The inheritance of schizophrenia spectrum disorders: a reanalysis of the Danish adoptee study data.

Rosenthal and colleagues earlier compared the frequency of schizophrenia spectrum disorders in two groups of persons adopted in infancy or early childhood: those with a psychotic parent (index group) and those whose biological parents had never had a psychiatric diagnosis or treatment (control group). They found significantly more disorder in the index group. Reanalysis of the original material using DSM-III and stricter exclusionary criteria applied to the parents yielded three times as many schizophrenia spectrum disorders in the index as in the control group. This difference remained statistically significant, supporting the operation of genetic factors in the transmission of the traits comprising the schizophrenic spectrum of disorders.

Behavioral and psychophysiological markers of disordered attention.

Behavioral and psychophysiological assays provide the most sensitive indication of whether a presumed neurotoxin has a deleterious effect on the nervous system. The effects of lead on the nervous system are strongly suggestive that this agent can produce disturbances in attention; moreover, there are clinical reports of such effects. The action of lead is also manifest in behaviors described as "hyperactive," or reflecting "minimal brain damage." The core symptom in both disorders is probably impairment in attention. The recent Diagnostic and Statistical Manual (DSM-III) of the American Psychiatric Association uses the term Attention Deficit Disorder to replace such terms as hyperactivity and minimal brain damage. Prior studies of the behavioral toxicity of lead may have used inadequate or incomplete assays of attention; this could in part account for the variability in outcomes. Recent research on attention suggests that it is a complex behavior consisting of a number of elements or components, each of which may be in part dependent upon a different region of the central nervous system. Behavioral assays should examine the components of attentive behavior using tests which are sensitive to the different elements. It is recommended that psychophysiological assays (using cognitive event-related potentials), although more difficult and costly to implement, be used as well. These assays may provide a more dynamic view of altered information processing in the brain and help to localize and characterize the behavioral impairment.

Event-related potential abnormalities correlate with structural brain alterations and clinical features in patients with chronic schizophrenia.

Patients with schizophrenia appear to have abnormalities in both brain structures and information processing. Several recent reports have suggested that correlations exist between such measures. We examined the volume of several brain regions using magnetic resonance imaging (MRI), and also assessed both information processing, using brain event-related potentials (ERPs), and clinical symptomatology in sixteen medicated patients with schizophrenia. Subjects were tested using auditory and visual discrimination tasks. From the ERPs elicited by stimuli presented with relative probabilities of 0.1, the N100, N200, and P300 components were identified and measured. All subjects also had MRI scans that included 12 contiguous coronal sections, each 1 cm thick. From these scans, the following structures were identified and the volume or area quantified: third ventricle, lateral ventricles (partial), amygdala and hippocampus (one slice), partial brain volume (in one slice through the parietal lobe), and total prefrontal and temporal lobe gray and white matter in both cortical regions. Significant correlations were found between hippocampal area and the amplitude of the auditory and visual N200, and between the right hippocampus and the visual P300. Lower but significant correlations were seen between auditory P300 and measures of left temporal lobe structures. Auditory P300 amplitude correlated inversely with positive symptoms of schizophrenia. These preliminary results suggest that the ERP abnormalities in patients with schizophrenia are associated with temporal lobe pathology.

A nosology of disorders of attention.

The trailblazing research on sleep mechanisms and petit mal epilepsy, conducted during the period from 1940 through 1970, illuminated the brain substrate for normal consciousness and attention, as well as their disorders. This research helped inform and structure our neuropsychologically based model of the "elements" of attention. The model has been used to assess attention in the research laboratory and clinic, and has led to a "nosology of disorders of attention," which is presented here in preliminary form. The nosology reviews the possible causes of the symptom(s) of impaired attention, as well as suggesting a blueprint for future research in this area.

Neurocysticercosis and performance on neuropsychologic tests: a family study in Ecuador.

Neurocysticercosis (NCC) is a common neurologic disorder in developing countries, where it may pose a major public health challenge. Recently, the disorder has become more commonly diagnosed in developed countries as a result of the influx of migrants from countries where the disease is endemic. The clinical syndrome associated with NCC includes neurologic, physical, and functional problems. Since the locus of the infection is mainly the central nervous system, there is a risk of neuropsychologic dysfunction. This study was conducted in Ecuador in a group of 123 subjects (49 males and 74 females, 9-62 years of age) from a community sample that was part of a larger neuroepidemiologic inquiry. A discriminant function procedure was used to select the tests that would be most sensitive at distinguishing between affected and nonaffected individuals. The results suggest that behavioral functions that include aspects of inhibitory control, motor, and visual-motor output are impaired in adolescent and adult subjects with NCC.

