Sex disparities in popliteal artery aneurysms.

OBJECTIVE: Only 5% of patients with popliteal artery aneurysms (PAAs) are female. Evidence on PAA treatment and outcomes in women is therefore scarce. The POPART Registry provides one of Europe's largest data collections regarding PAA treatment. Data on clinical presentation, aneurysm morphology, and perioperative outcomes after open surgical PAA repair in women will be presented. METHODS: POPART is a multicenter, noninterventional registry for open and endovascular PAA repair, with 42 participating centers in Germany and Luxembourg. All patients aged >18 years who have been treated for PAA since 2010 are eligible for study inclusion. Data collection is based on an online electronic case report form. RESULTS: Of the 1236 PAAs, 58 (4.8%) were in women. There were no significant differences in age or cardiopulmonary comorbidities. However, female patients had a lower prevalence of contralateral PAAs and abdominal aortic aneurysms (P < .05). PAAs in women were more likely to be symptomatic before surgery (65.5% vs 49.4%; P = .017), with 19% of women presenting with acute limb ischemia (vs 11%; P = .067). Women had smaller aneurysm diameters than men (22.5 mm vs 27 mm; P = .004) and became symptomatic at smaller diameters (20 mm vs 26 mm; P = .002). Only 8.6% of women and 11.6% of men underwent endovascular aneurysm repair (P > .05); therefore, the perioperative outcome analysis focused on open surgical repair. In total, 23.5% of women and 16.9% of men developed perioperative complications (P > .05). There were no differences in major cardiovascular events (P > .05), but women showed a higher incidence of impaired wound healing (15.7% vs 7.2%; P = .05) and major amputation (5.9% vs 1.1%; P = .027). Female sex was significantly associated with the need for nonvascular reinterventions within 30 days after surgery (odds ratio: 2.48, 95% confidence interval: 1.26-4.88), whereas no significant differences in the odds for vascular reinterventions were observed (odds ratio: 1.98, 95% confidence interval: 0.68-5.77). In the multiple logistic regression model, female sex, symptomatic PAAs, poor quality of outflow vessels, and graft material other than vein graft were independently associated with perioperative reinterventions. CONCLUSIONS: Women have smaller PAAs, are more likely to be symptomatic before treatment, and are more often affected by nonvascular reinterventions in the perioperative course. As our understanding of aneurysmatic diseases in women continues to expand, sex-specific treatment strategies and screening options for women in well-selected cohorts with modified screening protocols should be continuously re-evaluated.

A framework for advancing sustainable magnetic resonance imaging access in Africa.

Magnetic resonance imaging (MRI) technology has profoundly transformed current healthcare systems globally, owing to advances in hardware and software research innovations. Despite these advances, MRI remains largely inaccessible to clinicians, patients, and researchers in low-resource areas, such as Africa. The rapidly growing burden of noncommunicable diseases in Africa underscores the importance of improving access to MRI equipment as well as training and research opportunities on the continent. The Consortium for Advancement of MRI Education and Research in Africa (CAMERA) is a network of African biomedical imaging experts and global partners, implementing novel strategies to advance MRI access and research in Africa. Upon its inception in 2019, CAMERA sets out to identify challenges to MRI usage and provide a framework for addressing MRI needs in the region. To this end, CAMERA conducted a needs assessment survey (NAS) and a series of symposia at international MRI society meetings over a 2-year period. The 68-question NAS was distributed to MRI users in Africa and was completed by 157 clinicians and scientists from across Sub-Saharan Africa (SSA). On average, the number of MRI scanners per million people remained at less than one, of which 39% were obsolete low-field systems but still in use to meet daily clinical needs. The feasibility of coupling stable energy supplies from various sources has contributed to the growing number of higher-field (1.5 T) MRI scanners in the region. However, these systems are underutilized, with only 8% of facilities reporting clinical scans of 15 or more patients per day, per scanner. The most frequently reported MRI scans were neurological and musculoskeletal. The CAMERA NAS combined with the World Health Organization and International Atomic Energy Agency data provides the most up-to-date data on MRI density in Africa and offers a unique insight into Africa's MRI needs. Reported gaps in training, maintenance, and research capacity indicate ongoing challenges in providing sustainable high-value MRI access in SSA. Findings from the NAS and focused discussions at international MRI society meetings provided the basis for the framework presented here for advancing MRI capacity in SSA. While these findings pertain to SSA, the framework provides a model for advancing imaging needs in other low-resource settings.

