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The sleep Sustained 61 period is typically a time of basal activity of the sympathetic nervous Paroxysmal 24 system carbidopa 125mg with mastercard, except in patients with pheochromocytoma (see Fig 125mg carbidopa. Pallor 44 Retinopathy: Grades I and II 40 Grades III and IV 53 Abdominal mass 9 Associated multiple endocrine 6 adenomatosis 4 discount carbidopa 125mg otc. The values for urinary excretion of norepinephrine are shown for norm al persons and 1000 patients with essential hypertension as m ean plus or m inus SD order cheap carbidopa on-line. Values for patients with pheochrom ocytom a are indicated by sym bols. N ote that the scale is logarithm ic and the highest value for patients with norm al or essential hypertension was less than 30 Patient I µg, whereas the lowest value for a patient with pheochrom ocytom a Patient II was about 75 µg. M ost patients with pheochrom ocytom as had val- Patient III ues an order of m agnitude higher than the highest value for Patient IV Patient V patients with essential hypertension. N ote the Test Sensitivity, % Specificity, % displacem ent of the left kidney (right) by Abdominal plain radiograph ≈40 ≈50 a suprarenal m ass. Intravenous pyelogram ≈60 ≈75 Adrenal isotopic scan ≈85 ≈85 (meta-iodobenzoylguanidine) Adrenal computed tomographic scan >95 >95 FIGURE 4-33 Localization of pheochrom ocytom a. O nce the diagnosis of pheochrom ocytom a has been m ade it is very im portant to localize the tum or preoperatively so that the surgeon m ay rem ove it with a m inim um of physical m anipulation. Com puted tom ographic scan or M RI appears to be the most effective and safest techniques for this purpose. The patient should be treated with -adrenergic blocking agents for 7 to 10 days before surgery so that the contracted extracellular fluid volume can be expanded by vasodilation. Three patients have left adrenal tum ors, and in m ocytom a. The black arrows identify the adrenal tum or in one patient (panel B) the tum or is on the right adrenal. A B FIGURE 4-36 (see Color Plates) A and B, Pathologic appearance of pheochrom ocytom a before tum or had gross areas of hem orrhage noted by the dark areas (panel A) and after (panel B) sectioning. Netter FH: Endocrine system and selected metabolic diseases. In Ciba 7: Lifton RP, Dluhy RG, Powers M : H ereditary hypertension caused by Collection of M edical Illustrations, vol. Lifton RP, Dluhy RG, Powers M : A glucocorticoid-rem ediable aldos- 3. W einberger M H , Fineberg N S: The diagnosis of prim ary aldosteronism Springer-Verlag; 1977:97. Grim CE, W einberger M H : Fam ilial, dexam ethasone-suppressible pheochrom ocytom a: detection by m easurem ent of urinary norepineph- norm okalem ic hyperaldosteronism. Kem DC, W einberger M H , M ayes D, N ugent CA: Saline suppression of plasm a aldosterone and plasm a renin activity in hypertension. Bauer his chapter reviews the currently available classes of drugs used in the treatment of hypertension. To best appreciate the com- Tplexity of selecting an antihypertensive agent, an understanding of the pathophysiology of hypertension and the pharmacology of the various drug classes used to treat it is required. A thorough under- standing of these mechanisms is necessary to appreciate more fully the workings of specific antihypertensive agents. Among the factors that modulate high blood pressure, there is considerable overlap. The drug treatment of hypertension takes advantage of these integrated mecha- nisms to alter favorably the hemodynamic pattern associated with high blood pressure. There are a large num ber of control m echanism s involved product of cardiac output (CO ) and peripheral vascular resistance in every type of hypertension. M any hypertensive patients appear to be sodium sensitive, as first suggested by studies in 19 hypertensive subjects who were observed after “norm al” (109 m m ol/d), “low” (9 m m ol/d), and “high” (249 m m ol/d) sodium intake. This figure shows the percent increase in m ean blood pressure in salt-sensitive (SS) and non–salt-sensi- 20 tive (N SS) patients with hypertension when their diet was changed from low sodium to high sodium. An increase in cardiac output has been suggested 19 as a m echanism for hypertension, particularly in its early border- 18 line phase [3,4]. Sodium and water retention have been theorized 17 to be the initiating events. Sequential changes following salt load- 16 4 % ing are