Virtual reality-based analgesia: towards a novel framework for the biopsychosocial management of chronic pain.

Virtual reality (VR) holds unmeasured potential as a multicomponent tool for managing chronic pain by adapting conventional in-person biopsychosocial pain management strategies into one virtual space. We review recent evidence showcasing the successful integration of cognitive behavioural therapy, mindfulness-based stress reduction, embodiment techniques, and physical therapy into VR environments, demonstrating positive outcomes in patients with chronic pain. We propose that future clinical and basic research build on this by integrating pain neuroscience techniques to help better understand pathophysiological pain mechanisms and treatment response. This could help facilitate early assessment and personalised treatment of chronic pain using a VR-based biopsychosocial approach.

The acceptability of lifestyle medicine for the treatment of mental illness: perspectives of people with and without lived experience of mental illness.

OBJECTIVE: While lifestyle medicine can be highly effective for treating a range of mental illnesses these approaches are grossly underutilised and have not been systematically implemented into health care systems. Understanding the acceptability of lifestyle medicine is a critical first step to remediate this. This study evaluated the acceptability of lifestyle medicine relative to pharmacotherapy and psychotherapy, and explore perspectives of people with and without lived experience of mental illness. METHODS: Six hundred and forty-nine adult Australian residents (62.6% female; 53.6% with a lifetime diagnosis of mental illness) completed an online survey based on the Theoretical Framework of Acceptability assessing the acceptability of lifestyle medicine, pharmacotherapy and psychotherapy for treating mental illness. RESULTS: Most participants felt positive about lifestyle medicine (76.9%) and felt that such approaches aligned with their personal values (74.9%). They understood how lifestyle medicine worked (86.4%) and believed it would be effective (69.6%). Lived experience of mental illness was associated with greater perceived burden and lower self-efficacy to engage in lifestyle medicine activities (both p < 0.001). While there was a clear preference for psychotherapy and lifestyle medicine over pharmacotherapy, pharmacotherapy was perceived as least effortful (p < .001) and participants were least confident in their ability to engage in lifestyle medicine (p < 0.05). CONCLUSION: The findings indicate strong acceptability of lifestyle medicine for mental illness, a preference for non-pharmacological treatment approaches, and an understanding of the challenges associated with making long-term healthy lifestyle modifications amongst people who have lived experience of mental illness.

Lifestyle risk factors for obsessive-compulsive symptoms and related phenomena: What should lifestyle interventions target?

OBJECTIVE: Understanding the impact of lifestyle on mental illness symptoms is important for informing psycho-education and developing interventions which target mental and physical comorbidities. Obsessive-compulsive and related disorders can have a significant impact on health-related quality of life and physical health. However, our understanding of the impact of lifestyle on obsessive-compulsive symptoms and broader compulsive and impulsive problematic repetitive behaviours is limited. AIMS: We investigated whether lifestyle factors predicted change in obsessive-compulsive symptoms and problematic repetitive behaviours in a general population sample over a 3-month period. METHODS: Eight hundred thirty-five participants completed an online questionnaire battery assessing lifestyle and mental health. Of these, 538 participants completed the same battery 3 months later. We conducted negative binomial regressions to analyse the association of lifestyle factors at baseline with future (1) obsessive-compulsive symptoms, (2) compulsive problematic repetitive behaviours and (3) impulsive problematic repetitive behaviours, adjusting for baseline obsessive-compulsive symptoms and problematic repetitive behaviours. RESULTS: Lower vegetable (p = 0.020) and oily fish (p = 0.040) intake and lower moderate intensity physical activity (p = 0.008) predicted higher obsessive-compulsive symptoms at follow-up. Higher intake of high-fat foods (p < 0.001) predicted higher compulsive problematic repetitive behaviours at follow-up. No lifestyle factors significantly predicted impulsive problematic repetitive behaviours at follow-up. CONCLUSION: Our results speak to the potential importance of lifestyle quality screening, education and lifestyle interventions (e.g. an anti-inflammatory diet) for individuals experiencing compulsivity-related behaviours and/or symptoms. Further research into potential mechanisms of action will allow for more targeted approaches to lifestyle interventions for transdiagnostic compulsive behaviours.

Lattices in a product of trees, hierarchically hyperbolic groups and virtual torsion-freeness.

