Defining clinical phenotypes from electronic health record (EHR)–derived data proves crucial for clinical decision support, population health endeavors, and translational research. EHR diagnoses now commonly draw from a finely grained clinical terminology—either native SNOMED CT or a vendor-supplied terminology mapped to SNOMED CT concepts as the standard for EHR interoperability. Accordingly, electronic clinical quality measures (eCQMs) increasingly define clinical phenotypes with SNOMED CT value sets. The work of creating and maintaining list-based value sets proves daunting, as does insuring that their contents accurately represent the clinically intended condition.The goal of the research was to compare an intensional (concept hierarchy-based) versus extensional (list-based) value set approach to defining clinical phenotypes using SNOMED CT–encoded data from EHRs by evaluating value set conciseness, time to create, and completeness.Starting from published Centers for Medicare and Medicaid Services (CMS) high-priority eCQMs, we selected 10 clinical conditions referenced by those eCQMs. For each, the published SNOMED CT list-based  value set was downloaded from the Value Set Authority Center (VSAC). Ten corresponding SNOMED CT hierarchy-based intensional value sets for the same conditions were identified within our EHR. From each hierarchy-based intensional value set, an exactly equivalent full extensional value set was derived enumerating all included descendant SNOMED CT concepts. Comparisons were then made between (1) VSAC-downloaded list-based  value sets, (2) corresponding hierarchy-based intensional value sets for the same conditions, and (3) derived list-based  value sets exactly equivalent to the hierarchy-based intensional value sets. Value set conciseness was assessed by the number of SNOMED CT concepts needed for definition. Time to construct the value sets for local use was measured. Value set completeness was assessed by comparing contents of the downloaded extensional versus intensional value sets. Two measures of content completeness were made: for individual SNOMED CT concepts and for the mapped diagnosis clinical terms available for selection within the EHR by clinicians.The 10 hierarchy-based intensional value sets proved far simpler and faster to construct than exactly equivalent derived extensional value set lists, requiring a median 3 versus 78 concepts to define and 5 versus 37 minutes to build. The hierarchy-based intensional value sets also proved more complete: in comparison, the 10 downloaded 2018 extensional value sets contained a median of just 35% of the intensional value sets’ SNOMED CT concepts and 65% of mapped EHR clinical terms.In the EHR era, defining conditions preferentially should employ SNOMED CT concept hierarchy-based  value sets rather than extensional lists. By doing so, clinical guideline and eCQM authors can more readily engage specialists in vetting condition subtypes to include and exclude, and streamline broad EHR implementation of condition-specific decision support promoting guideline adherence for patient benefit. Given widespread adoption of electronic health records (EHRs) certified to follow terminology standards, why does achieving interoperable clinical phenotype definitions remain challenging? Practical approaches to analytic interoperability among EHR-originated datasets would provide value both for population health analytics and clinical research -3. CliniAccordingly, clinical quality measures derived from EHR data increasingly define clinical phenotypes with SNOMED CT concept value sets, analogous to the International Classification of Diseases (ICD) code value sets traditionally defined for claims data. Initial SNOMED CT value sets primarily have taken an “extensional” form—that is, an enumerated list of terms—in keeping with the long-standing structure of ICD code value sets . But SNOIn this study, we examined value sets defining 10 conditions referenced by 2018 Centers for Medicare and Medicaid Services (CMS) high-priority electronic clinical quality measures (eCQMs) for adults. We compare corresponding intensional versus extensional SNOMED CT value sets for their conciseness, time to construct, and completeness of SNOMED CT concept inclusion. We also compare their completeness in covering the SNOMED CT-mapped clinical terms selectable by clinicians within the EHR as patient Problem List entries and encounter diagnoses, since those selections ultimately drive clinical phenotypes for population health activities and pragmatic clinical studies employing EHR source data.Transactional source data from administrative and clinical information systems typically include diagnosis information encoded in either ICD or SNOMED CT. Value sets of specified ICD or SNOMED CT terms define conditions  for use in clinical guidelines, clinical quality measures, and patient