bioRxiv Subject Collection: Neuroscience's Journal

Parkinson's disease-related Miro1 mutation induces mitochondrial dysfunction and loss of dopaminergic neurons in vitro and in vivo
The complex and heterogeneous nature of Parkinson disease (PD) is still not fully understood, however, increasing evidence supports mitochondrial impairments as a major driver of neurodegeneration in PD. Recently, the regulator of mitochondrial homeostasis Miro1 has been linked genetically and pathophysiologically to PD. Using 2D and 3D patient-based induced pluripotent stem cells models, including an isogenic control, showed that the Miro1 p.R272Q mutation leads to mitochondrial impairments including increased oxidative stress, disrupted mitochondrial bioenergetics and altered metabolism. This was accompanied by increased alpha-synuclein levels in 2D dopaminergic neurons and by a significant reduction of dopaminergic neurons within midbrain organoids. Knock-in mice expressing mutant p.R285Q Miro1 (orthologue of the human p.R272Q mutation) confirmed the PD-specific dopaminergic neuronal loss in the substantia nigra, accumulation of striatal phosphorylated alpha-synuclein accompanied by behavioral alterations. These findings demonstrate that mutant Miro1 is sufficient to comprehensively model PD-relevant phenotypes in vitro and in vivo, reinforcing its pivotal role in PD pathogenesis.

Specialization of the Human Hippocampal Long Axis Revisited
The hippocampus possesses anatomical differences along its long axis. Here the functional specialization of the human hippocampal long axis was explored using network-anchored precision functional MRI (N = 11) paired with behavioral analyses (N=266). Functional connectivity analyses demonstrated that the anterior hippocampus was preferentially correlated with a cerebral network associated with remembering, while the posterior hippocampus was correlated with a distinct network associated with behavioral salience. Seed regions placed within the hippocampus recapitulated the distinct cerebral networks. Functional characterization using task data within the same intensively sampled individuals discovered a functional double dissociation between the anterior and posterior hippocampal regions. The anterior hippocampal region was sensitive to remembering and imagining the future, specifically tracking the process of scene construction, while the posterior hippocampal region displayed transient responses to targets in an oddball detection task and to transitions between task blocks. These findings suggest specialization along the long axis of the hippocampus with differential responses reflecting the functional properties of the partner cerebral networks.

Higher-order thalamocortical projections selectively control excitability via NMDAR and mGluRI-mediated mechanisms.
The apical dendrites of layer (L) 2/3 pyramidal neurons in the mouse somatosensory cortex integrate synaptic input from long-range projections. Among those, inputs from the higher-order thalamic posteromedial nucleus may facilitate sensory-evoked cortical activity, but it remains elusive how this role emerges. Here we show using ex vivo dendritic recordings that these projections provide dense synaptic input to broad tufted neurons residing predominantly in L2 and cooperate with other inputs to produce NMDA spikes. They have the unique capacity to block two-pore domain potassium leak channels via group 1 metabotropic glutamate receptor (mGluRI) signaling, which increases excitability. Slender tufted L2/3 neurons and other long-range projections fail to invoke these mechanisms. In vivo imaging of calcium signals confirms the presence of mGluRI-dependent modulation of feedback-mediated spiking in L2. Our results imply that higher-order thalamocortical projections regulate neuronal excitability in a cell type and input-selective manner through fast NMDAR and mGluRI-dependent mechanisms.

Replay shapes abstract cognitive maps for efficient social navigation
To make adaptive social decisions, people must anticipate how information flows through their social network. While this requires knowledge of how people are connected, networks are too large to have firsthand experience with every possible route between individuals. How, then, are people able to accurately track information flow through social networks? We find that people cache abstract knowledge about social network structure as they learn who is friends with whom, which enables the identification of efficient routes between remotely-connected individuals. These cognitive maps of social networks, which are built immediately after learning, are then reshaped through overnight rest. During these extended periods of rest, a replay-like mechanism helps to make these maps increasingly abstract, which especially privileges improvements in social navigation accuracy for the longest communication paths spanning distinct communities. Together, these findings provide mechanistic insight into the sophisticated mental representations humans use for social navigation.

