Search

Inhibition of the P50 evoked electroencephalographic response to the second of paired auditory stimuli has been frequently examined as a neurophysiological deficit in schizophrenia. The National Institute of Mental Health Consortium on the Genetics of Schizophrenia (COGS) examined this endophenotype in a 7 center multi-site study. Recordings were analyzed from 181 probands with schizophrenia, 429 of their first degree relatives, and 333 community comparison control subjects. Most probands were being treated with second generation neuroleptic medications. Highly significant differences in P50 inhibition, measured as either the ratio of amplitudes or their difference in response to the two stimuli, were found between the probands and the community comparison sample. There were no differences between the COGS sites for these findings. For the ratio parameter, an admixture analysis indicated that nearly 40% of the relatives demonstrated deficiencies in P50 inhibition that are comparable to the deficit found in the probands. These results indicate that P50 auditory evoked potentials can be recorded across multiple sites and reliably demonstrate a physiological abnormality in schizophrenia. The appearance of the physiological abnormality in a substantial proportion of clinically unaffected first degree relatives is consistent with the hypothesis that deficits in cerebral inhibition may be a familial neurobiological risk factor for the illness.

The antisaccade task is a widely used technique to measure failure of inhibition, an important cause of cognitive and clinical abnormalities found in schizophrenia. Although antisaccade performance, which reflects the ability to inhibit prepotent responses, is a putative schizophrenia endophenotype, researchers have not consistently reported the expected differences between first-degree relatives and comparison groups. Schizophrenia participants (n=219) from the large Consortium on the Genetics of Schizophrenia (COGS) sample (n=1078) demonstrated significant deficits on an overlap version of the antisaccade task compared to their first-degree relatives (n=443) and community comparison subjects (CCS; n=416). Although mean antisaccade performance of first-degree relatives was intermediate between schizophrenia participants and CCS, a linear mixed-effects model adjusting for group, site, age, and gender found no significant performance differences between the first-degree relatives and CCS. However, admixture analyses showed that two components best explained the distributions in all three groups, suggesting two distinct doses of an etiological factor. Given the significant heritability of antisaccade performance, the effects of a genetic polymorphism is one possible explanation of our results.

The current study examined characteristics of coping patterns adopted by college students in mainland China. In particular, it examined the coping strategies adopted by subjects with schizotypal personality (SPD) features compared to those without SPD features, and compared the relative effectiveness of their coping. Four types of coping flexibility were identified among the college sample (n=427), including active-inflexible, passive-inflexible, active-inconsistent, and passive-inconsistent styles. The passive-inconsistent style was related to the worst outcomes. When comparing subjects with SPD features with those without SPD features, subjects with SPD features endorsed significantly more emotion-focused strategies in uncontrollable situations than those without SPD features. The SPD group experienced higher levels of trait anxiety, depression, paranoid ideation and general health problems. The SPD group also generally perceived more, less controllable stress than the non-SPD group and randomly used all four categories of coping strategies.

Glucose injections attenuate deficits in memory under several conditions in both rodents and humans. The present study examined effects of glucose on memory in two such amnesic populations, scopolamine-treated and old mice, and then assessed effects of glucose on brain [3H]2-deoxyglucose (2DG) uptake. In Experiment 1A, scopolamine (3 mg/kg, i.p.) significantly impaired performance of mice tested in a spontaneous alternation task. Glucose (100 mg/kg, i.p.) administration did not itself affect alternation performance, but when administered with scopolamine, it attenuated the deficit in alternation performance. Scopolamine (3 mg/kg) also resulted in significant reductions in brain 2DG uptake in hippocampus and in thalamus (Experiment 1B). Glucose (100 mg/kg) injections did not themselves affect 2DG uptake, but when administered with scopolamine, they attenuated the scopolamine-induced reductions in 2DG uptake, with the largest reversal occurring in hippocampus. Glucose similarly enhanced spontaneous alternation behavior (Experiment 2A) and hippocampal 2DG uptake (Experiment 2B) in 2-year-old mice. These findings provide additional evidence that the brain becomes more sensitive to circulating glucose in several amnestic conditions and, more generally, extend the view that circulating levels of glucose influence a wide range of brain activities.

Previous studies in rats show that disrupting circadian light-dark rhythms leads to impairments in memory. In particular, both phase delays and phase advances of the light:dark cycle initiated after inhibitory (passive) avoidance training result in impaired retention. The present study examined this phenomenon in mice and, using a retrieval design, examined whether glucose or epinephrine could attenuate deficits in memory. Groups of mice were first trained on an inhibitory avoidance task during the light portion of the illumination cycle. They were then maintained for a 72-h train-test interval either under the same schedule of illumination or one with a phase advance of 4 h. Thirty minutes before testing, groups were injected with saline, glucose (1, 10, 100, 250, or 500 mg/kg), or epinephrine (0.1 mg/kg). The results showed that (1) retention was significantly impaired in phase-shifted mice relative to nonphase-shifted controls and (2) both glucose (100 mg/kg) and epinephrine attenuated the deficit in memory. These findings indicate that altered illumination schedules disrupt memory in mice as well as in rats. In addition, they suggest that glucose may be a useful treatment to attenuate deficits in memory associated with impaired biological rhythms.

