About

Douglas L. Rothman is a Professor of Biomedical Engineering at Yale University, with additional appointments in Radiology & Biomedical Imaging. He holds a Ph.D. from Yale University. His research focuses on the development of magnetic resonance spectroscopy and magnetic resonance imaging methods to non-invasively image metabolic and neurotransmitter pathways in humans and animal models. Rothman's work contributes to advancing imaging techniques that provide insights into brain function and metabolism, supporting breakthroughs in biomedical imaging and neuroscience.

Research topics

• Endocrinology
• Biology
• Medicine
• Pathology
• Biotechnology
• Chemistry
• Neuroscience
• Internal medicine
• Biochemistry
• Radiology

Selected publications

• Q‐MRS: Quantitative Magnetic Resonance Spectral Analysis Using Deep Learning

  NMR in Biomedicine · 2026-04-08

  article

  Quantification of magnetic resonance spectroscopy (MRS) data using linear combination modeling (LCM) is challenging, partly due to the large number of spectral parameters to be estimated. Popular conventional LCM approaches often place soft constraints on signal amplitude ratios to improve fitting stability, at the cost of introducing bias. Meanwhile, existing deep learning (DL) methods tend to oversimplify the problem by omitting important spectral parameters, limiting their real-world utility. With these considerations in mind, we developed Q-MRS, a DL framework based on a Convolutional vision Transformer (CvT) that combines the strengths of a convolutional neural network (CNN) and a Transformer. The model was trained on a large dataset of simulated spectra and evaluated on high-quality 3T GABA-edited MEGA-PRESS data acquired from health adults in the medial parietal lobe. On simulated data with known ground-truth metabolite levels, the CvT outperformed two baseline models, a simple CNN and an Inception network. When applied to the in vivo data, Q-MRS produced fit quality and concentration estimates comparable with those of two established LCM methods, LCModel and Osprey, without imposing constraints on metabolite amplitude ratios. These results suggest that the proposed method is a promising approach for MRS analysis.

  PublisherDOI

• Impact of obesity on aromatic amino acids and brain glucose during acute hyperglycemia

  American Journal of Physiology-Endocrinology and Metabolism · 2026-02-05

  articleOpen access

  We related early insulin resistance-associated peripheral factors with brain glucose measured by 13 C magnetic resonance spectroscopy during acute hyperglycemia in young, healthy adults with and without obesity. Plasma amino acids including aromatic amino acids and glucagon were higher in obesity during acute hyperglycemia. There were negative correlations between aromatic amino acids and glucagon with the change in brain glucose. These findings may be related to brain oxidative stress and neurotransmitter synthesis in obesity.

  PublisherOA PDFDOI

• Computational modeling of neurotransmitter cycling predicts human brain glutamate and GABA dynamics in response to administration of exogenous ketones

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-02-14

  articleOpen accessSenior author

  Administration of ketones is used as a therapeutic option in multiple conditions, including epilepsy, mental health disorders, and brain aging. A proposed mechanism of action involves the modulation of glutamate and GABA, the brain's primary excitatory and inhibitory neurotransmitters, which jointly regulate the excitatory-inhibitory balance. However, the precise mechanism by which ketones influence these neurotransmitters remains unclear. In this study, we hypothesize that ketones modulate glutamate and GABA alterations in the pseudo-malate-aspartate shuttle (PMAS). To test this, we developed a computational model of neurotransmitter cycling centered on the PMAS, simulating the temporal dynamics and steady-state concentrations of glutamate and GABA as functions of ketone metabolism. We then compared the model outputs with MRS data from ketone administration experiments, which showed agreement with the model predictions, providing quantitative support for our proposed mechanism that ketones modulate neurotransmitters through the PMAS. Building on this consistency, we performed metabolic control analysis to identify key enzymes that modulate selectively glutamate and GABA. Overall, the model provides researchers and clinicians with a framework for hypothesis testing and treatment optimization, while also serving as a foundation for future model expansions.

