Subjective Uncontrollability over Aversive Events Reduces Working Memory Performance and Related Large-Scale Network Interactions.

Lack of control over significant events may induce a state of learned helplessness that is characterized by cognitive, motivational, and affective deficits. Although highly relevant in the pathogenesis of several mental disorders, the extent of the cognitive deficits induced by experiences of uncontrollability and the neural mechanisms underlying such deficits in humans remain poorly understood. Using functional magnetic resonance imaging (fMRI), we tested here whether uncontrollability over aversive events impairs subsequent working memory performance and, if so, which neural processes are involved in such deficits. We assessed working memory and the involved neurocircuitry in the MRI scanner before and after participants underwent a task in which they could either learn to avoid electric shocks or had no instrumental control over shocks. Our results show that subjective, but not objective, uncontrollability over aversive events impaired working memory performance. This impact of subjective uncontrollability was linked to altered prefrontal and parahippocampal activities and connectivity as well as decreased crosstalk between frontoparietal executive and salience networks. Our findings show that the perceived uncontrollability over aversive events, rather than the aversive events themselves or the actual, objective control over them, disrupts subsequent working memory processes, most likely through altered crosstalk between prefrontal, temporal, and parietal areas.

Fear Without Context: Acute Stress Modulates the Balance of Cue-Dependent and Contextual Fear Learning.

During a threatening encounter, people can learn to associate the aversive event with a discrete preceding cue or with the context in which the event took place, corresponding to cue-dependent and context-dependent fear conditioning, respectively. Which of these forms of fear learning prevails has critical implications for fear-related psychopathology. We tested here whether acute stress may modulate the balance of cue-dependent and contextual fear learning. Participants (N = 72) underwent a stress or control manipulation 30 min before they completed a fear-learning task in a virtual environment that allowed both cued and contextual fear learning. Results showed equally strong cue- and context-dependent fear conditioning in the control group. Stress, however, abolished contextual fear learning, which was directly correlated with the activity of the stress hormone cortisol, and made cue-dependent fear more resistant to extinction. These results are the first to show that stress favors cue-dependent over contextual fear learning.

Case Report: Plasticity in Central Sensory Finger Representation and Touch Perception After Microsurgical Reconstruction of Infraclavicular Brachial Plexus Injury.

After brachial plexus injury (BPI), early microsurgery aims at facilitating reconnection of the severed peripheral nerves with their orphan muscles and sensory receptors and thereby reestablishing communication with the brain. In order to investigate this sensory recovery, here we combined functional magnetic resonance imaging (fMRI) and tactile psychophysics in a patient who suffered a sharp, incomplete amputation of the dominant hand at the axilla level. To determine somatosensory detection and discomfort thresholds as well as sensory accuracy for fingers of both the intact and affected hand, we used electrotactile stimulation in the framework of a mislocalization test. Additionally, tactile stimulation was performed in the MRI scanner in order to determine the cortical organization of the possibly affected primary somatosensory cortex. The patient was able to detect electrotactile stimulation in 4 of the 5 fingertips (D1, D2, D4, D5), and in the middle phalanx in D3 indicating some innervation. The detection and discomfort threshold were considerably higher at the affected side than at the intact side, with higher detection and discomfort thresholds for the affected side. The discrimination accuracy was rather low at the affected side, with stimulation of D1/D2/D3/D4/D5 eliciting most commonly a sensation at D4/D1/D3/D2/D5, respectively. The neuroimaging data showed a mediolateral succession from D2 to D5 to D1 to D4 (no activation was observed for D3). These results indicate a successful regrowth of the peripheral nerve fibers from the axilla to four fingertips. The data suggest that some of the fibers have switched location in the process and there is a beginning of cortical reorganization in the primary somatosensory cortex, possibly resulting from a re-education of the brain due to conflicting information (touch vs. vision).

Cognitive performance shows domain specific associations with regional cortical thickness in multiple sclerosis.