Glucose administration enhances memory in several amnestic populations, including old humans and rodents. The present experiment demonstrates that glucose also enhances measures of sleep in old rats. Three-hour day-time sleep EEGs were assessed in 3- and 24-month-old rats. The animals received injections of saline or glucose (100, 500, and 1000 mg/kg) on different days in a counter-balanced order. At doses of 100 and 500 mg/kg, glucose augmented the duration of paradoxical sleep bouts and total paradoxical sleep time in old, but not young, rats. Within 2 weeks after the sleep tests, measures of several brain neurotransmitter functions were obtained. Glucose was more effective in enhancing paradoxical sleep in those individual aged rats with high levels of hippocampal choline acetyltransferase and occipital cortex serotonin concentrations than in aged rats with lower levels on these neurochemical measures. The findings suggest that glucose attenuates selective age-related sleep deficits in old rats. More generally, these results add to a growing body of evidence indicating that moderate doses of peripheral glucose can influence a variety of CNS measures.

Background N100 evoked potential amplitude and gating abnormalities have been widely observed in schizophrenia patients. However, previous studies have been inconclusive as to whether similar deficits are present in unaffected family members. The Consortium on the Genetics of Schizophrenia (COGS) is a multisite National Institute of Mental Health (NIMH) initiative examining neurocognitive and neurophysiological measures as endophenotypes for genetic studies of schizophrenia. We report initial results from the COGS dataset of auditory N100 amplitude and gating as candidate endophenotypes. Methods Evoked potential data were acquired from 142 schizophrenia probands, 373 unaffected first-degree relatives, and 221 community comparison subjects (CCS), using an auditory paired-click stimulation paradigm. Amplitude of the N100 response to each click and the click 2/click 1 ratio were dependent variables. Heritability was estimated based on kinships using Solar v.2.1.2. Group differences were examined after subjects were categorized as either "broad" or "narrow," based on the presence (broad) or absence (narrow) of nonpsychotic psychiatric comorbidity. Results Heritability estimates were .40 and .29 for click1 and click2 amplitudes and .22 for the ratio. Broad and narrow patients both had impaired click 1 amplitudes. Broad relatives, but not narrow relatives, exhibited similar impairments. There were no group differences for either click 2 amplitude or the gating ratio. Conclusions N100 amplitude is a heritable measure that is abnormal in patients and a subset of relatives for whom psychiatric comorbidity may be a genetically associated phenotype. Auditory N100 gating, although heritable, is less viable as a schizophrenia endophenotype.

Amphetamine, epinephrine, and glucose enhance memory storage when administered shortly after training. Amphetamine enhancement of memory storage may be mediated by peripheral epinephrine actions, and epinephrine enhancement of memory storage may involve increases in blood glucose levels. Amphetamine and possibly epinephrine also enhance memory retrieval when administered shortly before testing. To examine the parallels in pharmacological enhancement of memory storage and retrieval, we tested the effects on memory of injections of amphetamine (1.0 mg/kg), epinephrine (0.05 mg/kg), or glucose (100 mg/kg) administered prior to retention tests in mice. Mice were trained in a one-trial inhibitory (passive) avoidance task. Thirty minutes prior to testing, each mouse received an injection of saline, amphetamine, epinephrine, or glucose. In a second experiment, rats were trained on a one-trial inhibitory avoidance task and were administered glucose (100,250, or 500 mg/kg) prior to testing. The results indicate that amphetamine, epinephrine, and glucose all significantly enhanced learned performance, supporting the view that similar neuroendocrine systems may contribute to both memory storage and retrieval. In addition, these findings provide another demonstration that peripheral glucose injections modify behavior.

