- About this Journal ·
- Abstracting and Indexing ·
- Aims and Scope ·
- Annual Issues ·
- Article Processing Charges ·
- Author Guidelines ·
- Bibliographic Information ·
- Citations to this Journal ·
- Contact Information ·
- Editorial Board ·
- Editorial Workflow ·
- Free eTOC Alerts ·
- Publication Ethics ·
- Recently Accepted Articles ·
- Reviewers Acknowledgment ·
- Submit a Manuscript ·
- Subscription Information ·
- Table of Contents
Journal of Biomedicine and Biotechnology
Volume 2012 (2012), Article ID 587590, 8 pages
Posterior Circulation Stroke: Animal Models and Mechanism of Disease
1Division of Physiology, Department of Basic Science, Loma Linda University School of Medicine, 11041 Campus Street, Risley Hall, CA 92354, USA
2Department of Family Medicine, Charles Drew University of Medicine and Science, Los Angeles, CA 90059-2518, USA
Received 10 January 2012; Revised 6 March 2012; Accepted 12 March 2012
Academic Editor: Andrea Vecchione
Copyright © 2012 Tim Lekic and Chizobam Ani. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Posterior circulation stroke refers to the vascular occlusion or bleeding, arising from the vertebrobasilar vasculature of the brain. Clinical studies show that individuals who experience posterior circulation stroke will develop significant brain injury, neurologic dysfunction, or death. Yet the therapeutic needs of this patient subpopulation remain largely unknown. Thus understanding the causative factors and the pathogenesis of brain damage is important, if posterior circulation stroke is to be prevented or treated. Appropriate animal models are necessary to achieve this understanding. This paper critically integrates the neurovascular and pathophysiological features gleaned from posterior circulation stroke animal models into clinical correlations.
The posterior circulation is an understudied brain region that is affected by stroke. When translational research progresses to clinical trials, most trials will enroll very few or completely exclude posterior stroke patients [1–5]. Though posterior circulation strokes are too uncommon in many population centers to achieve sufficient numbers, other studies try to control for the heterogeneity between the anterior and posterior circulations [6, 7]. This leads to evidence-based guidelines which may not sufficiently represent some important spectrums of stroke. For these reasons, experimental animal models could be a useful tool to address emerging posterior circulation treatment strategies . In this paper, we will integrate clinical features with animal models in describing characteristics of posterior circulation strokes, including the neurovascular features, and pathophysiology mechanisms founded from these experimental models.
2. Hemodynamic Posterior Circulation
The posterior circulation originates from the paired vertebral arteries and a single basilar artery, to supply the inferior thalamus, occipital lobes, midbrain, cerebellum, and brainstem. At the pontomedullary junction, the vertebral arteries fuse to form the basilar artery, which then courses along the ventral aspect of the pons and mesencephalon . From the basilar artery, dorsolateral (circumferential) superficial vessels branch out to the lateral sides and course toward the cerebellum, while deep (paramedian) branches perforate directly into the brainstem, along the ventral aspect. The basilar artery terminates at the mesencephalic cistern, with perforator branches to parts of the diencephalon, and bifurcation into the paired posterior cerebral arteries (PCAs). The PCAs course laterally to combine with the posterior communicating arteries (PComAs) and then continue to supply parts of the occipital and temporal cortices. The circumferential, paramedian, and other perforator branches are called terminal vascular branches, which lack collateral flow and may potentiate focal ischemia during vertebrobasilar vessel occlusions. The pontine paramedian and the lateral cerebellar circumferential branches are the most common sites of hemorrhage. Several clinical syndromes (Table 1) are described for posterior circulation vascular injuries [10, 11].
Vascular reserve within the basilar circulation includes bidirectional flow through the AICA, PICA, and cerebellar leptomeninges [12, 13]. The leptomeningeal interconnections between cerebellar arteries are similar to the cerebral pial network and can reverse blood flow back through the tributaries of the basilar artery . Outside the posterior circulation, the direction of blood flow can be reversed through hemodynamic connections between PComA (posterior communicating artery), first PCA segment, and carotid circulation . Increased PComA vessel luminal size is directly proportional to improved patient outcome after basilar artery and first segmental PCA occlusions . Patients with PComAs greater than 1 mm in diameter have less ischemic injury during carotid territory occlusions . During basilar artery occlusion, PComAs reverse blood flow through the basilar bifurcation, PCA, and SCA (quadrigeminal plate) . However, individual variations in arterial anatomy and the collateral circulation are common (asymmetric or single vertebral arteries, SCA and AICA branching variants, small PComAs) and these can narrow the basilar artery, diminishing vascular reserve, and leading to a greater incidence and severity of stroke [14–18].
3. Transient Posterior Brain Injury
Around ten years ago (vertebrobasilar), transient ischemic attack (TIA) was defined as follows: “a brief episode of neurologic dysfunction caused by focal brain ischemia, with clinical symptoms typically lasting less than one hour, and without evidence of acute infarction” . VTIAs are half the duration of carotid territory TIAs  and generally perceived by clinicians as having a more benign course [20–25]. Consequently, VTIA patients receive less clinical investigation and treatment [26–28]. However, a systematic review of sixteen-thousand patients found no differences between carotid and vertebrobasilar TIAs, in the rate of stroke, death, or disability . In fact, VTIAs are more likely to convert into full-on strokes during the acute-phase, and a third will have a stroke within 5 years [29, 30].
