D-ꞵ-hydroxybutyrate stabilizes hippocampal CA3-CA1 circuit during acute insulin resistance.

The brain primarily relies on glycolysis for mitochondrial respiration but switches to alternative fuels such as ketone bodies (KBs) when less glucose is available. Neuronal KB uptake, which does not rely on glucose transporter 4 (GLUT4) or insulin, has shown promising clinical applicability in alleviating the neurological and cognitive effects of disorders with hypometabolic components. However, the specific mechanisms by which such interventions affect neuronal functions are poorly understood. In this study, we pharmacologically blocked GLUT4 to investigate the effects of exogenous KB D-ꞵ-hydroxybutyrate (D-ꞵHb) on mouse brain metabolism during acute insulin resistance (AIR). We found that both AIR and D-ꞵHb had distinct impacts across neuronal compartments: AIR decreased synaptic activity and long-term potentiation (LTP) and impaired axonal conduction, synchronization, and action potential properties, while D-ꞵHb rescued neuronal functions associated with axonal conduction, synchronization, and LTP.

D-ß-hydroxybutyrate stabilizes hippocampal CA3-CA1 circuit during acute insulin resistance.

1.The brain primarily relies on glycolysis for mitochondrial respiration but switches to alternative fuels such as ketone bodies (KBs) when less glucose is available. Neuronal KB uptake, which does not rely on glucose transporter 4 (GLUT4) or insulin, has shown promising clinical applicability in alleviating the neurological and cognitive effects of disorders with hypometabolic components. However, the specific mechanisms by which such interventions affect neuronal functions are poorly understood. In this study, we pharmacologically blocked GLUT4 to investigate the effects of exogenous KB D-P-hydroxybutyrate (D-ßHb) on mouse brain metabolism during acute insulin resistance (AIR). We found that both AIR and D-ßHb had distinct impacts across neuronal compartments: AIR decreased synaptic activity and long-term potentiation (LTP) and impaired axonal conduction, synchronization, and action potential (AP) properties, while D- PHb rescued neuronal functions associated with axonal conduction, synchronization and LTP.

Leveraging Julia's automated differentiation and symbolic computation to increase spectral DCM flexibility and speed.

Using neuroimaging and electrophysiological data to infer neural parameter estimations from theoretical circuits requires solving the inverse problem. Here, we provide a new Julia language package designed to i) compose complex dynamical models in a simple and modular way with ModelingToolkit.jl, ii) implement parameter fitting based on spectral dynamic causal modeling (sDCM) using the Laplace approximation, analogous to MATLAB implementation in SPM12, and iii) leverage Julia's unique strengths to increase accuracy and speed by employing Automatic Differentiation during the fitting procedure. To illustrate the utility of our flexible modular approach, we provide a method to improve correction for fMRI scanner field strengths (1.5T, 3T, 7T) when fitting models to real data.

Brain signaling becomes less integrated and more segregated with age.

The integration-segregation framework is a popular first step to understand brain dynamics because it simplifies brain dynamics into two states based on global vs. local signaling patterns. However, there is no consensus for how to best define what the two states look like. Here, we map integration and segregation to order and disorder states from the Ising model in physics to calculate state probabilities, Pint and Pseg, from functional MRI data. We find that integration/segregation decreases/increases with age across three databases, and changes are consistent with weakened connection strength among regions rather than topological connectivity based on structural and diffusion MRI data.

Ion gradient-driven bifurcations of a multi-scale neuronal model.

Metabolic limitations within the brain frequently arise in the context of aging and disease. As the largest consumers of energy within the brain, ion pumps that maintain the neuronal membrane potential are the most affected when energy supply becomes limited. To characterize the effects of such limitations, we analyze the ion gradients present in a conductance-based (Morris-Lecar) neural mass model. We show the existence and locations of Neimark-Sacker and period-doubling bifurcations in the sodium, calcium, and potassium reversal potentials and demonstrate that these bifurcations form physiologically relevant bounds of ion gradient variability. Within these bounds, we show how depolarization of the gradients causes decreased neural activity. We also show that the depolarization of ion gradients decreases inter-regional coherence, causing a shift in the critical point at which the coupling occurs and thereby inducing loss of synchrony between regions. In this way, we show that the Larter-Breakspear model captures ion gradient variability present at the microscale level and propagates these changes to the macroscale effects such as those observed in human neuroimaging studies.

