Showing papers in "Dialogues in Clinical Neuroscience in 2001"

Cerebral aging: integration of brain and behavioral models of cognitive function.

Abstract: There are substantial declines in behavioral measures of cognitive function with age, including decreased function of executive processes and long-term memory. There is also evidence that, with age, there is a decrease in brain volume, particularly in the frontal cortex. When young and older adults perform cognitive tasks that depend heavily on frontal function, neuroimaging evidence indicates that older adults recruit additional brain regions in order to perform the tasks. This additional neural recruitment is termed “dedifferentiation,” and can take multiple forms. This recruitment of additional neural tissue with age to perform cognitive tasks was not reflected in the behavioral literature, and suggests that there is more plasticity in the ability to organize brain function than was previously suspected. We review both behavioral and neuroscience perspectives on cognitive aging, and then connect the findings in the two areas. From this integration, we suggest important unresolved questions and directions for future research.

Psychosocial treatment in schizophrenia.

Abstract: Optimism about the use of psychosocial treatment for schizophrenia has waxed and waned over the years, but there is now a growing consensus that psychosocial interventions play an essential role in the rehabilitation and management of people with schizophrenia. 1-3 Psychosocial treatment may not “work” if the term work is narrowly applied to remission of acute episodes, control of symptoms, and prevention of relapses. However, these are not the only criteria by which an intervention for this complex disease should be judged. Schizophrenia is characteristically a multiply handicapping, chronic disorder involving marked impairments in social role functioning (eg, as a spouse or a worker), excess rates of medical illness, and poor quality of life. Medication is generally a necessary component of treatment, but is rarely sufficient given the diffuse nature of residual neurocognitive impairment and the history of social and functional failures that mark adolescent and adult development. Psychosocial interventions can play a critical role in a comprehensive intervention program, and are probably necessary components if treatment is viewed in the context of the patient's overall level of functioning, quality of life, and compliance with prescribed treatments. Current thinking suggests that, in addition to medication, effective care, and management, patients with schizophrenia require: Problem-specific psychosocial treatment Family psychoeducation Day hospital/vocational rehabilitation and educational opportunities Access to crisis counseling Easily available inpatient psychiatric care Supervised residential liging arrangements Case management to obtain entitiements and coordinate the various facets of treatment Issues to be considered in the design and implementation of psychological treatment programs for schizophrenia Progress in treatment should be expected to be slow and marked by periodic disruptions and periods of regression. Consequently, it is important that treatment be long term, extending over months and years. Treatment should also be guided by concrete, short-term goals that are likely to be achieved (eg, to attend day hospital at least twice a week for 1 month). While there are a number of illness characteristics that are common to most patients, there are extensive individual differences, as well as differences within the same patient over time. Thus, treatment must be tailored to the needs of each patient and adjusted as the patient changes. Regardelss of the severity of illness, the patient must be included as a parther in treatment planning and goal setting in order to secure effective cooperation. Treatment should be conducted in collaboration with the patient, not done to the patient. Effective treatment targets specific skills or problem areas that the patient can agree to work on (eg, social skills, drug use, or vocational skills). Nonspecific group or individual psychotherapy is not effective. The illness is marked by significant deficits in memory, attention, and exectuve functioning that have major effects on the treatment process. Treatment must be adapted to these impaiments if patients are to be able to learn and retain what is discussed in sessions. Treatment should inadvertently become a memory or attention test. Four psychosocial treatment approaches have received substantial empirical support and warrant further study: Social skills training. This treatment approach, which can be provided to patients either individually or in groups, involves systematically teaching patients specific behaviors that are critical for success in social interactions.4,5 Developed over 25 years ago, it is probably the most widely studied psychological treatment method for individuals with schizophrenia, and there is an extensive literature documenting its efficacy.6 Family psychoeducation. The most important development in psychosocial treatment over the last two decades has been the emphasis on the positive effects of family participation in the treatment process. Several different models of family intervention have been developed and tested.7,8 The different approaches to working with families share a number of common elements referred to as psychoeducation: a collaborative, respectful relationship with the family, the provision of information about schizophrenia and its treatment, and teaching family members less stressful and more constructive strategies for communication and solving problems. A number of carefully controlled studies have shown that patients in families who receive this type of family therapy have better outcomes than patients with families who do not receive therapy, and that familymembers report less distress as well. Cognitive therapy. Antipsychotic medications are primarily effective for reducing positive symptoms, but even the new-generation medications are not highly effective for all patients. Recently, there has been increased interest in teaching patients coping strategies for controlling residual symptoms. A number of laboratories in the United Kingdom have reported very promising findings for interventions that employ cognitive behavior therapy techniques (eg, self-talk, rational analysis) to reduce distress associated with both hallucinations and delusions.9,10 Further research is warranted to explore the stability and generalizability of these approaches. Cognitive rehabilitation. As indicated above, schizophrenia is marked by neurocognitive impairments that have a significant impact on community functioning and are only partially ameliorated bymedication. Consequently, considerable effort has been devoted to development of cognitive rehabilitation programs to increase memory capacity, attention, and high level problem-solving skills.11,12 Most of these techniques employ repetitive practice on neurocognitive tasks using computers. The evidence to date documents that test performance can be improved, but it is yet to be determined if there is a real increase in cognitive capacity or, most importantly, if the effects generalize to the community.13 In conclusion, there is now a new generation of psychosocial treatment techniques that have yieldied very promising results. It is likely that, as more breakthroughs occur in the biological treatment of schizophrenia (eg, the effects of clozapine on improving the functioning of treatment refractory patients), psychological treatments will assume an even more important rolein both facilitating the adjustment of patients, as they move from institutional settings to the community, and improving their quality of life.

