Florian Beissner

The Autonomic Brain: An Activation Likelihood Estimation Meta-Analysis for Central Processing of Autonomic Function

The autonomic nervous system (ANS) is of paramount importance for daily life. Its regulatory action on respiratory, cardiovascular, digestive, endocrine, and many other systems is controlled by a number of structures in the CNS. While the majority of these nuclei and cortices have been identified in animal models, neuroimaging studies have recently begun to shed light on central autonomic processing in humans. In this study, we used activation likelihood estimation to conduct a meta-analysis of human neuroimaging experiments evaluating central autonomic processing to localize (1) cortical and subcortical areas involved in autonomic processing, (2) potential subsystems for the sympathetic and parasympathetic divisions of the ANS, and (3) potential subsystems for specific ANS responses to different stimuli/tasks. Across all tasks, we identified a set of consistently activated brain regions, comprising left amygdala, right anterior and left posterior insula and midcingulate cortices that form the core of the central autonomic network. While sympathetic-associated regions predominate in executive- and salience-processing networks, parasympathetic regions predominate in the default mode network. Hence, central processing of autonomic function does not simply involve a monolithic network of brain regions, instead showing elements of task and division specificity.

The Somatosensory Link in Fibromyalgia: Functional Connectivity of the Primary Somatosensory Cortex Is Altered by Sustained Pain and Is Associated With Clinical/Autonomic Dysfunction

Fibromyalgia (FM) is a chronic functional pain syndrome characterized by widespread pain, significant pain catastrophizing, sympathovagal dysfunction, and amplified temporal summation for evoked pain. While several studies have demonstrated altered resting brain connectivity in FM, studies have not specifically probed the somatosensory system and its role in both somatic and nonsomatic FM symptoms. Our objective was to evaluate resting primary somatosensory cortex (S1) connectivity and to explore how sustained, evoked deep tissue pain modulates this connectivity.

A data-driven approach to mapping cortical and subcortical intrinsic functional connectivity along the longitudinal hippocampal axis.

The hippocampus (HPC) is functionally heterogeneous along the longitudinal anterior–posterior axis. In rodent models, gene expression maps define at least three discrete longitudinal subregions, which also differ in function, and in anatomical connectivity with the rest of the brain. In humans, equivalent HPC subregions are less well defined, resulting in a lack of consensus in neuroimaging approaches that limits translational study. This study determined whether a data‐driven analysis, namely independent component analysis (ICA), could reproducibly define human HPC subregions, and map their respective intrinsic functional connectivity (iFC) with the rest of the brain. Specifically, we performed ICA of resting‐state fMRI activity spatially restricted within the HPC, to determine the configuration and reproducibility of functional HPC components. Using dual regression, we then performed multivariate analysis of iFC between resulting HPC components and the whole brain, including detailed connectivity with the hypothalamus, a functionally important connection not yet characterized in human. We found hippocampal ICA resulted in highly reproducible longitudinally discrete components, with greater functional heterogeneity in the anterior HPC, consistent with animal models. Anterior hippocampal components shared iFC with the amygdala, nucleus accumbens, medial prefrontal cortex, posterior cingulate cortex, midline thalamus, and periventricular hypothalamus, whereas posterior hippocampal components shared iFC with the anterior cingulate cortex, retrosplenial cortex, and mammillary bodies. We show that spatially masked hippocampal ICA with dual regression reproducibly identifies functional subregions in the human HPC, and maps their respective brain intrinsic connectivity. Hum Brain Mapp 37:462–476, 2016.