Opioid analgesia alters corticospinal coupling along the descending pain system in healthy participants.

Opioids are potent analgesic drugs with widespread cortical, subcortical, and spinal targets. In particular, the central pain system comprising ascending and descending pain pathways has high opioid receptor densities and is thus crucial for opioid analgesia. Here, we investigated the effects of the opioid remifentanil in a large sample (n = 78) of healthy male participants using combined corticospinal functional MRI. This approach offers the possibility to measure BOLD responses simultaneously in the brain and spinal cord, allowing us to investigate the role of corticospinal coupling in opioid analgesia. Our data show that opioids altered activity in regions involved in pain processing such as somatosensory regions, including the spinal cord and pain modulation such as prefrontal regions. Moreover, coupling strength along the descending pain system, that is, between the anterior cingulate cortex, periaqueductal gray, and spinal cord, was stronger in participants who reported stronger analgesia during opioid treatment while participants that received saline showed reduced coupling when experiencing less pain. These results indicate that coupling along the descending pain pathway is a potential mechanism of opioid analgesia and can differentiate between opioid analgesia and unspecific reductions in pain such as habituation.

Expectation and dyspnoea: the neurobiological basis of respiratory nocebo effects.

Cues such as odours that do not per se evoke bronchoconstriction can become triggers of asthma exacerbations. Despite its clinical significance, the neural basis of this respiratory nocebo effect is unknown.We investigated this effect in a functional magnetic resonance imaging (fMRI) study involving 36 healthy volunteers. The experiment consisted of an experience phase in which volunteers experienced dyspnoea while being exposed to an odorous gas ("Histarinol"). Volunteers were told that Histarinol induces dyspnoea by bronchoconstriction. This was compared with another odorous gas which did not evoke dyspnoea. Dyspnoea was actually induced by a concealed, resistive load inserted into the breathing system. In a second, expectation phase, Histarinol and the control gas were both followed by an identical, very mild load. Respiration parameters were continuously recorded and participants rated dyspnoea intensity after each trial.Dyspnoea ratings were significantly higher in Histarinol compared with control conditions, both in the experience and in the expectation phase, despite identical physical resistance in the expectation phase. Insula fMRI signal matched the actual load, i.e. a significant difference between Histarinol and control in the experience phase, but no difference in the expectation phase. The periaqueductal gray showed a significantly higher fMRI signal during the expectation of dyspnoea. Finally, Histarinol-related deactivations during the expectation phase in the rostral anterior cingulate cortex mirrored similar responses for nocebo effects in pain.These findings highlight the neural basis of expectation effects associated with dyspnoea, which has important consequences for our understanding of the perception of respiratory symptoms.

Association of nocebo hyperalgesia and basic somatosensory characteristics in a large cohort.

Medical outcomes are strongly affected by placebo and nocebo effects. Prediction of who responds to such expectation effects has proven to be challenging. Most recent approaches to prediction have focused on placebo effects in the context of previous treatment experiences and expectancies, or personality traits. However, a recent model has suggested that basic somatosensory characteristics play an important role in expectation responses. Consequently, this study investigated not only the role of psychological variables, but also of basic somatosensory characteristics. In this study, 624 participants underwent a placebo and nocebo heat pain paradigm. Additionally, individual psychological and somatosensory characteristics were assessed. While no associations were identified for placebo responses, nocebo responses were associated with personality traits (e.g. neuroticism) and somatosensory characteristics (e.g. thermal pain threshold). Importantly, the associations between somatosensory characteristics and nocebo responses were among the strongest. This study shows that apart from personality traits, basic somatosensory characteristics play an important role in individual nocebo responses, in agreement with the novel idea that nocebo responses result from the integration of top-down expectation and bottom-up sensory information.

