Comprehensive Physiology Wiley Online Library

Using Deep Brain Stimulation to Unravel the Mysteries of Cardiorespiratory Control

Full Article on Wiley Online Library



Abstract

This article charts the history of deep brain stimulation (DBS) as applied to alleviate a number of neurological disorders, while in parallel mapping the electrophysiological circuits involved in generating and integrating neural signals driving the cardiorespiratory system during exercise. With the advent of improved neuroimaging techniques, neurosurgeons can place small electrodes into deep brain structures with a high degree accuracy to treat a number of neurological disorders, such as movement impairment associated with Parkinson's disease and neuropathic pain. As well as stimulating discrete nuclei and monitoring autonomic outflow, local field potentials can also assess how the neurocircuitry responds to exercise. This technique has provided an opportunity to validate in humans putative circuits previously identified in animal models. The central autonomic network consists of multiple sites from the spinal cord to the cortex involved in autonomic control. Important areas exist at multiple evolutionary levels, which include the anterior cingulate cortex (telencephalon), hypothalamus (diencephalon), periaqueductal grey (midbrain), parabrachial nucleus and nucleus of the tractus solitaries (brainstem), and the intermediolateral column of the spinal cord. These areas receive afferent input from all over the body and provide a site for integration, resulting in a coordinated efferent autonomic (sympathetic and parasympathetic) response. In particular, emerging evidence from DBS studies have identified the basal ganglia as a major sub‐cortical cognitive integrator of both higher center and peripheral afferent feedback. These circuits in the basal ganglia appear to be central in coupling movement to the cardiorespiratory motor program. © 2020 American Physiological Society. Compr Physiol 10:1085‐1104, 2020.

Figure 1. Figure 1. Brain areas are known to be involved in autonomic control. Shaded areas are approximate regions. Note that the insula is in the mesial temporal lobe lateral to the basal ganglia which is not shown and the area, therefore, appears out of the picture. Midline structures are surrounded by a broken line.
Figure 2. Figure 2. (A,B) To perform deep brain stimulation, the target is accurately planned on an MRI scan and custom targeting software (such as Renishaw Neuroinspire® depicted here). (C) Surgery is performed to insert the electrode using a stereotactic frame. Intraoperative testing may be used in awake patients. (D) The brain electrodes are connected via a subcutaneous extension wire to an implantable pulse generator placed in a subcutaneous pocket. Courtesy of Dr. Binith Cheeran, Abbott Neuromodulation.
Figure 3. Figure 3. Looking at the mechanisms of the effect of DBS on autonomic parameters. A microneurographer (inset) can record from the autonomic fibers within the peroneal muscle. Comparing DBS On and Off shows that stimulation of the dorsal subthalamic nucleus increases muscle sympathetic nerve activity and is associated with a small increase in BP. Adapted, with permission, from Sverrisdottir YB, et al., 2014 236.
Figure 4. Figure 4. Study of DBS patients allows a number of investigations to elucidate brain function in the context of cardiorespiratory function. This particular study used subjects with indwelling DBS electrodes in the pedunculopontine nucleus (PPN) for the treatment of Parkinson's disease. (A) Position of electrode contacts studied in a group of patients undergoing PPN stimulation. (B) Local field potentials (LFPs) tell us how the PPN is changing electrically. Here, the patient undergoes head‐up tilt testing (HUTT) (blue vertical line) and there is a resultant reduction in alpha (8–12 Hz) activity in the PPN. (C) Physiological testing demonstrates that PPN stimulation reduces the postural drop in BP on HUTT. “On” refers to stimulation “On” rather than levodopa effects. (D) DTI analysis demonstrates connections between PPN and other brain areas. Adapted, with permission, from Hyam JARH, et al., 2019 131.
Figure 5. Figure 5. BP changes resulting from intraoperative stimulation of two different areas of the PAG in a single subject. (A) BP reduction resulted from ventral stimulation in the first position studied. (B) As the electrode was advanced, stimulation posteriorly in the dorsal PAG resulted in increased BP. (C) An axial MRI showing an electrode contact in the left PAG (arrow). (D) A schematic sagittal section in the midline to show the electrode position relative to surrounding structures.


Figure 1. Brain areas are known to be involved in autonomic control. Shaded areas are approximate regions. Note that the insula is in the mesial temporal lobe lateral to the basal ganglia which is not shown and the area, therefore, appears out of the picture. Midline structures are surrounded by a broken line.


Figure 2. (A,B) To perform deep brain stimulation, the target is accurately planned on an MRI scan and custom targeting software (such as Renishaw Neuroinspire® depicted here). (C) Surgery is performed to insert the electrode using a stereotactic frame. Intraoperative testing may be used in awake patients. (D) The brain electrodes are connected via a subcutaneous extension wire to an implantable pulse generator placed in a subcutaneous pocket. Courtesy of Dr. Binith Cheeran, Abbott Neuromodulation.


Figure 3. Looking at the mechanisms of the effect of DBS on autonomic parameters. A microneurographer (inset) can record from the autonomic fibers within the peroneal muscle. Comparing DBS On and Off shows that stimulation of the dorsal subthalamic nucleus increases muscle sympathetic nerve activity and is associated with a small increase in BP. Adapted, with permission, from Sverrisdottir YB, et al., 2014 236.


Figure 4. Study of DBS patients allows a number of investigations to elucidate brain function in the context of cardiorespiratory function. This particular study used subjects with indwelling DBS electrodes in the pedunculopontine nucleus (PPN) for the treatment of Parkinson's disease. (A) Position of electrode contacts studied in a group of patients undergoing PPN stimulation. (B) Local field potentials (LFPs) tell us how the PPN is changing electrically. Here, the patient undergoes head‐up tilt testing (HUTT) (blue vertical line) and there is a resultant reduction in alpha (8–12 Hz) activity in the PPN. (C) Physiological testing demonstrates that PPN stimulation reduces the postural drop in BP on HUTT. “On” refers to stimulation “On” rather than levodopa effects. (D) DTI analysis demonstrates connections between PPN and other brain areas. Adapted, with permission, from Hyam JARH, et al., 2019 131.


Figure 5. BP changes resulting from intraoperative stimulation of two different areas of the PAG in a single subject. (A) BP reduction resulted from ventral stimulation in the first position studied. (B) As the electrode was advanced, stimulation posteriorly in the dorsal PAG resulted in increased BP. (C) An axial MRI showing an electrode contact in the left PAG (arrow). (D) A schematic sagittal section in the midline to show the electrode position relative to surrounding structures.
References
 1.Abbas MM, Xu Z, Tan LCS. Epidemiology of Parkinson's disease – east versus west. Mov Disord Clin Pract 5: 14‐28, 2018.
 2.Akram H, Miller S, Lagrata S, Hariz M, Ashburner J, Behrens T, Matharu M, Zrinzo L. Optimal deep brain stimulation site and target connectivity for chronic cluster headache. Neurology 89: 2083‐2091, 2017.
 3.Alam M, Smirk FH. Observations in man upon blood pressure raising reflex arising from the voluntary muscles. J Physiol 89: 372‐383, 1937.
 4.Allen GV, Cechetto DF. Functional and anatomical organization of cardiovascular pressor and depressor sites in the lateral hypothalamic area: I. Descending projections. J Comp Neurol 315: 313‐332, 1992.
 5.Allen GV, Cechetto DF. Functional and anatomical organization of cardiovascular pressor and depressor sites in the lateral hypothalamic area. II. Ascending projections. J Comp Neurol 330: 421‐438, 1993.
 6.An X, Bandler R, Ongur D, Price JL. Prefrontal cortical projections to longitudinal columns in the midbrain periaqueductal gray in macaque monkeys. J Comp Neurol 401: 455‐479, 1998.
 7.Antman EM, Loscalzo J. Precision medicine in cardiology. Nat Rev Cardiol 13: 591‐602, 2016.
 8.Asmussen E, Johansen SH, Jorgensen M, Nielsen M. On the nervous factors controlling respiration and circulation during exercise. Experiments with curarization. Acta Physiol Scand 63: 343‐350, 1965.