Brain mechanisms of hallucinogens and entactogens.

Abstract: This review focuses on recent brain imaging and behavioral studies of sensory gating functions, which assess similarities between the effects of classic hallucinogens (eg, psilocybin), dissociative anesthetics (eg, ketamine), and entactogens (eg, 3,4-methylenedioxymethamphetamine [MDMA]) in humans. Serotonergic hallucinogens and psychotomimetic anesthetics produce overlapping psychotic syndromes associated with a marked activation of the prefrontal cortex (hyperfrontality) and other overlapping changes in temporoparietal, striatal, and thalamic regions, suggesting that both classes of drugs act upon a common final pathway. Together with the observation that both hallucinogens and N-methyl-oaspartate (NMDA) antagonists disrupt sensory gating in rats by acting on 5-hydroxytryptamine (serotonin) 5-HT(2) receptors located in cortico-striato-thalamic circuitry these findings suggest that disruption of cortico-subcortical processing leading to sensory overload of the cortex is a communality of these psychoses. In contrast to hallucinogens, the entactogen MDMA produces an emotional state of positive mood, concomitant with an activation of prefrontolimbiclparalimbic structures and a deactivation of amygdala and thalamus.

Characteristics, experience, and treatment of schizophrenia in China.

Abstract: Assessment of differences in the characteristics, experience, and treatment of schizophrenia between China and the West highlights the importance of the interaction of biological and sociocultural factors in the onset and course of the disorder. China reports a much higher prevalence of schizophrenia in urban areas than in rural areas and, surprisingly a higher prevalence in women than in men. Despite differences in the diagnostic criteria for schizophrenia, the pattern of positive, negative, and cognitive symptoms is similar to that seen in the West. Almost ail medical treatment for schizophrenia is provided from specialized psychiatric hospitals, most of which are situated in urban centers. Antipsychotic medication (often the generic clozapine) is the mainstay of inpatient treatment. China developed a variety of innovative community-based treatment models in the 1980s, but the social and economic changes of the 1990s have made ii difficult to generalize these models. Overall, approximately 70% of the estimated 4.8 million persons with schizophrenia in China do not receive regular treatment.

Psychosis in children: diagnosis and treatment.

Abstract: The diagnosis of childhood psychosis raises a host of unresolved problems, despite the Diagnostic and Statistical Manual Of Mental Disorders, 4th edition, Text Revision (DSM-IV-TR) giving identical symptoms and definitions for children, adolescents, and adults. The fantasy lives of children, and issues of developing language and cognition (including retardation), all impair diagnostic accuracy, particularly when differentiating between childhood-onset schizophrenia (COS) (≤12 years), bipolar affective disorder, major depressive disorder, and even obsessive-compulsive disorder and attention-deficit/hyperactivity disorder: the catch-all classification, psychosis not otherwise specified (PNOS), is always available for conundra that prove unsolvable. Typical if nonpathognomonic features include neurocognitive difficulties. Multiple screening instruments and specialized versions of semistructured diagnostic interviews are available. Although smooth-pursuit eye-tracking movements may prove a genetic marker for COS, etiologies are likely to be oligogenetic rather than related to a single gene. No specific biological markers or neuroimages have been identified. As such, psychoses may be indicative of a more general pattern of brain dysfunction. Drug treatments are largely based on the adult literature because of a dearth of controlled data below age 18. There are still no rigorous studies of psychosocial treatments and psychotherapy specific to childhood psychosis.

