Noradrenergic Regulation of Cognitive Flexibility: No Effects of Stress, Transcutaneous Vagus Nerve Stimulation, and Atomoxetine on Task-switching in Humans.

Cognitive flexibility allows us to adaptively switch between different responsibilities in important domains of our daily life. Previous work has elucidated the neurochemical basis underlying the ability to switch responses to a previously nonreinforced exemplar and to switch between attentional sets. However, the role of neuromodulators in task switching, the ability to rapidly switch between two or more cognitive tasks afforded by the same stimuli, is still poorly understood. We attempted to fill this gap by manipulating norepinephrine levels using stress manipulation (Study 1a, n = 48; between-group design), transcutaneous vagus nerve stimulation at two different intensities (Study 1b, n = 48; sham-controlled between-group design), and pharmacological manipulation (Study 2, n = 24; double-blind crossover design), all of which increased salivary cortisol measures. Participants repeatedly switched between two cognitive tasks (classifying a digit as high/low [Task 1] or as odd/even [Task 2]), depending on the preceding cue. On each trial, a cue indicated the task to be performed. The cue-stimulus interval was varied to manipulate the time to prepare for the switch. Participants showed typical switch costs, which decreased with the time available for preparation. None of the manipulations modulated the size of the switch costs or the preparation effect, as supported by frequentist and Bayesian model comparisons. Task-switching performance reflects a complex mix of cognitive control and bottom-up dynamics of task-set representations. Our findings suggest that norepinephrine does not affect either of these aspects of cognitive flexibility.

Genomics of human aggression: current state of genome-wide studies and an automated systematic review tool.

There are substantial differences, or variation, between humans in aggression, with its molecular genetic basis mostly unknown. This review summarizes knowledge on the genetic contribution to variation in aggression with the following three foci: (1) a comprehensive overview of reviews on the genetics of human aggression, (2) a systematic review of genome-wide association studies (GWASs), and (3) an automated tool for the selection of literature based on supervised machine learning. The phenotype definition 'aggression' (or 'aggressive behaviour', or 'aggression-related traits') included anger, antisocial behaviour, conduct disorder, and oppositional defiant disorder. The literature search was performed in multiple databases, manually and using a novel automated selection tool, resulting in 18 reviews and 17 GWASs of aggression. Heritability estimates of aggression in children and adults are around 50%, with relatively small fluctuations around this estimate. In 17 GWASs, 817 variants were reported as suggestive (P ≤ 1.0E), including 10 significant associations (P ≤ 5.0E). Nominal associations (P ≤ 1E) were found in gene-based tests for genes involved in immune, endocrine, and nervous systems. Associations were not replicated across GWASs. A complete list of variants and their position in genes and chromosomes are available online. The automated literature search tool produced literature not found by regular search strategies. Aggression in humans is heritable, but its genetic basis remains to be uncovered. No sufficiently large GWASs have been carried out yet. With increases in sample size, we expect aggression to behave like other complex human traits for which GWAS has been successful.

Quantifying the contrast of the human locus coeruleus in vivo at 7 Tesla MRI.

The locus coeruleus is a small brainstem nucleus which contains neuromelanin cells and is involved in a number of cognitive functions such as attention, arousal and stress, as well as several neurological and psychiatric disorders. Locus coeruleus imaging in vivo is generally performed using a T1-weighted turbo spin echo MRI sequence at 3 Tesla (T). However, imaging at high magnetic field strength can increase the signal-to-noise ratio and offers the possibility of imaging at higher spatial resolution. Therefore, in the present study we explored the possibility of visualizing the locus coeruleus at 7T. To this end, twelve healthy volunteers participated in three scanning sessions: two with 3T MRI and one with 7T MRI. The volumes of the first 3T session were used to segment the locus coeruleus, whereas the volumes of the second 3T and the 7T session were used to quantify the contrast of the locus coeruleus with several reference regions across eight different structural sequences. The results indicate that several of the 7T sequences provide detectable contrast between the locus coeruleus and surrounding tissue. Of the tested sequences, a T1-weighted sequence with spectral presaturation inversion recovery (SPIR) seems the most promising method for visualizing the locus coeruleus at ultra-high field MRI. While there is insufficient evidence to prefer the 7T SPIR sequence over the 3T TSE sequence, the isotropic voxels at 7T are an important advantage when visualizing small structures such as the locus coeruleus.

In vivo visualization of the locus coeruleus in humans: quantifying the test-retest reliability.

