Reactivation-induced motor skill learning.

Learning motor skills commonly requires repeated execution to achieve gains in performance. Motivated by memory reactivation frameworks predominantly originating from fear-conditioning studies in rodents, which have extended to humans, we asked the following: Could motor skill learning be achieved by brief memory reactivations? To address this question, we had participants encode a motor sequence task in an initial test session, followed by brief task reactivations of only 30 s each, conducted on separate days. Learning was evaluated in a final retest session. The results showed that these brief reactivations induced significant motor skill learning gains. Nevertheless, the efficacy of reactivations was not consistent but determined by the number of consecutive correct sequences tapped during memory reactivations. Highly continuous reactivations resulted in higher learning gains, similar to those induced by full extensive practice, while lower continuity reactivations resulted in minimal learning gains. These results were replicated in a new independent sample of subjects, suggesting that the quality of memory reactivation, reflected by its continuity, regulates the magnitude of learning gains. In addition, the change in noninvasive brain stimulation measurements of corticospinal excitability evoked by transcranial magnetic stimulation over primary motor cortex between pre- and postlearning correlated with retest and transfer performance. These results demonstrate a unique form of rapid motor skill learning and may have far-reaching implications, for example, in accelerating motor rehabilitation following neurological injuries.

Neuromodulation of Visual Cortex Reduces the Intensity of Intrusive Memories.

Aversive events can be reexperienced as involuntary and spontaneous mental images of the event. Given that the vividness of retrieved mental images is coupled with elevated visual activation, we tested whether neuromodulation of the visual cortex would reduce the frequency and negative emotional intensity of intrusive memories. Intrusive memories of a viewed trauma film and their accompanied emotional intensity were recorded throughout 5 days. Functional connectivity, measured with resting-state functional magnetic resonance imaging prior to film viewing, was used as predictive marker for intrusions-related negative emotional intensity. Results indicated that an interaction between the visual network and emotion processing areas predicted intrusions' emotional intensity. To test the causal influence of early visual cortex activity on intrusions' emotional intensity, participants' memory of the film was reactivated by brief reminders 1 day following film viewing, followed by inhibitory 1 Hz repetitive transcranial magnetic stimulation (rTMS) over early visual cortex. Results showed that visual cortex inhibitory stimulation reduced the emotional intensity of later intrusions, while leaving intrusion frequency and explicit visual memory intact. Current findings suggest that early visual areas constitute a central node influencing the emotional intensity of intrusive memories for negative events. Potential neuroscience-driven intervention targets designed to downregulate the emotional intensity of intrusive memories are discussed.

Early Visual Cortex Stimulation Modifies Well-Consolidated Perceptual Gains.

Perception thresholds can improve through repeated practice with visual tasks. Can an already acquired and well-consolidated perceptual skill be noninvasively neuromodulated, unfolding the neural mechanisms involved? Here, leveraging the susceptibility of reactivated memories ranging from synaptic to systems levels across learning and memory domains and animal models, we used noninvasive brain stimulation to neuromodulate well-consolidated reactivated visual perceptual learning and reveal the underlying neural mechanisms. Subjects first encoded and consolidated the visual skill memory by performing daily practice sessions with the task. On a separate day, the consolidated visual memory was briefly reactivated, followed by low-frequency, inhibitory 1 Hz repetitive transcranial magnetic stimulation over early visual cortex, which was individually localized using functional magnetic resonance imaging. Poststimulation perceptual thresholds were measured on the final session. The results show modulation of perceptual thresholds following early visual cortex stimulation, relative to control stimulation. Consistently, resting state functional connectivity between trained and untrained parts of early visual cortex prior to training predicted the magnitude of perceptual threshold modulation. Together, these results indicate that even previously consolidated human perceptual memories are susceptible to neuromodulation, involving early visual cortical processing. Moreover, the opportunity to noninvasively neuromodulate reactivated perceptual learning may have important clinical implications.