On familial factors in the attentional deficit in schizophrenia: a review and report of two new subject samples.

We review the literature on attentional impairment in schizophrenics and their first-degree relatives and present new information from ongoing family studies of the disorder in Ireland and Israel. Subjects were administered a neuropsychological test battery (the NIMH Attention Battery) intended to measure four different elements of attention: encode, focus/execute, sustain, and shift. Results from both samples indicated that schizophrenic subjects performed most poorly on the tests, the control subjects performed best, and the scores of the relatives fell somewhere between the other two groups. Separation among subject groups was most significant for those tests comprising the focus/execute and sustain elements. Some of the results indicate, as well, that tests of auditory sustained attention may be the most discriminating of all. Overall comparison of the Irish and Israeli cohorts revealed striking differences. While within cohort differences remained, subjects from the Irish sample performed more poorly on many of the tests than Israeli subjects. This between-cohort difference was not found in the sustain element, as measured by the Continuous Performance Test. The socio-cultural implications of these findings are discussed with respect to future neuropsychological studies of schizophrenia.

Analysis of the attention deficit in schizophrenia: a study of patients and their relatives in Ireland.

County Roscommon, a rural area in the western part of Ireland, was the site of a family study of schizophrenia. As part of this study, we have assessed several elements of attention, identified by principal components analysis in previous investigations, in a group of subjects with schizophrenia, first-degree relatives of subjects with schizophrenia and age- and education-matched controls. The schizophrenic subjects performed significantly more poorly than the controls; the performance of the relatives fell somewhere between the other two groups. Those relatives with a DSM-III-R diagnosis (most frequently, alcohol abuse or an affective disorder) tended to perform more poorly on some of the attention elements than relatives without a diagnosis; in contrast, control subjects with diagnoses were not distinguishable from other controls. The attention elements appeared to differ in their capacity to differentiate the groups and each seemed to have a distinctive profile. The effects of alcohol abuse were also considered. The results obtained with this cohort may provide clues concerning the pathophysiological basis of schizophrenia and the heterogeneity of its expression.

Effects of gamma-hydroxybutyrate on the performance of monkeys in a Go/No-go visual discrimination task.

It has been suggested that monkeys, administered gamma-hydroxybutyrate (GHB), manifest a state resembling petit mal status. This implies that an animal would produce erroneous responses immediately prior to, and discontinue behaviors requiring any cognitive effort concurrently with, an episode of GHB-induced generalized 3 cps wave-spike bursts in the EEG. This prediction was not confirmed in the present study. Rhesus macaques (Macaca mulatta) were trained to perform in a visual discrimination Go/No-go test. Thereafter bipolar transcortical electrodes were implanted in the hemisphere contralateral to the preferred hand. All monkeys discontinued to lever-press for water reward when administered GHB (125 or 250 mg/kg, esophageal intubation) and exhibited signs of reduced postural control and somnolence punctuated by episodes of hypermotility about 40-50 min after GHB. However, the monkey's difficulties in completing the program were not associated with the development of generalized hypersynchronous EEG activity. While occasional wave-spike bursts did occur, they were poorly regulated, often 'focal' (i.e. developed only in isolated areas), and had a frequency of 1.5-2 cps. In this state, animals could be easily roused by sensory stimuli. All of them reacted with a characteristic aversive-aggressive display when confronted by a direct gaze. These effects are interpreted to be more consistent with characterization of GHB activity as that of a potent hypnotic rather than a convulsant agent.

Research on schizophrenia in the NIMH Laboratory of Psychology and Psychopathology, 1954-1987.