Multiple Sclerosis (MS) patients often suffer from significant cognitive impairment. Earlier research has shown relationships between regional cortical atrophy and cognitive deterioration. However, due to a large number of neuropsychological assessments and a heterogenous pattern of cognitive deficits in MS patients, reported associations patterns are also heterogenous. Using an extensive neuropsychological battery of 23 different tasks, we explored domain (attention/information processing, memory, spatial processing, executive functioning) and task-specific associations with regional cortical thickness in a representative sample of MS patients (N = 97). Cortical regions associated with multiple cognitive tasks in the left hemisphere were predominantly located in the inferior insula (attention p < 0.001, memory p = 0.047, spatial processing p = 0.004, executive functioning p = 0.037), the gyrus frontalis superior (attention p = 0.015, memory p = 0.037, spatial processing p = 0.033, executive functioning p = 0.017) and temporal medial (attention p < 0.001, memory two clusters p = 0.016 and p < 0.001, executive functioning p = 0.016). In the right hemisphere, we detected the strongest association in the sulcus interparietalis with five cluster (attention SDMT p = 0.003 and TAP_DA p < 0.001; memory Rey recall p = 0.013 and VLMT verbal learning p = 0.016; spatial processing Rey copy p < 0.001). We replicated parts of our results in an independent sample of 30 mildly disabled MS patients. Moreover, comparisons to 29 healthy controls showed that the regional associations seemed to represent rather pathophysiological dependency than a physiological one. We believe that our results may prove useful in diagnosis and rehabilitation of cognitive impairments and may serve as guidance in future magnetic resonance imaging (MRI) studies.

How representative are neuroimaging samples? Large-scale evidence for trait anxiety differences between fMRI and behaviour-only research participants.

Over the past three decades, functional magnetic resonance imaging (fMRI) has become crucial to study how cognitive processes are implemented in the human brain. However, the question of whether participants recruited into fMRI studies differ from participants recruited into other study contexts has received little to no attention. This is particularly pertinent when effects fail to generalize across study contexts: for example, a behavioural effect discovered in a non-imaging context not replicating in a neuroimaging environment. Here, we tested the hypothesis, motivated by preliminary findings (N = 272), that fMRI participants differ from behaviour-only participants on one fundamental individual difference variable: trait anxiety. Analysing trait anxiety scores and possible confounding variables from healthy volunteers across multiple institutions (N = 3317), we found robust support for lower trait anxiety in fMRI study participants, consistent with a sampling or self-selection bias. The bias was larger in studies that relied on phone screening (compared with full in-person psychiatric screening), recruited at least partly from convenience samples (compared with community samples), and in pharmacology studies. Our findings highlight the need for surveying trait anxiety at recruitment and for appropriate screening procedures or sampling strategies to mitigate this bias.

Dissociable neural signatures of passive extinction and instrumental control over threatening events.

Aberrant fear learning processes are assumed to be a key factor in the pathogenesis of anxiety disorders. Thus, effective behavioral interventions to reduce dysfunctional fear responding are needed. Beyond passive extinction learning, instrumental control over threatening events is thought to diminish fear. However, the neural mechanisms underlying instrumental control-and to what extent these differ from extinction-are not well understood. We therefore contrasted the neural signatures of instrumental control and passive extinction using an aversive learning task, relative to a control condition. Participants (n = 64) could either learn to exert instrumental control over electric shocks, received a yoked number and sequence of shocks without instrumental control or did not receive any shocks. While both passive extinction and instrumental control reduced threat-related skin conductance responses (SCRs) relative to pre-extinction/control, instrumental control resulted in a significantly more pronounced decrease of SCRs. Instrumental control was further linked to decreased striatal activation and increased cross talk of the ventromedial prefrontal cortex (vmPFC) with the amygdala, whereas passive extinction was associated with increased vmPFC activation. Our findings demonstrate that instrumental learning processes may shape Pavlovian fear responses and that the neural underpinnings of instrumental control are critically distinct from those of passive extinction learning.

(Lack of) Effects of noradrenergic stimulation on human working memory performance.

