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Synesthesia describes cross-over processes that can generate 'extra' conscious percepts, such as seeing additional color when reading numbers. While existing research focuses on the mechanisms and effects of synesthetic associations, it often overlooks its most distinctive feature: unique sensory phenomenology. Here, we introduce pupillometry as an objective physiological measure of synesthetic color phenomenology. Across 16 grapheme-color synesthetes and two matched control groups, pupil responses tracked the brightness of synesthetic colors under constant physical visual input, scaling with self-reported strength. Synesthetic colors elicited pupil dynamics comparable to real colors, dissociating synesthetes from non-synesthetes. These responses emerged too rapidly to reflect imagery and scaled with reported color brightness, revealing cross-over caused genuine perceptual processing. Controls required to generate color associations showed greater effort-linked pupil dilation than synesthetes or controls who did not report colors, providing evidence for the effortless nature of synesthesia. Synesthesia thus provides a tractable human model for studying physiologically measurable phenomenology. Perception feels like a window onto the world, but it never is. What we see is built from what reaches the eye and from what the brain adds. In synesthesia, that second part is easy to spot. People with synesthesia involuntarily experience additional sensations triggered by ordinary stimuli, for example, seeing the number 5 as always appearing red, or hearing a trumpet and perceiving it as bright yellow. This is not imagination or a choice; the experience simply happens. The most common form is grapheme-color synesthesia, where letters and numbers reliably evoke specific colors. Synesthesia is not a 'disease', most synesthetes enjoy the additional sensations and find them useful (e.g., the additional colors help to remember a telephone number). Although synesthesia has been studied for decades, measuring it objectively has proven difficult because researchers have had to rely largely on self-report. Strauch, Leenaars and Rouw studied what happens to the eyes when people experience the colours. They tested 16 grapheme-color synesthetes and two matched control groups of 16 participants each, measuring pupil sizes while the participants viewed gray digits. Synesthetes' pupils became smaller for digits evoking brighter synesthetic colors and became larger for darker ones despite identical physical stimulation of the digits on the screen. Pupil responses were also stronger for digits for which synesthetes had reported a strong color association. Synesthetes did not seem to use visual imagery to evoke their colors, as their pupil responses were too fast for deliberate imagery. The control group, who had to report a random color with digits, did not show effects in their pupil size related to color brightness. Furthermore, controls needed more effort to perform the task. I.e., their pupils widened more than those of synesthetes doing the same task, and more than in controls with no color task. Pupillometry offers researchers a low-cost, objective tool for identifying synesthesia. Objective measurement helps demonstrate that synesthetic experiences are 'real' and offers a method to objectively map out (variations in) synesthetic experiences. This is particularly important for synesthetic children, who are often misunderstood when they report their experiences during schoolwork involving letters or digits. Pupillometry makes synesthesia usable as a model for a larger question. Because the sensory extra (the color) has no physical counterpart on the screen, the method opens a way to study how the brain builds conscious perception.

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Flecainide is class Ic antiarrhythmic drug with a narrow therapeutic range. Adverse drug reactions during flecainide therapy are predominately cardiac in nature. Severe neurological adverse drug reactions have rarely been described. We describe the case of a 71-year-old female who developed myoclonus and severe asthenia requiring intubation and management in the neuroscience intensive care unit. Immediate discontinuation of flecainide and supportive care to allow for drug elimination was the primary treatment. Resolution of flecainide neurotoxicity resolved after 5 days of stopping flecainide. Clinicians should be cognizant of potential neurologic toxicity of flecainide.

Protein S-palmitoylation is a dynamic and reversible post-translational modification (PTM) that governs diverse cellular processes, yet its study remains constrained by the indirect and ensemble-averaging nature of classical biochemical assays. Here, we report a nanopore-based platform, PALM-Scan (palmitoylation analysis via label-free monitoring and signature capture on nanopore) that directly transduces physicochemical signatures of S-palmitoylated peptides into digital electrical signals. Using an engineered Mycobacterium smegmatis porin A (M2-MspA) nanopore, PALM-Scan enables sequence-independent identification of S-palmitoylation and simultaneously differentiates S-palmitoylation from other cysteine-directed PTMs, including S-nitrosylation and S-glutathionylation, without probes or enrichment. We further demonstrate its translational potential by successfully detecting and distinguishing S-palmitoylated subpopulations of disease-relevant biomarkers, including mouse beclin-1 (BECN1)- and glial fibrillary acidic protein (GFAP)-derived peptides, in complex mixtures with minimal sample input. In summary, by integrating label-free operation, single-molecule resolution, and multiplex discrimination, PALM-Scan provides a transformative tool for interrogating S-palmitoylation dynamics in both basic research and biomedical applications.

