Self-regulating arousal via pupil-based biofeedback.

The brain's arousal state is controlled by several neuromodulatory nuclei known to substantially influence cognition and mental well-being. Here we investigate whether human participants can gain volitional control of their arousal state using a pupil-based biofeedback approach. Our approach inverts a mechanism suggested by previous literature that links activity of the locus coeruleus, one of the key regulators of central arousal and pupil dynamics. We show that pupil-based biofeedback enables participants to acquire volitional control of pupil size. Applying pupil self-regulation systematically modulates activity of the locus coeruleus and other brainstem structures involved in arousal control. Furthermore, it modulates cardiovascular measures such as heart rate, and behavioural and psychophysiological responses during an oddball task. We provide evidence that pupil-based biofeedback makes the brain's arousal system accessible to volitional control, a finding that has tremendous potential for translation to behavioural and clinical applications across various domains, including stress-related and anxiety disorders.

Daily biofeedback to modulate heart rate oscillations affects structural volume in hippocampal subregions targeted by the locus coeruleus in older adults but not younger adults.

Using data from a clinical trial, we tested the hypothesis that daily sessions modulating heart rate oscillations affect older adults' volume of a region-of-interest (ROI) comprised of adjacent hippocampal subregions with relatively strong locus coeruleus (LC) noradrenergic input. Younger and older adults were randomly assigned to one of two daily biofeedback practices for 5 weeks: (1) engage in slow-paced breathing to increase the amplitude of oscillations in heart rate at their breathing frequency (Osc+); (2) engage in self-selected strategies to decrease heart rate oscillations (Osc-). The interventions did not significantly affect younger adults' hippocampal volume. Among older adults, the two conditions affected volume in the LC-targeted hippocampal ROI differentially as reflected in a significant condition × time-point interaction on ROI volume. These condition differences were driven by opposing changes in the two conditions (increased volume in Osc+ and decreased volume in Osc-) and were mediated by the degree of heart rate oscillation during training sessions.

Phasic activation of the locus coeruleus attenuates the acoustic startle response by increasing cortical arousal.

An alerting sound elicits the Acoustic Startle Response (ASR) that is dependent on the sound volume and organisms' state, which is regulated by neuromodulatory centers. The locus coeruleus (LC) neurons respond to salient stimuli and noradrenaline release affects sensory processing, including auditory. The LC hyperactivity is detrimental for sensorimotor gating. We report here that priming microstimulation of the LC (100-ms at 20, 50, and 100 Hz) attenuated the ASR in rats. The ASR reduction scaled with frequency and 100 Hz-stimulation mimicked pre-exposure to a non-startling tone (prepulse). A rapid (~ 40 ms) EEG desynchronization following the LC stimulation suggested that the ASR reduction was due to elevated cortical arousal. The effects of LC stimulation on the ASR and EEG were consistent with systematic relationships between the ASR, awake/sleep state, and the cortical arousal level; for that matter, a lower ASR amplitude corresponded to a higher arousal level. Thus, the LC appears to modulate the ASR circuit via its diffuse ascending projections to the forebrain saliency network. The LC modulation directly in the brainstem and/or spinal cord may also play a role. Our findings suggest the LC as a part of the brain circuitry regulating the ASR, while underlying neurophysiological mechanisms require further investigation.

A literature review on the neurophysiological underpinnings and cognitive effects of transcutaneous vagus nerve stimulation: challenges and future directions.