4. Ischemic Posterior Brain Injury
One-quarter of all ischemic strokes are located in the vertebrobasilar (VB) territory [31, 32]. These are usually caused by thrombi/emboli and rarely from vertebral artery dissection of C1-2 vertebral level trauma . Patients with large vessel (basilar artery or intracranial VA) occlusions affecting the brainstem tend to have a worse prognosis while small lacunar occlusions generally do well, so long as cardiorespiratory centers are intact (; clinical features are summarized in Table 1).
Patient outcomes after VB ischemic stroke have been somewhat the subject of debate. The Oxfordshire Community Stroke Project  prospectively followed 129 patients and found a 14% mortality and 18% major disability rate, while the New England Medical Centre Posterior Circulation Registry (NEMC-PCR)  found a 4% (death) and 18% (disability) rate, with a prospective study of 407 patients. For basilar artery occlusion (BAO), the most severe form of VB ischemic stroke, a systematic analysis of 10 published case series and 344 patients, reported an overall death or dependency rate of 76% , while the NEMC-PCR study with 87 patients reported poor outcomes in 28–58% of patients .
5. Hemorrhagic Posterior Brain Injury
One-fifth of all intracerebral hemorrhage (ICH) occurs in the cerebellum or brainstem [36, 37]. Brainstem hemorrhages have a 65% mortality rate and around 40% after cerebellar hemorrhage [38–40]. Prolonged endovascular cerebrovascular damage from uncontrolled hypertension leads to arteriosclerotic and amyloid angiopathic changes, vessel fragility, and rupture at the deep cerebellar vessels or brainstem basilar (paramedian) branches [37, 41]. Less common relations to occurrence are cancer, coagulopathy, or vascular anomalies (arterial-venous malformations, aneurysms, cavernomas, and dural arteriovenous fistulas) [37, 41]. For most patients, supportive care is the only treatment rendered, since surgery is only available for one-quarter of hospitalized cerebellar hemorrhage patients, and the brainstem is not surgically accessible [42–45]. Mechanisms of infratentorial hemorrhage have never been studied and to this end we have developed animal models using collagenase to address this brain hemorrhage subpopulation [46, 47].
6. Animal Studies
Experimental models are available to study ischemic posterior circulation stroke . Many animal studies of anterior circulation ischemic stroke have demonstrated impaired autoregulation after ischemic stroke. The extent of which would depend on occlusion duration and extent of reperfusion hyperemia [49–51]. These mechanisms warrant further study—this can be achieved using available animal models of posterior circulation stroke. Under experimental conditions, the standardized progressive hypotension in rats showed that autoregulatory kinetics remained intact at the cerebrum, while a progressive loss of autoregulatory efficacy in the cerebellum . As a next step, however, changes in mean arterial blood pressure (MABP) and CO2 levels (in cats) while measuring blood flow (hydrogen clearance method) in the cerebrum, cerebellum, and spinal cord found greater susceptibility to pressure-dependant ischemia in the cerebrum and spinal cord than cerebellum, which was relatively resistant .
Corroborative studies  used transcranial Doppler methods for comparing blood flow in supratentorial and infratentorial brain compartments during increasing intracranial pressures, in the rabbit experimental model. Essentially, the maximum vasomotor activity amplitude of occurred 30 seconds later in the basilar artery, compared with the carotids. Such reports demonstrate that delays are present in the effect of intracranial pressure upon hindbrain microvascular tone. Using a canine experimental model of permanent occlusion to posterior cerebral artery perforators  with the ability to monitor cerebral blood flow (autoregulation) and carbon dioxide reactivity, in response to induced hypotension/hypertension, it was found that cerebral cortex maintained autoregulation and carbon dioxide reactivity, while thalamic autoregulation was maintained in hypotension, but not during episodic hypertension. On the other hand, the midbrain retained marked impaired autoregulation and carbon dioxide reactivity. Such findings reveal differential brain vulnerability following permanent vascular occlusions. In essence, animal studies indicate that brainstem nuclei decompensated compared to forebrain regions, despite abundant amounts of posterior collateral circulation.
The animal model of bilateral carotid ligation using spontaneously hypertensive rats showed impaired autoregulation in the cerebrum . However, the addition of stepwise drops in mean arterial pressures caused impairment of cerebellar autoregulation as well. Hypothetically, it is possible that vulnerability to hypotension in areas distant from the stroke ictus is modulated by alpha-adrenoceptor (vasoconstrictive) neurons responding to cerebral (transtentorial) hypertension signals . The collateral vascular compensation may be a function of age, since bilateral carotid occlusion causes greater dependence upon basilar flow in adult rats, compared to dependence upon extracerebral midline collaterals in younger experimental animals .
7. Animal Models: Vascular Responses to Stroke
Experimental studies reveal that similar cerebrovascular mechanisms are found after ischemic and hemorrhagic stroke . Normally, cerebrovascular autoregulation maintains optimal brain tissue perfusion through arterial constriction/dilation in response to local levels of CO2 and systemic variations of blood pressures (MABP) . Human stroke leads to damaged cerebral autoregulation capacity and greater dependence upon systemic arterial pressure [61–63] occurring after both carotid and vertebrobasilar-based vascular territories [62, 64]. This impairment is recognized as an important mechanism of secondary brain injury and edema formation, following human ischemic stroke  and intracerebral hemorrhage . There is a rationale behind the tight hemodynamic and respiratory control in the intensive care units.
