Higher locus coeruleus MRI contrast is associated with lower parasympathetic influence over heart rate variability

The locus coeruleus (LC) is a key node of the sympathetic nervous system and suppresses parasympathetic activity that would otherwise increase heart rate variability. In the current study, we examined whether LC-MRI contrast reflecting neuromelanin accumulation in the LC was associated with high-frequency heart rate variability (HF-HRV), a measure reflecting parasympathetic influences on the heart. Recent evidence indicates that neuromelanin, a byproduct of catecholamine metabolism, accumulates in the LC through young and mid adulthood, suggesting that LC-MRI contrast may be a useful biomarker of individual differences in habitual LC activation. We found that, across younger and older adults, greater LC-MRI contrast was negatively associated with HF-HRV during fear conditioning and spatial detection tasks. This correlation was not accounted for by individual differences in age or anxiety. These findings indicate that individual differences in LC structure relate to key cardiovascular parameters

Neurophysiological investigations of drug resistant epilepsy patients treated with vagus nerve stimulation to differentiate responders from non-responders

Background and purpose In patients treated with vagus nerve stimulation (VNS) for drug resistant epilepsy (DRE), up to a third of patients will eventually not respond to the therapy. As VNS therapy requires surgery for device implantation, prediction of response prior to surgery is desirable. It is hypothesized that neurophysiological investigations related to the mechanisms of action of VNS may help to differentiate VNS responders from non-responders prior to the initiation of therapy. Methods In a prospective series of DRE patients, polysomnography, heart rate variability (HRV) and cognitive event related potentials were recorded. Polysomnography and HRV were repeated after 1 year of treatment with VNS. Polysomnography, HRV and cognitive event related potentials were compared between VNS responders (>= 50% reduction in seizure frequency) and non-responders. Results Fifteen out of 30 patients became VNS responders after 1 year of VNS treatment. Prior to treatment with VNS, the amount of deep sleep (NREM 3), the HRV high frequency (HF) power and the P3b amplitude were significantly different in responders compared to non-responders (P = 0.007; P = 0.001; P = 0.03). Conclusion Three neurophysiological parameters, NREM 3, HRV HF and P3b amplitude, were found to be significantly different in DRE patients who became responders to VNS treatment prior to initiation of their treatment with VNS. These non-invasive recordings may be used as characteristics for response in future studies and help avoid unsuccessful implantations. Mechanistically these findings may be related to changes in brain regions involved in the so-called vagal afferent network

Effect of parasympathetic stimulation on brain activity during appraisal of fearful expressions

Autonomic nervous system activity is an important component of human emotion. Mental processes influence bodily physiology, which in turn feeds back to influence thoughts and feelings. Afferent cardiovascular signals from arterial baroreceptors in the carotid sinuses are processed within the brain and contribute to this two-way communication with the body. These carotid baroreceptors can be stimulated non-invasively by externally applying focal negative pressure bilaterally to the neck. In an experiment combining functional neuroimaging (fMRI) with carotid stimulation in healthy participants, we tested the hypothesis that manipulating afferent cardiovascular signals alters the central processing of emotional information (fearful and neutral facial expressions). Carotid stimulation, compared with sham stimulation, broadly attenuated activity across cortical and brainstem regions. Modulation of emotional processing was apparent as a significant expression-by-stimulation interaction within left amygdala, where responses during appraisal of fearful faces were selectively reduced by carotid stimulation. Moreover, activity reductions within insula, amygdala, and hippocampus correlated with the degree of stimulation-evoked change in the explicit emotional ratings of fearful faces. Across participants, individual differences in autonomic state (heart rate variability, a proxy measure of autonomic balance toward parasympathetic activity) predicted the extent to which carotid stimulation influenced neural (amygdala) responses during appraisal and subjective rating of fearful faces. Together our results provide mechanistic insight into the visceral component of emotion by identifying the neural substrates mediating cardiovascular influences on the processing of fear signals, potentially implicating central baroreflex mechanisms for anxiolytic treatment targets

How Does the Body Affect the Mind? Role of Cardiorespiratory Coherence in the Spectrum of Emotions

The brain is considered to be the primary generator and regulator of emotions; however, afferent signals originating throughout the body are detected by the autonomic nervous system (ANS) and brainstem, and, in turn, can modulate emotional processes. During stress and negative emotional states, levels of cardiorespiratory coherence (CRC) decrease, and a shift occurs toward sympathetic dominance. In contrast, CRC levels increase during more positive emotional states, and a shift occurs toward parasympathetic dominance. Te dynamic changes in CRC that accompany different emotions can provide insights into how the activity of the limbic system and afferent feedback manifest as emotions. The authors propose that the brainstem and CRC are involved in important feedback mechanisms that modulate emotions and higher cortical areas. That mechanism may be one of many mechanisms that underlie the physiological and neurological changes that are experienced during pranayama and meditation and may support the use of those techniques to treat various mood disorders and reduce stress