 9.Asmussen E, Nielsen M. Experiments on nervous factors controlling respiration and circulation during exercise employing blocking of the blood flow. Acta Physiol Scand 60: 103‐111, 1964.
 10.Aziz TZ, Peggs D, Sambrook MA, Crossman AR. Lesion of the subthalamic nucleus for the alleviation of 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐induced parkinsonism in the primate. Mov Disord 6: 288‐292, 1991.
 11.Baig F, Kelly MJ, Lawton MA, Ruffmann C, Rolinski M, Klein JC, Barber T, Lo C, Ben‐Shlomo Y, Okai D, Hu MT. Impulse control disorders in Parkinson disease and RBD: A longitudinal study of severity. Neurology 93: e675‐e687, 2019.
 12.Baille G, De Jesus AM, Perez T, Devos D, Dujardin K, Charley CM, Defebvre L, Moreau C. Ventilatory dysfunction in Parkinson's disease. J Parkinsons Dis 6: 463‐471, 2016.
 13.Bain P, Aziz T, Liu X, Nandi D. Deep Brain Stimulation. Oxford: Oxford University Press, 2009.
 14.Bandler R, Keay KA, Floyd N, Price J. Central circuits mediating patterned autonomic activity during active vs. passive emotional coping. Brain Res Bull 53: 95‐104, 2000.
 15.Bartsch T, Levy MJ, Knight YE, Goadsby PJ. Differential modulation of nociceptive dural input to [hypocretin] orexin A and B receptor activation in the posterior hypothalamic area. Pain 109: 367‐378, 2004.
 16.Basnayake S, Hyam JA, Pereira EA, Schweder PM, Brittain JS, Aziz TZ, Green AL, Paterson DJ. Identifying cardiovascular neurocircuitry involved in the exercise pressor reflex in humans using functional neurosurgery. J Appl Physiol 110: 881‐891, 2011.
 17.Basnayake SD, Green AL, Paterson DJ. Mapping the central neurocircuitry that integrates the cardiovascular response to exercise in humans. Exp Physiol 97: 29‐38, 2012.
 18.Bechbache RR, Duffin J. The entrainment of breathing frequency by exercise rhythm. J Physiol 272: 553‐561, 1977.
 19.Behrens TE, Woolrich MW, Walton ME, Rushworth MF. Learning the value of information in an uncertain world. Nat Neurosci 10: 1214‐1221, 2007.
 20.Benabid AL, Pollak P, Gervason C, Hoffmann D, Gao DM, Hommel M, Perret JE, de Rougemont J. Long‐term suppression of tremor by chronic stimulation of the ventral intermediate thalamic nucleus. Lancet 337: 403‐406, 1991.
 21.Benabid AL, Pollak P, Hommel M, Gaio JM, de Rougemont J, Perret J. Traitement du tremblement parkinsonien par stimulation chronique du noyau ventral intermedaire du thalamus. Rev Neurol (Paris) 145: 320‐323, 1989.
 22.Benabid AL, Pollak P, Louveau A, Henry S, de Rougemont J. Combined (thalamotomy and stimulation) stereotactic surgery of the VIM thalamic nucleus for bilateral Parkinson disease. Appl Neurophysiol 50: 344‐346, 1987.
 23.Benarroch E. Central Autonomic Network: Functional Organization and Clinical Correlations. New York: Wiley‐Blackwell, 1998.
 24.Benarroch EE. New findings on the neuropathology of multiple system atrophy. Auton Neurosci‐Basic Clin 96: 59‐62, 2002.
 25.Benarroch EE, Schmeichel AM. Depletion of corticotrophin‐releasing factor neurons in the pontine micturition area in multiple system atrophy. Ann Neurol 50: 640‐645, 2001.
 26.Benarroch EE, Schmeichel AM, Dugger BN, Sandroni P, Parisi JE, Low PA. Dopamine cell loss in the periaqueductal gray in multiple system atrophy and Lewy body dementia. Neurology 73: 106‐112, 2009.
 27.Benarroch EE, Schmeichel AM, Low PA, Parisi JE. Depletion of ventromedullary NK‐1 receptor‐immunoreactive neurons in multiple system atrophy. Brain 126: 2183‐2190, 2003.
 28.Bergman H, Wichmann T, DeLong MR. Reversal of experimental parkinsonism by lesions of the subthalamic nucleus. Science 249: 1436‐1438, 1990.
 29.Bittar RG, Burn SC, Bain PG, Owen SL, Joint C, Shlugman D, Aziz TZ. Deep brain stimulation for movement disorders and pain. J Clin Neurosci 12: 457‐463, 2005.
 30.Bittencourt AS, Carobrez AP, Zamprogno LP, Tufik S, Schenberg LC. Organization of single components of defensive behaviors within distinct columns of periaqueductal gray matter of the rat: Role of N‐methyl‐D‐aspartic acid glutamate receptors. Neuroscience 125: 71‐89, 2004.
 31.Blaho A, Sutovsky S, Valkovic P, Siarnik P, Sykora M, Turcani P. Decreased baroreflex sensitivity in Parkinson's disease is associated with orthostatic hypotension. J Neurol Sci 377: 207‐211, 2017.
 32.Blain GM AM, Proctor LT, Sebranek JJ, Pegelow DF, Dempsey JA. Group III and IV muscle afferents contribute to ventilatory and cardiovascular response to rhythmic exercise in humans. J Appl Physiol 109: 966‐976, 2010.
 33.Blomstedt P, Olivecrona M, Sailer A, Hariz MI. Dittmar and the history of stereotaxy; or rats, rabbits, and references. Neurosurgery 60: 198‐201; discussion 201‐192, 2007.
 34.Boccard SG, Pereira EA, Moir L, Aziz TZ, Green AL. Long‐term outcomes of deep brain stimulation for neuropathic pain. Neurosurgery 72: 221‐230; discussion 231, 2013.
 35.Boccard SGJ, Prangnell SJ, Pycroft L, Cheeran B, Moir L, Pereira EAC, Fitzgerald JJ, Green AL, Aziz TZ. Long‐term results of deep brain stimulation of the anterior cingulate cortex for neuropathic pain. World Neurosurg 106: 625‐637, 2017.
 36.Borghammer P. Is constipation in Parkinson's disease caused by gut or brain pathology? Parkinsonism Relat Disord 55: 6‐7, 2018.
 37.Brice J, McLellan L. Suppression of intention tremor by contingent deep‐brain stimulation. Lancet 1: 1221‐1222, 1980.
 38.Brown T. Note on physiology of basal ganglia and midbrain of anthropoid ape especially in reference to act of laughter. J Physiol 49: 195‐207, 1915.
 39.Bruehl S, Chung OY. Interactions between the cardiovascular and pain regulatory systems: An updated review of mechanisms and possible alterations in chronic pain. Neurosci Biobehav Rev 28: 395‐414, 2004.
 40.Bunjo ZBS, Chandran AS, Zacest A. Orthostatic hypotension following deep brain stimulation in parkinson's disease: A systematic review. Br J Neurosurg, 2019.
 41.Burns SM, Wyss JM. The involvement of the anterior cingulate cortex in blood pressure control. Brain Res 340: 71‐77, 1985.
 42.Cameron AA, Khan IA, Westlund KN, Willis WD. The efferent projections of the periaqueductal gray in the rat: A Phaseolus vulgaris‐leucoagglutinin study. II. Descending projections. J Comp Neurol 351: 585‐601, 1995.
 43.Campbell BC, McLean CA, Culvenor JG, Gai WP, Blumbergs PC, Jakala P, Beyreuther K, Masters CL, Li QX. The solubility of alpha‐synuclein in multiple system atrophy differs from that of dementia with Lewy bodies and Parkinson's disease. J Neurochem 76: 87‐96, 2001.
 44.Carrive P, Bandler R. Control of extracranial and hindlimb blood flow by the midbrain periaqueductal grey of the cat. Exp Brain Res 84: 599‐606, 1991.
