Effects of different sleep restriction protocols on sleep architecture and daytime vigilance in healthy men.

Sleep is regulated by complex biological systems and environmental influences, neither of which is fully clarified. This study demonstrates differential effects of partial sleep deprivation (SD) on sleep architecture and psychomotor vigilance task (PVT) performance using two different protocols (sequentially) that each restricted daily sleep to 3 hours in healthy adult men. The protocols differed only in the period of sleep restriction; in one, sleep was restricted to a 3-hour block from 12:00 AM to 3:00 AM, and in the other, sleep was restricted to a block from 3:00 AM to 6:00 AM. Subjects in the earlier sleep restriction period showed a significantly lower percentage of rapid-eye-movement (REM) sleep after 4 days (17.0 vs. 25.7 %) and a longer latency to the onset of REM sleep (L-REM) after 1 day (78.8 vs. 45.5 min) than they did in the later sleep restriction period. Reaction times on PVT performance were also better (i.e. shorter) in the earlier SR period on day 4 (249.8 vs. 272 ms). These data support the view that earlier-night sleep may be more beneficial for daytime vigilance than later-night sleep. The study also showed that cumulative declines in daytime vigilance resulted from loss of total sleep time, rather than from specific stages, and underscored the reversibility of SR effects with greater amounts of sleep.

Concurrent validation of schizotaxia: a pilot study.

BACKGROUND: Many first-degree relatives of patients with schizophrenia show deficits in clinical, neuropsychological, neurobiological and social domains, in the absence of psychosis. We recently reformulated Meehl's concept of schizotaxia to conceptualize the liability to schizophrenia, and we proposed preliminary criteria based on the presence of negative symptoms and neuropsychological deficits. Here we investigate the concurrent validity of schizotaxia by comparing a group of subjects who met criteria for schizotaxia with a group who did not on independent measures of clinical function, and on lifetime rates of selected comorbid psychiatric disorders. METHODS: Twenty-seven adults who were first-degree, biological relatives of patients with schizophrenia were evaluated for schizotaxia based on our predetermined criteria involving negative symptoms and neuropsychological deficits. Subjects also received portions of the Diagnostic Interview for Genetic Studies, the Structured Interview for Schizotypy, the Family Interview for Genetic Studies, the DSM-IV Global Assessment of Functioning, the Physical Anhedonia Scale, the Social Adjustment Scale and the Symptom Checklist-90-Revised. Subjects who met criteria for schizotaxia were compared with those who did not on each of the clinical measures, and on their rates of comorbid DSM-IV psychiatric diagnoses. RESULTS: Eight subjects met criteria for schizotaxia, and 19 did not. Subjects with schizotaxia showed significantly lower levels of function on each of the clinical scales. Differences in comorbid psychiatric diagnoses were not significant, although the rate of lifetime substance abuse diagnoses in the schizotaxic group (50%) approached levels that are often seen in schizophrenia. CONCLUSIONS: These findings provide the first evidence of concurrent validation for a proposed syndrome of schizotaxia. They are also consistent with the view that the vulnerability to schizophrenia may be defined, at least partially, although larger studies to assess both the concurrent and predictive validity of schizotaxia will be required to confirm these results.

Genes, environment and schizophrenia.

BACKGROUND: Data from family, twin and adoption studies show overwhelming evidence of a substantial genetic component in schizophrenia and although molecular genetic studies have been more difficult to replicate, recent improvements in technology have resulted in the implication of genes at several chromosomal loci. Nevertheless, it remains clear that environmental factors both add to and interact with genetic factors to produce the disorder. AIMS: To incorporate genetic and environmental risk factors into a neurodevelopmental model in order to conceptualise the liability to schizophrenia. METHOD: A representative selection of the literature related to this issue is reviewed, together with a reformulation of Meehl's term 'schizotaxia' to describe the liability to the disorder. RESULTS: The literature supports a multi-factorial view of the liability to schizophrenia, which includes both genetic and environmental components. CONCLUSIONS: Schizotaxia provides a useful way to conceptualise both the liability for schizophrenia, and also the development of treatment strategies aimed at the eventual prevention of the illness.

Towards the prevention of schizophrenia.

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.

Toward reformulating the diagnosis of schizophrenia.

OBJECTIVE: 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. METHOD: The historical development of diagnostic criteria for schizophrenia is reviewed in the context of recent published data on the biology and development of schizophrenia. RESULTS: 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. CONCLUSIONS: 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.

Schizophrenia: family studies and treatment of spectrum disorders.