A bipolar taxonomy of adult human brain sulcal morphology related to timing of fetalsulcation and trans-sulcal gene expression gradients
We developed a computational pipeline (now provided as a resource) for measuring morphological similarity between cortical surface sulci to construct a sulcal phenotype network (SPN) from each magnetic resonance imaging (MRI) scan in an adult cohort (N=34,725; 45-82 years). Networks estimated from pairwise similarities of 40 sulci on 5 morphological metrics comprised two clusters of sulci, represented also by the bipolar distribution of sulci on a linear-to-complex dimension. Linear sulci were more heritable and typically located in unimodal cortex; complex sulci were less heritable and typically located in heteromodal cortex. Aligning these results with an independent fetal brain MRI cohort (N=228; 21-36 gestational weeks), we found that linear sulci formed earlier, and the earliest and latest-forming sulci had the least between-adult variation. Using high-resolution maps of cortical gene expression, we found that linear sulcation is mechanistically underpinned by trans-sulcal gene expression gradients enriched for developmental processes.

Characterizing Molecular and Synaptic Signatures in Mouse Models of Late-Onset Alzheimer's Disease Independent of Amyloid and Tau Pathology
INTRODUCTION: MODEL-AD is creating and distributing novel mouse models with humanized, clinically relevant genetic risk factors to more accurately mimic LOAD than commonly used transgenic models. METHODS: We created the LOAD2 model by combining APOE4, Trem2*R47H, and humanized amyloid-beta. Mice aged up to 24 months were subjected to either a control diet or a high-fat/high-sugar diet (LOAD2+HFD) from two months of age. We assessed disease-relevant outcomes, including in vivo imaging, biomarkers, multi-omics, neuropathology, and behavior. RESULTS: By 18 months, LOAD2+HFD mice exhibited cortical neuron loss, elevated insoluble brain A{beta}42, increased plasma NfL, and altered gene/protein expression related to lipid metabolism and synaptic function. In vivo imaging showed age-dependent reductions in brain region volume and neurovascular uncoupling. LOAD2+HFD mice also displayed deficits in acquiring touchscreen-based cognitive tasks. DISCUSSION: Collectively the comprehensive characterization of LOAD2+HFD mice reveal this model as important for preclinical studies that target features of LOAD independent of amyloid and tau.

Dopamine-iron homeostasis interaction rescues mitochondrial fitness in Parkinson's disease
Imbalances of iron and dopamine metabolism along with mitochondrial dysfunction have been linked to the pathogenesis of Parkinson's disease (PD). We have previously suggested a direct link between iron homeostasis and dopamine metabolism, as dopamine can increase cellular uptake of iron into macrophages thereby promoting oxidative stress responses. In this study, we investigated the interplay between iron, dopamine, and mitochondrial activity in neuroblastoma SH-SY5Y cells and human induced pluripotent stem cell (hiPSC)-derived dopaminergic neurons differentiated from a healthy control and a PD patient with a mutation in the -synuclein (SNCA) gene. In SH-SY5Y cells, dopamine treatment affected the expression of transmembrane iron transporters and cellular iron accumulation. Furthermore, dopamine supplementation led to decreased mitochondrial respiration and reduced mitochondrial fitness, including reduced mtDNA copy number and citrate synthase activity, increased oxidative stress and impaired aconitase activity. In dopaminergic neurons derived from a healthy control individual, dopamine showed comparable effects as observed in SH-SY5Y cells. The hiPSC-derived PD neurons harboring an endogenous SNCA mutation demonstrated altered mitochondrial iron homeostasis, reduced mitochondrial capacity along with increased oxidative stress and alterations of tricarboxylic acid cycle linked metabolic pathways compared with control neurons. Importantly, dopamine treatment of these PD neurons promoted a rescue effect by increasing mitochondrial respiration, activating antioxidant stress response, and normalizing altered metabolite levels linked to mitochondrial function. These observations provide evidence that dopamine affects iron homeostasis, intracellular stress responses and mitochondrial function in healthy cells, while dopamine supplementation can restore this disturbed regulatory network in PD cells.