  PublisherOA PDFDOI

• Ketosis Elevates Antioxidants and Enhances Neural Function Through Improved Bioenergetics: A 1H MR Spectroscopy Study

  Proceedings on CD-ROM - International Society for Magnetic Resonance in Medicine. Scientific Meeting and Exhibition/Proceedings of the International Society for Magnetic Resonance in Medicine, Scientific Meeting and Exhibition · 2025-09-16

  article

  Motivation: Ketosis offers benefits to brain health across a range of diseases and disorders. Goal(s): Ketosis alters levels of neuroactive amino acids and enhances neural function. Its influence on other metabolites, and how ketosis improves neural function, remain unclear. Approach: In a within-subjects design (N=63), we measured the neurochemical effects of acute ketosis on the human brain using 7T 1H MRS and the impact on neural function using rsfMRI. Results: Ketones, but not glucose, elevated antioxidants and energy markers while altering E/I neurotransmitter ratios. Higher fasting Glc levels were associated with increased neuroinflammation markers. Increased bioenergetics correlated with greater improvements in neural function. Impact: The combination of metabolic and functional neuroimaging data in our study provides a comprehensive view of how ketosis affects brain chemistry and functional network dynamics, offering insights for developing novel treatment strategies for a variety of psychiatric and neurodegenerative disorders.

  PublisherDOI

• A Bird's‐Eye View of Glycolytic Upregulation in Activated Brain: The Major Fate of Lactate Is Release From Activated Tissue, Not Shuttling to Nearby Neurons

  Journal of Neurochemistry · 2025-06-01 · 13 citations

  reviewOpen accessCorresponding

  ABSTRACT Glucose is the major, obligatory fuel for the brain, and nearly all glucose is oxidized in the awake, resting state. However, during activation, much of the glucose is not oxidized even though adequate oxygen is available, ATP demand is increased, and glycolysis generates less ATP than oxidation. The fate of the lactate produced by glycolysis is a highly debated topic, in part because its origin and fate in the living brain are difficult to measure. One idea has been that astrocytes generate lactate and shuttle it to neurons as a major fuel, but critical elements of the shuttle model are not validated, and there is no compelling evidence to support shuttling coupled with oxidation in vivo. Metabolic brain imaging reveals rapid loss of labeled metabolites of glucose from activated tissue that is mediated by lactate transporters and gap junctional trafficking among astrocytes. Lactate is highly labeled by [ 13 C‐ and 14 C]glucose, it is diffusible, and it is quickly released to blood and the perivascular‐lymphatic drainage system. During intense sensory stimulation, astrocytic glycogen is consumed at half the rate of glucose by all brain cells; it is a major fuel. The oxygen‐carbohydrate metabolic mismatch increases when glycogen is included in the calculation, revealing that glycogen is not oxidized. Although the energetics of brain activation is complex, metabolic modeling with comparison to a wide range of experimental data relating metabolism to neurotransmission strongly supports two concepts: (i) glycogenolysis in astrocytes spares blood‐borne glucose for activated neurons, and (ii) the increase in cerebral blood flow in excess of oxygen consumption removes protons produced by glycolytic metabolism to maintain tissue pH, pO 2 , and pCO 2 homeostasis. Several studies have identified processes and situations that involve neuronal aerobic glycolysis, and a better understanding of the roles of glycolysis in neuron‐astrocyte interactions and functional metabolism in the normal and diseased brain is required. image

  PublisherOA PDFDOI

• The pathogenicity of the glutamate metabolic cycle in schizophrenia determined by hippocampal spectroscopic profiling