Early path dominance as a principle for neurodevelopment.

We perform targeted attack, a systematic computational unlinking of the network, to analyze its effects on global communication across the brain network through its giant cluster. Across diffusion magnetic resonance images from individuals in the UK Biobank, Adolescent Brain Cognitive Development Study and Developing Human Connectome Project, we find that targeted attack procedures on increasing white matter tract lengths and densities are remarkably invariant to aging and disease. Time-reversing the attack computation suggests a mechanism for how brains develop, for which we derive an analytical equation using percolation theory. Based on a close match between theory and experiment, our results demonstrate that tracts are limited to emanate from regions already in the giant cluster and tracts that appear earliest in neurodevelopment are those that become the longest and densest.

Acute administration of ketone beta-hydroxybutyrate downregulates 7T proton magnetic resonance spectroscopy-derived levels of anterior and posterior cingulate GABA and glutamate in healthy adults.

Glucose metabolism is impaired in brain aging and several neurological conditions. Beneficial effects of ketones have been reported in the context of protecting the aging brain, however, their neurophysiological effect is still largely uncharacterized, hurdling their development as a valid therapeutic option. In this report, we investigate the neurochemical effect of the acute administration of a ketone d-beta-hydroxybutyrate (D-ßHB) monoester in fasting healthy participants with ultrahigh-field proton magnetic resonance spectroscopy (MRS). In two within-subject metabolic intervention experiments, 7 T MRS data were obtained in fasting healthy participants (1) in the anterior cingulate cortex pre- and post-administration of D-ßHB (N = 16), and (2) in the posterior cingulate cortex pre- and post-administration of D-ßHB compared to active control glucose (N = 26). Effect of age and blood levels of D-ßHB and glucose were used to further explore the effect of D-ßHB and glucose on MRS metabolites. Results show that levels of GABA and Glu were significantly reduced in the anterior and posterior cortices after administration of D-ßHB. Importantly, the effect was specific to D-ßHB and not observed after administration of glucose. The magnitude of the effect on GABA and Glu was significantly predicted by older age and by elevation of blood levels of D-ßHB. Together, our results show that administration of ketones acutely impacts main inhibitory and excitatory transmitters in the whole fasting cortex, compared to normal energy substrate glucose. Critically, such effects have an increased magnitude in older age, suggesting an increased sensitivity to ketones with brain aging.

Type 2 diabetes mellitus accelerates brain aging and cognitive decline: Complementary findings from UK Biobank and meta-analyses.