The parietal operculum preferentially encodes heat pain and not salience.

Substantial controversy exists as to which part of brain activity is genuinely attributable to pain-related percepts and which activity is due to general aspects of sensory stimulation, such as its salience, or the accompanying arousal. The challenge posed by this question rests largely in the fact that pain per se exhibits highly intense but unspecific characteristics. These therefore should be matched by potential control conditions. Here, we used a unique combination of functional magnetic resonance imaging (fMRI) and behavioral and autonomic measures to address this longstanding debate in pain research. Subjects rated perceived intensity in a sequence alternating between heat and sound stimuli. Neuronal activity was monitored using fMRI. Either modality was presented in 6 different intensities, 3 of which lay above the pain threshold (for heat) or the unpleasantness threshold (for sound). We performed our analysis on 26 volunteers in which psychophysiological responses (as per skin conductance responses [SCRs]) did not differ between the 2 stimulus modalities. Having thus ascertained a comparable amount of stimulation-related but unspecific activation, we analyzed stimulus-response functions (SRFs) after painful stimulation and contrasted them with those of the matched acoustic control condition. Furthermore, analysis of fMRI data was performed on the brain surface to circumvent blurring issues stemming from the close proximity of several regions of interest located in heavily folded cortical areas. We focused our analyses on insular and peri-insular regions that are strongly involved in processing of painful stimuli. We employed an axiomatic approach to determine areas showing higher activation in painful compared to nonpainful heat and, at the same time, showing a steeper SRF for painful heat compared to unpleasant sound. Intriguingly, an area in the posterior parietal operculum emerged, whose response showed a pain preference after satisfying all axiomatic constraints. This result has important implications for the interpretation of functional imaging findings in pain research, because it clearly demonstrates that there are areas where activity following painful stimulation is not due to general attributes or results of sensory stimulation, such as salience or arousal. Conversely, several areas did not conform to the formulated axioms to rule out general factors as explanations.

How Stereotypes Affect Pain.

Stereotypes are abundant in everyday life - and whereas their influence on cognitive and motor performance is well documented, a causal role in pain processing is still elusive. Nevertheless, previous studies have implicated gender-related stereotype effects in pain perception as potential mediators partly accounting for sex effects on pain. An influence of stereotypes on pain seems indeed likely as pain measures have proven especially susceptible to expectancy effects such as placebo effects. However, so far empirical approaches to stereotype effects on pain are correlational rather than experimental. In this study, we aimed at documenting gender-related stereotypes on pain perception and processing by actively manipulating the participants' awareness of common stereotypical expectations. We discovered that gender-related stereotypes can significantly modulate pain perception which was mirrored by activity levels in pain-associated brain areas.

Hedonic processing in humans is mediated by an opioidergic mechanism in a mesocorticolimbic system.

It has been hypothesized that the pleasure of a reward in humans is mediated by an opioidergic system involving the hypothalamus, nucleus accumbens and the amygdala. Importantly, enjoying the pleasure of a reward is distinct from incentive salience induced by cues predicting the reward. We investigated this issue using a within subject, pharmacological challenge design with the opioid receptor antagonist naloxone and fMRI. Our data show that blocking opioid receptors reduced pleasure associated with viewing erotic pictures more than viewing symbols of reward such as money. This was paralleled by a reduction of activation in the ventral striatum, lateral orbitofrontal cortex, amygdala, hypothalamus and medial prefrontal cortex. Crucially, the naloxone induced activation decrease was observed at reward delivery, but not during reward anticipation, indicating that blocking opioid receptors decreases the pleasure of rewards in humans. Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).

Classification and characterisation of brain network changes in chronic back pain: A multicenter study.