depicted. The resultant high cardiac output perfuses the 15 peripheral tissues in excess of their m etabolic requirem ents, result- 20 % ing in a norm al autoregulatory (vasoconstrictor) pressure. Shown here are segm ental changes in the im portant cardiovascular hem odynam ic variables in the first 16 60 % few weeks following the onset of short-term salt-loading hyperten- 14 sion. N ote especially that the arterial pressure increases ahead of 20 % 12 the increase in total peripheral resistance. M ost established cases of hypertension dashed line indicates results after 10 years; dotted line indicates results are associated with an increase in peripheral vascular resistance. BP— blood pressure; CI— cardiac index; DAP— diastolic These alterations m ay be related to a functional constriction, the arterial blood pressure; HR— heart rate; M AP— mean arterial pressure; type observed under the influence of circulating or tissue-generated SAP— systolic arterial blood pressure; SI— stroke index; TPRI— total vasoconstrictors, or m ay be a result of structural alterations in the peripheral resistance index; VO2— oxygen consumption. Solid line indicates values at start of the study; Johansen; with perm ission. There are 12 currently available classes of antihypertensive agents. Diuretics: benzothiadiazides, loop, and potassium-sparing -adrenergic and 1/ -adrenergic antagonists Central 2-adrenergic agonists Central/peripheral adrenergic neuronal-blocking agent Peripheral 1-adrenergic antagonists Moderately selective peripheral 1-adrenergic antagonist Peripheral adrenergic neuronal blocking agents Direct-acting vasodilators Calcium antagonists Angiotensin-converting enzyme inhibitors Tyrosine hydroxylase inhibitor Angiotensin II receptor antagonists FIGURE 7-6 H em odynam ic response to diuretics. Diuretics reduce m ean arterial BP pressure by their initial natriuretic effect. Acutely, this is achieved by a reduction in cardiac output m ediated by a reduction in plasm a and extracellular fluid volum es. Initially, peripheral vascular resistance is increased, m ediated in part by stim ulation of the renin- PV angiotensin system. During sustained diuretic therapy, cardiac output returns to pretreatm ent levels, probably reflecting restoration of ISF plasma volume. Chronic blood pressure control now correlates with a reduction in peripheral vascular resistance. BP— blood pressure; CO CO — cardiac output; ISF— interstitial fluid; PRA— plasm a renin CO activity; PV— plasma volume; Rx— treatment; TPR— total peripheral TPR TPR resistance. DIURETICS: BENZOTHIADIAZIDES (PARTIAL LIST) AND RELATED DIURETICS Generic (trade) name First dose, mg Usual dose Maximum dose Duration of action, h Hydrochlorothiazide (G) 12. DIURETICS: LOOP Generic (trade) name First dose, mg Usual dose Maximum dose Duration of action, h Bumetanide (G) 0. DIURETICS: POTASSIUM -SPARING DIURETICS Generic (trade) name First dose, mg Usual dose Maximum dose Duration of action, h Spironolactone (G) 25 50–1 00 mg QD 400 48–72 (Aldactone) Amiloride (G) 5 5–10 mg QD 20 24 (Midamor) Triamterene (G) 50 50-100 mg bid 300 7–9 (Dyrenium) (G)— generic available. Diuretics: benzothiadiazides and related agents, loop diuretics, diuretics. Because of their steep dose-response curves and natri- and potassium -sparing agents. A partial list of benzothiadiazides uretic potency, they are especially useful when the glom erular and their related agents is given. W ith the exception of inda- filtration rate is less than 30 m L/m in/1. The third group pam ide and m etolazone, their dose-response curves are shallow; is the potassium -sparing diuretics. The m ajor therapeutic use of they should not be used when the glom erular filtration rate is these drugs is to attenuate the loss of potassium induced by the less than 30 m L/m in/1. This figure depicts the The diuretic/natriuretic action of potassium-sparing diuretics is m ajor sites and m echanism s of action of diuretic drugs. Because Na+ uptake is blocked, distal convoluted tubule and inhibiting N a+ - Cl- cotransport the lumen negative voltage is reduced, inhibiting K+ secretion. CA— carbonic predicated on their gaining access to the lum inal side of anhydrase; CAI— carbonic anhydrase inhibitor; CD— collecting duct; the thick ascending lim b of the loop of H enle and inhibiting DCT— distal convoluted tubule; DT— distal tubule; LH— loop of N a+ - K+ -2Cl- electroneutral cotransport by com peting for Henle; PC— principal