Locus Coeruleus Magnetic Resonance Imaging in Neurological Diseases

Locus coeruleus (LC) is the main noradrenergic nucleus of the brain, and its degeneration is considered to be key in the pathogenesis of neurodegenerative diseases. In the last 15 years,MRI has been used to assess LC in vivo, both in healthy subjects and in patients suffering from neurological disorders. In this review, we summarize the main findings of LC-MRI studies, interpreting them in light of preclinical and histopathological data, and discussing its potential role as diagnostic and experimental tool

Magnetic resonance imaging of the human locus coeruleus: A systematic review

The locus coeruleus (LC), the major origin of noradrenergic modulation of the central nervous system, innervates extensive areas throughout the brain and is implicated in a variety of autonomic and cognitive functions. Alterations in the LC-noradrenergic system have been associated with healthy ageing and neuropsychiatric disorders including Parkinson's disease, Alzheimer's disease and depression. The last decade has seen advances in imaging the structure and function of the LC, and this paper systematically reviews the methodology and outcomes of sixty-nine structural and functional MRI studies of the LC in humans. Structural MRI studies consistently showed lower LC signal intensity and volume in clinical groups compared to healthy controls. Within functional studies, the LC was activated by a variety of tasks/stimuli and had functional connectivity to a range of brain regions. However, reported functional LC location coordinates were widely distributed compared to previously published neuroanatomical locations. Methodological and demographic factors potentially contributing to these differences are discussed, together with recommendations to optimize the reliability and validity of future LC imaging studies

The locus coeruleus: the central relay between neuronal network activation and sympathetic responses in cognitive control

The ability of humans to integrate different body processes is most important for survival. The neuro-visceral integration model suggests that both cognitions and emotions are regulated by superior brain systems also involved in the regulation of autonomic function. Therefore, cognitive performance and affective processing is closely linked to autonomic responses. In order to improve the understanding of human behavior and associated dysfunctions, we need to acquire a better understanding of the interplay between the central nervous system (CNS) and peripheral autonomic nervous system (ANS) in cognitive control. A pivotal role of the noradrenergic neurotransmitter system in cognitive control has been suggested. In the present thesis, functional fMRI was used to expand our knowledge of the brain body interaction in cognitive control with the locus coeruleus (LC), which is the main production site of noradrenaline in the brain, as central relay nucleus. Broad functional connections of the LC to cortical and subcortical regions predominantly involved in executive function were found. The paramount importance of the LC in cognitive control was emphasized by an increase of its activation proportional to the increase of cognitive load. In patients with schizophrenia, this relation was absent indicating a deficient role of the LC-noradrenergic system. Furthermore, LC BOLD activation was associated with pupillary dilation which supports the interpretation of the LC playing a pivotal role in controlling sympathetic autonomic function. With these findings, I was able to link the cognitive control network to the sympathetic nervous system with the LC as central relay nucleus. Thus, the present thesis contributes to an extension of the current state-of-the-art in neuropsychology.Die Fähigkeit des menschlichen Körpers verschiedenste Prozesse zu integrieren garantiert das Überleben. Das Neuroviszerale Integrationsmodell geht davon aus, dass Kognitionen sowie Emotionen von übergeordneten kortikalen Netzwerken reguliert werden, die ebenfalls für die Regulation unseres autonomen Nervensystems zuständig sind. Demzufolge sind die kognitive Leistungsfähigkeit sowie affektive Verarbeitungsprozesse sehr eng mit Reaktionen des sympathischen und parasympathischen Nervensystems assoziiert. Das bessere Verständnis der Interaktion zwischen dem zentralen und peripher autonomen Nervensystem ist essentiell, um menschliches Verhalten sowie daraus resultierende Dysfunktionen einordnen und behandeln zu können. In Zusammenhang mit kognitiven Kontrollprozessen hebt die aktuelle Studienlage zunehmend die besondere Rolle des Neurotransmitters Noradrenalin hervor. Mittels funktioneller Magnetresonanztomografie wurde in der vorliegenden Dissertation eine Erweiterung des Verständnisses der wechselseitigen Beziehung zwischen dem zentralen und autonomen Nervensystem während kognitiver Kontrollprozesse untersucht. Der Locus coeruleus (LC), der den Hauptlieferanten von Noradrenalin im Gehirn darstellt, wurde als zentrale Umschaltstruktur angenommen. Weit verzweigte funktionelle Konnektivitäten des LC zu kortikalen und subkortikalen Strukturen des kognitiven Kontrollnetzwerks konnten identifiziert werden. Die enorme Wichtigkeit des LC bei der Bearbeitung kognitiver Aufgaben wurde durch den proportionalen Anstiegt dessen Aktivierung mit kognitiver Anstrengung bestärkt. Bei an Schizophrenie erkrankten Patienten wurde dieser Zusammenhang nicht gefunden. Dies weist auf eine abnorme Funktionsweise des noradrenergen Hirnstammkerns bei diesem Störungsbild hin. Ein weiterer wichtiger Befund war die Korrelation von LC BOLD Aktivierung und Pupillenweite. Dies bestärkt die Interpretation, dass der LC eine zentrale Rolle in der Kontrolle des sympathischen Nervensystems einnimmt. Mit der vorliegenden Dissertation war es möglich das kognitive Kontrollnetzwerk mit dem sympathischen Nervensystem zu verlinken, wobei der Locus coeruleus eine zentrale Umschaltstelle darstellt. Ein wichtiger Beitrag zu den aktuellen Kenntnissen der Neuropsychologie konnte geleistet werden

