Markus Breimhorst

Insular Cortex Activity Is Associated with Effects of Negative Expectation on Nociceptive Long-Term Habituation

It is generally accepted that acute painful experience is influenced by context information shaping expectation and modulating attention, arousal, stress, and mood. However, little is known about the nature, duration, and extent of this effect, particularly regarding the negative expectation. We used a standardized longitudinal pain paradigm and painful heat test stimuli in healthy participants over a time course of 8 consecutive days, inducing nociceptive habituation over time. Thirty-eight healthy volunteers were randomly assigned to two different groups. One group received the information that the investigators expected the pain intensity to increase over time (context group). The other group was not given any information (control group). All participants rated the pain intensity of the daily standardized pain paradigm on a visual analog scale. In agreement with previous studies the pain ratings in the control group habituated over time. However, the context group reported no change of pain ratings over time. Functional imaging data showed a difference between the two groups in the right parietal operculum. These data suggest that a negative context not only has an effect on immediate pain but can modulate perception of pain in the future even without experience/conditioning. Neuronally, this process is mediated by the right opercular region.

Meta-analysis of real-time fMRI neurofeedback studies using individual participant data: How is brain regulation mediated?

An increasing number of studies using real-time fMRI neurofeedback have demonstrated that successful regulation of neural activity is possible in various brain regions. Since these studies focused on the regulated region(s), little is known about the target-independent mechanisms associated with neurofeedback-guided control of brain activation, i.e. the regulating network. While the specificity of the activation during self-regulation is an important factor, no study has effectively determined the network involved in self-regulation in general. In an effort to detect regions that are responsible for the act of brain regulation, we performed a post-hoc analysis of data involving different target regions based on studies from different research groups. We included twelve suitable studies that examined nine different target regions amounting to a total of 175 subjects and 899 neurofeedback runs. Data analysis included a standard first- (single subject, extracting main paradigm) and second-level (single subject, all runs) general linear model (GLM) analysis of all participants taking into account the individual timing. Subsequently, at the third level, a random effects model GLM included all subjects of all studies, resulting in an overall mixed effects model. Since four of the twelve studies had a reduced field of view (FoV), we repeated the same analysis in a subsample of eight studies that had a well-overlapping FoV to obtain a more global picture of self-regulation. The GLM analysis revealed that the anterior insula as well as the basal ganglia, notably the striatum, were consistently active during the regulation of brain activation across the studies. The anterior insula has been implicated in interoceptive awareness of the body and cognitive control. Basal ganglia are involved in procedural learning, visuomotor integration and other higher cognitive processes including motivation. The larger FoV analysis yielded additional activations in the anterior cingulate cortex, the dorsolateral and ventrolateral prefrontal cortex, the temporo-parietal area and the visual association areas including the temporo-occipital junction. In conclusion, we demonstrate that several key regions, such as the anterior insula and the basal ganglia, are consistently activated during self-regulation in real-time fMRI neurofeedback independent of the targeted region-of-interest. Our results imply that if the real-time fMRI neurofeedback studies target regions of this regulation network, such as the anterior insula, care should be given whether activation changes are related to successful regulation, or related to the regulation process per se. Furthermore, future research is needed to determine how activation within this regulation network is related to neurofeedback success.

Ultra-Marathon Runners Are Different: Investigations into Pain Tolerance and Personality Traits of Participants of the TransEurope FootRace 2009

Susceptibility to pain varies among individuals and may predispose to a higher risk for pain disorders. Thus, it is of interest to investigate subjects who exhibit higher resistance to pain. We therefore tested pain tolerance and assessed personality traits of ultra‐marathon athletes who are able to run 4487 km (2789 mi) over 64 days without resting days and compare the results to controls.

