Current work

Functional neuroimaging of the human spinal cord

Functional neuroimaging has greatly expanded knowledge about brain function with significant scientific and clinical implications. In contrast, functional spinal cord neuroimaging is far less developed, and there are certainly no practical methods to guide clinical care. Despite the important role of the human spinal cord in sensory, motor and automatic functions, it has been underrepresented in neuroimaging research. This limited amount of research may partly stem from the technical challenges that arise when imaging the human spinal cord. Our team performed the first in-human fUSI of the spinal cord – a major milestone in translating fUSI in human studies. By imaging the spinal cord in patients, who undergo epidural spinal cord stimulation (ESCS) surgery for chronic back pain treatment, we demonstrated that fUSI is capable of: i) detecting and characterizing hemodynamic changes induced by ESCS and ii) predicting the spinal cord state within a single trial of stimulation. Our ultimate goal is to elucidate the mechanism of action (MOA) of SCS for chronic back pain treatment and to develop translational clinical monitoring systems that will assist in evaluating the effectiveness of SCS and other therapeutic neuromodulation – a technology that currently does not exist.

(A) Patients undergo a T10 partial laminectomy for standard-of-care implantation of an epidural electrical spinal cord stimulator at the T8–T9 level under general anesthesia. (B) A 15-MHz functional ultrasound probe is secured to a retractor-mounted surgical arm and positioned through the laminectomy window to image the spinal cord. (C) Electrical stimulation is delivered in 10 ON–OFF cycles, each consisting of a 30-s stimulation (ON) period followed by a 30-s rest (OFF) period. (D) Representative power Doppler vascular map of the spinal cord.

Brain and spinal-cord mechanisms of urination

Micturition is a vital physiological function essential for homeostasis and quality of life. Disorders such as incontinence, retention, and overactive bladder affect hundreds of millions worldwide, with high prevalence in aging populations and patients with spinal cord or neurological disorders. Despite their impact, the neural mechanisms underlying normal and pathological micturition—especially at the spinal level—remain poorly understood. Our team has pioneered the use of functional ultrasound imaging (fUSI) to study the neural mechanisms of micturition across both animal models and humans. In preclinical studies, we mapped the spatiotemporal patterns of brain and spinal cord activity associated with different phases of the micturition cycle, revealing previously inaccessible mesoscopic dynamics. Building on this foundation, we conducted the first in-human spinal fUSI experiments during micturition, providing unprecedented insight into the hemodynamic correlates of bladder control at the level of the brain and spinal cord. This line of work lays the foundation for a new mechanistic understanding of the neural control of micturition. Our long-term vision is to leverage these insights to develop novel neuromodulation strategies for treating urinary disorders, such as incontinence and retention, and to create translational neuroimaging tools that can monitor spinal cord function during lower urinary tract interventions - capabilities that currently do not exist.

A graphical representation of the human urodynamic model developed to study spinal cord activity during micturition. The spinal cord fUSI acquisition was performed simultaneously during bladder filling and emptying through a laminar window using a miniaturized 15.6 MHz, 128-channel, linear ultrasound transducer array

Mechanism of action of deep brain stimulation (DBS) in treatment-resistant schizophrenia

Mounting evidence suggests that DBS may be an effective treatment strategy for cognitive dysfunction in schizophrenia. However, the mechanism by which DBS improves cognitive functions such as memory has yet to be elucidated. Determining how DBS modulates abnormal cerebral blood volume (CBV) will improve our treatment paradigms. To do so, we record hemodynamic activity using fUSI across the septo-hippocampal network including areas such as hippocampus and thalamus, following MK-801 administration, and evaluate the effects of DBS on CBV and functional connectivity. MK-801 is a well-established model of NMDA receptor hypofunction in schizophrenia. So far, we have evaluated the effects of drug injection and DBS in rats under anesthesia. We found that MK-801 causes a strong reduction of blood flow changes in key areas of the septo-hippocampal network, such as the hippocampus and the medial Prefrontal cortex. However, low frequency DBS in the medial septal nucleus reverses the blood flow reduction. Hence, it seems that DBS MSN alters the septo-hippocampal circuit by modulating the vascular activity, a finding that open new avenues on improving the effectiveness of DBS neuromodulation for schizophrenia.