Background. Chronic pain is a common, often disabling condition thought to involve a combination of peripheral and central neurobiological factors. However, the extent and nature of changes in the brain is poorly understood. Methods. We investigated brain network architecture using resting-state fMRI data in chronic back pain patients in the UK and Japan (41 patients, 56 controls), as well as open data from USA. We applied machine learning and deep learning (conditional variational autoencoder architecture) methods to explore classification of patients/controls based on network connectivity. We then studied the network topology of the data, and developed a multislice modularity method to look for consensus evidence of modular reorganisation in chronic back pain. Results. Machine learning and deep learning allowed reliable classification of patients in a third, independent open data set with an accuracy of 63%, with 68% in cross validation of all data. We identified robust evidence of network hub disruption in chronic pain, most consistently with respect to clustering coefficient and betweenness centrality. We found a consensus pattern of modular reorganisation involving extensive, bilateral regions of sensorimotor cortex, and characterised primarily by negative reorganisation - a tendency for sensorimotor cortex nodes to be less inclined to form pairwise modular links with other brain nodes. Furthermore, these regions were found to display increased connectivity with the pregenual anterior cingulate cortex, a region known to be involved in endogenous pain control. In contrast, intraparietal sulcus displayed a propensity towards positive modular reorganisation, suggesting that it might have a role in forming modules associated with the chronic pain state. Conclusion. The results provide evidence of consistent and characteristic brain network changes in chronic pain, characterised primarily by extensive reorganisation of the network architecture of the sensorimotor cortex.

Anterior cingulate cortex connectivity is associated with suppression of behaviour in a rat model of chronic pain.

A cardinal feature of persistent pain that follows injury is a general suppression of behaviour, in which motivation is inhibited in a way that promotes energy conservation and recuperation. Across species, the anterior cingulate cortex is associated with the motivational aspects of phasic pain, but whether it mediates motivational functions in persistent pain is less clear. Using burrowing behaviour as an marker of non-specific motivated behaviour in rodents, we studied the suppression of burrowing following painful confirmatory factor analysis or control injection into the right knee joint of 30 rats (14 with pain) and examined associated neural connectivity with ultra-high-field resting state functional magnetic resonance imaging. We found that connectivity between anterior cingulate cortex and subcortical structures including hypothalamic/preoptic nuclei and the bed nucleus of the stria terminalis correlated with the reduction in burrowing behaviour observed following the pain manipulation. In summary, the findings implicate anterior cingulate cortex connectivity as a correlate of the motivational aspect of persistent pain in rodents.

Evidence for a spinal involvement in temporal pain contrast enhancement.

Spatiotemporal filtering and amplification of sensory information at multiple levels during the generation of perceptual representations is a fundamental processing principle of the nervous system. While for the visual and auditory system temporal filtering of sensory signals has been noticed for a long time, respective contrast mechanisms within the nociceptive system became only recently subject of investigations, mainly in the context of offset analgesia (OA) subsequent to noxious stimulus decreases. In the present study we corroborate in a first experiment the assumption that offset analgesia involves a central component by showing that an OA-like effect accounting for 74% of a corresponding OA reference can be evoked by decomposing the stimulus offset into two separate box-car stimuli applied within the same dermatome but to separate populations of primary afferent neurons. In order to draw conclusions about the levels of the CNS at which temporal filtering of nociceptive information takes place during OA we investigate in a second experiment neuronal activity in the spinal cord during a painful thermal stimulus offset employing high-resolution fMRI in healthy volunteers. Pain-related BOLD responses in the spinal cord were significantly reduced during OA and their time course followed widely behavioral hypoalgesia, but not the thermal stimulation profile. In summary, the results suggest that temporal pain contrast enhancement during OA comprises a central mechanism and this mechanism becomes already effective at the level of the spinal cord.

Altered Signaling in the Descending Pain-modulatory System after Short-Term Infusion of the µ-Opioid Agonist Remifentanil.