Animal studies show that the vertebrobasilar vessels have a greater capacity to mechanically vasodilate and vasoconstrict compared to carotid-based vasculature, suggesting greater dynamic autoregulatory ability [67–69]. This may be a mechanism enabling the hindbrain to divert blood flow to the carotid system during cerebrovascular strain, since drops in total brain perfusion lead to proportionally greater diminished flow across the basilar compared to the middle-cerebral artery . When systemic CO2 and blood pressure changes are superimposed upon permanent posterior cerebral artery occlusion, in dogs, this showed graded autoregulatory decompensation caudally from the supratentorial region to the brainstem, while carotid-based autoregulation was preserved . Experiments in rats show cerebral sparing, while systemic hypotension causes progressive decline in cerebellar autoregulatory kinetics, and carotid autoregulatory kinetics remain intact . The impairment of cerebellar autoregulation also occurs after bilateral carotid ligation in spontaneously hypertensive rats . Conversely, the combination of hypocapnia with systemic hypotension, in cats, caused greater ischemic susceptibility in cortical brain-regions compared with the cerebellum . Cerebellar autoregulatory kinetics may, therefore, accommodate CO2 fluctuation more favorably, in the face of hypoperfusion, while drops in arterial pressures, without systemic CO2 change, would affect the cerebellum more severely .
In most species, the cerebellum and brainstem have an abundance of white matter tracts. Magnetic resonance imaging (MRI) perfusion and diffusion studies in humans have determined white matter to have an infarction threshold of 20 mL/100 g/minute, while gray matter can sustain flow down to infarctions starting at 12 mL/100 g/minute . A greater density of white matter tracts in the hindbrain would imply greater vulnerability to ischemic injury. Therefore the viability of brainstem cardiorespiratory centers during periods of severe systemic hypotension, global cerebral ischemia, and cardiac arrest will necessitate further study.
8. Animal Models: Neural Consequences from Stroke
Animal models show that ischemic interruption of cerebral blood flow leads to hypoxic and anoxic brain injury, increased neuronal excitability, and cell death . Reperfusion injury further augments this damage through free radial production and mitochondrial dysfunction [73, 74] and similar mechanisms are at play after hemorrhagic stroke also . Neurons in the CA1 hippocampal region are particularly vulnerable to ischemia; yet, experimentally, these cells are more resistant to damage than several areas of the hindbrain [75, 76]. Electrophysiological studies after hypoxic injury have shown greater neuronal excitability in the hypoglossal (CNXII) and dorsal vagal motor (DVMN) cranial nuclei of the brainstem compared to hippocampal CA1 regions . Animal models show that anoxia of the hypoglossal nucleus will have both greater initial injury and impaired recovery compared with these temporal lobe neurons . In vitro simulation of ischemic reperfusion injury, using cell cultures of oxygen-glucose deprivation followed by reoxygenation (OGD-R), showed greater free-radical injury (lipid peroxidation) and mitochondrial impairment in cerebellar cells compared to cerebral cortical cell culture . Experiments comparing cerebellum with brainstem injury, after vertebral arterial occlusions in gerbils, showed greatest amount of cell death near regions controlling coordination and balance (cerebellar interpositus and lateral vestibular nuclei), while brainstem cardiorespiratory areas remain relatively more intact . The scattered mosaic nature of brainstem nuclei means that this is not simply a redistribution of blood flow and is likely a feature of the neuronal environment, and this deserves further study.
Experimental studies reveal significant cerebellar fastigial nuclei (FN) involvement in the regulation of blood pressure and flow [79–81]. This occurs via integration of autonomic signals from vestibular and cerebellar Purkinje neurons [82, 83]. FN also modulate the function of adjacent medullary structures and autonomic spinal intermediolateral column neurons [84, 85]. In primates, these nuclei interconnect with vestibular (lateral and inferior), reticular (lateral, paramedian, and gigantocellular), and cervical spinal anterior gray neurons . Animal models demonstrate that electrical stimulation of the FN leads to pressor responses with tachycardia, as mediated by fibers passing through, or very close to, the FN, while chemical activation causes a depressor response, with bradycardia via intrinsic FN neuronal activity [87–89]. Taken together, cerebellar fastigial nuclei serve important cardiovascular functions, the manner of which is of significant clinical interest, since cerebellar injury in association with cardiopulmonary consequences is a common occurrence [90–93].
Neurons of the area postrema (AP) also contribute to cardiovascular regulation [94–97]. Biochemically, the cell-surface receptors of circulating molecules: angiotensin II (AT1), and vasopressin (V1), are expressed within this brain region [98–100]. Here, the angiotensin II neurohormone can reset the baroreflex to higher blood pressure levels through indirect interactions with the nucleus of the solitary tract and interconnections within the medulla [101–103]. These nuclei can also modulate the cardiovascular regulatory effects of other neuropeptides—such as vasopressin. While this homeostatic effector readily binds somatic V2 type receptors, causing peripheral vasoconstriction, V1 receptor binding-interactions within the area postrema will paradoxically enhance baroreflex sensitivity towards activation at lower threshold pressure set-points [104–106]. All together, these pathways help keep the balance of complex cerebrovascular systems.
9. Development and Gender
Young children exhibit sex differences in the autoregulatory capacity between anterior and posterior circulations. Female children, ages 4–8 years, have higher flow velocities for both the middle cerebral and basilar arteries, while both sexes exhibit greater flow velocity in the middle cerebral compared to basilar arteries . Later, autoregulatory capacities begin to emerge with females (10–16 years old) having greater capacity in the basilar artery than males, but males having the advantage of greater MCA autoregulatory index . Up through adolescence, however, females continue to have higher flow velocities (compared to males) for both the middle cerebral and basilar arteries. This may indicate a gender-specific ability to handle an occlusive thrombus in the hindbrain. Further studies are needed to understand these gender differences.