(A) Schematic illustration of connectivity between the MSN and ROIs. Arrowheads represent axonal projections to and/or from MSN. (B) Diagram of the protocol for the 60 min of continuous fUSI acquisition. After 5 min, saline or 1.0 mg/kg MK-801 was injected. After a total of 45 min of either theta, gamma, or no stimulation was applied for 5 min followed by 10 more minutes of recording (C) Experimental setup showing the deep brain stimulation (DBS) electrodes implanted in the left hemisphere, while imaging was performed in the sagittal plane of the right hemisphere (D) Power Doppler–based vascular maps in a sagittal plane with regions of interest (ROIs) - hippocampus (HPF), medial prefrontal cortex (mPFC), hypothalamus (HYT), thalamus (TLM), pallidum (PDM), and striatum (STM) - superimposed. (E) DBS effects on pD signal during and post stimulation onset in MK-801 treated mice. [red: theta stim, blue: gamma stim and black: no-stim].

Computational and neural mechanisms of motor inhibition: A study with Parkinson’s disease patients

How people select, cancel and switch actions in response to environmental demands is a fundamental neurobiological question that is of high impact for understanding how the human brain functions. Many neurological and psychiatric disorders, such as Parkinson’s disease (PD) and obsessive compulsive disorder (OCD), point to impaired brain circuitry responsible for these motor inhibition functions. In collaboration with the department of neurosurgery at UT Southwestern Medical Center, we develop neurocomputational models to better understand the mechanisms of motor inhibition. The models are evaluated by concurrently record and stimulate from diﬀerent sectors of the subthalamic nucleus (STN) and cortex in PD patients that undergo therapeutic electrode implantation for deep brain stimulation (DBS). The resulting technology has the potential to enhance neuromodulatory interventions, identify new therapeutic targets from movement disorders and devise novel dynamic therapies, such as closed-loop DBS

(A) Three putatively different hyperdirect pathways for three kinds of STN-mediated pause functions associated with selecting, switching and stopping actions. (B) The architecture of the neurocomputational framework designed to model the mechanisms and computations of motor inhibition during selecting, switching and stopping actions.

Previous work

Motor decisions under uncertainty

Decision-making is a fundamental component of behavior. It has enormous significance to society and medicine. Financial and political decisions are paramount to society; many societal problems have a basis in poor decisions. Decision-making also has important clinical applications. The base cause of drug addiction is the pharmacological bypassing of the brain's reward circuitry. Using experimental and computational techniques, we aim to understand the neurobiology of motor decisions

Functional ultrasound imaging in non-human primates (NHPs)

Psychophysical and neurophysiological studies in non-human primate (NHPs) to understand the mechanisms of motor decisions

High-density neural interfaces require the ability to observe large-scale patterns of neural activity with high spatiotemporal resolution. Ideally, to facilitate their application in research and potential clinical studies, such interfaces should be non-invasive or minimally invasive. Current methods to monitor neural activity fall short of these criteria. Recently, functional ultrasound (fUS) was introduced as an revolutionary technology to monitor brain activity with an order of magnitude improved spatial and temporal resolution compared to functional MRI (100 µm and < 10 ms) using transducers that can be mounted on freely moving animals. In collaboration with the Andersen Lab and Shapiro Lab at Caltech, and the Tanter Lab at the Institute Langevin, ESPCI in Paris-France, we are working on developing ultrasonic brain-machine interfaces (BMIs)

2D and 3D vascular maps around the posterior parietal

cortex (PPC) of two non-human primates (NHPs)