We construct cocompact lattices in a product of trees which are not virtually torsion-free. This gives the first examples of hierarchically hyperbolic groups which are not virtually torsion-free.

The role of psychological distress in the relationship between lifestyle and compulsivity: An analysis of independent, bi-national samples.

BACKGROUND: Poor mental health is a state of psychological distress that is influenced by lifestyle factors such as sleep, diet, and physical activity. Compulsivity is a transdiagnostic phenotype cutting across a range of mental illnesses including obsessive-compulsive disorder, substance-related and addictive disorders, and is also influenced by lifestyle. Yet, how lifestyle relates to compulsivity is presently unknown, but important to understand to gain insights into individual differences in mental health. We assessed (a) the relationships between compulsivity and diet quality, sleep quality, and physical activity, and (b) whether psychological distress statistically contributes to these relationships. METHODS: We collected harmonized data on compulsivity, psychological distress, and lifestyle from two independent samples (Australian n = 880 and US n = 829). We used mediation analyses to investigate bidirectional relationships between compulsivity and lifestyle factors, and the role of psychological distress. RESULTS: Higher compulsivity was significantly related to poorer diet and sleep. Psychological distress statistically mediated the relationship between poorer sleep quality and higher compulsivity, and partially statistically mediated the relationship between poorer diet and higher compulsivity. CONCLUSIONS: Lifestyle interventions in compulsivity may target psychological distress in the first instance, followed by sleep and diet quality. As psychological distress links aspects of lifestyle and compulsivity, focusing on mitigating and managing distress may offer a useful therapeutic approach to improve physical and mental health. Future research may focus on the specific sleep and diet patterns which may alter compulsivity over time to inform lifestyle targets for prevention and treatment of functionally impairing compulsive behaviors.

Capsaicin-Induced Changes in Electrical Pain Perception Threshold Can Be Used to Assess the Magnitude of Secondary Hyperalgesia in Humans.

OBJECTIVES: Areas of secondary hyperalgesia can be assessed using quantitative sensory testing (QST). Delivering noxious electrocutaneous stimulation could provide added benefit by allowing multiple measurements of the magnitude of hyperalgesia. We aimed to characterize the use of electrical pain perception (EPP) thresholds alongside QST as a means by which to measure changes in pain thresholds within an area of secondary mechanical hyperalgesia. METHODS: EPP and heat pain thresholds (HPTs) were measured at five distinct points at baseline and following 1% capsaicin cream application, one within a central zone and four within a secondary zone. Areas of secondary mechanical hyperalgesia were mapped using QST. In a further 14 participants, capsaicin-induced reduction in EPP thresholds was mapped using a radial lines approach across 24 points. RESULTS: There was a reduction in EPP threshold measured at the four points within the secondary zone, which was within the mapped area of mechanical secondary hyperalgesia. The magnitude of secondary hyperalgesia could be split into a mild (∼4% reduction) and severe (∼21% reduction) area within an individual subject. There was no reduction in HPT within the secondary zone, but there was a reduction in both HPT and EPP threshold within the primary zone. EPP mapping revealed differences in the magnitude and spread of hyperalgesia across all subjects. CONCLUSIONS: Measuring capsaicin-induced reduction in EPP thresholds can be used to map hyperalgesic areas in humans. This semi-automated approach allows rapid assessment of the magnitude of hyperalgesia, both within an individual subject and across a study population.

Primary Motor Cortex Transcranial Direct Current Stimulation Modulates Temporal Summation of the Nociceptive Withdrawal Reflex in Healthy Subjects.

OBJECTIVE: Transcranial direct current stimulation (tDCS) over the primary motor cortex (M1) has shown efficacy in a number of chronic pain conditions. Despite attempts to dissect the analgesic mechanisms, it is unknown whether M1 tDCS modulates the central integration of spinal nociception. To test this, we investigated the top-down modulation of spinal excitability using temporal summation (TS) of the nociceptive withdrawal reflex (NWR). METHODS: In this randomized, blinded, cross-over study, eight healthy subjects received electrically evoked TS of the NWR, which was delivered at 5 Hz at a threshold and a suprathreshold (1.1× threshold) to elicit TS resulting in different levels of pain. Subjects were asked to rate their pain after each stimulation. Changes in the TS of the NWR and pain ratings were investigated following 20 minutes of 2-mA anodal tDCS or sham stimulation applied over M1. RESULTS: Baseline recordings showed that TS of the NWR was induced with both threshold and suprathreshold stimulation. Suprathreshold stimulation was also associated with a higher pain intensity rating. After brain stimulation, there was no effect over the lower-intensity TS of the NWR or pain ratings in both the tDCS and sham conditions. However, tDCS reduced TS of the NWR and associated pain ratings following higher-intensity suprathreshold stimulation. CONCLUSIONS: These results indicate that M1 tDCS can indirectly modulate the central integration of suprathreshold nociceptive processing in the spinal cord. It is possible that the analgesic efficacy of tDCS is dependent on plasticity induced within pain pathways following repeated, high-intensity stimulation, which may explain the beneficial effects seen in chronic pain patients.

