted outcomes after adjustment. Conclusions: Nearly half of the hospitalized patients with TBE included in this study developed long-term sequelae, which were predominantly neurocognitive and mild in severity. Age was the primary independent predictor of worse outcomes, while acute neurological deficits such as paresis and tremor also indicated increased risk. These findings highlight the substantial burden of post-encephalitic syndrome and the need for structured long-term follow-up in TBE survivors. Full article

Background/Objectives: Constructional apraxia (CA) is an impairment in combining simple elements into coherent spatial configurations without basic motor deficits. Although common in neurodegenerative disorders, the qualitative features of visuo-constructional errors and their role in differentiating dementia types remain unclear. This systematic review aimed to synthesize patterns of visuo-constructional errors in dementia and mild cognitive impairment (MCI), exploring distinctive qualitative features associated with different neurodegenerative conditions. Methods: A systematic literature search was conducted in PubMed, Scopus, and Web of Science for studies published between January 1990 and January 2026, following PRISMA guidelines. Studies on adults with dementia or MCI assessing drawing/copying abilities through standardized tasks and qualitative error analysis were included. Reviews, meta-analyses, case reports, non-English articles, and studies not explicitly assessing constructional apraxia were excluded. The quality of evidence was assessed using an adapted version of the Newcastle–Ottawa Scale. Results: A total of 25 studies were included, showing heterogeneous and condition-specific visuo-constructional deficits. Spatial errors and simplifications were the most common across disorders, while perseverations, rotations, and closing-in phenomena were less frequent. Alzheimer’s disease was mainly associated with spatial disorganization, omissions, and conceptual errors linked to temporo-parietal dysfunction; frontotemporal dementia with executive deficits such as perseverations and planning impairments; Lewy body and Parkinson’s disease dementias with visuospatial and attentional alterations; and Huntington’s disease with simplifications and executive dysfunction related to fronto-striatal involvement. Conclusions: No single error pattern was pathognomonic, but qualitative assessment of constructional errors may provide clinically useful information when integrated with the broader neuropsychological profile. Full article

Background/Objectives: Cognitive impairment can compromise toothbrushing and other oral self-care functions, increasing the risk of oral diseases and related complications. However, how toothbrushing ability declines across stages of cognitive impairment remains unclear. This study aimed to describe functional deficits in toothbrushing among older adults with different levels of cognitive function. Method: Sixty-five older adults (14 cognitively healthy and 51 with documented cognitive impairment) were classified into five cognitive levels based on Standardized Mini-Mental State Examination scores. Participants completed a toothbrushing task as they normally would at home. Performance was videotaped, coded, and evaluated across four domains (task initiation, completion, thoroughness, and quality) with total scores reflecting overall toothbrushing ability. Overall performance, functional deficits, and assistance needs were analyzed in relation to cognitive levels. Results: Participants averaged 76.5 years of age. Toothbrushing ability declined gradually with worsening cognitive impairment, followed by a sharp deterioration at the profound stage (e.g., SMMSE ≤ 5). Compared with cognitively healthy participants (n = 14), those with mild cognitive impairment (MCI, n = 20) or mild (n = 10), moderate (n = 10), or severe dementia (n = 11) lost an average of 3%, 8%, 12%, and 37% of overall toothbrushing ability, respectively. Brushing efficiency declined earlier and more rapidly, decreasing by 13% in MCI and up to 46% in severe dementia (p < 0.001). All participants with MCI or mild dementia completed the task independently, whereas 20% with moderate dementia and 80% with severe dementia required assistance to initiate or complete the task. Conclusions: Overall toothbrushing ability remains relatively preserved until the later stages of cognitive impairment, but brushing quality deteriorates much earlier and quicker. These findings highlight the importance of early caregiver–patient partnerships, functionally tailored oral self-care rehabilitation, and personalized caregiver training to support oral hygiene among older adults with cognitive impairment. Full article

Schizophrenia remains a debilitating global health challenge where pharmacologic treatment has been stagnant for over seventy years, relying almost exclusively on the blockade of dopamine receptors. While this mechanism controls positive psychosis, it frequently fails to address negative symptoms or cognitive impairment and carries a significant burden of metabolic and motor adverse effects. This review evaluates the scientific and clinical validation of xanomeline–trospium (Cobenfy^®; investigational name KarXT), the first approved antipsychotic with a completely non-dopaminergic mechanism of action. We synthesize data ranging from the unique structural biology of the bitopic M1/M4 muscarinic receptor agonist xanomeline to the pharmacokinetic innovation of using the peripheral antagonist trospium chloride to mitigate systemic toxicity. Comprehensive analyses of the EMERGENT clinical trial program demonstrate that this combination significantly reduces heterogeneous schizophrenia symptoms with a safety profile distinct from current standards of care, specifically avoiding weight gain and extrapyramidal movement disorders. Furthermore, we contrast this success with the recent failures of other novel mechanisms and explore the potential for precision medicine through the identification of muscarinic receptor deficit biotypes. We conclude that M1/M4 muscarinic receptor agonism represents an important advance toward circuit-based therapeutics that may help overcome some of the limitations inherent to dopamine-centered pharmacotherapy. Full article