Background: Type 2 diabetes mellitus (T2DM) is known to be associated with neurobiological and cognitive deficits; however, their extent, overlap with aging effects, and the effectiveness of existing treatments in the context of the brain are currently unknown. Methods: We characterized neurocognitive effects independently associated with T2DM and age in a large cohort of human subjects from the UK Biobank with cross-sectional neuroimaging and cognitive data. We then proceeded to evaluate the extent of overlap between the effects related to T2DM and age by applying correlation measures to the separately characterized neurocognitive changes. Our findings were complemented by meta-analyses of published reports with cognitive or neuroimaging measures for T2DM and healthy controls (HCs). We also evaluated in a cohort of T2DM-diagnosed individuals using UK Biobank how disease chronicity and metformin treatment interact with the identified neurocognitive effects. Results: The UK Biobank dataset included cognitive and neuroimaging data (N = 20,314), including 1012 T2DM and 19,302 HCs, aged between 50 and 80 years. Duration of T2DM ranged from 0 to 31 years (mean 8.5 ± 6.1 years); 498 were treated with metformin alone, while 352 were unmedicated. Our meta-analysis evaluated 34 cognitive studies (N = 22,231) and 60 neuroimaging studies: 30 of T2DM (N = 866) and 30 of aging (N = 1088). Compared to age, sex, education, and hypertension-matched HC, T2DM was associated with marked cognitive deficits, particularly in executive functioning and processing speed. Likewise, we found that the diagnosis of T2DM was significantly associated with gray matter atrophy, primarily within the ventral striatum, cerebellum, and putamen, with reorganization of brain activity (decreased in the caudate and premotor cortex and increased in the subgenual area, orbitofrontal cortex, brainstem, and posterior cingulate cortex). The structural and functional changes associated with T2DM show marked overlap with the effects correlating with age but appear earlier, with disease duration linked to more severe neurodegeneration. Metformin treatment status was not associated with improved neurocognitive outcomes. Conclusions: The neurocognitive impact of T2DM suggests marked acceleration of normal brain aging. T2DM gray matter atrophy occurred approximately 26% ± 14% faster than seen with normal aging; disease duration was associated with increased neurodegeneration. Mechanistically, our results suggest a neurometabolic component to brain aging. Clinically, neuroimaging-based biomarkers may provide a valuable adjunctive measure of T2DM progression and treatment efficacy based on neurological effects. Funding: The research described in this article was funded by the W. M. Keck Foundation (to LRMP), the White House Brain Research Through Advancing Innovative Technologies (BRAIN) Initiative (NSFNCS-FR 1926781 to LRMP), and the Baszucki Brain Research Fund (to LRMP). None of the funding sources played any role in the design of the experiments, data collection, analysis, interpretation of the results, the decision to publish, or any aspect relevant to the study. DJW reports serving on data monitoring committees for Novo Nordisk. None of the authors received funding or in-kind support from pharmaceutical and/or other companies to write this article.

Detection of COVID-19 using multimodal data from a wearable device: results from the first TemPredict Study.

Early detection of diseases such as COVID-19 could be a critical tool in reducing disease transmission by helping individuals recognize when they should self-isolate, seek testing, and obtain early medical intervention. Consumer wearable devices that continuously measure physiological metrics hold promise as tools for early illness detection. We gathered daily questionnaire data and physiological data using a consumer wearable (Oura Ring) from 63,153 participants, of whom 704 self-reported possible COVID-19 disease. We selected 73 of these 704 participants with reliable confirmation of COVID-19 by PCR testing and high-quality physiological data for algorithm training to identify onset of COVID-19 using machine learning classification. The algorithm identified COVID-19 an average of 2.75 days before participants sought diagnostic testing with a sensitivity of 82% and specificity of 63%. The receiving operating characteristic (ROC) area under the curve (AUC) was 0.819 (95% CI [0.809, 0.830]). Including continuous temperature yielded an AUC 4.9% higher than without this feature. For further validation, we obtained SARS CoV-2 antibody in a subset of participants and identified 10 additional participants who self-reported COVID-19 disease with antibody confirmation. The algorithm had an overall ROC AUC of 0.819 (95% CI [0.809, 0.830]), with a sensitivity of 90% and specificity of 80% in these additional participants. Finally, we observed substantial variation in accuracy based on age and biological sex. Findings highlight the importance of including temperature assessment, using continuous physiological features for alignment, and including diverse populations in algorithm development to optimize accuracy in COVID-19 detection from wearables.

Development of an MRI-Compatible Nasal Drug Delivery Method for Probing Nicotine Addiction Dynamics.