Comparison of Paresthesia Mapping With Anatomic Placement in Burst Spinal Cord Stimulation: Long-Term Results of the Prospective, Multicenter, Randomized, Double-Blind, Crossover CRISP Study.

OBJECTIVES: Spinal cord stimulation (SCS) is an effective therapy for chronic intractable pain. Conventional SCS involves electrode placement based on intraoperative paresthesia mapping; however, newer paradigms like burst may allow for anatomic placement of leads. Here, for the first time, we report the one-year safety and efficacy of burst SCS delivered using a lead placed with conventional, paresthesia mapping, or anatomic placement approach in subjects with chronic low back pain (CLBP). MATERIALS AND METHODS: Subjects with CLBP were implanted with two leads. The first lead was placed to cross the T8/T9 disc and active contacts for this lead were chosen through paresthesia mapping. The second lead was placed at the T9/T10 spinal anatomic landmark. Subjects initially underwent a four-week, double-blinded, crossover trial with a two-week testing period with burst SCS delivered through each lead in a random order. At the end of trial period, subjects expressed their preference for one of the two leads. Subsequently, subjects received burst SCS with the preferred lead and were followed up at 3, 6, and 12 months. Pain intensity (visual analog scale), quality-of-life (EuroQol-5D instrument), and disability (Oswestry Disability Index) were evaluated at baseline and follow-up. RESULTS: Forty-three subjects successfully completed the trial. Twenty-one preferred the paresthesia mapping lead and 21 preferred the anatomic placement lead. Anatomic placement lead was activated in one subject who had no preference. The pain scores (for back and leg) significantly improved from baseline for both lead placement groups at all follow-up time points, with no significant between-group differences. CONCLUSIONS: This study demonstrated that equivalent clinical benefits could be achieved with burst SCS using either paresthesia mapping or anatomic landmark-based approaches for lead placement. Nonparesthesia-based approaches, such as anatomic landmark-based lead placement investigated here, have the potential to simplify implantation of SCS and improve current surgical practice.

Maximal aerobic capacity is associated with hippocampal cognitive reserve in older adults with amnestic mild cognitive impairment.

Maximal aerobic capacity (MAC) has been associated with preserved neural tissue or brain maintenance (BM) in healthy older adults, including the hippocampus. Amnestic mild cognitive impairment (aMCI) is considered a prodromal stage of Alzheimer's disease. While aMCI is characterized by hippocampal deterioration, the MAC-hippocampal relationship in these patients is not well understood. In contrast to healthy individuals, neurocognitive protective effects in neurodegenerative populations have been associated with mechanisms of cognitive reserve (CR) altering the neuropathology-cognition relationship. We investigated the MAC-hippocampal relationship in aMCI (n = 29) from the perspectives of BM and CR mechanistic models with structural MRI and a memory fMRI paradigm using both group-level (higher-fit patients vs. lower-fit patients) and individual level (continuous correlation) approaches. While MAC was associated with smaller hippocampal volume, contradicting the BM model, higher-fit patients demonstrated statistically significant lower correlation between hippocampal volume and memory performance compared with the lower-fit patients, supporting the model of CR. In addition, while there was no difference in brain activity between the groups during low cognitive demand (encoding of familiar stimuli), higher MAC level was associated with increased cortical and sub-cortical activation during increased cognitive demand (encoding of novel stimuli) and also with bilateral hippocampal activity even when controlling for hippocampal volume, suggesting for an independent effect of MAC. Our results suggest that MAC may be associated with hippocampal-related cognitive reserve in aMCI through altering the relationship between hippocampal-related structural deterioration and cognitive function. In addition, MAC was found to be associated with increased capacity to recruit neural resources during increased cognitive demands.

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.

Repeated oral ketamine for out-patient treatment of resistant depression: randomised, double-blind, placebo-controlled, proof-of-concept study.

