We describe an fMRI experiment examining the functional connectivity (FC) between regions of the brain associated with semantic and phonological processing. We wished to explore whether L-Dopa administration affects the interaction between language network components in semantic and phonological categorization tasks, as revealed by FC. We hypothesized that L-Dopa would decrease FC due to restriction of the semantic network. During two test sessions (placebo and L-Dopa) each participant performed two fMRI runs, involving phonological and semantic processing. A number of brain regions commonly activated by the two tasks were chosen: left inferior frontal, left posterior temporal and left fusiform gyri, and left parietal cortex. FC was calculated and further analyzed for effects of either the drug or task. No drug effect was found. A significant main effect for task was found, with a greater average correlation for the phonological task than for the semantic task. These findings suggest that language areas are activated in a more synchronous manner for phonological tasks than for semantic tasks. This may relate to the fact that phonological tasks are mediated to a greater extent within language areas, whereas semantic tasks likely require greater interaction outside of the language areas. Alternatively, this may be due to differences in the attentional requirements of the two tasks.

Objective

To perform a pilot study to examine a range of cognitive flexibility tasks early in cocaine withdrawal.

Background

Previous neuropsychological investigations of cocaine withdrawal have conflicted regarding whether impaired cognitive flexibility occurs. However, most studies have examined patients later in withdrawal. Anxiety and yohimbine-induced panic are greatest early in withdrawal, and both anxiety and increased noradrenergic tone can impair cognitive flexibility.

Method

Twelve patients acutely withdrawing from cocaine were compared with gender-, age-, and estimated premorbid intelligence–matched control subjects on tests of cognitive flexibility as well as verbal fluency, verbal memory, spatial memory, and attention.

Results

As predicted, impairments were found on the cognitive flexibility tasks. Impairments also were present in verbal fluency and verbal memory but not spatial memory or attention.

Conclusions

We propose that the cognitive flexibility impairment may relate to the increased noradrenergic activation recently described in cocaine withdrawal. Impairments on verbal tasks may also relate to an impaired flexibility in the search of semantic networks. Further research will explore the effects of pharmacologic manipulation of the noradrenergic system on cognition in acute withdrawal. Recently, propranolol has been shown to benefit patients in cocaine withdrawal. Further research will explore whether impaired cognitive flexibility related to altered noradrenergic tone could serve as a mechanism for this treatment response.

Objective

Previous research on the physical health consequences of childhood abuse and other adversities has been based on data from young or middle-aged adults. This study addressed the question of whether childhood abuse and other adversities have lasting, detectable consequences for inflammation and cell aging late in life, and whether the effects are large enough to be discernible beyond that of a major chronic stressor, dementia family caregiving.

Method

In this community sample of 132 healthy older adults (mean age = 69.70, SD=10.14), including 58 dementia family caregivers and 74 noncaregivers, blood samples were analyzed for interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF-α), and telomere length, a measure of cell aging. Depressive symptoms were assessed by the Center for Epidemiological Studies Depression Scale (CES-D).

Results

After controlling for age, caregiving status, gender, body mass index, exercise, and sleep, the presence of multiple childhood adversities was related to both heightened IL-6 (.37 ± .03 vs. .44 ± .03 log10 pg/mL) and shorter telomeres (6.51 ± .17 vs. 5.87 ± .20 Kb), compared to the absence of adversity; the telomere difference could translate into a 7–15 year difference in lifespan. Abuse was associated with heightened IL-6 and TNF-α levels, and, for TNF-α, this relationship was magnified in caregivers compared to controls. Moreover, abuse and caregiving status were significantly and independently associated with higher levels of depressive symptoms.

Conclusions

Adverse childhood events are related to continued vulnerability among older adults, enhancing the impact of chronic stressors. Childhood adversities cast a very long shadow.

