Converging evidence for gamma synchrony deficits in schizophrenia.

BACKGROUND: In electroencephalogram (EEG) studies of auditory steady-state responses (ASSRs), patients with schizophrenia show a deficit in power and/or phase-locking, particularly at the 40 Hz frequency where these responses resonate. In addition, studies of the transient gamma-band response (GBR) elicited by single tones have revealed deficits in gamma power and phase-locking in schizophrenia. We examined the degree to which the 40 Hz ASSR and the transient GBR to single tones are correlated and whether they assess overlapping or distinct gamma-band abnormalities in schizophrenia. METHODS: EEG was recorded during 40 Hz ASSR and auditory oddball paradigms from 28 patients with schizophrenia or schizoaffective disorder (SZ) and 25 age- and gender-matched healthy controls (HC). The ASSR was elicited by 500 ms click trains, and the transient GBR was elicited by the standard tones from the oddball paradigm. Gamma phase and magnitude values, calculated using Morlet wavelet transformations, were used to derive total power and phase-locking measures. RESULTS: Relative to HC, SZ patients had significant deficits in total gamma power and phase-locking for both ASSR- and GBR-based measures. Within both groups, the 40 Hz ASSR and GBR phase-locking measures were significantly correlated, with a similar trend evident for the total power measures. Moreover, co-varying for GBR substantially reduced 40 Hz ASSR power and phase-locking differences between the groups. CONCLUSIONS: 40 Hz ASSR and transient GBR measures provide very similar information about auditory gamma abnormalities in schizophrenia, despite the overall enhancement of 40 Hz ASSR total power and phase-locking values relative to the corresponding GBR values.

Computer simulations of neural information processing and the schizophrenia-mania dichotomy.

Recent developments in artificial intelligence use computer simulations of complex neural systems to model associative memory and gestalt-seeking during cognition. Perturbations imposed on such computer simulations caused catastrophic breakdowns of neural functioning. The resulting cognitive disturbances assumed two forms, one "schizophreniclike" and the other "maniclike." The former was induced by memory overload and resulted in misperceptions, loose associations, and also parasitic processing states that pathologically controlled the flow of associations. The latter was caused by increased randomness of neural activity, which induced "jumps" from one gestalt to another. The relationship between this differential model of psychotic disturbances and other studies of schizophrenia and mania were explored.

Schizophrenia as a disorder of developmentally reduced synaptic connectivity.

Recent postmortem and neuroimaging studies of schizophrenia delineate changes in brain structure and volume that appear to arise from a reduction of neuritic processes (such as dendrites and synapses) rather than loss of neuronal or glial cell bodies. To account for these findings, we propose a pathophysiological model of reduced synaptic connectivity arising from disturbances of brain development active during perinatal and adolescent periods. We review a computer simulation of the elimination of the synaptic connections that models normal cognitive development and psychotic symptom formation. We describe the model's key parameters and discuss how they can account for important aspects of schizophrenia, including its unique symptoms, short- and long-term course, typical age of onset, neurodevelopmental deficits, limited neurodegenerative progression, sex differences, and more. We discuss some of the model's predictions and questions raised for basic research, early detection, and preventive intervention.

A comparative study of manic vs schizophrenic speech disorganization.

Recent studies have indicated that thought disorder occurs among manics at least to the same degree as among schizophrenics. The present study assumes that thought disorder can be considered as an abnormality of language whereby listeners are unable to organize speech into a single, coherent "whole." A model of language processing is presented that predicts that the incoherence of manic speech is due to shifts from one coherent discourse structure to another, while the ability of schizophrenic speakers to construct any discourse structure is deficient. A discourse analysis was applied to normal, manic, and schizophrenic speech samples. The two hypotheses were supported. The implications of these findings in light of other investigations of mania and schizophrenia are discussed.

The cost of a food-borne outbreak of hepatitis A in Denver, Colo.

BACKGROUND: In 1992, a food-borne outbreak of hepatitis A associated with a catering facility in Denver, Colo, resulted in 43 secondary cases of hepatitis A and the potential exposure of approximately 5000 patrons. OBJECTIVES: To assess (1) disease control costs, including state and local health department personnel costs, provision and administration of immune globulin, and cost of extra hepatitis A serologic tests performed; (2) business losses; and (3) cost of the cases' illnesses. METHODS: Cost data were collected from hospitals, health maintenance organizations, health departments, laboratories, the caterer's insurance company, and the catering facility involved in the outbreak. RESULTS: The total costs assessed in the outbreak from a societal perspective were $809,706. Disease control costs were $689,314, which included $450,397 for 16,293 immune globulin injections and $105,699 for 2777 hours of health department personnel time. The cases' medical costs were $46,064, or 7% of the disease control costs. CONCLUSIONS: The cases' medical costs and productivity losses were only a minor component of the total cost of this outbreak. The high cost of food-borne outbreaks should be taken into account in economic analyses of the vaccination of food handlers with inactivated hepatitis A vaccine.