Background Startle and its inhibition by weak lead stimuli (“prepulse inhibition”: PPI) are studied to understand the neurobiology of information processing in patients and community comparison subjects (CCS). PPI has a strong genetic basis in infrahumans, and there is evidence for its heritability, stability and reliability in humans. PPI has gained increasing use as an endophenotype to identify vulnerability genes for brain disorders, including schizophrenia. Genetic studies now often employ multiple, geographically dispersed test sites to accommodate the need for large and complex study samples. Here, we assessed the feasibility of using PPI in multi-site studies. Methods Within a 7-site investigation with multiple measures, the Consortium on the Genetics of Schizophrenia conducted a methodological study of acoustic startle and PPI in CCS. Methods were manualized, videotaped and standardized across sites with intensive in-person training sessions. Equipment was acquired and programmed at the “PPI site” (UCSD), and stringent quality assurance (QA) procedures were used. Testing was completed on 196 CCS over 2.5 years, with 5 primary startle dependent measures: eyeblink startle magnitude, habituation, peak latency, latency facilitation and PPI. Results Analyses identified significant variability across sites in some but not all primary measures, and determined factors both within the testing process and subject characteristics that influenced a number of test measures. QA procedures also identified non-standardized practices with respect to testing methods and procedural “drift”, which may be particularly relevant to multi-site studies using these measures. Conclusion With thorough oversight and QA procedures, measures of acoustic startle PPI can be acquired reliably across multiple testing sites. Nonetheless, even among sites with substantial expertise in utilizing psychophysiological measures, multi-site studies using startle and PPI as dependent measures require careful attention to methodological procedures.

BackgroundEvaluation of individuals at high genetic risk of schizophrenia is a powerful method for identifying precursors of the illness.AimsTo identify aspects of personality, psychopathology and social development that differentiate high-risk and control individuals.MethodAdolescent and young-adult first-degree relatives (n=35) of people with schizophrenia or schizoaffective disorder and a control group (n=55) were compared on 36 measures at baseline of a longitudinal study Measures differentiating high-risk and control participants were related to four genetic loading indices.ResultsHigh-risk participants older than 17 years showed more physical anhedonia, less positive involvement with peers and more problems with peers, siblings and the opposite gender. Older high-risk individuals also were less cooperative, less self-directed and less reward-dependent. Problems with peers and the opposite gender, as well as reward dependence, were related linearly to genetic loading.ConclusionsAlterations in personality traits and social development are present in high-risk individuals, and may be markers for genetic liability toward the illness.

The antisaccade task is a promising schizophrenia endophenotype; it is stable over time and reflects neurophysiological deficits present in both schizophrenia subjects and their first-degree relatives. Meaningful genetic research requires large sample sizes that are best ascertained using multi-site study designs. To establish the criterion validity of the antisaccade task in a multi-site design, the Consortium on the Genetics of Schizophrenia (COGS) examined whether seven sites could detect previously reported antisaccade deficits in schizophrenia subjects. Investigators presented 3 blocks of 20 antisaccade stimuli to 143 schizophrenia subjects and 195 comparison subjects. Frequent collaborator communication, standardized training, and ongoing quality assurance optimized testing uniformity. Data were discarded from only 1.2% of subjects due to poor quality, reflecting the high fidelity of data collection and scoring methods. All sites detected a significant difference in the proportion of correct antisaccades between schizophrenia and comparison subjects (p

Research clearly shows that both nature and nurture play important roles in the genesis of psychopathology. In this paper, we focus on 'gene-environment interaction' in mental disorders, using genetic control of sensitivity to the environment as our definition of that term. We begin with an examination of methodological issues involving gene-environment interactions, with examples concerning psychiatric and neurological conditions. Then we review the interactions in psychiatric disorders using twin, adoption and association designs. Finally, we consider gene-environment interactions in selected neurodevelopmental disorders (autism and schizophrenia).

Schizotaxia is a stable syndrome of neuropsychological deficits and negative symptoms found in relatives of schizophrenic patients. These may represent special vulnerability to schizophrenia. Five areas of deficit are enumerated and suggestions as to the potential value of pre-illness interventions are discussed.

Fine-tuning of neuronal connections during development is regulated through environmental interactions. Some fine-tuning occurs through changes in gene expression and/or epigenetic gene-specific DNA methylation states. DNA methylation occurs by transfer of a methyl group from S-adenosyl methionine to cytosine residues in the dinucleotide sequence CpG. Although CpG sequences spread throughout the genome are usually heavily methylated, those occurring in CpG islands in the promoter regions of genes are less methylated. In most cases, the extent of DNA methylation correlates with the extent of gene inactivation. Other known epigenetic mechanisms include histone deacetylation and chromatin remodeling, RNA inhibition, RNA modification, and DNA rearrangement. Exposure memory expressed as epigenetic DNA modifications allows genomic plasticity and short-term adaptation of each generation to their environment. Environmental factors that affect DNA methylation include diet, proteins, drugs, and hormones. Induced methylation changes may produce altered gene response upon subsequent hormonal stimulation. The gene-specific DNA methylation state may be preserved upon transmission through mitosis and meiosis. An increasing amount of data implicates a role for DNA methylation in multi-factorial psychiatric disorders. For example, L-methionine treatment can exacerbate psychosis; while valproate, a drug producing hypomethylated DNA, reduces such symptoms. Hypermethylation of the promoter region of the RELN gene correlates with reduced gene expression. This gene's protein Reelin, which is necessary for neuronal migration and synaptogenesis, is reduced in schizophrenia and bipolar disorder, suggesting hypermethylation of the promoter region in these disorders. Some evidence implicates methylation of the promoter regions of the DRD2 and HTR2A genes in schizophrenia and mood disorders as well. DNA methylation usually increases with age, although hypomethylation of the promoter region of the amyloid A4 precursor gene during aging may play a role in Alzheimer's disease. More studies are needed to define the role of methylomics and other epigenetic phenomena in the nervous system.