A plausible model of schizophrenia must incorporate psychological and social, as well as neuro developmental, risk factors.

Abstract: Subtle alterations in brain development caused by genes or early environmental hazards, such as obstetric complications, play a role in projecting some individuals on a trajectory toward schizophrenia. High-risk and cohort studies demonstrate that children destined to develop schizophrenia tend to have delayed milestones and subtle neuromotor and cognitive impairments (particularly in coordination and language). These neurocognitive problems lead to difficulties in interpersonal relations, and their progressive alienation makes these at-risk children more likely to harbor odd or paranoid ideas. This cascade of increasingly deviant development may then be compounded by brain maturational changes during adolescence with a resultant lability of the dopaminergic response to stress. As a result, the individual is more susceptible to the effects of the abuse of dopamine-releasing drugs, and to other risk factors such as migration or stressful life events; social isolation may be a common pathway underlying several of the social risk factors.

Therapeutic approaches to age-associated neurocognitive disorders.

Abstract: The United Nations projects that the number of individuals with dementia in developed countries alone will be approximately 36,7 million by the year 2050. International recognition of the significant emotional and economic burden of Alzheimer's disease has been matched by a dramatic increase in the development of pharmacological and nonpharmacological approaches to this illness in the past decade. Changing demographics have underscored the necessity to develop similar approaches for the remediation of the cognitive impairment associated with more benign syndromes, such as mild cognitive impairment (MCI) and age-associated cognitive decline (AACD). The present article aims to provide an overview of the most current therapeutic approaches to age-associated neurocognitive disorders. Additionally, it discusses the conceptual and methodological issues that surround the design, implementation, and interpretation of such approaches.

Treatments for chronic psychosis.

Abstract: Psychosis is a mental condition characterized by hallucinations, delusions, and thought disorder; it spans diagnostic entities that respond to similar therapeutic approaches Psychosis has no fully described tissue pathology, as vet, but is still identified and assessed symptomatically The first generation of antipsychotic drugs was developed in the middle of the 20th century The second generation of drugs arrived in the 1990s This new group of antipsychotic drugs has potent therapeutic actions on the positive symptoms of psychosis with far fewer side effects, especially motor effects However, each of the new drugs has its own characteristic clinical and pharmacological features that affect individual patient response Understanding these individual drug characteristics can promote optimal drug choice and use in conditions of chronic psychosis

Genetic basis of cognitive disability.

Abstract: The importance of genetic influences on cognitive disability has been recognized for a long time, but molecular analysis has only recently begun to yield insights into the pathogenesis of this common and disabling condition. The availability of genome sequences has enabled the characterization of the chromosomal deletions and trisomies that result in cognitive disability, and mutations in rare single-gene conditions are being discovered. The molecular pathology of cognitive disability is turning out to be as heterogeneous as the condition itself, with unexpected complexities even in apparently simple gene-deletion syndromes. One remarkable finding from studies on X-linked mental retardation is that mutations in different small guanosine triphosphate (GTP)-binding proteins result in cognitive disability without other somatic features. Advances are also being made in cognitive disability with polygenic origins, such as dyslexia and autism. However, the genetic basis of mild intellectual disability has yet to be satisfactorily explained.

Suicidal behavior in schizophrenia and family history of suicide.

