Neuroinflammation is associated with a broad spectrum of neurodegenerative and psychiatric diseases. The core process in neuroinflammation is activation of microglia, the innate immune cells of the brain. We measured the neuroinflammatory response produced by a systemic administration of the Escherichia coli lipopolysaccharide (LPS; also called endotoxin) in humans with the positron emission tomography (PET) radiotracer [ 11 C]PBR28, which binds to translocator protein, a molecular marker that is up-regulated by microglial activation. In addition, inflammatory cytokines in serum and sickness behavior profiles were measured before and after LPS administration to relate brain microglial activation with systemic inflammation and behavior. Eight healthy male subjects each had two 120-min [ 11 C]PBR28 PET scans in 1 d, before and after an LPS challenge. LPS (1.0 ng/kg, i.v.) was administered 180 min before the second [ 11 C]PBR28 scan. LPS administration significantly increased [ 11 C]PBR28 binding 30-60%, demonstrating microglial activation throughout the brain. This increase was accompanied by an increase in blood levels of inflammatory cytokines, vital sign changes, and sickness symptoms, well-established consequences of LPS administration. To our knowledge, this is the first demonstration in humans that a systemic LPS challenge induces robust increases in microglial activation in the brain. This imaging paradigm to measure brain microglial activation with [ 11 C]PBR28 PET provides an approach to test new medications in humans for their putative antiinflammatory effects.neuroinflammation | PBR28 | endotoxin | microglia | cytokines

Impulsivity, often defined as a human behavior characterized by the inclination of an individual to act on urge rather than thought, with diminished regard to consequences, encompasses a range of maladaptive behaviors which are in turn affected by distinct neural systems. Congruent with the above definition, behavioral studies have consistently shown that the underlying construct of impulsivity is multidimensional in nature. However, research to date has been inconclusive regarding the different domains or constructs that constitute this behavior. In addition there is also no clear consensus as to whether self-report and laboratory based measures of impulsivity measure the same or different domains. The current study aimed to: 1) characterize the underlying multidimensional construct of impulsivity using a sample with varying degrees of putative impulsivity related to substance misuse, including subjects who were at-risk of substance use or addicted (ARA), and 2) assess relationships between self-report and laboratory measures of impulsivity, using a principal component-based factor analysis. In addition, our supplementary goal was to evaluate the structural constructs of impulsivity within each group separately (healthy and ARA). We used five self-report measures (Behavioral Inhibition System/Behavioral Activation System (BIS/BAS), Barratt Impulsivity Scale-11, Padua Inventory, Zuckerman Sensation Seeking Scale (SSS), and Sensitivity to Punishment and Sensitivity to Reward Questionnaire) and two computer based laboratory tasks (Balloon Analog Risk Task and the Experiential Delay Task) to measure aspects of impulsivity in a total of 176 adult subjects. Subjects included healthy controls (N=89), non-alcoholic subjects with family histories of alcoholism (FHP; N=36) and both former (N=20) and current (N=31) cocaine users. Subjects with a family history of alcoholism and cocaine abusers were grouped together as “at-risk/addicted” (ARA) to evaluate our supplementary goal. Our overall results revealed the multidimensional nature of the impulsivity construct as captured optimally through a five factor solution that accounted for nearly 70% of the total variance. The five factors/components were imputed as follows “Self-Reported Behavioral Activation”, “Self-Reported Compulsivity and Reward/Punishment”, “Self-Reported Impulsivity”, “Behavioral Temporal Discounting” and “Behavioral Risk-Taking.” We also found that contrary to previously published reports, there was significant overlap between certain laboratory and self-report measures, indicating that they might be measuring the same impulsivity domain. In addition, our supplemental analysis also suggested that the impulsivity constructs were largely, but not entirely the same within the healthy and ARA groups.

https://clinicaltrials.gov/ct2/show/NCT00588731.

