Molecular genetics of psychopathologies: a search for simple answers to complex problems.

Molecular genetics is helping define the contribution of genetic involvement in behavioral disorders. At this time, however, a severely limiting factor for DNA linkage studies of these disorders remains the definition of the phenotype. An example of this is found in the group of studies examining linkage of schizophrenia to the 5q location. Although various broad clinical interpretations of the schizophrenia phenotype were used to test for linkage, all but one study reported findings negative for linkage of schizophrenia to the 5q area. We offer a strategy based on family studies using segregation data of behavioral subtypes. We apply this strategy using molecular genetic technology to our study of psychopathology in patients. This approach offers the possibility of a clearer definition of the phenotype and is suggested for use in both linkage and association studies of neuropsychiatric disorders.

Quantitative analysis of trabecular microstructure by 400 MHz nuclear magnetic resonance imaging.

A new approach for the quantitative analysis of trabecular microstructure, based on high-field proton nuclear magnetic resonance (NMR) imaging, is presented. NMR is ideal because it provides high contrast between the marrow proton signal and the bone, which appears with background intensity. Images from 1 cm3 defatted specimens of trabecular bone, suspended in water doped with 1 mM Gd(DTPA) to shorten T1 to about 300 ms, can be obtained at a resolution on the order of 30-50 microns and slice thickness of 150 microns, in 10 minutes at 400 MHz proton frequency. Digital image processing algorithms were designed and evaluated for the measurement of bone area fraction, perimeter length, mean trabecular thickness, and separation. Bone area fraction derived from the NMR images was found to be in excellent agreement with bone volume fraction measured independently (slope = 0.96, r2 = 0.924, p < 0.0001). Errors in the mean trabecular thickness and separation were < 6%. The effects of finite imaging slice thickness and signal-to-noise ratio (SNR) were also evaluated. The data suggest a resolution of 50 x 50 x 200 microns 3 and an SNR on the order of 10 to provide safe margins for precise and accurate structural analysis by means of the algorithms presented in this paper. The method allows simultaneous measurement at multiple locations within the specimen volume without the need for physical sectioning.

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.

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.

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.

Locus of control and mental health in adolescence and adulthood.

Eighty-nine subjects of the original sample of the National Institute of Mental Health joint study by the United States and Israel, known as the Israeli High-Risk Study, were given a clinical interview and a questionnaire measuring locus of control (LOC) during the second phase of the study, when the subjects were adolescents. During phases 3 and 4, approximately 8 and 15 years later, the subjects were psychiatrically assessed and 56 of them repeated the LOC questionnaire. The two measures of LOC were correlated, as were general assessments of mental health (MH). Adolescent LOC was related to lifetime MH, although LOC and MH were not related to each other concurrently in either adolescence or adulthood. The best predictive model for lifetime MH outcomes was a combination of adolescent MH and LOC variables; background variables, including parental schizophrenia, were superfluous. The data suggest that whereas adolescent MH is the best predictor of general MH, adolescent LOC is the better predictor of schizophrenia and major affective disorders.

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.

Matching pulmonary structure and perfusion via combined dynamic multislice CT and thin-slice high-resolution CT.

Taking advantage of two scan modes of an electron beam CT scanner (Imatron), we have developed a method utilizing x-ray CT for relating pulmonary perfusion to global and regional anatomy. A high temporal resolution mode, used to follow bolus contrast agent, is combined with a high spatial resolution mode to obtain the structure-function fusion. A software module has been developed for our image analysis package (VIDA) to automatically calculate physiologic parameters of flow and integrate these color coded functional measurements into a corresponding high spatial resolution data set. We present the scanning methodology details and give examples from our physiologic based research to demonstrate strengths of combining dynamic and high resolution CT to uniquely characterize pulmonary normal and pathophysiology.

Relationship between NMR transverse relaxation, trabecular bone architecture, and strength.