Abstract: Suicide is a complex behavior with dramatic personal, familial, and economic consequences. “Suicidal behavior” refers to three different behaviors: completed suicide, suicide attempts (SA), and suicidal ideation. Completed suicide and SA, but not ideation, are behaviors on the same continuum and expressions of the same liability, according to family and biological studies.1,2 Suicide is the leading cause of premature death in schizophrenia, and 2% to 12% of people who commit suicide suffer from schizophrenia. Harris and Barraclough3 estimated that the standardized mortality ratio (100 x sum of observed deaths /sum of expected deaths) in schizophrenia is 845. Various studies have reported a lifetime suicide rate of 10% to 13% in people suffering from schizophrenia. Recently, Inskip et al4 reanalyzed most of the previous studies using generalized linear modeling. They concluded that this rate is closer to 4% (in this meta-analysis the lifetime suicide rate was 6% for affective disorder and 7% for alcohol dependence). SAs occur quite often in schizophrenia: their frequency ranges from 20% to 55%. More than 50% of schizophrenic suicide attempters report more than one SA. SA is considered to be one of the most powerful predictors of future SA and completed suicide. Genetic factors contribute to the liability to suicidal behavior, and heritability of suicidal behavior is estimated to be 45%. 5 A family history of suicide increases the risk for suicide and SA.6 The impact of a family history of suicide has been studied mainly in depression, and much less frequently in patients with schizophrenia.6,7 It remains to be determined whether a family history influences SA characteristics in schizophrenia. The goals of the present study were twofold: To determine and compare the frequency of a family history of suicide in patients with schizophrenia and in normal controls. To determine the influence of a family history of suicide on the frequency of SA in patients with schizophrenia and on SA characteristics.

Cognitive toxicity of drugs used in the elderly.

Abstract: The aged are an extremely heterogeneous population that is growing worldwide, included are healthy and agile individuals in their early sixties, as well as an increasing number of people over the age of 35. Pharmacotherapy is expected to continue its prominent role in the medical management of a wide range of conditions that affect older people. Adverse consequences of all kinds complicate the use of medications, and such events seem to increase in incidence with polypharmacy. Cognitive impairment can occur during the course of treatment with a wide range of medications and can have a variety of presentations, Both the number of concurrent medications that older individuals routinely use and physiologic changes in these patients render them more susceptible to developing cognitive toxicity. Most of the frequently implicated medications carry documentation of their ability to cause cognitive disturbances in their package labeling, suggesting that the level of vigilance for adverse effects during the course of their use should always be high. Such caution can be used to guide appropriate drug treatment of the aged so that clinicians do not need to opt for undertreatment to avoid toxicity.

Can premorbid and prodromal markers associated with psychosis be utilized for early detection and secondary prevention of schizophrenia

Abstract: The rationale for identifying markers of latent schizophrenia is the evidence that early treatment speeds remission and lessens long-term deterioration. Unfortunately hovever, although the childhood and adolescence of individual psychotics often reveal premorbid deviations from established norms, while epidemiological studies identify cognitive performance and social adjustment as potential premorbid markers, such signs vary widely and no typical prodrome has been identified. Illness-related events or behaviors are not the only factors precipitating the transition from premorbid to prodrome: educational and socioeconomic status are also involved, it follows that there is a controversy surrounding the secondary prevention of schizophrenia: because of the poor specificity of premorbid and prodromal markers, treating such patients implies thai an unacceptably high proportion of individuals who will not ultimately develop florid schizophrenia will be exposed to stigma of a provisional diagnosis of severe mental illness as well as to the adverse effects of treatment Schizophrenia, therefore, is an aggravated illustration of the dilemmas facing much preventive therapy.

Treating age-related changes in somatotrophic hormones, sleep, and cognition.

Abstract: Many of the body's systems that function to maintain optimal health and well-being decline with advancing age. Aerobic capacity, muscle mass, and strength all progressively decline. Significant sleep disturbances are associated with increases in morbidity and mortality. Cognition declines, impacting an older individual's ability to function independently. Interventions that could at least stabilize or possibly improve functional capacity, sleep quality, and cognitive function have the theoretical potential to prolong an older individual's ability to live independently, and interest in their possible utility is growing rapidly. One such intervention may be stimulation of the “somatotrophic” axis via growth hormone-releasing hormone (GHRH). Here we review the evidence for such somatotrophic interventions. We also report preliminary findings on the effects of chronic GHRH treatment on the somatotrophic hormones, body composition, functional status, sleep, and cognitive function of healthy older men and women from two major GHRH intervention studies, one recently completed and the other ongoing.

Genetics of inherited human epilepsies.

Abstract: Major advances have recently been made in our understanding of the genetic basis of monogenic inherited epilepsies. Progress has been particularly spectacular with respect to idiopathic epilepsies, with the discovery that mutations in ion channel subunits are implicated. However, important advances have also been made in many inherited symptomatic epilepsies, for which direct molecular diagnosis is now possible, simplifying previously complex investigations, it is expected that identification of the genes implicated in familial forms of epilepsies will lead to a better understanding of the underlying pathophysiological mechanisms of these disorders and to the development of experimental models and new therapeutic strategies, in this article, we review the clinical and genetic data concerning most of the inherited human epilepsies.

