Role of White Matter Microstructure in Impulsive Behavior.

OBJECTIVE: Increased impulsivity is a hallmark trait of some neuropsychiatric illnesses, including addiction, traumatic brain injury, and externalizing disorders. The authors hypothesized that altered cerebral white matter microstructure may also underwrite normal individual variability in impulsive behaviors and tested this among healthy individuals. METHODS: Impulsivity and diffusion tensor imaging (DTI) data were collected from 74 healthy adults (32 women; mean age=36.6 years [SD=13.6]). Impulsivity was evaluated using the Barratt Impulsiveness Scale-11, which provides a total score and scores for three subdomains: attentional, motor, and nonplanning impulsiveness. DTI was processed using the Enhancing Neuro Imaging Genetics Through Meta Analysis-DTI analysis pipeline to measure whole-brain and regional white matter fractional anisotropy (FA) values in 24 tracts. RESULTS: Whole-brain total average FA was inversely correlated with motor impulsiveness (r=-0.32, p=0.007) and positively correlated with nonplanning impulsiveness (r=0.29, p=0.02); these correlations were significant after correction for multiple comparisons. Additional significant correlations were observed for motor impulsiveness and regional FA values for the corticospinal tract (r=-0.29, p=0.01) and for nonplanning impulsiveness and regional FA values for the superior fronto-occipital fasciculus (r=0.32, p=0.008). CONCLUSIONS: These results provide initial evidence that the motor and nonplanning subdomains of impulsive behavior are linked to specific white matter microstructural connectivity, supporting the notion that impulsivity is in part a network-based construct involving white matter microstructural integrity among otherwise healthy populations.

Association of working memory and elevated overnight urinary norepinephrine in patients with schizophrenia.

INTRODUCTION: Norepinephrine has both central and peripheral origins and is known to influence cognitive processes in attention, learning, and working memory, but the research regarding the impact of norepinephrine on cognition in schizophrenia remains sparse, and mainly focuses on centrally regulated noradrenergic effects. This study examined the relationship between cumulative overnight norepinephrine levels in the urine and working memory in patients with schizophrenia and healthy controls. METHODS: Urinary catecholamines were collected overnight in patients with schizophrenia (n = 75) and healthy controls (n = 33). Working memory was assessed using the digit sequencing task. RESULTS: Patients showed significantly higher average levels of overnight norepinephrine (t(103.10) = -3.16, p = 0.002) and reduced working memory performance (t(90) = 3.87, p = 0.001) compared with healthy individuals. There was a significant negative correlation between norepinephrine and working memory in patients (r = -0.38, p = 0.005), but not in controls (r = 0.08, p = 0.67). After controlling for age, sex, antipsychotic medications, and serotonin-norepinephrine reuptake inhibitor-based antidepressants, the correlation remained significant (r = -0.41, p = 0.004). CONCLUSIONS: High peripheral overnight levels of urinary norepinephrine are associated with lower working memory performance in patients with schizophrenia. These results parallel previous studies suggesting that high levels of central norepinephrine may result in working memory impairments. As norepinephrine rapidly breaks down and usually does not pass through the blood-brain barrier, the potential effect of peripheral cumulative norepinephrine on working memory is intriguing, and needs to be further investigated.

Genetic versus stress and mood determinants of sleep in the Amish.

Sleep is essential to the human brain and is regulated by genetics with many features conserved across species. Sleep is also influenced by health and environmental factors; identifying replicable genetic variants contributing to sleep may require accounting for these factors. We examined how stress and mood disorder contribute to sleep and impact its heritability. Our sample included 326 Amish/Mennonite individuals with a lifestyle with limited technological interferences with sleep. Sleep measures included Pittsburgh Sleep Quality Index (PSQI), bedtime, wake time, and time to sleep onset. Current stress level, cumulative life stressors, and mood disorder were also evaluated. We estimated the heritability of sleep features and examined the impact of current stress, lifetime stress, mood diagnosis on sleep quality. The results showed current stress, lifetime stress, and mood disorder were independently associated with PSQI score (p < .05). Heritability of PSQI was low (0-0.23) before and after accounting for stress and mood. Bedtime, wake time, and minutes to sleep time did show significant heritability at 0.44, 0.42, and 0.29. However, after adjusting for shared environment, only heritability of wake time remained significant. Sleep is affected by environmental stress and mental health factors even in a society with limited technological interference with sleep. Wake time may be a more biological marker of sleep as compared to the evening measures which are more influenced by other household members. Accounting for nongenetic and partially genetic determinants of sleep particularly stress and mood disorder is likely important for improving the precision of genetic studies of sleep.

A nonapoptotic endothelial barrier-protective role for caspase-3.

Noncanonical roles for caspase-3 are emerging in the fields of cancer and developmental biology. However, little is known of nonapoptotic functions of caspase-3 in most cell types. We have recently demonstrated a disassociation between caspase-3 activation and execution of apoptosis with accompanying cytoplasmic caspase-3 sequestration and preserved endothelial barrier function. Therefore, we tested the hypothesis that nonapoptotic caspase-3 activation promotes endothelial barrier integrity. Human lung microvascular endothelial cells were exposed to thrombin, a nonapoptotic stimulus, and endothelial barrier function was assessed using electric cell-substrate impedance sensing. Actin cytoskeletal rearrangement and paracellular gap formation were assessed using phalloidin staining. Cell stiffness was evaluated using magnetic twisting cytometry. In addition, cell lysates were harvested for protein analyses. Caspase-3 was inhibited pharmacologically with pan-caspase and a caspase-3-specific inhibitor. Molecular inhibition of caspase-3 was achieved using RNA interference. Cells exposed to thrombin exhibited a cytoplasmic activation of caspase-3 with transient and nonapoptotic decrease in endothelial barrier function as measured by a drop in electrical resistance followed by a rapid recovery. Inhibition of caspases led to a more pronounced and rapid drop in thrombin-induced endothelial barrier function, accompanied by increased endothelial cell stiffness and paracellular gaps. Caspase-3-specific inhibition and caspase-3 knockdown both resulted in more pronounced thrombin-induced endothelial barrier disruption. Taken together, our results suggest cytoplasmic caspase-3 has nonapoptotic functions in human endothelium and can promote endothelial barrier integrity.