Associations between music and dance relationships, rhythmic proficiency, and spatiotemporal movement modulation ability in adults with and without mild cognitive impairment
Background: Personalized dance-based movement therapies may improve cognitive and motor function in individuals with mild cognitive impairment (MCI), a precursor to Alzheimer's disease. While age- and MCI-related deficits reduce individuals' abilities to perform dance-like rhythmic movement sequences (RMS)-spatial and temporal modifications to movement-it remains unclear how relationships to dance and music affect the ability to perform RMS. Objective: Characterize associations between RMS performance and music or dance relationships, as well as the ability to perceive rhythm and meter (rhythmic proficiency) in adults with and without MCI. Methods: We used wearable inertial sensors to evaluate the ability of 12 young adults (YA; age=23.9{+/-}4.2 yrs; 9F), 26 older adults without MCI (OA; age=86.1{+/-}8.5 yrs; 16F), and 18 adults with MCI (MCI; age=70.8{+/-}6.2 yrs; 10F) to accurately perform spatial, temporal, and spatiotemporal RMS. To quantify self-reported music and dance relationships and rhythmic proficiency, we developed Music (MRQ) and Dance Relationship Questionnaires (DRQ), and a rhythm assessment (RA), respectively. We correlated MRQ, DRQ, and RA scores against RMS performance for each group separately. Results: The OA and YA groups exhibited better MRQ and RA scores than the MCI group (p<0.006). Better MRQ and RA scores were associated with better temporal RMS performance for only the YA and OA groups (r2=0.18-0.41; p<0.030). DRQ scores were not associated with RMS performance in any group. Conclusions: Cognitive deficits in adults with MCI likely limit the extent to which relationships to music or rhythmic proficiency improve the ability to perform temporal aspects of dance-based therapies.

Visual imagery vividness correlates with afterimage brightness and sharpness
Afterimages are illusory, conscious visual perseverations commonly induced by preceding light stimulation. A retinal centric view on the physiological source of afterimages is dominant. In addition, post-retinal mechanisms have been considered in the formation and modulation of afterimage perception, including cortical processes. A cortical role in afterimage perception posits possible shared neural mechanisms between afterimages and other conscious perceptions that emerge completely from central neural sources (e.g., imagery, hallucination, and dreams). To examine this hypothesis, we tested a perceptual link between afterimages and visual imagery. Framing the current experiment, we review more than a century of literature that evidences post-retinal processes in afterimage perception. Subsequently, we present an innovative afterimage perception reporting paradigm, validated on image stimuli, that allowed participants to indicate the perceived sharpness, contrast, and duration of their afterimages. From these perceptual reports, we discovered a novel category of evidence for cortical mechanisms in afterimage perception: the vividness of visual imagery positively correlates with afterimage brightness and sharpness. This result motivates future investigations on the neural mechanisms of afterimage perception and encourages implementing afterimages as a model perception to interrogate other kinds of conscious experience with known cortical origin.

Neural Interoceptive Processing is Modulated by Deep Brain Stimulation for Treatment Resistant Depression
Background: A critical advance in depression research is to clarify the hypothesized role of interoceptive processing in neural mechanisms of treatment efficacy. This study tests whether cortical interoceptive processing, as indexed by the heartbeat-evoked potential (HEP), is modulated by deep brain stimulation (DBS) to the subcallosal cingulate (SCC) for treatment resistant depression (TRD). Methods: Eight patients with TRD were enrolled in a study of SCC DBS safety and efficacy. Electroencephalography (EEG) and symptom severity measures were sampled in a laboratory setting over the course of a six-month treatment protocol. The primary outcome measure was an EEG-derived HEP, which reflects cortical processing of heartbeat sensation. Cluster-based permutation analyses were used to test the effect of stimulation and time in treatment on the HEP. The change in signal magnitude after treatment was correlated with change in depression severity as measured by the 17-item Hamilton Depression Rating Scale. Results: HEP amplitude was greater after 24 weeks of treatment (t(7)=-4.40, p=.003, g=-1.38, 95% Cl [-2.3, -0.42]), and this change was inversely correlated with latency of treatment response (rho = -0.75, 95% Cl [-0.95, -0.11], p=.03). An acute effect of DBS was also observed, but as a decrease in HEP amplitude (t(6) =6.66, p<.001, g=2.19, 95% Cl [0.81, 3.54]). HEP differences were most pronounced over left posterior sensors from 405-425 ms post-stimulus. Conclusion: Brain-based evidence substantiates a theorized link between interoception and depression, and suggests an interoceptive contribution to the mechanism of treatment efficacy with deep brain stimulation for severe depression.

