Traumatic Events, Posttraumatic Stress Disorder, and Central Sensitization in Chronic Pain Patients of a German University Outpatient Pain Clinic.

OBJECTIVE: Posttraumatic stress disorder (PTSD) and traumatic life events are often coupled to chronic pain, possibly linked by central sensitization. We wanted to assess the prevalence of traumatic events and PTSD in chronic pain patients of a German university hospital outpatient pain clinic. Moreover, we evaluated the extent of indicators and co-occurring traits of central sensitization in comorbid patients. METHODS: We retrospectively divided 914 chronic pain patients into four groups depending on their trauma severity: no trauma, accidental trauma, interpersonal trauma, and PTSD. We collected electronic pain drawings focusing on pain area and widespreadness, as well as information about pain intensity, sleep impairment, disability, stress, anxiety, depression, and somatization. Differences between groups were calculated using Kruskal-Wallis with post-hoc Mann-Whitney tests. RESULTS: Of 914 patients, 231 (25%) had no trauma, 210 (23%) had accidental traumas, 283 (31%) had interpersonal traumas, 99 (11%) had PTSD, and 91 (10%) could not be classified. We observed statistically significant differences between groups in pain area and widespreadness, as well as maximal pain, sleep impairment, disability, stress, anxiety, depression, and somatization. The severity of symptoms increased with trauma severity. CONCLUSIONS: Traumatic life events and PTSD are frequent in chronic pain patients. The increased pain area and widespreadness, as well as the increased negative impact on co-occurring traits of sensory sensitivity (anxiety, depression, somatization), are compatible with central sensitization in comorbid patients. Therefore, a heightened awareness of the comorbidity between traumatic experiences and chronic pain is recommended.

The Central Inflammatory Network: A Hypothalamic fMRI Study of Experimental Endotoxemia in Humans.

INTRODUCTION: Inflammation is a mechanism of the immune system that is part of the reaction to pathogens or injury. The central nervous system closely regulates inflammation via neuroendocrine or direct neuroimmune mechanisms, but our current knowledge of the underlying circuitry is limited. Therefore, we aimed to identify hypothalamic centres involved in sensing or modulating inflammation and to study their association with known large-scale brain networks. METHODS: Using high-resolution functional magnetic resonance imaging (fMRI), we recorded brain activity in healthy male subjects undergoing experimental inflammation from intravenous endotoxin. Four fMRI runs covered key phases of the developing inflammation: pre-inflammatory baseline, onset of endotoxemia, onset of pro-inflammatory cytokinemia, and peak of pro-inflammatory cytokinemia. Using masked independent component analysis, we identified functionally homogeneous subregions of the hypothalamus, which were further tested for changes in functional connectivity during inflammation and for temporal correlation with tumour necrosis factor and adrenocorticotropic hormone serum levels. We then studied the connection of these inflammation-associated hypothalamic subregions with known large-scale brain networks. RESULTS: Our results show that there are at least 6 hypothalamic subregions associated with inflammation in humans including the paraventricular nucleus, supraoptic nucleus, dorsomedial hypothalamus, bed nucleus of the stria terminalis, lateral hypothalamic area, and supramammillary nucleus. They are functionally embedded in at least 3 different large-scale brain networks, namely a medial frontoparietal network, an occipital-pericentral network, and a midcingulo-insular network. CONCLUSION: Measuring how the hypothalamus detects or modulates systemic inflammation is a first step to understand central nervous immunomodulation.

Combination of acupuncture and medical training therapy on tension type headache: Results of a randomised controlled pilot study.

