Proof of mechanism investigation of Transcutaneous auricular vagus nerve stimulation through simultaneous measurement of autonomic functions: a randomized controlled trial protocol.

BACKGROUND: The autonomic nervous system plays a vital role in regulating physiological functions. Transcutaneous auricular vagus nerve stimulation (taVNS) is a method that provides insights into autonomic nerve modulation. This paper presents a research protocol investigating proof of mechanism for the impact of taVNS on autonomic functions and aims to both deepen theoretical understanding and pave the way for clinically relevant applications. METHODS: This protocol employs a single-blind, randomized cross-over design involving 10 healthy male participants. Simultaneous assessment of both the afferent and efferent aspects of the vagus nerve will be performed by integrating physiological measures, magnetic resonance imaging, and a questionnaire survey. Electrocardiogram will be measured to assess changes in heart rate, as a primary outcome, and heart rate variability. Active taVNS and sham stimulation will be compared, which ensures precision and blinding. Electrical stimulation will be applied to the left concha cymba and the left lobule for the active and sham conditions, respectively. The specific parameters of taVNS involve a pulse width of 250 µs, a frequency of 25 Hz, and a current adjusted to the perception threshold (0.1 mA ≤ 5 mA), delivered in cycles of 32 s on and 28 s off. CONCLUSIONS: This research investigates proof of mechanism for taVNS to elucidate its modulatory effects on the central and peripheral components of the autonomic nervous system. Beyond theoretical insights, the findings will provide a foundation for designing targeted neuromodulation strategies, potentially benefiting diverse patient populations experiencing autonomic dysregulation. By elucidating the neural mechanisms, this study contributes to the evolution of personalized and effective clinical interventions in the field of neuromodulation. TRIAL REGISTRATION: JRCT, jRCTs032220332, Registered 13 September 2022; https://jrct.niph.go.jp/latest-detail/jRCTs032220332 .

Interoceptive training impacts the neural circuit of the anterior insula cortex.

Interoception is the perception of afferent information that arises from anywhere and everywhere within the body. Recently, interoceptive accuracy could be enhanced by cognitive training. Given that the anterior insula cortex (AIC) is a key node of interoception, we hypothesized that resting functional connectivity (RSFC) from AIC was involved in an effect of interoceptive training. To address this issue, we conducted a longitudinal intervention study using interoceptive training and obtained RSFC using fMRI before and after the intervention. A heartbeat perception task evaluated interoceptive accuracy. Twenty-two healthy volunteers (15 females, age 19.9 ± 2.0 years) participated. After the intervention, interoceptive accuracy was enhanced, and anxiety levels and somatic symptoms were reduced. Also, RSFC from AIC to the dorsolateral prefrontal cortex (DLPFC), superior marginal gyrus (SMG), anterior cingulate cortex (ACC), and brain stem, including nucleus tractus solitarius (NTS) were enhanced, and those from AIC to the visual cortex (VC) were decreased according to enhanced interoceptive accuracy. The neural circuit of AIC, ACC, and NTS is involved in the bottom-up process of interoception. The neural circuit of AIC, DLPFC, and SMG is involved in the top-down process of interoception, which was thought to represent the cognitive control of emotion. The findings provided a better understanding of neural underpinnings of the effect of interoceptive training on somatic symptoms and anxiety levels by enhancing both bottom-up and top-down processes of interoception, which has a potential contribution to the structure of psychotherapies based on the neural mechanism of psychosomatics.

Paradoxical somatic information processing for interoception and anxiety in alexithymia.

The concept of alexithymia has garnered much attention in an attempt to understand the psychological mechanisms underlying the experience of feeling an emotion. In this study, we aimed to understand how the interoceptive processing in an emotional context relates to problems of alexithymia in recognizing self-emotions. Therefore, we prepared experimental conditions to induce emotional awareness based on interoceptive information. As such, we asked participants to be aware of interoception under an anxiety-generating situation anticipating pain, having them evaluate their subjective anxiety levels in this context. High alexithymia participants showed attenuated functional connectivity within their 'interoception network', particularly between the insula and the somatosensory areas when they focused on interoception. In contrast, they had enhanced functional connectivity between these regions when they focused on their anxiety about pain. Although access to somatic information is supposed to be more strongly activated while attending to interoception in the context of primary sensory processing, high alexithymia individuals were biased as this process was activated when they felt emotions, suggesting they recognize primitive and unprocessed bodily sensations as emotions. The paradoxical somatic information processing may reflect their brain function pathology for feeling emotions and their difficulty with context-dependent emotional control.