Functional imaging of sympathetic activation during mental stress

Activation of the sympathetic nervous system (SNS) is essential in adapting to environmental stressors and in maintaining homeostasis. This reaction can also turn into maladaptation, associated with a wide spectrum of stress-related diseases. Up to now, the cortical mechanisms of sympathetic activation in acute mental stress have not been sufficiently characterized. We therefore investigated cerebral activation applying functional magnetic resonance imaging (fMRI) during performance of a mental stress task with graded levels of difficulty, i.e. four versions of a Stroop task (Colour Word Interference Test, CWT) in healthy subjects. To analyze stress-associated sympathetic activation, skin conductance and heart rate were continuously recorded. The results show that sympathetic activation through mental stress is associated with distinct cerebral regions being immediately involved in task performance (visual, motor, and premotor areas). Other activated regions (right insula, dorsolateral superior frontal gyrus, cerebellar regions) are unrelated to task performance. These latter regions have previously been considered to be involved in mediating different stress responses. The results might furthermore serve as a basis for future investigations of the connection between these cortical regions in the generation of stress-related diseases.

Comparison of anterior cingulate vs. insular cortex as targets for real-time fMRI regulation during pain stimulation

Real-time functional magnetic resonance imaging (rt-fMRI) neurofeedback allows learning voluntary control over specific brain areas by means of operant conditioning and has been shown to decrease pain perception. To further increase the effect of rt-fMRI neurofeedback on pain, we directly compared two different target regions of the pain network, notably the anterior insular cortex (AIC) and the anterior cingulate cortex (ACC). Participants for this prospective study were randomly assigned to two age-matched groups of 14 participants each (7 females per group) for AIC and ACC feedback. First, a functional localizer using block-design heat pain stimulation was performed to define the pain-sensitive target region within the AIC or ACC. Second, subjects were asked to down-regulate the BOLD activation in four neurofeedback runs during identical pain stimulation. Data analysis included task-related and functional connectivity analysis. At the behavioral level, pain ratings significantly decreased during feedback vs. localizer runs, but there was no difference between AIC and ACC groups. Concerning neuroimaging, ACC and AIC showed consistent involvement of the caudate nucleus for subjects that learned down-regulation (17/28) in both task-related and functional connectivity analysis. The functional connectivity toward the caudate nucleus is stronger for the ACC while the AIC is more heavily connected to the ventrolateral prefrontal cortex. Consequently, the ACC and AIC are suitable targets for real-time fMRI neurofeedback during pain perception as they both affect the caudate nucleus, although functional connectivity indicates that the direct connection seems to be stronger with the ACC. Additionally, the caudate, an important area involved in pain perception and suppression, could be a good rt-fMRI target itself. Future studies are needed to identify parameters characterizing successful regulators and to assess the effect of repeated rt-fMRI neurofeedback on pain perception.

Pain in chemotherapy-induced neuropathy – More than neuropathic?

Summary In chemotherapy‐induced neuropathy, different pain patterns might help to identify subgroups with predominant neuropathic or musculoskeletal pain and thereby allow a more specific treatment. Abstract Chemotherapy‐induced neuropathy (CIN) is an adverse effect of chemotherapy. Pain in CIN might comprise neuropathic and nonneuropathic (ie, musculoskeletal) pain components, which might be characterized by pain patterns, electrophysiology, and somatosensory profiling. Included were 146 patients (100 female, 46 male; aged 56 ± 0.8 years) with CIN arising from different chemotherapy regimens. Patients were characterized clinically through nerve conduction studies (NCS) and quantitative sensory testing (QST). Questionnaires for pain (McGill) and anxiety/depression (Hospital Anxiety and Depression Scale) were supplied. Patients were followed‐up after 17 days. Large‐ (61%) and mixed‐ (35%) fibre neuropathies were more frequent than small‐fibre neuropathy (1.4%). The 5 major chemotherapeutic regimens impacted differently on large‐ but not on small‐fibre function and did not predict painfulness. Chronic pain associated with CIN was reported in 41.7%. Painless and painful CIN did not differ in QST profiles or electrophysiological findings, but different somatosensory patterns were found in CIN subgroups (pain at rest [RestP], n = 25; movement‐associated pain [MovP], n = 15; both pain characteristics [MovP+RestP], n = 21; or no pain [NonP], n = 85): small‐fibre function (cold‐detection threshold, CDT: z score: −1.46 ± 0.21, P < 0.01) was most impaired in RestP; mechanical hyperalgesia was exclusively found in MovP (z score: +0.81 ± 0.30, P < 0.05). “Anxiety” discriminated between painful and painless CIN; “CDT” and “anxiety” discriminated between patients with ongoing (RestP) and movement‐associated pain (MovP) or pain components (MovP+RestP). The detrimental effect of chemotherapy on large fibres failed to differentiate painful from painless CIN. Patients stratified for musculoskeletal or neuropathic pain, however, differed in psychological and somatosensory parameters. This stratification might allow for the application of a more specific therapy.