The term ‘dementia’ encompasses a diverse group of progressive neurodegenerative disorders, the common feature of which is the deterioration of higher cortical functions. This process not only involves memory deficits and language communication disorders, but also executive dysfunction and loss of emotional control, which ultimately leads to a complete loss of the patient’s independence. Within this group of disorders, Alzheimer’s disease (AD) presents the most serious clinical challenge, characterized by a unique neuropathological triad: the presence of extracellular β-amyloid plaques, intracellular neurofibrillary tangles of tau protein, and widespread dysfunction of cholinergic transmission. The cholinergic hypothesis remains the cornerstone of the current understanding of cognitive impairment in AD. It posits that progressive dementia is caused by the selective degeneration of neurons in the anterior basal forebrain, resulting in a drastic reduction in acetylcholine (ACh) levels in the synaptic cleft. In the absence of a causal treatment, acetylcholinesterase inhibitors (AChEIs) remain the standard of care. Their pharmacological action is based on the inhibition of the AChE enzyme, which allows neurotransmission deficits to be compensated for by prolonging the half-life of acetylcholine at the synapse. This literature review presents a synthesis of the efficacy and safety of classic and novel AChEIs. A comprehensive search of the PubMed, Scopus, and Cochrane Library databases was conducted for clinical data published up to 2026. Evidence from key trials indicates that standard AChEIs induce significant cognitive stabilization compared to placebo, with rivastigmine maximizing daily living parameters via transdermal delivery. However, their therapeutic impact remains strictly symptomatic without arresting neurodegeneration. Conversely, emerging agents like huperzine A and the translation-blocker Posiphen demonstrate disease-modifying potential by modulating CSF biomarkers associated with amyloid and tau proteins. Clinically, while traditional regimens are limited by gastrointestinal toxicities, transitioning toward innovative multi-target structures represents a necessary shift to address both cognitive decline and neurodegeneration. Full article

Background/Objectives. Parkinson’s disease (PD) is a multifactorial neurodegenerative disorder characterized by dopaminergic neuron loss, α-synuclein pathology, neuroinflammation, and cognitive decline. Synaptamide (N-Docosahexaenoylethanolamine (DHEA)) is an endogenous lipid mediator with documented anti-inflammatory and neurogenic properties, but its effects in PD models remain unexplored. This study aimed to evaluate the neuroprotective potential of synaptamide in a subchronic MPTP-induced mouse model of PD. Methods. Male C57BL/6 mice received MPTP (30 mg/kg/day, i.p., 5 days) with or without synaptamide (10 mg/kg/day, s.c., 13 days). Behavioral tests (open field, Y-maze, elevated plus maze, novel object recognition (NOR)) were performed, followed by immunohistochemical analysis of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra, and Western blotting for α-synuclein, p-α-synuclein, TH, and IL1β in brain homogenates and serum. In vitro Neuro-2a cells were co-treated with MPP⁺ (100 µM) and synaptamide (0.1–10 µM) for cytotoxicity assessment (MTS assay). Results. Synaptamide (10 µM) significantly attenuated MPP⁺-induced cytotoxicity in Neuro-2a cells. In vivo, MPTP caused a marked loss of TH⁺-neurons in the substantia nigra, which was prevented by synaptamide treatment. Importantly, this subchronic MPTP model recapitulates early biochemical alterations (e.g., α-synuclein phosphorylation at Ser129) rather than mature Lewy body pathology, a limitation that should be considered when interpreting these findings. Although no motor deficits or anxiety-like behavior were observed, the NOR test revealed MPTP-induced long-term memory impairment, which was fully restored by synaptamide. Conclusions. These findings suggest that synaptamide may exert effects on pathological processes associated with PD, warranting further investigation into its potential role in combination or supportive therapy for this disease. Full article

Objectives: Neuroinflammation is recognized as a significant characteristic of Alzheimer’s disease (AD). Currently, there is a notable absence of effective pharmacological agents to prevent or treat neuroinflammatory processes associated with AD. Heat shock protein 70 (HSP70) is pivotal in the progression of neuroinflammation. In this study, we explored the potential of maltol, a Maillard reaction product derived from red ginseng, as a therapeutic agent for neuroinflammation. Methods: In vitro, HMC3 microglial cell models were developed to examine the regulatory effects of gradient concentrations of maltol (12.5, 25, 50 μM) on the TLR4/MyD88/NF-κB p65 signaling pathway, neuroinflammation, and pyroptosis. Analyses of the GEO database and Gene Set Enrichment Analysis (GSEA) were performed to identify the core targets of maltol, followed by HSP70 gene silencing experiments to validate the targeted regulatory mechanism. Results: Maltol significantly mitigated LPS-induced neuronal damage and cognitive deficits in mice. It effectively suppressed microglia-mediated neuroinflammation and pyroptosis, reversed oxidative stress-induced neuronal ferroptosis, and inhibited neuronal apoptosis. In vitro experiments demonstrated that maltol obstructed TLR4/MyD88 binding, thereby inhibiting NF-κB p65-mediated neuroinflammation and pyroptosis, while also alleviating excessive ROS accumulation to enhance oxidative stress and ferroptosis. Bioinformatics analysis identified HSP70 as a crucial target for the anti-inflammatory and antioxidant effects of maltol. Subsequent gene silencing experiments confirmed that maltol exerted its inhibitory effects on LPS-induced neuroinflammation and pyroptosis in an HSP70-dependent manner. Conclusions: Maltol exhibits significant protective effects against Alzheimer’s disease-related neuroinflammation, oxidative stress, pyroptosis, and ferroptosis through the targeting of HSP70. This study elucidates the molecular mechanisms by which maltol improves neuroinflammatory injury and provides a novel theoretical foundation and therapeutic strategy for the intervention of Alzheimer’s disease neuroinflammation using traditional Chinese medicine. Full article