The Role of the Thalamus in the Neurological Mechanism of Subjective Sleepiness: An fMRI Study.

PURPOSE: The thalamus, the region that forms the attentional network and transmits external sensory signals to the entire brain, is important for sleepiness. Herein, we examined the relationship between activity in the thalamus-seed brain network and subjective sleepiness. MATERIALS AND METHODS: Fifteen healthy male participants underwent an experiment comprising a baseline evaluation and two successive interventions, a 9-day sleep extension followed by 1-night total sleep deprivation. Pre- and post-intervention tests included the Karolinska sleepiness scale and neuroimaging for arterial spin labeling and functional connectivity. We examined the association between subjective sleepiness and the functional magnetic resonance imaging indices. RESULTS: The functional connectivity between the left or right thalamus and various brain regions displayed a significant negative association with subjective sleepiness, and the functional connectivity between the left and right thalamus displayed a significant positive association with subjective sleepiness. The graph theory analysis indicated that the number of positive functional connectivity related to the thalamus showed a strong negative association with subjective sleepiness, and conversely, the number of negative functional connectivity showed a positive association with subjective sleepiness. Arterial spin labeling analysis indicated that the blood flow in both the left and right thalami was significantly negatively associated with subjective sleepiness. Functional connectivity between the anterior cingulate cortex and salience network areas of the left insular cortex, and that between the anterior and posterior cingulate cortices showed a strong positive and negative association with subjective sleepiness, respectively. CONCLUSION: Subjective sleepiness and the thalamic-cortical network dynamics are strongly related, indicating the application of graph theory to study sleepiness and consciousness. These results also demonstrate that resting functional connectivity largely reflects the "state" of the subject, suggesting that the control of sleep and conscious states is essential when using functional magnetic resonance imaging indices as biomarkers.

Decreased activity in the reward network of chronic insomnia patients.

In modern society, many people have insomnia. Chronic insomnia has been noted as a risk factor for depression. However, there are few functional imaging studies of the brain on affective functions in chronic insomnia. This study aimed to investigate brain activities induced by emotional stimuli in chronic insomnia patients. Fifteen patients with primary insomnia and 30 age and gender matched healthy controls participated in this study. Both groups were presented images of fearful, happy, and neutral expressions consciously and non-consciously while undergoing MRI to compare the activity in regions of the brain responsible for emotions. Conscious presentation of the Happy-Neutral contrast showed significantly lower activation in the right orbitofrontal cortex of patients compared to healthy controls. The Happy-Neutral contrast presented in a non-conscious manner resulted in significantly lower activation of the ventral striatum, right insula, putamen, orbitofrontal cortex and ventral tegmental area in patients compared to healthy controls. Our findings revealed that responsiveness to positive emotional stimuli were decreased in insomniac patients. Specifically, brain networks associated with rewards and processing positive emotions showed decreased responsiveness to happy emotions especially for non-conscious image. The magnitude of activity in these areas also correlated with severity of insomnia, even after controlling for depression scale scores. These findings suggest that insomnia induces an affective functional disorder through an underlying mechanism of decreased sensitivity in the regions of the brain responsible for emotions and rewards to positive emotional stimuli.

Effects of interoceptive training on decision making, anxiety, and somatic symptoms.