Several studies suggest that prenatal stress is a possible risk factor in the development of autism spectrum disorders. However, many children exposed to stress prenatally are born healthy and develop typically, suggesting that other factors must contribute to autism. Genes that contribute to stress reactivity may, therefore, exacerbate prenatal stress-mediated behavioral changes in the adult offspring. One candidate gene linked to increased stress reactivity encodes the serotonin transporter. Specifically, an insertion/deletion (long/short allele) polymorphism upstream of the serotonin transporter gene correlates with differential expression and function of the serotonin transporter and a heightened response to stressors. Heterozygous serotonin transporter knockout mice show reductions in serotonin transporter expression similar to the human short polymorphism. In this study, the role of prenatal stress and maternal serotonin transporter genotype were assessed in mice to determine whether their combined effect produces reductions in social behavior in the adult offspring. Pregnant serotonin transporter heterozygous knockout and wild-type dams were placed in either a control condition or subjected to chronic variable stress. The adult offspring were subsequently assessed for social interaction and anxiety using a 3-chamber social approach task, ultrasonic vocalization detection, elevated-plus maze and an open field task. Results indicated that prenatal stress and reduced serotonin transporter expression of the dam may have the combined effect of producing changes in social interaction and social interest in the offspring consistent with those observed in autism spectrum disorder. This data indicates a possible combined effect of maternal serotonin transporter genotype and prenatal stress contributing to the production of autistic-like behaviors in offspring.

L-dopa, which is a precursor for dopamine, acts to amplify strong signals, and dampen weak signals as suggested by previous studies. The effect of L-dopa has been demonstrated in language studies, suggesting restriction of the semantic network. In this study, we aimed to examine the effect of L-dopa on language processing with fMRI using Independent Component Analysis (ICA). Two types of language tasks (phonological and semantic categorization tasks) were tested under two drug conditions (placebo and L-dopa) in 16 healthy subjects. Probabilistic ICA (PICA), part of FSL, was implemented to generate Independent Components (IC) for each subject for the four conditions and the ICs were classified into task-relevant source groups by a correlation threshold criterion. Our key findings include: (i) The highly task-relevant brain regions including the Left Inferior Frontal Gyrus (LIFG), Left Fusiform Gyrus (LFUS), Left Parietal lobe (LPAR) and Superior Temporal Gyrus (STG) were activated with both L-dopa and placebo for both tasks, and (ii) as compared to placebo, L-dopa was associated with increased activity in posterior regions, including the superior temporal area (BA 22), and decreased activity in the thalamus (pulvinar) and inferior frontal gyrus (BA 11/47) for both tasks. These results raise the possibility that L-dopa may exert an indirect effect on posterior regions mediated by the thalamus (pulvinar).

A decrease in interaction between brain regions is observed in individuals with autism spectrum disorder (ASD), which is believed to be related to restricted neural network access in ASD. Propranolol, a beta-adrenergic antagonist, has revealed benefit during performance of tasks involving flexibility of access to networks, a benefit also seen in ASD. Our goal was to determine the effect of propranolol on functional connectivity in ASD during a verbal decision making task as compared to nadolol, thereby accounting for the potential spurious fMRI effects due to peripheral hemodynamic effects of propranolol. Ten ASD subjects underwent fMRI scans after administration of placebo, propranolol or nadolol, while performing a phonological decision making task. Comparison of functional connectivity between pre-defined ROI-pairs revealed a significant increase with propranolol compared to nadolol, suggesting a potential imaging marker for the cognitive effects of propranolol in ASD.

Objective

Our purpose is to examine the effect of D2/D3 agonists on semantic priming.

Background

Dopamine appears to restrict the semantic network in semantic priming. However, which dopamine receptor mediates this effect is unknown.

Methods

To better understand the receptors involved, 15 nondemented Parkinson disease patients performed a lexical decision task before and one hour after they received their first morning medication dose, eight after D2 and D3 agonists pramipexole or ropinirole, and seven after levodopa. Semantic priming was measured for closely, distantly, and unrelated word pairs across a stimulus onset asynchrony of 700 ms.

Results

Closely related pairs were recognized significantly faster than unrelated and distantly related pairs before the drugs, as well as after D2/D3 agents. After levodopa, closely related pairs remained faster than unrelated, but not faster than distantly related pairs.

Conclusion

This suggests that D1 receptors may mediate the dopaminergic modulation of semantic priming.

