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ScienceWeek
MEDICAL BIOLOGY: ON CEREBRAL ANEURYSMS
The following points are made by D.B. Ellegala and A.L. Day (New Engl. J. Med. 2005 352:121):
1) The brain derives its blood supply from two internal carotid arteries, which supply most of the cerebrum, and two vertebral arteries, which merge to form the basilar artery and supply the brain stem, the cerebellum, and the visual cortex of the cerebrum. These vessels shed most of their external supporting layers as they enter the skull and are therefore considerably thinner and more fragile than vessels elsewhere in the body. On penetrating the dura mater, each vessel traverses the subarachnoid space at the base of the skull, where communications are established between the major trunks to form the circle of Willis. The hemodynamic stresses (high pressure and pulsations) on the distal wall between the two exiting branches can weaken that region and, over time, lead to the formation of saccular (berry) aneurysms. Once established, these aneurysms carry a risk of rupture that varies with their location, size, and wall thickness.
2) A ruptured cerebral aneurysm is an intracranial catastrophe, associated with very high morbidity and mortality. When an aneurysm ruptures, blood spurts into the subarachnoid space under arterial pressure, continuing until increased local or generalized intracranial pressure stops the bleeding. Acute hydrocephalus may develop as the blood fills the subarachnoid space and impedes the normal flow and absorption of cerebrospinal fluid. Focal clot formation or parenchymal edema and irritation can disturb the regulation of cardiac or respiratory function or further increase the intracranial pressure, culminating in death. Aneurysmal subarachnoid hemorrhage is associated with mortality rates between 25 and 50 percent from the consequences of the initial bleeding. Half of untreated survivors have an additional bleeding episode at least once within the next six months, and among such patients, morbidity and mortality are even higher.[1] Even with aggressive modern treatment, good neurologic function is restored in less than one third of all affected patients.
3) If the patient survives the immediate effects of the bleeding episode and reaches a medical facility alive, the initial management must be directed toward stabilizing or reversing acute life-threatening conditions, including tissue hypoxia from seizures or respiratory depression, cardiovascular dysfunction, hydrocephalus, and focal intracranial clots. Particularly in obtunded patients, the establishment of an airway and urgent ventriculostomy with drainage of cerebrospinal fluid can be lifesaving, since these procedures reduce the effects of brain hypoxia, acute hydrocephalus, and increased intracranial pressure.
4) Once the patient's condition has stabilized, the primary focus of treatment becomes the prevention of rebleeding. The cause and site of the subarachnoid hemorrhage are determined by means of some form of arteriography. The best method of obliterating the aneurysm is then selected and implemented, usually within 24 hours after presentation, unless a life-threatening clot necessitates emergency surgical evacuation. The selection of the appropriate treatment -- either open surgery (clipping) or an endovascular approach (coiling) -- is based primarily on the age and clinical status of the patient and the size, shape, and location of the aneurysm; the decision is best made by a team that is proficient in both methods.[2-5]
References (abridged):
1. Jane JA, Winn HR, Richardson AE. The natural history of intracranial aneurysms: rebleeding rates during the acute and long term period and implication for surgical management. Clin Neurosurg 1977;24:176-184
2. Samson D, Batjer HH, Bowman G, et al. A clinical study of the parameters and effects of temporary arterial occlusion in the management of intracranial aneurysms. Neurosurgery 1994;34:22-28
3. Selman WR, Spetzler RF, Roski RA, Roessmann U, Crumrine R, Macko R. Barbiturate coma in focal cerebral ischemia: relationship of protection to timing of therapy. J Neurosurg 1982;56:685-690
4. Ridenour TR, Warner DS, Todd MM, McAllister AC. Mild hypothermia reduces infarct size resulting from temporary but not permanent focal ischemia in rats. Stroke 1992;23:733-738
5. Berman MF, Solomon RA, Mayer SA, Johnston SC, Yung PP. Impact of hospital-related factors on outcome after treatment of cerebral aneurysms. Stroke 2003;34:2200-2207
New Engl. J. Med. http://www.nejm.org
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NEUROSCIENCE: ON BLOOD FLOW IN THE BRAIN
The following points are made by C. Peppiatt and D. Attwell (Nature 2004 431:137):
1) Like all tissues, the brain needs energy to function, and this comes in the form of oxygen and glucose carried in the blood. The brain's information-processing capacity is limited by the amount of energy available(1). Thus, as has been recognized for more than a century, blood flow is increased to brain areas where nerve cells are active(2). This increase in flow provides the basis for functional magnetic resonance imaging of brain activity(2), but exactly how the flow is increased is uncertain.