Stem-cell-based in vitro models offer promising potential to elucidate human brain cell functions and interactions, but limitations in reproducibility, maturation and cell-type diversity persist. Especially, prolonged incorporation of mature microglia and studies of neuroinflammation have proven challenging. Here, we developed a human induced pluripotent stem cell-based three-dimensional cortical brain tissue model (3BTM) containing neurons, astrocytes and microglia with high reproducibility, maturity and viability. 3BTMs show morphological, functional and proteomic maturation of all cell types, leading to high similarity to their in vivo counterparts. Incorporated microglia survive for over 6 months and display mature morphology, functions and gene expression. Importantly, when engineered to model Alzheimer's disease pathology, 3BTMs recapitulate key disease hallmarks, including amyloid deposition, increased phospho-tau levels and neuroinflammation, with microglia shifting their transcriptional landscape to disease-relevant signatures. Treatment of Alzheimer's disease 3BTMs with anti-Aβ immunotherapy cleared deposits and largely reversed disease signatures in glia. Together, our microglia-containing model provides a platform for studying physiological and pathological states of human brain tissue.

Epilepsy is a prevalent neurological disease, with one-third of individuals becoming nonresponsive to antiepileptic drugs and developing drug-refractory epilepsy (DRE). Here we identify activation of cyclic GMP-AMP synthase (cGAS), a double-stranded DNA sensor that induces type I interferon (IFN) signaling, in human DRE brain tissue. Microglia from individuals with DRE exhibit a robust type I IFN signature and the activation of upstream cGAS-STING signaling. Further, in mouse models of Dravet syndrome, a genetic form of DRE, we similarly detect activation of the cGAS pathway. We show that microglial cGAS can be activated by DNA released from hyperexcitable neurons. Genetic reduction and pharmacological inhibition of cGAS attenuates seizure phenotypes, reduces glial inflammatory signatures and normalizes neuronal transcriptomic changes in mice with Dravet syndrome. Together, these findings identify cGAS-mediated neuroimmune signaling as a contributor to seizure pathology in Dravet syndrome and highlight this pathway as a potential therapeutic target.

Despite increased awareness of its multi-dimensional nature, pain remains often underestimated, and its management across different therapeutic areas remains complex. A patient-centred approach is needed to bridge the gap between clinical assessment and individual experience. This project aimed to explore the pain experience across different therapeutic areas through narrative medicine (NM). DIAMOND, the project name, is not an acronym but a symbol meant to shed light on physical and mental pain. DIAMOND involved 19 Italian centres and collected narratives from patients experiencing chronic pain, epilepsy, Gram-positive infections or depression, as well as from their caregivers and treating clinicians. Narratives and socio-demographic data were collected anonymously via a dedicated platform. Narratives were analysed using MAXQDA (VERBI Software, Berlin, Germany), applying NM classifications and content analysis; metaphors used by participants to describe pain were also analysed. Narratives were collected from 64 patients and 56 caregivers; 20 clinicians contributed 40 parallel charts, all of which were included in the analysis. Pain emerged as a deeply embodied and emotional experience, often described through metaphors of darkness, oppression and distortion. At diagnosis, fear, anxiety and disbelief predominated; however, over time, some participants reported acceptance and resilience. Caregivers described significant emotional, relational and economic burdens, often reporting feelings of helplessness and a sense of responsibility. Clinicians presented more progressive narratives, often focusing on technical aspects of care. The narratives revealed a perceptual gap between patients, caregivers and clinicians, especially regarding the emotional meaning of illness and treatment. The narrative process was seen as beneficial by most participants, supporting inner reflection. This pioneering NM initiative mapped the lived experience of pain across multiple conditions, incorporating the perspectives of patients, caregivers and clinicians. NM proved essential in identifying unmet needs and emotional drivers of care, fostering more empathetic, patient-centred approaches in pain management.