Substance abuse is a fundamentally dynamic disease, characterized by repeated oscillation between craving, drug self-administration, reward, and satiety. To model nicotine addiction as a control system, a magnetic resonance imaging (MRI)-compatible nicotine delivery system is needed to elicit cyclical cravings. Using a concentric nebulizer, inserted into one nostril, we delivered each dose equivalent to a single cigarette puff by a syringe pump. A control mechanism permits dual modes: one delivers puffs on a fixed interval programmed by researchers; with the other, subjects press a button to self-administer each nicotine dose. We tested the viability of this delivery method for studying the brain's response to nicotine addiction in three steps. First, we established the pharmacokinetics of nicotine delivery, using a dosing scheme designed to gradually achieve saturation. Second, we lengthened the time between microdoses to elicit craving cycles, using both fixed-interval and subject-driven behavior. Finally, we demonstrate a potential application of our device by showing that a fixed-interval protocol can reliably identify neuromodulatory targets for pharmacotherapy or brain stimulation. Our MRI-compatible nasal delivery method enables the measurement of neural circuit responses to drug doses on a single-subject level, allowing the development of data-driven predictive models to quantify individual dysregulations of the reward control circuit causing addiction.

Metabolism modulates network synchrony in the aging brain.

Brain aging is associated with hypometabolism and global changes in functional connectivity. Using functional MRI (fMRI), we show that network synchrony, a collective property of brain activity, decreases with age. Applying quantitative methods from statistical physics, we provide a generative (Ising) model for these changes as a function of the average communication strength between brain regions. We find that older brains are closer to a critical point of this communication strength, in which even small changes in metabolism lead to abrupt changes in network synchrony. Finally, by experimentally modulating metabolic activity in younger adults, we show how metabolism alone-independent of other changes associated with aging-can provide a plausible candidate mechanism for marked reorganization of brain network topology.

Unique scales preserve self-similar integrate-and-fire functionality of neuronal clusters.

Brains demonstrate varying spatial scales of nested hierarchical clustering. Identifying the brain's neuronal cluster size to be presented as nodes in a network computation is critical to both neuroscience and artificial intelligence, as these define the cognitive blocks capable of building intelligent computation. Experiments support various forms and sizes of neural clustering, from handfuls of dendrites to thousands of neurons, and hint at their behavior. Here, we use computational simulations with a brain-derived fMRI network to show that not only do brain networks remain structurally self-similar across scales but also neuron-like signal integration functionality ("integrate and fire") is preserved at particular clustering scales. As such, we propose a coarse-graining of neuronal networks to ensemble-nodes, with multiple spikes making up its ensemble-spike and time re-scaling factor defining its ensemble-time step. This fractal-like spatiotemporal property, observed in both structure and function, permits strategic choice in bridging across experimental scales for computational modeling while also suggesting regulatory constraints on developmental and evolutionary "growth spurts" in brain size, as per punctuated equilibrium theories in evolutionary biology.

The Refractory Period Matters: Unifying Mechanisms of Macroscopic Brain Waves.

The relationship between complex brain oscillations and the dynamics of individual neurons is poorly understood. Here we utilize maximum caliber, a dynamical inference principle, to build a minimal yet general model of the collective (mean field) dynamics of large populations of neurons. In agreement with previous experimental observations, we describe a simple, testable mechanism, involving only a single type of neuron, by which many of these complex oscillatory patterns may emerge. Our model predicts that the refractory period of neurons, which has often been neglected, is essential for these behaviors.

Ground-truth "resting-state" signal provides data-driven estimation and correction for scanner distortion of fMRI time-series dynamics.