Reliability of quantitative sensory testing in the assessment of somatosensory function after high-frequency stimulation-induced sensitisation of central nociceptive pathways.

ABSTRACT: The high frequency stimulation (HFS) model can be used alongside quantitative sensory testing (QST) to assess the sensitisation of central nociceptive pathways. However, the validity and between-session reliability of using QST z -score profiles to measure changes in mechanical and thermal afferent pathways in the HFS model are poorly understood. In this study, 32 healthy participants underwent QST before and after HFS (5× 100 Hz trains; 10× electrical detection threshold) in the same heterotopic skin area across 2 repeated sessions. The only mechanical QST z -score profiles that demonstrated a consistent gain of function across repeated test sessions were mechanical pain threshold (MPT) and mechanical pain sensitivity (MPS), which were associated with moderate and good reliability, respectively. There was no relationship between HFS intensity and MPT and MPS z -score profiles. There was no change in low intensity, but a consistent facilitation of high-intensity pin prick stimuli in the mechanical stimulus response function across repeated test sessions. There was no change in cold pain threshold (CPT) and heat pain threshold (HPT) z -score profiles across session 1 and 2, which were associated with moderate and good reliability, respectively. There were inconsistent changes in the sensitivity to innocuous thermal QST parameters, with cool detection threshold (CDT), warm detection threshold (WDT), and thermal sensory limen (TSL) all producing poor reliability. These data suggest that HFS-induced changes in MPS z -score profiles is a reliable way to assess experimentally induced central sensitisation and associated secondary mechanical hyperalgesia in healthy participants.

PEAK Mood, Mind, and Marks: a pilot study of an intervention to support university students' mental and cognitive health through physical exercise.

Introduction: Regular exercise has the potential to enhance university students' mental and cognitive health. The PEAK Mood, Mind and Marks program (i.e., PEAK) is a neuroscience-informed intervention developed using the Behaviour Change Wheel to support students to exercise three or more times per week to benefit their mental and cognitive health. This pilot study assessed the impact of PEAK on exercise, mental and cognitive health, and implementation outcomes. Methods: PEAK was delivered to 115 undergraduate university students throughout a 12-week university semester. The primary outcome was weekly exercise frequency. Secondary outcomes were: time spent engaged in moderate-vigorous exercise, sedentary behaviour and perceived mental health and cognitive health. All were measured via online self-report questionnaires. Qualitative interviews with 15 students investigated influences on engagement, the acceptability and appropriateness of PEAK, and its mechanisms of behaviour change. Paired t-tests, Wilcoxon Signed-Rank tests and template analysis were used to analyse quantitative and qualitative data, respectively. Results: On average, 48.4% of students engaged in the recommended frequency of three or more exercise sessions per week. This proportion decreased towards the end of PEAK. Sedentary behaviour significantly decreased from baseline to end-point, and moderate-vigorous exercise significantly increased among students' who were non-exercisers. Mental wellbeing, stress, loneliness, and sense of belonging to the university significantly improved. There were no significant changes in psychological distress. Concentration, memory, and productivity significantly improved. Sixty-eight percent of students remained engaged in one or more components of PEAK at end-point. Qualitative data indicated students found PEAK to be acceptable and appropriate, and that it improved aspects of their capability, opportunity, and motivation to exercise. Conclusions: Students are receptive to an exercise-based program to support their mental and cognitive health. Students exercise frequency decreased; however, these figures are likely a conservative estimate of students exercise engagement. Students valued the neuroscience-informed approach to motivational and educational content and that the program's goals aligned with their academic goals. Students identified numerous areas PEAK's content and implementation can be optimised, including use of a single digital delivery platform, more opportunities to connect with peers and to expand the content's cultural inclusivity.