µ-Opioid receptor agonists are widely used within the contemporary treatment of pain, but abrupt opioid suspension, even after short-term infusion, can paradoxically increase the sensitivity to noxious stimuli, a phenomenon that has been, for example, reported after application of the fast-acting µ-opioid receptor agonist remifentanil. To investigate the mechanisms underlying the effects of discontinuation of remifentanil application on pain processing in the human CNS, we analyzed neuronal responses to thermal stimuli before and after a short-term infusion of remifentanil (30 min 0.1 µg/kg body weight/min) compared with control in the brain, brainstem, and spinal cord in drug-naive male volunteers using fMRI. Subsequent to remifentanil suspension, we observed reduced heat pain thresholds and increased neuronal responses in pain-encoding as well as in key regions of the descending pain-modulatory system, such as the periaqueductal gray matter, the nucleus cuneiformis, and the rostral ventromedial medulla. Moreover, the spinal pain-related multivoxel activity pattern showed an opioid-specific change after drug suspension. Importantly, remifentanil suspension increased the functional coupling between the nucleus cuneiformis and the rostral anterior cingulate cortex, and the coupling strength between the rostral anterior cingulate cortex and the nucleus cuneiformis correlated negatively with the individual pain threshold after opioid suspension. These findings demonstrate that, already subsequent to a short-term infusion of the µ-opioid receptor agonist remifentanil, signaling in the descending pain-modulatory system is fundamentally altered and that these changes are directly related to the behavioral sensitivity to pain.SIGNIFICANCE STATEMENT Opioids are widely used in modern medicine, but, in addition to their known side effects, it is increasingly recognized that opioids can also increase sensitivity to pain subsequent to their use. Using the fast-acting µ-opioid receptor agonist remifentanil and fMRI in healthy male volunteers, this study demonstrates how signaling changes occur along the entire descending pain-modulatory pathway after opioid discontinuation and how these alterations are closely linked to increased behavioral pain sensitivity. Particularly by revealing modified responses in pain-modulatory brainstem regions that have been previously demonstrated to be causally involved in acute opioid withdrawal effects in rodents, the data provide a plausible neuronal mechanism by which the increased sensitivity to pain after opioid suspension is mediated in humans.

Nocebo-induced modulation of cerebral itch processing - An fMRI study.

It has been shown repeatedly that perceiving itch-related pictures or listening to a lecture on itch can enhance itch sensation and scratching behaviour (Niemeier and Gieler, 2000; Holle et al., 2012; Lloyd et al., 2013), indicating that itch is strongly influenced by expectations. Using fMRI, we investigated the neural correlates of the itch-related nocebo effect in healthy male and female human subjects. Itch sensation on the left forearm was induced by cutaneous histamine application and thermally modulated, with cooling leading to higher itch. Nocebo-induced aggravation of histaminergic itch was achieved by ostensibly treating volunteers with "transcutaneous electrical nerve stimulation (TENS)" about which subjects were instructed that it would increase itch. During a conditioning phase subjects indeed experienced stronger itch due to slightly altered cooling and histamine concentrations, but attributed it to the alleged "TENS stimulation". Importantly, in the subsequent test phase where no "TENS" or electrical stimulation was applied, volunteers significantly reported stronger itch during the nocebo as compared to the control condition. Comparing BOLD responses during nocebo in contrast to control, we observed increased activity in contralateral (right) rolandic operculum. Opercular involvement was repeatedly reported in studies related to the expectation of stimulus intensification and might thus represent an early area integrating expectation information with somatosensory information. Finally, functional coupling between the insula and the periaqueductal gray (PAG) was enhanced specifically in the nocebo condition. This cortex-PAG interaction indicates that context-dependent top-down modulation during itch might represent a shared mechanism with other modalities such as pain.

Suppression of Striatal Prediction Errors by the Prefrontal Cortex in Placebo Hypoalgesia.

