Treatment/Management

Analgesic Effects of Alpha Rhythm Entrainment Through Passive Visual Stimulation

The cortical alpha rhythm (7-14Hz) plays a central role in the top-down control (or “gating”) of somatosensory information. Based on knowledge that acute noxious stimuli induce a suppression of cortical alpha rhythms, we investigated whether therapeutically augmenting alpha rhythms have analgesic effects. The cortical alpha rhythm was augmented using external sensory stimuli using a process known as entrainment, in which neural oscillations naturally adapt to the frequency of the driving stimulus. In particular, visual entrainment at 10Hz can be observed widely throughout the cortex, potentially impacting the top-down modulation of nociceptive processing. Our studies provided the first evidence that visual alpha entrainment reduces the perceived intensity of experimental pain and suppresses acute nociceptive processing. EEG source modelling revealed that increased alpha power and decreased nociceptive processing overlapped in precuneus and posterior cingulate cortex, with further reductions in nociceptive processing in insula cortex. Extending this work, we conducted a proof-of-concept controlled study in 28 patients with chronic pain comparing 10 Hz (alpha) and 7 Hz (control) frequency blocks in a randomized cross-over design. Frontal alpha power increased when stimulating at 10 Hz when compared to 7 Hz, correlating with a reduction in chronic pain intensity and unpleasantness.

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Non-Invasive Neuromodulation of Brain Rhythms – How Can We Translate Basic Insights into Novel Pain Treatments?

Neuronal oscillations, or brain rhythms, are a basic feature of neuronal signaling and communication. They can be recorded at different locations and frequencies from very low frequencies below 1 Hz up to 100 Hz. Recent studies in animals and humans have provided converging evidence that brain rhythms play a crucial role in the processing of pain. Moreover, evidence accumulates that abnormal brain rhythms figure prominently in the pathology of chronic pain. These basic science insights open up entirely novel perspectives for the treatment of pain by modulating brain rhythms. The current workshop will provide an up-to-date overview of novel treatment strategies of pain based on the non-invasive modulation of brain rhythms. We will specifically discuss most recent findings indicating how emerging transcranial alternating current stimulation (tACS) techniques, refined neurofeedback protocols, and sensory entrainment approaches can be used for the treatment of pain. Thus, the workshop will show how neuroscientific insights can translate into urgently needed novel therapeutic strategies for chronic pain.

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Brain Rhythms and Pain

The chair will provide a brief introduction on the role of neuronal oscillations (or brain rhythms) in the brain processing of pain. This will provide the rationale for the three main presentations on different non-invasive neuromodulation techniques to modulate brain rhythms for the treatment of pain.

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Targeting Impaired Alpha Oscillations in Chronic Pain with Transcranial Alternating Current Stimulation

Alpha oscillations are a fundamental human brain rhythm that modulates engagement of cortical circuits with afferent input. We hypothesized that chronic low back pain is reflected in a pathological hyperexcitability of sensory-motor circuits that can be detected by EEG as a downregulation of alpha oscillations. We further hypothesized that tACS at 10 Hz (in the alpha frequency) can be used to restore these impaired alpha oscillations and thereby reduce the pain symptoms. To test these hypotheses, we performed a pilot double-blind placebo-controlled study in people with chronic low back pain. We found that pain symptoms correlated with impairment of alpha oscillations at baseline. Importantly, alpha-tACS enhanced and restored these alpha oscillations, which correlated with improved pain ratings. More studies are urgently needed to replicate and expand on our findings. Next-generation tACS strategies that use individualized stimulation waveforms and real-time feedback may further increase efficacy of this approach. Studies of multiday stimulation paradigms as we have recently used in clinical trials of tACS for the treatment of depression and schizophrenia represent a further, highly promising avenue towards targeted non-pharmacological treatments for chronic pain by modulating brain rhythms.

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Neurofeedback as a Tool to Understand and Manage Pain

EEG-based Neurofeedback is a well-established neuromodulatory approach which is increasingly used to identify causal relationships between oscillatory brain activity and behavior and perception. Moreover, it has been proposed to support the treatment of various neuropsychiatric disorders including pain. Neurofeedback is, however, associated with significant methodological challenges including blinding and the use of appropriate control conditions. Most likely, these challenges have contributed to the large variability in previous findings and could partially explain why a consensus regarding the efficacy of neurofeedback for pain management is still lacking. To address these shortcomings, an interdisciplinary board of leading scientists recently published guidelines on the conduct and reporting of neurofeedback studies (CredNF checklist). In combination with other open science practices, these can aid the development of robust experimental designs and help to further explore the potential of neurofeedback as a tool to understand and manage pain. In my talk, I will provide an overview of previous pain-related neurofeedback studies and introduce the CredNF checklist. Building on these insights, I will present first data from a current study conducted at the PainLabMunich, which exemplifies how open science practices can improve the study of pain using neurofeedback.