A substantial part of the contribution of genetic studies to the treatment of schizophrenia involves its emphasis on reliable and valid diagnoses. One consequence of this focus is the recognition that schizophrenic illness is broader than the diagnostic entity of schizophrenia itself, and instead consists of a "spectrum" of related disorders. Because some of the symptoms in these disorders differ from each other, they provide an opportunity to determine which ones reflect a common etiology. To the extent that such symptoms are identifiable, they may provide a foundation for treatment and even prevention strategies. In this paper, we focus on a clinical condition - "schizotaxia" - that may reflect the liability for schizophrenia. To characterize the nature and extent of this proposed syndrome, we will review results from family studies in our laboratory, and consider conceptual foundations and criteria for assessment. A more general consideration of treatment strategies for schizophrenia spectrum disorders follows, along with suggestions for future research. Our initial attempts to treat and validate schizotaxia are encouraging, and raise the possibility that early treatment might eventually prevent or attenuate the development of other, more severe disorders in the schizophrenia spectrum, including schizophrenia itself.

Schizophrenia: vulnerability versus disease.

One of the most important trends in the treatment of schizophrenia involves its early diagnosis and intervention. The ultimate goal of research is the prevention of the disorder, A major impediment to the development of prevention strategies, however, is that we do not yet know what the liability for schizophrenia is before the onset of psychosis. Consequently, early treatment attempts are focused on the "prodrome," which involves the early symptoms of psychosis. In a companion paper, we recently suggested that prevention work should focus not only on the prodrome, but also on "schizotaxia," which is a clinically meaningful condition that may reflect the vulnerability to schizophrenia in the absence of psychosis. Because schizotaxia can be assessed prior to the prodrome, studies of schizotaxia might lead to more effective prevention programs. We continue the characterization of schizotaxia in this paper by focusing on the etiological roots of schizotaxia, plus its likely neurodevelopmental course, clinical expression, and treatment. Finally, the importance of including neurobiological variables in the conceptualization and eventual diagnosis of schizotaxia is reviewed.

Schizophrenia: a review of genetic studies.

Despite the complexities of schizophrenia, notable progress has been achieved in its diagnosis and treatment over the last 25 years. In this article we review the genetic research that provides the foundation for continued advances. One of the bases of our current understanding involves the observation that schizophrenia often runs in families. The development and utilization of stringent, reliable diagnostic criteria, together with the advent of modern family, twin, and adoption paradigms, demonstrate the importance of genetic factors in understanding the familial basis of the disorder. Refinements in diagnostic criteria have also enabled advances in understanding the likely mode--or modes--of genetic transmission of both schizophrenia and related disorders. After reviewing representative studies in these areas, we examine genetic linkage studies and our progress toward identifying the genes that cause schizophrenia. Although consistent results have been difficult to obtain and much work remains to be done, evidence for areas of vulnerability has been converging at particular chromosomal sites (e.g., 6p, 8p, and 22q), allowing for cautious optimism. Finally, we discuss challenges and prospects for the new millennium, including the clinical and ethical implications of genetic investigations.

Treatment of nonpsychotic relatives of patients with schizophrenia: four case studies.

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: These 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.

The genetics of schizophrenia.

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.

Conceptualization of the liability for schizophrenia: clinical implications.

Historically, the Diagnostic and Statistical Manual of Mental Disorders (DSM) diagnostic criteria for schizophrenia have emphasized several features, including symptoms of psychosis, a dissociation of symptoms from their etiology, a reliance on clinical symptoms, and a categorical approach to classifying the disorder. Although these emphases are quite useful, they have limitations. We review these here, and stress the importance of incorporating recent data on the genetic /biological and neurodevelopmental origins of schizophrenia into current conceptions of the disorder. We also review "schizotaxia, " which is a concept thai embodies this point of view, occurs before the onset of psychosis, and is hypothesized to represent the liability for schizophrenia. If our hypothesis on this point is correct, the identification of schizotaxic individuals will eventually facilitate the development of prevention strategies by identifying a premorbid (but clinically significant) condition for schizophrenia. Moreover, the identification of biological or neuropsychological components of schizotaxia will provide more specific bases for developing novel treatment interventions. Our initial attempts to develop protocols for the assessment and treatment of schizotaxia are encouraging, and will be reviewed.

Comparative effects of schizophrenia and temporal lobe epilepsy on memory.

