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.

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.

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.

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.