2) Glucose and oxygen are provided to neurons through the walls of capillaries, the blood flow through which is controlled by the smooth muscle surrounding precapillary arterioles. Dedicated neuronal networks in the brain signal to the smooth muscle to constrict or dilate arterioles and thus decrease or increase blood flow(2); for example, neurons that release the neurotransmitter molecule noradrenaline constrict arterioles. In addition, the neuronal activity associated with information processing increases local blood flow. This is in part due to neurons that release the transmitter glutamate, which raises the intracellular concentration of Ca2+ ions in other neurons, thereby activating the enzyme nitric oxide (NO) synthase and leading to the release of NO. This in turn dilates arterioles(4).
3) A radical addition to this scheme came with the claim of Zonta et al(5) that glutamate also works through astrocytes in the brain to dilate arterioles. Glutamate raises the Ca2+ concentration in astrocytes, and thus activates the enzyme phospholipase A2, which produces a fatty acid, arachidonic acid. This is converted by the enzyme cyclooxygenase into prostaglandin derivatives, which dilate arterioles. An attractive aspect of a role for astrocytes in controlling blood flow is that, although most of their cell membrane surrounds neurons and so can sense neuronal glutamate release, they also send out an extension, called an endfoot, close to blood vessels: thus, astrocyte anatomy is ideal for regulating blood flow in response to local neuronal activity. In this scheme, a rise in the Ca2+ levels in astrocytes, just like in neurons, would dilate arterioles and increase local blood flow.
4) But new data contradict these results. Mulligan and MacVicar(3) inserted a "caged" form of Ca2+ into astrocytes in brain slices taken from rats and mice. By using light to suddenly uncage the Ca2+, they found that an increase in the available Ca2+ concentration within astrocytes produces a constriction of nearby arterioles that could powerfully decrease local blood flow (the 23% decrease in diameter seen would increase the local resistance to blood flow threefold, by Poiseuille's law). These authors demonstrate that this constriction results from Ca2+ activating phospholipase A2 to generate arachidonic acid, as above; the twist is that this arachidonic acid is then processed by a cytochrome P450 enzyme (CYP) into a constricting derivative.
References (abridged):
1. Laughlin, S. B. & Sejnowski, T. J. Science 301, 1870-1874 (2003)
2. Attwell, D. & Iadecola, C. Trends Neurosci. 25, 621-625 (2002)
3. Mulligan, S. J. & MacVicar, B. A. Nature 431, 195-199 (2004)
4. Faraci, F. M. & Breese, K. R. Circ. Res. 72, 476-480 (1993)
5. Zonta, M. et al. Nature Neurosci. 6, 43-50 (2003)
Nature http://www.nature.com/nature
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ON BRAIN PLASTICITY AND STROKE
Notes by ScienceWeek:
In human brain research, the term "plasticity" refers to the ability of various regions of the brain to assume specific functions as the result of experience, and also the ability of various regions of the brain to assume the functions of other regions that are damaged by disease or trauma ("adaptive plasticity"). Important questions concerning the biological basis of plasticity are a) What are the neural mechanisms responsible for plasticity? and b) What are the conditions which limit plasticity? Until recently, the primary source of evidence in this field was "anecdotal" -- evidence from individual clinical cases. That has changed: during the past decade, numerous studies have been carried out using non-invasive methods to monitor ongoing localized brain activity in conscious subjects, and evidence concerning plasticity and other characteristics of human brain function is rapidly mounting.
The following points are made by N.P. Azari and R.J. Seitz (American Scientist 2000 88:426):
1) When a particular neural network is damaged, as often happens in a stroke, the system fails and function is initially lost because no other neurons in the brain are "wired" to do the task formerly performed by the damaged network. The result may be paralysis or the loss of speech or the inability to comprehend speech or any one of a number of actions. But many people who have suffered a stroke regain some or most of the lost functions after a brief recovery period, sometimes in a matter of weeks.
