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      Potential Deep Brain Stimulation Targets for the Management of Refractory Hypertension

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          Hypertension is the single greatest contributor to human disease and mortality affecting over 75 million people in the United States alone. Hypertension is defined according to the American College of Cardiology as systolic blood pressure (SBP) greater than 120 mm Hg and diastolic blood pressure (DBP) above 80 mm Hg measured on two separate occasions. While there are multiple medication classes available for blood pressure control, fewer than 50% of hypertensive patients maintain appropriate control. In fact, 0.5% of patients are refractory to medical treatment which is defined as uncontrolled blood pressure despite treatment with five classes of antihypertensive agents. With new guidelines to define hypertension that will increase the incidence of hypertension world-wide, the prevalence of refractory hypertension is expected to increase. Thus, investigation into alternative methods of blood pressure control will be crucial to reduce comorbidities such as higher risk of myocardial infarction, cardiovascular accident, aneurysm formation, heart failure, coronary artery disease, end stage renal disease, arrhythmia, left ventricular hypertrophy, intracerebral hemorrhage, hypertensive enchaphelopathy, hypertensive retinopathy, glomerulosclerosis, limb loss due to arterial occlusion, and sudden death. Recently, studies demonstrated efficacious treatment of neurological diseases with deep brain stimulation (DBS) for Tourette’s, depression, intermittent explosive disorder, epilepsy, chronic pain, and headache as these diseases have defined neurophysiology with anatomical targets. Currently, clinical applications of DBS is limited to neurological conditions as such conditions have well-defined neurophysiology and anatomy. However, rapidly expanding knowledge about neuroanatomical controls of systemic conditions such as hypertension are expanding the possibilities for DBS neuromodulation. Within the central autonomic network (CAN), multiple regions play a role in homeostasis and blood pressure control that could be DBS targets. While the best defined autonomic target is the ventrolateral periaqueductal gray matter, other targets including the subcallosal neocortex, subthalamic nucleus (STN), posterior hypothalamus, rostrocaudal cingulate gyrus, orbitofrontal gyrus, and insular cortex are being further characterized as potential targets. This review aims to summarize the current knowledge regarding neurologic contribution to the pathophysiology of hypertension, delineate the complex interactions between neuroanatomic structures involved in blood pressure homeostasis, and then discuss the potential for using DBS as a treatment for refractory hypertension.

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          The functional neuroanatomy of the human orbitofrontal cortex: evidence from neuroimaging and neuropsychology.

          The human orbitofrontal cortex is an important brain region for the processing of rewards and punishments, which is a prerequisite for the complex and flexible emotional and social behaviour which contributes to the evolutionary success of humans. Yet much remains to be discovered about the functions of this key brain region, and new evidence from functional neuroimaging and clinical neuropsychology is affording new insights into the different functions of the human orbitofrontal cortex. We review the neuroanatomical and neuropsychological literature on the human orbitofrontal cortex, and propose two distinct trends of neural activity based on a meta-analysis of neuroimaging studies. One is a mediolateral distinction, whereby medial orbitofrontal cortex activity is related to monitoring the reward value of many different reinforcers, whereas lateral orbitofrontal cortex activity is related to the evaluation of punishers which may lead to a change in ongoing behaviour. The second is a posterior-anterior distinction with more complex or abstract reinforcers (such as monetary gain and loss) represented more anteriorly in the orbitofrontal cortex than simpler reinforcers such as taste or pain. Finally, we propose new neuroimaging methods for obtaining further evidence on the localisation of function in the human orbitofrontal cortex.
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            Deep brain stimulation to reward circuitry alleviates anhedonia in refractory major depression.

            Deep brain stimulation (DBS) to different sites allows interfering with dysfunctional network function implicated in major depression. Because a prominent clinical feature of depression is anhedonia--the inability to experience pleasure from previously pleasurable activities--and because there is clear evidence of dysfunctions of the reward system in depression, DBS to the nucleus accumbens might offer a new possibility to target depressive symptomatology in otherwise treatment-resistant depression. Three patients suffering from extremely resistant forms of depression, who did not respond to pharmacotherapy, psychotherapy, and electroconvulsive therapy, were implanted with bilateral DBS electrodes in the nucleus accumbens. Stimulation parameters were modified in a double-blind manner, and clinical ratings were assessed at each modification. Additionally, brain metabolism was assessed 1 week before and 1 week after stimulation onset. Clinical ratings improved in all three patients when the stimulator was on, and worsened in all three patients when the stimulator was turned off. Effects were observable immediately, and no side effects occurred in any of the patients. Using FDG-PET, significant changes in brain metabolism as a function of the stimulation in fronto-striatal networks were observed. No unwanted effects of DBS other than those directly related to the surgical procedure (eg pain at sites of implantation) were observed. Dysfunctions of the reward system--in which the nucleus accumbens is a key structure--are implicated in the neurobiology of major depression and might be responsible for impaired reward processing, as evidenced by the symptom of anhedonia. These preliminary findings suggest that DBS to the nucleus accumbens might be a hypothesis-guided approach for refractory major depression.
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              Subcallosal cingulate gyrus deep brain stimulation for treatment-resistant depression.

              A preliminary report in six patients suggested that deep brain stimulation (DBS) of the subcallosal cingulate gyrus (SCG) may provide benefit in treatment-resistant depression (TRD). We now report the results of these and an additional 14 patients with extended follow-up. Twenty patients with TRD underwent serial assessments before and after SCG DBS. We determined the percentage of patients who achieved a response (50% or greater reduction in the 17-item Hamilton Rating Scale for Depression [HRSD-17]) or remission (scores of 7 or less) after surgery. We also examined changes in brain metabolism associated with DBS, using positron emission tomography. There were both early and progressive benefits to DBS. One month after surgery, 35% of patients met criteria for response with 10% of patients in remission. Six months after surgery, 60% of patients were responders and 35% met criteria for remission, benefits that were largely maintained at 12 months. Deep brain stimulation therapy was associated with specific changes in the metabolic activity localized to cortical and limbic circuits implicated in the pathogenesis of depression. The number of serious adverse effects was small with no patient experiencing permanent deficits. This study suggests that DBS is relatively safe and provides significant improvement in patients with TRD. Subcallosal cingulate gyrus DBS likely acts by modulating brain networks whose dysfunction leads to depression. The procedure is well tolerated and benefits are sustained for at least 1 year. A careful double-blind appraisal is required before the procedure can be recommended for use on a wider scale.

                Author and article information

                Front Neurosci
                Front Neurosci
                Front. Neurosci.
                Frontiers in Neuroscience
                Frontiers Media S.A.
                25 February 2019
                : 13
                Department of Neurological Surgery, Neurological Institute, University Hospitals Cleveland Medical Center , Cleveland, OH, United States
                Author notes

                Edited by: Mikhail Lebedev, Duke University, United States

                Reviewed by: Rohit Ramchandra, The University of Auckland, New Zealand; J. Luis Lujan, Mayo Clinic College of Medicine and Science, United States

                *Correspondence: Jonathan P. Miller, jonathan.miller@

                These authors have contributed equally to this work

                This article was submitted to Neuroprosthetics, a section of the journal Frontiers in Neuroscience

                Copyright © 2019 Ems, Garg, Ostergard and Miller.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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                Figures: 0, Tables: 0, Equations: 0, References: 68, Pages: 8, Words: 0


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