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• W2026907501 abstract "The great psychiatrists of the late nineteenth and early twentieth century, who initially identified schizophrenia as a discrete illness, assiduously sought to identify its neural mechanisms, but were unsuccessful in their search. The pathophysiology and etiology of schizophrenia remain among the tantalizing puzzles of modern medicine, although considerable progress has been made during recent years, as this minireview will summarize. Two recent reports in Nature highlight some of the advances that have occurred. The work of 13Silbersweig D.A Stern E Frith C Cahill C Holmes A Grootoonk S Seaward J McKenna P Chua S.E Schnorr L Jones T Frackowiak R.S.J Nature. 1995; 378: 176-179Crossref PubMed Scopus (766) Google Scholar has suggested that a key symptom of schizophrenia, auditory hallucinations (“hearing voices” without a perceptual stimulus), may be related to increases in cerebral blood flow in subcortical and limbic regions of the brain. The work of 7Dolan R.J Fletcher P Frith C.D Friston K.J Frackowiak R.S.J Grasby P.M Nature. 1995; 378: 180-182Crossref PubMed Scopus (327) Google Scholar has suggested that impairments in cognition, another key feature of the illness, may be due to dysfunctions in the cingulate cortex that are reversed by dopamine agonists. To understand the significance and implications of these advances toward assembling the schizophrenia puzzle, we must examine their historical and conceptual context. Investigations of schizophrenia have come from four major perspectives. Contemporary research on the mechanisms of schizophrenia encompasses all four and ideally seeks to integrate these perspectives. The earliest era of schizophrenia research emphasized neuropathology. Inspired by the advances achieved at the turn of the century, psychiatrists such as Kraepelin, Nissl, Brodmann, and Alzheimer studied postmortem tissue from patients suffering from a variety of disorders. They were successful in finding a specific neuropathology for senile dementia, which Kraepelin began to refer to as Alzheimer's Disease after his friend and colleague described its plaques and tangles. Kraepelin noted that changes could also be seen in the cortex in schizophrenia, but not in any characteristic pattern. He speculated that the disease might be localized to specific regions that were consistent with the clinical presentation, suggesting that the prefrontal and temporal cortex would be the most probable sites of abnormality. Subsequent investigators searched in vain for a gross anatomic pathology; consequently, by the mid-twentieth century, schizophrenia was temporarily abandoned by the anatomists, who regarded it as “the graveyard of neuropathology.” Neuropathology is currently enjoying a renaissance, however, as investigators have begun to note some characteristic features that may provide a clue as to its pathophysiology or etiology (5Bogerts B Schizophrenia Bull. 1993; 19: 431-445Crossref PubMed Scopus (243) Google Scholar). For example, one consistent finding is the absence of gliosis, which suggests that schizophrenia is not due to a typical neurodegenerative process. Instead, this observation suggests that the primary abnormality may involve a neurodevelopmental process. Other investigators have confirmed Kraepelin's early speculations about prefrontal and temporal cortex and also highlighted interactions with other regions such as the thalamus, hippocampal complex, and cingulate gyrus (e.g.,14Weinberger D.R Berman K.F Illowsky B.P Arch. Gen. Psychiatry. 1988; 45: 609-615Crossref PubMed Scopus (528) Google Scholar, 1Andreasen N.C Arndt S Swayze V Cizadlo T Flaum M O'Leary D.S Ehrhardt J Yuh W.T.C Science. 1994; 266: 294-298Crossref PubMed Scopus (627) Google Scholar, 2Andreasen N.C Flashman L Flaum M Arndt S Swayze V O'Leary D.S Ehrhardt J.C Yuh W.T.C J. Am. Med. Assoc. 1994; 272: 1763-1769Crossref Scopus (288) Google Scholar, 11Selemon L.D Rajkowska G Goldman-Rakic P.S Arch. Gen. Psychiatry. 1995; 52: 805-818Crossref PubMed Scopus (744) Google Scholar, 12Shenton M.E Kikinis R Jolesz F.A Pollak S.D LeMay M Wible C.G Hokama H Martin J Metcalf D Coleman M N. Engl. J. Med. 1992; 327: 604-612Crossref PubMed Scopus (1014) Google Scholar). Schizophrenia research was given a new impetus during the 1960s by the development of apparent “miracle drugs,” which substantially reduced the symptoms of the disorder and were even transiently considered a potential cure. Emphasis temporarily shifted in the direction of viewing schizophrenia as a chemical brain disorder. After several seminal studies indicated that the therapeutic efficacy of the new medications was closely correlated with their ability to block dopamine type 2 receptors, the dopamine hypothesis of schizophrenia was developed (6Carlsson M Carlsson A Schizophrenia Bull. 1990; 16: 425-432Crossref PubMed Scopus (299) Google Scholar; Seeman et al., 1976). This hypothesis suggests that psychotic disorders, which are characterized by symptoms such as delusions and hallucinations (key features of schizophrenia), are due to a functional excess of dopamine. The dopamine hypothesis