Zhiying Zhao

Sex-dependent neural effect of oxytocin during subliminal processing of negative emotion faces

&NA; In line with animal models indicating sexually dimorphic effects of oxytocin (OXT) on social‐emotional processing, a growing number of OXT‐administration studies in humans have also reported sex‐dependent effects during social information processing. To explore whether sex‐dependent effects already occur during early, subliminal, processing stages the present pharmacological fMRI‐study combined the intranasal‐application of either OXT or placebo (n = 86–43 males) with a backward‐masking emotional face paradigm. Results showed that while OXT suppressed inferior frontal gyrus, dorsal anterior cingulate and anterior insula responses to threatening face stimuli in men it increased them in women. In women increased anterior cingulate reactivity during subliminal threat processing was also positively associated with trait anxiety. On the network level, sex‐dependent effects were observed on amygdala, anterior cingulate and inferior frontal gyrus functional connectivity that were mainly driven by reduced coupling in women following OXT. Our findings demonstrate that OXT produces sex‐dependent effects even at the early stages of social‐emotional processing, and suggest that while it attenuates neural responses to threatening social stimuli in men it increases them in women. Thus in a therapeutic context OXT may potentially produce different effects on anxiety disorders in men and women. HighlightsOxytocin (OXT) induced sex‐dependent effect on BOLD level and functional connectivity.OXT decreased neural responses to negative faces in men but increased them in women.Increased ACC activity after OXT was positively linked with trait anxiety in women.OXT decreased functional connectivity in women.Sex might be an important factor moderating the putative anxiolytic effects of OXT.

Voluntary control of anterior insula and its functional connections is feedback-independent and increases pain empathy.

Real-time functional magnetic resonance imaging (rtfMRI)-assisted neurofeedback (NF) training allows subjects to acquire volitional control over regional brain activity. Emerging evidence suggests its potential clinical utility as an effective non-invasive treatment approach in mental disorders. The therapeutic potential of rtfMRI-NF training depends critically upon whether: (1) acquired self-regulation produces functionally relevant changes at behavioral and brain network levels and (2) training effects can be maintained in the absence of feedback. To address these key questions, the present study combined rtfMRI-NF training for acquiring volitional anterior insula (AI) regulation with a sham-controlled between-subject design. The functional relevance of acquired AI control was assessed using both behavioral (pain empathy) and neural (activity, functional connectivity) indices. Maintenance of training effects in the absence of feedback was assessed two days later. During successful acquisition of volitional AI up-regulation subjects exhibited stronger empathic responses, increased AI-prefrontal coupling in circuits involved in learning and emotion regulation and increased resting state connectivity within AI-centered empathy networks. At follow-up both self-regulation and increased connectivity in empathy networks were fully maintained, although without further increases in empathy ratings. Overall these findings support the potential clinical application of rtfMRI-NF for inducing functionally relevant and lasting changes in emotional brain circuitry.

Analysis of Gait Rhythm Fluctuations for Neurodegenerative Diseases by Phase Synchronization and Conditional Entropy

Previous studies have revealed that gait rhythm fluctuations convey important information, which is useful for understanding certain types of neurodegenerative diseases such as Amyotrophic Lateral Sclerosis (ALS), Huntingtons disease (HD) and Parkinsons disease (PD). However, previous investigations only focused on the locomotor patterns of each individual foot rather than the relations between both feet. Therefore, in our study, phase synchronization (the index ρ) and conditional entropy (Hc) were applied to the five types of time series pairs of gait rhythms (stride time, swing time, stance time, % swing time and % stance time). The results revealed that compared with the patients with ALS, HD and PD, gait rhythms of normal subjects have the strongest phase synchronization property and minimum conditional entropy value. In addition, the indices ρ and Hc cannot only significantly differentiate among the four groups of subjects (ALS, HD, PD and control) but also have the ability to discriminate between any two of these subject groups. Finally, three representative classifiers were utilized in order to evaluate the possible capabilities of the indices ρ and Hc to distinguish the patients with neurodegenerative diseases from the healthy subjects, and achieved maximum area under the curve (AUC) values of 0.959, 0.928 and 0.824 for HD, PD and ALS detection, respectively. In summary, our study provides insight into the relational analysis between gait rhythms measured from both feet, and suggests that it should be considered seriously in the future studies investigating the impact of neurodegenerative disease and potential therapeutic intervention.

