Biology subjects

Rothman, D.

Publications and source records attributed to Rothman, D..

5 recordsLinked to original sources

bioRxiv2026

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

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 brains 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 through the pseudomalate-spartate 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 and found agreement with the model predictions, providing quantitative support for the model. Building on this agreement, we performed metabolic control analysis, which identified partial displacement of glucose metabolism through the PMAS as the dominant mechanism underlying the observed reductions in glutamate and GABA and revealed key enzymes that selectively modulate each neurotransmitter. 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.

neuroscience↗

bioRxiv2025

Imagined Speech Reconstruction with 3D Neural Metabolism and Large Language Model Integration

Cognitive linguistics posits that language underpins human thought, and this principle has influenced the study and development of large language models (LLMs). In particular, several studies have investigated the metabolic costs of sentence formation using neuroimaging techniques such as positron emission tomography, functional magnetic resonance imaging, electroencephalography (EEG), and imagined speech reconstruction (ISR). In this study, EEG data corresponding to imagined English-language speech phonemes were used for ISR, in combination with an LLM trained on an abridged autobiography. The LLM-generated text responses guided the synthesis of EEG data from relevant phonemes, which were then used to estimate corresponding metabolic activity, and the changes in simulated neurometabolic and electrical parameters were visually represented. Notably, introducing pseudorandom variance significantly (p < 0.001) enhanced the models ability to reflect biological variability. Future directions include expanding the ISR system with lightweight or locally run LLMs, incorporating training data from larger and more diverse populations, and utilizing truly random variability sources. Further optimization for broader hardware compatibility and implementation--such as neural phantoms, emotional context integration, or human-computer interaction platforms--offer promising pathways for advancement. Overall, this work establishes a foundation for the next generation of biologically inspired, modular, and adaptable ISR systems for both research and practical applications.

neuroscience↗

bioRxiv2022

Choroid plexus tissue perfusion and secretory function in rats measured by non-invasive MRI reveal significant effects of anesthesia

The choroid plexus (ChP) of the cerebral ventricles is a source of cerebrospinal fluid (CSF) production and also plays a key role in immune surveillance at the level of blood-to-CSF-barrier (BCSFB). In this study, we quantify ChP blood perfusion and BCSFB mediated water exchange from arterial blood into ventricular CSF using non-invasive continuous arterial spin labelling magnetic resonance imaging (CASL-MRI). Systemic administration of anti-diuretic hormone (vasopressin) was used to validate BCSFB mediated water exchange as a metric of choroidal CSF secretory function. To further investigate the coupling between ChP perfusion and CSF secretory function, we characterized the effects of two anesthetic regimens known to have large-scale differential effects on cerebral blood flow. For quantification of ChP blood perfusion a multi-compartment perfusion model was employed, and we discovered that partial volume correction improved measurement accuracy. Vasopressin significantly reduced both ChP blood perfusion and CSF secretory function. ChP perfusion was significantly higher with pure isoflurane anesthesia (2-2.5%) when compared to a balanced anesthesia with dexmedetomidine and low-dose isoflurane (1.0 %), however there was no significant difference in BCSFB water secretory function. In summary, here we introduce a non-invasive, robust, and spatially resolved in vivo imaging platform to quantify ChP perfusion as well as BCSFB water secretory function which can be applied to study coupling of these two key parameters in future clinical translational studies.

neuroscience↗

bioRxiv2020

Systematic Chemogenetic Library Assembly

The assembly of chemogenetic libraries composed of chemical probes provides tremendous value to biomedical research, but requires substantial effort to ensure diversity as well as quality of the contents. We are assembling a chemogenetic library by data mining and crowdsourcing institutional expertise. We are sharing our methodology, lessons learned, and disclosing our current collection of 4186 compounds with their primary annotated gene targets.

bioinformatics↗

bioRxiv2019

Peculiar cases of a \"sleeping\" brain in alert cancer patients

Cognitive and constitutional symptomatology is common in cancer patients but the causes are not well understood. To investigate whether cancers cause these symptoms by changing cerebral metabolism, we measured the cerebral rate of glucose consumption (CMRglc) in patients diagnosed with a lung lesion.\n\nMethodsThe CMRglc was quantified in 20 patients undergoing 18F-FDG PET for lesion staging. The cognitive status was assessed by neuropsychological testing.\n\nResultsParadoxically, despite being alert three of the patients had CMRglc typical of people who are in deep sleep or anesthetized. All three had cancers, two died within 2 months of scanning. Remaining patients including four with early stage cancer had CMRglc within normal range.\n\nConclusionsWe speculate that the low CMRglc reflects a switch to an alternative energy source that is mediated by cancers remotely. Identifying the underlying mechanism and the alternative energy sources may help to understand how cancers can change body metabolism.

cancer biology↗