registries . Two catTo be certified for the Meaningful Use program in the United States, EHRs must be able to transmit patient diagnosis information to another EHR using SNOMED CT–encoded concepts ,11. ThusExtensional value sets refer to simple lists of codes or concepts. ICD value sets traditionally have been constructed this way, in keeping with the structure of ICD ,13. As tExtensional value sets, as specifically enumerated lists, are brittle and prone to “break” or become stale with updates to the underlying terminology. SNOMED CT updates can include addition of new clinical concepts or refining an existing concept by creating or expanding its “descendant” concepts. Preexisting extensional value set lists cannot handle these automatically and may require frequent reupdating after new SNOMED CT version releases, followed by reimportation or copying into every EHR or other system employing the value set.Some extensional value sets include many items, which inhibits rapid human comprehension of exactly which subtypes of a given clinical condition are being included and excluded. Thus clinical vetting of such value sets becomes laborious. Similarly, construction of the value set and performing quality assurance are correspondingly difficult and labor-intensive. Inaccuracies in value sets can significantly affect clinical quality measure calculations .SNOMED CT intensional value sets, by contrast, are rule-based and leverage the polyhierarchy structure of SNOMED CT. That is, one can include or exclude an entire “tree” of real-world condition subtypes via a single reference to a SNOMED CT concept and all its descendants. Combining such tree references with simple Boolean logic (or with SNOMED CT Expression Constraint Language) enables efficient definition of a desired clinical phenotype . For insPossible benefits of SNOMED CT intensional value sets include closely matching how clinicians think about what condition subtypes to include or exclude from a given clinical phenotype. Being able to reference the entire tree of a concept’s descendants enables far simpler, succinct value set definitions that are easier to understand and construct. Additionally, they should be more resilient to change and less likely to omit descendants and break with future SNOMED CT concept additions. Consequently, intensional value sets have potential to be simultaneously simpler and more complete and thus more useful for population health analytics and clinical research using EHR data.For each of 10 conditions , evaluate the differences between an intensional (concept hierarchy-based) versus extensional (list-based) SNOMED CT value set approach in (1) conciseness, (2) time to create, and (3) completeness of both SNOMED CT concepts included and relevant clinical terms available for clinician selection in an EHR.Value sets included in this study were identified starting from the CMS website for choosing Merit-Based Incentive Payment System (MIPS) quality measures . MIPS meNext, the online VSAC “search value sets” feature was employed to find condition-defining SNOMED CT value sets for these measures . Value sCreation of EHR vendor-neutral SNOMED CT intensional value sets and automatic derivation of extensional value sets were both done using Symedical , a clinical terminology management and mapping software tool for health care professionals. SNOMED CT intensional value sets (groupers) for EHR-based registry and clinical decision support functionality were created using the grouper management features of our EHR, Epic (Epic Systems Corporation). The clinical terminology vocabulary within University of Texas Southwestern Medical Center’s Epic EHR during this study was the proprietary IMO Problem IT terminology, version 2018 R1 , mapped to the SNOMED CT International Edition July 2017 release and the SNOMED CT US Edition September 2017 release.Using the VSAC website’s “export value set results” feature, the list of codes for each SNOMED CT extensional value set was exported to Excel (Microsoft Corp) for subsequent comparison.Comparable intensional (rule-based) value set diagnosis groupers for these conditions were established in our EHR. The majority already existed, having been created for disease registries and/or clinical decision support ; two werTo enable meaningful direct comparison with intensional value sets, two combinations of VSAC value sets were performed prior to comparing the SNOMED CT concept lists: (1) chronic kidney disease, stage 5, (CKD-5) was combined with end-stage renal disease (ESRD) since clinically they refer to the same condition, and so only one intensional value set covered both, and (2) major depression including remission was combined with dysthymia, as together they constitute the condition of depressive disorders covered by a single intensional value set. This yielded a final set of 10 clinical conditions for