Learning of the same task subserved by substantially different mechanisms between patients with Body Dysmorphic Disorder and healthy individuals
It is generally believed that learning of a perceptual task involving low-level neuronal mechanisms is similar between individuals. However, it is unclear whether this assumption also applies to individuals with psychiatric disorders that are known to have altered brain activation during visual processing. We investigated this question in patients with body dysmorphic disorder (BDD), a psychiatric disorder characterized by distressing or impairing preoccupation with nonexistent or slight defects in one's physical appearance, and in healthy controls. Participants completed six training sessions on separate days on a visual detection task for human faces with low spatial frequency (LSF) components. Brain activation during task performance was measured with functional magnetic resonance imaging (fMRI) on separate days prior to and after training. The behavioral results showed that both groups of participants improved on the visual detection task to a similar extent through training. Despite this similarity in behavioral improvement, neuronal changes in the Fusiform Face Area (FFA), a core cortical region involved in face processing, with training were substantially different between groups. First, activation in the right FFA for LSF faces relative to High Spatial Frequency (HSF) faces that were used as an untrained control increased after training in BDD patients but decreased in controls. Second, resting state functional connectivity between left and right FFAs decreased after training in BDD patients but increased in controls. Contrary to the assumption that learning of a perceptual task is subserved by the same neuronal mechanisms across individuals, our results indicate that the neuronal mechanisms involved in learning of a face detection task differ fundamentally between patients with BDD and healthy individuals. The involvement of different neuronal mechanisms for learning of even simple perceptual tasks in patients with BDD might reflect the brain's adaptations to altered functions imposed by the psychiatric disorder.

Dynamical structure-function correlations provide robust and generalizable signatures of consciousness in humans
Resting-state functional magnetic resonance imaging evolves through a repertoire of functional connectivity patterns which might reflect ongoing cognition, as well as the contents of conscious awareness. We investigated whether the dynamic exploration of these states can provide robust and generalizable markers for the state of consciousness in human participants, across loss of consciousness induced by general anaesthesia or slow wave sleep. By clustering transient states of functional connectivity, we demonstrated that brain activity during unconsciousness is dominated by a recurrent pattern primarily mediated by structural connectivity and with a reduced capacity to transition to other patterns. Our results provide evidence supporting the pronounced differences between conscious and unconscious brain states in terms of whole-brain dynamics; in particular, the maintenance of rich brain dynamics measured by entropy is a critical aspect of conscious awareness. Collectively, our results may have significant implications for our understanding of consciousness and the neural basis of human awareness, as well as for the discovery of robust signatures of consciousness that are generalizable among different brain conditions.

The role of kinesthetic and visuospatial cues in pain-induced movement avoidance
Background: Avoidance of movements is an important factor in chronic pain. Previous experiments have investigated the involved learning mechanisms by pairing movements with painful stimuli but, usually, other visuospatial cues are concurrently presented during learning. Therefore, participants might primarily avoid these visuospatial rather than the movement-related cues, potentially invalidating related interpretations of pain-induced movement avoidance. Here, we separated kinesthetic from visuospatial cues to investigate their respective contribution to avoidance learning. Methods: Participants used a hand-held robotic manipulandum and, during an acquisition phase, received painful stimuli when performing center-out movements. Pain stimuli could be avoided by choosing a curved rather than direct movement trajectories. To distinguish the contribution of kinesthetic vs. visuospatial cues we used two generalization contexts: either participants executed novel movements passing through the same location at which pain had previously been presented in the acquisition phase; or they executed the same pain-associated movements after having been reseated, so that the hand did not pass through the pain-associated location. Results: Avoidance generalization was comparable in both contexts, and remarkably, highly correlated between them. Our findings suggest that both visuospatial and kinesthetic cues available during acquisition were associated with pain and led to avoidance. Conclusions: Our research corroborates the fear-avoidance pain model and previous studies' findings that pain can become associated with movements. However, our study indicates that visuospatial cues also play a critical role. Future studies should distinguish movement-related and space-related associations in pain learning. Significance: Chronic pain is a significant health issue typically attributed to maladaptive learning of pain- movement associations and movement avoidance. We demonstrate that visual cues can play a similarly important role as movement cues in pain learning. This aspect has not previously been considered and has likely confounded previous research findings. Keywords: Chronic pain, learning, conditioning, motor avoidance, fear avoidance

Circuit-motivated generalized affine models characterize stimulus-dependent visual cortical shared variability
Correlated variability in the visual cortex is modulated by stimulus properties. The stimulus dependence of correlated variability impacts stimulus coding and is indicative of circuit structure. An affine model combining a factor proportional to mean stimulus response and an additive offset has been proposed to explain how correlated variability in primary visual cortex (V1) depends on stimulus orientations. However, whether the affine model could be extended to explain modulations by other stimulus variables or variability shared between two brain areas is unknown. Motivated by a simple neural circuit mechanism, we modified the affine model to better explain the contrast-dependence of neural variability shared within either primary or secondary visual cortex (V1 or V2) as well as the orientation-dependence of neural variability shared between V1 and V2. Our results bridge neural circuit mechanisms and statistical models, and provide a parsimonious explanation for the stimulus-dependence of correlated variability within and between visual areas.

