A neural network simulation of hallucinated "voices" and associated speech perception impairments in schizophrenic patients.

The mechanism of hallucinated speech, a symptom commonly reported by schizophrenic patients, is unknown. The hypothesis that these hallucinations arise from pathologically altered working memory underlying speech perception was explored. A neural network computer simulation of contextually guided sequential word detection based on Elman (1990a,b) was studied. Pruning anatomic connections or reducing neuronal activation in working memory caused word "percepts" to emerge spontaneously (i.e., in the absence of external "speech inputs"), thereby providing a model of hallucinated speech. These simulations also demonstrated distinct patterns of word detection impairments when inputs were accompanied by varying levels of noise. In a parallel human study, the ability to shadow noisecontaminated, connected speech was assessed. Schizophrenic patients reporting hallucinated speech demonstrated a pattern of speech perception impairments similar to a simulated neural network with reduced anatomic connectivity and enhanced neuronal activation. Schizophrenic patients not reporting this symptom did not demonstrate these speech perception impairments. Neural network simulations and human empirical data, when considered together, suggested that the primary cause of hallucinated "voices" in schizophrenia is reduced neuroanatomic connectivity in verbal working memory.

Effects of long-term psychiatric hospitalization for young, treatment-refractory patients.

Although short-term hospitalization has been shown to be effective in helping severely impaired psychiatric patients improve, such improvement is for some only temporary. Young, treatment-refractory patients who have failed to respond to previous brief hospitalization and outpatient treatments may benefit more from longer-term hospitalization. The authors report on a three-and-a-half-year follow-up study of 55 young adult and adolescent treatment-refractory inpatients after long-term hospitalization. Significant improvements in recidivism, quality of life, and overall functioning were found between discharge and the follow-up assessment. The authors conclude that potential benefits of long-term hospitalization for this subgroup warrant further empirical study.

Cerebrospinal fluid monoamine precursor and metabolite levels in children treated for leukemia: age and sex effects and individual variability.

Lumbar cerebrospinal fluid (CSF) was obtained from children during and following treatment for acute lymphoblastic leukemia (ALL). One hundred ninety-two CSF samples from 50 subjects, which were selected to minimize the effects of the disease and its treatment (i.e., to approach "normality" as closely as possible), were analyzed for the monoamine precursors tyrosine (Tyr) and tryptophan (Trp) and the metabolites homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA). Levels of HVA (p less than 0.0001), 5-HIAA (p less than 0.002), and Tyr (p less than 0.05) decreased with age from 3 to 17 years. Significant correlations were observed between the acid metabolites HVA and 5-HIAA (r = 0.79) and between the amino acid precursors Tyr and Trp (r = 0.71). Within individuals, levels of all four compounds were relatively stable over time, with total mean coefficient of variation ranging from 20% to 25%. No significant sex differences for CSF levels of HVA, 5-HIAA, Tyr, or Trp were found. Assessment of CSF monoamine precursors and metabolites in children treated for ALL may provide a method for understanding the chronic effect of CNS trauma on the ontogeny of monoamine systems.

Computed tomographic brain scanning in four neuropsychiatric disorders of childhood.

CAT scans were performed in 66 patients with neuropsychiatric disorders of childhood (infantile autism, attention deficit disorder, Tourette's disorder, and language disorder) and a control group of 20 medical patients. Ventricular volume and brain density were determined by quantitative, computer-based methods by researchers blind to the patients' diagnoses. There were no significant differences among diagnostic groups or between neuropsychiatric patients and medical control patients in total ventricular volume, right-left ventricular volume ratio, ventricular asymmetries, ventricle-brain ratios, or brain density.

Short- and long-term treatment of Tourette's syndrome with clonidine: a clinical perspective.

Thirteen patients with Gilles de la Tourette's syndrome were treated with clonidine (0.125 to 0.3 mg/d) for at least 60 weeks. In a single-blind, placebo-controlled trial, 6 of the 13 patients were judged to be unequivocal responders to clonidine, and 6 other patients had an equivocal response. There was significant improvement in motor and phonic tics, as well as in associated behavior problems, and there were no serious side effects. Tolerance to clonidine did not develop. Further placebo-controlled, randomized, double-blind studies of clonidine in Tourette's syndrome are needed to establish the drug's efficacy.

Whole blood serotonin and tryptophan levels in Tourette's disorder: effects of acute and chronic clonidine treatment.

