Clinical neuroscience research最新文献

Schizophrenia is a pervasive neuropsychiatric disorder with worldwide prevalence. Family and adoption studies indicate a strong genetic component of disease susceptibility. However, epidemiological studies also point to a role for infections and other environmental factors in disease etiology. We review the evidence for a role for infectious agents in the etiopathogenesis of schizophrenia and related disorders, focusing on the apicomplexan parasite Toxoplasma gondii. We discuss the epidemiological evidence for a role for this agent, as well as potential mechanisms of gene–environmental interactions which are consistent with the genetic components of disease susceptibility. We describe how the potential role of infections as causative agents of complex disorders such as schizophrenia are not consistent with classical postulates of causation such as the Koch Postulates, but may be consistent with more modern concepts of how infectious agents can interact with genetic determinants to result in disease in susceptible individuals. We outline the research approaches which are necessary to define associations between infectious agents and complex disorders. The successful association between infectious agents and diseases such as schizophrenia might lead to new methods for treatment and prevention of these devastating disorders.

A mechanism exists by which the brain communicates with cells of the immune system to regulate their activity. This mechanism involves the release of norepinephrine from sympathetic nerve terminals located within the parenchyma of lymphoid tissue, and the subsequent binding of norepinephrine to specific adrenergic receptors (ARs) expressed on the immune cells residing therein. The purpose of this chapter is to summarize the data in support of AR expression on the cell surface of immune cells involved in adaptive immunity, namely the T and B lymphocytes that recognize and respond to a specific antigen by secreting cytokine or antibody, respectively. This chapter will also give a few examples of how these findings may have functional relevance for certain clinical conditions.

Administration of cytokines to animals can elicit many effects on the brain, particularly neuroendocrine and behavioral effects. Cytokine administration also alters neurotransmission, which may underlie these effects. The most well studied effect is the activation of the hypothalamo–pituitary–adrenocortical (HPA) axis, especially that by interleukin-1 (IL-1). Peripheral and central administration of IL-1 also induces norepinephrine (NE) release in the brain, most markedly in the hypothalamus. Small changes in brain dopamine (DA) are occasionally observed, but these effects are not regionally selective. IL-1 also increases brain concentrations of tryptophan, and the metabolism of serotonin (5-HT) throughout the brain in a regionally non-selective manner. Increases of tryptophan and 5-HT, but not NE, are also elicited by IL-6, which also activates the HPA axis, although it is much less potent in these respects than IL-1. IL-2 has modest effects on DA, NE and 5-HT. Like IL-6, tumor necrosis factor-α (TNFα) activates the HPA axis, but affects NE and tryptophan only at high doses. The interferons (IFN's) induce fever and HPA axis activation in man, but such effects are weak or absent in rodents. The reported effects of IFN's on brain catecholamines and serotonin have been very varied. However, interferon-γ, and to a lesser extent, interferon-α, have profound effects on the catabolism of tryptophan, effectively reducing its concentration in plasma, and may thus limit brain 5-HT synthesis.

Administration of endotoxin (LPS) elicits responses similar to those of IL-1. Bacterial and viral infections induce HPA activation, and also increase brain NE and 5-HT metabolism and brain tryptophan. Typically, there is also behavioral depression. These effects are strikingly similar to those of IL-1, suggesting that IL-1 secretion, which accompanies many infections, may mediate these responses. Studies with IL-1 antagonists, support this possibility, although in most cases the antagonism is incomplete, suggesting the existence of multiple mechanisms. Because LPS is known to stimulate the secretion of IL-1, IL-6 and TNFα, it seems likely that these cytokines mediate at least some of the responses, but studies with antagonists indicate that there are multiple mechanisms. The neurochemical responses to cytokines are likely to underlie the endocrine and behavioral responses. The NE response to IL-1 appears to be instrumental in the HPA activation, but other mechanisms exist. Neither the noradrenergic nor the serotonergic systems appear to be involved in the major behavioral responses. The significance of the serotonin response is unknown.

Introduction: cognitive/behavioral testing, structural imaging, and functional imaging, has demonstrated atypical cerebral asymmetries in patients with attention-deficit/hyperactivity disorder (ADHD). However, few studies directly examined the nature of hemispheric specialization and interaction in this population. Methods: the present experiment applied techniques from behavioral laterality research to assess directly left/right brain dynamics in unmedicated adults with ADHD (n=21) and controls (n=22). We used a lateralized lexical decision task to assess hemispheric differences in word recognition and cross-callosal interhemispheric transfer of linguistic information. Results: analysis of variance indicated that ADHD subjects were impaired relative to controls in identifying words in both hemispheres (P=0.001). Furthermore, ADHD subjects exhibited decreased effects for ‘word regularity’ (P=004), enhanced effects of ‘word frequency’ (P=007), and an increased bias for ‘nonword’ responses overall (P=03), as well as during left visual field trials in particular (P=01). Conclusions: adult subjects with ADHD demonstrated poor linguistic processing. Group differences in sensitivity to semantic and phonological linguistic variables, along with differences in response biases, suggested that ADHD subjects had reduced left hemisphere and enhanced right hemisphere involvement during our task. These findings are relevant to current research investigating ‘endophenotypes’ in ADHD, as laterality indices may prove useful in etiological research, particularly molecular genetic investigations, and highlights the relevance of brain laterality research in clinical psychiatry.