Neural network models of schizophrenia.

There is considerable neurobiological evidence suggesting that schizophrenia is associated with reduced corticocortical connectivity. The authors describe two neural network computer simulations that explore functional consequences of these abnormalities. The first utilized an "attractor" neural network capable of content-addressable memory. Application of a pruning rule that eliminated weaker connections over longer distances produced functional fragmentation and the emergence of localized, "parasitic" attractors that intruded into network dynamics. These pathologies generally were expressed only when input information was ambiguous and provide models for delusions and cognitive disorganization. A second neural network simulation examined effects of corticocortical pruning in a speech perception network. Excessive pruning caused the network to produce percepts spontaneously, that is, in the absence of inputs, thereby simulating hallucinations. The "hallucinating" network also demonstrated subtle impairments in narrative speech perception. A parallel study of human patients found similar impairments when comparing hallucinating patients with nonhallucinating patients. In addition, the authors have used transcranial magnetic stimulation (TMS) to directly probe speech perception neurocircuitry in patients with these hallucinations. As predicted by the neural network model, the authors confirmed that "suppressive" low-frequency TMS reduces auditory hallucinations. Neural network simulations provide empirically testable concepts linking phenomenological, cognitive, and neurobiological findings in schizophrenia.

Cortical instability and the mechanism of mania: a neural network simulation and perceptual test.

BACKGROUND: A previous neural network simulation suggested that manic states arise from excessive levels of noise that destabilize neural representations. The Necker cube stick figure provides a simple perceptual task that assesses stability of gestalt-type representations. METHODS: A neural network was developed that included a simulation of the Necker cube task. Noise was added to induce maniclike jumps from one representation to another. A parallel study of Necker cube perception was conducted with 16 patients diagnosed with manic-spectrum disorder, 18 patients with schizophrenia, and 19 normal control subjects. Cognitive speed and rate of indiscriminate responses were assessed using an auditory continuous performance task. RESULTS: During processing of the "Necker cube" stimulus, the reversal rate of the noise-destabilized "manic" network was increased by 30%. In the human subject study, the median score of Necker cube reversal rates for manic-spectrum patients was roughly twice that of normal control subjects and patients with schizophrenia. Accelerated reversal rates in the manic-spectrum group were not attributable to excessive cognitive speed or higher rates of indiscriminate responses. CONCLUSIONS: The two studies, considered together, support the hypothesis that excessive cortical noise destabilizes neural representations in manic-spectrum patients.

A randomized clinical trial of repetitive transcranial magnetic stimulation in the treatment of major depression.

BACKGROUND: Multiple groups have reported on the use of repetitive transcranial magnetic stimulation (rTMS) in treatment-resistant major depression. The purpose of this study is to assess the efficacy of rTMS in unmedicated, treatment-resistant patients who meet criteria for major depression. METHODS: Depressed subjects, who had failed to respond to a median of four treatment trials, were assigned in a randomized double-blind manner to receive either active (n = 10; 20 2-sec trains of 20 Hz stimulation with 58-sec intervals; delivered at 80% motor threshold with the figure-of-eight coil positioned over the left dorsolateral prefrontal cortex) or sham (n = 10; similar conditions with the coil elevated and angled 45 degrees tangentially to the scalp) rTMS. These sequences were applied during 10 consecutive weekdays. Continuous electroencephalogram sampling and daily motor threshold determinations were also obtained. RESULTS: The group mean 25-item Hamilton Depression Rating Scale (HDRS) score was 37.2 (+/- 2.0 SEM) points. Adjusted mean decreases in HDRS scores were 14.0 (+/- 3.7) and 0.2 (+/- 4.1) points for the active and control groups, respectively (p <.05). One of 10 subjects receiving active treatment demonstrated a robust response (i.e., HDRS decreased from 47 to 7 points); three other patients demonstrated 40-45% decreases in HDRS scores. No patients receiving sham treatment demonstrated partial or full responses. CONCLUSIONS: A 2-week course of active rTMS resulted in statistically significant but clinically modest reductions of depressive symptoms, as compared to sham rTMS in a population characterized by treatment resistance.

Transcranial magnetic stimulation of left temporoparietal cortex in three patients reporting hallucinated "voices".