The locus coeruleus (LC) is a brainstem nucleus involved in important cognitive functions. Recent developments in neuroimaging methods and scanning protocols have made it possible to visualize the human LC in vivo by utilizing a T1-weighted turbo spin echo (TSE) scan. Despite its frequent use and its application as a biomarker for tracking the progress of monoaminergic-related neurodegenerative diseases, no study to date has investigated the reproducibility and inter-observer variability of LC identification using this TSE scan sequence. In this paper, we aim to quantify the test-retest reliability of LC imaging by assessing stability of the TSE contrast of the LC across two independent scan sessions and by quantifying the intra- and inter-rater reliability of the TSE scan. Additionally, we created a probabilistic LC atlas which can facilitate the spatial localization of the LC in standardized (MNI) space. Seventeen healthy volunteers participated in two scanning sessions with a mean intersession interval of 2.8 months. We found that for intra-rater reliability the mean Dice coefficient ranged between 0.65 and 0.74, and inter-rater reliability ranged between 0.54 and 0.64, showing moderate reproducibility. The mean LC contrast was 13.9% (SD 3.8) and showed scan-rescan stability (ROI approach: ICC = 0.63; maximum intensity approach: ICC = 0.53). We conclude that localization and segmentation of the LC in vivo are a challenging but reliable enterprise although clinical or longitudinal studies should be carried out carefully.

Catecholaminergic Neuromodulation Shapes Intrinsic MRI Functional Connectivity in the Human Brain.

UNLABELLED: The brain commonly exhibits spontaneous (i.e., in the absence of a task) fluctuations in neural activity that are correlated across brain regions. It has been established that the spatial structure, or topography, of these intrinsic correlations is in part determined by the fixed anatomical connectivity between regions. However, it remains unclear which factors dynamically sculpt this topography as a function of brain state. Potential candidate factors are subcortical catecholaminergic neuromodulatory systems, such as the locus ceruleus-norepinephrine system, which send diffuse projections to most parts of the forebrain. Here, we systematically characterized the effects of endogenous central neuromodulation on correlated fluctuations during rest in the human brain. Using a double-blind placebo-controlled crossover design, we pharmacologically increased synaptic catecholamine levels by administering atomoxetine, an NE transporter blocker, and examined the effects on the strength and spatial structure of resting-state MRI functional connectivity. First, atomoxetine reduced the strength of inter-regional correlations across three levels of spatial organization, indicating that catecholamines reduce the strength of functional interactions during rest. Second, this modulatory effect on intrinsic correlations exhibited a substantial degree of spatial specificity: the decrease in functional connectivity showed an anterior-posterior gradient in the cortex, depended on the strength of baseline functional connectivity, and was strongest for connections between regions belonging to distinct resting-state networks. Thus, catecholamines reduce intrinsic correlations in a spatially heterogeneous fashion. We conclude that neuromodulation is an important factor shaping the topography of intrinsic functional connectivity. SIGNIFICANCE STATEMENT: The human brain shows spontaneous activity that is strongly correlated across brain regions. The factors that dynamically sculpt these inter-regional correlation patterns are poorly understood. Here, we test the hypothesis that they are shaped by the catecholaminergic neuromodulators norepinephrine and dopamine. We pharmacologically increased synaptic catecholamine levels and measured the resulting changes in intrinsic fMRI functional connectivity. At odds with common understanding of catecholamine function, we found (1) overall reduced inter-regional correlations across several levels of spatial organization; and (2) a remarkable spatial specificity of this modulatory effect. Our results identify norepinephrine and dopamine as important factors shaping intrinsic functional connectivity and advance our understanding of catecholamine function in the central nervous system.

The accessory stimulus effect is mediated by phasic arousal: A pupillometry study.

People usually respond faster to a visual stimulus when it is immediately preceded by a task-irrelevant, auditory accessory stimulus (AS). This AS effect occurs even in choice reaction time tasks, despite the fact that the AS carries no information about the correct response. Researchers often assume that the AS effect is mediated by a phasic arousal burst evoked by the AS, but direct evidence for that assumption is lacking. We conducted a pupillometry study to directly test the phasic arousal hypothesis. Participants carried out a demanding choice reaction time task with accessory stimuli occurring on 25% of the trials. Pupil diameter, a common index of arousal, was measured throughout the task. Standard analyses of task performance and pupil diameter showed that participants exhibited the typical AS effect, and that accessory stimuli evoked a reliable early pupil dilation on top of the more protracted dilation associated with the imperative stimulus. Moreover, regression analyses at the single-trial level showed that variation in reaction times on AS trials was selectively associated with pupil dilation during the early time window within which the AS had an effect, such that particularly large AS-evoked dilations were associated with especially fast responses. These results provide the first evidence that the AS effect is mediated by AS-evoked phasic arousal.