OBJECTIVES: The aim of this study was to compare the effects of acupuncture and medical training therapy alone and in combination with those of usual care on the pain sensation of patients with frequent episodic and chronic tension-type headache. DESIGN: This was a prospective single-centre randomised controlled trial with four balanced treatment arms. The allocation was carried out by pre-generated randomisation lists in the ratio 1:1:1:1 with different permutation block sizes. SETTING: The study was undertaken in the outpatient clinic of Rehabilitation Medicine of the Hannover Medical School.Participants and interventions: Ninety-six adult patients with tension-type headache were included and randomised into usual care (n = 24), acupuncture (n = 24), medical training (n = 24), and combination of acupuncture and medical training (n = 24). One patient was excluded from analysis because of withdrawing her/his consent, leaving 95 patients for intention to treat analysis. Each therapy arm consisted of 6 weeks of treatment with 12 interventions. Follow-up was at 3 and 6 months. MAIN OUTCOME MEASURES: Pain intensity (average, maximum and minimum), frequency of headache, responder rate (50% frequency reduction), duration of headache and use of headache medication.Clinical results: The combination of acupuncture and medical training therapy significantly reduced mean pain intensity compared to usual care (mean = -38%, standard deviation = 25%, p = 0.012). Comparable reductions were observed for maximal pain intensity (-25%, standard deviation = 20%, 0.014) and for minimal pain intensity (-35%, standard deviation = 31%, 0.03). In contrast, neither acupuncture nor medical training therapy differed significantly from usual care. No between-group differences were found in headache frequency, mean duration of headache episodes, and pain medication intake. At 3 months, the majority of all patients showed a reduction of at least 50% in headache frequency. At 6 months, significantly higher responder rates were found in all intervention groups compared to usual care. CONCLUSIONS: In contrast to monotherapy, only the combination of acupuncture and medical training therapy was significantly superior in reduction of pain intensity compared to usual care.Trial registration: Registered on 11 February 2019. German Clinical Trials Register, DRKS00016723.

Lateralization and Bodily Patterns of Segmental Signs and Spontaneous Pain in Acute Visceral Disease: Observational Study.

BACKGROUND: The differential diagnosis of acute visceral diseases is a challenging clinical problem. Older literature suggests that patients with acute visceral problems show segmental signs such as hyperalgesia, skin resistance, or muscular defense as manifestations of referred visceral pain in somatic or visceral tissues with overlapping segmental innervation. According to these sources, the lateralization and segmental distribution of such signs may be used for differential diagnosis. Segmental signs and symptoms may be accompanied by spontaneous (visceral) pain, which, however, shows a nonsegmental distribution. OBJECTIVE: This study aimed to investigate the lateralization (ie, localization on one side of the body, in preference to the other) and segmental distribution (ie, surface ratio of the affected segments) of spontaneous pain and (referred) segmental signs in acute visceral diseases using digital pain drawing technology. METHODS: We recruited 208 emergency room patients that were presenting for acute medical problems considered by triage as related to internal organ disease. All patients underwent a structured 10-minute bodily examination to test for various segmental signs and spontaneous visceral pain. They were further asked their segmental symptoms such as nausea, meteorism, and urinary retention. We collected spontaneous pain and segmental signs as digital drawings and segmental symptoms as binary values on a tablet PC. After the final diagnosis, patients were divided into groups according to the organ affected. Using statistical image analysis, we calculated mean distributions of pain and segmental signs for the heart, lungs, stomach, liver/gallbladder, and kidneys/ureters, analyzing the segmental distribution of these signs and the lateralization. RESULTS: Of the 208 recruited patients, 110 (52.9%) were later diagnosed with a single-organ problem. These recruited patients had a mean age of 57.3 (SD 17.2) years, and 40.9% (85/208) were female. Of these 110 patients, 85 (77.3%) reported spontaneous visceral pain. Of the 110, 81 (73.6%) had at least 1 segmental sign, and the most frequent signs were hyperalgesia (46/81, 57%), and muscle resistance (39/81, 48%). While pain was distributed along the body midline, segmental signs for the heart, stomach, and liver/gallbladder appeared mostly ipsilateral to the affected organ. An unexpectedly high number of patients (37/110, 33.6%) further showed ipsilateral mydriasis. CONCLUSIONS: This study underlines the usefulness of including digitally recorded segmental signs in bodily examinations of patients with acute medical problems.

Human subsystems of medial temporal lobes extend locally to amygdala nuclei and globally to an allostatic-interoceptive system.