Brain stimulation approaches are important to gain causal mechanistic insights into the relevance of functional brain regions and/or neurophysiological systems for human cognitive functions. In recent years, transcutaneous vagus nerve stimulation (tVNS) has attracted considerable popularity. It is a noninvasive brain stimulation technique based on the stimulation of the vagus nerve. The stimulation of this nerve activates subcortical nuclei, such as the locus coeruleus and the nucleus of the solitary tract, and from there, the activation propagates to the cortex. Since tVNS is a novel stimulation technique, this literature review outlines a brief historical background of tVNS, before detailing underlying neurophysiological mechanisms of action, stimulation parameters, cognitive effects of tVNS on healthy humans, and, lastly, current challenges and future directions of tVNS research in cognitive functions. Although more research is needed, we conclude that tVNS, by increasing norepineprine (NE) and gamma-aminobutyric acid (GABA) levels, affects NE- and GABA-related cognitive performance. The review provides detailed background information how to use tVNS as a neuromodulatory tool in cognitive neuroscience and outlines important future leads of research on tVNS.

In vivo anatomical mapping of human locus coeruleus functional connectivity at 3 T MRI.

The locus coeruleus (LC) is involved in numerous crucial brain functions and several disorders like depression and Alzheimer's disease. Recently, the LC resting-state functional connectivity (rs-fc) has been investigated in functional MRI by calculating the blood oxygen level-dependent (BOLD) response extracted using Montreal Neurological Institute (MNI) space masks. To corroborate these results, we aimed to investigate the LC rs-fc at native space by improving the identification of the LC location using a neuromelanin sensitive sequence. Twenty-five healthy male participants (mean age 24.8 ± 4.2) were examined in a Siemens MAGNETOM Prisma 3 T MRT applying a neuromelanin sensitive T1TSE sequence and functional MRI. We compared the rs-fc of LC calculated by a MNI-based approach with extraction of the BOLD signal at the exact individual location of the LC after applying CompCor and field map correction. As a measure of advance, a marked increase of regional homogeneity (ReHo) of time series within LC could be achieved with the subject-specific approach. Furthermore, the methods differed in the rs-fc to the right temporoparietal junction, which showed stronger connectivity to the LC in the MNI-based method. Nevertheless, both methods comparably revealed LC rs-fc to multiple brain regions including ACC, bilateral thalamus, and cerebellum. Our results are relevant for further research assessing and interpreting LC function, especially in patient populations examined at 3 T MRI.

Orexin as a modulator of fear-related behavior: Hypothalamic control of noradrenaline circuit.

Fear is an important physiological function for survival. It appears when animals or humans are confronted with an environmental threat. The amygdala has been shown to play a highly important role in emergence of fear. Hypothalamic orexin neurons are activated by fearful stimuli to evoke a 'defense reaction' with an increase in arousal level and sympathetic outflow to deal with the imminent danger. However, how this system contributes to the emergence of fear-related behavior is not well understood. Orexin neurons in the hypothalamus send excitatory innervations to noradrenergic neurons in the locus coeruleus (NALC) which express orexin receptor 1 (OX1R) and send projections to the lateral amygdala (LA). Inhibition of this di-synaptic orexin → NALC → LA pathway by pharmacological or opto/chemogenetic methods reduces cue-induced fear expression. Excitatory manipulation of this pathway induces freezing, a fear-related behavior that only occurs when the environment contains some elements suggestive of danger. Although, fear memory helps animals respond to a context or cue previously paired with an aversive stimulus, fear-related behavior is sometimes evoked even in a distinct context containing some similar elements, which is known as fear generalization. Our recent observation suggests that the orexin → NALC → LA pathway might contribute to this response. This review focuses on recent advances regarding the role of hypothalamic orexin neurons in behavioral fear expression. We also discuss the potential effectiveness of orexin receptor antagonists for treating excessive fear response or overgeneralization seen in anxiety disorder and post-traumatic stress disorder (PTSD).

No modulation of pupil size and event-related pupil response by transcutaneous auricular vagus nerve stimulation (taVNS).