 45.Carrive P, Bandler R. Viscerotopic organization of neurons subserving hypotensive reactions within the midbrain periaqueductal grey: A correlative functional and anatomical study. Brain Res 541: 206‐215, 1991.
 46.Carrive P, Bandler R, Dampney RA. Anatomical evidence that hypertension associated with the defence reaction in the cat is mediated by a direct projection from a restricted portion of the midbrain periaqueductal grey to the subretrofacial nucleus of the medulla. Brain Res 460: 339‐345, 1988.
 47.Cechetto D. Forebrain control of healthy and diseased hearts. In: Armour JAAJ, editor. Basic and Clinical Neurocardiology. New York: OUP, 2004.
 48.Cechetto DF, Calaresu FR. Central pathways relaying cardiovascular afferent information to amygdala. Am J Phys 248: R38‐R45, 1985.
 49.Cechetto DF, Saper CB. Neurochemical organization of the hypothalamic projection to the spinal cord in the rat. J Comp Neurol 272: 579‐604, 1988.
 50.Cechetto DFGA. The amygdala and cardiovascular control. J Neurosurg Anesthesiol 13: 329‐332, 2001.
 51.Chamberlin NL, Saper CB. Topographic organization of respiratory responses to glutamate microstimulation of the parabrachial nucleus in the rat. J Neurosci 14: 6500‐6510, 1994.
 52.Chassoux F, Navarro V, Catenoix H, Valton L, Vignal JP. Planning and management of SEEG. Neurophysiol Clin 48: 25‐37, 2018.
 53.Chaturvedi A, Butson CR, Lempka SF, Cooper SE, McIntyre CC. Patient‐specific models of deep brain stimulation: Influence of field model complexity on neural activation predictions. Brain Stimul 3: 65‐67, 2010.
 54.Chefer SI, Talan MI, Engel BT. Central neural correlates of learned heart rate control during exercise: Central command demystified. J Appl Physiol 83: 1448‐1453, 1997.
 55.Chong RK, Bedford TG. Heart rate, blood pressure, and running speed responses to mesencephalic locomotor region stimulation in anesthetized rats. Pflugers Arch 434: 280‐284, 1997.
 56.Chouchou F, Mauguière F, Vallayer O, Catenoix H, Isnard J, Montavont A, Jung J, Pichot V, Rheims S, Mazzola L. How the insula speaks to the heart: Cardiac responses to insular stimulation in humans. Hum Brain Mapp 40: 2611‐2622, 2019.
 57.Coenen VA, Gielen FL, Castro‐Prado F, Abdel Rahman A, Honey CR. Noradrenergic modulation of subthalamic nucleus activity in human: Metoprolol reduces spiking activity in microelectrode recordings during deep brain stimulation surgery for Parkinson's disease. Acta Neurochir 150: 757‐762; discussion 762, 2008.
 58.Coffey R. Deep brain stimulation for chronic pain: Results of two multicenter trials and a structured review. Pain Med 2: 183‐192, 2001.
 59.Comroe JHSC. Reflexes from the limbs as a factor in the hyperpnea of muscular exercise. Am J Phys Regul Integr Comp Phys 138: 536‐547, 1943.
 60.Coon EA, Cutsforth‐Gregory JK, Benarroch EE. Neuropathology of autonomic dysfunction in synucleinopathies. Mov Disord 33: 349‐358, 2018.
 61.Cooper IS. Chemopallidectomy: An investigative technique in geriatric parkinsonians. Science 121: 217‐218, 1955.
 62.Cooper IS. Results of 1,000 consecutive basal ganglia operations for parkinsonism. Ann Intern Med 52: 483‐499, 1960.
 63.Cooper IS. Effect of anterior choroidal artery ligation on involuntary movements and rigidity. Trans Am Neurol Assoc 3: 6‐7; discussion.
 64.Coote JH, Hilton SM, Perez‐Gonzalez JF. The reflex nature of the pressor response to muscular exercise. J Physiol 215: 789‐804, 1971.
 65.Coote JH, Hilton SM, Perez‐Gonzalez JF. Inhibition of the baroreceptor reflex on stimulation in the brain stem defence centre. J Physiol 288: 549‐560, 1979.
 66.Cortelli P, Guaraldi P, Leone M, Pierangeli G, Barletta G, Grimaldi D, Cevoli S, Bussone G, Baruzzi A, Montagna P. Effect of deep brain stimulation of the posterior hypothalamic area on the cardiovascular system in chronic cluster headache patients. Eur J Neurol 14: 1008‐1015, 2007.
 67.Craig AD. Forebrain emotional asymmetry: A neuroanatomical basis? Trends Cogn Sci 9: 566‐571, 2005.
 68.Critchley HD, Corfield DR, Chandler MP, Mathias CJ, Dolan RJ. Cerebral correlates of autonomic cardiovascular arousal: A functional neuroimaging investigation in humans. J Physiol 523 (Pt 1): 259‐270, 2000.
 69.Critchley HD, Mathias CJ, Josephs O, O'Doherty J, Zanini S, Dewar BK, Cipolotti L, Shallice T, Dolan RJ. Human cingulate cortex and autonomic control: Converging neuroimaging and clinical evidence. Brain 126: 2139‐2152, 2003.
 70.Daly WJ, Overley T. Modification of ventilatory regulation by hypnosis. J Lab Clin Med 68: 279‐285, 1966.
 71.Dampney RA, Coleman MJ, Fontes MA, Hirooka Y, Horiuchi J, Li YW, Polson JW, Potts PD, Tagawa T. Central mechanisms underlying short‐ and long‐term regulation of the cardiovascular system. Clin Exp Pharmacol Physiol 29: 261‐268, 2002.
 72.Dampney RA, Furlong TM, Horiuchi J, Iigaya K. Role of dorsolateral periaqueductal grey in the coordinated regulation of cardiovascular and respiratory function. Auton Neurosci 175: 17‐25, 2013.
 73.Delgado JM, Hamlin H, Koskoff YD. Electrical activity after stimulation and electrocoagulation of the human frontal lobe. Yale J Biol Med 28: 233‐244, 1955.
 74.Delgado JM, Johnston VS, Wallace JD, Bradley RJ. Operant conditioning of amygdala spindling in the free chimpanzee. Brain Res 22: 347‐362, 1970.
 75.Delgado JM, Rosvold HE, Looney E. Evoking conditioned fear by electrical stimulation of subcortical structures in the monkey brain. J Comp Physiol Psychol 49: 373‐380, 1956.
 76.Demeulemeester H, Feys H, Goris I, Zwaenepoel I, de Weerdt W, de Sutter P, Gybels J, Plets C, Nuttin B. Effect of the serotonin agonist 8‐OH‐DPAT on the sensorimotor system of the rat. Pharmacol Biochem Behav 70: 95‐103, 2001.
 77.Depaulis A, Keay KA, Bandler R. Quiescence and hyporeactivity evoked by activation of cell bodies in the ventrolateral midbrain periaqueductal gray of the rat. Exp Brain Res 99: 75‐83, 1994.
 78.Diedrich A, Porta A, Barbic F, Brychta RJ, Bonizzi P, Diedrich L, Cerutti S, Robertson D, Furlan R. Lateralization of expression of neural sympathetic activity to the vessels and effects of carotid baroreceptor stimulation. Am J Physiol Heart Circ Physiol 296: H1758‐H1765, 2009.
 79.Dittmar C. Über die Lage des sogenannten Gefaesszentrums in der Medulla oblongata [in German]. Bersaechs Ges Wiss Leipzig 25: 449‐469, 1873.
 80.Duggan AW, Morton CR. Periaqueductal grey stimulation: An association between selective inhibition of dorsal horn neurones and changes in peripheral circulation. Pain 15: 237‐248, 1983.
 81.Eldridge FL, Millhorn DE, Waldrop TG. Exercise hyperpnea and locomotion: Parallel activation from the hypothalamus. Science 211: 844‐846, 1981.
 82.Estanol B, Porras‐Betancourt M, Padilla‐Leyva MA, Senties‐Madrid H. Breve historia del reflejo barorreceptor: de Claude Bernard a Arthur C. Guyton Ilustrada con algunos experimentos clasicos. Arch Cardiol Mex 81: 330‐336, 2011.