Objective: Neuroinflammation contributes to cognitive impairment across neurodegenerative disorders. Prostaglandins (e.g., PGE₂, PGD₂, PGF₂α) and pro-inflammatory cytokines (TNF-α, IL-1β) are key mediators of lipopolysaccharide (LPS)-induced hippocampal dysfunction. Carvacrol (CRV), a monoterpenic phenol with anti-inflammatory and antioxidant properties, may mitigate these effects, but its impact on hippocampal prostaglandin profiles is not well-defined. Methods: BALB/c mice were randomly assigned to Control (PBS; n = 7), LPS (1 mg/kg, i.p.; n = 10), or LPS + CRV (50 mg/kg, p.o.; n = 7). Body weight was tracked daily for 7 days; rectal temperature was measured once before behavioral testing and euthanasia. Locomotion/anxiety were assessed by the open-field test (OFT; average speed, total distance, freezing, mobility rate) using ToxTrac. Spatial recognition memory was evaluated in the Y-maze novel-arm task (novel-arm entries, duration, total entries, discrimination index [DI]). Hippocampal PGE₂, PGD₂, PGF₂α, TNF-α, and IL-1β were quantified by ELISA. Data were analyzed by one-way ANOVA with Sidak’s post hoc test. Results: OFT measures did not differ among groups (p > 0.05), indicating no confounding locomotor deficits. In the Y-maze, LPS reduced novel-arm entries versus the Control (p = 0.0029), while LPS + CRV showed a nonsignificant increase versus LPS (p = 0.2406). Novel-arm duration differed among groups (p = 0.0033); LPS + CRV spent less time than LPS (p = 0.0128). Critically, DI showed a robust treatment effect (p < 0.0001): LPS markedly impaired DI versus the Control (p < 0.0001), and CRV significantly improved DI versus LPS (p < 0.0001). Biochemically, LPS elevated hippocampal PGE₂ (p < 0.0001) and PGF₂α (p = 0.0040); CRV normalized PGE₂ (p < 0.0001) but not PGF₂α (p = 0.2656). PGD₂ was unchanged. LPS increased TNF-α and IL-1β (both p < 0.0001), and CRV significantly reduced both versus LPS (both p < 0.0001). Conclusions: Acute LPS provokes prostaglandin- and cytokine-driven hippocampal inflammation with associated recognition memory deficits. Carvacrol attenuates cognitive impairment and suppresses hippocampal PGE₂, TNF-α, and IL-1β, supporting a mechanism involving modulation of the prostaglandin–cytokine axis. These findings highlight CRV as a candidate adjunct for inflammation-associated cognitive dysfunction. Full article

Twice-exceptional students—those who are both gifted and have one or more disabilities—and gifted learners, more broadly, represent persistently underserved populations within educational systems. Gifted learners frequently encounter provision that does not adequately engage their potential, such as standardised approaches that neither recognise nor respond to their learning requirements. Traditional identification and programming approaches often rely on deficit-based approaches that pathologise neurodivergence and frequently neglect the complex, asynchronous learning profiles characteristic of twice-exceptional students. This article advances a functional alignment framework proposing that generative artificial intelligence’s processing patterns may align with the cognitive characteristics of some gifted and twice-exceptional learners. The proposed functional alignment spans five dimensions: conceptual movement, knowledge integration, topic continuity, working memory, and pacing and temporal flexibility; this positions GenAI as a potentially compatible interactive platform for personalised, strengths-based learning. The functional alignment framework is explicitly theoretical, advancing propositions rather than demonstrated effects, and requires empirical validation. Positioning GenAI as a mediating platform has the potential to disrupt longstanding barriers to evidence-informed educational provision for gifted and twice-exceptional students. Through examining the intersection of gifted education, special education, and educational technology, this theoretical work outlines a trajectory for the field, characterised by flexible, personalised, strengths-based approaches that can be responsive to the student in front of the teacher, instead of the all-too-often default to one-size-fits-all approaches. Critical considerations of equity, teacher capability, and ethical implementation are addressed, theorising that GenAI’s transformative potential may only be realised through deliberate, theoretically informed application grounded in deep understanding of learner neurodivergence and a proposed pivot from GenAI literacy to GenAI fluency. This work contributes to reconceptualising gifted education as inherently inclusive, responsive, and oriented towards actualising potential for gifted and twice-/multi-exceptional learners. Full article