BACKGROUND: Ketamine has been demonstrated to improve depressive symptoms.AimsEvaluation of efficacy, safety and feasibility of repeated oral ketamine for out-patients with treatment-resistant depression (TRD). METHOD: In a randomised, double-blind, placebo-controlled, proof-of-concept trial, 41 participants received either 1 mg/kg oral ketamine or placebo thrice weekly for 21 days (ClinicalTrials.gov Identifier: NCT02037503). Evaluation was performed at baseline, 40 and 240 min post administration and on days 3, 7, 14 and 21. The main outcome measure was change in Montgomery-Åsberg Depression Rating Scale (MADRS). RESULTS: Twenty-two participants were randomised to the ketamine group, and 19 to the control, with 82.5% (n = 33) completing the study. In the ketamine group, a decrease in depressive symptoms was evident at all time points, whereas in the control group a decrease was evident only 40 min post administration. The reduction in MADRS score on day 21 was 12.75 in the ketamine group versus 2.49 points with placebo (P < 0.001). Six participants in the ketamine group (27.3%) achieved remission compared with none of the controls (P < 0.05). The number needed to treat for remission was 3.7. Side-effects were mild and transient. CONCLUSIONS: Repeated oral ketamine produced rapid and persistent amelioration of depressive symptoms in out-patients with TRD, and was well tolerated. These results suggest that add-on oral ketamine may hold significant promise in the care of patients suffering from TRD in the community.Declaration of interestNone.

Cannabis-based medicines for chronic pain management: current and future prospects.

PURPOSE OF REVIEW: The medicinal use of cannabis has recently become the focus of much medical, as well as political, attention. This reality of growing use but limited evidence creates unique dilemmas for the prescribing clinician. The purpose of this review is to explore current evidence and gaps in knowledge and offer some practical considerations. RECENT FINDINGS: There is robust preclinical data regarding the relevance of the endocannabinoid system to many pain-relevant processes. However, evidence to support cannabis-based medicines clinical use is still lacking. The best evidence to date is in managing neuropathic pain, although whether effects are clinically significant remains undetermined. However, the safety profile of cannabinoids seems favorable, especially by comparison to other medications used for pain control. SUMMARY: The endocannabinoid system is undoubtedly a new and exciting pharmaceutical target for chronic pain management, but transition from preclinical to clinical studies has so far proved difficult. Although it is reasonable to consider cannabinoids for otherwise unresponsive pain, care should be taken in frail clinical populations. As this has become a socioeconomic and political issue in which agendas often take precedence over due diligence, there is a pressing need for unbiased empirical data and high quality evidence to better inform prescribers and patients.

Postoperative Pain Management Among Native and Non-native Israeli Citizens-Data From the European PAIN-OUT Registry.

PURPOSE: It has been widely reported that minority groups receive inferior emergency pain management. We aimed to determine whether this is true in the postoperative setting, as effective postoperative analgesia is an essential component of high quality medical care. DESIGN: A retrospective case-control study of paired 248 postsurgical Israeli patients. METHODS: Data were gathered from the European Union's "PAIN-OUT" registry. Quality of care measures, composite pain score, composite side effect score, and composite emotional score were analyzed. FINDINGS: Composite pain, side effect, and emotional scores were significantly higher among natives compared with non-natives. Opioid consumption did not differ between the two groups. CONCLUSIONS: In this study, immigration status was not a predictor of inferior postoperative analgesia. In contrast, non-natives benefited more from analgesic care. We suggest this stems from differing patient expectations and attitudes toward pain management between the groups, with higher expectations for analgesia on the part of native patients accounting for these observations.

Neuromodulation of reinforced skill learning reveals the causal function of prefrontal cortex.