 83.Fabbri M, Coelho M, Guedes LC, Rosa MM, Abreu D, Goncalves N, Antonini A, Ferreira JJ. Acute response of non‐motor symptoms to subthalamic deep brain stimulation in Parkinson's disease. Parkinsonism Relat Disord 41: 113‐117, 2017.
 84.Farkas E, Jansen AS, Loewy AD. Periaqueductal gray matter projection to vagal preganglionic neurons and the nucleus tractus solitarius. Brain Res 764: 257‐261, 1997.
 85.Farkas E, Jansen AS, Loewy AD. Periaqueductal gray matter input to cardiac‐related sympathetic premotor neurons. Brain Res 792: 179‐192, 1998.
 86.Fernandes A, Galbo H, Kjaer M, Mitchell JH, Secher NH, Thomas SN. Cardiovascular and ventilatory responses to dynamic exercise during epidural anaesthesia in man. J Physiol 420: 281‐293, 1990.
 87.Fields HL, Vanegas H, Hentall ID, Zorman G. Evidence that disinhibition of brain stem neurones contributes to morphine analgesia. Nature 306: 684‐686, 1983.
 88.Finnegan TF, Chen SR, Pan HL. Effect of the {mu} opioid on excitatory and inhibitory synaptic inputs to periaqueductal gray‐projecting neurons in the amygdala. J Pharmacol Exp Ther 312: 441‐448, 2005.
 89.Fisher R, Salanova V, Witt T, Worth R, Henry T, Gross R, Oommen K, Osorio I, Nazzaro J, Labar D, Kaplitt M, Sperling M, Sandok E, Neal J, Handforth A, Stern J, DeSalles A, Chung S, Shetter A, Bergen D, Bakay R, Henderson J, French J, Baltuch G, Rosenfeld W, Youkilis A, Marks W, Garcia P, Barbaro N, Fountain N, Bazil C, Goodman R, McKhann G, Babu Krishnamurthy K, Papavassiliou S, Epstein C, Pollard J, Tonder L, Grebin J, Coffey R, Graves N, SANTE Study Group. Electrical stimulation of the anterior nucleus of thalamus for treatment of refractory epilepsy. Epilepsia 51: 899‐908, 2010.
 90.Frith CD, Allen HA. The skin conductance orienting response as an index of attention. Biol Psychol 17: 27‐39, 1983.
 91.Frysinger RC, Marks JD, Trelease RB, Schechtman VL, Harper RM. Sleep states attenuate the pressor response to central amygdala stimulation. Exp Neurol 83: 604‐617, 1984.
 92.Furgala A, Gorecka‐Mazur A, Fiszer U, Pietraszko W, Thor P, Moskala M, Potasz K, Bukowczan M, Polak J, Krygowska‐Wajs A. Ocena zmiennosci rytmu serca i cisnienia tetniczego u osob z choroba Parkinsona po obustronnej glebokiej stymulacji jadra niskowzgorzowego. Przegl Lek 72: 246‐252, 2015.
 93.Galeno TM, Brody MJ. Hemodynamic responses to amygdaloid stimulation in spontaneously hypertensive rats. Am J Phys 245: R281‐R286, 1983.
 94.Gandolfi M, Geroin C, Antonini A, Smania N, Tinazzi M. Understanding and treating pain syndromes in parkinson's disease. Int Rev Neurobiol 134: 827‐858, 2017.
 95.Garas Z, Komor K. Anderung des Plasmavolumens im Stehen bei Hypertonie. Vergleichsuntersuchungen in der normotensiven und hypertensiven Erkrankungsphase. Z Gesamte Innre Med Grenzgebiete 26: 199‐202, 1971.
 96.Garcia‐Ptacek S, Kramberger MG. Parkinson disease and dementia. J Geriatr Psychiatry Neurol 29: 261‐270, 2016.
 97.Gelsema AJ, McKitrick DJ, Calaresu FR. Cardiovascular responses to chemical and electrical stimulation of amygdala in rats. Am J Physiol 253: R712‐R718, 1987.
 98.Gentil AF, Eskandar EN, Marci CD, Evans KC, Dougherty DD. Physiological responses to brain stimulation during limbic surgery: Further evidence of anterior cingulate modulation of autonomic arousal. Biol Psychiatry 66: 695‐701, 2009.
 99.Giacobbe P, Mayberg HS, Lozano AM. Treatment resistant depression as a failure of brain homeostatic mechanisms: Implications for deep brain stimulation. Exp Neurol 219: 44‐52, 2009.
 100.Gillies MJHY, Hyam JA, Aziz TZ, Green AL. Direct neurophysiological evidence for a role of the human anterior cingulate cortex in central command. Auton Neurosci 216: 51‐58, 2019.
 101.Giraudin A, Le Bon‐Jego M, Cabirol MJ, Simmers J, Morin D. Spinal and pontine relay pathways mediating respiratory rhythm entrainment by limb proprioceptive inputs in the neonatal rat. J Neurosci 32: 11841‐11853, 2012.
 102.Goldstein D, Holmes C, Cannon RO 3rd, Eisenhofer G, Kopin IJ. Sympathetic cardioneuropathy in dysautonomias. N Engl J Med 336: 696‐702, 1997.
 103.Goldstein DS, Holmes C, Bentho O, Sato T, Moak J, Sharabi Y, Imrich R, Conant S, Eldadah BA. Biomarkers to detect central dopamine deficiency and distinguish Parkinson disease from multiple system atrophy. Parkinsonism Relat Disord 14: 600‐607, 2008.
 104.Goldstein DS, Holmes C, Kopin IJ, Sharabi Y. Intra‐neuronal vesicular uptake of catecholamines is decreased in patients with Lewy body diseases. J Clin Invest 121: 3320‐3330, 2011.
 105.Goldstein DS, Sewell L, Sharabi Y. Autonomic dysfunction in PD: A window to early detection? J Neurol Sci 310: 118‐122, 2011.
 106.Golestanirad L, Kirsch J, Bonmassar G, Downs S, Elahi B, Martin A, Iacono MI, Angelone LM, Keil B, Wald LL, Pilitsis J. RF‐induced heating in tissue near bilateral DBS implants during MRI at 1.5T and 3T: The role of surgical lead management. NeuroImage 184: 566‐576, 2019.
 107.Goodwin GM, McCloskey DI, Mitchell JH. Cardiovascular and respiratory responses to changes in central command durin isometric exercise at constant muscle tension. J Physiol 219: 40P‐41P, 1971.
 108.Goodwin GM, McCloskey DI, Mitchell JH. Cardiovascular and respiratory responses to changes in central command during isometric exercise at constant muscle tension. J Physiol 226: 173‐190, 1972.
 109.Green AL, Paterson DJ. Identification of neurocircuitry controlling cardiovascular function in humans using functional neurosurgery: Implications for exercise control. Exp Physiol 93: 1022‐1028, 2008.
 110.Green AL, Wang S, Bittar RG, Owen SL, Paterson DJ, Stein JF, Bain PG, Shlugman D, Aziz TZ. Deep brain stimulation: A new treatment for hypertension? J Clin Neurosci 14: 592‐595, 2007.
 111.Green AL, Wang S, Owen SL, Paterson DJ, Stein JF, Aziz TZ. Controlling the heart via the brain: A potential new therapy for orthostatic hypotension. Neurosurgery 58: 1176‐1183; discussion 1176‐1183, 2006.
 112.Green AL, Wang S, Owen SL, Xie K, Liu X, Paterson DJ, Stein JF, Bain PG, Aziz TZ. Deep brain stimulation can regulate arterial blood pressure in awake humans. Neuroreport 16: 1741‐1745, 2005.
 113.Green AL, Wang S, Purvis S, Owen SL, Bain PG, Stein JF, Guz A, Aziz TZ, Paterson DJ. Identifying cardiorespiratory neurocircuitry involved in central command during exercise in humans. J Physiol 578: 605‐612, 2007.