The search for allelic variants that cause monogenic disorders or predispose to common, complex polygenic phenotypes.

Abstract: The search for the mutant genes for monogenic disorders has been a spectacular success. This was accomplished because of the mapping and sequencing of the human genome, the determination of the sequence variability, the collection of well-characterized families with mendelian disorders, the development of statistical methods for linkage analysis, and laboratory methods for mutation search. The challenge of the genetic medicine is now to decipher the nucleotide sequence variants that predispose to common complex, polygenic phenotypes. The methodology for this challenge is in development and constant evolution, it is anticipated that, in the next 10 to 20 years, susceptibility alleles for these common disorders will be identified.

The French concept of “psychose hallucinatoire chronique” -a preliminary form of schizophrenia? The role of late-life psychosis in the anticipation hypothesis of schizophrenia

Abstract: The distinction between schizophrenia and chronic delusional syndromes (including the French concept of “psychose hallucinatoire chronique” [PHC] or chronic psychotic hallucinations, paraphrenia, and late paraphrenia) is currently used in various European countries, although there are no international criteria for chronic and bizarre delusions. The French concept of PHC is characterized by late-onset psychosis, predominantly in females, with rich and frequent hallucinations, but almost no dissociative features or negative symptoms. PHC and late-onset schizophrenia may have risk factors in common, which may help differentiate these disorders from young-onset schizophrenia, especially with regard to the potential role of (i) the estradiol hypothesis; (ii) the impact of sensory deficit; (Hi) putative specific brain abnormalities; or (iv) specific genetic mutations. In accordance with this hypothesis, and taking into account the familial aggregation analyses of PHC, here we evaluate the possibility that PHC represents a less severe form of schizophrenia, which would partly explain the “Sherman paradox” also observed in schizophrenia. The Sherman paradox describes the fact that multiplex families frequently have only one affected ascendant, meaning that an isolated sporadic case is at the origin of a highly loaded family. We thus propose that if unstable mutations are involved in the risk for schizophrenia, then PHC might represent a moderate disorder belonging to the schizophrenia spectrum phenotype.

Evolution of diagnostic criteria in psychoses.

Abstract: The term psychosis was first introduced in the mid-19th century for the separation of psychiatric disorders from neurological disorders within the neuroses The concept of psychosis has become gradually restricted from a generic term for psychiatric disorders to one of the major classes of mental illness, which was assumed to be the result of a disease process, and, more recently, to a symptom present in many psychiatric disorders In the course of this development, the diagnostic criteria for psychosis shifted from the severity of the clinical manifestations and the degree of impairment in social functioning to the presence of one or more symptoms in a set of psychopathological symptoms, which include hallucinations, formal thought disorder manifest in disorganized or odd speech, delusions, flat/inappropriate affect, avolition/apathy disorganized behavior, catatonic motor behavior, and depersonalization/derealization The changes in the conceptualization of psychosis and in the diagnostic criteria for psychosis are documented in the various editions of the Diagnostic and Statistical Manual of Mental Disorders of the American Psychiatric Association (from DSM-I to DSM-IV] and the International Classification of Diseases of the World Health Organization (from ICD-9 to ICD-10]

Cerebral aging: neuropsychological, neuroradiological, and neurometabolic correlates.

Abstract: The aging process is associated with a progressive cognitive decline, but both the extent of this decline and the profile of age-related cognitive changes remain to be clearly established. Currently, cognitive deficits associated with aging may be diagnosed under the categories of age-associated memory impairment, age-associated cognitive impairment, or the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) category of age-related cognitive decline. Age-related decline has been reported for several cognitive domains, such as language (eg, verb naming, verbal fluency), visuospatial abilities (eg, facial discrimination), executive functions (eg, set shifting, problem solving), and memory functions (eg, declarative learning, source memory). There is an age-related decline in brain cortical volume, which primarily involves association cortices and limbic regions. Studies of brain metabolic activity demonstrate an age-related decline in neocortical areas. Activation studies using cognitive tasks demonstrate that older healthy individuals have a different pattern of activation from younger subjects, suggesting thai older subjects may recruit additional brain areas in order to maintain performance.

Incorporation of molecular data and redefinition of phenotype: new approaches to genetic epidemiology of bipolar manic depressive illness and schizophrenia.