Attention-deficit/hyperactivity disorder (ADHD) is more common in boys than in girls, suggesting that prenatal androgen exposure may play a role in etiology. Click-evoked otoacoustic emissions (CEOAEs) and relative finger length are measures known to exhibit sex differences early in life, also suggesting that prenatal androgen exposure plays a contributing role. CEOAEs and the lengths of the fingers were measured in boys and girls aged 7–15 who were diagnosed as having different types of ADHD. All six possible pairwise length ratios were calculated for the four fingers of each hand. The CEOAEs measured in boys diagnosed as ADHD/Inattentive were substantially smaller than those of either the boys diagnosed as ADHD/Combined or the Control boys, whose mean CEOAEs were alike. Similarly, most of the finger-length ratios (FLRs) were smaller for boys diagnosed as ADHD/Inattentive than for either ADHD/Combined or Control boys. Both of these outcomes represent a hypermasculinization of the boys diagnosed as ADHD/Inattentive. Thus, two quite different physiological measures suggest that these boys diagnosed as ADHD/Inattentive may have been exposed to higher-than-normal levels of androgens at some stage early in development. In accord with both Cantwell's proposal for validating psychiatric disorders and previous suggestions in the literature, these findings support the hypothesis that the Combined and Inattentive groups represent different disorders, not versions of a single disorder.

There are large differences between nations in the diagnosis and management of children with marked impulsiveness and inattention. The differences extend to the names and definitions of disorder and the extent to which medication should be used. This paper uses data from a large randomized clinical trial of pharmacological and psychosocial treatments, conducted in North America, to clarify its implications for other parts of the world. A diagnostic algorithm was applied to 579 children, diagnosed with ADHD-Combined Type in the MTA trial, to generate the ICD-10 diagnosis of ‘hyperkinetic disorder’ (HD); only a quarter met these more stringent criteria. HD was a moderator of treatment response. The superiority of medication to behavioral treatment was greater for children with HD. Children with ADHD but not HD also showed some improvement with medication. The results provide evidence for the validity of HD as a subgroup of those presenting ADHD; and suggest that treatment with stimulants is a high priority in children with HD. Results also suggest that some children with other forms of ADHD will respond better to medication than to psychosocial intervention, and therefore that European guidelines should extend their indications.

Objective: To examine relationships among early smoke exposure (ESE), attention-deficit/hyperactivity disorder (ADHD), oppositional-defiant or conduct disorder (ODD/CD), and whether ESE affects symptom severity, comorbidity, and later treatment response. Study design: The Multimodal Treatment Study of Children with ADHD (MTA) had 468 children with ADHD and 279 others from the same classrooms (local normative comparison group, LNCG) with smoke-exposure data. We compared ESE as ‘gestational’ or ‘postnatal’ (ambient house smoke only, without gestational) between ADHD and LNCG, and tested its association with ADHD severity, comorbid ODD/CD, methylphenidate response, and differential treatment response to four randomly assigned treatments. Results: About 1/3 more ADHD than LNCG children had ESE (both types), but association with gestational smoke attenuated from P=0.024 to 0.094 when subjects with comorbid ODD/CD were excluded, although total smoke exposure retained significance (P=0.006). In the MTA/ADHD participants, comorbid ODD/CD, and parent/teacher-rated ADHD and ODD symptom severity were not associated with gestational smoking, but severity of ODD was associated with postnatal smoke, and for boys only, ADHD severity at 14 months associated with postnatal smoke. When ODD and CD were ‘unbundled’, CD was associated (P=0.005) with gestational smoke. Neither ESE moderated response to methylphenidate, optimal dose, 2-year growth slowing, or differential ODD symptom response to 14-months of 4 randomly assigned treatments. However, for ADHD symptoms, postnatal smoke moderated (P=0.008) the 14-month advantage of behavioral treatment (Beh) over community-treated comparison (CC): postnatally exposed boys benefited relatively more from Beh (d>0.5). ADHD symptom improvement also showed significant interaction of sex with gestational (P=0.015) and postnatal (P=0.044) smoke moderator effect for the contrast of MTA medication algorithm vs. Beh and CC: smoke-exposed girls did not show the usual algorithm superiority. Conclusions: These findings suggest possible moderating effects of postnatal ESE on the advantage of intensive behavioral treatment and sex-differential moderating effects of ESE on the advantage of intensive medication over behavioral treatment. This exploratory result requires replication. The findings do not convincingly support the hypothesis that the association of gestational smoking with offspring ADHD is accounted for by comorbid ODD/CD.