has formed the basis for drug development and for understanding mechanisms of drug action for several decades. Very recent advances in pharmacology have led to the development of a new class of “atypical” neuroleptics, however, which also have potent effects on other neurotransmitters such as serotonin. These new atypicals are, if anything, more efficacious than the traditional neuroleptics and have fewer side effects. They have led to a reconceptualization of the chemical basis of schizophrenia to include a range of neurotransmitters in addition to dopamine (Lieberman et al., 1993). Concurrent with the development of neuroleptic drugs and the dopamine hypothesis, investigators in the 1950s and 1960s also began to pursue the study of patterns of prevalence intensively; in particular, they began to investigate the familiality of schizophrenia. Studies of monozygotic and dizygotic twins and of adopted offspring of schizophrenic mothers support genetic transmission as one mechanism that may lead to schizophrenia, although these studies have rarely addressed its brain mechanisms. The development of neuroimaging techniques such as magnetic resonance (MR), single photon emission computed tomography (SPECT), and positron emission tomography (PET) has given investigators a new set of tools that permit in vivo study of brain abnormalities. The availability of these techniques is particularly valuable for the study of a disease such as schizophrenia, which affects many cognitive systems that are peculiar to human beings, such as language, making the illness more difficult to model and study in animals. These techniques permit the study of neuroanatomy, neurotransmission, neurochemistry, and neurophysiology. They also avoid many of the disadvantages of using postmortem tissue, such as the potential contamination of findings by effects of aging, previous treatment, tissue fixation, or preservation. The application of these techniques has complemented earlier work in neuropharmacology by permitting the direct study of the effects of drugs on brain function. It has also given neuropathology a new impetus by facilitating the study of links between symptoms and specific abnormalities in brain regions, as anticipated by Kraepelin and his colleagues. The symptoms of schizophrenia are multiple, as is summarized in Table 1. They are often divided into two groups: positive (involving excess or distortion of normal functions) and negative (involving loss or diminution of normal functions). Positive symptoms include hallucinations (abnormal perceptions occurring in the absence of a stimulus), delusions (abnormal inferences from normal perceptions), disorganized speech, and disorganized behavior (ranging from motor abnormalities to inappropriate social behavior). Negative symptoms include loss of volition and drive, loss of fluency of thought and language (alogia), and diminution in the ability to express emotions (blunted affect). No single one of these symptoms occurs in all patients, but all occur in some patients. An illness of this type is called “polythetic”, that is it is not defined or characterized by a single defining feature. The challenge to investigators seeking the mechanisms of schizophrenia is to identify a pathophysiological process that could account for this diversity of symptoms. This involves determining whether the illness is due to a single focal lesion in a key region or to multiple focal lesions that vary from patient to patient and reflect the variability in clinical presentation that is observed in patients. Two strategies are currently being pursued to investigate this issue.Table 1Symptoms of SchizophreniaNegative SymptomsPositive SymptomsSymptomFunction DiminishedSymptomFunction DistortedAlogiaFluency of speech/thoughtHallucinationsPerceptionAffective bluntingEmotional expressionDelusionsInferential thinkingAvolitionVolition and driveDisorganized speechThought/languageAnhedoniaHedonic capacityBizarre behaviorBehavioral monitoring Open table in a new tab A “bottom up” strategy applies the traditional localization approaches developed by nineteenth century European neurologists and expanded by Norman Geschwind; this strategy focuses on a key symptom, such as hallucinations, and seeks to identify specific brain regions that produce the symptom. Historically, this approach has used the reverse localization inherent in the lesion method: identifying brain regions involved in specific cognitive processes by seeing what is lost when damage occurs. More recently, neuroimaging techniques have permitted direct localization, allowing investigators to correlate regions that have altered functional activity or structure when a cognitive process is being actively used or a symptom occurs. Several MR studies have attempted to localize specific symptoms to specific brain regions and have noted relationships between symptoms and decreased size: e.g., disorganized speech and the planum temporale or hallucinations and the superior temporal gyrus (3Barta P.E Pearlson G.D Powers R.E Richards S.S Tune L.E Am. J. Psychiatry. 