Structure, biomechanical competence, and incremental NMR line broadening (R'2) of water in the intertrabecular spaces of cancellous bone were examined on 22 cylindrical specimens from the lumbar vertebral bodies of 16 human subjects 24-86 years old (mean, 60 years old). A strong association (r = 0.91; P < 0.0001) was found between Young's modulus of elasticity and R'2 for a wide range of values corresponding to cancellous bone of very different morphologic composition. NMR line broadening is caused by the inhomogeneity of the magnetic field induced as a consequence of the coexistence of two adjacent phases of different diamagnetic susceptibility--i.e., mineralized bone and water in the marrow spaces. Structural analyses performed by means of NMR microscopy and digital image processing indicated that the variation in R'2 is closely related to the trabecular microstructure. Mean trabecular plate density measured along the direction of the magnetic field was found to play a major role in predicting R'2 (r = 0.74; P < 0.0001). This behavior was confirmed when the plate density was varied in individual specimens, which was achieved by rotating the specimen, making use of the bone's structural anisotropy. It is concluded that the NMR transverse relaxation rate in human cancellous bone of the spine is significantly determined by trabecular structural parameters relevant to biomechanical strength. The results further underscore the important role played by the transverse trabeculae in contributing to cancellous bone strength. The work has implications on possible in vivo use of quantitative magnetic resonance for the assessment of fracture risk in osteoporotic patients.

Potential role of nuclear magnetic resonance for the evaluation of trabecular bone quality.

This paper discusses two novel applications of nuclear magnetic resonance (NMR) as an investigational tool for the assessment of cancellous bone microarchitecture. It further outlines extensions of the method for in vivo clinical evaluation of bone strength in patients with skeletal disorders such as osteoporosis. The first method relies on the hypothesis that the presence of two phases of different magnetic permeability, i.e., bone and bone marrow, causes a spatial nonuniformity of the magnetic field across the measurement volume. The resulting spread in resonance frequency shortens the decay time constant (T2*) of the time domain proton signal in bone marrow or its substitute (water). Increased trabecular spacing, such as it occurs in osteoporosis, reduces the spatial field inhomogeneity and thus prolongs T2*, which has been shown both in vitro and in vivo. Subjects with osteoporosis, characterized by either low bone mineral density and/or spine compression fractures, have T2* values that are significantly prolonged. The second method focuses on a direct measurement of micromorphometric parameters of cancellous bone, using the principles of proton NMR microscopy in conjunction with computer processing of the resulting digital images. Image contrast between the trabeculae and the intertrabecular space is based on the marrow protons providing a signal, as opposed to bone, which appears with background intensity. Once tissues have been classified (into bone and marrow), for example, by means of a histogram-based segmentation algorithm, bone area fraction, mean trabecular plate density (MTPD), and mean trabecular plate thickness (MTPT) can be computed without the need for further operator intervention.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Early and long-term effects of electroconvulsive therapy and depression on memory and other cognitive functions.

Twenty-seven medication-free, depressed patients (Research Diagnostic Criteria, endogenous subtype) were administered a comprehensive battery testing memory and other cognitive functions before and after a series of bilateral, brief-pulse electroconvulsive therapy (ECT) administered according to a dosage-titration procedure (8.9 +/- 1.981 treatments). A subset of patients (N = 14) were reexamined at 1 month and 6 months after the conclusion of the treatment. Anterograde (verbal and visuospatial tasks), as well as retrograde (famous and personal events), memory function was significantly impaired at the end of the ECT series. By 1 month follow-up, performance had improved to pre-ECT (depression) levels on both anterograde and retrograde tasks and exceeded these by 6 months. The memory deficits induced by ECT were not a consequence of generalized cognitive impairment. Furthermore, depression and ECT were shown to independently affect memory, and recovery from depression was not a consequence of the amnestic action of the treatment. The results generally confirm previous reports regarding the nature of ECT-induced memory impairment, in a different language and culture. They suggest that long-term effects of the treatment on memory are even less prominent than previously observed.

Performance of long-stay schizophrenics after drug withdrawal on matched immediate and delayed recall tasks.

Both anticholinergic and neuroleptic drugs were withdrawn from eight long-stay hospitalized chronic schizophrenics. These patients and normal controls were then tested on Calev, Venables & Monk's (1983) immediate and delayed matched recall tasks to evaluate their rate of forgetting of verbal well-encoded materials. The results showed rapid forgetting in schizophrenics. This finding suggests that a post-encoding deficit characterizes long-stay schizophrenics after drug withdrawal. Cognitive and brain pathologies that may explain these results are discussed.

