The worldwide obesity epidemic has been mainly attributed to lifestyle changes. However, who becomes obese in an obesity-prone environment is largely determined by genetic factors. In the last 20 years, important progress has been made in the elucidation of the genetic architecture of obesity. In parallel with successful gene identifications, the number of gene-environment interaction (GEI) studies has grown rapidly. This paper reviews the growing body of evidence supporting gene-environment interactions in the field of obesity. Heritability, monogenic and polygenic obesity studies provide converging evidence that obesity-predisposing genes interact with a variety of environmental, lifestyle and treatment exposures. However, some skepticism remains regarding the validity of these studies based on several issues, which include statistical modelling, confounding, low replication rate, underpowered analyses, biological assumptions and measurement precision. What follows in this review includes (1) an introduction to the study of GEI, (2) the evidence of GEI in the field of obesity, (3) an outline of the biological mechanisms that may explain these interaction effects, (4) methodological challenges associated with GEI studies and potential solutions, and (5) future directions of GEI research. Thus far, this growing body of evidence has provided a deeper understanding of GEI influencing obesity and may have tremendous applications in the emerging field of personalized medicine and individualized lifestyle recommendations.
The serotonin system has emerged as a potential target for anti-dyskinetic therapy in Parkinson's disease. In fact, serotonin neurons can convert L-DOPA into dopamine, and mediate its synaptic release. However, they lack a feedback control mechanism able to regulate synaptic dopamine levels, which leads to un-physiological stimulation of post-synaptic striatal dopamine receptors. Accordingly, drugs able to dampen the activity of serotonin neurons can suppress L-DOPA-induced dyskinesia in animal models of Parkinson's disease. Here, we investigated the ability of the 5-HT1A/1B receptor agonist anpirtoline to counteract L-DOPA-induced dyskinesia in L-DOPA-primed 6-OHDA-lesioned rats and MPTP-treated macaques. Results suggest that anpirtoline dose-dependently reduced dyskinesia both in rats and monkeys; however, the effect in MPTP-treated macaques was accompanied by a worsening of the Parkinson's disease score at significantly effective doses (1.5 and 2.0 mg/kg). At a lower dose (0.75 mg/kg), anpirtoline markedly reduced dyskinesia in 4 out of 5 subjects, but statistical significance was prevented by the presence of a non-responsive subject. These results provide further evidence that the serotonin neurons contribute both to the pro-dyskinetic effect of L-DOPA and to its therapeutic efficacy in the rat and monkey models of Parkinson's disease.
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.
The immune response that accompanies spinal cord injury contributes to both injury and reparative processes. It is this duality that is the focus of this review. Here, we consider the complex cellular and molecular immune responses that lead to the infiltration of leukocytes and glial activation, promote oxidative stress and tissue damage, influence wound healing, and subsequently modulate locomotor recovery. Immunomodulatory strategies to improve outcomes are gaining momentum as ongoing research carefully dissects those pathways which likely mediate cell injury from those which favor recovery processes. Current therapeutic strategies address divergent approaches including early immunoblockade and vaccination with immune cells to prevent early tissue damage and support a wound-healing environment that favors plasticity. Despite these advances, there remain basic questions regarding how inflammatory cells interact in the injured spinal cord. Such questions likely arise as a result of our limited understanding of immune cell/neural interactions in a dynamic environment that culminates in progressive cell injury, demyelination, and regenerative failure.
Neuroinflammation is a complex integration of the responses of all cells present within the CNS, including the neurons, macroglia, microglia and the infiltrating leukocytes. The initiating insult, environmental factors, genetic background and age/past experiences all combine to modulate the integrated response of this complex neuroinflammatory circuit. Here, we explore how these factors interact to lead to either neuroprotective versus neurotoxic inflammatory responses. We specifically focus on microglia and astrocytic regulation of autoreactive T cell responses.
All children with autism spectrum disorders have deficits in pragmatic aspects of communication; however, formal language abilities are extremely heterogeneous, ranging from nonverbal to superior linguistic skills. Recent studies have focused on defining different language phenotypes among verbal children. One subtype has been compared to specific language impairment (SLI), a language disorder that is diagnosed on the basis of delays and deficits in language acquisition in the absence of hearing impairment, frank neurological damage or co-morbid psychopathology. Two behavioral studies address the question of whether children with autism and language impairment have specific language deficits that are similar to those found in SLI. These experiments focused on phonological processing in a nonsense word repetition task, and use of grammatical morphology in conversational speech. The findings from these studies are discussed in the context of recent neuroimaging and genetic studies of autism.