Part I. The Etiology and Genetics of Schizophrenia The Genetic Basis of Schizophrenia Stephen V. Faraone, Stephen J. Glatt, and Levi Taylor Early Environmental Determinants of Schizophrenia Jason Schiffman, John Carter, Ricardo A. Machon, and Sarnoff Mednick Obstetric Risk Factors for Schizophrenia and Their Relationship to Genetic Predisposition: Following Ariadne's Double-Stranded Thread Through Early Development Stefano Marenco and Daniel R. Weinberger Part II. The Vulnerability to Schizophrenia The Nature of the Prodrome in Schizophrenia Jaak Rakfeldt and Thomas H. McGlashan The Nature of Schizotaxia Stephen V. Faraone, Ming T. Tsuang, and Sarah I. Tarbox A Neuropsychological Perspective on Vulnerability to Schizophrenia: Lessons From High-Risk Studies Allan F. Mirsky and Connie C. Duncan Neurocognitive Deficits in the Biological Relatives of Individuals With Schizophrenia William S. Kremen and Anne L. Hoff The Nature and Origin of Socioemotional Deficits in Schizophrenia Elaine Walker and Karen M. Hochman Neuroimaging Studies of Nonpsychotic First-Degree Relatives of People With Schizophrenia: Toward a Neurobiology of Vulnerability to Schizophrenia Larry J. Seidman, Heidi E. Wencel, Colm McDonald, Robin M. Murray, and Ming T. Tsuang Neurophysiological Endophenotypes in Early Detection of Schizophrenia Marina Myles-Worsley Is the Development of Schizophrenia Predictable? Paola Dazzan, Eugenia Kravariti, Paul Fearon, and Robin M. Murray Part III. Early Intervention and Prevention of Schizophrenia Prevention of Schizophrenia and Psychotic Behavior: Definitions and Methodological Issues C. Hendricks Brown and Stephen V. Faraone The Treatment of Schizotaxia Ming T. Tsuang, Sarah I. Tarbox, Levi Taylor, and William S.Stone Treatment of the Schizophrenia Prodrome Barbara Cornblatt, Todd Lencz, Christopher Smith, and Andrea Auther The Role of Genetic Counseling Debby W. Tsuang, Stephen V. Faraone, and Ming T. Tsuang Part IV. Challenges for the Near Future The Biology of Schizotaxia William S. Stone, Stephen J. Glatt, and Stephen V. Faraone Molecular Medicine and the Prospects for Prevention and Early Intervention in Schizophrenia William T. Carpenter, Jr. and James I. Koenig Index

Like schizophrenia, the biology of schizotaxia is multidimensional and complex. This point is underscored by other chapters in this volume that focus on abnormalities in brain imaging and sensory gating in nonpsychotic relatives of patients with schizophrenia. The goal of this chapter is to look forward by considering representative neurochemical areas in schizophrenia that are promising but largely unexplored in schizotaxia. In each case, a brief overview of a neurochemical disturbance in schizophrenia is outlined, followed by the relevance of that area for schizotaxia research. Four representative examples are reviewed, starting with abnormalities in dopamine (DA) neurotransmission. As a point of reference, each of the other areas discussed includes a discussion of how it relates to DA function. Moreover, each succeeding area of discussion focuses on a system that has a broader effect on brain function than does DA alone, to highlight the importance of multiple levels of analysis for an understanding of schizotaxia. After the discussion of DA, glutamate (GLU) function in schizophrenia is reviewed, followed by consideration of abnormalities in membrane phospholipids, and then a discussion of glucose regulation. We begin with a brief introduction to the neurochemistry of schizophrenia.

Schizotaxia is characterized by meaningful clinical symptoms that reflect an underlying liability to schizophrenia. Two research paradigms have provided the most data about the basic features of schizotaxia: studies of adult, first-degree relatives of schizophrenic patients, and studies of children of schizophrenic patients. It is useful to distinguish adult and child relatives because adults, unlike children, have lived through at least some of the highest risk period for schizophrenia. Although each age group includes schizotaxic individuals (20–50% of adult, firstdegree relatives show symptoms of schizotaxia [1,2]), schizotaxia in most adults (at least over the age of 35) is likely to be a relatively stable condition. In contrast, most children have yet to pass through the period of highest risk, and thus contain a higher percentage of individuals who will express psychosis. Thus, schizotaxia represents both a stable, clinically meaningful condition in its own right (in both adults and children) and, especially in a subset of children, a risk factor for subsequent psychopathology.