With recent advances in understanding of the neuroscience of risk taking, attention is now turning to genetic factors that may contribute to individual heterogeneity in risk attitudes. In this paper we test for genetic associations with risk attitude measures derived from both the psychology and economics literature. To develop a long-term prospective study, we first evaluate both types of risk attitudes and find that the economic and psychological measures are poorly correlated, suggesting that different genetic factors may underlie human response to risk faced in different behavioral domains. We then examine polymorphisms in a spectrum of candidate genes that affect neurotransmitter systems influencing dopamine regulation or are thought to be associated with risk attitudes or impulsive disorders. Analysis of the genotyping data identified two single nucleotide polymorphisms (SNPs) in the gene encoding the alpha 4 nicotine receptor (CHRNA4, rs4603829 and rs4522666) that are significantly associated with harm avoidance, a risk attitude measurement drawn from the psychology literature. Novelty seeking, another risk attitude measure from the psychology literature, is associated with several COMT (catechol-O-methyl transferase) SNPs while economic risk attitude measures are associated with several VMAT2 (vesicular monoamine transporter) SNPs, but the significance of these associations did not withstand statistical adjustment for multiple testing and requires larger cohorts. These exploratory results provide a starting point for understanding the genetic basis of risk attitudes by considering the range of methods available for measuring risk attitudes and by searching beyond the traditional direct focus on dopamine and serotonin receptor and transporter genes.

Previous research suggests that the noradrenergic system modulates certain types of cognitive flexibility. This study compared various doses of beta-adrenergic antagonists for their effect on cognitive flexibility in problem solving, and how task difficulty interacts with this effect, as well as the effect of beta-adrenergic antagonists on other tasks. Anagram task performance was compared in 72 subjects using a within-subject design for propranolol at 20mg, 40mg, 60mg, and placebo in a double-blinded manner, and the effects of subject ability and task difficulty were examined. We also examined the effect of the 40mg propranolol dose on a range of other tasks. Overall, more anagram problems were solved while on propranolol 40mg than on placebo. Subjects least able to solve the problems benefited significantly from 40mg of propranolol. Also, for all subjects the most difficult problems were solved more quickly with propranolol 40mg than placebo. Benefits were also seen for word fluency and backward digit span. Therefore, noradrenergic modulation of cognitive flexibility is affected by how much difficulty the subject is encountering when searching for the solution, a pattern consistent with what might be expected in an effect on the search of the semantic and associative network.

Caregivers of Alzheimer’s disease patients endure chronic stress associated with a decline of immune function. To assess the psychological and immunological changes of caregivers, we compared depressive symptoms, PBMC composition, in vitro activation-induced proliferation and cytokine production, and telomere length and telomerase activity of 82 individuals (41 caregivers and 41 age- and gender-matched controls). We found depressive symptoms were significantly higher in caregivers than in controls (p < 0.001). Correspondingly, caregivers had significantly lower T cell proliferation but higher production of immune-regulatory cytokines (TNF-α and IL-10) than controls in response to stimulation in vitro. We examined the impact of these changes on cellular replicative lifespan and found that caregivers had significantly shorter telomere lengths in PBMC than controls (6.2 and 6.4 kb, respectively, p < 0.05) with similar shortening in isolated T cells and monocytes and that this telomere attrition in caregivers was not due to an increase of shorter telomere possessing T cell subsets in PBMC. Finally, we showed that basal telomerase activity in PBMC and T cells was significantly higher in caregivers than in controls (p < 0.0001), pointing to an unsuccessful attempt of cells to compensate the excessive loss of telomeres in caregivers. These findings demonstrate that chronic stress is associated with altered T cell function and accelerated immune cell aging as suggested by excessive telomere loss.

A sub-dural surface microelectrode array designed to detect microfield evoked potentials has been developed. The device is comprised of an array of 350-micron square gold contacts, with bi-directional spacing of 150 microns, contained within a polyimide Kapton material. Cytotoxicity testing suggests that the device is suitable for use with animal and human patients. Implementation of the device in animal studies revealed that reliable evoked potentials could be acquired. Further work will be needed to determine how these microfield potentials, which demonstrate selectivity for one eye, relate to the distribution of the ocular dominance columns of the occipital cortex.