Classical learning theories predict extinction after the discontinuation of reinforcement through prediction errors. However, placebo hypoalgesia, although mediated by associative learning, has been shown to be resistant to extinction. We tested the hypothesis that this is mediated by the suppression of prediction error processing through the prefrontal cortex (PFC). We compared pain modulation through treatment cues (placebo hypoalgesia, treatment context) with pain modulation through stimulus intensity cues (stimulus context) during functional magnetic resonance imaging in 48 male and female healthy volunteers. During acquisition, our data show that expectations are correctly learned and that this is associated with prediction error signals in the ventral striatum (VS) in both contexts. However, in the nonreinforced test phase, pain modulation and expectations of pain relief persisted to a larger degree in the treatment context, indicating that the expectations were not correctly updated in the treatment context. Consistently, we observed significantly stronger neural prediction error signals in the VS in the stimulus context compared with the treatment context. A connectivity analysis revealed negative coupling between the anterior PFC and the VS in the treatment context, suggesting that the PFC can suppress the expression of prediction errors in the VS. Consistent with this, a participant's conceptual views and beliefs about treatments influenced the pain modulation only in the treatment context. Our results indicate that in placebo hypoalgesia contextual treatment information engages prefrontal conceptual processes, which can suppress prediction error processing in the VS and lead to reduced updating of treatment expectancies, resulting in less extinction of placebo hypoalgesia.SIGNIFICANCE STATEMENT In aversive and appetitive reinforcement learning, learned effects show extinction when reinforcement is discontinued. This is thought to be mediated by prediction errors (i.e., the difference between expectations and outcome). Although reinforcement learning has been central in explaining placebo hypoalgesia, placebo hypoalgesic effects show little extinction and persist after the discontinuation of reinforcement. Our results support the idea that conceptual treatment beliefs bias the neural processing of expectations in a treatment context compared with a more stimulus-driven processing of expectations with stimulus intensity cues. We provide evidence that this is associated with the suppression of prediction error processing in the ventral striatum by the prefrontal cortex. This provides a neural basis for persisting effects in reinforcement learning and placebo hypoalgesia.

Endogenous Testosterone and Exogenous Oxytocin Modulate Attentional Processing of Infant Faces.

Evidence indicates that hormones modulate the intensity of maternal care. Oxytocin is known for its positive influence on maternal behavior and its important role for childbirth. In contrast, testosterone promotes egocentric choices and reduces empathy. Further, testosterone decreases during parenthood which could be an adaptation to increased parental investment. The present study investigated the interaction between testosterone and oxytocin in attentional control and their influence on attention to baby schema in women. Higher endogenous testosterone was expected to decrease selective attention to child portraits in a face-in-the-crowd-paradigm, while oxytocin was expected to counteract this effect. As predicted, women with higher salivary testosterone were slower in orienting attention to infant targets in the context of adult distractors. Interestingly, reaction times to infant and adult stimuli decreased after oxytocin administration, but only in women with high endogenous testosterone. These results suggest that oxytocin may counteract the adverse effects of testosterone on a central aspect of social behavior and maternal caretaking.

Physiological brainstem mechanisms of trigeminal nociception: An fMRI study at 3T.

The brainstem is a major site of processing and modulation of nociceptive input and plays a key role in the pathophysiology of various headache disorders. However, human imaging studies on brainstem function following trigeminal nociceptive stimulation are scarce as brainstem specific imaging approaches have to address multiple challenges such as magnetic field inhomogeneities and an enhanced level of physiological noise. In this study we used a viable protocol for brainstem fMRI of standardized trigeminal nociceptive stimulation to achieve detailed insight into physiological brainstem mechanisms of trigeminal nociception. We conducted a study of 21 healthy participants using a nociceptive ammonia stimulation of the left nasal mucosa with an optimized MR acquisition protocol for high resolution brainstem echoplanar imaging in combination with two different noise correction techniques. Significant BOLD responses to noxious ammonia stimulation were observed in areas typically involved in trigeminal nociceptive processing such as the spinal trigeminal nuclei (sTN), thalamus, secondary somatosensory cortex, insular cortex and cerebellum as well as in a pain modulating network including the periaqueductal gray area, hypothalamus (HT), locus coeruleus and cuneiform nucleus (CNF). Activations of the left CNF were positively correlated with pain intensity ratings. Employing psychophysiological interaction (PPI) analysis we found enhanced functional connectivity of the sTN with the contralateral sTN and HT following trigeminal nociception. We also observed enhanced functional connectivity of the CNF with the RVM during painful stimulation thus implying an important role of these two brainstem regions in central pain processing. The chosen approach to study trigeminal nociception with high-resolution fMRI offers new insight into human pain processing and might thus lead to a better understanding of headache pathophysiology.