BACKGROUND: Interoception is the perception of afferent information that arises from any point within the body. Individual differences in interoception have been associated with affective processing and decision-making processing. The somatic marker hypothesis summarizes the potential effects of interoception on decision-making processes. According to this theory, individuals with interoceptive dysfunction exhibit disadvantageous decision making. Recently, enhancement of interoceptive accuracy, an element of interoception assessed by objective decision-making tasks, has been demonstrated using biofeedback. Garfinkle et al. developed an interoceptive training task, modified from the heartbeat perception task, which enhanced interoceptive accuracy and reduced anxiety symptoms. The purpose of this study was to determine the effects of interoceptive training on decision-making processes. Based on improvements in interoceptive accuracy, we hypothesized that decision-making scores would change in a manner indicative of increased rationality. METHODS: This longitudinal interventional study was performed with interoceptive training. Before and after the intervention, interoceptive accuracy and rationality of decision-making processes were assessed using a heartbeat perception task and rational decision-making tasks, respectively. Fourteen healthy volunteers (nine women; mean age, 21.9 ± 4.5 years) participated. The analysis included data from 12 participants. To detect individual differences in the effects of interoceptive accuracy on rationality of decision making, correlation analysis was conducted on change ratios of the indices of interoceptive accuracy and rationality of decision making. RESULTS: Interoceptive training resulted in significant enhancement of interoceptive accuracy scores and significant reductions in somatic symptom and state anxiety scores. In contrast, interoceptive training did not cause significant changes in decision-making indices. There was a significant positive correlation between change ratios of indices of interoceptive accuracy and rationality of decision making. CONCLUSIONS: The results suggested a causal relation between interoception and rationality of decision making. These findings will enhance the understanding of mechanisms underlying alterations of decision-making related to psychotherapy by focusing on interoception. TRIAL REGISTRATION: Trial registration number: UMIN000037548.

Two Days' Sleep Debt Causes Mood Decline During Resting State Via Diminished Amygdala-Prefrontal Connectivity.

Study objectives: Sleep debt (SD) has been suggested to evoke emotional instability by diminishing the suppression of the amygdala by the medial prefrontal cortex (MPFC). Here, we investigated how short-term SD affects resting-state functional connectivity between the amygdala and MPFC, self-reported mood, and sleep parameters. Methods: Eighteen healthy adult men aged 29 ± 8.24 years participated in a 2-day sleep control session (SC; time in bed [TIB], 9 hours) and 2-day SD session (TIB, 3 hours). On day 2 of each session, resting-state functional magnetic resonance imaging was performed, followed immediately by measuring self-reported mood on the State-Trait Anxiety Inventory-State subscale (STAI-S). Results: STAI-S score was significantly increased, and functional connectivity between the amygdala and MPFC was significantly decreased in SD compared with SC. Significant correlations were observed between reduced rapid eye movement (REM) sleep and reduced left amygdala-MPFC functional connectivity (FCL_amg-MPFC) and between reduced FCL_amg-MPFC and increased STAI-S score in SD compared with SC. Conclusions: These findings suggest that reduced MPFC functional connectivity of amygdala activity is involved in mood deterioration under SD, and that REM sleep reduction is involved in functional changes in the corresponding brain regions. Having adequate REM sleep may be important for mental health maintenance.

Unrecognized Sleep Loss Accumulated in Daily Life Can Promote Brain Hyperreactivity to Food Cue.

Epidemiological studies have shown that sleep debt increases the risk of obesity. Experimental total sleep deprivation (TSD) has been reported to activate the reward system in response to food stimuli, but food-related responses in everyday sleep habits, which could lead to obesity, have not been addressed. Here, we report that habitual sleep time at home among volunteers without any sleep concerns was shorter than their optimal sleep time estimated by the 9-day extended sleep intervention, which indicates that participants had already been in sleep debt in their usual sleep habits. The amygdala and anterior insula, which are responsible for both affective responses and reward prediction, were found to exhibit significantly lowered activity in the optimal sleep condition. Additionally, a subsequent one-night period of TSD reactivated the right anterior insula in response to food images; however, the activity level of amygdala remained lowered. These findings indicate that (1) our brain is at risk of hyperactivation to food triggers in everyday life, which could be a risk factor for obesity and lifestyle diseases, and (2) optimal sleep appears to reduce this hypersensitivity to food stimuli.

Recovery from Unrecognized Sleep Loss Accumulated in Daily Life Improved Mood Regulation via Prefrontal Suppression of Amygdala Activity.