Whole blood serotonin (WB5HT) and tryptophan (WBTRP) levels were studied in 20 patients (aged 8 to 45 years) with Tourette's disorder under medication-free baseline conditions and following acute and chronic clonidine treatment. Compared to 87 normal controls, Tourette's disorder patients had lower mean baseline WBTRP levels (mean +/- SEM: Tourette's, 5993 +/- 304 ng/ml vs. 6822 +/- 169 ng/ml; p less than .03). No significant differences in mean baseline WB5HT levels were found. Three hours after an acute dose of clonidine (2.5 - 5.1 micrograms/kg, p.o. at 9:00 A.M.), no mean differences were observed (baseline vs. post 3 hours) in WB5HT or WBTRP levels. However, following chronic treatment (greater than 3 weeks) with clonidine (3-8 micrograms/kg/day, p.o.), WB5HT levels were increased in 9 of 14 Tourette's disorder patients. The mean increases in WB5HT levels following chronic clonidine treatment were significant when WB5HT levels were expressed per 10(9) platelets. (mean +/- SEM: baseline, 471 +/- 45 ng/10(9) platelets vs. chronic, 697 +/- 82 ng/10(9) platelets, p = .02). No mean differences in WBTRP levels were observed after chronic clonidine treatment. These findings are discussed in light of a proposed intermediary role of 5HT systems in the mode of action of clonidine in the treatment of Tourette's disorder.

Attentional and perceptual measures: developmental changes.

A battery of 37 tasks was assembled for neuropsychiatric assessment of cognitive functioning, motor control, perceptual abilities, vigilance, and neuromaturational status. In order to determine developmental changes within a normal population, a test battery was administered to 90 middle-class grade school children (50 boys and 40 girls), who ranged in age from 4 to 14. Statistical assessment of left- and right-handed differences produced only one significant finding, which was probably due to environmental adaptation. The only clear sex difference indicated a gross motor advantage for boys walking backward on the balance beam. All 37 tests correlated with age--with true value correlations ranging from .39 to .87.

Clonidine in the treatment of Tourette syndrome: a review of data.

There are conflicting data concerning the efficacy of clonidine in TS. Some TS patients, probably 50% or more, experience substantial, long-term symptomatic improvement with minimal side effects. However, their profile of response is often variable, with behavioral symptoms appearing to show the most consistent improvement. Maximal benefit may not be evident for 4 to 6 months. A minority of patients do not respond, and a few worsen on clonidine. The need for additional double-blind trials is clear. Additional metabolic and pharmacologic investigations are needed to understand the determinants of the response of TS patients to clonidine. The response to acute doses of clonidine on sedation, growth hormone release, blood pressure, and plasma MHPG levels may be predictive of eventual therapeutic response. The variable response to clonidine, however, suggests that noradrenergic mechanisms in TS may not be of primary pathogenic importance. The study of interactions between neurochemical systems may help illuminate the pathophysiology of TS and lead the way to improved treatment of this disabling condition.

Attentional and perceptual disturbances in children with Tourette's syndrome, attention deficit disorder, and epilepsy.

Perceptual, motor, and neuromaturational competence were assessed using a battery of tasks with three groups of children with diagnosed disorders of Tourette's syndrome (TS), attentional deficit with no known organic substrate (Constitutional AD), and attentional deficit disorder in children with epilepsy (E-ADD). The purpose was to determine how the three groups related to each other on these measures and to establish clinical validation of the test battery. As predicted, the control and the TS groups did much better than the ADD and seizure groups. The TS group differed from the controls on only a handful of measures, whereas the constitutional ADD and E-ADD children were far more deviant than the TS children. The E-ADD children as a group suffered difficulties in virtually every area.

Assessment of brain function in clinical pediatric research: behavioral and biological strategies.

Psychobiological research in child psychiatry requires rigorous assessment of behavior and multiple perspectives on brain function through neurochemical, neuroendocrine, psychophysiological, and other advanced methods. The serious neuropsychiatric disorders of childhood, such as autism, attention deficit disorder, and language disorders, can be studied in complementary clinical protocols aimed at explicating patterns of behavioral and metabolic dysfunction which characterize various clinical syndromes. Clinical research with children raises sensitive ethical issues; the ethical problems can be addressed when children and families are active collaborators with the investigators and a long-term relationship is established. In this setting, participation in research can facilitate better treatment for a child. The use of novel biological strategies, such as pharmacological challenge tests, permits evaluation of the relation of specific neuronal systems to behavioral dimensions in clinical disorders. The development of a new treatment for Tourette's syndrome illustrates the integration of basic and clinical research methods.

Thyroid hormone in autistic children.

Thyroid hormone plays an important role in the pre- and postnatal development and function of the central nervous system. Disturbances in thyroid hormone regulation have been hypothesized in childhood autism. We evaluated blood indices of thyroid function, including serum thyroxine, triiodothyronine, and thyroid-stimulating hormone, in a large population of autistic children. No differences were found between autistic and normal children.