Examining the unique relationships between problematic use of the internet and impulsive and compulsive tendencies: network approach.

BACKGROUND: Both impulsivity and compulsivity have been identified as risk factors for problematic use of the internet (PUI). Yet little is known about the relationship between impulsivity, compulsivity and individual PUI symptoms, limiting a more precise understanding of mechanisms underlying PUI. AIMS: The current study is the first to use network analysis to (a) examine the unique association among impulsivity, compulsivity and PUI symptoms, and (b) identify the most influential drivers in relation to the PUI symptom community. METHOD: We estimated a Gaussian graphical model consisting of five facets of impulsivity, compulsivity and individual PUI symptoms among 370 Australian adults (51.1% female, mean age = 29.8, s.d. = 11.1). Network structure and bridge expected influence were examined to elucidate differential associations among impulsivity, compulsivity and PUI symptoms, as well as identify influential nodes bridging impulsivity, compulsivity and PUI symptoms. RESULTS: Results revealed that four facets of impulsivity (i.e. negative urgency, positive urgency, lack of premeditation and lack of perseverance) and compulsivity were related to different PUI symptoms. Further, compulsivity and negative urgency were the most influential nodes in relation to the PUI symptom community due to their highest bridge expected influence. CONCLUSIONS: The current findings delineate distinct relationships across impulsivity, compulsivity and PUI, which offer insights into potential mechanistic pathways and targets for future interventions in this space. To realise this potential, future studies are needed to replicate the identified network structure in different populations and determine the directionality of the relationships among impulsivity, compulsivity and PUI symptoms.

Responders and nonresponders to topical capsaicin display distinct temporal summation of pain profiles.

Introduction: Topical application of capsaicin can produce an ongoing pain state in healthy participants. However, approximately one-third report no pain response (ie, nonresponders), and the reasons for this are poorly understood. Objectives: In this study, we investigated temporal summation of pain (TSP) profiles, pain ratings and secondary hyperalgesia responses in responders and nonresponders to 1% topical capsaicin cream. Methods: Assessments were made at baseline and then during an early (ie, 15 minutes) and late (ie, 45 minutes) time points post-capsaicin in 37 healthy participants. Results: Participants reporting a visual analogue scale (VAS) rating of >50 were defined as responders (n = 24) and those with <50 VAS rating were defined as nonresponders (n = 13). There was a facilitation of TSP during the transition from an early to the late time point post-capsaicin (P<0.001) and the development of secondary hyperalgesia (P<0.05) in the responder group. Nonresponders showed no changes in TSP or secondary hyperalgesia during the early and late time points. There was an association between baseline TSP scores and the later development of a responder or nonresponder phenotype (r = 0.36; P = 0.03). Receiver operating characteristic analysis revealed that baseline TSP works as a good response predictor at an individual level (area under the curve = 0.75). Conclusion: These data suggest that responders and nonresponders have different facilitatory pain mechanisms. The assessment of TSP may help to identify participants with stronger endogenous pain facilitation who may be more likely to respond to topical capsaicin.

Narratives of the Origins of Kinky Sexual Desire Held by Users of a Kink-Oriented Social Networking Website.

Empirical research on the origins of kinky erotic desires (e.g., sadomasochism, bondage, domination/submission, roleplaying, sexual fetishism, etc.) has been limited and rarely rooted in the narratives of kinky people themselves. Among a sample of 260 self-identified kinky users of a kink-oriented social networking website living in 21 countries, we examined self-reported narratives of the origins of kink desires. An inductive coding process by four independent coders yielded 20 categories of responses, organized into five broad discourses about the origins of kinky desires: identity (e.g., personality, personal taste, and role exploration; 72.7% of responses), nurture (e.g., both traumatic and non-traumatic life experiences; 38.1% of responses), negation (e.g., disavowing or doubting a particular idea about the origins of their kink interests; 24.6% of responses), nature (e.g., biology and genetics; 22.7% of responses), and uncertainty (e.g., not being able to identify an origin of kinky desires; 10.4% of responses). Fewer than 19% of participants mentioned any kind of trauma in their responses. We discuss implications for scientific understandings of kinky sexual desire within the umbrella of sexual diversity.

Exposure to an Immersive Virtual Reality Environment can Modulate Perceptual Correlates of Endogenous Analgesia and Central Sensitization in Healthy Volunteers.

