Elevated representational similarity of voluntary action and inhibition in Tourette syndrome.

Many people with Tourette syndrome are able to volitionally suppress tics, under certain circumstances. To understand better the neural mechanisms that underlie this ability, we used functional magnetic resonance neuroimaging to track regional brain activity during performance of an intentional inhibition task. On some trials, Tourette syndrome and comparison participants internally chose to make or withhold a motor action (a button press), while on other trials, they followed 'Go' and 'NoGo' instructions to make or withhold the same action. Using representational similarity analysis, a functional magnetic resonance neuroimaging multivariate pattern analysis technique, we assessed how Tourette syndrome and comparison participants differed in neural activity when choosing to make or to withhold an action, relative to externally cued responses on Go and NoGo trials. Analyses were pre-registered, and the data and code are publicly available. We considered similarity of action representations within regions implicated as critical to motor action release or inhibition and to symptom expression in Tourette syndrome, namely the pre-supplementary motor area, inferior frontal gyrus, insula, caudate nucleus and primary motor cortex. Strikingly, in the Tourette syndrome compared to the comparison group, neural activity within the pre-supplementary motor area displayed greater representational similarity across all action types. Within the pre-supplementary motor area, there was lower response-specific differentiation of activity relating to action and inhibition plans and to internally chosen and externally cued actions, implicating the region as a functional nexus in the symptomatology of Tourette syndrome. Correspondingly, patients with Tourette syndrome may experience volitional tic suppression as an effortful and tiring process because, at the top of the putative motor decision hierarchy, activity within the population of neurons facilitating action is overly similar to activity within the population of neurons promoting inhibition. However, not all pre-supplementary motor area group differences survived correction for multiple comparisons. Group differences in representational similarity were also present in the primary motor cortex. Here, representations of internally chosen and externally cued inhibition were more differentiated in the Tourette syndrome group than in the comparison group, potentially a consequence of a weaker voluntary capacity earlier in the motor hierarchy to suppress actions proactively. Tic severity and premonitory sensations correlated with primary motor cortex and caudate nucleus representational similarity, but these effects did not survive correction for multiple comparisons. In summary, more rigid pre-supplementary motor area neural coding across action categories may constitute a central feature of Tourette syndrome, which can account for patients' experience of 'unvoluntary' tics and effortful tic suppression.

5-HT4 Receptor Agonist Effects on Functional Connectivity in the Human Brain: Implications for Procognitive Action.

BACKGROUND: Cognitive deficits are often comorbid with mood disorders and can cause significant functional impairment even after resolution of the primary mood symptoms. We do not currently have pharmacological treatments that adequately address these deficits. 5-HT4 receptor agonists show promise as potential procognitive agents in animal and early human translational studies. Optimal cognitive performance in humans is directly associated with appropriate functional connectivity between specific resting-state neural networks. However, so far the effect of 5-HT4 receptor agonism on resting-state functional connectivity (rsFC) in the brain in humans is unknown. METHODS: We collected resting-state functional magnetic resonance imaging scans from 50 healthy volunteers, of whom 25 received 6 days × 1 mg prucalopride (a highly selective 5-HT4 receptor agonist) and 25 received placebo in a randomized double-blind design. RESULTS: Network analyses identified that participants in the prucalopride group had enhanced rsFC between the central executive network and the posterior/anterior cingulate cortex. Seed analyses also showed greater rsFC between the left and right rostral anterior cingulate cortex and the left lateral occipital cortex, and reduced rsFC between the hippocampus and other default mode network regions. CONCLUSIONS: Similar to other potentially procognitive medications, low-dose prucalopride in healthy volunteers appeared to enhance rsFC between regions involved in cognitive networks and reduce rsFC within the default mode network. This suggests a mechanism for the behavioral cognitive enhancement previously seen with 5-HT4 receptor agonists in humans and supports the potential for 5-HT4 receptor agonists to be used in clinical psychiatric populations.

Community consensus on core open science practices to monitor in biomedicine.