Are Children the Better Placebo Analgesia Responders? An Experimental Approach.

UNLABELLED: There is little information regarding changes in placebo responsiveness with age, although first predictors of placebo responders such as psychological and physiological processes have been identified. Reviews and meta-analyses indicate that placebo response rates in randomized controlled trials (RCTs) are higher in children and adolescents compared with adults. As these studies cannot control for age-dependent differences in the natural course of the disease, biases might contribute to different placebo rates in RCTs. To avoid these biases, this study investigated age-related differences in placebo responsiveness between children and adults in a well-established experimental model of placebo analgesia combining classic conditioning and expectation. Our data confirm placebo analgesic responses in children, which did not differ in magnitude from those of adults. The influence of previous experience on subsequent treatment outcome was stronger in children than in adults, indicating an increased relevance of learning processes for treatment outcomes in children. Further studies are needed to understand the influence of treatment-related learning processes in children and adolescents, which might critically determine treatment responsiveness during adulthood. PERSPECTIVE: This study is the first to experimentally explore placebo analgesia and influences of previous experience on placebo responses in children compared with adults. We found comparable placebo responses in both groups and an increased relevance of learning processes for treatment outcomes in children.

Spinal cord-midbrain functional connectivity is related to perceived pain intensity: a combined spino-cortical FMRI study.

The dynamic interaction between ascending spinocortical nociceptive signaling and the descending control of the dorsal horn (DH) by brain regions such as the periaqueductal gray matter (PAG) plays a critical role in acute and chronic pain. To noninvasively investigate the processing of nociceptive stimuli in humans, previous fMRI studies either focused exclusively on the brain or, more recently, on the spinal cord. However, to relate neuronal responses in the brain to responses in the spinal cord and to assess the functional interplay between both sites in normal and aberrant conditions, fMRI of both regions within one experiment is necessary. Employing a new MRI acquisition protocol with two separate slice stacks, individually adapted resolutions and parameter settings that are dynamically updated to the optimized settings for the respective region we assessed neuronal activity in the spinal cord and in the brain within one measurement at 3 T. Using a parametric pain paradigm with thermal stimulation to the left radial forearm, we observed BOLD responses in the ipsilateral DH of the spinal segment C6 and corresponding neuronal responses in typical pain-processing brain regions. Based on correlations of adjusted time series, we are able to reveal functional connectivity between the spinal C6-DH and the thalamus, primary somatosensory cortex, bilateral insula, bilateral striatum, and key structures of the descending pain-modulatory system such as the PAG, the hypothalamus, and the amygdala. Importantly, the individual strength of the spinal-PAG coupling predicted individual pain ratings highlighting the functional relevance of this system during physiological pain signaling.

BOLD responses to itch in the human spinal cord.

Itch is an independent sensory modality and a very common symptom with manifold causes. However, the neuronal representation of itch perception in the central nervous system is not entirely understood and there is hardly any knowledge about neuronal correlates of itch in the human spinal cord. In the present study we aimed to identify itch-related neural activity in the cervical spinal cord in healthy volunteers employing high-resolution functional magnetic resonance imaging (fMRI). We studied histamine-induced itch on the radial forearm and modulated itch intensity by non-noxious cooling. To control for effects of thermal stimulation (i.e., cooling), volunteers also underwent an identical session without histamine. We studied histamine-induced itch on the radial forearm, by using a block design with alternating blocks of non-noxious cooling separated by blocks of skin temperature. Non-noxious cooling of histamine-treated skin compared to cooling of non-treated skin led to a significant increase in itch perception. On the neural level, itch was paralleled by activation in the dorsal horn of the spinal cord at the transition between spinal segment C5 and C6, ipsilateral to the side of stimulation. These results suggest that itch-related neural activity can be assessed noninvasively in humans at the spinal cord.