comparison. The eCQMs, VSAC value set identifiers, and extensional value set contents are available in Excel format in The pregnancy value set (2.16.840.1.113883.3.526.3.378) downloaded from VSAC was found to include concepts focused on pregnancy itself but in general did not include concepts for complications or disorders of pregnancy. Our existing EHR-based intensional value set for pregnancy deliberately included the latter to provide a broad net for identifying any pregnant patients via EHR-entered diagnoses and problems. Accordingly, to better match the VSAC contents, we constructed a second narrow intensional value set for pregnancy based on the pregnancy conditions listed in the VSAC extensional value set by deliberately omitting SNOMED CT concepts for pregnancy-related conditions . The VSAC extensional pregnancy value set was compared separately with both the broad and the narrow intensional pregnancy value sets.For each intensional value set, a corresponding extensional value set list was automatically derived using Symedical . These derived extensional value sets were downloaded and stored for subsequent analysis. The intensional value sets and corresponding derived extensional value sets are available in Excel format in Conciseness of value set definition was measured simply by the number of SNOMED CT concepts needed to fully define the set, either as a list  or the number of concepts in the defining rule . A dimensionless ratio to define was calculated in two forms:The time to create each of 11 intensional value sets  as well as 3 of the extensional value sets  in Symedical was measured. From this a best-fit linear equation was derived: time (min) = 0.4177*(# SNOMED CT concepts) + 3.8707. This corresponds to an obligate time of just under 4 minutes to create any value set  plus approximately 0.42 minutes (25 seconds) to add each SNOMED CT concept. The time to create the remaining extensional value sets was estimated using this equation.The difference in time to create an extensional versus an intensional value set was calculated as  – , expressed in minutes. The dimensionless ratio was calculated as  / .For each of 10 conditions, the list of SNOMED CT concepts included in the VSAC-downloaded set and the intensional-derived set were compared. The total number of concept discrepancies present in one set and not the other was assessed by summing two discrepancy types:Number of concepts present in the VSAC-downloaded set but not in the intensional-derived setNumber of concepts present in the intensional-derived set but not in the VSAC-downloaded setSince virtually all of the SNOMED CT concepts in the downloaded extensional value sets were included in the corresponding intensional-derived value set, the ratio of the two was calculated as:  / (# concepts in VSAC-downloaded set), expressed as a number greater than 1. The percentage of SNOMED CT concepts included in the downloaded extensional value set was calculated as: (# concepts in VSAC-downloaded set) / , expressed as a percentage.To evaluate the impact of condition-specific discrepancies, value sets were created in the EHR in both an intensional form (existing) and an extensional form . The EHR automatically creates a compiled list of IMO-sourced clinical terms mapped to the SNOMED CT value set. These IMO clinical terms comprise the diagnoses visible to clinicians for selection as Problem List entries and as diagnoses to associate with patient orders, encounters, and professional charges. The number of clinical terms compiled for each intensional and extensional value set was recorded. Comparisons were then performed on the number of clinical terms available for selection by clinicians in the EHR that would result in patient inclusion in a given clinical phenotype.Just as for SNOMED CT concept completeness, the ratio of the two was calculated as  / , expressed as a number greater than or equal to 1. The percentage of clinical terms covered by the downloaded extensional value set was calculated as  / , expressed as a percentage.Tabulated comparisons by each of the 10 conditions follow. Summary calculated measures are included at the bottom of each table. In addition to overall sums and ratios, the median of the 10 condition-specific values was selected as the primary measure of central tendency. This method was chosen a priori to avoid the potential for skew if one or more conditions exhibited marked difference from the others or contained many more concepts. The minimum, maximum, and range across the 10 conditions are also reported.For pregnancy, both the narrow and broad definitions are shown in tabular form; however, only the more narrow intensional value set based on the CMS extensional value set was used in all summary calculations (to avoid double-counting). Use of the narrow pregnancy definition reduces the reported differences between intensional and extensional