Dissociable Neural Mechanisms Underlying the Modulation of Pain and Anxiety? An fMRI Pilot Study

The down-regulation of pain through beliefs is commonly discussed as a form of emotion regulation. In line with this interpretation, the analgesic effect has been shown to co-occur with reduced anxiety and increased activity in the ventrolateral prefrontal cortex (VLPFC), which is a key region of emotion regulation. This link between pain and anxiety modulation raises the question whether the two effects are rooted in the same neural mechanism. In this pilot fMRI study, we compared the neural basis of the analgesic and anxiolytic effect of two types of threat modulation: a “behavioral control” paradigm, which involves the ability to terminate a noxious stimulus, and a “safety signaling” paradigm, which involves visual cues that signal the threat (or absence of threat) that a subsequent noxious stimulus might be of unusually high intensity. Analgesia was paralleled by VLPFC activity during behavioral control. Safety signaling engaged elements of the descending pain control system, including the rostral anterior cingulate cortex that showed increased functional connectivity with the periaqueductal gray and VLPFC. Anxiety reduction, in contrast, scaled with dorsolateral prefrontal cortex activation during behavioral control but had no distinct neural signature during safety signaling. Our pilot data therefore suggest that analgesic and anxiolytic effects are instantiated in distinguishable neural mechanisms and differ between distinct stress- and pain-modulatory approaches, supporting the recent notion of multiple pathways subserving top-down modulation of the pain experience. Additional studies in larger cohorts are needed to follow up on these preliminary findings

Treating breathlessness via the brain: changes in brain activity over a course of pulmonary rehabilitation

Breathlessness in chronic obstructive pulmonary disease (COPD) is often discordant with airway pathophysiology ("over-perception"). Pulmonary rehabilitation profoundly affects breathlessness, without influencing lung function. Learned associations influence brain mechanisms of sensory perception. We hypothesised that improvements in breathlessness with pulmonary rehabilitation may be explained by changing neural representations of learned associations.In 31 patients with COPD, we tested how pulmonary rehabilitation altered the relationship between brain activity during a breathlessness-related word-cue task (using functional magnetic resonance imaging), and clinical and psychological measures of breathlessness.Changes in ratings of breathlessness word cues positively correlated with changes in activity in the insula and anterior cingulate cortex. Changes in ratings of breathlessness-anxiety negatively correlated with activations in attention regulation and motor networks. Baseline activity in the insula, anterior cingulate cortex and prefrontal cortex correlated with improvements in breathlessness and breathlessness-anxiety.Pulmonary rehabilitation is associated with altered neural responses related to learned breathlessness associations, which can ultimately influence breathlessness perception. These findings highlight the importance of targeting learned associations within treatments for COPD, demonstrating how neuroimaging may contribute to patient stratification and more successful personalised therapy

Microstructural plasticity in nociceptive pathways after spinal cord injury.

OBJECTIVE To track the interplay between (micro-) structural changes along the trajectories of nociceptive pathways and its relation to the presence and intensity of neuropathic pain (NP) after spinal cord injury (SCI). METHODS A quantitative neuroimaging approach employing a multiparametric mapping protocol was used, providing indirect measures of myelination (via contrasts such as magnetisation transfer (MT) saturation, longitudinal relaxation (R1)) and iron content (via effective transverse relaxation rate (R2*)) was used to track microstructural changes within nociceptive pathways. In order to characterise concurrent changes along the entire neuroaxis, a combined brain and spinal cord template embedded in the statistical parametric mapping framework was used. Multivariate source-based morphometry was performed to identify naturally grouped patterns of structural variation between individuals with and without NP after SCI. RESULTS In individuals with NP, lower R1 and MT values are evident in the primary motor cortex and dorsolateral prefrontal cortex, while increases in R2* are evident in the cervical cord, periaqueductal grey (PAG), thalamus and anterior cingulate cortex when compared with pain-free individuals. Lower R1 values in the PAG and greater R2* values in the cervical cord are associated with NP intensity. CONCLUSIONS The degree of microstructural changes across ascending and descending nociceptive pathways is critically implicated in the maintenance of NP. Tracking maladaptive plasticity unravels the intimate relationships between neurodegenerative and compensatory processes in NP states and may facilitate patient monitoring during therapeutic trials related to pain and neuroregeneration