Transcutaneous auricular vagus nerve stimulation (taVNS) bears therapeutic potential for a wide range of medical conditions. However, previous studies have found substantial interindividual variability in responsiveness to taVNS, and no reliable predictive biomarker for stimulation success has been developed so far. In this study, we investigate pupil size and event-related pupil response as candidate biomarkers. Both measures have a direct physiological link to the activity of the locus coeruleus (LC), a brainstem structure and the main source of norepinephrine in the brain. LC activation is considered one of the key mechanisms of action of taVNS, therefore, we expected a clear increase of the pupillary measures under taVNS compared to sham (placebo) stimulation, such that it could serve as a prospective predictor for individual clinical and physiological taVNS effects in future studies. We studied resting pupil size and pupillary responses to target stimuli in an auditory oddball task in 33 healthy young volunteers. We observed stronger pupil responses to target than to standard stimuli. However, and contrary to our hypothesis, neither pupil size nor the event-related pupil response nor behavioral performance were modulated by taVNS. We discuss potential explanations for this negative finding and its implications for future clinical investigation and development of taVNS.

Music enhances activity in the hypothalamus, brainstem, and anterior cerebellum during script-driven imagery of affective scenes.

Music is frequently used to establish atmosphere and to enhance/alter emotion in dramas and films. During music listening, visual imagery is a common mechanism underlying emotion induction. The present functional magnetic resonance imaging (fMRI) study examined the neural substrates of the emotional processing of music and imagined scene. A factorial design was used with factors emotion valence (positive; negative) and music (withoutMUSIC: script-driven imagery of emotional scenes; withMUSIC: script-driven imagery of emotional scenes and simultaneously listening to affectively congruent music). The baseline condition was imagery of neutral scenes in the absence of music. Eleven females and five males participated in this fMRI study. Behavioural data revealed that during scene imagery, participants' subjective emotions were significantly intensified by music. The contrasts of positive and negative withoutMUSIC conditions minus the baseline (imagery of neutral scenes) showed no significant activation. When comparing the withMUSIC to withoutMUSIC conditions, activity in a number of emotion-related regions was observed, including the temporal pole (TP), amygdala, hippocampus, hypothalamus, anterior ventral tegmental area (VTA), locus coeruleus, and anterior cerebellum. We hypothesized that the TP may integrate music and the imagined scene to extract socioemotional significance, initiating the subcortical structures to generate subjective feelings and bodily responses. For the withMUSIC conditions, negative emotions were associated with enhanced activation in the posterior VTA compared to positive emotions. Our findings replicated and extended previous research which suggests that different subregions of the VTA are sensitive to rewarding and aversive stimuli. Taken together, this study suggests that emotional music embedded in an imagined scenario is a salient social signal that prompts preparation of approach/avoidance behaviours and emotional responses in listeners.

Functional MRI evidence of the cortico-olivary efferent pathway during active auditory target processing in humans.

Auditory target detection has been explored by a number of studies, but none have demonstrated activity in the auditory subcortical centers evoked by the top-down attentional mechanism related to target detection in humans. We applied functional magnetic resonance imaging (fMRI) with sparse sampling to explore activity in the auditory centers, particularly in the subcortex, during an active auditory target detection task. Fourteen healthy subjects with normal hearing tapped the left index finger in response to target tonal stimuli presented among other (non-target) stimuli during continuous white noise stimulation. General linear model, region-of-interest, and connectivity analyses were performed. In the cortex, bilateral auditory cortices as well as the cingulate gyrus, thalamus, and supramarginal gyrus were activated to target stimuli and functionally connected to each other. In the subcortex, the superior olivary complex (SOC) and locus coeruleus were activated to the target but not to the non-target or background noise stimuli. The SOC was the only auditory subcortical center that displayed connectivity to the auditory cortical areas as well as the cingulate and supramarginal gyri during target presentation but not during other conditions. SOC activation appears to be the first fMRI evidence of direct cortico-olivary projections in the human brain as well as SOC participation in auditory target detection. Our results may be an initial step towards developing a noninvasive methodology to evaluate the functional integrity of the auditory efferent system in humans.

Age-related differences in event-related potentials and pupillary responses in cued reaction time tasks.