Challenges and opportunities for brainstem neuroimaging with ultrahigh field MRI

The human brainstem plays a central role in connecting the cerebrum, the cerebellum and the spinal cord to one another, hosting relay nuclei for afferent and efferent signaling, and providing source nuclei for several neuromodulatory systems that impact central nervous system function. While the investigation of the brainstem with functional or structural magnetic resonance imaging has been hampered for years due to this brain structures physiological and anatomical characteristics, the field has seen significant advances in recent years thanks to the broader adoption of ultrahigh-field (UHF) MRI scanning. In the present review, we focus on the advantages offered by UHF in the context of brainstem imaging, as well as the challenges posed by the investigation of this complex brain structure in terms of data acquisition and analysis. We also illustrate how UHF MRI can shed new light on the neuroanatomy and neurophysiology underlying different brainstem-based circuitries, such as the central autonomic network and neurotransmitter/neuromodulator systems, discuss existing and foreseeable clinical applications to better understand diseases such as chronic pain and Parkinsons disease, and explore promising future directions for further improvements in brainstem imaging using UHF MRI techniques.

Investigating the Human Brainstem with Structural and Functional MRI

The brainstem is one of the least understood parts of the human brain despite its prime importance for the maintenance of basic vital functions. Owing to its role as a relay station between spinal cord, cerebellum, and neocortex, the brainstem contains vital nodes of all functional systems in the central nervous system, including the visual, auditory, gustatory, vestibular, somatic, and visceral senses, and the somatomotor as well as autonomic nervous systems. The brainstem also contains cholinergic, dopaminergic, noradrenergic, and serotonergic nuclei whose cortical and subcortical projections are essential to the regulation of arousal, behavior, and cognition. Despite this indisputable importance, the brainstem is still largely neglected in attempts to measure or model brain function, especially in human neuroscience. One reason for this neglect is that the anatomical characteristics of the brainstem, specifically its close vicinity to large arteries and ventricles, and the small size of its anatomical substructures, present inherent challenges to neuroimaging analysis. These properties make the brainstem a difficult structure to study with non-invasive methods like magnetic resonance imaging (MRI), as they place high demands on image acquisition as well as data analysis methods. Nevertheless, the field of brainstem-(f)MRI has significantly advanced in the past few years, largely due to the development of several new tools that facilitate studying this critical part of the human brain. Within this scope, the current goal of this research topic is to compile work representing the state of the art in functional and structural MRI of the human brainstem. We have assembled articles from a number of scientists who have made important contributions to this evolving field, and continue to shape it. The articles have been divided into a functional (Brooks et al., 2013; Henderson and Macefield, 2013; Ress and Chandrasekaran, 2013; Ritter et al., 2013) and a structural section (Deistung et al., 2013; Ford et al., 2013; Lambert et al., 2013; Yeo et al., 2013; Singleton et al., 2014). The functional section starts with a review by Brooks et al. (2013) that covers the central problem of physiological noise and presents strategies to suppress it. Ritter et al. (2013) have studied the nociceptive system and show its differential reactions to painful skin heating at different slopes. Ress and Chandrasekaran (2013) use the advantages of ultrahigh magnetic field strengths to study the substructure of the inferior colliculus and its tonotopic organization. The functional section concludes with Henderson and Macefield (2013) who provide a review of their extensive research on somatosensory and autonomic centers in the lower brainstem. The structural section begins with an article by Deistung et al. (2013) introducing quantitative susceptibility mapping as a new means to boost the identification of anatomical details in structural MRI images. Lambert et al. (2013) use quantitative MRI and tensor based morphometry in a large study sample to characterize aging in the human brainstem. Singleton et al. (2014) apply volumetric methods to demonstrate gray matter changes related to meditation and mindfulness-based intervention. Yeo et al. (2013) use probabilistic fiber tracking on diffusion-weighted images to delineate the ascending reticular activating system. Lastly, by using diffusion tensor imaging at ultra high field strengths, Ford et al. (2013) demonstrate precise tractography results of the human brainstem. The wealth of methods and applications covered by the authors indicates that functional and structural brainstem-MRI methods have developed to a point where they can be applied to study of a wide range of neuroscientific problems. It is the hope of the editors that the brainstem will soon lose its label of a terra incognita and become a region of major interest in the neuroscience community.