In mammals, the hippocampus, entorhinal, perirhinal, and parahippocampal cortices (i.e., core regions of the human medial temporal lobes, MTL) are locally interlaced with the adjacent amygdala nuclei at the structural and functional levels. At the global brain level, the human MTL has been described as part of the default mode network and amygdala nuclei as parts of the salience network, with both networks collectively forming a large-scale brain system supporting allostatic-interoceptive functions. We hypothesized (i) that intrinsic functional connectivity of slow activity fluctuations would reveal human MTL subsystems locally extending to the amygdala; and (ii) that these extended local subsystems would be globally embedded in large-scale brain systems supporting allostatic-interoceptive functions. Capitalizing on resting-state fMRI data of three independent samples of cognitively healthy adults (one main and two replication samples: N â€‹= â€‹101, 60, and 29, respectively), we analyzed the functional connectivity of fluctuating ongoing BOLD-activity within and outside the amygdala-MTL in a data-driven way using masked independent component and dual-regression analyses. We found that at the local level, MTL subsystems extend to the amygdala and are functionally organized along the longitudinal amygdala-MTL axis. These subsystems are characterized by consistent involvement of amygdala, hippocampus, and entorhinal cortex, but variable participation of perirhinal and parahippocampal regions. At the global level, amygdala-MTL subsystems selectively connect to salience, thalamic-brainstem, and default mode networks - the major cortical and subcortical components of the allostatic-interoceptive system. These findings provide evidence for integrated amygdala-MTL subsystems in humans, which are embedded within a larger allostatic-interoceptive system.

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 structure's 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 Parkinson's disease, and explore promising future directions for further improvements in brainstem imaging using UHF MRI techniques.

The neuropsychophysiology of tingling.

Tingling is a bodily sensation experienced under a variety of conditions from everyday experiences to experimental and therapeutic situations. It can be induced by both peripheral or afferent (external stimulation, peripheral pathology) and higher cognitive (expectation) processes. The paper summarizes the current scientific knowledge on the neurophysiological and psychological concomitants of the tingling sensation. Four possible models are identified and presented: the afferent, the attention-disclosed, the attention-evoked, and the efferent model. Of these, only the attention-disclosed model, i.e., attention discloses the sensation by opening the gate for suppressed sensory information, appears to be able to explain every aspect of the tingling phenomenon. Terminological issues and the possible role of the tingling phenomenon in medically unexplained symptoms, nocebo and placebo reactions, and body-oriented therapeutic interventions are also discussed.

Brain Circuitry Supporting Multi-Organ Autonomic Outflow in Response to Nausea.

While autonomic outflow is an important co-factor of nausea physiology, central control of this outflow is poorly understood. We evaluated sympathetic (skin conductance level) and cardiovagal (high-frequency heart rate variability) modulation, collected synchronously with functional MRI (fMRI) data during nauseogenic visual stimulation aimed to induce vection in susceptible individuals. Autonomic data guided analysis of neuroimaging data, using a stimulus-based (analysis windows set by visual stimulation protocol) and percept-based (windows set by subjects' ratings) approach. Increased sympathetic and decreased parasympathetic modulation was associated with robust and anti-correlated brain activity in response to nausea. Specifically, greater autonomic response was associated with reduced fMRI signal in brain regions such as the insula, suggesting an inhibitory relationship with premotor brainstem nuclei. Interestingly, some sympathetic/parasympathetic specificity was noted. Activity in default mode network and visual motion areas was anti-correlated with parasympathetic outflow at peak nausea. In contrast, lateral prefrontal cortical activity was anti-correlated with sympathetic outflow during recovery, soon after cessation of nauseogenic stimulation. These results suggest divergent central autonomic control for sympathetic and parasympathetic response to nausea. Autonomic outflow and the central autonomic network underlying ANS response to nausea may be an important determinant of overall nausea intensity and, ultimately, a potential therapeutic target.

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. © 2016 Wiley Periodicals, Inc.

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. © 2015 Wiley Periodicals, Inc.