1990; 147: 1457-1462PubMed Google Scholar, 12Shenton M.E Kikinis R Jolesz F.A Pollak S.D LeMay M Wible C.G Hokama H Martin J Metcalf D Coleman M N. Engl. J. Med. 1992; 327: 604-612Crossref PubMed Scopus (1014) Google Scholar). A recent innovative study by 13Silbersweig D.A Stern E Frith C Cahill C Holmes A Grootoonk S Seaward J McKenna P Chua S.E Schnorr L Jones T Frackowiak R.S.J Nature. 1995; 378: 176-179Crossref PubMed Scopus (766) Google Scholar used PET to examine the neural substrates of hallucinations in schizophrenia by capturing serial snapshots of brain blood flow at the moment when patients reported hearing voices. Although this study began with a single specific symptom, the investigative trail led the group to identify a complex distributed circuit that was active during hallucinations; this circuit included subcortical regions (thalamus, caudate, and putamen), anterior cingulate, and limbic cortex (hippocampus and parahippocampal gyrus). They note that their findings support a mechanism for auditory hallucinations that is based in deep brain structures, rather than a mechanism reflecting “inner speech” deriving from cortical language regions such as Broca's area. An alternative “top down” strategy seeks at the outset to identify a fundamental cognitive process and/or crucial region or circuit that could account for the entire range of heterogeneous symptoms observed. Examples of such fundamental processes include defects in information processing, attention, or working memory. Examples of crucial regions include prefrontal cortex (based on its complex patterns of connectivity and phylogenetic expansion in human beings) and the thalamus (based on its role as a filter or generator and its extensive connectivity; 1Andreasen N.C Arndt S Swayze V Cizadlo T Flaum M O'Leary D.S Ehrhardt J Yuh W.T.C Science. 1994; 266: 294-298Crossref PubMed Scopus (627) Google Scholar, 2Andreasen N.C Flashman L Flaum M Arndt S Swayze V O'Leary D.S Ehrhardt J.C Yuh W.T.C J. Am. Med. Assoc. 1994; 272: 1763-1769Crossref Scopus (288) Google Scholar). A substantial literature has been amassed in support of both anatomic and physiologic dysfunction in the prefrontal cortex, using MR, SPECT, PET, and postmortem tissue; some of these studies have proposed that a defect in working memory could be mediated through prefrontal abnormalities and would parsimoniously account for the basic cognitive deficit (8Goldman-Rakic P.S J. Neuropsych. Clin. Neurosci. 1994; 6: 348-357PubMed Google Scholar). Several recent studies have noted decreased prefrontal size and cortical volume. Exemplifying the resurgence of interest in neuropathology, a recent well-designed study of postmortem tissue by 11Selemon L.D Rajkowska G Goldman-Rakic P.S Arch. Gen. Psychiatry. 1995; 52: 805-818Crossref PubMed Scopus (744) Google Scholar has found that the decreased size may be due to a decrease in prefrontal neuropil, an abnormality that suggests an underlying neurodevelopmental mechanism. Recent studies also support a role for the thalamus in schizophrenia based on both MR and postmortem data (1Andreasen N.C Arndt S Swayze V Cizadlo T Flaum M O'Leary D.S Ehrhardt J Yuh W.T.C Science. 1994; 266: 294-298Crossref PubMed Scopus (627) Google Scholar). Impaired thalamic function or a misconnection between it and other key brain regions could lead to defects in sensory gating, information processing, modulation or integration of information transfer, or other fundamental cognitive processes. Since the thalamus and prefrontal cortex are closely interlinked, this connection is often viewed a key candidate circuit. Other cortical and subcortical regions have also been explored in more complex circuit models including almost all brain regions: temporal and parietal cortex, basal ganglia, anterior cingulate, and the hippocampal complex (3Barta P.E Pearlson G.D Powers R.E Richards S.S Tune L.E Am. J. Psychiatry. 1990; 147: 1457-1462PubMed Google Scholar, 4Benes F.M Arch. Gen. Psychiatry. 1995; 52: 1015-1018Crossref PubMed Scopus (55) Google Scholar, 9Liddle P.F Friston K.J Frith C.D Hirsch S.R Jones T Frackowiak R.S.J Br. J. Psychiatry. 1992; 60: 179-186Crossref Scopus (749) Google Scholar, 12Shenton M.E Kikinis R Jolesz F.A Pollak S.D LeMay M Wible C.G Hokama H Martin J Metcalf D Coleman M N. Engl. J. Med. 1992; 327: 604-612Crossref PubMed Scopus (1014) Google Scholar). Evidence is available to support a role for most of these regions, and key experiments during coming years will no doubt eventually determine how focal or distributed the abnormalities in schizophrenia actually are. Contemporary investigators of schizophrenia also debate as to whether the disease should be conceptualized as a chemical or anatomical defect. The impressive efficacy of antipsychotic drugs led several generations of clinical investigators to view schizophrenia as a “dopamine disease.” Primary emphasis was placed on determining the site of abnormality in the cascade of events modulating presynaptic signal formation and release and postsynaptic transduction. For many years, most investigators thought of the brain as a homogeneous soup, all parts of which were equally affected by disease processes and by neuroleptic medications used to treat them. The developing