The hindbrain injury pathogenesis, prevention, and treatment remain largely unknown, and animal models may be necessary to achieve this understanding. Furthermore, injury to this area can be particularly devastating. This brain region may have less innate neurovascular protective mechanisms and greater amount of cell death and injury in comparison to supratentorial strokes. Significant experimental study has been done for posterior circulation stroke. Future studies can choose from an array of animal models, to test interventions for reversing the mechanisms of injury in this brain region. The strength of this paper is related to the comprehensive nature of the information presented. In limitation, future reports will need to further critically appraise the reported data in the context of available evidence.
The authors wish to thank Professor John H. Zhang for his constant and consistent support and encouragement throughout the years.
- M. A. Foulkes, P. A. Wolf, T. R. Price, J. P. Mohr, and D. B. Hier, “The stroke data bank: design, methods, and baseline characteristics,” Stroke, vol. 19, no. 5, pp. 547–554, 1988.
- W. M. Clark, S. Wissman, G. W. Albers, J. H. Jhamandas, K. P. Madden, and S. Hamilton, “Recombinant tissue-type plasminogen activator (Alteplase) for ischemic stroke 3 to 5 hours after symptom onset. The ATLANTIS Study: a randomized controlled trial. Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke,” Journal of the American Medical Association, vol. 282, no. 21, pp. 2019–2026, 1999.
- W. Hacke, M. Kaste, C. Fieschi et al., “Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke: the European Cooperative Acute Stroke Study (ECASS),” Journal of the American Medical Association, vol. 274, no. 13, pp. 1017–1025, 1995.
- A. D. Mendelow and A. Unterberg, “Surgical treatment of intracerebral haemorrhage,” Current Opinion in Critical Care, vol. 13, no. 2, pp. 169–174, 2007.
- W. M. Clark, G. W. Albers, K. P. Madden, and S. Hamilton, “The rtPA (alteplase) 0- to 6-hour acute stroke trial, part A (A0276g) : results of a double-blind, placebo-controlled, multicenter study. Thromblytic therapy in acute ischemic stroke study investigators,” Stroke, vol. 31, no. 4, pp. 811–816, 2000.
- M. Macleod, “Current issues in the treatment of acute posterior circulation stroke,” CNS Drugs, vol. 20, no. 8, pp. 611–621, 2006.
- M. R. Macleod, S. M. Davis, P. J. Mitchell et al., “Results of a multicentre, randomised controlled trial of intra-arterial urokinase in the treatment of acute posterior circulation lschaemic stroke,” Cerebrovascular Diseases, vol. 20, no. 1, pp. 12–17, 2005.
- T. Lekic, P. R. Krafft, J. S. Coats, A. Obenaus, J. Tang, and J. H. Zhang, “Infratentorial strokes for posterior circulation folks: clinical correlations for current translational therapeutics,” Translational Stroke Research, vol. 2, no. 2, pp. 144–151, 2011.
- H. Duvemoy, Human Brain Stem Vessels, Springer, Berlin, Germany, 1999.
- L. Worthley and A. W. Holt, “Acute ischaemic stroke: part II. The vertebrobasilar circulation,” Critical care and Resuscitation, vol. 2, no. 2, pp. 140–145, 2000.
- A. Ferbert, H. Bruckmann, and R. Drummen, “Clinical features of proven basilar artery occlusion,” Stroke, vol. 21, no. 8, pp. 1135–1142, 1990.
- E. de Oliveira, H. Tedeschi, A. Rhoton, and D. Peace, “Microsurgical anatomy of the posterior circulation: vertebral and basilar arteries,” in Neurovascular Surgery, L. Carter, R. Spetzler, and M. Hamilton, Eds., pp. 25–34, McGraw-Hill, New York, NY, USA, 1995.
- J. R. Lister, A. L. Rhoton Jr., T. Matsushima, and D. A. Peace, “Microsurgical anatomy of the posterior inferior cerebellar artery,” Neurosurgery, vol. 10, no. 2, pp. 170–199, 1982.
- M. Bergui, P. Cerrato, and G. B. Bradac, “Stroke attributable to acute basilar occlusion,” Current Treatment Options in Neurology, vol. 9, no. 2, pp. 126–135, 2007.
- G. K. Steinberg, C. G. Drake, and S. J. Peerless, “Deliberate basilar or vertebral artery occlusion in the treatment of intracranial aneurysms. Immediate results and long-term outcome in 201 patients,” Journal of Neurosurgery, vol. 79, no. 2, pp. 161–173, 1993.
- D. F. Schomer, M. P. Marks, G. K. Steinberg et al., “The anatomy of the posterior communicating artery as a risk factor for ischemic cerebral infarction,” The New England Journal of Medicine, vol. 330, no. 22, pp. 1565–1570, 1994.
- V. Ganesan, W. K. Chong, T. C. Cox, S. J. Chawda, M. Prengler, and F. J. Kirkham, “Posterior circulation stroke in childhood: risk factors and recurrence,” Neurology, vol. 59, no. 10, pp. 1552–1556, 2002.
- S. Chaturvedi, T. G. Lukovits, W. Chen, and P. B. Gorelick, “Ischemia in the territory of a hypoplastic vertebrobasilar system,” Neurology, vol. 52, no. 5, pp. 980–983, 1999.
- G. W. Albers, L. R. Caplan, J. D. Easton et al., “Transient ischemic attack—proposal for a new definition,” The New England Journal of Medicine, vol. 347, no. 21, pp. 1713–1716, 2002.
- F. H. McDowell, J. Potes, and S. Groch, “The natural history of internal carotid and vertebral-basilar artery occlusion,” Neurology, vol. 11, no. 4, part 2, pp. 153–157, 1961.