Deficits in the noradrenergic system are associated with age-related cognitive decline, yet how healthy aging influences the functional properties of this arousal system is still poorly understood. We addressed this question in humans using pupillometry, a well-established indicator of activity levels in the locus coeruleus (LC), the main noradrenergic center in the brain. We recorded the pupillogram and the electroencephalogram of 36 young and 39 older adults, while they were engaged in cued reaction time tasks known to elicit LC responses in monkeys. Event-related potentials (ERPs) revealed significant group differences. Older adults showed higher cortical activation during preparatory processes reflected in enhanced cue-evoked frontocentral ERPs and reduced parietal ERPs at the time of the motor response. In contrast, the amplitude of the task-related pupillary responses did not show a significant group effect. Our findings suggest that aging-related changes in cortical processing during motor preparation and execution, as documented by electroencephalogram, are not accompanied by changes in the amplitude of activation of the LC, as documented by pupillography.

[THE INFLUENCE OF LOCUS COERULEUS ON DIFFERENT ACTIVITIES OF THE THALAMO-CORTICAL SYSTEMS].

As revealed from our experiments, in facilitation of passage of the thalamo-cortical visual signals a key role is attributed to variability of activity of visual neurons in reticular nucleus of the thalamus. It was demonstrated that a facilitatory action of locus coeruleus gets augmented following functional exclusion of the thalamic reticular nucleus. Nevertheless, stimulation of locus coeruleus stipulated facilitation of neuronal activity in the anterior part of thalamic reticular nucleus. Emerging from this data one may assume that in the inhibition of evoked responses from a sensorimotor area of the neocortex in response to stimulation of locus coeruleus a certain role is played by reticular nucleus of the thalamus. Namely, augmentation of neurons activity in the anterior part of the thalamic reticular nucleus must condition inhibition of neuronal activity in the ventral nuclei. In spite of the stated, it is not excluded locus coeruleus ha-ving an immediate, direct inhibitory action on the neuron activity within the sensorimotor cortex and thalamic ventral nucleus.

Modulating auditory selective attention by non-invasive brain stimulation: Differential effects of transcutaneous vagal nerve stimulation and transcranial random noise stimulation.

Selective attention is a basic process required to maintain goal-directed behavior by appropriately responding to target stimuli and suppressing reactions to non-target stimuli. It has been proposed that auditory selective attention is linked to the activity of the locus coeruleus-norepinergic (LC-NE) system and a large-scale fronto-parietal cortical network, but there is still sparse causal evidence for these assumptions. By applying transcutaneous vagal nerve stimulation (tVNS) and transcranial random noise stimulation (tRNS) over the frontal cortex, we systematically assessed the involvement of these subcortical and cortical components in the regulation of auditory selective attention. Using a single-blinded, sham-controlled, within-subject design we analyzed online effects of tVNS and tRNS in 20 healthy participants during an auditory oddball paradigm. We show significant stimulation-dependent modulations of auditory selective attention on the behavioral and electrophysiological level. Compared to sham, tVNS increased the P3 amplitude, while tRNS reduced the reaction time to target stimuli. Moreover, both techniques reduced the P3 latency. Our data provide evidence for the functional relevance of the subcortical NE system in the regulation of neural resources that allows a phasic response to incoming target stimuli. They indicate that frontal cortex structures are crucially involved in the successful evaluation of the respective information. Moreover, our results are in favor of the LC-P3 hypothesis claiming the vital role of the NE system in auditory selective attention and in the generation of the P3. Of note, the effects of tVNS on auditory selective attention are comparable with those evoked by pharmacological interventions and invasive vagal nerve stimulation.

Familiarity with social sounds alters c-Fos expression in auditory cortex and interacts with estradiol in locus coeruleus.