Objective Bipolar disorder is associated with high risk for suicide behavior that often develops in adolescence/young adulthood. Elucidation of involved neural systems is critical for prevention. This study of adolescents/young adults with bipolar disorder with and without history of suicide attempts combines structural, diffusion tensor and functional magnetic resonance imaging methods to investigate implicated abnormalities in structural and functional connectivity within fronto-limbic systems. Method Participants with bipolar disorder included 26 with a prior suicide attempt and 42 without attempts. Regional gray matter volume, white matter integrity and functional connectivity during processing of emotional stimuli were compared between groups and differences were explored for relationships between imaging modalities and associations with suicide-related symptoms and behaviors. Results Compared to the non-attempter group, the attempter group showed reductions in gray matter volume in orbitofrontal cortex, hippocampus and cerebellum; white matter integrity in uncinate fasciculus, ventral frontal and right cerebellum regions; and amygdala functional connectivity to left ventral and right rostral prefrontal cortex (p<0.05, corrected). In exploratory analyses, among attempters, right rostral prefrontal connectivity was negatively correlated with suicidal ideation (p<0.05), and left ventral prefrontal connectivity was negatively correlated with attempt lethality (p<0.05). Conclusions Adolescent/young adult suicide attempters with bipolar disorder demonstrate less gray matter volume and decreased structural and functional connectivity in a ventral fronto-limbic neural system subserving emotion regulation. Among suicide attempters, reductions in amygdala-prefrontal functional connectivity may be associated with severity of suicide ideation and attempt lethality.

We have shown previously that naturally occurring isothiocyanates derived from cruciferous vegetables and their N-acetylcysteine conjugates inhibit lung adenoma formation induced by tobacco carcinogens in A/J mice at the postinitiation stage. The tumor-inhibitory activity by these compounds is linked with activation of activator protein and induction of apoptosis in lung tissues, suggesting that these compounds may also inhibit the development of adenomas to adenocarcinomas in lung. In this study, the chemopreventive activity of phenethyl isothiocyanate and sulforaphane and their N-acetylcysteine conjugates during progression of lung adenomas to malignant tumors was investigated in A/J mice. Mice were divided into 14 groups and treated with a mixture of 3 Mmol benzo(a)pyrene [B(a)P] and 3 Mmol 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) given by gavage once weekly for 8 weeks. Twenty weeks after the beginning of carcinogen administration, a total of 20 mice in the treatment groups were sacrificed with an average yield of 7.3 F 4.5 lung adenomas per mouse. The remaining mice in each group were fed diets containing phenethyl isothiocyanate (3 and 1.5 mmol/kg diet), sulforaphane (3 and 1.5 mmol/kg diet), phenethyl isothiocyanate-N-acetylcysteine (8 and 4 mmol/kg diet), sulforaphane-N-acetylcysteine (8 and 4 mmol/kg diet) during weeks 21 to 42. Four mice in each of the high-dose treatment groups were sacrificed during weeks 28 and 36 and the bioassay was terminated during week 42; lung tissues were harvested for histopathologic examination of tumors and for cell proliferation (proliferating cell nuclear antigen) and apoptosis (caspase-3) assays using immunohistochemical staining. At termination, the incidence of adenocarcinoma in the 3 mmol/kg diet phenethyl isothiocyanate group and 8 mmol/kg diet phenethyl isothiocyanate-N-acetylcysteine group was reduced to 19% and 13%, respectively, compared with 42% in the carcinogen-treated control group. At the lower doses, phenethyl isothiocyanate and its N-acetylcysteine conjugate also inhibited the incidences of lung adenocarcinoma, however, the decreases were not statistically significant. The lung tumor incidences in groups treated with sulforaphane-N-acetylcysteine in the diet were also significantly reduced to 11% or 16%. Furthermore, the malignant lung tumor multiplicity was significantly reduced from 1.0 tumor/ mouse in the carcinogen-treated control group to 0.3 in the sulforaphane low-dose group, 0.3 and 0.4 in the two sulforaphane-N-acetylcysteine groups, and 0.4 in the phenethyl isothiocyanate high-dose group. The malignant tumor multiplicities in other treatment groups were also reduced (0.5-0.8 tumors/mouse), but not significantly. Unlike lung adenocarcinomas, both incidences and multiplicities of lung adenomas were not much affected by treatment with isothiocyanates or their conjugates. Immunohistochemical examination of the lung tumors from all time points indicated that significant reduction in proliferating cell nuclear antigen and induction...