Virtual reality (VR) has been shown to produce analgesic effects during different experimental and clinical pain states. Despite this, the top-down mechanisms are still poorly understood. In this study, we examined the influence of both a real and sham (ie, the same images in 2D) immersive arctic VR environment on conditioned pain modulation (CPM) and in a human surrogate model of central sensitization in 38 healthy volunteers. CPM and acute heat pain thresholds were assessed before and during VR/sham exposure in the absence of any sensitization. In a follow-on study, we used the cutaneous high frequency stimulation model of central sensitization and measured changes in mechanical pain sensitivity in an area of heterotopic sensitization before and during VR/sham exposure. There was an increase in CPM efficiency during the VR condition compared to baseline (P < .01). In the sham condition, there was a decrease in CPM efficiency compared to baseline (P < .01) and the real VR condition (P < .001). Neither real nor sham VR had any effect on pain ratings reported during the conditioning period or on heat pain threshold. There was also an attenuation of mechanical pain sensitivity during the VR condition indicating a lower sensitivity compared to sham (P < .05). We conclude that exposure to an immersive VR environment has no effect over acute pain thresholds but can modulate dynamic CPM responses and mechanical hypersensitivity in healthy volunteers. PERSPECTIVE: This study has demonstrated that exposure to an immersive virtual reality environment can modulate perceptual correlates of endogenous pain modulation and secondary hyperalgesia in a human surrogate pain model. These results suggest that virtual reality could provide a novel mechanism-driven analgesic strategy in patients with altered central pain processing.

Immunogenicity of single vaccination with BNT162b2 or ChAdOx1 nCoV-19 at 5-6 weeks post vaccine in participants aged 80 years or older: an exploratory analysis.

BACKGROUND: In several countries, extended interval COVID-19 vaccination regimens are now used to accelerate population coverage, but the relative immunogenicity of different vaccines in older people remains uncertain. In this study we aimed to assess the antibody and cellular responses of older people after a single dose of either the BNT162b2 vaccine (tozinameran; Pfizer-BioNTech) or ChAdOx1 nCoV-19 vaccine (Oxford University-AstraZeneca). METHODS: Participants aged 80 years or older, who did not live in a residential or care home or require assisted living, and had received a single dose of either the BNT162b2 vaccine or ChAdOx1 nCoV-19 vaccine were eligible to participate. Participants were recruited through local primary care networks in the West Midlands, UK. Blood samples and dried blood spots were taken 5-6 weeks after vaccination to assess adaptive immune responses using Elecsys electrochemiluminescence immunoassay and cellular responses by ELISpot. Primary endpoints were percentage response and quantification of adaptive immunity. FINDINGS: Between Dec 29, 2020, and Feb 28, 2021, 165 participants were recruited and included in the analysis. 76 participants had received BNT162b2 (median age 84 years, IQR 82-89; range 80-98) and 89 had received ChAdOx1 nCoV-19 (median age 84 years, 81-87; 80-99). Antibody responses against the spike protein were detectable in 69 (93%) of 74 BNT162b2 vaccine recipients and 77 (87%) of 89 ChAdOx1 nCoV-19 vaccine recipients. Median antibody titres were of 19·3 U/mL (7·4-79·4) in the BNT162b2 vaccine recipients and 19·6 U/mL (6·1-60·0) in the ChAdOx1 nCoV-19 vaccine recipients (p=0·41). Spike protein-specific T-cell responses were observed in nine (12%) of 73 BNT162b2 vaccine recipients and 27 (31%) of 88 ChAdOx1 nCoV-19 vaccine recipients, and median responses were three-times higher in ChAdOx1 nCoV-19 vaccine recipients (24 spots per 1 × 106 peripheral blood mononuclear cells) than BNT162b2 vaccine recipients (eight spots per 1 × 106 peripheral blood mononuclear cells; p<0·0001). Humoral and cellular immune responses against spike protein were correlated in both cohorts. Evidence of previous SARS-CoV-2 infection was seen in eight participants (n=5 BNT162b2 recipients and n=3 ChAdOx1 nCoV-19 recipients), and was associated with 691-times and four-times increase in humoral and cellular immune responses across the whole cohort. INTERPRETATION: Single doses of either BNT162b2 or ChAdOx1 nCoV-19 in older people induces humoral immunity in most participants, and is markedly enhanced by previous infection. Cellular responses were weaker, but showed enhancement after the ChAdOx1 nCoV-19 vaccine at the 5-6 week timepoint. FUNDING: Medical Research Council, National Institute for Health Research, and National Core Studies.