BACKGROUND: Prior studies suggest that auditory hallucinations of "voices" arise from activation of speech perception areas of the cerebral cortex. Low frequency transcranial magnetic stimulation (TMS) can reduce cortical activation. METHODS: We have studied three schizophrenic patients reporting persistent auditory hallucinations to determine if low frequency TMS could curtail these experiences. One hertz stimulation of left temporoparietal cortex was compared with sham stimulation using a double-blind, cross-over design. RESULTS: All three patients demonstrated greater improvement in hallucination severity following active stimulation compared to sham stimulation. Two of the three patients reported near total cessation of hallucinations for > or = 2 weeks. CONCLUSIONS: TMS may advance our understanding of the mechanism and treatment of auditory hallucinations.

Synaptic elimination, neurodevelopment, and the mechanism of hallucinated "voices" in schizophrenia.

OBJECTIVE: After peaking during childhood, synaptic density in the human frontal cortex declines by 30%-40% during adolescence because of progressive elimination of synaptic connections. The characteristic age at onset of schizophrenia--late adolescence and early adulthood--suggests that the disorder could arise from irregularities involving this neurodevelopmental process. METHOD: A computer simulation of a speech perception neural network was developed. Connections within the working memory component of the network were eliminated on the basis of a "Darwinian rule" in order to model loss of synapses. As a comparison, neuronal cell death, also postulated as being linked to both neurodevelopment and schizophrenia, was simulated. The authors determined whether these alterations at low levels could enhance perceptual capacity and at high levels produce spontaneous speech percepts that simulate hallucinated speech or "voices." RESULTS: Eliminating up to 65% of working memory connections improved perceptual ability; beyond that point, network performance declined and speech hallucinations emerged. Simulating excitotoxic neuronal loss at low levels also improved network performance, but in excess it did not produce hallucinations. CONCLUSIONS: The model demonstrates perceptual advantages of selective synaptic elimination as well as selective neuronal loss, suggesting a functional explanation for these aspects of neurodevelopment. The model predicts that psychosis arises from a pathological extension of one of these neurodevelopmental trends, namely, synaptic elimination.

Selective speech perception alterations in schizophrenic patients reporting hallucinated "voices".

OBJECTIVE: The authors tested a model of hallucinated "voices" based on a neural network computer simulation of disordered speech perception. METHOD: Twenty-four patients with schizophrenia spectrum disorders who reported hallucinated voices were compared with 21 patients with schizophrenia spectrum disorders who did not report voices and 26 normal subjects. Narrative speech perception was assessed through use of a masked speech tracking task with three levels of superimposed phonetic noise. A sentence repetition task was used to assess grammar-dependent verbal working memory, and an auditory continuous performance task was used to assess nonlanguage attention. RESULTS: Masked speech tracking task and sentence repetition performance by hallucinating patients was impaired relative to both nonhallucinating patients and normal subjects. Although both hallucinating and nonhallucinating patients demonstrated auditory attention impairments when compared to normal subjects, the two patient groups did not differ with respect to these variables. CONCLUSIONS: Results support the hypothesis that hallucinated voices in schizophrenia arise from disrupted speech perception and verbal working memory systems rather than from nonlanguage cognitive or attentional deficits.

Semantic organization of hallucinated "voices" in schizophrenia.

The authors found that the different hallucinated "voices" of four schizophrenic subjects reported over 1-3 weeks expressed semantic content that was at least as persistent as clauses sampled from single 5-7-minute conversational discourses of four comparison speakers. The high degree of semantic recurrence of voices from one day to the next may contribute to the mistaken belief that these experiences derive from a particular nonself agent or speaker.

Comparison of AIDS and HIV antibody surveillance data in Colorado.

We compared cumulative surveillance data for AIDS (May 1982-December 1986) and persons with positive HIV antibody tests (July 1985-December 1986) to examine the adequacy of each surveillance system in directing public health disease control activities. Neither AIDS nor HIV antibody surveillance data alone described the total extent of HIV infection. The geographic distribution of persons with positive HIV antibody tests was more widespread than the distribution of AIDS cases for all demographic and transmission categories. Ideally, preventive efforts should be based on a comprehensive surveillance system that indicates all persons who are infectious with HIV.

Increased incidence and prevalence of multiple sclerosis in Los Alamos County, New Mexico.

The incidence and prevalence of multiple sclerosis (MS) in Los Alamos County, New Mexico, were investigated because the number of reported cases appeared to have increased. The point prevalence on November 1, 1979, was 75.7 per 100,000, and average annual incidence rates for the period 1960-1969 and 1970-1979 were 3.4 and 3.7 per 100,000, respectively. The rates of MS in Los Alamos County were greater than expected from previous epidemiologic surveys of North America. The unusual ethnic composition and high socioeconomic level of the population probably contributed to the increases.

