Biology subjects

Lewis, L. D.

Publications and source records attributed to Lewis, L. D..

22 records · Page 2Linked to original sources

bioRxiv2023

Resting-state fMRI signals contain spectral signatures of local hemodynamic response timing

Functional magnetic resonance imaging (fMRI) has proven to be a powerful tool for noninvasively measuring human brain activity; yet, thus far, fMRI has been relatively limited in its temporal resolution. A key challenge is understanding the relationship between neural activity and the blood-oxygenation-level-dependent (BOLD) signal obtained from fMRI, generally modeled by the hemodynamic response function (HRF). The timing of the HRF varies across the brain and individuals, confounding our ability to make inferences about the timing of the underlying neural processes. Here we show that resting-state fMRI signals contain information about HRF temporal dynamics that can be leveraged to understand and characterize variations in HRF timing across both cortical and subcortical regions. We found that the frequency spectrum of resting-state fMRI signals significantly differs between voxels with fast versus slow HRFs in human visual cortex. These spectral differences extended to subcortex as well, revealing significantly faster hemodynamic timing in the lateral geniculate nucleus of the thalamus. Ultimately, our results demonstrate that the temporal properties of the HRF impact the spectral content of resting-state fMRI signals and enable voxel-wise characterization of relative hemodynamic response timing. Furthermore, our results show that caution should be used in studies of resting-state fMRI spectral properties, as differences can arise from purely vascular origins. This finding provides new insight into the temporal properties of fMRI signals across voxels, which is crucial for accurate fMRI analyses, and enhances the ability of fast fMRI to identify and track fast neural dynamics.

neuroscience↗

bioRxiv2022

Characterizing ketamine-induced dissociation using human intracranial neurophysiology: brain dynamics, network activity, and interactions with propofol

Subanesthetic doses of ketamine produce rapid and sustained anti-depressant effects in patients with treatment-resistant depression. Unfortunately, the usefulness of ketamine as a treatment is limited by its potential for abuse because of psychotropic side effects such as dissociation. Understanding the brain dynamics and the neural circuits involved in ketamines effects could lend insight into improved therapies for depression with fewer adverse effects. It is believed that ketamine acts via NMDA receptor and hyperpolarization-activated cyclic nucleotide-gated 1 (HCN1) channels to produce changes in oscillatory brain dynamics. Here we show, in humans, a detailed description of the principal oscillatory changes in cortical and subcortical structures by administration of a subanesthetic dose of ketamine. Using recordings from intracranial electrodes, we found that ketamine increased gamma oscillations within prefrontal cortical areas and the hippocampus--structures previously implicated in ketamines antidepressant effects. Furthermore, our studies provide direct evidence of a ketamine-induced 3 Hz oscillation in posteromedial cortex that has been proposed as a mechanism for its dissociative effects. By analyzing changes in neural oscillations after the addition of propofol, whose GABAergic activity antagonizes ketamines NMDA-mediated disinhibition alongside a shared HCN1 inhibitory effect, we identified brain dynamics that could be attributed to NMDA-mediated disinhibition versus HCN1 inhibition. Overall, our results imply that ketamine engages different neural circuits in distinct frequency-dependent patterns of activity to produce its antidepressant and dissociative sensory effects. These insights may help guide the development of novel brain dynamic biomarkers and therapeutics for depression.

neuroscience↗

bioRxiv2021

A temporal sequence of thalamic activity unfolds at transitions in behavioral arousal state

The moment of awakening from sleep reflects a profound transformation in neural activity and behavior. The thalamus is a key controller of arousal state, but whether its diverse nuclei exhibit coordinated or distinct activity at transitions in behavioral arousal state is not known. Using fast fMRI at ultra-high field (7 Tesla), we measured sub-second activity across thalamocortical networks and within nine thalamic nuclei to delineate these dynamics during spontaneous transitions in behavioral arousal state. We discovered a stereotyped sequence of activity across thalamic nuclei that preceded behavioral arousal after a period of inactivity, followed by widespread cortical deactivation. These thalamic dynamics were linked to whether participants remained awake or fell back asleep, with unified thalamic activation reflecting subsequent maintenance of awake behavior. These results provide an outline of the complex interactions across thalamocortical circuits that orchestrate arousal state transitions, and additionally, demonstrate that fast fMRI can resolve sub-second subcortical dynamics in the human brain.

neuroscience↗

bioRxiv2020

AMPK activation by metformin promotes survival of dormant ER+ breast cancer cells

PurposeDespite adjuvant anti-estrogen therapy for patients with estrogen receptor alpha (ER)-positive breast cancer, dormant residual disease can persist for years and eventually cause tumor recurrence. We sought to deduce mechanisms underlying the persistence of dormant cancer cells to identify therapeutic strategies. Experimental DesignMimicking the aromatase inhibitor-induced depletion of estrogen levels used to treat patients, we developed preclinical models of dormancy in ER+ breast cancer induced by estrogen withdrawal in mice. We analyzed tumor xenografts and cultured cancer cells for molecular and cellular responses to estrogen withdrawal and drug treatments. Publicly available clinical breast tumor gene expression datasets were analyzed for responses to neoadjuvant anti-estrogen therapy. ResultsDormant breast cancer cells exhibited upregulated 5 adenosine monophosphate-activated protein kinase (AMPK) levels and activity, and upregulated fatty acid oxidation. While the anti-diabetes AMPK-activating drug metformin slowed the estrogen-driven growth of cells and tumors, metformin promoted the persistence of estrogen-deprived cells and tumors through increased mitochondrial respiration driven by fatty acid oxidation. Pharmacologic or genetic inhibition of AMPK or fatty acid oxidation promoted clearance of dormant residual disease, while dietary fat increased tumor cell survival. ConclusionsAMPK has context-dependent effects in cancer, cautioning against the widespread use of an AMPK activator across disease settings. The development of therapeutics targeting fat metabolism is warranted in ER+ breast cancer. Statement of Translational RelevanceDormant cancer cells that survive adjuvant therapy can ultimately give rise to recurrent/advanced tumors that frequently develop resistance to all approved therapies. Patients with early-stage estrogen receptor alpha (ER)-positive breast cancer are typically treated with surgical resection followed by [≥]5 years of adjuvant anti-estrogen therapy that neutralizes ER and suppresses, but often does not eliminate, tumor-initiating cells. Estrogen withdrawal, which mimics aromatase inhibitor therapy, induced activation of the metabolic sensor 5 adenosine monophosphate-activated protein kinase (AMPK) and upregulated fatty acid oxidation (FAO) in preclinical models. Treatment with the anti-diabetes AMPK-activating drug metformin or high dietary fat intake promoted survival of dormant ER+ breast cancer cells, while anti-anginal drugs that inhibit FAO induced clearance of dormant tumor cells. These findings caution against using AMPK modulators with anti-estrogens in patients with ER+ breast cancer, and warrant testing of FAO inhibitors as anti-cancer agents in combination with anti-estrogens.

cancer biology↗