Subjective evaluation of experimental dyspnoea: effects of isocapnia and repeated exposure

Resistive respiratory loading is an established stimulus for the induction of experimental dyspnoea. In comparison to unloaded breathing, resistive loaded breathing alters end-tidal CO2 (PETCO2), which has independent physiological effects (e.g. upon cerebral blood flow). We investigated the subjective effects of resistive loaded breathing with stabilized PETCO2 (isocapnia) during manual control of inspired gases on varying baseline levels of mild hypercapnia increased PETCO2). Furthermore, to investigate whether perceptual habituation to dyspnoea stimuli occurs, the study was repeated over four experimental sessions. Isocapnic hypercapnia did not affect dyspnoea unpleasantness during resistive loading. A post hoc analysis revealed a small increase of respiratory unpleasantness during unloaded breathing at +0.6 kPa, the level that reliably induced isocapnia. We didnot observe perceptual habituation over the four sessions. We conclude that isocapnic respiratory loading allows stable induction of respiratory unpleasantness, making it a good stimulus for multi-session studies of dyspnoea

Implications of Placebo and Nocebo Effects for Clinical Practice: Expert Consensus

Background: Placebo and nocebo effects occur in clinical or laboratory medical contexts after administration of an inert treatment or as part of active treatments and are due to psychobiological mechanisms such as expectancies of the patient. Placebo and nocebo studies have evolved from predominantly methodological research into a far-reaching interdisciplinary field that is unravelling the neurobiological, behavioural and clinical underpinnings of these phenomena in a broad variety of medical conditions. As a consequence, there is an increasing demand from health professionals to develop expert recommendations about evidence-based and ethical use of placebo and nocebo effects for clinical practice. Methods: A survey and interdisciplinary expert meeting by invitation was organized as part of the 1st Society for Interdisciplinary Placebo Studies (SIPS) conference in 2017. Twenty-nine internationally recognized placebo researchers participated. Results: There was consensus that maximizing placebo effects and minimizing nocebo effects should lead to better treatment outcomes with fewer side effects. Experts particularly agreed on the importance of informing patients about placebo and nocebo effects and training health professionals in patient-clinician communication to maximize placebo and minimize nocebo effects. Conclusions: The current paper forms a first step towards developing evidence-based and ethical recommendations about the implications of placebo and nocebo research for medical practice, based on the current state of evidence and the consensus of experts. Future research might focus on how to implement these recommendations, including how to optimize conditions for educating patients about placebo and nocebo effects and providing training for the implementation in clinical practice. (C) 2018 S. Karger AG, Base

Dyspnea-related cues engage the prefrontal cortex - evidence from functional brain imaging in COPD

Dyspnea is the major source of disability in chronic obstructive pulmonary disease (COPD). In COPD, environmental cues (e.g. the prospect of having to climb stairs) become associated with dyspnea, and may trigger dyspnea even before physical activity commences. We hypothesised that brain activation relating to such cues would be different between COPD patients and healthy controls, reflecting greater engagement of emotional mechanisms in patients. Methods: Using FMRI, we investigated brain responses to dyspnea-related word cues in 41 COPD patients and 40 healthy age-matched controls. We combined these findings with scores of self-report questionnaires thus linking the FMRI task with clinically relevant measures. This approach was adapted from studies in pain that enables identification of brain networks responsible for pain processing despite absence of a physical challenge. Results: COPD patients demonstrate activation in the medial prefrontal cortex (mPFC), and anterior cingulate cortex (ACC) which correlated with the visual analogue scale (VAS) response to word cues. This activity independently correlated with patient-reported questionnaires of depression, fatigue and dyspnea vigilance. Activation in the anterior insula, lateral prefrontal cortex (lPFC) and precuneus correlated with the VAS dyspnea scale but not the questionnaires. Conclusions: Our findings suggest that engagement of the brain's emotional circuitry is important for interpretation of dyspnea-related cues in COPD, and is influenced by depression, fatigue, and vigilance. A heightened response to salient cues is associated with increased symptom perception in chronic pain and asthma, and our findings suggest such mechanisms may be relevant in COPD

Phantom limb pain and cortical reorganization: preventive and therapeutical effects of an NMDA-antagonist