Since its creation in 1954 (as the Laboratory of Psychology) through the present time, the Laboratory of Psychology and Psychopathology has devoted a major effort to the study of schizophrenia. Shakow's studies on impaired reaction time performance led to the development of the concept of segmental set; Rosenthal's work on genetic factors in the etiology of schizophrenia, as well as on the interaction of stress and diathesis, helped to illuminate the nature of transmission of schizophrenia. These investigations set standards of excellence for careful analysis of psychopathological behavior. Our present program of research on schizophrenia emphasizes autonomic, psychophysiological and event-related brain potential investigations of schizophrenic patients and long-term followup of a high-risk population in Israel. In this group, poor attention in children at genetic risk has proved to be a predictor of later development of a schizophrenia spectrum disorder. Our work also emphasizes a theoretical analysis of the neuropsychological elements that make up attention in relation to psychopathological states.

The Israeli High-Risk Study: reply to Kaffman.

Kaffman's critique (1986) of the Israeli High-Risk Study centers on a number of issues: research design, information reported, appropriateness of sample, and Kaffman's own direct experience with psychiatric populations in kibbutzim and elsewhere in Israel. I contend that Kaffman has not fully understood the goals, methods, design, or results of the investigation. The information reported was as complete as possible if it is borne in mind that many of the issues and problems he has raised were not considered in research done on psychiatric disorders 25 years ago. Nevertheless, I contend that the Israeli study meets currently accepted standards of psychiatric research, that the results are valid, and that they raise questions about possible pathogenic influences on vulnerable persons raised on kibbutzim.

Israeli High Risk Study: editor's introduction.

The National Institute of Mental Health joint study by the United States and Israel, known as the Israeli High-Risk Study,is a unique long-term followup investigation of children at genetic risk for schizophrenia. We compared the development of psychiatric disorder in two groups of such children, one group raised in kibbutz environments, the other by their own parents. Matched controls were studied as well. The subjects were evaluated at ages 11, 17, and 26; an extensive battery of cognitive and clinical tests, as well as psychophysiological and diagnostic procedures, was used. This issue of the Schizophrenia Bulletin reports and summarizes evaluations conducted when the subjects were in their early thirties, as well as some previously unreported data obtained when the subjects were 17 years old.

The Genain quadruplets.

The Genain quadruplets are a unique set of monozygous women who are concordant for schizophrenia but discordant for the severity of their disorder. They were studied by David Rosenthal and colleagues at the National Institute of Mental Health in the late 1950's when they were in their twenties and again in 1981 when they were 51. They are faring about as well now as they ever have in their adult lives. The results of psychological tests, some of which were repeated more than 20 years apart, are discussed, as are the effects of medication on attention and memory. The differential response of the Genains to neuroleptic drugs, as well as certain other findings in the 1981 study, leads to a different conclusion about the discordant severity of their disorder from that reached in 1963 by Rosenthal and Quinn. These observations emphasize the value of long-term followup studies in genetically related individuals, with repeated assessments of the same functions.

Introduction: the Israeli high-risk study.

The literature on theories of the etiology of schizophrenia (the "nature-nurture dilemma") is reviewed, and the rationale is explicated for a study comparing the development and outcome of kibbutz- and town-reared children of schizophrenic parents. Various possible outcomes of the kibbutz-rearing experience in vulnerable children are discussed. The research team and the time table are described.

The NIMH-Israeli schizophrenia project: the history of a high-risk study.

We have reviewed some of the difficulties encountered in bringing this study to completion. Among our special problems were the necessity of collecting large numbers of measures on a relatively small study population, the need to recruit and maintain a staff over long periods of time, the wide geographical separation between staff members responsible for design and those responsible for execution of the study, and the difficulties of conducting longitudinal research in a politically unstable part of the world. Centralization of data and data analysis proved a crucial step in bringing the study to its present level of completion.

Neuropsychological assessment of attention and its pathology in the Israeli cohort.

We assessed attention in 63 of the 98 traceable living subjects of the original 100 in the National Institute of Mental Health (NIMH) joint study of schizophrenia by the United states and Israel, known as the Israeli High-Risk Study cohort; their mean age was 32 years. These data were supplemented, for comparative purposes, with those obtained on 31 normal control and 17 schizophrenia subjects studied at NIMH. The results suggest that attention skills of the adult children of a parent with schizophrenia fall between those of schizophrenia patients and controls, and that measures of sustained attention and the ability to focus and execute provide the best discrimination among groups. Post hoc analyses revealed that poor scores on simple tests of attention obtained in childhood were associated with the development of disorders in adulthood. Low scores on a digit cancellation test at age 11, but not at age 17, predicted which of the children at genetic risk would develop schizophrenia spectrum disorders diagnosed at ages 26 and 32.