How Administration of the Beta-Blocker Propranolol Before Extinction can Prevent the Return of Fear.

Combining beta-blockers with exposure therapy has been advocated to reduce fear, yet experimental studies combining beta-blockers with memory reactivation have had contradictory results. We explored how beta-blockade might affect the course of safety learning and the subsequent return of fear in a double-blind placebo-controlled functional magnetic resonance imaging study in humans (N=46). A single dose of propranolol before extinction learning caused a loss of conditioned fear responses, and prevented the subsequent return of fear and decreased explicit memory for the fearful events in the absence of drug. Fear-related neural responses were persistently attenuated in the dorsal medial prefrontal cortex (dmPFC), increased in the hippocampus 24 h later, and correlated with individual behavioral indices of fear. Prediction error-related responses in the ventral striatum persisted during beta-blockade. We suggest that this pattern of results is most consistent with a model where beta-blockade can prevent the return of fear by (i) reducing retrieval of fear memory, via the dmPFC and (ii) increasing contextual safety learning, via the hippocampus. Our findings suggest that retrieval of fear memory and contextual safety learning form potential mnemonic target mechanisms to optimize exposure-based therapy with beta-blockers.

Transcutaneous Vagus Nerve Stimulation Enhances Post-error Slowing.

People tend to slow down after they commit an error, a phenomenon known as post-error slowing (PES). It has been proposed that slowing after negative feedback or unforeseen errors is linked to the activity of the locus coeruleus-norepinephrine (LC-NE) system, but there is little direct evidence for this hypothesis. Here, we assessed the causal role of the noradrenergic system in modulating PES by applying transcutaneous vagus nerve stimulation (tVNS), a new noninvasive and safe method to stimulate the vagus nerve and to increase NE concentrations in the brain. A single-blind, sham-controlled, between-group design was used to assess the effect of tVNS in healthy young volunteers (n = 40) during two cognitive tasks designed to measure PES. Results showed increased PES during active tVNS, as compared with sham stimulation. This effect was of similar magnitude for the two tasks. These findings provide evidence for an important role of the noradrenergic system in PES.

Noradrenergic and cholinergic effects on speed and sensitivity measures of phasic alerting.

An intense but task-irrelevant auditory accessory stimulus that is presented almost simultaneously with a visual imperative stimulus can reduce reaction times (RTs) to that stimulus. The information-processing locus and neural underpinnings underlying this phasic alerting effect are still poorly understood. The authors investigated a possible noradrenergic or cholinergic basis of the accessory stimulus effect in a double-blind pharmacological study (N = 18), in which healthy participants received a single dose of clonidine (an α2-adrenergic agonist), scopolamine (a muscarinic antagonist), and placebo in separate test sessions. A backward-masking procedure was used to examine, for the first time, the effect of accessory stimuli on perceptual sensitivity. The authors found that accessory stimuli enhanced perceptual sensitivity and decreased RTs to target stimuli, consistent with a recent hypothesis that phasic alerting speeds up stimulus encoding. In contrast to the authors' expectations, clonidine increased the accessory stimulus effect, a finding that seems at odds with earlier proposals that phasic alerting effects are mediated by a phasic noradrenergic response. Furthermore, the accessory stimulus effect was modulated to a similar extent by clonidine and scopolamine, suggesting that the effect of clonidine was not specific to the noradrenergic system. The results instead suggest that clonidine and scopolamine decrease general alertness and that these drug-related reductions in alertness yield room for compensatory performance improvements by phasic alerting.

Validity, reliability, and feasibility of clinical staging scales in dementia: a systematic review.

New staging systems of dementia require adaptation of disease management programs and adequate staging instruments. Therefore, we systematically reviewed the literature on validity and reliability of clinically applicable, multidomain, and dementia staging instruments. A total of 23 articles describing 12 staging instruments were identified (N = 6109 participants, age 65-87). Reliability was studied in most (91%) of the articles and was judged moderate to good. Approximately 78% of the articles evaluated concurrent validity, which was good to very good, while discriminant validity was assessed in only 25%. The scales can be applied in ±15 minutes. Clinical Dementia Rating (CDR), Global Deterioration scale (GDS), and Functional Assessment Staging (FAST) have been monitored on reliability and validity, and the CDR currently is the best-evidenced scale, also studied in international perspective, and is available in 14 languages. Taking into account the increasing differentiation of Alzheimer's disease in preclinical and predementia stages, there is an urgent need for global rating scales to be refined as well.