Autism is a pervasive developmental condition, characterized by impairments in non-verbal communication, social relationships and stereotypical patterns of behavior. A large body of evidence suggests that several aspects of face processing are impaired in autism, including anomalies in gaze processing, memory for facial identity and recognition of facial expressions of emotion. In search of neural markers of anomalous face processing in autism, much interest has focused on a network of brain regions that are implicated in social cognition and face processing. In this review, we will focus on three such regions, namely the STS for its role in processing gaze and facial movements, the FFA in face detection and identification and the amygdala in processing facial expressions of emotion. Much evidence suggests that a better understanding of the normal development of these specialized regions is essential for discovering the neural bases of face processing anomalies in autism. Thus, we will also examine the available literature on the normal development of face processing. Key unknowns in this research area are the neuro-developmental processes, the role of experience and the interactions among components of the face processing system in shaping each of the specialized regions for processing faces during normal development and in autism.
Recent functional imaging studies suggest deficits in connectivity between disparate and distant regions in the brains of autistic individuals. One possible explanation to these findings is the presence of modular abnormalities in the neocortex of autistic patients: a change in neuronal specialization within minicolumns that emphasizes short connecting fibers. In this study, we expand on previous findings by exploring the topography of minicolumnar abnormalities in autism. Our postmortem study included six patients with autism (DSM-IV-TR and ADI-R diagnosed) and six age-matched controls. Entire brain hemispheres were celloidin embedded, serially sectioned, and stained with gallocyanin. Digital photomicrographs of = 9 cortical areas (including paralimbic, heteromodal association, unimodal association, and primary areas) obtained at high magnification were assembled into montages covering the entire cortical thickness. Stained cell somata were segmented from neuropil by thresholding. Computer image analysis clustered neurons into minicolumnar fragments. The full width of the image region nearest each fragment and the width of the cell-dense core of the fragment were estimated. The difference between these two quantities can be used as a measure of the peripheral neuropil space of minicolumns. We found an interaction of diagnosis and region for peripheral neuropil space ( = 0.041). Post hoc analysis revealed significant differences ( < 0.05) for the frontopolar region (area 10) and the anterior cingulate gyrus (area 24). The frontopolar cortex is involved in executive functions by implementing control over internally generated thoughts and relational integration (combination of multiple cognitive rules). The anterior cingulate gyrus is involved in the analysis of socially salient information, including the processing of familiar faces. Pathological findings in these areas may provide a correlate to some of the more salient manifestations of autism.
This chapter will discuss the current knowledge of the contribution of systemic and local inflammation in acute and sub-chronic stages of experimental stroke in both the adult and neonate. It will review the role of specific cell types and interactions among blood cells, endothelium, glia, microglia, the extracellular matrix, and neurons – cumulatively called “neurovascular unit” – in stroke induction and evolution. Intracellular inflammatory signaling pathways such as nuclear factor kappa beta and mitogen-activated protein kinases, and mediators produced by inflammatory cells such as cytokines, chemokines, reactive oxygen species, and arachidonic acid metabolites, as well as the modifying role of age on these mechanisms, will be reviewed in relation to the potential for therapy in stroke and hypoxic–ischemic injury.
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.
Electroconvulsive therapy is the most rapidly acting and effective antidepressant treatment. For decades it was believed that the generalized seizure provided the necessary and sufficient conditions for efficacy, while the type and quantity of electricity determined the magnitude of cognitive effects. A series of randomized, double-masked trials at the New York State Psychiatric Institute has disproved this view. By systematically varying electrode placement, electrical dosage, and stimulus waveform, this work demonstrated that efficacy and cognitive effects are highly dependent on current paths and the current density within those paths. Specifically, antidepressant effects are contingent on the recruitment of a sufficiently large neuronal population in prefrontal cortex in seizure initiation. The anticonvulsant properties of ECT are reviewed and it is hypothesized that the magnitude of surround inhibition in a PFC network is the critical feature underlying these effects on efficacy. Given this localization, new forms of brain stimulation that elicit focal PFC seizures should have superior benefit/risk ratios. Magnetic seizure therapy has shown promise, but its development may be hindered by technical problems in delivering a sufficiently powerful stimulus. A new alternative, focal electrically administered seizure therapy (FEAST), is described and early work with non-human primates indicate that FEAST achieves a degree of focality in seizure expression that is not possible with traditional ECT.
Evidence implicating disturbances of intracellular Ca homeostasis has continued to accumulate, with a recent burst of new observations obtained using cultured cell lines from patients with bipolar disorder (BD) suggesting that disturbances occur in receptor-activated and store-operated calcium entry. The potential confounding effects of state of illness and medications on results obtained with various surrogate cellular models is reviewed, and the extent to which findings may reflect trait changes is considered. The role of ER and mitochondria in maintaining intracellular Ca homeostasis and in protecting against induction of apoptosis is now better understood. Disrupted Ca dynamics found in cell lines from BD patients point to disturbances in these homeostatic control modules in the pathophysiology of a subtype of BD. This notion is further supported by convergence of observations that, on the one hand, show therapeutic concentrations of lithium modifies intracellular Ca dynamics in non-human and human cell lines of different ontogeny, and on the other hand, demonstrate that this mood stabilizer modulates anti-apoptotic protein expression that counteracts mitochondrial/ER stress-induced impairment in Ca homeostasis.
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.