cell; PT— proximal tubule; TAL— thick ascend- the chloride site. The com plications of diuretic therapy are typically related to dose and duration of Side effects Mechanisms therapy, and they decrease with lower dosages. This table lists the m ost com m on Thiazide-type diuretic side effects of diuretics and their proposed Azotemia Enhanced proximal fluid and urea reabsorption secondary m echanism of action. In the absence of partial agonist activity (PAA), the acute system ic hem odynam ic effects are a decrease in heart rate and cardiac output and an increase Heart ↓ CO in peripheral vascular resistance proportional to the degree of cardio- β depression; blood pressure is unchanged.

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Responses to corticotropin- receptor subtypes and clinical indications carbidopa 300mg line. Curr Pharm Design releasing hormone in the hypercortisolism of depression and 1999;5:289–315 cheap 125mg carbidopa overnight delivery. The corticotropin-releasing efficacy of a 4-(butylethylamino)pyrrolo[2 generic carbidopa 300 mg on-line,3-d]pyrimidine: a cen- hormone stimulation test in patients with panic disorder buy genuine carbidopa on line. Am J trally active corticotropin-releasing factor1 receptor antagonist. Design and synthesis factor-like immunoreactivity in senile dementia of the Alzheimer of a series of nonpeptide high-affinity human corticotropin-re- type. Abnormalities in tuitary ACTH release and peripheral inflammation. R121919: a novel nonpeptide corticotropin-releasing factor1 77. Neu- in major depression: the first 20 patients treated. GAGE AND HENRIETTE VAN PRAAG HISTORIC PERSPECTIVE ture. Under a variety of culture conditions with different factors, these isolated cells can be induced to differentiate The idea that the adult brain retains the capacity to generate into glia and neurons (6–9). This later observation provided new neurons has been proposed several times over the last a mechanism for the neurogenesis in the adult. Mature com- 40 years, and in each case both conceptual and technical mitted neurons were not dividing, but rather a population constraints have led to resistance. Joseph Altman first re- of immature stem-like cells exists in the brain and it is likely ported that some dividing cells in the adult brain survived that it is the proliferation and differentiation of this popula- and differentiated into cells with morphology similar to tion that is resulting in neurogenesis. With this conceptual neurons using tritiated thymidine autoradiography (1). When contrasting adult neurogenesis with the extensive we have learned is that development never ended in some neurogenesis in development, adult neurogenesis seemed areas of the brain. The continued skepticism surrounding adult neurogenesis and the absence of defini- tive phenotypic markers limited the development of the CHARACTERIZATION OF CELL GENESIS field. In the mid-1970s and early 1980s Michael Kaplan IN VIVO reexamined the initial observations using the electron mi- Areas of Neurogenesis croscope and added substantial confidence that not only could neurogenesis occur in the adult brain, but also that Neurogenesis is a process that includes cell division, migra- the cells appear ultrastructurally, similar to sister cells in the tion, and differentiation. There appear, at present, to be dentate gyrus of the hippocampus, one of the structures only two areas of the brain where stems cells initially reside shown to be neurogenic (3). In the mid-1980s, Fernando and proliferate prior to migration and differentiation. Those Nottebohm and his student Steve Goldman further stimu- areas are the lateral subventricular and subgranular zones of lated this fledgling field by showing that songbirds experi- the dentate gyrus. The exact cell that corresponds to the ence a seasonal cell death and neurogenesis in a region of initiating stem cell in the lateral ventricle is a point of con- the brain important for song production (4). One view is that this cell is the ependymal cell continued to reveal more about the environment and molec- facing the ventricle (10), whereas an alternative view is that ular regulators of this process in the adult avian brain (5). In any case, after cell division one of brain, confusion over the mechanism origin of cell genesis the stem cells begins to differentiate and migrate in what in the adult brain persisted. This process continues throughout life; the functional impor- tance and