Many modern people suffer from sleep debt that has accumulated in everyday life but is not subjectively noticed [potential sleep debt (PSD)]. Our hypothesis for this study was that resolution of PSD through sleep extension optimizes mood regulation by altering the functional connectivity between the amygdala and prefrontal cortex. Fifteen healthy male participants underwent an experiment consisting of a baseline (BL) evaluation followed by two successive interventions, namely, a 9-day sleep extension followed by one night of total sleep deprivation (TSD). Tests performed before and after the interventions included a questionnaire on negative mood and neuroimaging with arterial spin labeling MRI for evaluating regional cerebral blood flow (rCBF) and functional connectivity. Negative mood and amygdala rCBF were significantly reduced after sleep extension compared with BL. The amygdala had a significant negative functional connectivity with the medial prefrontal cortex (FCamg-MPFC), and this negative connectivity was greater after sleep extension than at BL. After TSD, these indices reverted to the same level as at BL. An additional path analysis with structural equation modeling showed that the FCamg-MPFC significantly explained the amygdala rCBF and that the amygdala rCBF significantly explained the negative mood. These findings suggest that the use of our sleep extension protocol normalized amygdala activity via negative amygdala-MPFC functional connectivity. The resolution of unnoticed PSD may improve mood by enhancing frontal suppression of hyperactivity in the amygdala caused by PSD accumulating in everyday life.

Estimating individual optimal sleep duration and potential sleep debt.

In this study, we hypothesized that dynamics of sleep time obtained over consecutive days of extended sleep in a laboratory reflect an individual's optimal sleep duration (OSD) and that the difference between OSD and habitual sleep duration (HSD) at home represents potential sleep debt (PSD). We found that OSD varies among individuals and PSD showed stronger correlation with subjective/objective sleepiness than actual sleep time, interacting with individual's vulnerability of sleep loss. Furthermore, only 1 h of PSD takes four days to recover to their optimal level. Recovery from PSD was also associated with the improvement in glycometabolism, thyrotropic activity and hypothalamic-pituitary-adrenocortical axis. Additionally, the increase (rebound) in total sleep time from HSD at the first extended sleep would be a simple indicator of PSD. These findings confirmed self-evaluating the degree of sleep debt at home as a useful clinical marker. To establish appropriate sleep habits, it is necessary to evaluate OSD, vulnerability to sleep loss, and sleep homeostasis characteristics on an individual basis.

Neural Networks for Mindfulness and Emotion Suppression.

Mindfulness, an attentive non-judgmental focus on "here and now" experiences, has been incorporated into various cognitive behavioral therapy approaches and beneficial effects have been demonstrated. Recently, mindfulness has also been identified as a potentially effective emotion regulation strategy. On the other hand, emotion suppression, which refers to trying to avoid or escape from experiencing and being aware of one's own emotions, has been identified as a potentially maladaptive strategy. Previous studies suggest that both strategies can decrease affective responses to emotional stimuli. They would, however, be expected to provide regulation through different top-down modulation systems. The present study was aimed at elucidating the different neural systems underlying emotion regulation via mindfulness and emotion suppression approaches. Twenty-one healthy participants used the two types of strategy in response to emotional visual stimuli while functional magnetic resonance imaging was conducted. Both strategies attenuated amygdala responses to emotional triggers, but the pathways to regulation differed across the two. A mindful approach appears to regulate amygdala functioning via functional connectivity from the medial prefrontal cortex, while suppression uses connectivity with other regions, including the dorsolateral prefrontal cortex. Thus, the two types of emotion regulation recruit different top-down modulation processes localized at prefrontal areas. These different pathways are discussed.

Neural basis of hierarchical visual form processing of Japanese Kanji characters.

INTRODUCTION: We investigated the neural processing of reading Japanese Kanji characters, which involves unique hierarchical visual processing, including the recognition of visual components specific to Kanji, such as "radicals." METHODS: We performed functional MRI to measure brain activity in response to hierarchical visual stimuli containing (1) real Kanji characters (complete structure with semantic information), (2) pseudo Kanji characters (subcomponents without complete character structure), (3) artificial characters (character fragments), and (4) checkerboard (simple photic stimuli). RESULTS: As we expected, the peaks of the activation in response to different stimulus types were aligned within the left occipitotemporal visual region along the posterior-anterior axis in order of the structural complexity of the stimuli, from fragments (3) to complete characters (1). Moreover, only the real Kanji characters produced functional connectivity between the left inferotemporal area and the language area (left inferior frontal triangularis), while pseudo Kanji characters induced connectivity between the left inferotemporal area and the bilateral cerebellum and left putamen. CONCLUSIONS: Visual processing of Japanese Kanji takes place in the left occipitotemporal cortex, with a clear hierarchy within the region such that the neural activation differentiates the elements in Kanji characters' fragments, subcomponents, and semantics, with different patterns of connectivity to remote regions among the elements.