Schizophrenia is a biologic disorder whose etiology involves a combination of genetic and environmental risk factors. In this review, the authors update the conceptual basis of schizotaxia, consider evidence for its validity, and look toward its likely evolution in the future.

Background: Substantial evidence now shows that the genetic vulnerability to schizophrenia can be manifested clinically in first-degree relatives of people with schizophrenia, even without the full manifestations of the disorder. One pattern of problems observed involves the combination of negative symptoms and neuropsychological deficits. We have investigated whether a low dose of a novel antipsychotic medication, risperidone, could attenuate these clinical problems in non-psychotic, first-degree relatives, and report here findings from our first 4 cases. Methods: Twelve adults who were first-degree relatives of patients with schizophrenia were evaluated for the presence of negative symptoms and neuropsychological deficits (in attention and working memory, long-term verbal memory and executive functions). Four subjects who met our predetermined criteria, and who did not demonstrate medical contraindications, were enrolled in a 6-week trial of risperidone. Clinical and medical measures were assessed before, during and after treatment. Doses of risperidone started at 0.25 mg and were increased to 1.0–2.0 mg/day. Results: Three subjects showed substantial reductions in negative symptoms, and one subject showed modest reductions. All four subjects showed substantial improvements on some tests of attention and working memory. Side effects of risperidone were temporary and mainly mild. Conclusions: These initial findings support two conclusions. First, clinical deficits in non-psychotic first-degree relatives of people with schizophrenia are identifiable, and to a significant extent, reversible. Second, risperidone may eventually serve as an effective treatment for people whose lives are impaired by similar or related problems. Biol Psychiatry 1999;45:1412–1418 © 1999 Society of Biological Psychiatry

Behavioral genetic studies provide overwhelming evidence that genes contribute to schizophrenia. Recently, genetic studies have provided promising evidence that schizophrenia genes are linked to several chromosomal locations in affected family members. Despite this progress, individual genes for schizophrenia have yet to be identified. Future progress will depend, in part, on the selection of phenotypes that best reflect effects of etiologic genes. One such phenotype is schizotaxia, a clinically meaningful syndrome that reflects the genetic liability to schizophrenia in nonpsychotic individuals. The potential importance of schizotaxia, or similar concepts, for use in genetic studies, is discussed.

There is a growing emphasis on attempts to identify the early signs and symptoms of schizophrenia, largely because early detection and treatment of psychosis (i.e., secondary prevention) are associated with relatively favorable clinical outcomes. This raises the issue of whether prevention of psychosis itself is possible. The achievement of this goal will require the identification of a premorbid state that could serve as the foundation for treatment strategies aimed ultimately at the prevention of schizophrenia. Fortunately, evidence for such a state is emerging, in part because schizophrenia may result from a neurodevelopmental disorder that is associated with a variety of clinical, neurobiological, and neuropsychologic features occurring well before the onset of psychosis. These features may serve as both indicators of risk for subsequent deterioration and the foundation of treatment efforts. We reformulated Meehl's term schizotaxia to describe this liability and discuss here how its study could form the basis for future strategies of prevention. We also include a description of our initial attempts to devise treatment protocols for schizotaxia. It is concluded that schizotaxia is a feasible concept on which to base prevention efforts, and that treatment of adult schizotaxia may be among the next steps in the process.

The authors assess implications of DSM criteria for schizophrenia by reviewing the criteria's 1) emphasis on psychotic features, 2) dissociation of symptoms from their etiology, 3) exclusive reliance on clinical features but exclusion of biological indicators, and 4) classification of schizophrenia as a discrete category. The authors then discuss alternative conceptions of schizophrenia that take into account recent data concerning its genetic and neurodevelopmental origins and its pathophysiological substrates.The historical development of diagnostic criteria for schizophrenia is reviewed in the context of recent published data on the biology and development of schizophrenia.Growing evidence suggests that symptoms of psychosis may be a common end-state in a variety of disorders, including schizophrenia, rather than a reflection of the specific etiology of schizophrenia. Features occurring before the advent of psychosis that are clinical, biological, and/or neuropsychological in nature may constitute evidence of a genetic predisposition toward schizophrenia ("schizotaxia") and may provide more specific information about the genetic, pathophysiological, and developmental origins of schizophrenia.The success of efforts to treat and prevent schizophrenia will depend to an important extent on an accurate understanding of its causes. This goal can be furthered by conducting field trials to develop research criteria to assess the value of a developmentally sensitive, biologically informed approach to classification that would consider schizotaxia with psychosis (schizophrenia) and schizotaxia alone as distinct diagnostic conditions.