Placebo-Induced Somatic Sensations: A Multi-Modal Study of Three Different Placebo Interventions

Somatic sensations induced by placebos are a frequent phenomenon whose etiology and clinical relevance remains unknown. In this study, we have evaluated the quantitative, qualitative, spatial, and temporal characteristics of placebo-induced somatic sensations in response to three different placebo interventions: (1) placebo irritant solution, (2) placebo laser stimulation, and (3) imagined laser stimulation. The quality and intensity of evoked sensations were assessed using the McGill pain questionnaire and visual analogue scales (VAS), while subjects’ sensation drawings processed by a geographic information system (GIS) were used to measure their spatial characteristics. We found that all three interventions are capable of producing robust sensations most frequently described as “tingling” and “warm” that can reach consider-able spatial extent (≤ 205mm²) and intensity (≤ 80/100 VAS). Sensations from placebo stimulation were often referred to areas remote from the stimulation site and exhibit considerable similarity with referred pain. Interestingly, there was considerable similarity of qualitative features as well as spatial patterns across subjects and placebos. However, placebo laser stimulation elicited significantly stronger and more widespread sensations than placebo irritant solution. Finally, novelty seeking, a character trait assessed by the Temperament and Character Inventory and associated with basal dopaminergic activity, was less pronounced in subjects susceptible to report placebo-induced sensations. Our study has shown that placebo-induced sensations are frequent and can reach considerable intensity and extent. As multiple somatosensory subsystems are involved despite the lack of peripheral stimulus, we propose a central etiology for this phenomenon.

Neuroimaging brainstem circuitry supporting cardiovagal response to pain: A combined heart rate variability/ultrahigh-field (7 T) functional magnetic resonance imaging study

Central autonomic control nuclei in the brainstem have been difficult to evaluate non-invasively in humans. We applied ultrahigh-field (7 T) functional magnetic resonance imaging (fMRI), and the improved spatial resolution it affords (1.2 mm isotropic), to evaluate putative brainstem nuclei that control and/or sense pain-evoked cardiovagal modulation (high-frequency heart rate variability (HF-HRV) instantaneously estimated through a point-process approach). The time-variant HF-HRV signal was used to guide the general linear model analysis of neuroimaging data. Sustained (6 min) pain stimulation reduced cardiovagal modulation, with the most prominent reduction evident in the first 2 min. Brainstem nuclei associated with pain-evoked HF-HRV reduction were previously implicated in both autonomic regulation and pain processing. Specifically, clusters consistent with the rostral ventromedial medulla, ventral nucleus reticularis (Rt)/nucleus ambiguus (NAmb) and pontine nuclei (Pn) were found when contrasting sustained pain versus rest. Analysis of the initial 2-min period identified Rt/NAmb and Pn, in addition to clusters consistent with the dorsal motor nucleus of the vagus/nucleus of the solitary tract and locus coeruleus. Combining high spatial resolution fMRI and high temporal resolution HF-HRV allowed for a non-invasive characterization of brainstem nuclei, suggesting that nociceptive afference induces pain-processing brainstem nuclei to function in concert with known premotor autonomic nuclei in order to affect the cardiovagal response to pain.

Psychotherapy With Somatosensory Stimulation for Endometriosis-associated Pain: A Randomized Controlled Trial