The fMRI community has made great strides in decoupling neuronal activity from other physiologically induced T2* changes, using sensors that provide a ground-truth with respect to cardiac, respiratory, and head movement dynamics. However, blood oxygenation level-dependent (BOLD) time-series dynamics are also confounded by scanner artifacts, in complex ways that can vary not only between scanners but even, for the same scanner, between sessions. Unfortunately, the lack of an equivalent ground truth for BOLD time-series has thus far stymied the development of reliable methods for identification and removal of scanner-induced noise, a problem that we have previously shown to severely impact detection sensitivity of resting-state brain networks. To address this problem, we first designed and built a phantom capable of providing dynamic signals equivalent to that of the resting-state brain. Using the dynamic phantom, we then compared the ground-truth time-series with its measured fMRI data. Using these, we introduce data-quality metrics: Standardized Signal-to-Noise Ratio (ST-SNR) and Dynamic Fidelity that, unlike currently used measures such as temporal SNR (tSNR), can be directly compared across scanners. Dynamic phantom data acquired from four "best-case" scenarios: high-performance scanners with MR-physicist-optimized acquisition protocols, still showed scanner instability/multiplicative noise contributions of about 6-18% of the total noise. We further measured strong non-linearity in the fMRI response for all scanners, ranging between 8-19% of total voxels. To correct scanner distortion of fMRI time-series dynamics at a single-subject level, we trained a convolutional neural network (CNN) on paired sets of measured vs. ground-truth data. The CNN learned the unique features of each session's noise, providing a customized temporal filter. Tests on dynamic phantom time-series showed a 4- to 7-fold increase in ST-SNR and about 40-70% increase in Dynamic Fidelity after denoising, with CNN denoising outperforming both the temporal bandpass filtering and denoising using Marchenko-Pastur principal component analysis. Critically, we observed that the CNN temporal denoising pushes ST-SNR to a regime where signal power is higher than that of noise (ST-SNR > 1). Denoising human-data with ground-truth-trained CNN, in turn, showed markedly increased detection sensitivity of resting-state networks. These were visible even at the level of the single-subject, as required for clinical applications of fMRI.

Inferring a network from dynamical signals at its nodes.

We give an approximate solution to the difficult inverse problem of inferring the topology of an unknown network from given time-dependent signals at the nodes. For example, we measure signals from individual neurons in the brain, and infer how they are inter-connected. We use Maximum Caliber as an inference principle. The combinatorial challenge of high-dimensional data is handled using two different approximations to the pairwise couplings. We show two proofs of principle: in a nonlinear genetic toggle switch circuit, and in a toy neural network.

Diet modulates brain network stability, a biomarker for brain aging, in young adults.

Epidemiological studies suggest that insulin resistance accelerates progression of age-based cognitive impairment, which neuroimaging has linked to brain glucose hypometabolism. As cellular inputs, ketones increase Gibbs free energy change for ATP by 27% compared to glucose. Here we test whether dietary changes are capable of modulating sustained functional communication between brain regions (network stability) by changing their predominant dietary fuel from glucose to ketones. We first established network stability as a biomarker for brain aging using two large-scale (n = 292, ages 20 to 85 y; n = 636, ages 18 to 88 y) 3 T functional MRI (fMRI) datasets. To determine whether diet can influence brain network stability, we additionally scanned 42 adults, age < 50 y, using ultrahigh-field (7 T) ultrafast (802 ms) fMRI optimized for single-participant-level detection sensitivity. One cohort was scanned under standard diet, overnight fasting, and ketogenic diet conditions. To isolate the impact of fuel type, an independent overnight fasted cohort was scanned before and after administration of a calorie-matched glucose and exogenous ketone ester (d-ß-hydroxybutyrate) bolus. Across the life span, brain network destabilization correlated with decreased brain activity and cognitive acuity. Effects emerged at 47 y, with the most rapid degeneration occurring at 60 y. Networks were destabilized by glucose and stabilized by ketones, irrespective of whether ketosis was achieved with a ketogenic diet or exogenous ketone ester. Together, our results suggest that brain network destabilization may reflect early signs of hypometabolism, associated with dementia. Dietary interventions resulting in ketone utilization increase available energy and thus may show potential in protecting the aging brain.

Making Sense of Computational Psychiatry.

In psychiatry we often speak of constructing "models." Here we try to make sense of what such a claim might mean, starting with the most fundamental question: "What is (and isn't) a model?" We then discuss, in a concrete measurable sense, what it means for a model to be useful. In so doing, we first identify the added value that a computational model can provide in the context of accuracy and power. We then present limitations of standard statistical methods and provide suggestions for how we can expand the explanatory power of our analyses by reconceptualizing statistical models as dynamical systems. Finally, we address the problem of model building-suggesting ways in which computational psychiatry can escape the potential for cognitive biases imposed by classical hypothesis-driven research, exploiting deep systems-level information contained within neuroimaging data to advance our understanding of psychiatric neuroscience.