Accumulating evidence has suggested functional interactions between prefrontal cortex (PFC) and dissociable large-scale networks. However, how these networks interact in the human brain to enable complex behaviors is not well-understood. Here, using a combination of behavioral, brain stimulation and neuroimaging paradigms, we tested the hypothesis that human PFC is required for successful reinforced skill formation. We additionally tested the extent to which PFC-dependent skill formation is related to intrinsic functional communication with this region. We report that inhibitory noninvasive transcranial magnetic stimulation over lateral PFC, a hub region with a diverse connectivity profile, causally modulated effective reinforcement-based motor skill acquisition. Furthermore, PFC-dependent skill formation was strongly related to the strength of functional connectivity between the PFC and regions in the sensorimotor network. These results point to the involvement of lateral PFC in the neural architecture that underlies the acquisition of complex skills, and suggest that, in relation to skill acquisition, this region may be involved in functional interactions with sensorimotor networks.

Losing Neutrality: The Neural Basis of Impaired Emotional Control without Sleep.

Sleep deprivation has been shown recently to alter emotional processing possibly associated with reduced frontal regulation. Such impairments can ultimately fail adaptive attempts to regulate emotional processing (also known as cognitive control of emotion), although this hypothesis has not been examined directly. Therefore, we explored the influence of sleep deprivation on the human brain using two different cognitive-emotional tasks, recorded using fMRI and EEG. Both tasks involved irrelevant emotional and neutral distractors presented during a competing cognitive challenge, thus creating a continuous demand for regulating emotional processing. Results reveal that, although participants showed enhanced limbic and electrophysiological reactions to emotional distractors regardless of their sleep state, they were specifically unable to ignore neutral distracting information after sleep deprivation. As a consequence, sleep deprivation resulted in similar processing of neutral and negative distractors, thus disabling accurate emotional discrimination. As expected, these findings were further associated with a decrease in prefrontal connectivity patterns in both EEG and fMRI signals, reflecting a profound decline in cognitive control of emotion. Notably, such a decline was associated with lower REM sleep amounts, supporting a role for REM sleep in overnight emotional processing. Altogether, our findings suggest that losing sleep alters emotional reactivity by lowering the threshold for emotional activation, leading to a maladaptive loss of emotional neutrality. Significance statement: Sleep loss is known as a robust modulator of emotional reactivity, leading to increased anxiety and stress elicited by seemingly minor triggers. In this work, we aimed to portray the neural basis of these emotional impairments and their possible association with frontal regulation of emotional processing, also known as cognitive control of emotion. Using specifically suited EEG and fMRI tasks, we were able to show that sleep deprivation alters emotional reactivity by triggering enhanced processing of stimuli regarded previously as neutral. These changes were further accompanied by diminished frontal connectivity, reduced REM sleep, and poorer performance. Therefore, we suggest that sleep loss alters emotional reactivity by lowering the threshold for emotional activation, leading to a maladaptive loss of emotional neutrality.

Oral Delta-9-Tetrahydrocannabinol (THC) Increases Parasympathetic Activity and Supraspinal Conditioned Pain Modulation in Chronic Neuropathic Pain Male Patients: A Crossover, Double-Blind, Placebo-Controlled Trial.

BACKGROUND: Disordered autonomic nervous system regulation and supraspinal pain inhibition have been repeatedly described in chronic pain. We aimed to explore the effects of δ-9-tetrahydrocannabinol (THC), an emerging treatment option, on autonomic nervous system and central pain modulation measures in patients with chronic pain. METHODS: Twelve male patients with chronic radicular neuropathic pain participated in a randomized, double-blind, crossover, placebo-controlled, single-administration trial. Low/high frequency (LF/HF) heart rate variability (HRV) ratio and conditioned pain modulation (CPM) response were measured and resting-state functional magnetic resonance imaging (MRI) was performed at baseline and after sublingual administration of either 0.2 mg/kg oral THC or placebo. RESULTS: THC significantly reduced the LF/HF ratio compared with placebo (interaction effect F(1,11) = 20.5; p < 0.005) and significantly improved CPM responses (interaction effect F(1,9) = 5.2; p = 0.048). The THC-induced reduction in LF/HF ratio correlated with increased functional connectivity between the rostral ventrolateral medulla and the dorsolateral prefrontal cortex [T(10) = 6.4, cluster p-FDR < 0.005]. CONCLUSIONS: THC shifts the autonomic balance towards increased parasympathetic tone and improves inhibitory pain mechanisms in chronic pain. The increase in vagal tone correlates with connectivity changes in higher-order regulatory brain regions, suggesting THC exerts top-down effects. These changes may reflect a normalizing effect of THC on multiple domains of supraspinal pain dysregulation. CLINICAL TRIAL REGISTRY NUMBER: NCT02560545.