consequences of this process are not understood. Gage and Henriette van Praag: The Laboratory of Genetics, The stem cell in the adult mammalian subgranular zone The Salk Institute for Biological Studies, La Jolla, California. It remains formally possible that a more primitive cell exists elsewhere in the adult brain in a quiescent state, and migrates to the dentate gyrus where the cells begin to divide. However, from the subgranular zone, one of the progeny migrates into the granule cell layer once the cells divide; there the majority become neurons with axons extending to the CA3 pyramidal neurons and receiving synaptic connections. The function of these newly born cells is being investigated. Although these are the two principal areas where neuro- genesis occurs in the mammalian brain, cell genesis occurs throughout the adult brain including cortex, optic nerve, spinal cord, and many brainstem and forebrain structures. To date the function of this cell genesis in the normal intact brain and spinal cord is not known, but some of these new cells can become glial cells (13). A clear challenge for the future is to document all the areas of the adult brain where cell genesis continues, and to understand the normal func- tion as well as the factors that regulate this process. Mammalian Species in Which Adult Neurogenesis Is Documented The first studies demonstrating adult neurogenesis were in the rat. Subsequently, rabbit and cat were shown to exhibit FIGURE 8. Birth of new neurons in the adult hippocampus has been documented in a variety of species, including rodents and similar characteristics, although little additional work has humans. It was not until 1997 that Kempermann and associ- ates showed the mice retain neurogenesis and that signifi- cant genetic variability exists among mouse strains (16). Together these studies clearly ronmental stimulation as a regulator of neurogenesis, have demonstrate that neurogenesis, at least in the dentate gyrus, placed adult neurogenesis as paradigm for examining the is a process that persists throughout life and in all mamma- interactions of nature and nurture (17,18). The extent to which or whether neu- was debate in the mid-1980s as to whether nonhuman pri- rogenesis can occur in other brain areas remains an area of mates retained adult neurogenesis, a series of papers by intense investigation. Fuchs and associates beginning with tree shrew followed by marmosets and finally with Rhesus monkeys demonstrated and confirmed that neurogenesis in occurs in adult nonhu- PROPERTIES OF STEM CELLS IN VITRO man primates (19,20). Recently, Gould presented data sug- CNS Areas from Which Stem Cells Can Be gesting that neurogenesis occurs in the adult primate frontal Isolated cortex and concluded that the cells are derived from the subventricular zone where they migrate to specific cortical Neural stem cells can be derived from the adult brain and regions of the adult primate brain. This observation awaits propagated in vitro (6–8,10,11,23–26). One of the markers for determining cell neurogenesis, however, has only been documented convinc- division is bromo-deoxyuridine (BrdU); a traceable analogy ingly in two brain areas, the subventricular zone/olfactory of uridine, which in incorporated into the genome of, cells system and the dentate gyrus of the hippocampus. Administering BrdU and then ex- ingly, stem cells are found not only in these regions, but amining cell proliferation in tumor biopsies is occasionally also have been isolated from areas that are non-neurogenic used to monitor tumor progression in patients with cancer. However, cells isolated from areas outside son and colleagues (22)reported that in five of the cancer of the hippocampus and subventricular zone require high patients they examined who received BrdU at between 15 levels of FGF-2 in order to give rise to neurons, rather than days and over 2 years early, all of them showed neurogenesis only glial cells (29). These findings suggest that either differ- Chapter 8: Neurogenesis in Adult Brain 111 ent populations of stem cells exist in the nervous system stream (40). In addition, after implantation into the devel- or that they require unique culture conditions to become oping retina these cells showed properties of several types multipotent. Alternatively, the cells isolated from different of retinal neurons (37). Moreover, progenitors isolated from CNS regions may already be committed toward a specific a non-neurogenic