RATIONALE: Working memory depends on prefrontal cortex functioning, which is particularly sensitive to levels of noradrenaline. Studies in non-human primates have shown that modest levels of noradrenaline improve working memory, and that higher levels of noradrenaline impair working memory performance. However, research in humans provided inconsistent findings concerning noradrenergic effects on working memory. OBJECTIVE: The present study aimed at assessing dose-dependent effects of yohimbine, an alpha-2 adrenoceptor antagonist, on working memory performance in healthy humans. We further aimed to explore a potential interactive effect between noradrenergic arousal and lack of control over aversive events on working memory performance. METHODS: We used a double-blind, fully crossed, placebo-controlled, between-subject design. Participants (N = 121) performed an adaptive n-back task before and after oral administration of either a placebo, 20 mg, or 40 mg yohimbine and a manipulation of controllability, during which participants could either learn to avoid electric shocks (controllability groups), had no instrumental control over shock administration (uncontrollability groups), or did not receive any shocks (no-shock control group). RESULTS: While no significant results of noradrenergic stimulation through yohimbine were obtained using conventional frequentist analyses, additional Bayesian analyses provided strong evidence for the absence of an association between pharmacological treatment and working memory performance. We further observed no effect of controllability and no interaction between noradrenergic stimulation and the manipulation of controllability. CONCLUSIONS: Our results suggest that noradrenergic stimulation through yohimbine does not affect (non-spatial) working memory in healthy human participants.

Similar Expectation Effects for Immediate and Delayed Stimulus Repetitions.

A prior cue or stimulus allows prediction of the future occurrence of an event and therefore reduces the associated neural activity in several cortical areas. This phenomenon is labeled expectation suppression (ES) and has recently been shown to be independent of the generally observed effects of stimulus repetitions (repetition suppression, RS: reduced neuronal response after the repetition of a given stimulus). While it has been shown that attentional cueing is strongly affected by the length of the cue-target delay, we have no information on the temporal dynamics of expectation effects, as in most prior studies of ES the delay between the predictive cue and the target (i.e., the inter-stimulus interval, ISI) was in the range of a few hundred milliseconds. Hence, we presented participants with pairs of faces where the first face could be used to build expectations regarding the second one, in the sense that one gender indicated repetition of the same face while the other gender predicted the occurrence of novel faces. In addition, we presented the stimulus pairs with two different ISIs (0.5 s for Immediate and 1.75 or 3.75 s for Delayed ISIs). We found significant RS as well as a reduced response for correctly predicted when compared to surprising trials in the fusiform face area. Importantly, the effects of repetition and expectation were both independent of the length of the ISI period. This implies that Immediate and Delayed cue-target stimulus arrangements lead to similar expectation effects in the face sensitive-visual cortex.

Reduced rich-club connectivity is related to disability in primary progressive MS.

OBJECTIVE: To investigate whether the structural connectivity of the brain's rich-club organization is altered in patients with primary progressive MS and whether such changes to this fundamental network feature are associated with disability measures. METHODS: We recruited 37 patients with primary progressive MS and 21 healthy controls for an observational cohort study. Structural connectomes were reconstructed based on diffusion-weighted imaging data using probabilistic tractography and analyzed with graph theory. RESULTS: We observed the same topological organization of brain networks in patients and controls. Consistent with the originally defined rich-club regions, we identified superior frontal, precuneus, superior parietal, and insular cortex in both hemispheres as rich-club nodes. Connectivity within the rich club was significantly reduced in patients with MS (p = 0.039). The extent of reduced rich-club connectivity correlated with clinical measurements of mobility (Kendall rank correlation coefficient τ = -0.20, p = 0.047), hand function (τ = -0.26, p = 0.014), and information processing speed (τ = -0.20, p = 0.049). CONCLUSIONS: In patients with primary progressive MS, the fundamental organization of the structural connectome in rich-club and peripheral nodes was preserved and did not differ from healthy controls. The proportion of rich-club connections was altered and correlated with disability measures. Thus, the rich-club organization of the brain may be a promising network phenotype for understanding the patterns and mechanisms of neurodegeneration in MS.