Most United States children with neurodevelopmental disorders have not received genetic testing aligned with current guidelines. Integration of genetic counselors into non-genetics departments is a potential strategy to improve uptake, but prevalence and details of integrated care models are unknown. To characterize availability, utilization, and perceived need for genetic counselors across non-genetics departments caring for patients with neurodevelopmental disorders. Cross-sectional observational department-level survey. Child neurology, adult neurology, developmental pediatrics, child psychiatry, and adult psychiatry departments at Intellectual and Developmental Disabilities Research Centers. The survey was distributed to 67 departments across 15 institutions. The departmental response rate was 52% (35/67), with at least one response from 87% (13/15) of institutions. Presence/absence of dedicated genetic counselor(s), where "dedicated" was defined as hired by the department. This was a descriptive study only, with no comparative statistical analyses due to the exploratory nature. One third of departments (34%; 12/35) reported having dedicated clinical genetic counselors. Prevalence was highest in child neurology (67%; 8/12), followed by adult neurology (40%; 2/5) and developmental pediatrics (22%; 2/9), with none in child psychiatry (0/7) or adult psychiatry (0/2). In almost all departments with genetic counselors (92%; 11/12), they directly billed for their services, which universally included pre-test counseling/consent and post-test counseling. In departments without genetic counselors, only 39% (9/23) reported providers ordered their own genetic testing. Among all departments, over half (57%) were interested in adding/increasing genetic counseling support, while 26% were unsure and 17% uninterested. Insufficient funding was the most cited barrier; only one department reported insufficient need. Though currently implemented in only one third of departments, our findings suggest those with dedicated genetic counselors directly pursue genetic testing (without referring to genetics) more than those without genetic counselors. Interest in increasing or adding genetic counseling support was high, and though funding was a reported barrier, feasible funding models were described. In the context of limited medical geneticists and expanding precision therapies, alternate delivery models for neurodevelopmental genetic testing including genetic counselor integration in non-genetics departments may help to scale and sustain uptake.

Recognizing a familiar stimulus is essential to our everyday life. Recent studies revealed details of the nature of the neural dynamics of familiarity representations for human faces. Still, we know relatively little on how different familiar and non-familiar stimulus processing is for non-human face stimuli. Here we report the results of an EEG study, examining the neural dynamics of personally familiar human and dog faces. Participants viewed highly variable images of personally familiar and unfamiliar faces as well as of their own dogs and breed-matched unfamiliar ones. Multivariate pattern analyses were used to examine the time course of differential processing of familiar and unfamiliar human and dog face stimuli. Time-resolved classification revealed that familiarity is decodable from the EEG data from 90 ms onwards, similarly for human and non-human faces. The temporal dynamics were very similar for these categories. Familiarity information, starting at 140-160 ms, generalised across face categories and this generalisation was maintained in a very long time-window. In addition, temporal generalisation analysis showed that familiarity representations have an early, category-specific (90-140 ms) as well as a later, category-independent (>180 ms) processing stage. Our results extend previous human face familiarity evidence to another non-human face category and suggest that familiarity is a general, stimulus-invariant step during recognition memory processing.

Stress beliefs-general expectations about the nature and consequences of stress-have been linked to health and performance, yet their role in shaping responses to everyday stress remains less understood. This study examined whether stress beliefs moderate affective reactivity and stress regulation strategies in response to naturally occurring stressors in daily life. In a 7-day ecological momentary assessment study, 104 university students completed thrice-daily reports (1,939 observations) on social and work-related stressors, positive and negative affect, and two stress regulation strategies-situation selection and response modification-as proposed in the stress optimization model (Crum et al., 2020). At baseline, stress beliefs were assessed alongside variables to characterize the sample. Negative stress beliefs moderated the association between daily stressors and positive affect: Individuals with high negative stress beliefs showed reduced positive affect during social stress and no increase in positive affect under higher workload. By contrast, those with low or moderate negative stress beliefs maintained positive affect during social stress and showed increased positive affect under higher workload-consistent with a challengelike appraisal. Additionally, controllability beliefs buffered increases in negative affect in response to daily social stress, with lower beliefs linked to stronger affective reactivity. By contrast, stress beliefs did not moderate associations between daily stressors and the investigated stress regulation strategies. These findings suggest that stress beliefs tune affective reactivity to everyday social and work stressors, identifying them as a potential intervention target given the established links between affect and long-term health. The generalizability of these findings should be confirmed across broader populations. (PsycInfo Database Record (c) 2026 APA, all rights reserved).