- J. E. Olsson, R. Muller, and S. Bernell, “Long term anticoagulant therapy for TIAs and minor strokes with minimum residuum,” Stroke, vol. 7, no. 5, pp. 444–451, 1976.
- T. M. Turney, W. M. Garraway, and J. P. Whisnant, “The natural history of hemispheric and brainstem infarction in Rochester, Minnesota,” Stroke, vol. 15, no. 5, pp. 790–794, 1984.
- D. K. Ziegler and R. S. Hassanein, “Prognosis in patients with transient ischemic attacks,” Stroke, vol. 4, no. 4, pp. 666–673, 1973.
- J. Marshall, “The natural history of transient ischaemic cerebro-vascular attacks,” The Quarterly Journal of Medicine, vol. 33, pp. 309–324, 1964.
- J. Sivenius, P. J. Riekkinen, P. Smets, M. Laakso, and A. Lowenthal, “The European stroke prevention study (ESPS): results by arterial distribution,” Annals of Neurology, vol. 29, no. 6, pp. 596–600, 1991.
- E. Floßmann and P. M. Rothwell, “Prognosis of vertebrobasilar transient ischaemic attack and minor stroke,” Brain, vol. 126, no. 9, pp. 1940–1954, 2003.
- A. Culebras, C. S. Kase, J. C. Masdeu et al., “Practice guidelines for the use of imaging in transient ischemic attacks and acute stroke: a report of the Stroke Council, American Heart Association,” Stroke, vol. 28, no. 7, pp. 1480–1497, 1997.
- P. J. Martin, “Vertebrobasilar ischaemia,” Monthly Journal of the Association of Physicians, vol. 91, no. 12, pp. 799–811, 1998.
- J. C. Wehman, R. A. Hanel, C. A. Guidot, L. R. Guterman, and L. N. Hopkins, “Atherosclerotic occlusive extracranial vertebral artery disease: indications for intervention, endovascular techniques, short-term and long-term results,” Journal of Interventional Cardiology, vol. 17, no. 4, pp. 219–232, 2004.
- C. R. Hornig, C. Lammers, T. Buttner, O. Hoffmann, and W. Dorndorf, “Long-term prognosis of infratentorial transient ischemic attacks and minor strokes,” Stroke, vol. 23, no. 2, pp. 199–204, 1992.
- J. Bamford, P. Sandercock, M. Dennis, J. Burn, and C. Warlow, “Classification and natural history of clinical identifiable subtypes of cerebral infarction,” The Lancet, vol. 337, no. 8756, pp. 1521–1526, 1991.
- J. Bogousslavsky, G. Van Melle, and F. Regli, “The lausanne stroke registry: analysis of 1,000 consecutive patients with first stroke,” Stroke, vol. 19, no. 9, pp. 1083–1092, 1988.
- T. A. Glass, P. M. Hennessey, L. Pazdera et al., “Outcome at 30 days in the new England medical center posterior circulation registry,” Archives of Neurology, vol. 59, no. 3, pp. 369–376, 2002.
- P. J. Lindsberg and H. P. Mattle, “Therapy of basilar artery occlusion: a systematic analysis comparing intra-arterial and intravenous thrombolysis,” Stroke, vol. 37, no. 3, pp. 922–928, 2006.
- B. Voetsch, L. D. DeWitt, M. S. Pessin, and L. R. Caplan, “Basilar artery occlusive disease in the New England Medical Center Posterior Circulation Registry,” Archives of Neurology, vol. 61, no. 4, pp. 496–504, 2004.
- M. L. Flaherty, D. Woo, M. Haverbusch et al., “Racial variations in location and risk of intracerebral hemorrhage,” Stroke, vol. 36, no. 5, pp. 934–937, 2005.
- G. R. Sutherland and R. N. Auer, “Primary intracerebral hemorrhage,” Journal of Clinical Neuroscience, vol. 13, no. 5, pp. 511–517, 2006.
- M. L. Flaherty, M. Haverbusch, P. Sekar et al., “Long-term mortality after intracerebral hemorrhage,” Neurology, vol. 66, no. 8, pp. 1182–1186, 2006.
- K. Balci, T. Asil, M. Kerimoglu, Y. Celik, and U. Utku, “Clinical and neuroradiological predictors of mortality in patients with primary pontine hemorrhage,” Clinical Neurology and Neurosurgery, vol. 108, no. 1, pp. 36–39, 2005.
- M. D. Hill, F. L. Silver, P. C. Austin, and J. V. Tu, “Rate of stroke recurrence in patients with primary intracerebral hemorrhage,” Stroke, vol. 31, no. 1, pp. 123–127, 2000.
- A. I. Qureshi, S. Tuhrim, J. P. Broderick, H. H. Batjer, H. Hondo, and D. F. Hanley, “Spontaneous intracerebral hemorrhage,” The New England Journal of Medicine, vol. 344, no. 19, pp. 1450–1460, 2001.
- S. Tuhrim, “Intracerebral hemorrhage—improving outcome by reducing volume?” The New England Journal of Medicine, vol. 358, no. 20, pp. 2174–2176, 2008.
- O. Adeoye, D. Woo, M. Haverbusch et al., “Surgical management and case-fatality rates of intracerebral hemorrhage in 1988 and 2005,” Neurosurgery, vol. 63, no. 6, pp. 1113–1117, 2008.
- J. Morioka, M. Fujii, S. Kato et al., “Surgery for spontaneous intracerebral hemorrhage has greater remedial value than conservative therapy,” Surgical Neurology, vol. 65, no. 1, pp. 67–72, 2006.