The goal of this study was to further characterize episodic memory functioning in schizophrenia. This study compared verbal and visual learning and memory performance in (1) patients with schizophrenia (N = 35), (2) patients with temporal lobe epilepsy (TLE; N = 30), and (3) normal controls (N = 25). Results indicated significant memory impairments in patients with schizophrenia and TLE. "Savings" score measures of memory decay showed that the loss of information in schizophrenia and TLE was approximately equal, and quantitatively mild compared to that found in most neurologic groups with memory disorders. The severe difficulty shown by the schizophrenia group on a task of incidental recall suggested that the absence of instructional set added to a vulnerability to memory deficit. In contrast, relatively mildly impaired performance on paired associate learning suggested that patients with schizophrenia benefited from retrieval cues, multiple trials, and short (nonsupraspan) informational loads. Because patients with schizophrenia consisted of a relatively nonchronic sample with a mean IQ of 99.7, their memory disorder could not be attributed to schizophrenic dementia, nor was it accounted for by other potential confounds. Patients with schizophrenia, even those relatively early in the course of illness, have a mild episodic memory disorder.

Glucose enhancement of 24-h memory retrieval in healthy elderly humans.

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.

Glucose effects on cognition in adults with Down's syndrome.

Glucose enhances memory in a variety of individuals, including people with Alzheimer's disease. By 35 years of age, adults with Down's syndrome (DS) develop the characteristic plaques and tangles found in Alzheimer's disease, despite findings indicating that not all older DS individuals meet criteria for dementia. To examine the possibility that glucose enhances memory in adults with DS (mean age = 35 years, range = 19-55 years), adults with DS were given a battery of tests specifically designed for individuals with DS in glucose and control conditions. No participant met criteria for dementia, regardless of age. Glucose enhanced performance on tests requiring both long-term memory and auditory processing. In addition, increased age was associated with poorer performance on the majority of tests in the control condition, indicating that cognitive decline with aging may be more prevalent in DS than previously believed.

Memory scores in middle-aged rats predict later deficits in memory, paradoxical sleep, and blood glucose regulation in old age.

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.

Prenatal exposure to alcohol in adult rats: relationships between sleep and memory deficits, and effects of glucose administration on memory.

Previous studies show that prenatal exposure to alcohol results in sleep deficits in rats, including reductions in paradoxical sleep. Little is known, however, about the extent or duration of sleep impairments beyond the neonatal period. The present experiment examined effects of prenatal exposure on sleep in young adulthood. Three-hour, daytime sleep EEGs were obtained in 6-month-old female rats prenatally exposed to alcohol. Compared to isocaloric pair-fed and ad libitum control groups, the alcohol-exposed group showed reduced paradoxical sleep. Non-paradoxical sleep did not differ between groups. Concurrent deficits were obtained in radial arm maze, but not inhibitory (passive) avoidance, performance. One year later, at the age of 18 months, alcohol-exposed rats showed deficits in spontaneous alternation behavior which were reversed by administration of glucose (100 mg/kg). Deficits in paradoxical sleep at 6 months of age were highly correlated with deficits in spontaneous alternation behavior at 18 months of age, in individual, alcohol-exposed animals. These results provide the first evidence that prenatal exposure to alcohol results in selective and persistent deficits in sleep. They also show that measures of paradoxical sleep can predict impaired memory over a large portion of the life span, and suggest that glucose can attenuate memory deficits in this population.

Glucose attenuation of atropine-induced deficits in paradoxical sleep and memory.

When administered systemically, glucose attenuates deficits in memory produced by several classes of drugs, including cholinergic antagonists and opiate agonists. Glucose also enhances memory in aged rats, mice, and humans. In addition, glucose ameliorates age-related reductions in paradoxical sleep. Because deficits in paradoxical sleep are most marked in those individual aged rats that also have deficits in memory, treatments which improve one of these functions may similarly improve the other. The present experiments show that glucose attenuates deficits in paradoxical sleep and memory after atropine administration, with similar dose-response curves for both actions. In the first experiment, rats received saline, atropine (1 mg/kg), glucose (100 mg/kg) or combinations of atropine + glucose (10, 100, 250, and 500 mg/kg) 30 min before assessment on a spontaneous alternation task. In the second experiment, 3-h EEGs were assessed for spontaneous daytime sleep in rats administered saline, atropine (1 mg/kg), glucose (100 mg/kg) or combinations of atropine + glucose (10, 100 and 250 mg/kg). In both experiments, glucose significantly attenuated deficits at an optimal dose of 100 mg/kg. A third experiment assessed blood glucose levels after injections of atropine + glucose (100 mg/kg) and determined that blood glucose levels were similar to those produced by other treatments which enhance memory. These results are consistent with the view that paradoxical sleep and at least one test of memory are similarly influenced by atropine and glucose.

Sleep deficits in rats after NMDA receptor blockade.

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.

Enhancement of REM sleep with auditory stimulation in young and old rats.

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.