Event Detection and Classification from Multimodal Time Series with Application to Neural Data
The detection of events in time-series data is a common signal-processing problem. When the data can be modeled as a known template signal with an unknown delay in Gaussian noise, detection of the template signal can be done with a traditional matched filter. However, in many applications, the event of interest is represented in multimodal data consisting of both Gaussian and point-process time series. Neuroscience experiments, for example, can simultaneously record multimodal neural signals such as local field potentials (LFPs), which can be modeled as Gaussian, and neuronal spikes, which can be modeled as point processes. Currently, no method exists for event detection from such multimodal data, and as such our objective in this work is to develop a method to meet this need. Here we address this challenge by developing the multimodal event detector (MED) algorithm which simultaneously estimates event times and classes. To do this, we write a multimodal likelihood function for Gaussian and point-process observations and derive the associated maximum likelihood estimator of simultaneous event times and classes. We additionally introduce a cross-modal scaling parameter to account for model mismatch in real datasets. We validate this method in extensive simulations as well as in a neural spike-LFP dataset recorded during an eye-movement task, where the events of interest are eye movements with unknown times and directions. We show that the MED can successfully detect eye movement onset and classify eye movement direction. Further, the MED successfully combines information across data modalities, with multimodal performance exceeding unimodal performance. This method can facilitate applications such as the discovery of latent events in multimodal neural population activity and the development of brain-computer interfaces for naturalistic settings without constrained tasks or prior knowledge of event times.

Sex-specific Effects of the Endocannabinoid Agonist 2-Arachidonoylglycerol on Sleep and Circadian Disruptions during Fentanyl Withdrawal
Fentanyl has become the leading driver of opioid overdoses. Cessation of opioid use represents a challenge as the experience of withdrawal drives subsequent relapse. One of the most prominent withdrawal symptoms that can contribute to opioid craving and vulnerability to relapse is sleep disruption. The endocannabinoid agonist, 2-Arachidonoylglycerol (2-AG), may promote sleep and reduce withdrawal severity; however, the effects of 2-AG on sleep disruption during opioid withdrawal have yet to be assessed. Here, we investigate the effects of 2-AG administration on sleep-wake behavior and diurnal activity in mice during withdrawal from fentanyl. Sleep-wake activity was continuously recorded before and after chronic fentanyl administration in both male and female C57BL/6J mice. Immediately following cessation of fentanyl administration, 2-AG was administered intraperitoneally to investigate the impact of endocannabinoid agonism on opioid-induced sleep disruption. Female mice maintained higher activity levels in response to chronic fentanyl than male mice. Furthermore, fentanyl increased wake and decreased sleep during the light period and inversely increased sleep and decreased wake in the dark period in both sexes. 2-AG treatment increased arousal and decreased sleep in both sexes during first 24 hrs of withdrawal. On withdrawal day 2, only female showed increased wakefulness with no changes in males, but by withdrawal day 3 male mice displayed decreased rapid-eye movement sleep during the dark period with no changes in female mice. Overall, repeated administration of fentanyl altered sleep and diurnal activity and administration of the endocannabinoid agonist, 2-AG, had sex-specific effects on fentanyl-induced sleep and diurnal changes.

Taste Experience Enhances Cortical Response Reliability during Latent Enhancement of Taste Aversion Learning
Learning is not as simple as the association of paired stimuli in a vacuum. For example, benign experience with a taste stimulus weakens future conditioned taste aversions (CTA) to that taste, a phenomenon known as latent inhibition, and enhances later CTA to a novel taste (latent enhancement [LE]; Flores et al., 2016; Flores et al., 2018). Our recent investigations on how benign taste experience impacts cortical responses revealed an increase in the discriminability/salience of Gustatory Cortical (GC) responses to a new taste following experience offering a clue into potential underlying mechanisms for LE on CTA (Flores et al., 2022). Here, we predict that the previously reported increase in response discriminability following taste experience is associated with a reduction of variability that has been shown to promote learning. Our results support this prediction and reveal enhanced trial-to-trial consistency of single-neuron sucrose responses and coherent activity across ensemble neurons before CTA learning. Connecting this result to learning, we further show that the distinction between pre- and post-CTA sucrose responses are indeed greater in rats with prior benign taste experience. Overall, these results suggest that following benign experience, taste coding in GC becomes more reliable (at both the single-neuron and ensemble levels) providing a potential mechanism which may contribute to the stronger CTA acquisition seen in LE of learning.