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.

Advances in functional magnetic resonance imaging of the human brainstem.

The brainstem is of tremendous importance for our daily survival, and yet the functional relationships between various nuclei, their projection targets, and afferent regulatory areas remain poorly characterized. The main reason for this lies in the sub-optimal performance of standard neuroimaging methods in this area. In particular, fMRI signals are much harder to detect in the brainstem region compared to cortical areas. Here we describe and validate a new approach to measure activation of brainstem nuclei in humans using standard fMRI sequences and widely available tools for statistical image processing. By spatially restricting an independent component analysis to an anatomically defined brainstem mask, we excluded those areas from the analysis that were strongly affected by physiological noise. This allowed us to identify for the first time intrinsic connectivity networks in the human brainstem and to map brainstem-cortical connectivity purely based on functionally defined regions of interest.

Nurturing Hope: Reproductive Outcomes with Sinosomatics following Unsuccessful in vitro Fertilization Attempts.

INTRODUCTION: For women who have experienced failed attempts at in vitro fertilization (IVF) and face medical issues, leading to infertility, the renewed effort to seek fertility treatment, coupled with decreasing likelihood of success, can exert substantial emotional and physical strains. Consequently, many couples opt to discontinue treatment before attaining pregnancy. The objective of this study was to evaluate the reproductive outcomes in patients with unsuccessful prior IVF attempts who received a complementary treatment designed to alleviate emotional distress and burden. PATIENTS AND METHODS: A retrospective analysis of data from infertile patients who initiated the complementary intervention at a private clinic between January 2014 and December 2016 was conducted. Information on diagnosis, history of infertility, prior assisted reproductive technology treatments, mode of conception, and pregnancy outcomes were retrieved. RESULTS: The data of 133 patients with a history of one or more unsuccessful IVF treatments were analyzed. Patients had an average age of 36.7 years (±4.4 SD) and had been experiencing infertility for an average of 4.6 years (±2.7 SD). The two main causes of their infertility were endometriosis (36.1%, 48 patients) and diminished egg quality (31.6%, 42 patients). By May 2020, a significant proportion of the patients, 81.2% (108 patients), had achieved pregnancy, leading to 94 live births, which represents a 70.7% success rate. These pregnancies mostly resulted from natural cycle IVF (35.1%), donor cycles (23.4%), and conventional IVF (21.3%). The dropout rate was comparatively low at 23.3%. The median time from the start of complementary treatment to delivery was 18 months, with a range of 12-28 months. CONCLUSIONS: This study highlights the potential value of complementary treatment approaches in conjunction with standard medical care for women who have experienced unsuccessful IVF treatments in the past and thus face a reduced chance of motherhood. The reported 71% live birth rate is notably high, indicating that the inclusion of complementary treatments may provide women with past IVF failures a tangible opportunity for achieving successful pregnancy and childbirth. However, these findings need to be confirmed through randomized controlled studies.

Acupuncture--deep pain with an autonomic dimension?

Stimulation of acupuncture point Pc6, located above the median nerve, has been shown to be effective in treating nausea and vomiting. It has also frequently been reported to cause a heart rate reduction. The mechanism behind this autonomic reaction has not been clarified, so far. We combined brainstem-sensitive functional magnetic resonance imaging with heart rate recording and time-resolved rating of the needling sensation to measure neuronal correlates of sensations and autonomic reactions during acupuncture. On the cortical level, needling sensation activated typical pain-related areas, of which the ventromedial and dorsolateral prefrontal cortex and perigenual anterior cingulate cortex were further involved in mediating the heart rate response. In the brainstem, needling sensation activated nuclei of the descending pain control system, in which a network of hypothalamus, periaqueductal gray, rostral ventromedial medulla, and ventrolateral medulla was identified as the source of the heart rate changes. Our findings indicate that acupuncture may be a special pain stimulus, whose autonomic concomitants could explain its non-analgesic effects and in some cases even have a therapeutic potential.

Investigation of Acupuncture Sensation Patterns under Sensory Deprivation Using a Geographic Information System.