Oxytocin Modulates Attention Switching Between Interoceptive Signals and External Social Cues

Emotional experience involves an integrated interplay between processing of external emotional cues and interoceptive feedback, and this is impaired in a number of emotional disorders. The neuropeptide oxytocin (OT) enhances the salience of external social cues but its influence on interoception is unknown. The present pharmaco-fMRI study therefore investigated whether OT enhances interoceptive awareness and if it influences the interplay between interoceptive and salience processing. In a randomized, double-blind, between-subject, design study 83 subjects received either intranasal OT or placebo. In Experiment 1, subjects performed a heartbeat detection task alone, while in Experiment 2 they did so while viewing both neutral and emotional face stimuli. Interoceptive accuracy and neural responses in interoceptive and salience networks were measured. In Experiment 1, OT had no significant influence on interoceptive accuracy or associated activity in the right anterior insula (AI) and dorsal anterior cingulate cortex. However, in Experiment 2 when face stimuli were also presented, OT decreased interoceptive accuracy and increased right AI activation and its functional connectivity with the left posterior insula (PI), with the latter both being negatively correlated with accuracy scores. The present study provides the first evidence that while OT does not influence processing of interoceptive cues per se it may switch attention away from them towards external salient social cues by enhancing right AI responses and its control over the PI. Thus OT may help regulate the interplay between interoceptive and external salience processing within the insula and could be of potential therapeutic benefit for emotional disorders.

General and emotion-specific neural effects of ketamine during emotional memory formation

Abstract Animal studies suggest that N‐methyl‐D‐aspartate receptor (NMDAR) dependent signalling in limbic and prefrontal regions is critically involved in both cognitive and emotional functions. In humans, ketamine‐induced transient, and disorder associated chronic NMDAR hypofunction (i.e. in schizophrenia) has been associated with deficient performance in the domains of memory and higher‐order emotional functioning, as well as altered neural activity in the underlying limbic‐prefrontal circuits. To model the effects of NMDAR hypofunction on the integration of emotion and cognition the present pharmacological fMRI study applied the NMDAR antagonist ketamine (target plasma level=100 ng/ml) to 21 healthy volunteers in a within‐subject placebo‐controlled crossover design during encoding of neutral, positive and negative pictures. Our results show that irrespective of emotion, ketamine suppressed parahippocampal and medial prefrontal activity. In contrast, ketamine selectively increased amygdala and orbitofrontal activity during successful encoding of negative stimuli. On the network level ketamine generally increased medial prefrontal‐parahippocampal coupling while specifically decreasing amygdala‐orbitofrontal interplay during encoding of negative stimuli. On the behavioural level, ketamine produced generally decreased memory performance and abolished the emotional enhancement of memory after a wash‐out period of 5 days. The present findings suggest that ketamine produces general as well as valence‐specific effects during emotional memory formation. The pattern partly overlaps with alterations previously observed in patients with schizophrenia. HighlightsKetamine suppresses parahippocampal and prefrontal activity during encoding.Amygdala and orbitofrontal activity is increased for negative stimuli by ketamine.Ketamine generally increases medial prefrontal‐parahippocampal coupling.The general and emotion‐specific effects overlap with alterations in schizophrenia.

Oxytocin Increases the Perceived Value of Both Self- and Other-Owned Items and Alters Medial Prefrontal Cortex Activity in an Endowment Task

The neuropeptide oxytocin (OXT) can influence self-processing and may help motivate us to value the attributes of others in a more self-like manner by reducing medial prefrontal cortex (mPFC) responses. We do not know however whether this OXT effect extends to possessions. We tend to place a higher monetary value on specific objects that belong to us compared to others, known as the “endowment effect”. In two double-blind, between-subject placebo (PLC) controlled experiments in subjects from a collectivist culture, we investigated the influence of intranasal OXT on the endowment effect, with the second study incorporating functional magnetic resonance imaging (fMRI). In the task, subjects decided whether to buy or sell their own or others’ (mother/father/classmate/stranger) possessions at various prices. Both experiments demonstrated an endowment effect in the self-owned condition which extended to close others (mother/father) and OXT increased this for self and all other-owned items. This OXT effect was associated with reduced activity in the ventral mPFC (vmPFC) in the self-owned condition but increased in the mother-condition. For the classmate- and stranger-owned conditions OXT increased activity in the dorsal mPFC (dmPFC). Changes in vmPFC activation were associated with the size of the endowment effect for self- and mother-owned items. Functional connectivity between the dmPFC and ventral striatum (VStr) was reduced by OXT in self- and mother-owned conditions and between vmPFC and precuneus in the self-condition. Overall our results show that OXT enhances the endowment effect for both self- and other-owned items in Chinese subjects. This effect is associated with reduced mPFC activation in the self-condition but enhanced activation in all other-conditions and involves differential actions on both dorsal and ventral regions as well as functional connectivity with brain reward and other self-processing regions. Overall our findings suggest that OXT increases the perceived value of both self- and other-owned items by acting on neural circuitry involved in self-processing and reward.