The Influence of Trait Compulsivity and Impulsivity on Addictive and Compulsive Behaviors During COVID-19.

Background: The COVID-19 pandemic has resulted in high levels of psychological distress worldwide, with experts expressing concern that this could result in corresponding increases in addictive behaviors as individuals seek to cope with their distress. Further, some individuals may be at greater risk than others for developing problematic addictive behaviors during times of high stress, such as individuals with high trait impulsivity and compulsivity. Despite the potential of such knowledge to inform early detection of risk, no study to date has examined the influence of trait impulsivity and compulsivity on addictive behaviors during COVID-19. Toward this aim, the current study examined the association between impulsive and compulsive traits and problematic addictive and compulsive behaviors during the first COVID-19 lockdown in Australia. Methods: Eight hundred seventy-eight adults completed a cross-sectional online survey during the first lockdown, between late May to June 2020. Participants completed scales for addictive and compulsive behaviors for the period prior to and during lockdown for problematic eating, pornography, internet use, gambling, drinking, and obsessive-compulsive behaviors. Negative binomial regressions examined the associations between impulsivity, compulsivity, and their interaction with problematic behaviors during lockdown, controlling for age, gender, sample, psychological distress, exposure to COVID-related stressors, and pre-COVID problems. Results: Greater trait compulsivity was associated with more problematic obsessive-compulsive behaviors (p < 0.001) and less problematic drinking (p = 0.038) during lockdown. Further, trait compulsivity interacted with trait impulsivity in relation to problematic eating behaviors (p = 0.014) such that greater trait compulsivity was associated with more problems among individuals with low impulsivity only (p = 0.030). Finally, psychological distress and/or exposure to COVID-related stressors were associated with greater problems across all addictive and compulsive behaviors, as was severity of pre-COVID problems. Discussion: Trait compulsivity was associated with addictive and compulsive behaviors in different ways. Further, the finding that stress-related variables (psychological distress and COVID-related stressors) were associated with greater problems across all lockdown behaviors supports the idea that stress may facilitate, or otherwise be associated with, problematic behaviors. These findings highlight the need for interventions that enhance resilience to stress, which in turn may reduce risk for addictive and compulsive disorders.

Anodal transcranial direct current stimulation over the primary motor cortex attenuates capsaicin-induced dynamic mechanical allodynia and mechanical pain sensitivity in humans.

BACKGROUND: Anodal transcranial direct current stimulation over the primary cortex has been shown to activate regions of the brain involved in the descending modulation of pain sensitivity. However, more research is required to dissect the spinal cord analgesic mechanisms associated with the development of central sensitization. METHODS: In this randomized, double blind, crossover study 12 healthy participants had baseline mechanical stimulus response (S/R) functions measured before and after the development of capsaicin-induced ongoing pain sensitivity. The effects of 20 min of either real or sham transcranial direct current stimulation (tDCS, 2 mA) over the primary motor cortex on dynamic mechanical allodynia (DMA) and mechanical pain sensitivity (MPS) were then investigated. RESULTS: Topical application of capsaicin resulted in an increase in area under the pain ratings curve for both DMA (p < .01) and MPS (p < .01). The effects of tDCS on the area under the curve ratio (i.e. post-/pre-treatment) revealed significant analgesic effects over DMA (p < .05) and MPS (p < .05) when compared with sham. CONCLUSIONS: This study demonstrates that anodal tDCS over the primary motor cortex can reduce both dynamic and static forms of mechanical pain sensitivity associated with the development of DMA and MPS, respectively. The use of tDCS may provide a novel mechanism-driven therapy in chronic pain patients with altered mechanical S/R functions. SIGNIFICANCE: This research shows new evidence that anodal tDCS over the primary motor cortex can reduce dynamic and static forms of mechanical pain sensitivity in the capsaicin model of ongoing pain. By using this approach, it may be possible to provide mechanism-driven analgesia in chronic pain patients who have dynamic mechanical allodynia and/or secondary mechanical hyperalgesia.

Diffusion tensor imaging of lumbar spinal nerves reveals changes in microstructural integrity following decompression surgery associated with improvements in clinical symptoms: A case report.

