Continuous ASL perfusion fMRI investigation of higher cognition: Quantification of tonic CBF changes during sustained attention and working memory tasks

Arterial spin labeling (ASL) perfusion fMRI is an emerging method in clinical neuroimaging. Its non-invasiveness, absence of low frequency noise, and ability to quantify the absolute level of cerebral blood flow (CBF) make the method ideal for longitudinal designs or low frequency paradigms. Despite the usefulness in the study of cognitive dysfunctions in clinical populations, perfusion activation studies to date have been conducted for simple sensorimotor paradigms or with single-slice acquisition, mainly due to technical challenges. Using our recently developed amplitude-modulated continuous ASL (CASL) perfusion fMRI protocol, we assessed the feasibility of a higher level cognitive activation study in twelve healthy subjects. Taking advantage of the ASL noise properties, we were able to study tonic CBF changes during uninterrupted 6-min continuous performance of working memory and sustained attention tasks. For the visual sustained attention task, regional CBF increases (6–12 ml/100 g/min) were detected in the right middle frontal gyrus, the bilateral occipital gyri, and the anterior cingulate/medial frontal gyri. During the 2-back working memory task, significantly increased activations (7–11 ml/100 g/min) were found in the left inferior frontal/precentral gyri, the left inferior parietal lobule, the anterior cingulate/medial frontal gyri, and the left occipital gyrus. Locations of activated and deactivated areas largely concur with previous PET and BOLD fMRI studies utilizing similar paradigms. These results demonstrate that CASL perfusion fMRI can be successfully utilized for the investigation of the tonic CBF changes associated with high level cognitive operations. Increased applications of the method to the investigation of cognitively impaired populations are expected to follow

Neural Correlates of Post-Conventional Moral Reasoning: A Voxel-Based Morphometry Study

Going back to Kohlberg, moral development research affirms that people progress through different stages of moral reasoning as cognitive abilities mature. Individuals at a lower level of moral reasoning judge moral issues mainly based on self-interest (personal interests schema) or based on adherence to laws and rules (maintaining norms schema), whereas individuals at the post-conventional level judge moral issues based on deeper principles and shared ideals. However, the extent to which moral development is reflected in structural brain architecture remains unknown. To investigate this question, we used voxel-based morphometry and examined the brain structure in a sample of 67 Master of Business Administration (MBA) students. Subjects completed the Defining Issues Test (DIT-2) which measures moral development in terms of cognitive schema preference. Results demonstrate that subjects at the post-conventional level of moral reasoning were characterized by increased gray matter volume in the ventromedial prefrontal cortex and subgenual anterior cingulate cortex, compared with subjects at a lower level of moral reasoning. Our findings support an important role for both cognitive and emotional processes in moral reasoning and provide first evidence for individual differences in brain structure according to the stages of moral reasoning first proposed by Kohlberg decades ago

Moral Competence and Brain Connectivity: A Resting-State fMRI Study

Moral competence (MC) refers to the ability to apply certain moral orientations in a consistent and differentiated manner when judging moral issues. People greatly differ in terms of MC, however, little is known about how these differences are implemented in the brain. To investigate this question, we used functional magnetic resonance imaging and examined resting-state functional connectivity (RSFC) in n = 31 individuals with MC scores in the highest 15% of the population and n = 33 individuals with MC scores in the lowest 15%, selected from a large sample of 730 Master of Business Administration (MBA) students. Compared to individuals with lower MC, individuals with higher MC showed greater amygdala-ventromedial prefrontal connectivity, which may reflect better ability to cope with emotional conflicts elicited by moral dilemmas. Moreover, individuals with higher MC showed less inter-network connectivity between the amygdalar and fronto-parietal networks, suggesting a more independent operation of these networks. Our findings provide novel insights into how individual differences in moral judgment are associated with RSFC in brain circuits related to emotion processing and cognitive control

Baclofen-Induced Changes in the Resting Brain Modulate Smoking Cue Reactivity: A Double-blind Placebo-controlled Functional Magnetic Resonance Imaging Study in Cigarette Smokers

Objective: Smoking cue-(SC) elicited craving can lead to relapse in SC-vulnerable individuals. Thus, identifying treatments that target SC-elicited craving is a top research priority. Reduced drug cue neural activity is associated with recovery and is marked by a profile of greater tonic (resting) activation in executive control regions, and increased connectivity between executive and salience regions. Evidence suggests the GABA-B agonist baclofen can reduce drug cue-elicited neural activity, potentially through its actions on the resting brain. Based on the literature, we hypothesize that baclofen’s effects in the resting brain can predict its effects during SC exposure. Methods: In this longitudinal, double blind, placebo-controlled neuropharmacological study 43 non-abstinent, sated treatment-seeking cigarette smokers (63% male) participated in an fMRI resting-state scan and a SC-reactivity task prior to (T1) and 3 weeks following randomization (T2; baclofen: 80 mg/day; n = 21). Subjective craving reports were acquired before and after SC exposure to explicitly examine SC-induced craving. Results: Whole-brain full-factorial analysis revealed a group-by-time interaction with greater resting brain activation of the right dorsolateral prefrontal cortex (dlPFC) at T2 in the baclofen group (BAC) (pFWEcorr = 0.02), which was associated with reduced neural responses to SCs in key cue-reactive brain regions; the anterior ventral insula and ventromedial prefrontal cortex (pFWEcorr ＜ 0.01). BAC, but not the placebo group reported decreased SC-elicited craving (p = 0.02). Conclusion: Results suggest that baclofen mitigates the reward response to SCs through an increase in tonic activation of the dlPFC, an executive control region. Through these mechanisms, baclofen may offer SC-vulnerable smokers protection from SC-induced relapse