 114.Guyenet PG. Regulation of breathing and autonomic outflows by chemoreceptors. Compr Physiol 4: 1511‐1562, 2014.
 115.Guyenet PG, Darnall RA, Riley TA. Rostral ventrolateral medulla and sympathorespiratory integration in rats. Am J Phys 259: R1063‐R1074, 1990.
 116.Hariz GM, Rehncrona S, Blomstedt P, Limousin P, Hamberg K, Hariz M. Women pioneers in basal ganglia surgery. Parkinsonism Relat Disord 20: 137‐141, 2014.
 117.Hariz M. My 25 stimulating years with DBS in parkinson's disease. J Parkinsons Dis 7: S33‐S41, 2017.
 118.Herrera DG, Robertson HA. Activation of c‐fos in the brain. Prog Neurobiol 50: 83‐107, 1996.
 119.Hilton SM. Hypothalamic control of the cardiovascular responses in fear and rage. Sci Basis Med Annu Rev 217‐238, 1965.
 120.Hilton SM, Spyer KM. The hypothalamic depressor area and the baroreceptor reflex. J Physiol 200: 107P‐108P, 1969.
 121.Hilton SM, Spyer KM. Participation of the anterior hypothalamus in the baroreceptor reflex. J Physiol 218: 271‐293, 1971.
 122.Hilty L, Jancke L, Luechinger R, Boutellier U, Lutz K. Limitation of physical performance in a muscle fatiguing handgrip exercise is mediated by thalamo‐insular activity. Hum Brain Mapp 32: 2151‐2160, 2011.
 123.Hilty L, Langer N, Pascual‐Marqui R, Boutellier U, Lutz K. Fatigue‐induced increase in intracortical communication between mid/anterior insular and motor cortex during cycling exercise. Eur J Neurosci 34: 2035‐2042, 2011.
 124.Hogl B, Stefani A, Videnovic A. Idiopathic REM sleep behaviour disorder and neurodegeneration – an update. Nat Rev Neurol 14: 40‐55, 2018.
 125.Holroyd CB, Coles MGH. The neural basis of human error processing: Reinforcement learning, dopamine, and the error‐related negativity. Psychol Rev 109: 679‐709, 2002.
 126.Horn EM, Waldrop TG. Suprapontine control of respiration. Respir Physiol 114: 201‐211, 1998.
 127.Hosobuchi Y. Subcortical electrical stimulation for control of intractable pain in humans. Report of 122 cases (1970–1984). J Neurosurg 64: 543‐553, 1986.
 128.Huang YCB, Green AL, Denison TJ, Aziz TZ. Applying a sensing‐enabled system for ensuring safe anterior cingulate deep brain stimulation for pain. Brain Sci 9: pii: E150, 2019.
 129.Hyam JA, Kringelbach ML, Silburn PA, Aziz TZ, Green AL. The autonomic effects of deep brain stimulation – a therapeutic opportunity. Nat Rev Neurol 8: 391‐400, 2012.
 130.Hyam JA, Owen SL, Kringelbach ML, Jenkinson N, Stein JF, Green AL, Aziz TZ. Contrasting connectivity of the ventralis intermedius and ventralis oralis posterior nuclei of the motor thalamus demonstrated by probabilistic tractography. Neurosurgery 70: 162‐169; discussion 169, 2012.
 131.Hyam JARH, Huang Y, Martin S, Wang S, Rippey J, Coyne TJ, Stewart I, Kerr G, Silburn P, Paterson DJ, Aziz TZ, Green AL. Cardiovascular autonomic responses in patients with Parkinson disease to pedunculopontine deep brain stimulation. Clin Auton Res 29: 615‐624, 2019.
 132.Inoue M, Yagishita S, Ryo M, Hasegawa K, Amano N, Matsushita M. The distribution and dynamic density of oligodendroglial cytoplasmic inclusions (GCIs) in multiple system atrophy: A correlation between the density of GCIs and the degree of involvement of striatonigral and olivopontocerebellar systems. Acta Neuropathol (Berl) 93: 585‐591, 1997.
 133.Iwamoto GA, Wappel SM, Fox GM, Buetow KA, Waldrop TG. Identification of diencephalic and brainstem cardiorespiratory areas activated during exercise. Brain Res 726: 109‐122, 1996.
 134.Jain S, Goldstein DS. Cardiovascular dysautonomia in Parkinson disease: From pathophysiology to pathogenesis. Neurobiol Dis 46: 572‐580, 2012.
 135.Johansson J. Ueber die Einwirkung der Muskelthatigkeit auf die Athmung und die Hertzhiitigkeit. Skand Arch Physiol 5: 20‐66, 1893.
 136.Johnson PL, Lightman SL, Lowry CA. A functional subset of serotonergic neurons in the rat ventrolateral periaqueductal gray implicated in the inhibition of sympathoexcitation and panic. Ann N Y Acad Sci 1018: 58‐64, 2004.
 137.Jost WH. An update on the recognition and treatment of autonomic symptoms in Parkinson's disease. Expert Rev Neurother 17: 791‐799, 2017.
 138.Kaada BR. Somato‐motor, autonomic and electrocorticographic responses to electrical stimulation of rhinencephalic and other structures in primates, cat, and dog; a study of responses from the limbic, subcallosal, orbito‐insular, piriform and temporal cortex, hippocampus‐fornix and amygdala. Acta Physiol Scand Suppl 24: 1‐262, 1951.
 139.Kaada BR, Pribram KH, Epstein JA. Respiratory and vascular responses in monkeys from temporal pole, insula, orbital surface and cingulate gyrus; a preliminary report. J Neurophysiol 12: 347‐356, 1949.
 140.Kabat H, Magoun H, Ranson SW. Electrical stimulation of points in the forebrain and midbrain. The resultant alteration in blood pressure. Arch Neurol Psych 34: 931‐955, 1935.
 141.Kamath MV, Fallen EL. Power spectral analysis of heart rate variability: A noninvasive signature of cardiac autonomic function. Crit Rev Biomed Eng 21: 245‐311, 1993.
 142.Kaplan NM. The promises and perils of treating the elderly hypertensive. Am J Med Sci 305: 183‐197, 1993.
 143.Katz RL, Chai CY, Kahn N, Ngai SH, Share NN, Wang SC. Brainstem mechanisms subserving baroreceptor reflexes. Science 145: 1459‐1460, 1964.
 144.Kienbaum P, Karlssonn T, Sverrisdottir YB, Elam M, Wallin BG. Two sites for modulation of human sympathetic activity by arterial baroreceptors? J Physiol 531: 861‐869, 2001.
 145.King AB, Menon RS, Hachinski V, Cechetto DF. Human forebrain activation by visceral stimuli. J Comp Neurol 413: 572‐582, 1999.
 146.Kisely S, Li A, Warren N, Siskind D. A systematic review and meta‐analysis of deep brain stimulation for depression. Depress Anxiety 35: 468‐480, 2018.
 147.Kramer J, Jarboe M, Waldrop T. Periaqueductal grey neuronal responses to hindlimb muscle contraction in the cat. Soc Neurosci Abstr 22: 89, 1996.
 148.Kringelbach ML, Jenkinson N, Owen SL, Aziz TZ. Translational principles of deep brain stimulation. Nat Rev Neurosci 8: 623‐635, 2007.
 149.Krogh A, Lindhard J. The regulation of respiration and circulation during the initial stages of muscular work. J Physiol 47: 112‐136, 1913.
 150.Krout KE, Loewy AD. Periaqueductal gray matter projections to midline and intralaminar thalamic nuclei of the rat. J Comp Neurol 424: 111‐141, 2000.
 151.Kuch B, Parvanov T, Hense HW, Axmann J, Bolte HD. Short‐period heart rate variability in the general population as compared to patients with acute myocardial infarction from the same source population. Ann Noninvasive Electrocardiol 9: 113‐120, 2004.
 152.Kume A, Takahashi A, Hashizume Y, Asai J. A histometrical and comparative study on Purkinje cell loss and olivary nucleus cell loss in multiple system atrophy. J Neurol Sci 101: 178‐186, 1991.
