6 research outputs found

    Mapping and Modulating the Stomach-Brain Neuroaxis

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    The stomach and the brain interact closely with each other. Their interactions are central to digestive functions and the “gut feeling”. The neural pathways that mediate the stomach-brain interactions include the vagus nerve and the thoracic nerve. Through these nerves, the stomach can relay neural signals to a number of brain regions that span a central gastric network. This gastric network allows the brain to monitor and regulate gastric physiology and allows the stomach to influence emotion and cognition. Impairment of this gastric network may lead to both gastric and neurological disorders, e.g., anxiety, gastroparesis, functional dyspepsia, and obesity. However, the structural constituents and functional roles of the central gastric network remain unclear. In my dissertation research, I leveraged complementary techniques to characterize the central gastric network in rats across a wide range of scales and different gastric states. I used functional magnetic resonance imaging (fMRI) to map blood-oxygen-level-dependent (BOLD) activity synchronized with gastric electrical activity and to map brain activations induced by electrical stimulation applied to the vagus nerve or its afferent terminals on the stomach. I also used neurophysiology to characterize gastric neurons in the brainstem in response to gastric electrical stimulation. My results suggest that gastric neurons in the brainstem are selective to the orientation of gastric electrical stimulation. This electrical stimulation can also evoke neural activity beyond the brainstem and drive fast blood oxygenation level dependent (BOLD) activity in the central gastric network, primarily covering the cingulate cortex, somatosensory cortex, motor cortex, and insular cortex. Stimulating the vagus nerve – the primary neural pathway between the stomach and the brain, can evoke BOLD responses across widespread brain regions partially overlapped with the brain network evoked by gastric electrical stimulation. BOLD activity within the gastric network is also coupled to intrinsic gastric activity. Specifically, gastric slow waves are synchronized with the BOLD activity in the central gastric network. The synchronization manifests itself as the phase-coupling between BOLD activity and gastric slow waves as well as the correlation between BOLD activity and power fluctuations of gastric slow waves. This synchronization is primarily supported by the vagus nerve and varies across the postprandial and fasting states. My dissertation research contributes to the foundation of mapping and characterizing the central and peripheral mechanisms of gastric interoception and sheds new light on where and how to stimulate the peripheral nerves to modulate stomach-brain interactions.PHDBiomedical EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/170007/1/jccao_1.pd

    Novel Methods for Clinical Assessment of Nociception

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    Pain is a leading cause of morbidity in neuro-orthopaedic conditions, and remains an unmet clinical need. In this study, I aimed to advance the assessment of the pain states using novel objective methods in patients with neuro-orthopaedic disorders, and to develop biomarkers that could be useful in clinical trials of new therapies. Quantitative sensory testing, the current method of assessment of small fibre (nociceptor) function, was compared to novel objective methods including skin biopsy, contact heat evoked potentials (CHEPS) and functional magnetic resonance imaging (fMRI), in human volunteer models and patients. The clinical conditions studied were congenital insensitivity to pain presenting as orthopaedic disorders, complex regional pain syndrome, osteoarthritis, small-fibre pain syndromes, nerve and spinal root injuries. Cutaneous sensitisation biomarkers and mechanisms were identified in topical capsaicin pain models in human volunteers with study of skin biopsies, contact heat and laser evoked cerebral potentials, and fMRI. The models showed features observed in patients with neurogenic hypersensitivity, including hypersensitivity associated with regenerating nerve fibres. In patient groups, congenital insensitivity of pain patients showed absent CHEPS and lack of intra-epidermal nerve fibres, a novel finding. In patient groups with pain / hypersensitivity, CHEPS distinguished neuropathic from inflammatory mechanisms, while skin biopsies showed changes in nerve fibre density, particularly of nerve fibres positive for GAP43, a marker of regenerating nerve fibres, and of TRPV1, the heat and capsaicin receptor. As these changes require p38 MAP kinase activation in neurons, an inhibitor of p38MAP kinase was studied in a neuropathic pain clinical trial, which showed efficacy and support of the biomarkers. fMRI studies showed increased activation in regions of the brain associated with pain processing in the capsaicin model and painful osteoarthritis affecting the hand. These findings advance the assessment and understanding of pain disorders, and provide biomarkers for the development of new analgesics

    Ethobehavioral strategies for the study of fear in mice

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    Ethobehavioral strategies for the study of fear in mice

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