Cannabis oil extracts for chronic pain: what else can be learned from another structured prospective cohort?

Introduction: The use of medicinal cannabis for managing pain expands, although its efficacy and safety have not been fully established through randomized controlled trials. Objectives: This structured, prospective questionnaire-based cohort was aimed to assess long-term effectiveness and safety of cannabis oil extracts in patients with chronic pain. Methods: Adult Israeli patients licensed to use cannabis oil extracts for chronic pain were followed prospectively for 6 months. The primary outcome measure was change from baseline in average weekly pain intensity, and secondary outcomes were changes in related symptoms and quality of life, recorded before treatment initiation and 1, 3, and 6 months thereafter. Generalized linear mixed model was used to analyze changes over time. In addition, "responders" (≥30% reduction in weekly pain at any time point) were identified. Results: The study included 218 patients at baseline, and 188, 154, and 131 at 1, 3, and 6 months, respectively. At 6 months, the mean daily doses of cannabidiol and Δ9-tetrahydrocannabinol were 22.4 ± 24.0 mg and 20.8 ± 30.1 mg, respectively. Pain decreased from 7.9 ± 1.7 at baseline to 6.6 ± 2.2 at 6 months (F(3,450) = 26.22, P < 0.0001). Most secondary parameters also significantly improved. Of the 218 participants, 24% were "responders" but could not be identified by baseline parameters. "Responders" exhibited higher improvement in secondary outcomes. Adverse events were common but mostly nonserious. Conclusion: This prospective cohort demonstrated a modest overall long-term improvement in chronic pain and related symptoms and a reasonable safety profile with the use of relatively low doses of individually titrated Δ9-tetrahydrocannabinol and cannabidiol.

When the chimney is blocked: malignant renovascular hypertension after endovascular repair of abdominal aortic aneurysm.

BACKGROUND: The Chimney graft (CG) procedure is one of the novel modification techniques of the endovascular aneurysm repair (EVAR) surgery to treat suprarenal and juxtarenal abdominal aortic aneurysms. Other indications for the use of CG placement include thoracic and thoracoabdominal aneurysms with supraortic branches orifice involvement and cases of common iliac artery aneurysms with or without internal iliac artery involvement. The technique is used in patients who due to aortic-neck morphology and lack of adequate fixation and/or sealing zones are not eligible for standard EVAR. In this procedure, a parallel stent-graft is placed adjacent to the main body of the aortic endograft to maintain blood supply to renovisceral or supraortic branches, once the body of the aortic stent-graft is deployed. Symptomatic occlusions of the CG with novel renovascular hypertension were not described until now. CASE PRESENTATION: A-64-year-old male patient, presented with new-onset malignant hypertension, 13 months after an EVAR operation with CG placement to the left renal artery. The patient was on preventive clopidrogel therapy, which was withheld temporarily for several days, one month before presentation. Imaging studies revealed a novel form of iatrogenic renovascular hypertension, caused by occlusion of the CG. Any attempt to recanalize the covered stent or revascularize the left kidney was rejected and conservative treatment was chosen. Seven months after presentation, blood pressure was within normal ranges with little need for antihypertensive therapy. CONCLUSIONS: Physicians should be aware that the novel emerging techniques of EVAR to overcome the limitations of the aortic-neck anatomy may still adversely influence the renal outcome with potential development of new-onset hypertension.