 153.Kyuhou S, Gemba H. Two vocalization‐related subregions in the midbrain periaqueductal gray of the guinea pig. Neuroreport 9: 1607‐1610, 1998.
 154.Lacuey N, Hampson JP, Theeranaew W, Zonjy B, Vithala A, Hupp NJ, Loparo KA, Miller JP, Lhatoo SD. Cortical structures associated with human blood pressure control. JAMA Neurol 75: 194‐202, 2018.
 155.Leksell L. A stereotaxic apparatus for intracerebral surgery. Acta Chir Scand 99: 229‐233, 1949.
 156.Leone M, Franzini A, Bussone G. Stereotactic stimulation of posterior hypothalamic gray matter in a patient with intractable cluster headache. N Engl J Med 345: 1428‐1429, 2001.
 157.Li J, Mitchell JH. Glutamate release in midbrain periaqueductal gray by activation of skeletal muscle receptors and arterial baroreceptors. Am J Physiol Heart Circ Physiol 285: H137‐H144, 2003.
 158.Lovick TA. Ventrolateral medullary lesions block the antinociceptive and cardiovascular responses elicited by stimulating the dorsal periaqueductal grey matter in rats. Pain 21: 241‐252, 1985.
 159.Lovick TA. Inhibitory modulation of the cardiovascular defence response by the ventrolateral periaqueductal grey matter in rats. Exp Brain Res 89: 133‐139, 1992.
 160.Ludwig J, Remien P, Guballa C, Binder A, Binder S, Schattschneider J, Herzog J, Volkmann J, Deuschl G, Wasner G, Baron R. Effects of subthalamic nucleus stimulation and levodopa on the autonomic nervous system in Parkinson's disease. J Neurol Neurosurg Psychiatry 78: 742‐745, 2007.
 161.Malpas SC, Ninomiya I. A new approach to analysis of synchronized sympathetic nerve activity. Am J Phys 263: H1311‐H1317, 1992.
 162.Mantyh PW. Connections of midbrain periaqueductal gray in the monkey. II Descending efferent projections. J Neurophysiol 49: 582‐594, 1983.
 163.Martinmaki K, Rusko H, Kooistra L, Kettunen J, Saalasti S. Intraindividual validation of heart rate variability indexes to measure vagal effects on hearts. Am J Physiol Heart Circ Physiol 290: H640‐H647, 2006.
 164.May A, Bahra A, Buchel C, Frackowiak RS, Goadsby PJ. PET and MRA findings in cluster headache and MRA in experimental pain. Neurology 55: 1328‐1335, 2000.
 165.May A, Goadsby PJ. The trigeminovascular system in humans: Pathophysiologic implications for primary headache syndromes of the neural influences on the cerebral circulation. J Cereb Blood Flow Metab 19: 115‐127, 1999.
 166.McAllen RM, Malpas SC. Sympathetic burst activity: Characteristics and significance. Clin Exp Pharmacol Physiol 24: 791‐799, 1997.
 167.McCloskey DI, Mitchell JH. Reflex cardiovascular and respiratory responses originating in exercising muscle. J Physiol 224: 173‐186, 1972.
 168.McGaraughty S, Farr DA, Heinricher MM. Lesions of the periaqueductal gray disrupt input to the rostral ventromedial medulla following microinjections of morphine into the medial or basolateral nuclei of the amygdala. Brain Res 1009: 223‐227, 2004.
 169.McNeely HE, Mayberg HS, Lozano AM, Kennedy SH. Neuropsychological impact of Cg25 deep brain stimulation for treatment‐resistant depression: Preliminary results over 12 months. J Nerv Ment Dis 196: 405‐410, 2008.
 170.Meissner WG, Laurencin C, Tranchant C, Witjas T, Viallet F, Guehl D, Damier P, Houeto JL, Tison F, Eusebio A, Vital A, Streichenberger N, Lannes B, Maues de Paula A, Thobois S. Outcome of deep brain stimulation in slowly progressive multiple system atrophy: A clinico‐pathological series and review of the literature Parkinsonism. Relat Disord 24: 69‐75, 2016.
 171.Mendoza‐Velasquez JJF‐VJ, Barron‐velazquez E, Sosa‐Ortiz AL, Illigens B‐MW, Siepmann T. Autonomic dysfunction in alpha‐synucleinopathies. Front Neurol 10: 363, 2019.
 172.Mestivier D, Chau NP, Chanudet X, Bauduceau B, Larroque P. Relationship between diabetic autonomic dysfunction and heart rate variability assessed by recurrence plot. Am J Phys 272: H1094‐H1099, 1997.
 173.Mitchell JH. J.B. Wolffe memorial lecture. Neural control of the circulation during exercise. Med Sci Sports Exerc 22: 141‐154, 1990.
 174.Mordasini L, Kessler TM, Kiss B, Schupbach M, Pollo C, Kaelin‐Lang A. Bladder function in patients with dystonia undergoing deep brain stimulation. Parkinsonism Relat Disord 20: 1015‐1017, 2014.
 175.Morgan WP, Hirta K, Weitz GA, Balke B. Hypnotic perturbation of perceived exertion: Ventilatory consequences. Am J Clin Hypn 18: 182‐190, 1976.
 176.Morgan WP, Raven PB, Drinkwater BL, Horvath SM. Perceptual and metabolic responsivity to standard bicycle ergometry following various hypnotic suggestions. Int J Clin Exp Hypn 21: 86‐101, 1973.
 177.Moruzzi G. Paleocerebellar inhibition of vasomotor and respiratory carotid sinus reflexes. J Neurophysiol 3: 20‐22, 1940.
 178.Nashold BS Jr, Wilson WP, Slaughter DG. Sensations evoked by stimulation in the midbrain of man. J Neurosurg 30: 14‐24, 1969.
 179.Noack C, Schroeder C, Heusser K, Lipp A. Cardiovascular effects of levodopa in Parkinson's disease. Parkinsonism Relat Disord 20: 815‐818, 2014.
 180.Nowak M, Holm S, Biering‐Sorensen F, Secher NH, Friberg L. “Central command” and insular activation during attempted foot lifting in paraplegic humans. Hum Brain Mapp 25: 259‐265, 2005.
 181.O'Callaghan EL, Hart EC, Sims‐Williams H, Javed S, Burchell AE, Papouchado M, Tank J, Heusser K, Jordan J, Menne J, Haller H, Nightingale AK, Paton JF, Patel NK. Chronic deep brain stimulation decreases blood pressure and sympathetic nerve activity in a drug‐ and device‐resistant hypertensive patient. Hypertension 69: 522‐528, 2017.
 182.Odeh F, Antal M. The projections of the midbrain periaqueductal grey to the pons and medulla oblongata in rats. Eur J Neurosci 14: 1275‐1286, 2001.
 183.Olds J, Milner P. Positive reinforcement produced by electrical stimulation of septal area and other regions of rat brain. J Comp Physiol Psychol 47: 419‐427, 1954.
 184.Ongur D, An X, Price JL. Prefrontal cortical projections to the hypothalamus in macaque monkeys. J Comp Neurol 401: 480‐505, 1998.
 185.Ozawa T. Morphological substrate of autonomic failure and neurohormonal dysfunction in multiple system atrophy: Impact on determining phenotype spectrum. Acta Neuropathol (Berl) 114: 201‐211, 2007.
 186.Padley JR, Kumar NN, Li Q, Nguyen TB, Pilowsky PM, Goodchild AK. Central command regulation of circulatory function mediated by descending pontine cholinergic inputs to sympathoexcitatory rostral ventrolateral medulla neurons. Circ Res 100: 284‐291, 2007.
 187.Pagani M, Montano N, Porta A, Malliani A, Abboud FM, Birkett C, Somers VK. Relationship between spectral components of cardiovascular variabilities and direct measures of muscle sympathetic nerve activity in humans. Circulation 95: 1441‐1448, 1997.
 188.Papp MI, Lantos PL. The distribution of oligodendroglial inclusions in multiple system atrophy and its relevance to clinical symptomatology. Brain 117: 235‐243, 1994.