Contrasting Associations Between Heart Rate Variability and Brainstem-Limbic Connectivity in Posttraumatic Stress Disorder and Its Dissociative Subtype: A Pilot Study

Background: Increasing evidence points toward the need to extend the neurobiological conceptualization of posttraumatic stress disorder (PTSD) to include evolutionarily conserved neurocircuitries centered on the brainstem and the midbrain. The reticular activating system (RAS) helps to shape the arousal state of the brain, acting as a bridge between brain and body. To modulate arousal, the RAS is closely tied to the autonomic nervous system (ANS). Individuals with PTSD often reveal altered arousal patterns, ranging from hyper- to blunted arousal states, as well as altered functional connectivity profiles of key arousal-related brain structures that receive direct projections from the RAS. Accordingly, the present study aims to explore resting state functional connectivity of the RAS and its interaction with the ANS in participants with PTSD and its dissociative subtype. Methods: Individuals with PTSD (n = 57), its dissociative subtype (PTSD + DS, n = 32) and healthy controls (n = 40) underwent a 6-min resting functional magnetic resonance imaging and pulse data recording. Resting state functional connectivity (rsFC) of a central node of the RAS – the pedunculopontine nuclei (PPN) – was investigated along with its relation to ANS functioning as indexed by heart rate variability (HRV). HRV is a prominent marker indexing the flexibility of an organism to react adaptively to environmental needs, with higher HRV representing greater effective adaptation. Results: Both PTSD and PTSD + DS demonstrated reduced HRV as compared to controls. HRV measures were then correlated with rsFC of the PPN. Critically, participants with PTSD and participants with PTSD + DS displayed inverse correlations between HRV and rsFC between the PPN and key limbic structures, including the amygdala. Whereas participants with PTSD displayed a positive relationship between HRV and PPN rsFC with the amygdala, participants with PTSD + DS demonstrated a negative relationship between HRV and PPN rsFC with the amygdala. Conclusion: The present exploratory investigation reveals contrasting patterns of arousal-related circuitry among participants with PTSD and PTSD + DS, providing a neurobiological lens to interpret hyper- and more blunted arousal states in PTSD and PTSD + DS, respectively

How Is the Norepinephrine System Involved in the Antiepileptic Effects of Vagus Nerve Stimulation?

Vagus Nerve Stimulation (VNS) is an adjunctive treatment for patients suffering from inoperable drug-resistant epilepsy. Although a complete understanding of the mediators involved in the antiepileptic effects of VNS and their complex interactions is lacking, VNS is known to trigger the release of neurotransmitters that have seizure-suppressing effects. In particular, norepinephrine (NE) is a neurotransmitter that has been associated with the clinical effects of VNS by preventing seizure development and by inducing long-term plastic changes that could restore a normal function of the brain circuitry. However, the biological requisites to become responder to VNS are still unknown. In this review, we report evidence of the critical involvement of NE in the antiepileptic effects of VNS in rodents and humans. Moreover, we emphasize the hypothesis that the functional integrity of the noradrenergic system could be a determining factor to obtain clinical benefits from the therapy. Finally, encouraging avenues of research involving NE in VNS treatment are discussed. These could lead to the personalization of the stimulation parameters to maximize the antiepileptic effects and potentially improve the response rate to the therapy