When administered soon before or after training, glucose facilitates memory in rodents and in several populations of humans, including healthy elderly people. Thus, glucose appears to enhance memory formation in a time- and dose-dependent manner. By assessing the effects of glucose at the time of memory tests, the present experiment examined the role of glucose on memory retrieval in healthy elderly people. On four sessions separated by a week, glucose or saccharin were administered immediately before hearing a narrative prose passage, as in previous experiments, or immediately before being tested for recall of the passage (24 h after training). Subjects recalled significantly more information after glucose ingestion than after saccharin ingestion whether the glucose was given before acquisition or memory tests. In addition, recall was significantly better in the preacquisition glucose condition relative to recall in the retrieval glucose condition. These findings provide evidence that glucose enhances both memory storage and retrieval.

Age-related deficits in memory are correlated with deficits in paradoxical sleep and poor glucose tolerance in rats. The present experiment used a longitudinal design to determine whether memory or glucose tolerance in middle-aged rats could predict deficits in memory, sleep, and glucose tolerance in old age. Correlations were obtained between spontaneous alternation scores and glucose tolerance levels in middle age (14 months) and inhibitory avoidance, daytime sleep, and glucose tolerance levels in old age (24 months). Spontaneous alternation scores, but not glucose tolerance levels, predicted performance on all 3 behavioral and biological measures in old age. Measures of functional integrity, such as memory, may be sensitive predictors of subsequent age-related change in specific cognitive and neurobiological systems.

Deficits in social function are among the core features of autism and other neurodevelopmental disorders. Recent conceptualizations of social cognition include multiple dimensions, including theory of mind, social perception, social knowledge, social attribution, and emotional perception and expression. Recent studies show that social cognition, like ‘standard’ cognition, is related to functional outcomes in neurodevelopmental disorders such as schizophrenia and autism, by mediating effects of other variables (e.g. standard cognition), or by acting independently. This representative discussion reviews social cognition and focuses on its relationships with autistic spectrum disorders (ASD), and with more standard measures of cognition. It then reviews attempts to improve outcomes in autism over the last 25 years. Useful treatments for ASDs focus are initiated early, have multiple treatment targets, and are comprehensive as possible. In this framework, social cognition offers a set of interrelated treatment targets that are important because they affect outcome, and are promising because they are at least partially distinct from more standard measures of cognition in their effects on outcome. [N A J Med Sci. 2012;5(3):172-179.]

IntroductionThe Changsha study identifies adult, non-psychotic relatives of patients with schizophrenia who show deficits in neurocognitive, social, clinical and other dimensions, and who meet proposed diagnostic criteria for a liability syndrome for schizophrenia (’schizotaxia’).ObjectivesTo define and validate schizotaxia.AimsTo develop and validate diagnostic criteria for schizoaxia, and to reduce its symptoms using risperidone.MethodsWe investigated whether a low dose (2.0 mg) of risperidone, a second generation antipsychotic medication, could attenuate negative symptoms, neurocognitive deficits, and other measures of clinical and social function in subjects who met our research criteria for schizotaxia. One hundred eighty nine relatives were assessed at the Mental Health Institute, Second Xiangya Hospital, in Changsha, China. Eighty six of these individuals met criteria for schizotaxia, and 36 agreed to enter a 6-week, double-blind, placebo-controlled protocol.ResultsANCOVAs using age and gender as covariates showed significant improvement in the risperidone group (n = 20) on neurocognitive function (Wisconsin Card Sorting Test Total Errors and Perseverative Errors) and on a self-report measure of social function (Social Adjustment Scale), compared to the placebo-control group (n = 16). Effect sizes were small to medium. Notably, risperidone effect sizes were larger (medium to large) in a subset of subjects (risperidone = 15; placebo = 10) whose membership in the schizotaxic group was confirmed by cluster analysis.ConclusionsThe results are generally consistent with previous open-label investigations of risperidone administration in subjects with schizotaxia, and provide evidence that significant neurocognitive and clinical problems are amenable to remediation in non-psychotic relatives of people with schizophrenia.