OBJECTIVE: To evaluate whether psychotherapy with somatosensory stimulation is effective for the treatment of pain and quality of life in patients with endometriosis-related pain. METHODS: Patients with a history of endometriosis and chronic pelvic pain were randomized to either psychotherapy with somatosensory stimulation (ie, different techniques of acupuncture point stimulation) or wait-list control for 3 months, after which all patients were treated. The primary outcome was brain connectivity assessed by functional magnetic resonance imaging. Prespecified secondary outcomes included pain on 11-point numeric rating scales (maximal and average global pain, pelvic pain, dyschezia, and dyspareunia) and physical and mental quality of life. A sample size of 30 per group was planned to compare outcomes in the treatment group and the wait-list control group. RESULTS: From March 2010 through March 2012, 67 women (mean age 35.6 years) were randomly allocated to intervention (n=35) or wait-list control (n=32). In comparison with wait-list controls, treated patients showed improvements after 3 months in maximal global pain (mean group difference −2.1, 95% confidence interval [CI] −3.4 to −0.8; P=.002), average global pain (−2.5, 95% CI −3.5 to −1.4; P<.001), pelvic pain (−1.4, 95% CI −2.7 to −0.1; P=.036), dyschezia (−3.5, 95% CI −5.8 to −1.3; P=.003), physical quality of life (3.8, 95% CI 0.5–7.1, P=.026), and mental quality of life (5.9, 95% CI 0.6–11.3; P=.031); dyspareunia improved nonsignificantly (−1.8, 95% CI −4.4 to 0.7; P=.150). Improvements in the intervention group remained stable at 6 and 24 months, and control patients showed comparable symptom relief after delayed intervention. CONCLUSION: Psychotherapy with somatosensory stimulation reduced global pain, pelvic pain, and dyschezia and improved quality of life in patients with endometriosis. After 6 and 24 months, when all patients were treated, both groups showed stable improvements. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov, NCT01321840.

MICA-A toolbox for masked independent component analysis of fMRI data.

Independent component analysis (ICA) is a widely used technique for investigating functional connectivity (fc) in functional magnetic resonance imaging data. Masked independent component analysis (mICA), that is, ICA restricted to a defined region of interest, has been shown to detect local fc networks in particular brain regions, including the cerebellum, brainstem, posterior cingulate cortex, operculo‐insular cortex, hippocampus, and spinal cord. Here, we present the mICA toolbox, an open‐source GUI toolbox based on FSL command line tools that performs mICA and related analyses in an integrated way. Functions include automated mask generation from atlases, essential preprocessing, mICA‐based parcellation, back‐reconstruction of whole‐brain fc networks from local ones, and reproducibility analysis. Automated slice‐wise calculation and cropping are additional functions that reduce computational time and memory requirements for large analyses. To validate our toolbox, we tested these different functions on the cerebellum, hippocampus, and brainstem, using resting‐state and task‐based data from the Human Connectome Project. In the cerebellum, mICA detected six local networks together with their whole‐brain counterparts, closely replicating previous results. MICA‐based parcellation of the hippocampus showed a longitudinally discrete configuration with greater heterogeneity in the anterior hippocampus, consistent with animal and human literature. Finally, brainstem mICA detected motor and sensory nuclei involved in the motor task of tongue movement, thereby replicating and extending earlier results. Hum Brain Mapp 37:3544–3556, 2016.

More than DeQi: Spatial Patterns of Acupuncture-Induced Bodily Sensations

Acupuncture uses needles to stimulate certain parts of the body, inducing a specific sensation, termed DeQi, which regard as essential for acupunctures therapeutic effect. Here, we used the newly developed tool, bodily sensation mapping, to investigate the spatial configuration of acupuncture-induced sensations throughout the body. Twenty-five participants randomly received acupuncture stimulation or tactile stimulation using a von Frey filament at four different acupoints (HT7, PC6, ST36, and SP10) on the left side of the body. Subjects evaluated the characteristics of DeQi sensations and marked the areas of induced sensations on a body outline. We compared the psychophysical responses of DeQi sensations and visualized the spatial patterns of these sensations using statistical parametric mapping. We found greater intensity of DeQi sensations following acupuncture stimulation compared with tactile stimulation, with relatively small differences among the four acupoints. The sensation maps exhibited similar spatial patterns for acupuncture and tactile stimulation in the areas close to the stimulated sites. However, acupuncture was associated with additional sensations in areas remote from the stimulated sites. This study demonstrates that acupuncture stimulation produces greater DeQi sensations than tactile stimulation and results in the spreading of sensations to areas remote from the stimulus sites. Investigating the spatial patterns of acupuncture-induced sensations may be crucial for understanding the underlying mechanisms of acupuncture.