area such as the spinal cord, acquired the lineage. Indeed, there are no antigenic markers that allow morphologic characteristics of granule cell neurons when unambiguous identification of stem cells in the nervous sys- grafted into the dentate gyrus, and had a glial phenotype tem. In the subventricular zone, stem cells are suggested to when grafted back in to the spinal cord (41). These studies divide slowly, whereas and their offspring, progenitor cells, suggest that neural stem cells derived from the adult mam- may divide more frequently (31). Stem cells in this area malian brain retain multipotentiality. Recent research sug- have been suggested to ependymal cells (10)or a subclass gests that neuronal stem cells are multipotent outside the of glial cells in the subependymal zone (11). It was reported that neural progenitor cells and identity of the hippocampal stem cell remains to be repopulate experimentally depleted bone marrow and re- determined. It remains to be determined what the local cues are, that are driving the neuronal precursor cells to acquire such specific fates when Factors That Affect Proliferation and transplanted in vivo. Differentiation of Stem Cells In Vitro A variety of cytokines, neurotrophins, and conditioned media are used to culture neural progenitor cells (32–34). REGULATION OF PROLIFERATION AND The two major factors are EGF and FGF. Progenitor cells DIFFERENTIATION IN VIVO responsive to EGF have been isolated and cultured from adult mouse subventricular zone (6,7,31). FGF-2 has been The mechanisms that generate new granule cells in the den- found to be mitogenic for adult neural progenitors from tate gyrus are poorly understood. A variety of environmen- brain and spinal cord (9,27,28). FGF-2, however, is mem- tal, behavioral, genetic, neuroendocrine, and neurochemical ber of a family of 10 related, but genetically and functionally factors can regulate adult neurogenesis. Among those, only FGF-2 and FGF- cesses that lead to neurogenesis, cell proliferation and the 4 are mitogens for neural progenitor cells.

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Central nervous system formation in schizophrenia: a pilot study buy discount carbidopa. Br J Psychiatry 1994; trans-synaptic effects of acute axonal injury: a 1H magnetic 165:481–485 purchase carbidopa no prescription. Reproducibility of gence of prefrontal neuronal deficits and altered dopaminergic proton magnetic resonance spectroscopic imaging in patients behaviors in rats with neonatal hippocampal lesions cheap carbidopa 300mg amex. Cortical maldevelopment purchase carbidopa 125mg without prescription, anti- pattern of neurochemical pathology in schizophrenia as assessed psychotic drugs, and schizophrenia: a search for common by multislice proton magnetic resonance spectroscopic imaging. Regionally specific between dorsolateral prefrontal N-acetylaspartate measures and neuronal pathology in untreated patients with schizophrenia: a striatal dopamine activity in schizophrenia [see comments]. Biol proton magnetic resonance spectroscopic imaging study. Common pattern of between prefrontal neuronal N-acetylaspartate and activation cortical pathology in childhood-onset and adult-onset schizo- of the working memory cortical network in schizophrenia [see phrenia as identified by proton magnetic resonance spectro- comments]. Hippocampal N- function of the dorsolateral prefrontal cortex in schizophrenia acetyl aspartate in unaffected siblings of patients with schizo- revisited. A selective relation- [published erratum appears in Biol Psychiatry 1999;45(2):fol- ship between prefrontal N-acetylaspartate measures and nega- lowing 244]. Reduced hippocampal N- a proton magnetic resonance spectroscopy study [In Process acetylaspartate without volume loss in schizophrenia. Proton magnetic reso- on human brain GABA levels by nuclear magnetic resonance nance spectroscopy of the anterior cingulate region in schizo- spectroscopy. Reduced concentrations lism: in vivo 13C-NMR spectroscopy evidence for coupling of of thalamic N-acetylaspartate in male patients with schizophre- cerebral glucose consumption and glutamatergic neuronal activ- nia. Striatal dopamine D2 recep- resonance spectroscopic imaging of cortical gray and white mat- tors in tardive dyskinesia: PET study. Striatal D2 glutamate and glutamine in the medial prefrontal cortex of never-treated schizophrenic patients and healthy controls by dopaminergic receptors assessed with positron