The state of open science needs to be monitored to track changes over time and identify areas to create interventions to drive improvements. In order to monitor open science practices, they first need to be well defined and operationalized. To reach consensus on what open science practices to monitor at biomedical research institutions, we conducted a modified 3-round Delphi study. Participants were research administrators, researchers, specialists in dedicated open science roles, and librarians. In rounds 1 and 2, participants completed an online survey evaluating a set of potential open science practices, and for round 3, we hosted two half-day virtual meetings to discuss and vote on items that had not reached consensus. Ultimately, participants reached consensus on 19 open science practices. This core set of open science practices will form the foundation for institutional dashboards and may also be of value for the development of policy, education, and interventions.

The Effect of the 5-HT4 Agonist, Prucalopride, on a Functional Magnetic Resonance Imaging Faces Task in the Healthy Human Brain.

Depression is a common and often recurrent illness with significant negative impact on a global scale. Current antidepressants are ineffective for up to one third of people with depression, many of whom experience persistent symptomatology. 5-HT4 receptor agonists show promise in both animal models of depression and cognitive deficit. We therefore studied the effect of the 5-HT4 partial agonist prucalopride (1 mg daily for 6 days) on the neural processing of emotional faces in 43 healthy participants using a randomised placebo-controlled design. Participants receiving prucalopride were more accurate at identifying the gender of emotional faces. In whole brain analyses, prucalopride was also associated with reduced activation in a network of regions corresponding to the default mode network. However, there was no evidence that prucalopride treatment produced a positive bias in the neural processing of emotional faces. Our study provides further support for a pro-cognitive effect of 5-HT4 receptor agonism in humans. While our current behavioural and neural investigations do not suggest an antidepressant-like profile of prucalopride in humans, it will be important to study a wider dose range in future studies.

Interoceptive cardiac signals selectively enhance fear memories.

Fear is coupled to states of physiological arousal. We tested how learning and memory of threat, specifically conditioned fear, is influenced by interoceptive signals. Forty healthy individuals were exposed to two threat (conditioned stimuli [CS+], paired with electrocutaneous shocks) and two safety (CS-) stimuli, time-locked to either cardiac ventricular systole (when arterial baroreceptors signal cardiovascular arousal to brainstem), or diastole (when these afferent signals are quiescent). Threat learning was indexed objectively using skin conductance responses (SCRs). During acquisition of threat contingencies, cardiac effects dominated: Stimuli (both CS+ and CS-) presented at systole evoked greater SCR responses, relative to stimuli (both CS+ and CS-) presented at diastole. This difference was amplified in more anxious individuals. Learning of conditioned fear was established by the end of the acquisition phase, which was followed by an extinction phase when unpaired CSs were presented at either the same or switched cardiac contingencies. One day later, electrocutaneous shocks triggered the reinstatement of fear responses. Subsequent presentation of stimuli previously encoded at systole evoked higher SCRs. Moreover, only those participants for whom stimuli had the same cardiac-contingency over both acquisition and extinction phases retained conditioned fear memory (i.e., CS+ > CS-). Our findings reveal two important cardiac afferent effects on threat learning and memory: 1) Cardiac signals bias processing toward threat; and 2) cardiac signals are a context for fear memory; altering this context can disrupt the memory. These observations suggest how threat reactivity may be reinforced and maintained by both acute and enduring states of cardiac arousal. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Trait and state interoceptive abnormalities are associated with dissociation and seizure frequency in patients with functional seizures.

OBJECTIVE: Dissociative traits represent a disturbance in selfhood that may predispose to, and trigger, functional seizures (FSs). The predictive representation and control of the internal physiological state of the body (interoception) are proposed to underpin the integrity of the sense of self ("minimal selfhood"). Therefore, discrepancies between objective and subjective aspects of interoception may relate to symptom expression in patients with FSs. Here, we tested whether individual differences in trait measures of interoception relate to dissociative symptoms, and whether state interoceptive deficits predict FS occurrence. METHODS: Forty-one participants with FSs and 30 controls completed questionnaire ratings of dissociation, and measures of (1) interoceptive accuracy (IA)-objective performance on heartbeat detection tasks; (2) trait interoceptive sensibility-subjective sensitivity to internal sensations (using the Porges Body Perception Questionnaire); and (3) state interoceptive sensibility-subjective trial-by-trial measures of confidence in heartbeat detection. Interoceptive trait prediction error (ITPE) was calculated from the discrepancy between IA and trait sensibility, and interoceptive state prediction error (ISPE) from the discrepancy between IA and state sensibility. RESULTS: Patients with FSs had significantly lower IA and greater trait interoceptive sensibility than healthy controls. ITPE was the strongest predictor of dissociation after controlling for trait anxiety and depression in a regression model. ISPE correlated significantly with FS frequency after controlling for state anxiety. SIGNIFICANCE: Patients with FSs have disturbances in interoceptive processing that predict both dissociative traits reflecting the disrupted integrity of self-representation, and the expression of FSs. These findings provide insight into the pathophysiology of functional neurological disorder, and could lead to novel diagnostic and therapeutic approaches.