Nach Amputation einer Extremität treten bei vielen Patienten Phantomschmerzen (PS) auf. Grundlage dieser Schmerzen ist eine Sensibilisierung schmerzrelevanter Strukturen, an der NMDA-Rezeptoren beteiligt sind. In der vorliegenden Studie wurde der analgetische Effekt eines NMDA-Antagonisten auf chronische PS sowie eine mögliche präventive Wirkung bei akuten Patienten untersucht. In beiden Teilstudien wurde der NMDA-Antagonist Memantine über 4 Wochen eingenommen und doppelblind gegen ein Plazebopräparat getestet. Bei Patienten mit chronischem PS tritt unter Memantine keine Schmerzreduktion ein. In der Präventionsstudie berichten dagegen die Patienten, die zusätzlich zum NMDA-Antagonisten über 7 Tage eine Regionalanästhesie erhielten, weniger PS als die Vergleichsgruppe, die mit einer Kombination aus Regionalanästhesie und Plazebopräparat versorgt wurde. In der Gesamtgruppe der akuten Patienten zeigte sich, daß die Prävention umso erfolgreicher ist, je früher nach der Amputation die Behandlung beginnt. In vorherigen Studien variierte die Phantomschmerzintensität mit einer Reorganisation im primären somatosensorischen Kortex. Bei den chronischen Patienten der vorliegenden Studie verstärkt sich diese kortikale Reorganisation (kR) unter der Einnahme von Memantine. Die Zunahme tritt unabhängig von Veränderungen der Schmerzintensität auf. Bei den akuten Patienten unterscheiden sich die Personen, die den NMDA-Antagonisten erhielten, hinsichtlich der kR nicht von der Kontrollgruppe. Zwischen der Schmerzintensität und dem Ausmaß der Reorganisation findet sich hier keine signifikante Korrelation. Die Ergebnisse machen deutlich, daß Memantine in der verwendeten Dosierung zu keiner Verringerung chronischer PS führt. Dagegen zeigt die kombinierte Gabe mit einer Langzeit-Regionalanästhesie bei akuten traumatisch amputierten Patienten einen deutlichen präventiven Effekt. Ob die kombinierte Medikation der Regionalanästhesie als Monotherapie überlegen ist, bleibt zu klären.After limb amputations many patients develop persisting pain which is localized in the now missing limb. This phantom limb pain (PLP) seems to depend on a sensitization of pain related structures, which is primarily mediated by NMDA-receptors. In this study we tested the analgetic effect of an NMDA-receptor antagonist on chronic PLP after upper limb amputations (study 1) and its pain preventing effect in patients early after a traumatic deafferentation (study 2). In both studies the NMDA antagonist memantine that was given orally for four weeks was tested in a double blind placebo controlled trial. Following memantine patients with chronic PLP did not report a significant pain relief. In contrast the acute patients of study 2, who received memantine in addition to a long term regional anesthesia, developed significantly less pain than patients receiving regional anesthesia and placebo. In all acute patients the prevention of PLP was more effective the earlier the treatment started following amputation. Previous studies showed a positive correlation between the intensity of PLP and a reorganization in the primary somatosensory cortex. In our chronic patients the cortical reorganization was increased after application of the NMDA antagonist, but this increase did not vary systematically with changes in pain intensity. In the prevention study the acute patients receiving memantine did not differ from the placebo controls concerning reorganization. In these patients no correlation could be found between the intensity of PLP and the extent of reorganization. The results show that the used dosage of memantine does not sufficiently decrease chronic PLP. In contrast the application of memantine and long-term regional anesthesia shows a strong preventive effect in acute traumatically amputated patients. However, it remains to be determined whether the combined therapy is a more effective preventive regime than early and prolonged sufficient regional analgesia alone

The influence of negative emotions on pain: behavioural effects and neural mechanisms

The idea that pain can lead to feelings of frustration, worry, anxiety and depression seems obvious, particularly if it is of a chronic nature. However, there is also evidence for the reverse causal relationship in which negative mood and emotion can lead to pain or exacerbate it. Here, we review findings from studies on the modulation of pain by experimentally induced mood changes and clinical mood disorders. We discuss possible neural mechanisms underlying this modulatory influence focusing on the periaqueductal grey (PAG), amygdala, anterior cingulate cortex (ACC) and anterior insula as key players in both, pain and affective processing