emission tomog- proton magnetic resonance spectroscopy. Arch Gen Psychiatry raphy and 76-Br-bromospiperone in untreated patients. Dopamine D2 receptor magnetic resonance spectroscopy study of schizophrenia pa- density estimates in schizophrenia: a positron emission tomogra- phy study with 11C-N-methylspiperone. No elevated D2 temporal lobe in first-onset schizophrenic patients. Biol Psychia- dopamine receptors in neuroleptic-naive schizophrenic patients revealed by positron emission tomography and [11C]N-methyl- try 1999;45:1403–1411. A positron emission tomography study with [11C]raclopride. In vivo neurochemistry of the brain in schizophrenia as revealed by magnetic resonance chiatry 1990;47:213–219. N-acetylaspartate reduction in dorsolateral characteristics in neuroleptic-naive schizophrenic patients stud- prefrontal cortex of patients with schizophrenia as revealed by ied with Positron Emission Tomography. An I-123-IBZM single photon emission computerized nia: clinical, neurodevelopmental, and cognitive correlates. Proton magnetic resonance function and negative symptoms in drug-free patients with spectroscopy: an in vivo method of estimating hippocampal neu- schizophrenia. Br J Psy- ronal depletion in schizophrenia [published erratum appears in chiatry 1997;171:574–577. Hippocampal age-related changes in schizo- with positron Emission tomography and 76Br-bromolisuride. Proton magnetic D2 receptors and negative symptoms of schizophrenia. Br J resonance spectroscopy of the left medial temporal and frontal Pharmacol 1994;164:27–34. Proton magnetic reso- studied with positron emission tomography. Am J Psychiatry nance spectroscopy in the frontal and temporal lobes of neuro- 2000;157:269–271. Biol Psychiatry 1998; lobe proton magnetic resonance spectroscopy of patients with 43:263–269. Proton lobe 1H MR spectroscopy in childhood-onset schizophrenia. J magnetic resonance spectroscopy of the temporal lobes in Magn Reson Imaging 1998;8:841–846. Psychiatry spectroscopy of the left temporal and frontal lobes in schizophre- Res 1999;92:45–56. It is in this arena that functional neuroimaging has had the broadest HISTORIC PERSPECTIVE application and greatest impact in psychiatry. This now ex- tensive body of work has left no doubt that schizophrenia Functional neuroimaging studies utilize the fact that neu- is associated with measurable, objective signs of altered brain ronal activation results in regionally increased blood flow function, and clinical and pathophysiologic correlations and metabolism. This can be measured either by radiotracer have begun to emerge. Increasingly, it appears that dysfunction oglobin to oxyhemoglobin imaged by magnetic resonance of a system of functionally and/or structurally intercon- techniques (the blood oxygenation level dependent [BOLD] nected cortical and limbic brain regions is present to lesser effect). This work began in earnest some 50 years ago with or greater degrees, producing more or less psychopathology the pioneering studies of Seymour Kety and colleagues who in individual patients, and that certain brain regions, such developed the first reproducible, quantitative technique for as frontal cortex, may play a special role in this larger picture. When this method was applied to ticularly cognitive impairment. Although it is likely that at schizophrenia (1), these investigators found no alteration in least some of the functional abnormalities are generative of the overall average CBF level in patients, a result that has these features and not simply a response to them, clarifica- largely been confirmed by more recent studies; however, tion of this 'chicken versus egg' issue must be a crucial this finding did not rule out the existence of neurophysio- component of any research program in this area, and the logically meaningful changes in specific brain structures. Current functional ment of rigorous methods that could differentiate the func- neuroimaging has much to offer in guiding this quest, par- tional level of specific cortical regions, albeit with only 2- ticularly when combined with new information now avail- cm anatomic accuracy at best (2). This method, administra- able from other fields such as genetics and cognitive science. The resulting findings delineate their relationship to other neurobiological and of functional abnormality in the frontal lobe spurred a shift clinical properties of the illness, discuss conceptual issues in focus throughout many research