 189.Patel NK, Javed S, Khan S, Papouchado M, Malizia AL, Pickering AE, Paton JF. Deep brain stimulation relieves refractory hypertension. Neurology 76: 405‐407, 2011.
 190.Paterson DJ. Defining the neurocircuitry of exercise hyperpnoea. J Physiol 592: 433‐444, 2014.
 191.Paterson DJ, Wood GA, Marshall RN, Morton AR, Harrison AB. Entrainment of respiratory frequency to exercise rhythm during hypoxia. J Appl Physiol 62: 1767‐1771, 1987.
 192.Paterson DJ, Wood GA, Morton AR, Henstridge JD. The entrainment of ventilation frequency to exercise rhythm. Eur J Appl Physiol 55: 530‐537, 1986.
 193.Paus T. Primate anterior cingulate cortex: Where motor control, drive and cognition interface. Nat Rev Neurosci 2: 417‐424, 2001.
 194.Pereira EA, Green AL, Nandi D, Aziz TZ. Deep brain stimulation: Indications and evidence. Expert Rev Med Dev 4: 591‐603, 2007.
 195.Pereira EA, Lu G, Wang S, Schweder PM, Hyam JA, Stein JF, Paterson DJ, Aziz TZ, Green AL. Ventral periaqueductal grey stimulation alters heart rate variability in humans with chronic pain. Exp Neurol 223: 574‐581, 2010.
 196.Pereira EA, Paranathala M, Hyam JA, Green AL, Aziz TZ. Anterior cingulotomy improves malignant mesothelioma pain and dyspnoea. Br J Neurosurg 28: 471‐474, 2014.
 197.Pereira EA, Wang S, Peachey T, Lu G, Shlugman D, Stein JF, Aziz TZ, Green AL. Elevated gamma band power in humans receiving naloxone suggests dorsal periaqueductal and periventricular gray deep brain stimulation produced analgesia is opioid mediated. Exp Neurol 239: 248‐255, 2013.
 198.Pitts RFLM, Bronk DW. An analysis of hypothalamic cardiovascular control. Am J Phys 134: 359‐383, 1941.
 199.Plaha P, Gill SS. Bilateral deep brain stimulation of the pedunculopontine nucleus for Parkinson's disease. Neuroreport 16: 1883‐1887, 2005.
 200.Pool JL, Ransohoff J. Autonomic effects on stimulating rostral portion of cingulate gyri in man. J Neurophysiol 12: 385‐392, 1949.
 201.Priori A, Cinnante C, Genitrini S, Pesenti A, Tortora G, Bencini C, Barelli MV, Buonamici V, Carella F, Girotti F, Soliveri P, Magrini F, Morganti A, Albanese A, Broggi S, Scarlato G, Barbieri S. Non‐motor effects of deep brain stimulation of the subthalamic nucleus in Parkinson's disease: Preliminary physiological results. Neurol Sci 22: 85‐86, 2001.
 202.Pumprla J, Howorka K, Groves D, Chester M, Nolan J. Functional assessment of heart rate variability: Physiological basis and practical applications. Int J Cardiol 84: 1‐14, 2002.
 203.Randich A, Maixner W. The role of sinoaortic and cardiopulmonary baroreceptor reflex arcs in nociception and stress‐induced analgesia. Ann N Y Acad Sci 467: 385‐401, 1986.
 204.Rauch HG, Schonbachler G, Noakes TD. Neural correlates of motor vigour and motor urgency during exercise. Sports Med 43: 227‐241, 2013.
 205.Raymaekers S, Luyten L, Bervoets C, Gabriels L, Nuttin B. Deep brain stimulation for treatment‐resistant major depressive disorder: A comparison of two targets and long‐term follow‐up. Transl Psychiatry 7: e1251, 2017.
 206.Reis DJ, Cuenod M. Tonic influence of rostral brain structures on pressure regulatory mechanisms in the cat. Science 145: 64‐65, 1964.
 207.Reis DJ, Cuenod M. Central neural regulation of carotid baroreceptor reflexes in the cat. Am J Phys 209: 1267‐1277, 1965.
 208.Reis DJ, Cuenod MR. Evidence for supramedullary influence on carotid baroreceptor reflexes. Trans Am Neurol Assoc 87: 229‐231, 1962.
 209.Richardson DE, Akil H. Long term results of periventricular gray self‐stimulation. Neurosurgery 1: 199‐202, 1977.
 210.Rizvi TA, Ennis M, Behbehani MM, Shipley MT. Connections between the central nucleus of the amygdala and the midbrain periaqueductal gray: Topography and reciprocity. J Comp Neurol 303: 121‐131, 1991.
 211.Ross CA, Ruggiero DA, Park DH, Joh TH, Sved AF, Fernandez‐Pardal J, Saavedra JM, Reis DJ. Tonic vasomotor control by the rostral ventrolateral medulla: Effect of electrical or chemical stimulation of the area containing C1 adrenaline neurons on arterial pressure, heart rate, and plasma catecholamines and vasopressin. J Neurosci 4: 474‐494, 1984.
 212.Roy HAAT, Fitzgerald JJ, Green AL. Beta oscillations and urinary voiding in Parkinson disease. Neurology 90: e1530‐e1534, 2018.
 213.Roy S, Ashok Kumar J, Srivastava AK, Deepak KK. Cardiovagal baroreflex sensitivity in parkinson's disease and multiple‐system atrophy. J Clin Neurol 12: 218‐223, 2016.
 214.Rutan GH, Hermanson B, Bild DE, Kittner SJ, LaBaw F, Tell GS. Orthostatic hypotension in older adults. The Cardiovascular Health Study CHS Collaborative Research Group. Hypertension 19: 508‐519, 1992.
 215.Saha S. Role of the central nucleus of the amygdala in the control of blood pressure: Descending pathways to medullary cardiovascular nuclei. Clin Exp Pharmacol Physiol 32: 450‐456, 2005.
 216.Saul JP. Respiration and blood pressure variability: Mechanical and autonomic influences. Fundam Clin Pharmacol 12 (Suppl 1): 17s‐22s, 1998.
 217.Schobel HP, Ringkamp M, Behrmann A, Forster C, Schmieder RE, Handwerker HO. Hemodynamic and sympathetic nerve responses to painful stimuli in normotensive and borderline hypertensive subjects. Pain 66: 117‐124, 1996.
 218.Schurr PH, Merrington WR. The Horsley‐Clarke stereotaxic apparatus. Br J Surg 65: 33‐36, 1978.
 219.Seeley WW, Menon V, Schatzberg AF, Keller J, Glover GH, Kenna H, Reiss AL, Greicius MD. Dissociable intrinsic connectivity networks for salience processing and executive control. J Neurosci 27: 2349‐2356, 2007.
 220.Seifert F, Schuberth N, De Col R, Peltz E, Nickel FT, Maihofner C. Brain activity during sympathetic response in anticipation and experience of pain. Hum Brain Mapp 34: 1768‐1782, 2013.
 221.Seller H. Carl Ludwig and the localization of the medullary vasomotor center: Old and new concepts of the generation of sympathetic tone. Pflugers Arch 432: R94‐R98, 1996.
 222.Seminowicz DA, Mayberg HS, McIntosh AR, Goldapple K, Kennedy S, Segal Z, Rafi‐Tari S. Limbic‐frontal circuitry in major depression: A path modeling metanalysis. NeuroImage 22: 409‐418, 2004.
 223.Shannahoff‐Khalsa D. Lateralized rhythms of the central and autonomic nervous systems. Int J Psychophysiol 11: 225‐251, 1991.
 224.Shannahoff‐Khalsa DS, Boyle MR, Buebel ME. The effects of unilateral forced nostril breathing on cognition. Int J Neurosci 57: 239‐249, 1991.
 225.Simons JA. Swallowing dysfunctions in parkinson's disease. Int Rev Neurobiol 134: 1207‐1238, 2017.
 226.Sims‐Williams H, Matthews JC, Talbot PS, Love‐Jones S, Brooks JC, Patel NK, Pickering AE. Deep brain stimulation of the periaqueductal gray releases endogenous opioids in humans. NeuroImage 146: 833‐842, 2017.