2) The capacity of the brain to reorganize itself -- its "plasticity" -- in the process of learning a task is perhaps the most interesting phenomenon that distinguishes the nervous system from all other tissues in the body. The plasticity of the brain appears to be greatest when we are young (from infancy through early adolescence), a time when many of the neural pathways that will be used for the acquisition of language and motor skills are formed. But our ability to learn new languages and new skills as adults indicates that the brain retains a certain level of plasticity throughout our lives (although our potential for learning new languages and skills may be decreased).
3) Many studies have shown that stroke patients require time to regain function. During this time, the brain is evidently sorting out how it might compensate for the damaged neurons, and the subsequent process of neural recovery appears to occur in several stages:
a) Initially there is a passive tissue response in the first few hours and days following brain-tissue injury. This passive response involves the reperfusion of tissue deprived of blood-oxygen (ischemic tissue) and cessation of *inflammatory processes produced by brain damage. This leads to a regression of dysfunction associated with the temporary "shock" to the neurons in the vicinity of the lesion. Medical interventions that facilitate these early recovery processes determine the extent to which recovery will proceed to the subsequent stages.
b) In the days and weeks following a stroke, the brain begins active processes of recovery involving adaptive plasticity. In the early stages, this may include intra-system pathways, if any have survived undamaged, pathways that normally play a mere supporting role in the undamaged brain. Since such pathways have previously been involved in the task, only task relearning is necessary, and this may explain why recovery is sometimes seen within a few weeks following a stroke.
c) But if there is complete damage to a neural system, the brain may still have the capacity to recruit an alternative brain system, one not generally activated for the task by normal subjects. In such instances, the alternative system is naive to the task, so that the patient must relearn the task more or less completely. This requires more time, and evidence concerning alternative system pathways was until recently unavailable.
4) The authors conclude: "The existence of distinct stages in the recovery process has only become evident through the use of *functional imaging techniques. As the technology develops, we have little doubt that we will come to appreciate progressively finer aspects of adaptive plasticity and its role in a patient's recovery from brain lesions such as stroke."
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Notes by ScienceWeek:
inflammatory processes: In general, an "inflammatory change" is a response of tissues to irritation or injury. The response involves a dynamic complex of cellular and chemical reactions that occur in the affected blood vessels and adjacent tissues.
functional imaging techniques: The two main functional brain imaging techniques are *functional magnetic resonance imaging (fMRI) and *positron-emission tomography (PET).
functional magnetic resonance imaging (fMRI): We must first distinguish between magnetic resonance imaging (MRI) and "functional" magnetic resonance imaging (fMRI) as applied to the brain. The former is essentially a technique for examining morphology, while the latter is a technique for examining activity of brain tissue. Both techniques involve computerized analysis of data. In general, MRI involves magnetic coils producing a static magnetic field parallel to the long axis of the patient or subject, combined with inner concentric magnetic coils producing a static magnetic field perpendicular to the long axis. A radio-frequency coil specifically designed for the head perturbs the static fields to generate a magnetic resonance image. The interaction physics in this technique is that between the magnetic fields and atomic nuclei in brain tissue. "Sliced" views can be obtained from any angle, and the resolution is quite high and on the order of millimeters for current magnetic field strengths of 1.5 tesla. Functional magnetic resonance imaging (fMRI), the variant of MRI discussed here, is based on the fact that oxyhemoglobin, the oxygen-carrying form of hemoglobin, has a different magnetic resonance signal than deoxyhemoglobin, the oxygen-depleted form of hemoglobin. Activated brain areas utilize more oxygen, which transiently decreases the levels of oxyhemoglobin and increases the levels of deoxyhemoglobin, and within seconds the brain microvasculature responds to the local change by increasing the flow of oxygen-rich blood into the active area. This local response thus leads to an increase in the oxyhemoglobin-deoxyhemoglobin ratio, which forms the basis for the fMRI signal in this technique. Because of its high spatial resolution (millimeters) and high temporal resolution (seconds) compared to other imaging techniques, fMRI is now the technology of choice for studies of the functional architecture of the human brain.
positron-emission tomography (PET): This is a technique for producing cross-sectional images of the body after ingestion and systemic distribution of safely metabolized positron-emitting agents. The images are essentially functional or metabolic, since the ingested agents are metabolized in various tissues. Fluorodeoxyglucose and H(sub2)O(sup15) are common agents used for cerebral applications, and in cerebral applications of central importance to the technique is the fact that changes in the cellular activity of the brains of normal, awake humans and unanesthetized laboratory animals are invariably accompanied by changes in local blood flow and also changes in oxygen consumption.
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