specialty of chemical anatomy slowly demonstrated, however, that concentrations of neurotransmitters vary across brain regions; this integration of chemistry with anatomy has also slowly affected models of schizophrenia. For example, as shown in Figure 1, dopamine has a relatively narrow anatomic distribution in comparison with serotonin, suggesting that it may have more targeted effects on frontal and limbic regions, while serotonin may have a more global or modulatory effect. Further, subtypes of receptors (e.g., the D1/D5 family and the D2/D3/D4 family) also differ in their distribution. Contemporary thinking has progressed, therefore, from a “too much or too little of this or that neurotransmitter” model to models that postulate complex feedback loops involving excitatory and inhibitory interactions between multiple neurotransmitters, including both GABA and glutamate in addition to the classical biogenic amines (e.g.,6Carlsson M Carlsson A Schizophrenia Bull. 1990; 16: 425-432Crossref PubMed Scopus (299) Google Scholar, 10Lieberman J.A Koreen A.R Schizophrenia Bull. 1993; 19: 371-429Crossref PubMed Scopus (119) Google Scholar, 4Benes F.M Arch. Gen. Psychiatry. 1995; 52: 1015-1018Crossref PubMed Scopus (55) Google Scholar).Figure 1Differential Anatomic Distribution of Dopamine and Serotonin SystemsShow full captionThe dopamine system (A) projects relatively selectively to limbic regions, basal ganglia, and prefrontal cortex, while the serotonin system (B) has an extensive cortical distribution. Early versions of the dopamine hypothesis suggested that therapeutic effects of drugs occurred through limbic blockade, while side effects were caused by blockade in basal ganglia and perhaps prefrontal cortex. A specific D2 blocker for limbic regions was therefore hypothesized to be the ideal medication. Current views, based on the efficacy of atypical neuroleptics, suggest that a mixed profile affecting multiple transmitter systems may be more beneficial in reducing both symptoms and side effects.View Large Image Figure ViewerDownload Hi-res image Download (PPT) The dopamine system (A) projects relatively selectively to limbic regions, basal ganglia, and prefrontal cortex, while the serotonin system (B) has an extensive cortical distribution. Early versions of the dopamine hypothesis suggested that therapeutic effects of drugs occurred through limbic blockade, while side effects were caused by blockade in basal ganglia and perhaps prefrontal cortex. A specific D2 blocker for limbic regions was therefore hypothesized to be the ideal medication. Current views, based on the efficacy of atypical neuroleptics, suggest that a mixed profile affecting multiple transmitter systems may be more beneficial in reducing both symptoms and side effects. 7Dolan R.J Fletcher P Frith C.D Friston K.J Frackowiak R.S.J Grasby P.M Nature. 1995; 378: 180-182Crossref PubMed Scopus (327) Google Scholar recently reported a study that is an example of this type of integrative approach. This particular study examined the dopamine system in schizophrenia within the context of dual stimulations: the cognitive challenge of performing a verbal fluency task and a chemical stimulation with apomorphine (a dopamine agonist). Normal individuals showed increased blood flow in a prefrontal–thalamic–cingulate circuit during this task, while the patients had a failure of activation that appeared to be localized to the anterior cingulate; this failure was reversed, however, when they were given apomorphine. The anterior cingulate is a key region that has recently received considerable attention in studies of both cognition and schizophrenia. For example, it is active in a variety of different cognitive tasks, such as recognition memory for words, facial recognition, episodic memory, or story recall (Figure 2). Both PET and postmortem studies have suggested that abnormalities in this region may occur in schizophrenia. As Dolan et al. point out, it may have crucial modulatory or integrative effects on a variety of other cortical regions (e.g., frontal or temporal). This study illustrates well how contemporary research on the mechanisms of schizophrenia can attempt to understand the illness on multiple levels simultaneously, combining cognition, chemistry, and anatomy to create an interactive model of the disorder that is consistent with findings observed in other laboratories. Schizophrenia is a devastating illness that affects 1% of the population worldwide. Understanding of its mechanisms was handicapped for many years by the belief that it was a “psychological” illness, even though it was originally described as a brain disease by Kraepelin and others. Research on schizophrenia has returned to its roots in neuroscience; as a consequence, the study of its mechanisms has made enormous strides in recent years. Although we are still far from a complete solution of the schizophrenia puzzle, many pieces of the pattern have begun to fall into place." @default.
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• W2026907501 title "Pieces of the Schizophrenia Puzzle Fall into Place" @default.
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