Executive function (EF) is improved following a single bout of exercise. Recently, it has been proposed the timing between exercise and rest intervals (i.e., exercise density) within a single bout of exercise (or across days or months of exercise) may serve as an important moderator in the expression and/or magnitude of an EF benefit. Here, participants (N = 25) completed separate interval exercise conditions - as well as a non-exercise control - wherein ten 1-min intervals of exercise (40% of 1 repetition max leg extensions at 0.25 Hz) were interspersed with 1-min (high-density: HD) or 2-min (low-density: LD) of rest. Prior to and following exercise (∼5-min), the antisaccade task (i.e., saccade mirror-symmetrical to a target) was used to assess the inhibitory control component of EF. Antisaccades were selected given the task's hands- and language-free nature and because they are mediated via EF networks showing task-dependent single-bout exercise changes. Peak systolic middle cerebral artery velocity (MCAvpeak), perceived exertion, arousal and neuromuscular fatigue were measured to identify a potential psychophysiological metric associated with a putative density-linked postexercise EF change. Frequentist and Bayesian statistics demonstrated that the LD - but not HD - condition produced a pre- to postexercise reduction in antisaccade reaction times (RTs), and across LD and HD conditions psychophysiological metrics did not demonstrate an association with postexercise antisaccade RT changes. Hence, results provide nascent evidence that density may moderate a single bout postexercise inhibitory control benefit and demonstrate that density may provide a framework to understand the interdependent psychophysiological mechanisms contributing to the benefit.

Inferring the true cause of noise-distinguishing between volatility (environmental change) and stochasticity (outcome randomness)-is essential for learning in noisy environments. While most studies rely on binary outcomes, previous models are designed for continuous outcome and use ad hoc approximations to handle binary data, introducing theoretical inconsistencies and interpretational issues. Here, we develop a normative framework for inferring the causes of noise from binary feedback that remains faithful to the discrete nature of the generative process and underlying statistical structure. First, we establish a generative model using a state space approach tailored for binary outcomes and derive the corresponding hidden Markov model inference procedure. Second, we introduce a computational model combining the hidden Markov model with particle filtering to simultaneously infer volatility and stochasticity from binary outcomes. Third, we validate predictions through a 2 × 2 probabilistic reversal-learning task with human participants, systematically manipulating both noise parameters. Results show that participants adjust their learning rates consistent with model predictions, increasing learning rates under volatile conditions and decreasing them under high stochasticity. Our theoretical and experimental results offer a principled approach for dissociating volatility and stochasticity from binary outcomes, providing insights into learning processes relevant to typical cognition and psychiatric conditions. (PsycInfo Database Record (c) 2026 APA, all rights reserved).

Accurate assessment of Post-Amputation Pain (PAP) is essential for guiding appropriate clinical management and monitoring treatment outcomes. However, there is no established guidance on core assessment domains for PAP, which may result in clinicians and researchers overlooking pain domains that are critical for monitoring treatment efficacy. This review aimed to identify key features of assessment tools used to measure PAP in clinical trials. Articles published until June 2025 were identified through a systematic search of the following databases: PubMed (MEDLINE) via EBSCOhost, CINAHL (Cumulative Index to Nursing & Allied Health Literature) via EBSCOhost, and PsycINFO via EBSCOhost. Two reviewers independently conducted the screening of titles and abstracts, review of full-text articles, and data extraction. The results were analyzed descriptively. We identified 15 tools used to assess PAP across 158 clinical trials. Together, the tools assessed pain intensity, quality, frequency, duration, temporal pattern, location, interference, easing and aggravating factors, and response to treatment. There were inconsistencies in the assessment of these domains across the included studies. There is a lack of comprehensive tools specifically designed for assessing PAP. Establishing consensus on core measurement domains for PAP is a necessary step toward developing a robust, comprehensive, and validated tool with strong clinical utility. Exclusive reliance on unidimensional pain scales in people with limb amputations may mask clinically meaningful improvements in function, prosthesis use, and participation achieved through rehabilitation.Focusing on pain intensity alone may lead to incomplete evaluation of pain outcomes and misinformed clinical decision-making regarding treatment efficacy.Focusing solely on current pain fails to capture the fluctuating nature of post-amputation pain, increasing the risk of false-negative findings during assessment.Real-time, patient-reported pain tracking has the potential to improve symptom monitoring, reduce recall bias, and support adaptive, patient-centred rehabilitation for individuals with chronic post-amputation pain.