Internet Communication Disorder and the structure of the human brain: initial insights on WeChat addiction

WeChat represents one of the most popular smartphone-based applications for communication. Although the application provides several useful features that simplify daily life, a growing number of users spend excessive amounts of time on the application. This may lead to interferences with everyday life and even to addictive patterns of use. In the context of the ongoing discussion on Internet Communication Disorder (ICD), the present study aimed to better characterize the addictive potential of communication applications, using WeChat as an example, by examining associations between individual variations in tendencies towards WeChat addiction and brain structural variations in fronto-striatal-limbic brain regions. To this end levels of addictive tendencies, frequency of use and structural MRI data were assessed in n = 61 healthy participants. Higher tendencies towards WeChat addiction were associated with smaller gray matter volumes of the subgenual anterior cingulate cortex, a key region for monitoring and regulatory control in neural networks underlying addictive behaviors. Moreover, a higher frequency of the paying function was associated with smaller nucleus accumbens volumes. Findings were robust after controlling for levels of anxiety and depression. The present results are in line with previous findings in substance and behavioral addictions, and suggest a similar neurobiological basis in ICD.

Oxytocin Facilitates Approach Behavior to Positive Social Stimuli via Decreasing Anterior Insula Activity

Abstract Background The neuropeptide oxytocin can extensively modulate human social behavior and affective processing, and its effects can be interpreted in terms of mediating approach-avoidance motivational processes. However, little is known about how oxytocin mediates approach-avoidance behavior and particularly the underlying neural mechanisms. Methods In a randomized, double-blind, between-subject design, the present pharmaco-fMRI study used an approach-avoidance paradigm to investigate oxytocin’s effects on approach-avoidance behavior and associated neural mechanisms. Results Results revealed that oxytocin generally decreased activity in the right striatum irrespective of response (approach/avoidance) and social context, suggesting an inhibitory effect on motivational representation during both appetitive approach and aversive avoidance. Importantly, while on the behavioral level oxytocin selectively enhanced accuracy when approaching social positive stimuli, on the neural level it decreased left ventral and right dorsal anterior insula activity in response to social vs nonsocial positive stimuli compared with the placebo treatment. The left ventral anterior insula activity was negatively correlated with the corresponding accuracy difference scores in the oxytocin but not in the placebo group. Conclusion Given the role of the ventral anterior insula in emotional processing and the dorsal anterior insula in salience processing, the oxytocin-induced suppression of activity in these regions may indicate that oxytocin is acting to reduce interference from hyper-activity in core regions of the emotional and salience networks when approaching salient positive social stimuli and thereby to promote social interaction. Thus, oxytocin may be of potential therapeutic benefit for psychiatric disorders exhibiting avoidance of social stimuli.

A dimensional approach to determine common and specific neurofunctional markers for depression and social anxiety during emotional face processing

Major depression disorder (MDD) and anxiety disorder are both prevalent and debilitating. High rates of comorbidity between MDD and social anxiety disorder (SAD) suggest common pathological pathways, including aberrant neural processing of interpersonal signals. In patient populations, the determination of common and distinct neurofunctional markers of MDD and SAD is often hampered by confounding factors, such as generally elevated anxiety levels and disorder‐specific brain structural alterations. This study employed a dimensional disorder approach to map neurofunctional markers associated with levels of depression and social anxiety symptoms in a cohort of 91 healthy subjects using an emotional face processing paradigm. Examining linear associations between levels of depression and social anxiety, while controlling for trait anxiety revealed that both were associated with exaggerated dorsal striatal reactivity to fearful and sad expression faces respectively. Exploratory analysis revealed that depression scores were positively correlated with dorsal striatal functional connectivity during processing of fearful faces, whereas those of social anxiety showed a negative association during processing of sad faces. No linear relationships between levels of depression and social anxiety were observed during a facial‐identity matching task or with brain structure. Together, the present findings indicate that dorsal striatal neurofunctional alterations might underlie aberrant interpersonal processing associated with both increased levels of depression and social anxiety.

Oxytocin differentially modulates specific dorsal and ventral striatal functional connections with frontal and cerebellar regions

&NA; Interactions between oxytocin and the basal ganglia are central in current overarching conceptualizations of its broad modulatory effects on behavior. Whereas evidence from animal models emphasizes the critical role of the ventral striatum in the behavioral effects of oxytocin, region‐specific contributions of the basal ganglia have not been systematically explored in humans. The present study combined the randomized placebo‐controlled administration of oxytocin versus placebo in healthy men (n = 144) with fMRI‐based resting‐state functional connectivity to determine the modulatory role of oxytocin on the major basal ganglia pathways. Oxytocin specifically increased connectivity between ventral striatal and pallidal nodes with upstream frontal regions, whereas it decreased the strengths of downstream pathways between the dorsal striatum and posterior cerebellum. These pathways have previously been implicated in salience, reward and behavioral flexibility, thus shaping goal‐directed behavior. Given the importance of aberrant striatal intrinsic organization in autism, addiction and schizophrenia the present findings may suggest new mechanistic perspectives for the therapeutic potential of oxytocin in these disorders. HighlightsRandomized placebo‐controlled resting state pharmaco‐fMRI study (n = 144, males).Effects of oxytocin (OXT) on basal ganglia sub‐region connectivity were examined.OXT increased connectivity of ventral striatal & pallidal nodes with frontal regions.