The study of acupuncture-related sensations, like deqi and propagated sensations along channels (PSCs), has a long tradition in acupuncture basic research. The phenomenon itself, however, remains poorly understood. To study the connection between PSC and classical meridians, we applied a geographic information system (GIS) to analyze sketches of acupuncture sensations from healthy volunteers after laser acupuncture. As PSC can be subtle, we aimed at reducing the confounding impact of external stimuli by carrying out the experiment in a floatation tank under restricted environmental stimulation. 82.4% of the subjects experienced PSC, that is, they had line-like or 2-dimensional sensations, although there were some doubts that these were related to the laser stimulation. Line-like sensations on the same limb were averaged to calculate sensation mean courses, which were then compared to classical meridians by measuring the mean distance between the two. Distances ranged from 0.83 cm in the case of the heart (HT) and spleen (SP) meridian to 6.27 cm in the case of the kidney (KI) meridian. Furthermore, PSC was observed to "jump" between adjacent meridians. In summary, GIS has proven to be a valuable tool to study PSC, and our results suggest a close connection between PSC and classical meridians.

Do Chest Compresses with Mustard or Ginger Affect Warmth Regulation in Healthy Adults? A Randomized Controlled Trial.

Background: Chest compresses with mustard (MU) or ginger (GI) are a complementary treatment option for respiratory tract infections. However, little is known about their specific thermogenic qualities. This study examines the short-term effects of MU, GI, and chest compresses with warm water only (WA) on measurable and self-perceived body warmth in healthy adults. Methods: This was a single-center, randomized controlled trial with cross-over design (WA versus MU versus GI). 18 participants (23.7 ± 3.4 years; 66.7% female) received MU, GI, and WA in a random order on three different days with a mean washout period of 13.9 days. Chest compresses were applied to the thoracic back for a maximum of 20 minutes. The primary outcome measure was skin temperature of the posterior trunk (measured by infrared thermography) immediately following removal of the compresses (t1). Secondary outcome measures included skin temperature of the posterior trunk 10 minutes later (t2) and several parameters of self-perceived warmth at t1 and t2 (assessed with the Herdecke Warmth Perception Questionnaire). Results: Skin temperature of the posterior trunk was significantly higher with MU compared to WA and GI at t1 (p < 0.001 for both, primary outcome measure) and t2 (WA versus MU: p=0.04, MU versus GI: p < 0.01). Self-perceived warmth of the posterior trunk was higher with MU and GI compared to WA at t1 (1.40 ≥ d ≥ 1.79) and remained higher with GI at t2 (WA versus GI: d = 0.74). The overall warmth perception increased significantly with GI (d = 0.69), tended to increase with MU (d = 0.54), and did not change with WA (d = 0.36) between t0 and t1. Conclusions: Different effects on warmth regulation were observed when ginger and mustard were applied as chest compresses. Both substances induced self-perceived warming of the posterior trunk, but measurable skin temperature increased only with MU. Further research is needed to examine the duration of these thermogenic effects and how chest compresses with ginger or mustard might be incorporated into practice to influence clinical outcomes in respiratory tract infections.

The Immediate Effect of Sinapis nigra and Zingiber officinale as Thermogenic Substances during Footbaths: A Randomized Controlled Crossover Trial.