Adult outcomes of high-risk children: differential effects of town and kibbutz rearing.

We conducted a followup study 15 years after the initial examination of 46 of the Israeli children at risk for schizophrenia (index cases) and 44 of the control children. Thus, we were able to contact and examine 90 of the surviving 99 subjects of the investigation. Half of the subjects had grown up in the communal child-rearing setting of a kibbutz, and half had been raised by their own parents in cities in Israel. The kibbutz-index cases, at average age 25, show the highest incidence of psychiatric disorder. Environmental factors that may have led to this outcome are discussed.

Review of the NIMH Israeli Kibbutz-City Study and the Jerusalem Infant Development Study.

The National Institute of Mental Health (NIMH) Israeli Kibbutz-City Study has followed the development of offspring of schizophrenic parents from middle childhood through early adulthood. During childhood, a subgroup of offspring of schizophrenic patients showed clear neurobehavioral deficits often accompanied by poor social competence. Early followup data suggest that this subgroup of high-risk children is at greatest risk for adult schizophrenia spectrum illness. The Jerusalem Infant Development Study has followed a similar population of children at risk for schizophrenia from before birth through middle childhood. A subgroup of dysfunctioning in the high-risk children showed sensorimotor dysfunctioning in the first year of life, which was followed by perceptual, motor, and attentional dysfunctioning in childhood--identical to that found in the NIMH cohort. Results from both studies support the hypothesis that schizophrenic illness involves constitutional factors whose expression can be observed as early as infancy. Results also illustrate the importance of using data-analytic approaches that (1) look for subgroups within high-risk groups rather than only group differences between high- and low-risk groups, and (2) examine profiles of behavior rather than only single variables.

Twenty-five-year followup of the Israeli High-Risk Study: current and lifetime psychopathology.

Current and lifetime psychopathology was assessed in 50 Israeli children of parents with schizophrenia who were either of kibbutz families and raised collectively with the help of child care workers, or of urban families and raised by their parents. Index subjects were compared with 50 matched control children of healthy parents by means of the Schedule for Affective Disorders and Schizophrenia-Israel. Subjects were evaluated in adulthood at a mean age of 31 years; schizophrenia was found exclusively among children of ill parents, and no effect of town or kibbutz rearing on risk for schizophrenia was observed. Major affective illness was more common among kibbutz index subjects. Affective symptomatology observed in some index parents was evenly distributed among town and kibbutz parents and was not related to the diagnosis of affective disorders in at-risk children. Current adult functioning was similar between town-and kibbutz-raised subjects (and in general reflected good adjustment); an excess of personality disorders was found among index subjects. The present findings support the concept that both familial and environmental factors operate in the expression of psychopathology.

Overview and summary: twenty-five-year followup of high-risk children.

We report a 25-year followup of a group of 50 children at genetic risk for schizophrenia (by virtue of having a parent with the disorder) and 50 matched controls. The children who eventually developed schizophrenia spectrum disorders, including schizophrenia, were identifiable by cognitive-psychophysiological, neurointegrative, and social/personality traits in the preteenage period. The children at risk were also more likely to develop other Axis I disorders, chiefly affective. Moreover, the risk of Axis I disorders was significantly greater among children raised in the group atmosphere of a kibbutz than among those raised in their own nuclear families in cities and towns in Israel. The study is a unique contribution to knowledge of factors underlying the development of psychopathology.

Reanalysis of SCOR and anxiety measures in the Israeli High-Risk Study.

In an earlier study, skin conductance orienting response (SCOR) and anxiety measures obtained when the subjects of the Israeli High-Risk Study were 11 years old were analyzed, using adult diagnostic information, when the subjects were 26 years old. The present study considers similar data obtained from most of this sample when the subjects were 16 years old. As in the earlier analysis, those subjects who would receive a schizophrenia spectrum diagnosis at 26 had higher anxiety ratings at age 16. Nondiagnosed index subjects also had significantly higher anxiety ratings than the nondiagnosed controls. The subjects who would receive affective spectrum diagnoses at age 26 had the most hyporesponsive SCORs, as predicted, while the subjects who would later be diagnosed in the schizophrenia spectrum had an unexpected hyperresponsive SCOR to the dishabituation tone in a habituation series. Further consideration of the long-term stability of SCORs seems necessary; they may be related to the developing psychopathological processes.