- M. E. Fewel, B. G. Thompson, and J. T. Hoff, “Spontaneous intracerebral hemorrhage: a review,” Neurosurgical Focus, vol. 15, no. 4, article E1, 2003.
- T. Lekic, W. Rolland, R. Hartman et al., “Characterization of the brain injury, neurobehavioral profiles, and histopathology in a rat model of cerebellar hemorrhage,” Experimental Neurology, vol. 227, no. 1, pp. 96–103, 2011.
- T. Lekic, J. Tang, and J. H. Zhang, “A rat model of pontine hemorrhage,” Acta Neurochirurgica, Supplementum, no. 105, pp. 135–137, 2008.
- T. Lekic and J. H. Zhang, “Posterior circulation stroke and animal models,” Frontiers in Bioscience, vol. 13, no. 5, pp. 1827–1844, 2008.
- J. C. Drummond, Y. S. Oh, D. J. Cole, and H. M. Shapiro, “Phenylephrine-induced hypertension reduces ischemia following middle cerebral artery occlusion in rats,” Stroke, vol. 20, no. 11, pp. 1538–1544, 1989.
- M. J. Cipolla, A. L. McCall, N. Lessov, and J. M. Porter, “Reperfusion decreases myogenic reactivity and alters middle cerebral artery function after focal cerebral ischemia in rats,” Stroke, vol. 28, no. 1, pp. 176–180, 1997.
- L. Olah, C. Franke, W. Schwindt, M. Hoehn, and M. Fisher, “CO2 reactivity measured by perfusion MRI during transient focal cerebral ischemia in rats,” Stroke, vol. 31, no. 9, pp. 2236–2244, 2000.
- S. Merzeau, M. P. Preckel, B. Fromy, G. Lefthériotis, and J. L. Saumet, “Differences between cerebral and cerebellar autoregulation during progressive hypotension in rats,” Neuroscience Letters, vol. 280, no. 2, pp. 103–106, 2000.
- M. Sato, G. Pawlik, and W. D. Heiss, “Comparative studies of regional CNS blood flow autoregulation and responses to CO2 in the cat. Effects of altering arterial blood pressure and PaCO2 on rCBF of cerebrum, cerebellum, and spinal cord,” Stroke, vol. 15, no. 1, pp. 91–97, 1984.
- J. M. de Bray, F. Tranquart, J. L. Saumet, M. Berson, and L. Pourcelot, “Cerebral vasodilation capacity: acute intracranial hypertension and supra- and infra- tentorial artery velocity recording,” Clinical Physiology, vol. 14, no. 5, pp. 501–512, 1994.
- S. Matsumoto, S. Kuwabara, and K. Moritake, “Effects of cerebrovascular autoregulation and CO2 reactivity in experimental localized brainstem infarction,” Neurological Research, vol. 22, no. 2, pp. 197–203, 2000.
- O. Shiokawa, S. Sadoshima, K. Kusuda, Y. Nishimura, S. Ibayashi, and M. Fujishima, “Cerebral and cerebellar blood flow autoregulations in acutely induced cerebral ischemia in spontaneously hypertensive rats—transtentorial remote effect,” Stroke, vol. 17, no. 6, pp. 1309–1313, 1986.
- O. Shiokawa, S. Sadoshima, K. Fujii, H. Yao, and M. Fujishima, “Impairment of cerebellar blood flow autoregulation during cerebral ischemia in spontaneously hypertensive rats,” Stroke, vol. 19, no. 5, pp. 615–622, 1988.
- M. Choy, V. Ganesan, D. L. Thomas et al., “The chronic vascular and haemodynamic response after permanent bilateral common carotid occlusion in newborn and adult rats,” Journal of Cerebral Blood Flow and Metabolism, vol. 26, no. 8, pp. 1066–1075, 2006.
- G. Xi, R. F. Keep, and J. T. Hoff, “Mechanisms of brain injury after intracerebral haemorrhage,” Lancet Neurology, vol. 5, no. 1, pp. 53–63, 2006.
- S. S. Kety and C. F. Schmidt, “The effects of altered arterial tensions of carbon dioxide and oxygen on cerebral blood flow and cerebral oxygen consumption of normal young men,” The Journal of Clinical Investigation, vol. 27, no. 4, pp. 484–492, 1948.
- P. J. Eames, M. J. Blake, S. L. Dawson, R. B. Panerai, and J. F. Potter, “Dynamic cerebral autoregulation and beat to beat blood pressure control are impaired in acute ischaemic stroke,” Journal of Neurology Neurosurgery and Psychiatry, vol. 72, no. 4, pp. 467–472, 2002.
- S. L. Dawson, R. B. Panerai, and J. F. Potter, “Serial changes in static and dynamic cerebral autoregulation after acute ischaemic stroke,” Cerebrovascular Diseases, vol. 16, no. 1, pp. 69–75, 2003.
- S. Schwarz, D. Georgiadis, A. Aschoff, and S. Schwab, “Effects of body position on intracranial pressure and cerebral perfusion in patients with large hemispheric stroke,” Stroke, vol. 33, no. 2, pp. 497–501, 2002.
- S. L. Dawson, M. J. Blake, R. B. Panerai, and J. F. Potter, “Dynamic but not static cerebral autoregulation is impaired in acute ischaemic stroke,” Cerebrovascular Diseases, vol. 10, no. 2, pp. 126–132, 2000.