Medical cannabis for refractory cancer-related pain in a specialised clinical service: a cross-sectional study.

BACKGROUND AND OBJECTIVES: Cancer-related pain management in advanced stages presents a significant challenge that often requires a multidisciplinary approach. Although advancements in pharmacological and interventional therapies, a considerable number of patients still suffer from refractory pain, leading to unmet clinical needs. This study shares our experience with medical cannabis (MC) as a potential therapy for this specific population of patients with cancer-related refractory pain. METHODS: In a cross-sectional study, 252 consecutive refractory cancer-related pain patients (mean age=61.71, SD=14.02, 47.6% males) filled out detailed self-report questionnaires. Of these, 126 patients (55%) were treated with MC and 105 patients (45%) were not. RESULTS: Most patients received pain management from their oncologist, not a pain specialist. MC was mainly started for pain relief, sleep difficulties and anorexia. About 70% of patients reported subjective improvement from MC, with almost 40% reporting a significant improvement in coping with their illness. Side effects were generally mild, with fatigue and dizziness being the most common (21.78% and 23.46%, respectively). No patient required dedicated medical care for side effects. Of non-users, 65% had tried MC before and stopped due to lack of effectiveness or side effects (39.7% and 34.6%, respectively). CONCLUSION: Refractory cancer pain necessitates innovative approaches. This registry highlights that MC can effectively improve symptoms in non-responsive patients, with favourable safety profiles for this vulnerable population.

The Prevalence of Chronic Pain in the Adult Population in Israel: An Internet-Based Survey.

Background: Chronic pain (CP) prevalence in different studies has been inconsistent, ranging from 12% in Spain to 42% in the UK. Purpose: We conducted an internet-based survey in a representative cohort of Israeli adults assembled by a large professional survey company in order to probe the prevalence of CP in Israel. Methods: 8,300 Israeli adults comprising a representative cohort of the Israeli population were asked whether they were suffering from pain lasting over 3 months. 1647 participants responded (19.8% response rate). Of these, 515 (31.3%) had CP. Participants with CP were then asked a series of follow-up questions regarding their chronic pain. Statistical weights were used to correct for the distribution of the Israeli population based on sociodemographic characteristics. Results: CP patients were significantly older than respondents without pain. The average daily pain was 5.8/10 on a numerical rating scale. Common pain locations were axial skeleton and headaches. However, over half of patients reported pain in multiple body areas, and around a fifth had an undiagnosed chronic pain syndrome. Around 40% of pain patients reported to have visited a specialized pain clinic, and the same proportion has consulted several specialists. Despite this, a sizable proportion of high pain intensity patients were still left with no or inefficient treatment to alleviate their pain. Conclusions: This is the first internet survey conducted in Israel to estimate the incidence of CP, and the high CP prevalence documented is in agreement with previous reports from Europe and the USA. It also reaffirms the widespread existence of multifocal or widespread pain in clinical chronic pain and the correlation between pain intensity, impact on patients' quality of life and disability, and pain intractability. These data reaffirm the similarly major health burden CP presents across different countries and cultures.

Abnormal Visual Evoked Responses to Emotional Cues Correspond to Diagnosis and Disease Severity in Fibromyalgia.

Background: Chronic pain disorders are often associated with cognitive-emotional dysregulation. However, the relations between such dysregulation, underlying brain processes, and clinical symptom constellations, remain unclear. Here, we aimed to characterize the abnormalities in cognitive-emotional processing involved in fibromyalgia syndrome (FMS) and their relation to disease severity. Methods: Fifty-eight participants, 39 FMS patients (35F), and 19 healthy control subjects (16F) performed an EEG-based paradigm assessing attention allocation by extracting steady-state visually evoked potentials (ssVEP) in response to affective distractors presented during a cognitive task. Patients were also evaluated for pain severity, sleep quality, depression, and anxiety. Results: EEG ssVEP measurement indicated that, compared to healthy controls, FMS patients displayed impaired affective discrimination, and sustained attention to negative distractors. Moreover, patients displayed decreased task-related fronto-occipital EEG connectivity. Lack of adaptive attentional discrimination, measured via EEG, was predictive of pain severity, while impairments in fronto-occipital connectivity were predictive of impaired sleep. Conclusions: FMS patients display maladaptive affective attention modulation, which predicts disease symptoms. These findings support the centrality of cognitive-emotional dysregulation in the pathophysiology of chronic pain.