Creutzfeldt-Jakob disease after receipt of a previously unimplicated brand of dura mater graft.

BACKGROUND: Iatrogenic Creutzfeldt-Jakob disease (CJD) transmission via dura mater grafts has been reported in many countries. In September 1998, a 39-year-old Colorado woman was reported as having suspected CJD after receiving a dura mater graft 6 years earlier. METHODS: An investigation was initiated to confirm the diagnosis of CJD and assess the possible source of CJD transmission. The authors determined the presence or absence of other known CJD risk factors, checked for epidemiologic evidence of possible CJD transmission via neurosurgical instruments, and evaluated the procedures used in the collection and processing of the graft, including whether the donor may have had CJD. RESULTS: The CJD diagnosis was confirmed in the dural graft recipient by neuropathologic and immunodiagnostic evaluation of the autopsy brain tissue. She had no history of receipt of cadaveric pituitary hormones or corneal grafts or of CJD in her family. The authors found no patients who underwent a neurosurgical procedure within 6 months before or 5 months after the patient's surgery in 1992 who had been diagnosed with CJD. The dura mater was obtained from a 57-year-old man with a history of dysarthria, ataxia, and behavioral changes of uncertain origin. The graft was commercially prepared by use of a process that included treatment with 0.1 N sodium hydroxide and avoided commingling of dura from different donors. CONCLUSIONS: The patient's age, absence of evidence for other sources of CJD, the latent period, and the report of an unexplained neurologic illness in the donor of the dura mater indicate that the graft was the most likely source of CJD in this patient.

Risk factors for delayed immunization against measles, mumps, and rubella in Colorado two-year-olds.

OBJECTIVES: 1) To examine a wide range of potential risk factors for delayed childhood immunization against measles, mumps, and rubella and 2) to determine the parental response to proposed solutions regarding the problem of delayed childhood immunization. DESIGN: A case-control study in which subjects had (controls) or had not (cases) received measles, mumps, and rubella vaccine (MMR) by 2 years of age. Parents of subjects were also surveyed to find out whether they thought selected proposals to improve immunization rates would be successful. RESULTS: Maternal education of high school or less at the time of the child's birth, more than or equal to two moves between birth and age 2, maternal age < 21 years of age at the time of the child's birth, more than or equal to two older siblings, participation in The Special Supplemental Food Program for Women, Infants, and Children (WIC), participation in the federal food stamp program, and incorrect knowledge of the recommended age for MMR significantly elevated the odds ratio (OR) for delayed immunization. At least two older siblings (OR = 3.2), maternal age < 21 years of age at the time of the child's birth (OR = 2.8), and incorrect knowledge of the recommended age for MMR (OR = 2.7) remained significant risk factors in a multivariate logistic regression model. Insurance status and cost factors were not significant risk factors for delayed immunization. Parents though that reminders for immunization and a central record system would have made obtaining immunizations easier. CONCLUSIONS: Based on our findings of the importance of immunization knowledge and demographic characteristics as risk factors for delayed immunization, we suggest that a message (the recommended age for immunizations) and a target group for that message (families who move frequently, have older children, and are headed by younger parents) be evaluated as an intervention to improve immunization rates.

Nocturnal elevation of intraocular pressure in young adults.

PURPOSE: To distinguish 24-hour (circadian) and postural effects on intraocular pressure (IOP) in healthy young adults. METHODS: Thirty-three volunteers were housed in a sleep laboratory for 1 day under a strictly controlled 16-hour light and 8-hour dark environment. Sleep was encouraged in the dark period. Intraocular pressure was measured in each eye every 2 hours using a pneumatonometer. Researchers used night-vision goggles to perform IOP measurements in the dark, while the subject's light exposure was minimized. In the first group of 12 subjects, measurements were taken with subjects in the sitting position during the light-wake period and supine during the dark period. In the second group of 21 subjects, all IOP measurements were taken with the subjects supine. RESULTS: Average IOP was significantly higher in the dark period than in the light-wake period in both groups. The lowest IOP occurred in the last light-wake measurement, and the peak IOP occurred in the last dark measurement. The trough-peak difference in IOP was 8.2+/-1.4 mm Hg (mean +/- SEM) in the first group. Intraocular pressure changed sharply at the transitions between light and dark. In the second group, the trough-peak IOP difference was 3.8+/-0.9 mm Hg. Intraocular pressure changed gradually throughout the 24-hour period. In comparison with the sitting IOP in the first group, the supine IOP in the second group was significantly higher during the light-wake period. CONCLUSIONS: Circadian rhythms of IOP were shown in young adults, with the peaks occurring in the late dark period. A nocturnal IOP elevation can appear independent of body position change, but change of posture from upright to recumbent may contribute to the relative nocturnal IOP elevation.