- C. Dohmen, B. Bosche, R. Graf et al., “Identification and clinical impact of impaired cerebrovascular autoregulation in patients with malignant middle cerebral artery infarction,” Stroke, vol. 38, no. 1, pp. 56–61, 2007.
- J. Diedler, M. Sykora, A. Rupp et al., “Impaired cerebral vasomotor activity in spontaneous intracerebral hemorrhage,” Stroke, vol. 40, no. 3, pp. 815–819, 2009.
- H. Ito, I. Yokoyama, H. Iida et al., “Regional differences in cerebral vascular response to PaCO2 changes in humans measured by positron emission tomography,” Journal of Cerebral Blood Flow and Metabolism, vol. 20, no. 8, pp. 1264–1270, 2000.
- W. Hida, Y. Kikuchi, S. Okabe, H. Miki, H. Kurosawa, and K. Shirato, “CO2 response for the brain stem artery blood flow velocity in man,” Respiration Physiology, vol. 104, no. 1, pp. 71–75, 1996.
- M. Reinhard, Z. Waldkircher, J. Timmer, C. Weiller, and A. Hetzel, “Cerebellar autoregulation dynamics in humans,” Journal of Cerebral Blood Flow and Metabolism, vol. 28, no. 9, pp. 1605–1612, 2008.
- L. Garbin, F. Habetswallner, and A. Clivati, “Vascular reactivity in middle cerebral artery and basilar artery by transcranial Doppler in normals subjects during hypoxia,” Italian Journal of Neurological Sciences, vol. 18, no. 3, pp. 135–137, 1997.
- M. S. Bristow, J. E. Simon, R. A. Brown et al., “MR perfusion and diffusion in acute ischemic stroke: human gray and white matter have different thresholds for infarction,” Journal of Cerebral Blood Flow and Metabolism, vol. 25, no. 10, pp. 1280–1287, 2005.
- N. Fujiwara, H. Higashi, K. Shimoji, and M. Yoshimura, “Effects of hypoxia on rat hippocampal neurones in vitro,” Journal of Physiology, vol. 384, pp. 131–151, 1987.
- T. Back, “Pathophysiology of the ischemic penumbra—revision of a concept,” Cellular and Molecular Neurobiology, vol. 18, no. 6, pp. 621–638, 1998.
- F. Facchinetti, V. L. Dawson, and T. M. Dawson, “Free radicals as mediators of neuronal injury,” Cellular and Molecular Neurobiology, vol. 18, no. 6, pp. 667–682, 1998.
- R. Hata, M. Matsumoto, T. Hatakeyama et al., “Differential vulnerability in the hindbrain neurons and local cerebral blood flow during bilateral vertebral occlusion in gerbils,” Neuroscience, vol. 56, no. 2, pp. 423–439, 1993.
- D. F. Donnelly, C. Jiang, and G. G. Haddad, “Comparative responses of brain stem and hippocampal neurons to O2 deprivation: in vitro intracellular studies,” American Journal of Physiology, vol. 262, no. 5, pp. L549–L554, 1992.
- J. P. O'Reilly, C. Jiang, and G. G. Haddad, “Major differences in response to graded hypoxia between hypoglossal and neocortical neurons,” Brain Research, vol. 683, no. 2, pp. 179–186, 1995.
- A. Scorziello, C. Pellegrini, L. Forte, et al., “Differential vulnerability of cortical and cerebellar neurons in primary culture to oxygen glucose deprivation followed by reoxygenation,” Journal of Neuroscience Research, vol. 63, no. 1, pp. 20–26, 2001.
- L. O. Lutherer, B. C. Lutherer, and K. J. Dormer, “Bilateral lesions of the fastigial nucleus prevent the recovery of blood pressure following hypotension induced by hemorrhage or administration of endotoxin,” Brain Research, vol. 269, no. 2, pp. 251–257, 1983.
- M. Miura and D. J. Reis, “Cerebellum: a pressor response elicited from the fastigial nucleus and its efferent pathway in brainstem,” Brain Research, vol. 13, no. 3, pp. 595–599, 1969.
- F. Xu, T. Zhou, T. Gibson, and D. T. Frazier, “Fastigial nucleus-mediated respiratory responses depend on the medullary gigantocellular nucleus,” Journal of Applied Physiology, vol. 91, no. 4, pp. 1713–1722, 2001.
- N. Doba and D. J. Reis, “Role of the cerebellum and the vestibular apparatus in regulation of orthostatic reflexes in the cat,” Circulation Research, vol. 40, no. 4, pp. 9–18, 1974.
- B. J. Yates, “Vestibular influences on the autonomic nervous system,” Annals of the New York Academy of Sciences, vol. 781, pp. 458–373, 1996.
- M. M. Caverson, J. Ciriello, and F. R. Calaresu, “Direct pathway from cardiovascular neurons in the ventrolateral medulla to the region of the intermediolateral nucleus of the upper thoracic cord: an anatomical and electrophysiological investigation in the cat,” Journal of the Autonomic Nervous System, vol. 9, no. 2-3, pp. 451–475, 1983.
- R. A. Dampney, A. K. Goodchild, L. G. Robertson, and W. Montgomery, “Role of ventrolateral medulla in vasomotor regulation: a correlative anatomical and physiological study,” Brain Research, vol. 249, no. 2, pp. 223–235, 1982.
- R. R. Batton, A. Jayaraman, D. Ruggiero, and M. B. Carpenter, “Fastigial efferent projections in the monkey: an autoradiographic study,” Journal of Comparative Neurology, vol. 174, no. 2, pp. 281–305, 1977.
