Structural, Metabolic, and Functional Brain Abnormalities as a Result of Prenatal Exposure to Drugs of Abuse: Evidence from Neuroimaging

Prenatal exposure to alcohol and stimulants negatively affects the developing trajectory of the central nervous system in many ways. Recent advances in neuroimaging methods have allowed researchers to study the structural, metabolic, and functional abnormalities resulting from prenatal exposure to drugs of abuse in living human subjects. Here we review the neuroimaging literature of prenatal exposure to alcohol, cocaine, and methamphetamine. Neuroimaging studies of prenatal alcohol exposure have reported differences in the structure and metabolism of many brain systems, including in frontal, parietal, and temporal regions, in the cerebellum and basal ganglia, as well as in the white matter tracts that connect these brain regions. Functional imaging studies have identified significant differences in brain activation related to various cognitive domains as a result of prenatal alcohol exposure. The published literature of prenatal exposure to cocaine and methamphetamine is much smaller, but evidence is beginning to emerge suggesting that exposure to stimulant drugs in utero may be particularly toxic to dopamine-rich basal ganglia regions. Although the interpretation of such findings is somewhat limited by the problem of polysubstance abuse and by the difficulty of obtaining precise exposure histories in retrospective studies, such investigations provide important insights into the effects of drugs of abuse on the structure, function, and metabolism of the developing human brain. These insights may ultimately help clinicians develop better diagnostic tools and devise appropriate therapeutic interventions to improve the condition of children with prenatal exposure to drugs of abuse

Cholinergic blockade under working memory demands encountered by increased rehearsal strategies: evidence from fMRI in healthy subjects

The connection between cholinergic transmission and cognitive performance has been established in behavioural studies. The specific contribution of the muscarinic receptor system on cognitive performance and brain activation, however, has not been evaluated satisfyingly. To investigate the specific contribution of the muscarinic transmission on neural correlates of working memory, we examined the effects of scopolamine, an antagonist of the muscarinic receptors, using functional magnetic resonance imaging (fMRI). Fifteen healthy male, non-smoking subjects performed a fMRI scanning session following the application of scopolamine (0.4 mg, i.v.) or saline in a placebo-controlled, repeated measure, pseudo-randomized, single-blind design. Working memory was probed using an n-back task. Compared to placebo, challenging the cholinergic transmission with scopolamine resulted in hypoactivations in parietal, occipital and cerebellar areas and hyperactivations in frontal and prefrontal areas. These alterations are interpreted as compensatory strategies used to account for downregulation due to muscarinic acetylcholine blockade in parietal and cerebral storage systems by increased activation in frontal and prefrontal areas related to working memory rehearsal. Our results further underline the importance of cholinergic transmission to working memory performance and determine the specific contribution of muscarinic transmission on cerebral activation associated with executive functioning

Comparison of spatial working memory in children with prenatal alcohol exposure and those diagnosed with ADHD; A functional magnetic resonance imaging study

<p>Abstract</p> <p>Background</p> <p>Alcohol related neurodevelopmental disorder (ARND) falls under the umbrella of fetal alcohol spectrum disorder (FASD), but individuals do not demonstrate the facial characteristics associated with fetal alcohol syndrome (FAS), making diagnosis difficult. While attentional problems in ARND are similar to those found in attention-deficit/hyperactivity disorder (ADHD), the underlying impairment in attention pathways may be different.</p> <p>Methods</p> <p>Functional magnetic resonance imaging (fMRI) of a working memory (1-back) task of 63 children, 10 to 14 years old, diagnosed with ARND and ADHD, as well as typically developing (TD) controls, was conducted at 3 T. Diffusion tensor imaging (DTI) data were also acquired.</p> <p>Results</p> <p>Activations were observed in posterior parietal and occipital regions in the TD group and in dorsolateral prefrontal and posterior parietal regions in the ARND group, whereas the ADHD group activated only dorsolateral prefrontal regions, during the working memory component of the task (1-back minus 0-back contrast). The increases in frontal and parietal activity were significantly greater in the ARND group compared to the other groups. This increased activity was associated with reduced accuracy and increased response time variability, suggesting that ARND subjects exert greater effort to manage short-term memory load. Significantly greater intra-subject variability, demonstrated by fMRI region-of-interest analysis, in the ADHD and ARND groups compared to the TD group suggests that moment-to-moment lapses in attention contributed to their poorer task performance. Differences in functional activity in ARND subjects with and without a diagnosis of ADHD resulted primarily from reduced activation by the ARND/ADHD + group during the 0-back task. In contrast, children with ADHD alone clearly showed reduced activations during the 1-back task. DTI analysis revealed that the TD group had significantly higher total tract volume and number of fibers than the ARND group. These measures were negatively correlated with errors on the 1-back task, suggesting a link between white matter integrity and task performance.</p> <p>Conclusions</p> <p>fMRI activations suggest that the similar behavior of children with ARND and ADHD on a spatial working memory task is the result of different cognitive events. The nature of ADHD in children with ARND appears to differ from that of children with ADHD alone.</p

Intracellular free radical production by peripheral blood T lymphocytes from patients with systemic sclerosis: Role of NADPH oxidase and ERK1/2

INTRODUCTION: Abnormal oxidative stress has been described in systemic sclerosis (SSc) and previous works from our laboratory demonstrated an increased generation of reactive oxygen species (ROS) by SSc fibroblasts and monocytes. This study investigated the ability of SSc T lymphocytes to produce ROS, the molecular pathway involved, and the biological effects of ROS on SSc phenotype. METHODS: Peripheral blood T lymphocytes were isolated from serum of healthy controls or SSc patients by negative selection with magnetic beads and activated either with PMA or with magnetic beads coated with anti-CD3 and anti-CD28 antibodies. Intracellular ROS generation was measured using a DCFH-DA assay in a plate reader fluorimeter or by FACS analysis. CD69 expression and cytokine production were analyzed by FACS analysis. Protein expression was studied using immunoblotting techniques and mRNA levels were quantified by real-time PCR. Cell proliferation was carried out using a BrdU incorporation assay. RESULTS: Peripheral blood T lymphocytes from SSc patients showed an increased ROS production compared to T cells from healthy subjects. Since NADPH oxidase complex is involved in oxidative stress in SSc and we found high levels of gp91phox in SSc T cells, SSc T cells were incubated with chemical inhibititors or specific siRNAs against gp91phox. Inhibition of NADPH oxidase partially reverted CD69 activation and proliferation rate increase, and significantly influenced cytokine production and ERK1/2 activation. CONCLUSIONS: SSc T lymphocityes are characterized by high levels of ROS, generated by NADPH oxidase via ERK1/2 phosphorylation, that are essential for cell activation, proliferation, and cytokine production. These data confirm lymphocytes as key cellular players in the pathogenesis of systemic sclerosis and suggest a crucial link between ROS and T cell activation. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13075-015-0591-8) contains supplementary material, which is available to authorized users