 227.Sitsapesan H, Green AL, Aziz TZ, Pereira EA. The periaqueductal grey area and control of blood pressure in neurodegeneration. Clin Auton Res 23: 215‐219, 2013.
 228.Smith OA Jr, Nathan MA. Inhibition of the carotid sinus reflex by stimulation of the inferior olive. Science 154: 674‐675, 1966.
 229.Smith OA Jr, Rushmer RF, Lasher EP. Similarity of cardiovascular responses to exercise and to diencephalic stimulation. Am J Phys 198: 1139‐1142, 1960.
 230.Smith OJ, Nathan MA, Clarke NP. Central Nervous System Pathways Mediating Blood Pressure Changes. New York: American Heart Association, 1967.
 231.Spiegel EA, Wycis HT, Marks M, Lee AJ. Stereotaxic apparatus for operations on the human brain. Science 106: 349‐350, 1947.
 232.Spyer KM. Annual review prize lecture. Central nervous mechanisms contributing to cardiovascular control. J Physiol 474: 1‐19, 1994.
 233.Stocchi F, Torti M. Constipation in parkinson's disease. Int Rev Neurobiol 134: 811‐826, 2017.
 234.Subramanian HH. Descending control of the respiratory neuronal network by the midbrain periaqueductal grey in the rat in vivo. J Physiol 591: 109‐122, 2013.
 235.Sumi K, Katayama Y, Otaka T, Obuchi T, Kano T, Kobayashi K, Oshima H, Fukaya C, Yamamoto T, Ogawa Y, Iwasaki K. Effect of subthalamic nucleus deep brain stimulation on the autonomic nervous system in Parkinson's disease patients assessed by spectral analyses of R‐R interval variability and blood pressure variability. Stereotact Funct Neurosurg 90: 248‐254, 2012.
 236.Sverrisdottir YB, Green AL, Aziz TZ, Bahuri NF, Hyam J, Basnayake SD, Paterson DJ. Differentiated baroreflex modulation of sympathetic nerve activity during deep brain stimulation in humans. Hypertension 63: 1000‐1010, 2014.
 237.Sverrisdottir YB, Rundqvist B, Johannsson G, Elam M. Sympathetic neural burst amplitude distribution: A more specific indicator of sympathoexcitation in human heart failure. Circulation 102: 2076‐2081, 2000.
 238.Sweet WH, Mark VH, Hamlin H. Radiofrequency lesions in the central nervous system of man and cat: Including case reports of eight bulbar pain‐tract interruptions. J Neurosurg 17: 213‐225, 1960.
 239.Thayer JF, Lane RD. A model of neurovisceral integration in emotion regulation and dysregulation. J Affect Disord 61: 201‐216, 2000.
 240.Thayer JF, Lane RD. Claude Bernard and the heart‐brain connection: Further elaboration of a model of neurovisceral integration. Neurosci Biobehav Rev 33: 81‐88, 2009.
 241.Thornton JM, Aziz T, Schlugman D, Paterson DJ. Electrical stimulation of the midbrain increases heart rate and arterial blood pressure in awake humans. J Physiol 539: 615‐621, 2002.
 242.Thornton JM, Guz A, Murphy K, Griffith AR, Pedersen DL, Kardos A, Leff A, Adams L, Casadei B, Paterson DJ. Identification of higher brain centres that may encode the cardiorespiratory response to exercise in humans. J Physiol 533: 823‐836, 2001.
 243.Trachani E, Constantoyannis C, Sakellaropoulos GC, Stavrinou ML, Nikiforidis G, Chroni E. Heart rate variability in Parkinson's disease unaffected by deep brain stimulation. Acta Neurol Scand 126: 56‐61, 2012.
 244.Tsai HCCC, Pan JI, Hsieh HJ, Tsai ST, Hung HY, Chen SY. Acute stimulation effect of the ventral capsule/ventral striatum in patients with refractory – compulsive disorder – a double‐blinded trial. Neuropsychiatr Dis Treat 10: 63‐69, 2014.
 245.Valenstein E. Brain Control: A Critical Examination of Brain Stimulation and Psychosurgery. New York: John Wiley & Sons, 1973, p. 60‐61, 164‐168.
 246.Van der Horst VG, Holstege G. Sensory and motor components of reproductive behavior: Pathways and plasticity. Behav Brain Res 92: 157‐167, 1998.
 247.Van Straaten JJ. Abolition of electrically induced cortical seizures by stereotactic thalamic lesions. Evidence for descending thalamopontine medullar spinal connections in the centrencephalic epileptic system of the cat. Neurology 25: 141‐149, 1975.
 248.Vigneri S, Guaraldi P, Calandra‐Buonaura G, Terlizzi R, Cecere A, Barletta G, Cortelli P. Switching on the deep brain stimulation: Effects on cardiovascular regulation and respiration. Auton Neurosci 166: 81‐84, 2012.
 249.Waldrop TG, Stremel RW. Muscular contraction stimulates posterior hypothalamic neurons. Am J Phys 256: R348‐R356, 1989.
 250.Ward AA Jr. The cingular gyrus, area 24. J Neurophysiol 11: 13‐23, 1948.
 251.Wieling W, Schatz IJ. The consensus statement on the definition of orthostatic hypotension: A revisit after 13 years. J Hypertens 27: 935‐938, 2009.
 252.Wilkinson DJTJ, Lambert GW, Jennings GL, Schwarz RG, Jefferys D, Turner AG, Esler MD. Sympathetic activity in patients with panic disorder at rest, under laboratory mental stress, and during panic attacks. Arch Gen Psychiatry 55: 511‐520, 1998.
 253.Williams CA, Roberts JR, Freels DB. Changes in blood pressure during isometric contractions to fatigue in the cat after brain stem lesions: Effects of clonidine. Cardiovasc Res 24: 821‐833, 1990.
 254.Williamson JW, McColl R, Mathews D. Evidence for central command activation of the human insular cortex during exercise. J Appl Physiol 94: 1726‐1734, 2003.
 255.Williamson JW, McColl R, Mathews D, Mitchell JH, Raven PB, Morgan WP. Hypnotic manipulation of effort sense during dynamic exercise: Cardiovascular responses and brain activation. J Appl Physiol 90: 1392‐1399, 2001.
 256.Williamson JW, McColl R, Mathews D, Mitchell JH, Raven PB, Morgan WP. Brain activation by central command during actual and imagined handgrip under hypnosis. J Appl Physiol 92: 1317‐1324, 2002.
 257.Wilson MF, Clarke NP, Smith OA, Rushmer RF. Interrelation between central and peripheral mechanisms regulating blood pressure. Circ Res 9: 491‐496, 1961.
 258.Winge K, Fowler CJ. Bladder dysfunction in Parkinsonism: Mechanisms, prevalence, symptoms, and management. Mov Disord 21: 737‐745, 2006.
 259.Yasui Y, Cechetto DF, Saper CB. Evidence for a cholinergic projection from the pedunculopontine tegmental nucleus to the rostral ventrolateral medulla in the rat. Brain Res 517: 19‐24, 1990.
 260.Young RF, Rinaldi PC. Brain Stimulation. New York: Springer, 1997, p. 288‐290.
 261.Zahn TP, Grafman J, Tranel D. Frontal lobe lesions and electrodermal activity: Effects of significance. Neuropsychologia 37: 1227‐1241, 1999.
 262.Zernov D. Encephalometer: Device for estimation of parts of brain in humans [in Russian]. Proc Soc Physicomed Moscow Univ 2: 70‐80, 1889.
 263.Zuntz N, Geppert J. Uber die Natur der normalen Atemreize und den ort ihrer Wirkung. Arch Gen Physiol 38: 337‐338, 1886.

Contact Editor

Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite

Alexander L. Green, David J. Paterson. Using Deep Brain Stimulation to Unravel the Mysteries of Cardiorespiratory Control. Compr Physiol null, 10: 1085-1104. doi: 10.1002/cphy.c190039