Effects of Badminton Expertise on Representational Momentum: A Combination of Cross-Sectional and Longitudinal Studies

Representational momentum (RM) has been found to be magnified in experts (e.g., sport players) with respect to both real and implied motion in expert-familiar domains. However, it remains unclear whether similar effects can be achieved in expert-unfamiliar domains, especially within the context of implied motion. To answer this question, we conducted two independent experiments using an implied motion paradigm and examined the expert effects of badminton training on RM in both adult and child players. In Experiment 1, we used a cross-sectional design and compared RM between adult professional badminton players and matched controls. The results revealed significantly enhanced RM for adult players, supporting the expert effect in expert-unfamiliar domains for implied motion. However, cross-sectional studies could not ascertain whether the observed expert effect was due to innate factors or expertise acquirement. Therefore, in Experiment 2, we used a longitudinal design and compared RM between two groups of child participants, naming child players who had enrolled professional badminton training program at a sports school and age-matched peer non-players who attended an ordinary primary school without sports training. Before training, there were no differences in RM among child players, their non-player peers, and adult non-players. However, after 4 years of badminton training, child players demonstrated significantly enhanced RM compared to themselves prior to training. The increased RM observed in both adult and child players suggests that badminton expertise modulates implied motion RM

Post-Conventional Moral Reasoning is Associated With Increased Ventral Striatal Activity at Rest and During Task

People vary considerably in moral reasoning. According to Kohlberg’s theory, individuals who reach the highest level of post-conventional moral reasoning judge moral issues based on deeper principles and shared ideals rather than self-interest or adherence to laws and rules. Recent research has suggested the involvement of the brain’s frontostriatal reward system in moral judgments and prosocial behaviors. However, it remains unknown whether moral reasoning level is associated with differences in reward system function. Here, we combined arterial spin labeling perfusion and blood oxygen level-dependent functional magnetic resonance imaging and measured frontostriatal reward system activity both at rest and during a sequential risky decision making task in a sample of 64 participants at different levels of moral reasoning. Compared to individuals at the pre-conventional and conventional level of moral reasoning, post-conventional individuals showed increased resting cerebral blood flow in the ventral striatum and ventromedial prefrontal cortex. Cerebral blood flow in these brain regions correlated with the degree of post-conventional thinking across groups. Post-conventional individuals also showed greater task-induced activation in the ventral striatum during risky decision making. These findings suggest that high-level post-conventional moral reasoning is associated with increased activity in the brain’s frontostriatal system, regardless of task-dependent or task-independent states

Two nights of recovery sleep restores hippocampal connectivity but not episodic memory after total sleep deprivation

Sleep deprivation significantly impairs a range of cognitive and brain function, particularly episodic memory and the underlying hippocampal function. However, it remains controversial whether one or two nights of recovery sleep following sleep deprivation fully restores brain and cognitive function. In this study, we used functional magnetic resonance imaging (fMRI) and examined the effects of two consecutive nights (20-hour time-in-bed) of recovery sleep on resting-state hippocampal connectivity and episodic memory deficits following one night of total sleep deprivation (TSD) in 39 healthy adults in a controlled in-laboratory protocol. TSD significantly reduced memory performance in a scene recognition task, impaired hippocampal connectivity to multiple prefrontal and default mode network regions, and disrupted the relationships between memory performance and hippocampal connectivity. Following TSD, two nights of recovery sleep restored hippocampal connectivity to baseline levels, but did not fully restore memory performance nor its associations with hippocampal connectivity. These findings suggest that more than two nights of recovery sleep are needed to fully restore memory function and hippocampal-memory associations after one night of total sleep loss

Gender Differences in Sleep Deprivation Effects on Risk and Inequality Aversion: Evidence from an Economic Experiment

Excessive working hours—even at night—are becoming increasingly common in our modern 24/7 society. The prefrontal cortex (PFC) is particularly vulnerable to the effects of sleep loss and, consequently, the specific behaviors subserved by the functional integrity of the PFC, such as risk-taking and pro-social behavior, may be affected significantly. This paper seeks to assess the effects of one night of sleep deprivation on subjects’ risk and social preferences, which are probably the most explored behavioral domains in the tradition of Experimental Economics. This novel cross-over study employs thirty-two university students (gender-balanced) participating to 2 counterbalanced laboratory sessions in which they perform standard risk and social preference elicitation protocols. One session was after one night of undisturbed sleep at home, and the other was after one night of sleep deprivation in the laboratory. Sleep deprivation causes increased sleepiness and decreased alertness in all subjects. After sleep loss males make riskier decisions compared to the rested condition, while females do the opposite. Females likewise show decreased inequity aversion after sleep deprivation. As for the relationship between cognitive ability and economic decisions, sleep deprived individuals with higher cognitive reflection show lower risk aversion and more altruistic behavior. These results show that one night of sleep deprivation alters economic behavior in a gender-sensitive way. Females’ reaction to sleep deprivation, characterized by reduced risky choices and increased egoism compared to males, may be related to intrinsic psychological gender differences, such as in the way men and women weigh up probabilities in their decision-making, and/or to the different neurofunctional substrate of their decision-making.The authors acknowledge financial support from the Spanish Ministry of Economic Competititveness (ECO2012-34928), Italian Ministry of University and Research MIUR (PRIN 20103S5RN3_002), Generalitat Valenciana (Research Projects Gruposo3/086), the Instituto Valenciano de Investigaciones Económicas (IVIE), and the Ministero della Salute (RF-2009-1528677)

Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure fl ux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defi ned as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (inmost higher eukaryotes and some protists such as Dictyostelium ) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the fi eld understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation it is imperative to delete or knock down more than one autophagy-related gene. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways so not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field