  Research Square · 2025-04-30

  preprintOpen accessSenior author
  PublisherOA PDFDOI

• Functional MRI with UTE to investigate stimulus-driven CSF flow

  Proceedings on CD-ROM - International Society for Magnetic Resonance in Medicine. Scientific Meeting and Exhibition/Proceedings of the International Society for Magnetic Resonance in Medicine, Scientific Meeting and Exhibition · 2025-09-16

  article

  Motivation: Dynamics of CSF-flow has been shown to relate to whole-cortex BOLD signals during intense stimulation, but the relationship with blood-flow is not known. Goal(s): Determine the correspondence of flow-mediated UTE-fMRI signals in whole-cortex and CSF. Approach: UTE-fMRI and BOLD-EPI were performed at 7T on 12 humans. Correlations between time-courses were calculated in atlas-based regions. Results: We detected anticorrelated task-evoked UTE signal changes in whole-cortex and CSF. On the other hand, BOLD signals in whole-cortex correlated with those in CSF, with no clear task-evoked signal changes seen in these regions during stimulation. Impact: Since UTE-fMRI signals are mediated by flow dynamics, they enable determining the relationship between blood-flow and CSF-flow more directly than BOLD. This opportunity is critical for understanding how the brain ensures global homeostasis during the demands of regional activity.

  PublisherDOI

• Brain Energy Constraints and Vulnerability

  2025-01-01

  book-chapterOpen access

  As a highly active organ, the awake brain operates at near capacity. It has limited ability to increase delivery of blood, and hence oxygen and glucose, due to restrictions dictated by capillary density and the space within the skull. In addition, the chemoelectric operating environment (homeostasis) of the brain restricts the amount of glucose and oxygen that can be supplied and the level of generated protons (H+) and CO2 that can be tolerated without impacting brain functions. This chapter describes the neurochemical basis of how the brain operates carefully within these homeostatic limits: why they exist and what can happen when these limits are infringed.

  PublisherOA PDFDOI

• Modeling Neurotransmitter Cycling: Predicting Glu and GABA Dynamics in Response to Ketone Body Administration

  Proceedings on CD-ROM - International Society for Magnetic Resonance in Medicine. Scientific Meeting and Exhibition/Proceedings of the International Society for Magnetic Resonance in Medicine, Scientific Meeting and Exhibition · 2025-09-16

  articleSenior author

  Motivation: Therapeutic interventions involving ketone bodies are gaining traction in various clinical and experimental settings. One hypothesized mechanism for their efficacy is modulation of glutamate and GABA, the brain's primary excitatory and inhibitory neurotransmitters. However, how ketones influence these neurotransmitters remains unclear, limiting broader therapeutic application. Goal(s): Here, we aimed to explore the mechanism of ketone modulation on neurotransmitter activity and to predict these effects. Approach: We developed a computational model to simulate the temporal dynamics and steady-state concentrations of glutamate and GABA as a function of ketone metabolism across varying conditions. Results: We validated our model using MRS data from ketone administration experiments. Impact: We present the first computational model linking brain substrates to neurotransmitter cycling, providing clinicians and researchers with a tool to test hypotheses and optimize treatments. The model is available to the community via Neuroblox, a brain function modeling platform.

  PublisherDOI

• Brain and body energy metabolism and potential for treatment of psychiatric disorders

  Nature Mental Health · 2025-06-25 · 15 citations

  articleOpen access
  PublisherOA PDFDOI

Recent grants

• Validation of GABA MRS as a Biomarker of Inhibition

  NIH · $1.7M · 2016–2021

• 13C MRS Studies of Brain Mitochondrial Metabolism in Insulin Resistance

  NIH · $2.1M · 2014–2021

• NIH Grant R01NS051854

  NIH · $2.6M · 2010

• Glucoregulatory Hormone Interactions in Diabetes

  NIH · $9.3M · 1977–2025

• NIH Grant R01NS037527

  NIH · $3.5M · 2009

Frequent coauthors

• Robert G. Shulman

  Yale University

  290 shared

• Kevin L. Behar

  Yale University

  267 shared

• Fahmeed Hyder

  Yale University

  263 shared

• Robin A. de Graaf

  184 shared

• Graeme F. Mason

  Yale University

  183 shared

• Gerald I. Shulman

  Howard Hughes Medical Institute

  139 shared

• Ognen A. C. Petroff

  Yale University

  85 shared

• Kitt Falk Petersen

  Yale University

  73 shared

Education

• Ph.D., molecular biochemistry and biophysics

  Yale University

  1987