When a social sound category initially gains behavioral significance to an animal, plasticity events presumably enhance the ability to recognize that sound category in the future. In the context of learning natural social stimuli, neuromodulators such as norepinephrine and estrogen have been associated with experience-dependent plasticity and processing of newly salient social cues, yet continued plasticity once stimuli are familiar could disrupt the stability of sensorineural representations. Here we employed a maternal mouse model of natural sensory cortical plasticity for infant vocalizations to ask whether the engagement of the noradrenergic locus coeruleus (LC) by the playback of pup-calls is affected by either prior experience with the sounds or estrogen availability, using a well-studied cellular activity and plasticity marker, the immediate early gene c-Fos. We counted call-induced c-Fos immunoreactive (c-Fos-IR) cells in both LC and physiologically validated fields within the auditory cortex (AC) of estradiol or blank-implanted virgin female mice with either 0 or 5-days prior experience caring for vocalizing pups. Estradiol and pup experience interacted both in the induction of c-Fos-IR in the LC, as well as in behavioral measures of locomotion during playback, consistent with the neuromodulatory center's activity being an online reflection of both hormonal and experience-dependent influences on arousal. Throughout core AC, as well as in a high frequency sub-region of AC and in secondary AC, a main effect of pup experience was to reduce call-induced c-Fos-IR, irrespective of estradiol availability. This is consistent with the hypothesis that sound familiarity leads to less c-Fos-mediated plasticity, and less disrupted sensory representations of a meaningful call category. Taken together, our data support the view that any coupling between these sensory and neuromodulatory areas is situationally dependent, and their engagement depends differentially on both internal state factors like hormones and external state factors like prior experience.

Coupling of respiration and attention via the locus coeruleus: Effects of meditation and pranayama.

The locus coeruleus (LC) has established functions in both attention and respiration. Good attentional performance requires optimal levels of tonic LC activity, and must be matched to task consistently. LC neurons are chemosensitive, causing respiratory phrenic nerve firing to increase frequency with higher CO2 levels, and as CO2 level varies with the phase of respiration, tonic LC activity should exhibit fluctuations at respiratory frequency. Top-down modulation of tonic LC activity from brain areas involved in attentional regulation, intended to optimize LC firing to suit task requirements, may have respiratory consequences as well, as increases in LC activity influence phrenic nerve firing. We hypothesize that, due to the physiological and functional overlaps of attentional and respiratory functions of the LC, this small neuromodulatory nucleus is ideally situated to act as a mechanism of synchronization between respiratory and attentional systems, giving rise to a low-amplitude oscillation that enables attentional flexibility, but may also contribute to unintended destabilization of attention. Meditative and pranayama practices result in attentional, emotional, and physiological enhancements that may be partially due to the LC's pivotal role as the nexus in this coupled system. We present original findings of synchronization between respiration and LC activity (via fMRI and pupil dilation) and provide evidence of a relationship between respiratory phase modulation and attentional performance. We also present a mathematical dynamical systems model of respiratory-LC-attentional coupling, review candidate neurophysiological mechanisms of changes in coupling dynamics, and discuss implications for attentional theory, meditation, and pranayama, and possible therapeutic applications.

Transcutaneous vagus nerve stimulation (tVNS) modulates flow experience.

Flow has been defined as a pleasant psychological state that people experience when completely absorbed in an activity. Previous correlative evidence showed that the vagal tone (as indexed by heart rate variability) is a reliable marker of flow. So far, it has not yet been demonstrated that the vagus nerve plays a causal role in flow. To explore this we used transcutaneous vagus nerve stimulation (tVNS), a novel non-invasive brain stimulation technique that increases activation of the locus coeruleus (LC) and norepinephrine release. A sham/placebo-controlled, randomized cross-over within-subject design was employed to infer a causal relation between the stimulated vagus nerve and flow as measured using the Flow Short-Scale in 32 healthy young volunteers. In both sessions, while being stimulated, participants had to rate their flow experience after having performed a task for 30 min. Active tVNS, compared to sham stimulation, decreased flow (as indexed by absorption scores). The results can be explained by the network reset theory, which assumes that high-phasic LC activity promotes a global reset of attention over exploitation of the current focus of attention, allowing rapid behavioral adaptation and resulting in decreased absorption scores. Furthermore, our findings corroborate the hypothesis that the vagus nerve and noradrenergic system are causally involved in flow.