Animal models are important tools for investigating the neurobiological mechanisms underlying psychiatric disorders, particularly given the methodological limitations associated with human studies. In bipolar disorder (BD), the development of animal models with adequate translational relevance remains challenging due to the heterogeneous and multifactorial nature of the condition. Among the available models, intracerebroventricular (ICV) administration of ouabain (OUA), an endogenous cardiac steroid and Na+/K+-ATPase inhibitor, has been extensively used to investigate behavioral and molecular alterations in BD. This review summarizes recent evidence on the molecular alterations in the OUA-induced animal model of BD and discusses how these changes may contribute to the behavioral outcomes observed in this model. The available literature indicates that OUA administration induces both manic-like and depressive-like behaviors and, in some cases, mixed states. Also, the model shows a pharmacological response to established treatments, although the effects of antidepressants are more complex. At the molecular level, OUA inhibits Na+/K+-ATPase activity, which could disrupt ionic homeostasis and modulate intracellular signaling pathways. However, alterations in Na+/K+-ATPase activity appear to be region-dependent, with conflicting findings reported in some brain areas (e.g., the hippocampus). Other pathways impacted by OUA include glycogen synthase kinase-3 (GSK-3), protein kinase C (PKC), and extracellular signal-regulated kinase (ERK), although some heterogeneity has been reported, particularly regarding GSK-3 signaling. In addition, OUA administration is associated with alterations in neurotransmitter and neurotrophic signaling, inflammatory mediators, oxidative stress parameters, and cell death-related pathways. In contrast, current evidence does not indicate significant effects on epigenetic enzyme activity, with limited evidence. Taken together, these findings support the utility of the OUA model as an experimental approach to investigating biological mechanisms underlying the pathophysiology of BD.

Affective valence and reinforcement learning (RL) are increasingly recognized to be closely connected, yet the exact nature of their relationship remains unclear. Here, we investigated how RL-related computations contribute to affective valence, and how affective valence, in turn, contributes to RL. Applying an original computational method, we found that affective experience during RL tasks was best explained by a combination of three prominent theoretical perspectives: valence is determined by reward, prediction errors, and counterfactual comparisons. Further, we found that actions were reinforced by affective responses in addition to external rewards: participants preferred choice options that led to more positive affect, in addition to preferring options that led to greater reward. Altogether, our results illuminate the role of RL computations in affective experience and of affect in RL, providing mechanistic insight into affect, learning, and choice. Moreover, our studies validate a powerful new computational framework for future research on these topics.

In noisy environments, visible speech articulations improve listening comprehension. The benefit derives from several sources, including articulatory timing and shape. Recent research has shown that visual cortex encodes a categorical representation of articulatory features and that visual speech can benefit both acoustic and phonetic feature processing separately. The present study advances the hypothesis that the shape of the articulators specifically influences the categorization of auditory speech in terms of its phonetic features. We tested this by linearly modeling electroencephalographic responses to natural, continuous speech (in noise) in terms of the acoustic and articulatory features of the speech. We compared the performance of these models in conditions where the speech was accompanied by a natural video of the speaker with their mouth visible, and a video where their mouth was covered by a dynamic ellipse obscuring articulatory shape but preserving dynamics. The dynamic mask reduced comprehension, neural processing of phonetic features, the associated multisensory benefits, and indices of visual-only linguistic processing over occipital scalp. Our findings support substantial visual involvement in speech comprehension, derived largely from the shape of the articulators. They also corroborate several proposals involving audiovisual speech processing hierarchy and the nature of the information contained in visible speech.