Twenty-four-hour pattern of intraocular pressure in the aging population.

PURPOSE: To characterize the 24-hour pattern of intraocular pressure (IOP) in a sample of the aging human population. METHODS: Twenty-one healthy volunteers 50 to 69 years of age were housed in a sleep laboratory for 24 hours. Experimental conditions were strictly controlled with a 16-hour light period and an 8-hour dark period. Sleep was encouraged in the dark period. Intraocular pressure was measured using a pneumatonometer every 2 hours (total of 12 times). Measurements were taken in both the sitting position and the supine position during the light/wake period but only in the supine position during the dark period. RESULTS: When the sitting IOP data from the light/wake period and the supine IOP data from the dark period were considered, elevation and reduction of IOP occurred around the scheduled lights-off and lights-on transitions, respectively. Mean IOP in the dark period was significantly higher than mean IOP in the light/wake period. The trough appeared at the end of the light/wake period, and the peak appeared at the beginning of the dark period. The magnitude of trough-peak difference was 8.6+/-0.8 mm Hg (mean +/- SEM). Cosine fits of 24-hour IOP data showed a significant 24-hour rhythm. When IOP data from just the supine position were analyzed, the trough-peak IOP difference was 3.4+/-0.7 mm Hg, with similar clock times for the trough and the peak. Cosine fits of supine IOP data showed no statistically significant 24 hour rhythm. CONCLUSIONS: Nocturnal elevation of IOP occurred in this sample of the aging population. The trough of IOP appeared at the end of the light/wake period, and the peak appeared at the beginning of the dark period. The main factor in the nocturnal IOP elevation appeared to be the shift from daytime upright posture to supine posture at night.

Elevation of human intraocular pressure at night under moderate illumination.

PURPOSE: An endogenous elevation of intraocular pressure (IOP) occurs at night in healthy young adults. The authors studied whether or not this IOP elevation can be detected under moderate illumination. METHODS: Twenty-five healthy volunteers, ages 18 to 25 years, were housed overnight in a sleep laboratory under a strictly controlled light-dark environment. Intraocular pressure was measured in the supine position every 2 hours, using a pneumatonometer. An 8-hour sleep period was assigned to each volunteer according to individual's accustomed sleep cycle. In the early part of this assigned period, sleep was encouraged with room lights off. Researchers performed IOP measurements at two time points with the aid of night vision goggles. In the middle to the late part of the assigned period, lights were turned on twice for a 1-hour interval. The light intensity was the same as before the bedtime. At the ending of each light period, IOP was measured under illumination. RESULTS: Average IOP was significantly higher in the assigned sleep period versus outside the period. The trough of mean IOP occurred just before the bedtime, and then IOP gradually increased and peaked at the end of the 8-hour assigned sleep period. The difference between the trough and peak IOP was 3.5 +/- 0.7 mm Hg (mean +/- SEM, n = 25). Within the assigned sleep period, the average IOP determined under illumination was significantly higher than the average IOP preceding the illumination. CONCLUSIONS: Elevation of IOP occurred during the assigned sleep period with two 1-hour light exposures of moderate intensity. Environmental light at night had no significant effect on the nocturnal IOP elevation in healthy young adults.

Urban and rural traumatic brain injuries in Colorado.

PURPOSE: The purpose of this study was to compare and contrast the epidemiology of traumatic brain injury among urban and rural residents of Colorado. METHODS: Cases of traumatic brain injury (ICD 800, 801, 803, 804, 850-854) for 1991 and 1992 from the Colorado surveillance system of hospitalized and fatal traumatic brain injuries were used. Urban cases resided in counties designated by the U.S. Census Bureau as metropolitan statistical areas (MSA). Rural cases were divided into two groups: "rural, nonremote," if the country of residence was adjacent to an MSA county or if it had a population of 2500, and "rural, remote," if not. RESULTS: Average annual age-adjusted rates of hospitalized and fatal traumatic brain injury varied significantly from 97.8 per 100,000 population for the most urban group to 172.1 per 100,000 population for the residents of rural, remote counties. Similarly, total mortality ranged from 18.1 per 100,000 population among residents of the most urban counties to 33.8 among residents of rural, remote counties. Prehospital mortality ranged from 10.0 to 27.7 traumatic brain injuries per 100,000 population. CONCLUSIONS: These results provide justification for expanding efforts to prevent traumatic brain injury to include the small, but high-risk group of residents in rural areas.