Abstract: Considerable advances have been made in identifying specific genetic components of bipolar manic depressive illness (BP) and schizophrenia (SZ), despite their complex inheritance. Meta-analysis of all published whole-genome linkage scans reveals overall support for illness genes in several chromosomal regions. In two of these regions, on the lonq arm of chromosome 13 and on the long arm of chromosome 22, the combined studies of BP and SZ are consistent with a common susceptibility locus for the two disorders. This lends some plausibility to the hypothesis of some shared genetic predispositions for BP and SZ. Other linkages are supported by multiple studies of specific chromosomal regions, most notably two regions on chromosome 6 in SZ. The velocardiofacial syndrome is associated with deletions very close to the linkage region on chromosome 22, and with psychiatric manifestations of both BP and SZ. Endophenotypes of SZ, previously demonstrated to be heritable, have been found to have chromosomal linkage in at least one study. These include eye-tracking abnormalities linked to the short arm of chromosome 6, and abnormality of the P50 cortical evoked potential linked to chromosome 15. Variants in specific genes have been associated with susceptibility to illness, and other genes have been associated with susceptibility to side effects of pharmacological treatment. These genetic findings may eventually be part of an integrated genetic, environmental, and interactive-factor epidemiology of the major mental illnesses.

Brain aging research at the close of the 20th century: from bench to bedside.

Abstract: Remarkable and continued growth in the field of brain aging research has been fueled by a confluence of factors. Developments in molecular biology, imaging, and genetics coupled with the imperative caused by the aging of the population has created fertile ground for improved understanding of the interaction between brain function and behavior. Aging changes in neurochemical systems may account for the spectrum of cognitive and behavioral states of successfully aged pen sons, but may also contribute to enhanced vulnerability to depressive or dementing illness. In particular, the refinement of in vivo imaging approaches to investigating the structure and function of the aging brain has provided the opportunity to strengthen our knowledge of the biological substrate of the aging brain and neuropsychiatrie disorders, and translate these into therapeutics.

Treatment of the special patient with schizophrenia.

Abstract: Special patient populations with schizophrenia have received little attention. These populations include adolescents, the elderly, substance abusers, and patients who are considered treatment-resistant. Interest in these populations is rapidly growing, especially with regard to their treatment with second-generation antipsychotics. This article describes the treatment of special patient populations and summarizes the research that has been done in this field.

Brain abnormalities underlying limb apraxia in corticobasal degeneration: an fMRI study

Abstract: Corticobasal degeneration is a neurodegenerative disease characterized, by cortical dysfunction and extrapyramidal signs. The most consistent symptom is a unilateral limb apraxia, which consists of an isolated disorder of gestural production involving primarily the upper limb. The objective of this study is to investigate the functional abnormalities that may underlie motor dysfunction, and those which might correlate to the severity of limb apraxia.

Huntington's disease: from gene to potential therapy.

Abstract: Huntington's disease (HD) is a progressive, late-onset neurodegenerative illness with autosomal dominant inheritance that affects one in 10 000 individuals in Western Europe. The disease is caused by a polyglutamine repeat expansion located in the N-terminal region of the huntingtin protein. The mutation is likely to act by a gain of function, but the molecular mechanisms by which it leads to neuronal dysfunction and cell death are not yet known. The normal function of huntingtin in cell metabolism is also unclear. There is no therapy for HD. Research on HD should help elucidate the pathogenetic mechanism of this illness in order to develop successful treatments to prevent or slow down symptoms. This article presents new results in HD research focusing on in vivo and in vitro model systems, potential molecular mechanisms of HD, and the development of therapeutic strategies.

The schizophrenia prodrome: promise for prevention.

Abstract: Converging theoretical, psychopharmacological, neurodevelopmental advances have led to increasing interest in preventive intervention in schizophrenia. In particular, evidence suggests that early treatment is associated with a better prognosis. Furthermore, based on the reported reduction in severe side effects, the new novel antipsychotics potentially provide the tools for early intervention. Nevertheless, initiation of intervention during the prodrome has become controversial because of such unresolved issues as: (i) how to accurately identify susceptible individuals who are in true need of preventive intervention; (ii) at what developmental point in the prodrome medication should be initiated; (iii) how long medication should be continued; and (iv) what medication is optimal for each phase of the prodrome. By adopting a naturalistic, prospective research strategy, the Recognition and Prevention (RAP) program now underway in New York has been designed to address these and other important questions involved in prodromal research and treatment.