A Multicriteria Decision Analysis Comparing Pharmacotherapy for Chronic Neuropathic Pain, Including Cannabinoids and Cannabis-Based Medical Products.

Background: Pharmacological management of chronic neuropathic pain (CNP) still represents a major clinical challenge. Collective harnessing of both the scientific evidence base and clinical experience (of clinicians and patients) can play a key role in informing treatment pathways and contribute to the debate on specific treatments (e.g., cannabinoids). A group of expert clinicians (pain specialists and psychiatrists), scientists, and patient representatives convened to assess the relative benefit-safety balance of 12 pharmacological treatments, including orally administered cannabinoids/cannabis-based medicinal products, for the treatment of CNP in adults. Methods: A decision conference provided the process of creating a multicriteria decision analysis (MCDA) model, in which the group collectively scored the drugs on 17 effect criteria relevant to benefits and safety and then weighted the criteria for their clinical relevance. Findings: Cannabis-based medicinal products consisting of tetrahydrocannabinol/cannabidiol (THC/CBD), in a 1:1 ratio, achieved the highest overall score, 79 (out of 100), followed by CBD dominant at 75, then THC dominant at 72. Duloxetine and the gabapentinoids scored in the 60s, amitriptyline, tramadol, and ibuprofen in the 50s, methadone and oxycodone in the 40s, and morphine and fentanyl in the 30s. Sensitivity analyses showed that even if the pain reduction and quality-of-life scores for THC/CBD and THC are halved, their benefit-safety balances remain better than those of the noncannabinoid drugs. Interpretation: The benefit-safety profiles for cannabinoids were higher than for other commonly used medications for CNP largely because they contribute more to quality of life and have a more favorable side effect profile. The results also reflect the shortcomings of alternative pharmacological treatments with respect to safety and mitigation of neuropathic pain symptoms. Further high-quality clinical trials and systematic comprehensive capture of clinical experience with cannabinoids is warranted. These results demonstrate once again the complexity and multimodal mechanisms underlying the clinical experience and impact of chronic pain.

Pain Management - A Decade's Perspective of a New Subspecialty.

OBJECTIVE: Pain management is increasingly recognized as a formal medical subspecialty worldwide. Israel was among the first to offer a board-certified subspecialty, formalized by the Israeli Medical Association in 2010 which is open to all clinicians with a state-recognized specialization. This paper aims at evaluating the current program across several quality control measures. DESIGN: A survey among pain medicine specialists who graduated from the Israeli Pain Management subspecialty. METHODS: All 43 graduates of the program were sent a web-based questionnaire, each related to a different time in the participants' residency period - prior to, during and after training. RESULTS: Forty-one physicians responded to the survey (95% response rate). The most common primary specialty was Anesthesiology (44%), followed by Family Medicine (22%). One-third of the respondents applied to the program over five years after completing their initial residency. Two-thirds reported that they acquired all or most of the professional tools required by a pain specialist. Insufficient training was mentioned regarding addiction management (71%), special population needs (54%) and interventional treatment (37%). A high proportion (82%) responded that the examination contributed to their training and almost all perceived their period of subspecialty as having a positive value in their personal development. Two-thirds of respondents had not yet actively engaged beyond the clinical aspect with other entities responsible for formulating guidelines and other strategic decision-making. CONCLUSION: We hope the findings of this first-of-a-kind survey will encourage other medical authorities to construct formal training in pain medicine and enable this discipline to further evolve.