Oxytocin attenuates trust as a subset of more general reinforcement learning, with altered reward circuit functional connectivity in males.

Oxytocin (OT) is an endogenous neuropeptide that, while originally thought to promote trust, has more recently been found to be context-dependent. Here we extend experimental paradigms previously restricted to de novo decision-to-trust, to a more realistic environment in which social relationships evolve in response to iterative feedback over twenty interactions. In a randomized, double blind, placebo-controlled within-subject/crossover experiment of human adult males, we investigated the effects of a single dose of intranasal OT (40 IU) on Bayesian expectation updating and reinforcement learning within a social context, with associated brain circuit dynamics. Subjects participated in a neuroeconomic task (Iterative Trust Game) designed to probe iterative social learning while their brains were scanned using ultra-high field (7T) fMRI. We modeled each subject's behavior using Bayesian updating of belief-states ("willingness to trust") as well as canonical measures of reinforcement learning (learning rate, inverse temperature). Behavioral trajectories were then used as regressors within fMRI activation and connectivity analyses to identify corresponding brain network functionality affected by OT. Behaviorally, OT reduced feedback learning, without bias with respect to positive versus negative reward. Neurobiologically, reduced learning under OT was associated with muted communication between three key nodes within the reward circuit: the orbitofrontal cortex, amygdala, and lateral (limbic) habenula. Our data suggest that OT, rather than inspiring feelings of generosity, instead attenuates the brain's encoding of prediction error and therefore its ability to modulate pre-existing beliefs. This effect may underlie OT's putative role in promoting what has typically been reported as 'unjustified trust' in the face of information that suggests likely betrayal, while also resolving apparent contradictions with regard to OT's context-dependent behavioral effects.

From Anxious to Reckless: A Control Systems Approach Unifies Prefrontal-Limbic Regulation Across the Spectrum of Threat Detection.

Here we provide an integrative review of basic control circuits, and introduce techniques by which their regulation can be quantitatively measured using human neuroimaging. We illustrate the utility of the control systems approach using four human neuroimaging threat detection studies (N = 226), to which we applied circuit-wide analyses in order to identify the key mechanism underlying individual variation. In so doing, we build upon the canonical prefrontal-limbic control system to integrate circuit-wide influence from the inferior frontal gyrus (IFG). These were incorporated into a computational control systems model constrained by neuroanatomy and designed to replicate our experimental data. In this model, the IFG acts as an informational set point, gating signals between the primary prefrontal-limbic negative feedback loop and its cortical information-gathering loop. Along the cortical route, if the sensory cortex provides sufficient information to make a threat assessment, the signal passes to the ventromedial prefrontal cortex (vmPFC), whose threat-detection threshold subsequently modulates amygdala outputs. However, if signal outputs from the sensory cortex do not provide sufficient information during the first pass, the signal loops back to the sensory cortex, with each cycle providing increasingly fine-grained processing of sensory data. Simulations replicate IFG (chaotic) dynamics experimentally observed at both ends at the threat-detection spectrum. As such, they identify distinct types of IFG disconnection from the circuit, with associated clinical outcomes. If IFG thresholds are too high, the IFG and sensory cortex cycle for too long; in the meantime the coarse-grained (excitatory) pathway will dominate, biasing ambiguous stimuli as false positives. On the other hand, if cortical IFG thresholds are too low, the inhibitory pathway will suppress the amygdala without cycling back to the sensory cortex for much-needed fine-grained sensory cortical data, biasing ambiguous stimuli as false negatives. Thus, the control systems model provides a consistent mechanism for IFG regulation, capable of producing results consistent with our data for the full spectrum of threat-detection: from fearful to optimal to reckless. More generally, it illustrates how quantitative characterization of circuit dynamics can be used to unify a fundamental dimension across psychiatric affective symptoms, with implications for populations that range from anxiety disorders to addiction.