The Late Positive Event-Related Potential Component is Time-Locked to the Decision in Recognition Memory Tasks
Two event-related potential (ERP) components are commonly observed in recognition memory tasks: the Frontal Negativity (FNRHH) and the Late Positive Component (LPC). These components are widely interpreted as neural correlates of familiarity and recollection, respectively. However, the interpretation of LPC effects is complicated by inconsistent results regarding the timing of ERP amplitude differences. There are also mixed findings regarding how LPC amplitudes covary with decision confidence. Critically, LPC effects have almost always been measured using fixed time windows relative to memory probe stimulus onset, yet it has not been determined whether LPC effects are time-locked to the stimulus or the recognition memory decision. To investigate this, we analysed a large (n=IEX) existing dataset recorded during recognition memory tasks with post-decisional confidence ratings. We used ERP deconvolution to disentangle contributions to LPC effects (defined as differences between hits and correct rejections) that were time-locked to either the stimulus or the vocal old/new response. We identified a left-lateralised parietal LPC effect that was time-locked to the vocal response rather than probe stimulus onset. We also isolated a response-locked, midline parietal ERP correlate of confidence that influenced measures of LPC amplitudes at left parietal electrodes. Our findings demonstrate that, contrary to widespread assumptions, the LPC effect is time-locked to the recognition memory decision and is best measured using response-locked ERPs. By extension, differences in response time distributions across conditions of interest may lead to substantial measurement biases when analysing stimulus-locked ERPs. Our findings highlight important confounding factors that further complicate the interpretation of existing stimulus-locked LPC effects as neural correlates of recollection. We recommend that future studies adopt our analytic approach to better isolate LPC effects and their sensitivity to manipulations in recognition memory tasks.

A single computational objective drives specialization of streams in visual cortex
Human visual cortex is organized into dorsal, lateral, and ventral streams. A long-standing hypothesis is that the functional organization into streams emerged to support distinct visual behaviors. Here, we use a neural network-based computational model and a massive fMRI dataset to test how visual streams emerge. We find that models trained for stream-specific visual behaviors poorly capture neural responses and organization. Instead, a self-supervised Topographic Deep Artificial Neural Network, which encourages nearby units to respond similarly, successfully predicts neural responses, spatial segregation, and functional differentiation across streams. These findings challenge the prevailing view that streams evolved to separately support different behaviors, and suggest instead that functional organization arises from a single principle: balancing general representation learning with local spatial constraints.

Cerebrovascular-balance relationships reveal mechanisms of neuromotor resilience to dual-task cognitive loading
BACKGROUND: Age-related decline in cerebrovascular health precipitates cognitive dysfunction and can be attenuated by habitual physical activity. Cognitive interference in balance control is well-known clinically and reflects compromised neuromotor resilience. However, whether cerebrovascular health affects cognitive-balance dual-tasking with aging is unclear. METHODS: Thirty participants (76+4years) completed clinical balance/cognitive testing under single-task and dual-task conditions. Balance performance was assessed as the total distance traversed during a challenging beam walking task. Cognitive performance was assessed as response time (RT) during a working-memory n-back test. Transcranial Doppler ultrasound was used to measure resting middle cerebral artery blood velocity (MCAv). We tested whether MCAv was associated with single-task and dual-task interference (DTI) in balance and cognitive performance and the effects of age and physical activity level on this relationship. RESULTS: During single-tasking, higher MCAv associated with higher balance function (r=0.40, p=0.033), while no relationship was observed for cognitive performance. Dual-tasking strengthened relationships between MCAv and DTI across domains of balance (r=0.442, p=0.016) and cognition (r=0.328, p=0.089); for cognitive DTI, this effect was driven by individuals [≥]75years old (r=0.54, p=0.031). Individuals [≥]75years exhibited greater cognitive DTI (p=0.049), yet achieved similar balance DTI compared to those <75. Regardless of age, participants with higher MCAv demonstrated greater dual-task prioritization of balance control over cognitive performance (r=0.410, p=0.030). Physically-active participants with higher MCAv also showed less balance DTI (r=0.621, p=0.003), while there was no relationship in under-active/sedentary individuals or within the cognitive domain. CONCLUSIONS: Our results support a key role of cerebrovascular health in neuromotor resilience to cognitive loading, which may emerge earlier in brain aging processes affecting balance control compared to cognition. Cerebrovascular health may support peoples ability to prioritize balance in the face of competing attentional demands, and may mediate the positive effects of physical activity on cortically-mediated balance control.