Autism and schizophrenia are among many psychiatric and neurological disorders that share overlapping clinical features and involve widespread psychiatric and cognitive impairments. Other examples include different dementing disorders, which often produce similar clinical symptoms in their later stages, and disorders involving psychosis, such as schizophrenia and bipolar I disorder with psychotic features. The situation is complicated somewhat by a reliance on clinical symptoms to make diagnoses in psychiatry 1, but are complicated even more so by the nature of the disorders themselves. Many psychiatric (and other medical) disorders and normal functions have multiple causes, and many causal factors may be sufficient, often in combination with other causal factors, to contribute to the development or maintenance of a disorder.2,3 The multi-factorial and complex nature of autism and schizophrenia adds to the difficulty of establishing their etiologies. Nevertheless, the importance of identifying etiological factors is often an essential step in the development of new treatment strategies. While there are several potential paradigms that might be utilized to progress towards this goal, one is to assess the potential importance of overlapping symptoms in these syndromes. This approach can help determine whether observed similarities reflect common etiological factors, such as a continuum between schizophrenic and autistic spectrums, or whether they more likely reflect superficial similarities, (such as problems in attention that may result from any number of disparate causes). In this paper, we focus on apparent overlaps between schizophrenia and autism spectrum disorders, which both reflect common, clinically significant spectrums. Until these disorders came to be viewed as distinct in the 1970s, they were viewed as different phases of the same problem, with autism manifesting as an earlier phase of schizophrenia.4,5 Although they are viewed separately now, they do intersect along several dimensions, including, for example, problems with social interaction and emotion, verbal and nonverbal communication, and odd or inflexible behavior. It is not clear, however, whether these and other shared clinical features reflect common underlying etiological factors. Moreover, the question is complicated by heterogeneity of symptoms, differences in age of onset, environmental factors and responses to treatment. In the interests of maximizing clarity and also emphasizing cognition, we will focus somewhat on adolescents and adults whose overall cognitive abilities are above IQs of 70 (i.e., above DSM-IV ranges required for diagnoses of mental retardation). For the autism spectrum disorders, this mainly includes a composite group of individuals who are commonly diagnosed with high-functioning autism/Asperger syndrome (HFA/AS). Reviews of the schizophrenia spectrum will focus on schizophrenia itself, but will also include other DSM-IV disorders such as schizoaffective disorder (depressed type) and schizotypal personality disorder, where appropriate. The aim of this paper is not to argue for or against existing theories in either schizophrenia or autism, but to explore representative evidence about the nature of overlaps between them. Evidence for common etiological components, if present, may then provide an impetus for the development of research strategies aimed at clarifying etiology further and at developing/validating clinical interventions. The remainder of the paper is organized into five sections. Representative overlaps between schizophrenia and HFA/AS will be reviewed briefly in four dimensions, including: 1/ cognition, 2/ social functioning, 3/ structural brain abnormalities, and 4/ genetics. We conclude by considering implications for etiology, clinical interventions and future research.

Autism is a group of highly complicated neurodevelopment disorders affecting 1 in every 110 children born in USA. The etiology and pathophysiology are poorly understood and it currently has no universally accepted therapy or cure. Stem cell replacement therapy via transplantation potentially reverse brain hypo perfusion and immune dysfunction, which are considered to be two major pathophysiology mechanisms of autism. Recent advances in the in vitro study of disease modeling of autism reveals disease-specific cellular defects and reversible symptoms, opens the possibility of cell therapy and offers new hopes for cures. However, this new therapy is still in its infancy. There are many technological barrier such as immune-rejection, tissue migration and integration, cancer risk, safety concern, proper development in the inner environment and clinical barriers of individual sensitivity and liability, disease complexity, and more, which will need to be overcome before reaching new era of therapy. It will be necessary to conduct in vivo animal studies and then further clinical trials, however, before any potential clinical application in autism and other human disease can be realized. [N A J Med Sci.2011;4(3):134-138.]

Auditory stimulation applied during rapid eye movement (REM) sleep enhances the duration of REM sleep in cats and humans. The present experiment investigated whether auditory stimulation would enhance REM sleep in young (3-6 months) rats, and also in old (22-24 months) rats which have impaired REM sleep. Baseline sleep records were obtained on two days. Sleep patterns were then assessed during auditory stimulation test sessions. In young rats, auditory stimulation was administered during each REM sleep bout. In old rats, auditory stimulation was administered on a fixed schedule (10 min of stimulation alternating with 15 min quiet). The day after the stimulation session, an additional sleep record (Day 2) was obtained for each rat. In young rats, auditory stimulation enhanced both REM sleep duration and total REM sleep time. In the old rats, which showed impaired sleep measures as compared to young animals, auditory stimulation enhanced both total REM sleep time and the number of REM sleep periods. Residual proactive effects of auditory stimulation (Day 2) were observed in both young and old rats. Thus, auditory stimulation is an effective manipulation with which to augment REM sleep in both young and old rats, and partially attenuates REM sleep impairments in old rats.