Within-session sensitization and between-session habituation: a robust physiological response to repetitive painful heat stimulation.

Habituation and sensitization are important behavioural responses to repeated exposure of painful stimuli. Whereas within‐session response dynamics to nociceptive stimuli is well characterized, little is known about long‐term behaviour due to repetitive nociceptive stimulation. We used a standardized longitudinal heat pain paradigm in 66 healthy participants, 21 patients with chronic low back pain and 22 patients with depression who received daily sessions of 60 suprathreshold heat stimuli (48u2009°C each) for eight consecutive days. All three groups showed the same response: Repeated painful stimulation over several days resulted in substantially decreased pain ratings to identical painful stimuli. The decreased perception of pain over time was associated with a very robust increase in pain ratings in each single pain session, i.e., all participants sensitized within sessions and habituated between sessions. This uniform pattern was equally present in all examined groups. Chronic pain and depression do not seem to interfere with short‐term sensitization and long‐term habituation in this model of repetitive phasic heat pain.

Stress and thermoregulation: Different sympathetic responses and different effects on experimental pain

Stress and thermoregulation both activate the sympathetic nervous system (SNS) but might differently affect pain. Studies investigating possible interactions in patients are problematic because of the high prevalence of SNS disturbances in patients. We therefore analyzed the influence of these different sympathetic challenges on experimentally‐induced pain in healthy subjects. SNS was activated in two different ways: by mental stress (Stroop task, mental arithmetic task), and by thermoregulatory stimulation using a water‐perfused thermal suit (7°C, 32°C, or 50°C). Attentional effects of the mental stress tasks were controlled by using easy control tasks.

Sensory and sympathetic correlates of heat pain sensitization and habituation in men and women

Habituation and sensitization are important behavioural responses to repeated exposure to painful stimuli, but little is known about the factors determining sensory, affective and sympathetic habituation to repeated pain stimulation in men and women.

Do Intensity Ratings and Skin Conductance Responses Reliably Discriminate Between Different Stimulus Intensities in Experimentally Induced Pain

UNLABELLEDnThe present study addresses the question whether pain-intensity ratings and skin conductance responses (SCRs) are able to detect different intensities of phasic painful stimuli and to determine the reliability of this discrimination. For this purpose, 42 healthy participants of both genders were assigned to either electrical, mechanical, or laser heat-pain stimulation (each n = 14). A whole range of single brief painful stimuli were delivered on the right volar forearm of the dominant hand in a randomized order. Pain-intensity ratings and SCRs were analyzed. Using generalizability theory, individual and gender differences were the main contributors to the variability of both intensity ratings and SCRs. Most importantly, we showed that pain-intensity ratings are a reliable measure for the discrimination of different pain stimulus intensities in the applied modalities. The reliability of SCR was adequate when mechanical and heat stimuli were tested but failed for the discrimination of electrical stimuli. Further studies are needed to reveal the reason for this lack of accuracy for SCRs when applying electrical pain stimuli.nnnPERSPECTIVEnOur study could help researchers to better understand the relationship between pain and activation of the sympathetic nervous system. Pain researchers are furthermore encouraged to consider individual and gender differences when measuring pain intensity and the concomitant SCRs in experimental settings.