Morphological correlates of sex differences in acoustic startle response and prepulse inhibition through projections from locus coeruleus to cochlear root neurons.

The noradrenergic locus coeruleus (LC) plays an important role in the promotion and maintenance of arousal and alertness. Our group recently described coerulean projections to cochlear root neurons (CRNs), the first relay of the primary acoustic startle reflex (ASR) circuit. However, the role of the LC in the ASR and its modulation, prepulse inhibition (PPI), is not clear. In this study, we damaged LC neurons and fibers using a highly selective neurotoxin, DSP-4, and then assessed ASR and PPI in male and female rats. Our results showed that ASR amplitude was higher in males at 14 days after DSP-4 injection when compared to pre-administration values and those in the male control group. Such modifications in ASR amplitude did not occur in DSP-4-injected females, which exhibited ASR amplitude within the range of control values. PPI differences between males and females seen in controls were not observed in DSP-4-injected rats for any interstimulus interval tested. DSP-4 injection did not affect ASR and PPI latencies in either the male or the female groups, showing values that were consistent with the sex-related variability observed in control rats. Furthermore, we studied the noradrenergic receptor system in the cochlear nerve root using gene expression analysis. When compared to controls, DSP-4-injected males showed higher levels of expression in all adrenoceptor subtypes; however, DSP-4-injected females showed varied effects depending on the receptor type, with either up-, downregulations, or maintenance of expression levels. Lastly, we determined noradrenaline levels in CRNs and other LC-targeted areas using HPLC assays, and these results correlated with behavioral and adrenoceptor expression changes post DSP-4 injection. Our study supports the participation of LC in ASR and PPI, and contributes toward a better understanding of sex-related differences observed in somatosensory gating paradigms.

[Acupuncture at Shangjuxu (ST37) to Inhibit Distention of Colon Induced Discharge Reaction of LC: an Experimental Study].

OBJECTIVE: To study possible mechanisms of Shangjuxu (ST37) and the large intestine. METHODS: Totally 40 SD rats were selected. The distension of end colon was used as injured afferent stimulus. Activities of locus coeruleus (LC) neurons were recorded by extracellular microelectrode technique. Shangjuxu (ST37) and Hegu (L14) were needled to observe general features of discharge reactions, distention of colon induced discharge reactions of LC, and its effects on distention of colon induced discharge reactions of LC. RESULTS: Distention of colon could induce incrased discharge of LC neurons by 127.33% ± 45.48%. But needling at Shangjuxu (ST37) and Hegu (L14) could inhibit this injured response by 38.24% ± 7.69% and 21.29% ± 13.16% respectively (all P < 0.01). CONCLUSIONS: Needling at Shangjuxu (ST37) and afferent signals of colon distension converged and interacted with each other. Needling at Shangjuxu (ST37) could significantly inhibit colon distension induced discharge of LC neurons, which might be one of mechanisms for Shangjuxu (ST37) and the large intestine relationship.

Neural substrates underlying the tendency to accept anger-infused ultimatum offers during dynamic social interactions.

