Volitional limbic neuromodulation exerts a beneficial clinical effect on Fibromyalgia.

Volitional neural modulation using neurofeedback has been indicated as a potential treatment for chronic conditions that involve peripheral and central neural dysregulation. Here we utilized neurofeedback in patients suffering from Fibromyalgia - a chronic pain syndrome that involves sleep disturbance and emotion dysregulation. These ancillary symptoms, which have an amplificating effect on pain, are known to be mediated by heightened limbic activity. In order to reliably probe limbic activity in a scalable manner fit for EEG-neurofeedback training, we utilized an Electrical Finger Print (EFP) model of amygdala-BOLD signal (termed Amyg-EFP), that has been successfully validated in our lab in the context of volitional neuromodulation. We anticipated that Amyg-EFP-neurofeedback training aimed at limbic down modulation would improve chronic pain in patients suffering from Fibromyalgia, by reducing sleep disorder improving emotion regulation. We further expected that improved clinical status would correspond with successful training as indicated by improved down modulation of the Amygdala-EFP signal. Thirty-Four Fibromyalgia patients (31F; age 35.6 ±â€¯11.82) participated in a randomized placebo-controlled trial with biweekly Amyg-EFP-neurofeedback sessions or sham neurofeedback (n = 9) for a total duration of five consecutive weeks. Following training, participants in the real-neurofeedback group were divided into good (n = 13) or poor (n = 12) modulators according to their success in the neurofeedback training. Before and after treatment, self-reports on pain, depression, anxiety, fatigue and sleep quality were obtained, as well as objective sleep indices. Long-term clinical follow-up was made available, within up to three years of the neurofeedback training completion. REM latency and objective sleep quality index were robustly improved following the treatment course only in the real-neurofeedback group (time × group p < 0.05) and to a greater extent among good modulators (time × sub-group p < 0.05). In contrast, self-report measures did not reveal a treatment-specific response at the end of the neurofeedback training. However, the follow-up assessment revealed a delayed improvement in chronic pain and subjective sleep experience, evident only in the real-neurofeedback group (time × group p < 0.05). Moderation analysis showed that the enduring clinical effects on pain evident in the follow-up assessment were predicted by the immediate improvements following training in objective sleep and subjective affect measures. Our findings suggest that Amyg-EFP-neurofeedback that specifically targets limbic activity down modulation offers a successful principled approach for volitional EEG based neuromodulation treatment in Fibromyalgia patients. Importantly, it seems that via its immediate sleep improving effect, the neurofeedback training induced a delayed reduction in the target subjective symptom of chronic pain, far and beyond the immediate placebo effect. This indirect approach to chronic pain management reflects the substantial link between somatic and affective dysregulation that can be successfully targeted using neurofeedback.

Cannabis analgesia in chronic neuropathic pain is associated with altered brain connectivity.

OBJECTIVE: To characterize the functional brain changes involved in δ-9-tetrahydrocannabinol (THC) modulation of chronic neuropathic pain. METHODS: Fifteen patients with chronic radicular neuropathic pain participated in a randomized, double-blind, placebo-controlled trial employing a counterbalanced, within-subjects design. Pain assessments and functional resting state brain scans were performed at baseline and after sublingual THC administration. We examined functional connectivity of the anterior cingulate cortex (ACC) and pain-related network dynamics using graph theory measures. RESULTS: THC significantly reduced patients' pain compared to placebo. THC-induced analgesia was correlated with a reduction in functional connectivity between the anterior cingulate cortex (ACC) and the sensorimotor cortex. Moreover, the degree of reduction was predictive of the response to THC. Graph theory analyses of local measures demonstrated reduction in network connectivity in areas involved in pain processing, and specifically in the dorsolateral prefrontal cortex (DLPFC), which were correlated with individual pain reduction. CONCLUSION: These results suggest that the ACC and DLPFC, 2 major cognitive-emotional modulation areas, and their connections to somatosensory areas, are functionally involved in the analgesic effect of THC in chronic pain. This effect may therefore be mediated through induction of functional disconnection between regulatory high-order affective regions and the sensorimotor cortex. Moreover, baseline functional connectivity between these brain areas may serve as a predictor for the extent of pain relief induced by THC.

Mindfulness Meditation Modulates Pain Through Endogenous Opioids.