Recent developments in the pathogenesis, diagnosis, and therapy of prion diseases.

Abstract: Prions continue to pose a formidable challenge to life sciences. While human prion diseases are still rare, the incidence of a new variant of Creutzfeldt-Jakob disease in the United Kingdom is increasing exponentially - raising fears that it might develop into a major epidemic. This disease is likely to represent the result of human infection with bovine prions. Therefore, understanding how prions replicate and damage the brain, and how their action may be possibly counteracted, has become a major public health issue. Here I examine some current hypotheses concerning the links between bovine and human prion diseases, and the mechanisms by which prions reach and damage the central nervous system after having entered the body at extracerebral sites.

Toward a modern search for schizophrenia genes.

Abstract: Genetic epidemiology has provided consistent evidence that schizophrenia has a genetic component It is now clear that this genetic component is complex and polygenic, with several genes interacting in epistasis. Although molecular studies have failed to identify any DNA variant that clearly contributes to vulnerability to schizophrenia, several regions have been implicated by linkage studies. To overcome the difficulties in the search for schizophrenia genes, it is necessary (i) to use methods of analysis that are appropriate for complex multifactorial disorders; (ii) to gather large enough clinical samples; and (iii) in the absence of genetic validity of the diagnostic classification currently used, to apply new strategies in order to better define the affected phenotypes. For this purpose, we describe here two strategies: (i) the candidate symptom approach, which concerns affected subjects and uses proband characteristics as the affected phenotype, such as age at onset, severity, and negative/positive symptoms; and (ii) the endophenotypic approach, which concerns unaffected relatives and has already provided positive findings with phenotypes, such as P50 inhibitory gating or eye-movement dysfunctions.

Perceptual skill and brain physiology in subgroups of persons with schizophrenia

Abstract: Persons with schizophrenia (SZ) are often noted to have difficulties making judgments associated with categories or abstractions. It is not routinely appreciated, that some people with this syndrome are unable to make simple perceptual classifications. In recent studies by our group,1,2 the behavioral impact of small frequency differences and the brain response to those differences were studied in volunteers with SZ and healthy normal volunteers (NV). From these investigations, we learned, thai SZ volunteers are sensitive to small changes in tone frequency in ways that NVs are not. This observation has also been reported and extended by Javill and his colleagues.3,4 Some SZ volunteers are unusually sensitive to simple lone frequency differences. This report describes our findings in a group of 18 SZ inpatients. A more detailed discussion of these data has been published elsewhere.2 It is not understood why persons with SZ are unable to recognize the physical differences between similar objects or stimuli when they are presented sequentially over time. Deficits in attention and working memory in this group are being extensively explored. One approach to this problem is derived from stimuli that are either extremely similar or extremely different in their psychophysical characteristics. In this investigation, we studied 18 SZ volunteers who were admitted to the Residential Research Unit of the Maryland Psychiatric Research Center. Twelve NVs were recruited from the community by newspaper advertisements. The SZ participants were withdrawn from antipsychotic medication prior to their brain-imaging studies. Both groups were given extensive practice on a “forced-choice” tone recognition task. Briefly, this task consists of recognizing a tone that is presented for a short time interval (100 ms). The volunteer is given 2 s in which to decide whether the tone is relatively “high” or “low” in frequency with respect, to the block of stimuli provided. Only two frequencies are presented within a blocked set of trials. During training, the subjects practiced on blocks of trials in which the tones were far apart in frequency on some occasions and close together in frequency in other sets. Through repetition, all NVs and most SZ participants were able to dramatically improve their accuracy in making difficult distinctions. Following training on 2000 to 3000 trials, spread out over a 2- to 3-week training phase, the participants engaged in positron emission tomography (PET) studies. Regional cerebral blood flow (using bolus oxygen-15) was measured in participants while engaged in each of three different, behavioral conditions: resting, sensory-motor control, and decision. During the resting condition, no tones were presented; during the sensory-motor task, subjects alternated their hands used to press buttons in time with the tones being presented; and during the decision task, subjects were expected to make recognition decisions about the stimuli. Behavioral results of these studies revealed that SZ persons were extremely diverse in their ability to improve with practice. One third of the SZ participants were unable to increase accuracy or increase speed with practice. That group was also unable to make accurate judgments about, tones that, were similar. Only if the tones were more than 10% different could they distinguish the differences accurately. In marked contrast, NVs were able to make 80% accurate judgments when stimuli differed by little more than 1 % ; the majority of the SZ volunteers performed well (80% accuracy) when stimuli were about 2% different. Physiologically, the SZ participants who were unable to improve with learning exhibited marked cingulate cortex abnormalities (Figure 1 and Figure 2). TTttey were unable to increase cingulate activity when shifting from the sensory-motor task to the decision condition. This impaired SZ group also exhibited significantly reduced activity in the right promoter cortex. Figure 1. Healthy volunteers minus unmedicated schizophrenia (SZ) patients: tone decision minus motor control at comparable performance. Healthy comparison subjects exhibit significantly greater neural activity in the anterior cingulate cortex when they shift from ... Figure 2. Volunteers with schizophrenia (SZ) able to make tone recognitions only when the difference between stimulus frequencies was greater than 10%, were compared with SZ persons able to make accurate decisions when the stimuli differed by no more than 2%. The ... Large differences in tones permitted the highly impaired group to make accurate decisions, but this group was unable to improve with practice. The marked inactivity in this group's anterior cingulate and prcmotor regions may account for their inability to gain with training. The cingulate appears to be fundamentally important for error recognition and correction.5-8 The right premotor region is similarly vital for attention and working memory functions.9-12 This study emphasizes the cognitive heterogeneity of the SZ group. By providing each subject with an individually determined difficulty level, we were able to make useful observations regarding the presence of an initially unapparent subgroup. This subgroup's inability to make auditory judgments as well as the cohorts with SZ emphasizes the role of cingulate and prefrontal cortex in making simple perceptual decisions. With further work using functional magnetic resonance imaging, it will be possible to identify at what point various affected groups fail to encode sensory information, or fail to make use of that information in their responses.