Previous research on communicative outcomes in children treated for nonsyndromic craniosynostosis (NSC) has yielded inconsistent findings, with reported prevalence rates of communicative difficulties varying widely. These discrepancies are attributable to small samples, heterogeneous age groups, and reliance on indirect or non-domain-specific outcome measures. There remains a need for systematic, age-specific screening using validated tools to clarify the nature and prevalence of communicative vulnerabilities in this population. The primary aim was to assess guardian-reported communicative abilities in a consecutive cohort of 5-year-old children treated for NSC and compare outcomes with normative data. Secondary aims were to examine whether reported difficulties were predominantly speech-language based or pragmatic, and to explore differences related to NSC subtype and timing of surgery. This cross-sectional study included 157 children treated for NSC at a national craniofacial centre in Sweden. Guardians completed the Children's Communication Checklist-2 (CCC-2) as part of routine 5-year follow-up. General Communication Composite (GCC) scores and subscale profiles were analysed and compared with published normative data. Group differences across synostosis type and surgical timing were examined using parametric and non-parametric statistical methods. Eighty-five percent of children scored within the normative range on the GCC. Fifteen percent scored below the clinical cut-off, a proportion not significantly different from the normative sample. Group-level differences were primarily observed in the domains of speech and language, with significantly lower scores in speech and syntax, while pragmatic difficulties were uncommon. No significant differences were found between craniosynostosis subtypes. Earlier surgery was associated with higher GCC scores in children with metopic NSC only. Most children treated for NSC demonstrate age-appropriate communicative abilities at 5 years of age. However, subtle vulnerabilities in speech and syntax were present in a subset of children. These findings support the use of screening in routine follow-up to identify children who may benefit from further assessment, while suggesting that broad language disorder-like profiles are uncommon in this population. What is already known on this subject Previous studies report highly variable rates of speech and language difficulties in children treated for nonsyndromic craniosynostosis (NSC), ranging from low to markedly elevated prevalence. What this study adds to the existing knowledge In a large consecutive cohort of 5-year-old children treated for NSC, 85% showed age-appropriate communicative abilities as rated by their guardians and did not differ significantly from normative data. Group-level differences were confined to speech- and language domains (speech and syntax), while pragmatic difficulties were uncommon. Earlier surgery was associated with higher communication scores in children with metopic NSC only. What are the potential or actual clinical implications of this study? Routine screening at follow-up is supported to identify speech- and language vulnerabilities in a minority of children treated for NSC. Broad language disorder-like profiles appear uncommon, suggesting that monitoring of speech and syntax may be more clinically relevant than global language screening alone. Most 5‐year‐old children treated for nonsyndromic craniosynostosis had guardian‐reported communication abilities within the normative range, and the proportion scoring below the CCC‐2 clinical cut‐off did not differ significantly from normative data. Communication vulnerabilities were mainly observed in speech and syntax, whereas pragmatic difficulties and broad language disorder–like profiles were uncommon. Systematic communication screening can support routine craniofacial follow‐up by identifying children who require comprehensive speech and language assessment, without subjecting all children to extensive assessment solely on the basis of their craniosynostosis diagnosis.

Parasites and infections are one of the major costs associated with group living and high host density. Although infection threat can influence the behavior of both uninfected and infected individuals, investigations have focused on the responses of uninfected individuals. Here we describe the effects on, and response to, terrestrial snails, Cepaea nemoralis, treated with either a bacterial or viral pathogenic stimulus. Brief exposure of untreated (uninfected) snails to the mucus associated chemical cues of snails acutely treated with either the bacterial cell wall component, lipopolysaccharide (LPS), or the viral mimetic, polyinosinic:polycytidylic acid (Poly I:C), elicited active behavioral avoidance and antinociceptive responses (decreased sensitivity to noxious stimuli). Treated (infected) snails also avoided and displayed antinociceptive responses to the chemical cues of snails with either a simulated bacterial or viral infection; however, each according to their own treatment (infection) status. LPS (bacterial) treated snails avoided the cues of Poly I:C (viral), but not LPS, treated conspecifics, whereas Poly I:C treated snails primarily avoided the mucus associated cues of LPS, but not Poly I:C, treated individuals. These findings show that chemical mediated behavioral avoidance of bacterial and viral threat is affected by both the nature of the infection threat and the infection status of the individual.

Targeting oxidative phosphorylation (OXPHOS) represents an attractive therapeutic strategy in acute myeloid leukemia, which exhibits exceptional dependence on mitochondrial respiration compared to normal hematopoietic cells. However, clinical attempts to exploit this vulnerability have been limited by on-target toxicity to healthy tissue. Here, we comprehensively compare the cellular consequences of inhibiting distinct nodes of the electron transport chain in AML. We demonstrate that selective inhibition of the F1 subunit of ATP synthase with EB2023 (ammocidin A) delivers an energetic stress to AML cells without the profound redox stress that characterizes complex I inhibition, preventing NAD+/NADH imbalance and allowing continued TCA cycling. Further, the duration of OXPHOS inhibition is transient in nature in vivo, a finding revealed through pharmacokinetic and serial pharmacodynamic monitoring of AMPK phosphorylation accompanied by OPA1-mediated mitochondrial structural remodeling that primes AML cells for BCL2 inhibitor synergy. EB2023 in combination with venetoclax demonstrates potent anti-AML activity across cell lines and patient-derived xenograft models at doses that spare normal hematopoietic progenitors and avoid the neuropathy and sustained detrimental systemic metabolic rewiring in healthy tissues associated with prior efforts to target OXPHOS. These findings establish F1-selective ATP synthase inhibition as a clinically actionable therapeutic strategy in AML and establish the duration of OXPHOS inhibition as a critical and previously underappreciated determinant of therapeutic index.