Computerized Exposure Therapy for Spider Phobia: Effects of Cardiac Timing and Interoceptive Ability on Subjective and Behavioral Outcomes.

OBJECTIVE: Spider phobia is a common form of anxiety disorder for which exposure therapy is an effective first-line treatment. Motivated by the observed modulation of threat processing by afferent cardiac signals, we tested the hypothesis that interoceptive information concerning cardiovascular arousal can influence the outcomes of computerized exposure therapy for spider phobia. METHOD: Fifty-three normal healthy participants with high spider phobia scores underwent one of the following three modified computerized exposure protocols, defined by the timing of exposure to brief spider stimuli within the cardiac cycle: systole (during afferent baroreceptor firing); diastole (during baroreceptor-quiescent interbeat interval); random (noncontingent on cardiac cycle). Outcomes were judged on phobic and anxiety measures and physiological data (skin conductance). Individuals were also rated on interoceptive accuracy. RESULTS: MANCOVA analysis showed that timing group affected the outcome measures (F(10,80) = 2.405, p = .015) and there was a group interaction with interoception ability (F(15,110) = 1.808, p = .045). Subjective symptom reduction was greatest in the systolic group relative to the other two groups (diastolic (t = 3.115, ptukey = .009); random (t = 2.438, ptukey = .048)), with greatest reductions in those participants with lower interoceptive accuracy. Behavioral aversion reduced more in cardiac-contingent groups than the noncontingent (random) group (diastolic (t = 3.295, ptukey = .005); systolic (t = 2.602, ptukey = .032)). Physiological (skin conductance response) responses remained strongest for spider stimuli presented at cardiac systole. CONCLUSIONS: Interoceptive information influences exposure benefit. The reduction in the subjective expression of fear/phobia is facilitated by "bottom-up" afferent signals, whereas improvement in the behavioral expression is further dependent on "top-down" representation of self-related physiology (heart rhythm). Individual interoceptive differences moderate these effects, suggesting means to personalize therapy.

Face perception enhances insula and motor network reactivity in Tourette syndrome.

Tourette syndrome is a neurodevelopmental disorder, characterized by motor and phonic tics. Tics are typically experienced as avolitional, compulsive, and associated with premonitory urges. They are exacerbated by stress and can be triggered by external stimuli, including social cues like the actions and facial expressions of others. Importantly, emotional social stimuli, with angry facial stimuli potentially the most potent social threat cue, also trigger behavioural reactions in healthy individuals, suggesting that such mechanisms may be particularly sensitive in people with Tourette syndrome. Twenty-one participants with Tourette syndrome and 21 healthy controls underwent functional MRI while viewing faces wearing either neutral or angry expressions to quantify group differences in neural activity associated with processing social information. Simultaneous video recordings of participants during neuroimaging enabled us to model confounding effects of tics on task-related responses to the processing of faces. In both Tourette syndrome and control participants, face stimuli evoked enhanced activation within canonical face perception regions, including the occipital face area and fusiform face area. However, the Tourette syndrome group showed additional responses within the anterior insula to both neutral and angry faces. Functional connectivity during face viewing was then examined in a series of psychophysiological interactions. In participants with Tourette syndrome, the insula showed functional connectivity with a set of cortical regions previously implicated in tic generation: the presupplementary motor area, premotor cortex, primary motor cortex, and the putamen. Furthermore, insula functional connectivity with the globus pallidus and thalamus varied in proportion to tic severity, while supplementary motor area connectivity varied in proportion to premonitory sensations, with insula connectivity to these regions increasing to a greater extent in patients with worse symptom severity. In addition, the occipital face area showed increased functional connectivity in Tourette syndrome participants with posterior cortical regions, including primary somatosensory cortex, and occipital face area connectivity with primary somatosensory and primary motor cortices varied in proportion to tic severity. There were no significant psychophysiological interactions in controls. These findings highlight a potential mechanism in Tourette syndrome through which heightened representation within insular cortex of embodied affective social information may impact the reactivity of subcortical motor pathways, supporting programmed motor actions that are causally implicated in tic generation. Medicinal and psychological therapies that focus on reducing insular hyper-reactivity to social stimuli may have potential benefit for tic reduction in people with Tourette syndrome.