In managing our way through interpersonal conflict, anger might be crucial in determining whether the dispute escalates to aggressive behaviors or resolves cooperatively. The Ultimatum Game (UG) is a social decision-making paradigm that provides a framework for studying interpersonal conflict over division of monetary resources. Unfair monetary UG-offers elicit anger and while accepting them engages regulatory processes, rejecting them is regarded as an aggressive retribution. Ventro-medial prefrontal-cortex (vmPFC) activity has been shown to relate to idiosyncratic tendencies in accepting unfair offers possibly through its role in emotion regulation. Nevertheless, standard UG paradigms lack fundamental aspects of real-life social interactions in which one reacts to other people in a response contingent fashion. To uncover the neural substrates underlying the tendency to accept anger-infused ultimatum offers during dynamic social interactions, we incorporated on-line verbal negotiations with an obnoxious partner in a repeated-UG during fMRI scanning. We hypothesized that vmPFC activity will differentiate between individuals with high or low monetary gains accumulated throughout the game and reflect a divergence in the associated emotional experience. We found that as individuals gained more money, they reported less anger but also more positive feelings and had slower sympathetic response. In addition, high-gain individuals had increased vmPFC activity, but also decreased brainstem activity, which possibly reflected the locus coeruleus. During the more angering unfair offers, these individuals had increased dorsal-posterior Insula (dpI) activity which functionally coupled to the medial-thalamus (mT). Finally, both vmPFC activity and dpI-mT connectivity contributed to increased gain, possibly by modulating the ongoing subjective emotional experience. These ecologically valid findings point towards a neural mechanism that might nurture pro-social interactions by modulating an individual's dynamic emotional experience.

Non-invasive Access to the Vagus Nerve Central Projections via Electrical Stimulation of the External Ear: fMRI Evidence in Humans.

BACKGROUND: Tract-tracing studies in cats and rats demonstrated that the auricular branch of the vagus nerve (ABVN) projects to the nucleus tractus solitarii (NTS); it has remained unclear as to whether or not the ABVN projects to the NTS in humans. OBJECTIVE: To ascertain whether non-invasive electrical stimulation of the cymba conchae, a region of the external ear exclusively innervated by the ABVN, activates the NTS and the "classical" central vagal projections in humans. METHODS: Twelve healthy adults underwent two fMRI scans in the same session. Electrical stimulation (continuous 0.25ms pulses, 25Hz) was applied to the earlobe (control, scan #1) and left cymba conchae (scan #2). Statistical analyses were performed with FSL. Two region-of-interest analyses were performed to test the effects of cymba conchae stimulation (compared to baseline and control, earlobe, stimulation) on the central vagal projections (corrected; brainstem P < 0.01, forebrain P < 0.05), followed by a whole-brain analysis (corrected, P < 0.05). RESULTS: Cymba conchae stimulation, compared to earlobe (control) stimulation, produced significant activation of the "classical" central vagal projections, e.g., widespread activity in the ipsilateral NTS, bilateral spinal trigeminal nucleus, dorsal raphe, locus coeruleus, and contralateral parabrachial area, amygdala, and nucleus accumbens. Bilateral activation of the paracentral lobule was also observed. Deactivations were observed bilaterally in the hippocampus and hypothalamus. CONCLUSION: These findings provide evidence in humans that the central projections of the ABVN are consistent with the "classical" central vagal projections and can be accessed non-invasively via the external ear.

Altered hypothalamic functional connectivity with autonomic circuits and the locus coeruleus in migraine.

The hypothalamus has been implicated in migraine based on the manifestation of autonomic symptoms with the disease, as well as neuroimaging evidence of hypothalamic activation during attacks. Our objective was to determine functional connectivity (FC) changes between the hypothalamus and the rest of the brain in migraine patients vs. control subjects. This study uses fMRI (functional magnetic resonance imaging) to acquire resting state scans in 12 interictal migraine patients and 12 healthy matched controls. Hypothalamic connectivity seeds were anatomically defined based on high-resolution structural scans, and FC was assessed in the resting state scans. Migraine patients had increased hypothalamic FC with a number of brain regions involved in regulation of autonomic functions, including the locus coeruleus, caudate, parahippocampal gyrus, cerebellum, and the temporal pole. Stronger functional connections between the hypothalamus and brain areas that regulate sympathetic and parasympathetic functions may explain some of the hypothalamic-mediated autonomic symptoms that accompany or precede migraine attacks.