BACKGROUND: Recent evidence supports the beneficial effects of mindfulness meditation on pain. However, the neural mechanisms underlying this effect remain poorly understood. We used an opioid blocker to examine whether mindfulness meditation-induced analgesia involves endogenous opioids. METHODS: Fifteen healthy experienced mindfulness meditation practitioners participated in a double-blind, randomized, placebo-controlled, crossover study. Participants rated the pain and unpleasantness of a cold stimulus prior to and after a mindfulness meditation session. Participants were then randomized to receive either intravenous naloxone or saline, after which they meditated again, and rated the same stimulus. RESULTS: A (3) × (2) repeated-measurements analysis of variance revealed a significant time effect for pain and unpleasantness scores (both P <.001) as well as a significant condition effect for pain and unpleasantness (both P <.2). Post hoc comparisons revealed that pain and unpleasantness scores were significantly reduced after natural mindfulness meditation and after placebo, but not after naloxone. Furthermore, there was a positive correlation between the pain scores following naloxone vs placebo and participants' mindfulness meditation experience. CONCLUSIONS: These findings show, for the first time, that meditation involves endogenous opioid pathways, mediating its analgesic effect and growing resilient with increasing practice to external suggestion. This finding could hold promising therapeutic implications and further elucidate the fine mechanisms involved in human pain modulation.

Comparison between human awake, meditation and drowsiness EEG activities based on directed transfer function and MVDR coherence methods.

This study examined the electroencephalogram functional connectivity (coherence) and effective connectivity (flow of information) of selected brain regions during three different attentive states: awake, meditation and drowsiness. For the estimation of functional connectivity (coherence), Welch and minimum variance distortionless response (MVDR) methods were compared. The MVDR coherence was found to be more suitable since it is both data and frequency dependent and enables higher spectral resolution, while Welch's periodogram-based approach is both data and frequency independent. The directed transfer function (DTF) method was applied in order to estimate the effective connectivity or brain's flow of information between different regions during each state. DTF enables to identify the main brain areas that initiate EEG activity and the spatial distribution of these activities with time. Analysis was conducted using the EEG data of 30 subjects (ten awake, ten drowsy and ten meditating) focusing on six main electrodes (F3, F4, C3, C4, P3, P4, O1 and O2). For each subject, EEG data were recorded during 5-min baseline and 15 min of a specific condition (awake, meditation or drowsiness). Statistical analysis included the Kruskal-Wallis (KW) nonparametric analysis of variance followed by post hoc tests with Bonferroni alpha correction. The results reveal that both states of drowsiness and meditation states lead to a marked difference in the brain's flow of information (effective connectivity) as shown by DTF analyses. In specific, a significant increase in the flow of information in the delta frequency band was found only in the meditation condition and was further found to originate from frontal (F3, F4), parietal (P3, P4) and occipital (O1, O2) regions. Altogether, these results suggest that a change in attentiveness leads to significant changes in the spectral profile of the brain's information flow as well as in its functional connectivity and that these changes can be captured using coherence and DTF analyses.

Emotional processing of personally familiar faces in the vegetative state.

BACKGROUND: The Vegetative State (VS) is a severe disorder of consciousness in which patients are awake but display no signs of awareness. Yet, recent functional magnetic resonance imaging (fMRI) studies have demonstrated evidence for covert awareness in VS patients by recording specific brain activations during a cognitive task. However, the possible existence of incommunicable subjective emotional experiences in VS patients remains largely unexplored. This study aimed to probe the question of whether VS patients retain a brain ability to selectively process external stimuli according to their emotional value and look for evidence of covert emotional awareness in patients. METHODS AND FINDINGS: In order to explore these questions we employed the emotive impact of observing personally familiar faces, known to provoke specific perceptual as well as emotional brain activations. Four VS patients and thirteen healthy controls first underwent an fMRI scan while viewing pictures of non-familiar faces, personally familiar faces and pictures of themselves. In a subsequent imagery task participants were asked to actively imagine one of their parent's faces. Analyses focused on face and familiarity selective regional brain activations and inter-regional functional connectivity. Similar to controls, all patients displayed face selective brain responses with further limbic and cortical activations elicited by familiar faces. In patients as well as controls, Connectivity was observed between emotional, visual and face specific areas, suggesting aware emotional perception. This connectivity was strongest in the two patients who later recovered. Notably, these two patients also displayed selective amygdala activation during familiar face imagery, with one further exhibiting face selective activations, indistinguishable from healthy controls. CONCLUSIONS: Taken together, these results show that selective emotional processing can be elicited in VS patients both by external emotionally salient stimuli and by internal cognitive processes, suggesting the ability for covert emotional awareness of self and the environment in VS patients.