OBJECTIVE: Warm footbaths infused with Sinapis nigra (mustard, or MU) or Zingiber officinale (ginger, or GI) are used for various thermoregulatory conditions, but little is known about how they are perceived by individuals, both short- and long-term. We analyzed the immediate and long-term effects of MU and GI on warmth and stimulus perception in healthy adults. METHODS: Seventeen individuals (mean age 22.1±2.4 years; 11 female) received three footbaths (mean temperature was 40 ± 0.2°C, administered between 1:30 and 6:30 p.m.) in a randomized order with a crossover design: 1. with warm water only (WA), 2. with warm water and MU, and 3. with warm water and GI. Warmth and stimulus perception at the feet were assessed at the 1st, 5th, 10th, 15th, and 20th minute of the footbaths, in the late evening (EVE), and the following morning (MG). We further assessed well-being (at EVE and MG) and sleep quality (at MG). The primary outcome measure was the warmth perception at the feet at the 10th minute of the footbath. RESULTS: At the 10th minute of the footbath, warmth perception at the feet was significantly higher with MU and GI compared to WA. The immediate thermogenic effects pointed to a quick increase in warmth and stimulus perception with MU, a slower increase with GI, and a gradual decrease with WA. Regarding the long-term effects, warmth and stimulus perception were still higher after GI compared to WA at EVE and MG. No differences were seen for general well-being and sleep quality. CONCLUSION: Thermogenic substances can significantly alter the dynamics of warmth and stimulus perception when added to footbaths. The different profiles in the application of GI and MU could be relevant for a more differentiated and specific use of both substances in different therapeutic indications.

fMRI of the brainstem using dual-echo EPI.

The brainstem is the part of the human brain that plays a pivotal role in the maintenance of many critical body functions. Due to the elevated level of cardiogenic noise, few fMRI studies have investigated the brainstem so far. Cardiac-gated echo-planar imaging with acquisition of two echoes per excitation (dual-echo EPI) is one method that significantly reduces cardiogenic noise and, thus, allows for fMRI measurements of the brainstem. As information on optimal preprocessing approaches for brainstem-fMRI data is still scarce, the goal of this study was to compare different combinations of normalization and smoothing procedures as implemented in standard fMRI software packages and to identify the combinations yielding optimal results for dual-echo EPI. 21 healthy subjects were measured while executing a simple motor paradigm to activate the facial and trigeminal motor nucleus in the brainstem. After motion correction and calculation of T(2)*-maps the data were preprocessed with 24 combinations of standard normalization (SPM classic, SPM unified, FSL, ABC) and smoothing procedures (pre-/post-smoothing with 3mm-, 4.5mm- and 6mm-kernel) before undergoing first- and second-level statistical analysis. Activation results were compared for first-level and second-level statistics using two anatomically defined regions of interest. Five methods were found to be sensitive for activation of both nuclei. These included FSL normalization with 3mm and 4.5mm pre-smoothing as well as 3mm post-smoothing, SPM unified normalization with 3mm pre-smoothing and ABC normalization with 4.5mm pre-smoothing. All these methods can be recommended for normalization and smoothing when analyzing fMRI data of the brainstem acquired by cardiac-gated dual-echo EPI.

Resting state fMRI reveals increased subthalamic nucleus-motor cortex connectivity in Parkinson's disease.

Parkinson's disease (PD) is associated with abnormal hypersynchronicity in basal ganglia-thalamo-cortical loops. The clinical effectiveness of subthalamic nucleus (STN) high frequency stimulation indicates a crucial role of this nucleus within the affected motor networks in PD. Here we investigate alterations in the functional connectivity (FC) profile of the STN using resting state BOLD correlations on a voxel-by-voxel basis in functional magnetic resonance imaging (fMRI). We compared early stage PD patients (n=31) during the medication-off state with healthy controls (n=44). The analysis revealed increased FC between the STN and cortical motor areas (BA 4 and 6) in PD patients in accordance with electrophysiological studies. Moreover, FC analysis of the primary motor cortex (M1) hand area revealed that the FC increase was primarily found in the STN area within the basal ganglia. These findings are in good agreement with recent experimental data, suggesting that an increased STN-motor cortex synchronicity mediated via the so called hyperdirect motor cortex-subthalamic pathway might play a fundamental role in the pathophysiology of PD. An additional subgroup analysis was performed according to the presence (n=16) or absence (n=15) of tremor in patients. Compared to healthy controls tremor patients showed increased STN FC specifically in the hand area of M1 and the primary sensory cortex. In non-tremor patients, increased FC values were also found between the STN and midline cortical motor areas including the SMA. Taken together our results underline the importance of the STN as a key node for the modulation of BG-cortical motor network activity in PD patients.