domains in the field that and controversies, examine methodologic considerations remains a prevailing force today. In the 1980s, the advent (including technical constraints), summarize new tech- of tomographic methods, such as single photon emission computed tomography (SPECT) and PET, which both use radioactive compounds as tracers, brought improved in- Karen Faith Berman: National Institute of Mental Health, Intramural terregional spatial resolution on the order of 5 to 6 mm Research Program, Bethesda, Maryland and allowed measurement of subcortical regional function. A particular advantage ing (fMRI) has emerged as the premier technique for neu- for research in schizophrenia is that neural activity during ropsychiatric functional neuroimaging. By taking advantage correct and incorrect trials can be measured separately and of the differential paramagnetic properties of oxyhemoglo- compared, allowing more incisive study of the mechanism bin versus deoxyhemoglobin and the altered ratio between of cognitive failure and better experimental control of po- them that occurs when blood volume and blood flow change tential confounds based in performance discrepancies that in response to neural activation, BOLD fMRI uses intrinsic often occur between patient and control groups. Event- properties of the blood itself rather than an extrinsic contrast related fMRI has very recently come into wide use in neu- or tracer agent, to generate maps of brain function. It is, roimaging of cognitive systems in healthy subjects, but as thus, entirely noninvasive, and measurements can be re- of this writing has had only limited application to the study peated over time, conferring significant advantage in experi- of schizophrenia. In this approach, blood flow and other measures advance brought further improvements in spatial resolution such as MR spectroscopy, neuroreceptor measurements, and as well as enhanced temporal resolution, which, although electrophysiology (with MEG or EEG) are determined in still slow (several seconds) compared to neuronal signaling the same patients. One example of the richness of the data (on the order of 200 ms), improved to the degree that event- that can be gleaned is the use of PET or fMRI to measure related neural activity could be recorded with anatomic blood flow in conjunction with EEG or MEG. PET and precision heretofore unavailable with electrophysiologic fMRI allow localization of the brain regions that work to- methods. On the other hand, EEG and MEG TECHNICAL PERSPECTIVE have relatively poorer spatial resolution, but provide fine time resolution (i. Combining these meth- As can be seen in the preceding brief history, over the years ods, together with the application of the advanced computa- the sophistication of the questions that could be asked and tional cross-registration and source localization techniques the hypotheses about schizophrenia that could be tested that now exist, provides exponentially more information have paralleled the development of new brain imaging tech- than any of these techniques alone. For example, this allows nologies and analytic methods. This parallel development the determination of the sequence in which various finely is evident in the evolution of the science from the search localized regions are activated during cognition and the test- for regionally specific pathologic function to that in neural ing of the hypothesis that this sequence of events is altered systems, and from measures sensitive only to static patho- in schizophrenia. Although this specific multimodal ap- physiology to explorations of the dynamic interplay among proach has not been applied in schizophrenia, other exam- regions in those neural systems. Therefore, a brief discussion ples are described in the following. New Vistas in Data Analysis The analytic approaches for the two data collection modali- New Vistas in Data Acquisition ties discussed, event-related fMRI and fusion of spatial and Event-related fMRI is a relatively recent class of experimen- temporal neurofunctional data (i. Another recent set of analytic methods ad- fMRI and PET approaches that blocked together relatively dresses the growing appreciation that the transduction be- long (e. This approach has much in common with tradi- uted components of neural systems (interregional integra- tional evoked-potential electrophysiology and offers advan- tion of neural function).

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