Functional neuroimaging of the human spinal cord –
chronic back pain treatment
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 laminectomy for implantation of ESCS. Ultrasound probe is placed on the spinal cord dura in a transverse orientation. (B) Schematic representation of spinal cord fUSI through a laminar window - green area illustrates approximately the field of view. (C) Statistical parameter map (SPM) shows localized areas with significantly higher blood flow during stimulation. (D) Event-related average (ERA) waveform of a selected ROI.
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) 3D mice brain model with fUSI probe positioning (blue bar) and regions of interest (ROIs) superimposed onto the vascular map of the sagittal mouse brain. (B) The septo-hippocampal network (C) Experimental protocol for assessing the effects of MK-801 and MSN DBS in CBV and functional connectivity in the mouse brain. (D) Event related average (ERA) temporal course curves of the CBV changes relative to baseline (2 min average CBV before injection) in the Hippocampus after saline [blue] and 1.0mg/kg MK-801 [red ]) injection. (E) Event related average (ERA) temporal course curves of the CBV changes relative to pre-stimulation (2 min average CBV before injection) in the Hippocampus for no-stimulation [nS, black curve], 5 min gamma frequency stimulation [gS, blue curve] and 5 min theta frequency stimulation [tS, red curve] in MK-801 animals.
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.
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)