- K. Chida, C. Iadecola, M. D. Underwood, and D. J. Reis, “A novel vasodepressor response elicited from the rat cerebellar fastigial nucleus: the fastigial depressor response,” Brain Research, vol. 370, no. 2, pp. 378–382, 1986.
- K. Chida, C. Iadecola, and D. J. Reis, “Lesions of rostral ventrolateral medulla abolish some cardio- and cerebrovascular components of the cerebellar fastigial pressor and depressor responses,” Brain Research, vol. 508, no. 1, pp. 93–104, 1990.
- T. J. Parry and J. C. McElligott, “Kainic administration in the fastigial nucleus produces differential cardiovascular effects in awake and anesthetized rats,” Brain Research, vol. 635, no. 1-2, pp. 27–36, 1994.
- M. L. Chen, M. B. Witmans, M. A. Tablizo et al., “Disordered respiratory control in children with partial cerebellar resections,” Pediatric Pulmonology, vol. 40, no. 1, pp. 88–91, 2005.
- P. M. Macey, L. A. Henderson, K. E. Macey et al., “Brain morphology associated with obstructive sleep apnea,” American Journal of Respiratory and Critical Care Medicine, vol. 166, no. 10, pp. 1382–1387, 2002.
- R. Kumar, P. M. Macey, M. A. Woo, J. R. Alger, T. G. Keens, and R. M. Harper, “Neuroanatomic deficits in congenital central hypoventilation syndrome,” Journal of Comparative Neurology, vol. 487, no. 4, pp. 361–371, 2005.
- M. A. Woo, P. M. Macey, G. C. Fonarow, M. A. Hamilton, and R. M. Harper, “Regional brain gray matter loss in heart failure,” Journal of Applied Physiology, vol. 95, no. 2, pp. 677–684, 2003.
- P. Ylitalo, H. Karppanen, and M. K. Paasonen, “Is the area postrema a control centre of blood pressure?” Nature, vol. 247, no. 5435, pp. 58–59, 1974.
- M. D. Joy and R. D. Lowe, “Evidence that the area postrema mediates the central cardiovascular response to angiotensin II,” Nature, vol. 228, no. 5278, pp. 1303–1304, 1970.
- C. J. Price, T. D. Hoyda, and A. V. Ferguson, “The area postrema: a brain monitor and integrator of systemic autonomic state,” Neuroscientist, vol. 14, no. 2, pp. 182–194, 2008.
- S. Sisó, M. Jeffrey, and L. González, “Sensory circumventricular organs in health and disease,” Acta Neuropathologica, vol. 120, no. 6, pp. 689–705, 2010.
- R. Gerstberger and F. Fahrenholz, “Autoradiographic localization of V1 vasopressin binding sites in rat brain and kidney,” European Journal of Pharmacology, vol. 167, no. 1, pp. 105–116, 1989.
- Z. Lenkei, M. Palkovits, P. Corvol, and C. Llorens-Cortès, “Expression of angiotensin type-1 (AT1) and type-2 (AT2) receptor mRNAs in the adult rat brain: a functional neuroanatomical review,” Frontiers in Neuroendocrinology, vol. 18, no. 4, pp. 383–439, 1997.
- J. Huang, Y. Hara, J. Anrather, R. C. Speth, C. Iadecola, and V. M. Pickel, “Angiotensin II subtype 1A (AT1A) receptors in the rat sensory vagal complex: subcellular localization and association with endogenous angiotensin,” Neuroscience, vol. 122, no. 1, pp. 21–36, 2003.
- J. W. Osborn, G. D. Fink, A. F. Sved, G. M. Toney, and M. K. Raizada, “Circulating angiotensin II and dietary salt: converging signals for neurogenic hypertension,” Current Hypertension Reports, vol. 9, no. 3, pp. 228–235, 2007.
- S. McMullan, A. K. Goodchild, and P. M. Pilowsky, “Circulating angiotensin II attenuates the sympathetic baroreflex by reducing the barosensitivity of medullary cardiovascular neurones in the rat,” Journal of Physiology, vol. 582, no. 2, pp. 711–722, 2007.
- B. Xue, H. Gole, J. Pamidimukkala, and M. Hay, “Role of the area postrema in angiotensin II modulation of baroreflex control of heart rate in conscious mice,” American Journal of Physiology, vol. 284, no. 3, pp. H1003–H1007, 2003.
- R. Oikawa, Y. Nasa, R. Ishii et al., “Vasopressin V1A receptor enhances baroreflex via the central component of the reflex arc,” European Journal of Pharmacology, vol. 558, no. 1–3, pp. 144–150, 2007.
- T. A. Koshimizu, Y. Nasa, A. Tanoue et al., “V1a vasopressin receptors maintain normal blood pressure by regulating circulating blood volume and baroreflex sensitivity,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 20, pp. 7807–7812, 2006.
- B. F. Cox, M. Hay, and V. S. Bishop, “Neurons in area postrema mediate vasopressin-induced enhancement of the baroreflex,” American Journal of Physiology, vol. 258, no. 6, part 2, pp. H1943–H1946, 1990.
- N. Tontisirin, S. L. Muangman, P. Suz et al., “Early childhood gender differences in anterior and posterior cerebral blood flow velocity and autoregulation,” Pediatrics, vol. 119, no. 3, pp. e610–e615, 2007.
- M. S. Vavilala, M. S. Kincaid, S. L. Muangman, P. Suz, I. Rozet, and A. M. Lam, “Gender differences in cerebral blood flow velocity and autoregulation between the anterior and posterior circulations in healthy children,” Pediatric Research, vol. 58, no. 3, pp. 574–578, 2005.