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Mechanistic Brain-Based Treatments for Chronic Pain

There is ample evidence that brain mechanisms contribute to the development and maintenance of chronic pain. Such mechanisms involve sensitization with changes in primary somatosensory cortex and insula, a shift from nociceptive to emotional brain networks, alterations in somatosensory and motor processing, dysfunctional reward processing involving prefrontal and striatal networks or deficient processing of and learning about appetitive events with changes in striatal and orbitofrontal regions. We discuss novel interventions that target these mechanisms involving brain stimulation, virtual and augmented reality applications, neurofeedback, training with brain computer interfaces, pharmacologically aided pain extinction retraining as well as novel behavioral, physical and pharmacological interventions and their combination that target these brain circuits. We also show that matching of patients to their best fitting treatment greatly enhances the efficacy of these interventions and discuss behavioral, physical and neural biomarkers of patient to treatment matching and treatment outcome.

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Biobehavioral Interventions Targeting Learning-Related Alterations in Brain Circuits

We will present data on key brain changes  in primary somatosensory cortex, insula, anterior cingulate cortex, striatum and frontal cortex related to chronic pain based on our work on brain circuits involved in appetitive and aversive pavlovian conditioning, operant conditioning of pain reward and relief, spouse responding to pain and phantom limb pain. Specific interventions to target these brain changes involve behavioral interventions such as pain extinction retraining, its combination with cannabinoids, and the inclusion of neurofeedback and virtual and augmented reality based interventions. We show that an assignment of patients based on the key mechanism that is relevant for their type of pain boosts effect sizes and reduces drop out numbers. We also provide evidence that aberrant brain changes can be normalized by these targeted treatment approaches.

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Brain-Based Treatments Targeting Aberrant Sensorimotor Cortex Excitability in the Transition to Chronic Pain

This presentation will explore novel brain-based treatments designed to target aberrant sensorimotor cortex excitability in the transition from acute to chronic pain. An increasing body of research suggests low sensorimotor cortex excitability in the acute stage of musculoskeletal pain could be a risk factor for the development of chronic pain. Treatments designed to raise sensorimotor cortex excitability when pain is acute could therefore provide an avenue for early intervention, potentially halting the transition to chronic pain. Non-invasive brain stimulation is one technique that can modulate sensorimotor cortex excitability and influence broader cortical processing through widespread network effects. This presentation will examine non-invasive brain stimulation (transcranial direct current stimulation, repetitive transcranial magnetic stimulation) as a potential treatment in individuals with musculoskeletal pain, focusing on the cortical mechanisms of action. In addition, new data investigating the effect of nicotine on sensorimotor cortex excitability in pain will be presented.

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Neurofeedback Treatment to Modulate Sensorimotor Cortical Representation of Phantom Limb Pain

Abnormal cortical activities relating to the chronic pain is a therapeutic target of neurofeedback and neuromodulation. Phantom limb pain has been attributed to the abnormal cortical reorganization of the sensorimotor cortex after the amputation of a limb and partial or complete deafferentation. We have developed a Brain-Computer Interface (BCI) based on magnetoencephalography (MEG) signals to control a robotic hand or virtual hand so that the cortical representation of the phantom hand is modulated to relieve the pain. A ten-minutes training to use the BCI changed the cortical representation of phantom hand movements and the pain significantly. Moreover, an intensive training for 3 days reduced the pain significantly for 5 days compared to the sham training in a randomized cross-over trial. The neurofeedback training to modulate the abnormal cortical representation that causes the pain will be the mechanisms-based treatment for the chronic pain.

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What’s New in Combination Pharmacotherapy for Neuropathic Pain? From Bench to Bedside

Laura Stone will illustrate the therapeutic potential of combination pharmacotherapy by highlighting – with recent examples – additive and synergistic analgesic interactions using preclinical investigative techniques. The rationale for picking certain targets for combinations will be presented as will issues of adverse drug interactions.

Ian Gilron will provide a recently updated evidence-based review of combination pharmacotherapy for neuropathic pain in order to highlight critical issues surrounding optimal combinations and necessary improvements for future combination trials. Key issues relating to combination therapy will be discussed including: 1) safety 2) simultaneous versus sequential “add-on” therapy; and 3) optimal use of fixed dose combinations.

Flemming Bach will discuss combination pharmacotherapy in the context of real-world neuropathic pain. This will include a review of safe and effective evidence-based pain management practices by discussing known adverse drug interactions. The challenges and limitations of combination therapy with currently available drugs will also be presented. In particular consideration of the narrow therapeutic window due to cognitive side effects represent an obstacle and calls for consideration of alternative combination approaches.

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