N-Methyl-D-aspartate (NMDA) receptor blockade disrupts a variety of functions associated with neural plasticity, including acquisition of learned responses and long-term potentiation. Deficits in memory are significantly correlated with deficits in measures of paradoxical sleep in several amnesic populations. The present experiment therefore assessed whether NPC 12626, a competitive NMDA receptor antagonist, also disrupts sleep. NPC 12626 (1, 10, 50, and 100 mg/kg) or saline was administered to Sprague-Dawley rats 30 min prior to 3-h daytime recording periods. Paradoxical sleep was selectively impaired at all but the highest dose, which prevented all sleep during the recording period. Some deficits in nonparadoxical sleep first appeared at the 10 mg/kg dose but did not became prominent until the 50 mg/kg dose. The results thus show that NPC 12626 impairs sleep states in rats and demonstrate that paradoxical sleep is particularly susceptible to the effects of NMDA receptor blockade. These findings, along with previous evidence that NMDA antagonists impair waking measures of arousal, provide evidence that all sleep-wake states are impaired by NMDA receptor blockade. More generally, the results suggest that some brain mechanisms underlying sleep and memory may share common elements.

Glucose administration near the time of training or testing elevates blood glucose levels and enhances memory in rodents and humans. The magnitude of increases in circulating glucose levels predicts later retention performance in these and several other situations. Thus, circulating glucose levels appear to contribute to the regulation of memory storage processes. Phlorizin is an inhibitor of glucose transport, which, in view of the effects of glucose on memory, should impair memory. However, rats and mice injected with phlorizin before training in an inhibitory (passive) avoidance task demonstrated significantly enhanced memory performance compared to that of control animals. The effective dose of phlorizin did not significantly change regional brain-relative 3H-2-deoxyglucose uptake or plasma glucose levels. To summarize, phlorizin is a potent memory-enhancing drug. While the mechanism of this enhancement is unknown, it does not appear to include changes in blood glucose levels or brain glucose uptake.

Recent findings indicate that glucose antagonizes several behavioral effects of cholinergic antagonists and augments those of cholinergic agonists. For example, scopolamine elicits increased locomotor activity, an action which is attenuated by glucose and by combined treatment with glucose and physostigmine at doses which are individually without effect. Opiate and catecholamine agonists, such as morphine and amphetamine, also elicit hyperactivity. The present study examined interactions of glucose and physostigmine with morphine- and amphetamine-induced hyperactivity. Mice received saline, morphine (10 mg/kg), or amphetamine (1 mg/kg) 50 min prior to testing, followed by saline, physostigmine (0.01, 0.05, 0.1, or 0.2 mg/kg), or glucose (10, 50, 100, or 500 mg/kg) administered 20 min prior to activity testing in an open field. Physostigmine significantly attenuated both morphine- and amphetamine-induced increases in activity, but higher doses were required to attenuate the effects of amphetamine. Like physostigmine, glucose significantly attenuated morphine-induced activity levels, but unlike physostigmine, glucose did not attenuate amphetamine-induced activity. Thus, the behavioral effects of morphine were more susceptible to modification by physostigmine and glucose than were the effects of amphetamine. The attenuation of morphine-induced hyperactivity demonstrates a similarity between glucose and cholinergic agonists, and also indicates that glucose may inhibit, directly or indirectly, opiate functions. More generally, these findings add to the evidence that circulating glucose levels selectively influence a growing list of behavioral and neurobiological functions.

Context Exploration of the genetic architecture of specific endophenotypes may be a powerful strategy for understanding the genetic basis of schizophrenia. Objective To characterize the genetic architecture of some key endophenotypic measures selected for their reported heritabilities in schizophrenia. Design Family-based heritability study. Setting Seven sites across the United States. Participants At the time of these initial data analyses, the members of 183 nuclear families ascertained through probands with schizophrenia had been assessed for these endophenotypes. Main Outcome Measures Variance component models were used to assess the heritability of and the environmental and genetic correlations among the endophenotypes. The Consortium on the Genetics of Schizophrenia assesses the neurophysiologic measures of prepulse inhibition of acoustic startle, P50 event-related potential suppression, and the antisaccade task for eye movements and the neurocognitive measures of the Continuous Performance Test (Degraded Stimulus version), the California Verbal Learning Test, the Letter-Number Sequencing test, and 6 measures from the University of Pennsylvania Computerized Neurocognitive Battery. The heritabilities of these 12 measures are the focus of this article. Results All of the endophenotypes and the University of Pennsylvania Computerized Neurocognitive Battery measures were found to be significantly heritable ( P ≤ .005), with heritabilities ranging from 24% to 55%. Significant environmental and genetic correlations were also observed between many of the endophenotypic measures. Conclusion This is the first large-scale, multisite, family-based heritability study of a collection of endophenotypes for schizophrenia and suggests that endophenotypes are important measures to consider in characterizing the genetic basis of schizophrenia.