Impact of the genome project on the identification of disease genes.

Abstract: Cognitive defects and neurological diseases represent a major issue for human health, especially in aging populations. An estimated 15% of people >65 years are affected by mild-to-severe conditions of genetic origin affecting the central nervous system. Etiological factors of common neurological and psychiatric disorders remain elusive, apart from a few genes associated with rare disorders, such as one form of Alzheimer's disease(APP),a form of amyotrophic lateral sclerosis (SOD1), expanded polyglutamine track in Huntington's disease, and several types of ataxia or ion channel-associated conditions. With the human DNA sequence unveiled as a huge book of 3 gigabases,1,2how can we exploit the genome readout to identify disease-associated alleles and what is the projected impact for clinical genetics? The “book of life” is complete to >90% of euchromatic gene-rich regions, opening unprecedented possibilities for the characterization of all genes. The emerging human catalogue is thought to contain about 30 000 genes. Until now, factors underlying inherited conditions were mostly identified by positional cloning without prior knowledge of their biochemical function, and the catalogue unlocks the door to fast in silico searching(Figure 1, Parti I). Figure 1. The human genome catalogue unlocks the door to fast in silico searching and the design of novel high-throughput genotyping strategie. Complex molecular processes govern organogenesis and fitness builds upon the correct orchestration of gene actions throughout life. Most clinical phenotypes result from alterations of genetic instructions perturbing this tightly regulated system, while being strongly influenced by individual genetic makeup. The profound transition seen with the sequence information is the ability to foster novel concepts in our way of addressing biology as a global entity. Comprehensive studies of genome landscape and common polymorphisms will help identify causal and susceptibility factors at a much greater pace(Figure 1, Parts II and III). Although 60% of human genes have no characterized function yet, the sequence provides a body of information for the design of global strategies in functional genomics, for instance, using molecular evolution to underpin function by inference. Comparative genomics is one of the most powerful approaches to deciphering the molecular basis of disease pathogenesis(Figure 2). Figure 2. Genome sequences boost the power of model organisms and comparative genomics for identifying disease genes and understanding their function. Another essential approach to extracting biological meaning from the genetic message is illustrated by global transcriptome analysis(Figure 3).Grasping how global gene expression is processed into phenotype will be essential to any progress in molecular medicine. Hunting for disease-associated alleles by surveying dynamic biological systems at all relevant developmental stages and in all relevant tissues brings novel perspectives that will allow the correlation of molecular phenotype with clinical phenotype. Figure 3. Global analysis of the transcriptome by complex hybridization on assays: identifying and spotting all of the ≈ 16 000 to 20 000 genes that could be expressed in the human brain.