Response inhibition on the stop signal task improves during cardiac contraction.

Motor actions can be facilitated or hindered by psychophysiological states of readiness, to guide rapid adaptive action. Cardiovascular arousal is communicated by cardiac signals conveying the timing and strength of individual heartbeats. Here, we tested how these interoceptive signals facilitate control of motor impulsivity. Participants performed a stop signal task, in which stop cues were delivered at different time points within the cardiac cycle: at systole when the heart contracts (T-wave peak, approximately 300 ms following the R-wave), or at diastole between heartbeats (R-wave peak). Response inhibition was better at systole, indexed by a shorter stop signal reaction time (SSRT), and longer stop signal delay (SSD). Furthermore, parasympathetic control of cardiovascular tone, and subjective sensitivity to interoceptive states, predicted response inhibition efficiency, although these cardiovascular and interoceptive correlations did not survive correction for multiple comparisons. This suggests that response inhibition capacity is influenced by interoceptive physiological cues, such that people are more likely to express impulsive actions during putative states of lower cardiovascular arousal, when frequency and strength of cardiac afferent signalling is reduced.

Impact of intranasal oxytocin on interoceptive accuracy in alcohol users: an attentional mechanism?

Interoception, i.e. the perception and appraisal of internal bodily signals, is related to the phenomenon of craving, and is reportedly disrupted in alcohol use disorders. The hormone oxytocin influences afferent transmission of bodily signals and, through its potential modulation of craving, is proposed as a possible treatment for alcohol use disorders. However, oxytocin's impact on interoception in alcohol users remains unknown. Healthy alcohol users (n = 32) attended two laboratory sessions to perform tests of interoceptive ability (heartbeat tracking: attending to internal signals and, heartbeat discrimination: integrating internal and external signals) after intranasal administration of oxytocin or placebo. Effects of interoceptive accuracy, oxytocin administration and alcohol intake, were tested using mixed-effects models. On the tracking task, oxytocin reduced interoceptive accuracy, but did not interact with alcohol consumption. On the discrimination task, we found an interaction between oxytocin administration and alcohol intake: Oxytocin, compared with placebo, increased interoceptive accuracy in heavy drinkers, but not in light social drinkers. Our study does not suggest a pure interoceptive impairment in alcohol users but instead potentially highlights reduced flexibility of internal and external attentional resource allocation. Importantly, this impairment seems to be mitigated by oxytocin. This attentional hypothesis needs to be explicitly tested in future research.

Sleep and the heart: Interoceptive differences linked to poor experiential sleep quality in anxiety and depression.

Interoception is the sense through which internal bodily changes are signalled and perceived. Individual differences in interoception are linked to emotional style and vulnerability to affective disorders. Here we test how experiential sleep quality relates to dimensions of interoceptive ability. 180 adults (42 'non-clinical' individuals, 138 patients accessing mental health services) rated their quality of sleep before performing tests of cardiac interoception. Poor sleep quality was associated with lower measures of interoceptive performance accuracy, and higher self-report measures of interoceptive sensibility in individuals with diagnoses of depression and/or anxiety. Additionally, poor sleep quality was associated with impaired metacognitive interoceptive awareness in patients with diagnoses of depression (alone or with anxiety). Thus, poor sleep quality, a common early expression of psychological disorder, impacts cardiac interoceptive ability and experience across diagnoses. Sleep disruption can contribute to the expression of affective psychopathology through effects on perceptual and interpretative dimensions of bodily awareness.

Feedback from the heart: Emotional learning and memory is controlled by cardiac cycle, interoceptive accuracy and personality.

