Functional Ultrasound Imaging of Spinal Cord Hemodynamic Responses to Epidural Electrical Stimulation: A Feasibility Study

This study presents the first implementation of functional ultrasound (fUS) imaging of the spinal cord to monitor local hemodynamic response to epidural electrical spinal cord stimulation (SCS) on two small and large animal models. SCS has been successfully applied to control chronic refractory pain and recently was evolved to alleviate motor impairment in Parkinson's disease and after spinal cord injury. At present, however, the mechanisms underlying SCS remain unclear, and current methods for monitoring SCS are limited in their capacity to provide the required sensitivity and spatiotemporal resolutions to evaluate functional changes in response to SCS. fUS is an emerging technology that has recently shown promising results in monitoring a variety of neural activities associated with the brain. Here we demonstrated the feasibility of performing fUS on two animal models during SCS. We showed in vivo spinal cord hemodynamic responses measured by fUS evoked by different SCS parameters. We also demonstrated that fUS has a higher sensitivity in monitoring spinal cord response than electromyography. The high spatial and temporal resolutions of fUS were demonstrated by localized measurements of hemodynamic responses at different spinal cord segments, and by reliable tracking of spinal cord responses to patterned electrical stimulations, respectively. Finally, we proposed optimized fUS imaging and post-processing methods for spinal cord. These results support feasibility of fUS imaging of the spinal cord and could pave the way for future systematic studies to investigate spinal cord functional organization and the mechanisms of spinal cord neuromodulation in vivo

신경병성 통증에 관한 뇌내 대사성 글루타메이트 수용체 5 관련 기전 연구

학위논문 (박사)-- 서울대학교 대학원 : 자연과학대학 뇌인지과학과, 2018. 2. 김상정.Neuropathic pain is a pathological pain caused by damage to the peripheral or central nervous system. As symptoms of neuropathic pain are often intractable, patients suffer from long-lasting severe pain and easily develop abnormal mental problems such as depression and anxiety. However, underlying mechanisms are not fully understood. I investigated the brain-level mechanisms of neuropathic pain in an animal model of spinal nerve ligation, using brain imaging techniques of positron emission tomography (PET), electrophysiological recording, pharmacological and genetic manipulation and animal behavior analysis. Metabotropic glutamate receptor 5 (mGluR5) was a particular target, as this molecule plays a pivotal role in the plastic change of the neurons. This thesis consists of three research parts and a review part. In chapter 1, it is shown that the mGluR5 level in the medial prefrontal cortex (mPFC) is increased in neuropathic pain state, and this upregulation is responsible for the amplified aversive perception and negative moods. Chapter 2 deals with brain patterns of the mGluR5 levels which encode the degree of neuropathic pain behavior. A method I developed for the objective evaluation of neuropathic pain using the patterns in the PET image is introduced. In chapter 3, mGluR5 activity in the periaqueductal gray (PAG) region is focused. I found that the mGluR5 within the PAG is persistently active in normal state, and a conditional inactivation of it drives chronic pain. Chapter 4 discusses molecular mechanisms underlying the sustained activation of mGluR5. As a whole, this thesis illustrates how the pain becomes chronic and why it is not treated well. The alteration of the brain in neuropathic pain state and underlying mechanisms are revealed, focusing on the mGluR5. Based on the mechanisms, this thesis identifies mGluR5 in the brain regions as therapeutic targets for the treatment of chronic neuropathic pain. In addition, a method for decoding the status of the individual neuropathic pain subject is demonstrated. This method evaluates the pain status objectively using the information of mGluR5 patterns in the brain, and thus is applicable for a diagnostic purpose in the clinic. This thesis provides new insight into the brain signature of neuropathic pain, and offers a novel perspective on the status of mGluR5 in physiological and pathological conditions.1. Chapter 1. Upregulation of prefrontal metabotropic glutamate receptor 5 mediates neuropathic pain and negative mood symptoms after spinal nerve injury in rats 1 1.1 Summary 1 1.2 Introduction 2 1.3 Results 4 1.4 Discussion 22 2. Chapter 2. Distinct corticolimbic patterns of metabotropic glutamate receptor 5 encode the degree of neuropathic pain 29 2.1 Summary 29 2.2 Introduction 30 2.3 Results 33 2.4 Discussion 54 3. Chapter 3. Dysregulation of metabotropic glutamate receptor 5 in the periaqueductal gray perpetuates neuropathic pain 67 3.1 Summary 67 3.2 Introduction 68 3.3 Results 70 3.4 Discussion 91 4. Chapter 4. Sustained activity of metabotropic glutamate receptor: Homer, arrestin, and beyond 93 4.1 Summary 93 4.2 Introduction 94 4.3 Main 96 4.4 Conclusion 112 5. Materials and Methods 113 6. References 129 7. Abstract in Korean (국문 초록) 145Docto

The ACC is a critical hub for neuropathic pain- induced depression

Besides chronic stress, chronic pain is one of the prevalent determinants for depression. Indeed, around 50% of chronic pain patients develop mood disorders. Alterations in brain regions implicated in pain processing may also be involved in affective processing, thus potentially be responsible of mood disorders. However, the underlying mechanisms of this comorbidity are not yet elucidated. Here, we studied the role of the anterior cingulate cortex (ACC) in the somatosensory, aversive and anxiodepressive consequences of neuropathic pain. We showed that a permanent lesion or temporal inhibition of ACC pyramidal neurons blocked the development or suppressed the expression of an anxiodepressive phenotype in neuropathic mice. In addition, anxiodepressive-like behavior coincided with ACC hyperactivity. In conclusion we show that the ACC is a critical hub for neuropathic pain-induced depression