The outcomes from spinal nerve decompression surgery are highly variable with a sizable proportion of elderly foraminal stenosis patients not regaining good pain relief. A better understanding of nerve root compression before and following decompression surgery and whether these changes are mirrored by improvements in symptoms may help to improve clinical decision-making processes. This case study used a combination of diffusion tensor imaging (DTI), clinical questionnaires and motor neurophysiology assessments before and up to 3 months following spinal decompression surgery. In this case report, a 70-year-old women with compression of the left L5 spinal nerve root in the L5-S1 exit foramina was recruited to the study. At 3 months following surgery, DTI revealed marked improvements in left L5 microstructural integrity to a similar level to that seen in the intact right L5 nerve root. This was accompanied by a gradual improvement in pain-related symptoms, mood and disability score by 3 months. Using this novel multimodal approach, it may be possible to track concurrent improvements in pain-related symptoms, function and microstructural integrity of compressed nerves in elderly foraminal stenosis patients undergoing decompression surgery.

Isotope Depletion Mass Spectrometry (ID-MS) for Accurate Mass Determination and Improved Top-Down Sequence Coverage of Intact Proteins.

Top-down mass spectrometry (MS) is an increasingly important technique for protein characterization. However, in many biological MS experiments, the practicality of applying top-down methodologies is still limited at higher molecular mass. In large part, this is due to the detrimental effect resulting from the partitioning of the mass spectral signal into an increasing number of isotopic peaks as molecular mass increases. Reducing the isotopologue distribution of proteins via depletion of heavy stable isotopes was first reported over 20 years ago (Marshall, A. G.; Senko, M. W.; Li, W.; Li, M.; Dillon, S., Guan, S.; Logan, T. M.. Protein Molecular Mass to 1 Da by 13C, 15N Double-Depletion and FT-ICR Mass Spectrometry. J. Am. Chem. Soc. 1997, 119, 433-434.) and has been demonstrated for several small proteins. Here we extend this approach, introducing a new highly efficient method for the production of recombinant proteins depleted in 13C and 15N and demonstrating its advantages for top-down analysis of larger proteins (up to ∼50 kDa). FT-ICR MS of isotopically depleted proteins reveals dramatically reduced isotope distributions with monoisotopic signal observed up to 50 kDa. In top-down fragmentation experiments, the reduced spectral complexity alleviates fragment-ion signal overlap, the presence of monoisotopic signals allows assignment with higher mass accuracy, and the dramatic increase in signal-to-noise ratio (up to 7-fold) permits vastly reduced acquisition times. These compounding benefits allow the assignment of ∼3-fold more fragment ions than comparable analyses of proteins with natural isotopic abundances. Finally, we demonstrate greatly increased sequence coverage in time-limited top-down experiments-highlighting advantages for top-down LC-MS/MS workflows and top-down proteomics.

Interlaboratory Study for Characterizing Monoclonal Antibodies by Top-Down and Middle-Down Mass Spectrometry.

The Consortium for Top-Down Proteomics (www.topdownproteomics.org) launched the present study to assess the current state of top-down mass spectrometry (TD MS) and middle-down mass spectrometry (MD MS) for characterizing monoclonal antibody (mAb) primary structures, including their modifications. To meet the needs of the rapidly growing therapeutic antibody market, it is important to develop analytical strategies to characterize the heterogeneity of a therapeutic product's primary structure accurately and reproducibly. The major objective of the present study is to determine whether current TD/MD MS technologies and protocols can add value to the more commonly employed bottom-up (BU) approaches with regard to confirming protein integrity, sequencing variable domains, avoiding artifacts, and revealing modifications and their locations. We also aim to gather information on the common TD/MD MS methods and practices in the field. A panel of three mAbs was selected and centrally provided to 20 laboratories worldwide for the analysis: Sigma mAb standard (SiLuLite), NIST mAb standard, and the therapeutic mAb Herceptin (trastuzumab). Various MS instrument platforms and ion dissociation techniques were employed. The present study confirms that TD/MD MS tools are available in laboratories worldwide and provide complementary information to the BU approach that can be crucial for comprehensive mAb characterization. The current limitations, as well as possible solutions to overcome them, are also outlined. A primary limitation revealed by the results of the present study is that the expert knowledge in both experiment and data analysis is indispensable to practice TD/MD MS.