Performance of long-stay schizophrenics on matched verbal and visuospatial recall tasks.

A verbal and a visuospatial recall task were compared for discriminating power, using the matched-tasks methodology. These tasks were administered to long-hospitalized schizophrenics. No evidence of a differential deficit, that is, better recall of either the verbal or the visuospatial materials, emerged in the patients. The results replicate a former finding showing no difference between verbal and visuospatial recall in schizophrenics, using memory tasks which were less sensitive as left- and right-hemisphere measures and a non-verbal task less affected by verbal mediation. This replication questions the assumption that the hemispheric differences observed in schizophrenics affect such memory tasks.

Facilitation of ECT by caffeine pretreatment.

In this study, eight patients participated in a standardized protocol to assess the effects of caffeine on seizures in ECT. Caffeine sodium benzoate (500-2000 mg) was administered intravenously 10 minutes before ECT, and seizure duration was compared with that of a previous treatment unmodified by caffeine. Seizure duration was significantly increased during ECTs preceded by caffeine. Three other patients given caffeine when seizures of adequate duration could no longer be elicited at maximal stimulus levels experienced longer seizures. Administration of caffeine was not associated with significant cardiovascular or other (including cognitive) adverse effects.

Performance of chronic schizophrenics on matched word and design recall tasks.

Matched word and design recall tasks were constructed and used to assess the performance of chronic schizophrenics on neuroleptics alone and on both neuroleptic and anticholinergic drugs. The two groups of patients performed at an equally low level on both tasks, without evidence for a differential deficit. The tasks did, however, evoke a differential deficit in clustering performance for designs as opposed to words. Although clustering, which is based on recall, is not necessarily as well matched for words and designs as recall itself, this result suggests a lateralized dysfunction in brain structures related to use of mnemonic organization at retrieval.

Verbal and non-verbal recall by depressed and euthymic affective patients.

This study uses matched-tasks methodology in order to test memory function in depressed and euthymic patients with major affective disorder. Neither drug-free depressed patients nor lithium-treated euthymic patients show a differential deficit in verbal versus non-verbal recall. However, while euthymic patients show no memory impairment, drug-free depressives do show poor memory functioning. The results support the view that memory deficits observed in affective patients in the depressed state are transient, secondary manifestations of depression and are neither indicative of underlying organic pathology, nor of abnormal hemispheric laterality. This suggests that memory impairment in depression can be treated by treating depressive symptoms, both chemically and behaviourally. The results also support the view that prophylactic lithium treatment has no adverse effects on these memory tasks.

Psychophysiological reactivity in high-risk children.

This study was designed to test and extend previous reports of differences in autonomic responsivity between offspring of schizophrenic patients and control subjects. In specific, greater galvanic skin response (GSR) to stimuli and quicker GSR recovery have been reported in high-risk children. In the present study we found no evidence of autonomic hyperactivity, as evidenced by GSR to tones, in high-risk as compared to control subjects. There was some trend for index subjects to show slower GSR recoveries than control subjects, which is opposite to findings from earlier studies. Subjects were also presented with the Information Detection Test, in which GSR responses to emotionally meaningful vs. neutral stimuli were compared. Index children were less reactive than control subjects to the meaningful stimuli, and they discriminated between meaningful and neutral stimuli more poorly. Our findings do not confirm the learning theory of schizophrenia suggested by Mednick, but do suggest that developmental lags in high-risk as compared to control children may contribute to the psychophysiological differences that we found.

Perceptual-motor and memory performance of high-risk children.

Subjects were examined with a battery of protocols based on principles of experimental psychology and designed to measure motor control, perceptual-motor coordination, attention, learning, and memory. Differences between index and control subjects were found on the mirror-drawing protocol, reflecting visual-motor coordination, and the distractibility protocol, in which subjects divided their attention between verbal and visual stimuli. There were no differences in subjects due to conditions of rearing, and no interactions. Differences between index and control children were subtle, and tended not to appear on simpler tasks. The stage of processing leading to poor performance by the index children awaits further study for elucidation.