Feedback processing is critical to trial-and-error learning. Here, we examined whether interoceptive signals concerning the state of cardiovascular arousal influence the processing of reinforcing feedback during the learning of 'emotional' face-name pairs, with subsequent effects on retrieval. Participants (N=29) engaged in a learning task of face-name pairs (fearful, neutral, happy faces). Correct and incorrect learning decisions were reinforced by auditory feedback, which was delivered either at cardiac systole (on the heartbeat, when baroreceptors signal the contraction of the heart to the brain), or at diastole (between heartbeats during baroreceptor quiescence). We discovered a cardiac influence on feedback processing that enhanced the learning of fearful faces in people with heightened interoceptive ability. Individuals with enhanced accuracy on a heartbeat counting task learned fearful face-name pairs better when feedback was given at systole than at diastole. This effect was not present for neutral and happy faces. At retrieval, we also observed related effects of personality: First, individuals scoring higher for extraversion showed poorer retrieval accuracy. These individuals additionally manifested lower resting heart rate and lower state anxiety, suggesting that attenuated levels of cardiovascular arousal in extraverts underlies poorer performance. Second, higher extraversion scores predicted higher emotional intensity ratings of fearful faces reinforced at systole. Third, individuals scoring higher for neuroticism showed higher retrieval confidence for fearful faces reinforced at diastole. Our results show that cardiac signals shape feedback processing to influence learning of fearful faces, an effect underpinned by personality differences linked to psychophysiological arousal.

Mind-wandering and alterations to default mode network connectivity when listening to naturalistic versus artificial sounds.

Naturalistic environments have been demonstrated to promote relaxation and wellbeing. We assess opposing theoretical accounts for these effects through investigation of autonomic arousal and alterations of activation and functional connectivity within the default mode network (DMN) of the brain while participants listened to sounds from artificial and natural environments. We found no evidence for increased DMN activity in the naturalistic compared to artificial or control condition, however, seed based functional connectivity showed a shift from anterior to posterior midline functional coupling in the naturalistic condition. These changes were accompanied by an increase in peak high frequency heart rate variability, indicating an increase in parasympathetic activity in the naturalistic condition in line with the Stress Recovery Theory of nature exposure. Changes in heart rate and the peak high frequency were correlated with baseline functional connectivity within the DMN and baseline parasympathetic tone respectively, highlighting the importance of individual neural and autonomic differences in the response to nature exposure. Our findings may help explain reported health benefits of exposure to natural environments, through identification of alterations to autonomic activity and functional coupling within the DMN when listening to naturalistic sounds.

Automaticity and localisation of concurrents predicts colour area activity in grapheme-colour synaesthesia.

In grapheme-colour synaesthesia (GCS), the presentation of letters or numbers induces an additional 'concurrent' experience of colour. Early functional MRI (fMRI) investigations of GCS reported activation in colour-selective area V4 during the concurrent experience. However, others have failed to replicate this key finding. We reasoned that individual differences in synaesthetic phenomenology might explain this inconsistency in the literature. To test this hypothesis, we examined fMRI BOLD responses in a group of grapheme-colour synaesthetes (n=20) and matched controls (n=20) while characterising the individual phenomenology of the synaesthetes along dimensions of 'automaticity' and 'localisation'. We used an independent functional localiser to identify colour-selective areas in both groups. Activations in these areas were then assessed during achromatic synaesthesia-inducing, and non-inducing conditions; we also explored whole brain activations, where we sought to replicate the existing literature regarding synaesthesia effects. Controls showed no significant activations in the contrast of inducing > non-inducing synaesthetic stimuli, in colour-selective ROIs or at the whole brain level. In the synaesthete group, we correlated activation within colour-selective ROIs with individual differences in phenomenology using the Coloured Letters and Numbers (CLaN) questionnaire which measures, amongst other attributes, the subjective automaticity/attention in synaesthetic concurrents, and their spatial localisation. Supporting our hypothesis, we found significant correlations between individual measures of synaesthetic phenomenology and BOLD responses in colour-selective areas, when contrasting inducing against non-inducing stimuli. Specifically, left-hemisphere colour area responses were stronger for synaesthetes scoring high on phenomenological localisation and automaticity/attention, while right-hemisphere colour area responses showed a relationship with localisation only. In exploratory whole brain analyses, the BOLD response within several other areas was also correlated with these phenomenological factors, including the intra-parietal sulcus, insula, precentral and supplementary motor areas. Our findings reveal a network of regions underlying synaesthetic phenomenology and they help reconcile the diversity of previous results regarding colour-selective BOLD responses during synaesthesia, by establishing a bridge between neural responses and individual synaesthetic phenomenology.