value sets so that the summary findings and conclusions shown are conservative. Were the broad pregnancy definition selected instead, the magnitude of effects would be larger. All tables are available in Excel format in We expected that intensional value sets should be more concise to construct by leveraging the hierarchical supertype-subtype structure of SNOMED CT. For the full extensional value sets derived from the intensional rules, the median number of concepts-to-define was 78.5 concepts. The median ratio of concepts needed to fully define an equivalent extensional value set was 25 times that needed for the intensional value set rule.As one example, the clinical phenotype of personality disorder is specified by 26 SNOMED CT concepts in the downloaded extensional value set . In contNot surprisingly, more concise value sets are easier and faster to construct, perform quality assurance on, review, and update as needed. As shown in SNOMED CT is updated twice yearly  and an iThe vast majority of discrepancies between the two sets of extensional lists  were present in the intensional-derived list only and missing from the VSAC-downloaded list ; 1.3%  selectable by clinicians that are in extensional versus intensional value set compiled lists  value sets for the same conditions. Intensional value set definitions were far more concise , faster to construct (median 5 vs 37 minutes each), and more complete. VSAC-downloaded value sets were missing a median 65% of the SNOMED CT concepts included in the intensional rule-based value sets and 35% of the mapped diagnosis clinical terms selectable by clinicians within the EHR.The conciseness of intensional value sets expedites construction in the EHR. This should also streamline vetting with busy clinical experts and harmonizing multiple value set specifications of the same real-world condition. Many systems will directly import large extensional value set files, mitigating the value set construction time/workload difference for those organizations. Still, someone must create the source value sets initially and periodically update them, and some customer organizations will have to enter them manually as well. For those, the large time reduction offered by intensional value set definitions remains an advantage. Because intensional value sets are rule-based and can include references to all descendants of a parent concept, they are more likely to include all relevant concepts than an enumerated list. That is, they are less likely to inadvertently omit descendant concepts and more likely to remain complete following future SNOMED CT updates.Pragmatic clinical trials, registries, and other clinical and translational research studies employing EHR data for computable clinical phenotypes  rely on having as accurate and complete value sets to define primary and comorbid conditions as feasible ,20. ConcWith the expansion of clinically integrated networks and cross-institution specialty registries to provide and measure value-based care, definition of subpopulations of patients becomes crucial for risk assessment and tailored interventions ,30-32. MWith the expansion in medical knowledge and appreciation of the complexities of achieving optimal care for subpopulations of patients with a wide variety of conditions, the number of clinical practice guidelines continues to grow ,34. SignYet current guidelines can be difficult to implement as point-of-care clinical decision support to help “make the right thing the easy thing to do” for busy clinicians within their daily work tool, the EHR -53. Non–Translating prose definition of conditions covered by guideline, conditions excluded, and comorbid conditions into value sets implementable in EHRs to cover clinical terms/codes present in EHRs in practiceTranslating prose definitions of medication types and/or procedure types into EHR-implementable value setsTranslating prose descriptions  into implementable decision algorithms for clinical decision support logic EHRs have local codes that can hamper implementation, but increasingly these are mapped to standard terminology codes to achieve interoperability with other EHRs as organizations participate in health information exchanges .To accelerate implementation, we propose that specialty guideline and eCQM writing committees include a medical informaticist . During initial guideline development discussion and through subsequent detailed specification, the medical informaticist could then assist specialist experts on the committee in expressing the clinical conditions relevant to the guideline or eCQM in a SNOMED CT supertype-subtype form, readily implementable in an EHR or other internet-accessible repository as a concise, easily shareable intensional rule .Doing so would avoid the considerable extra work of constructing a de novo extensional value set, vetting the full list with clinical experts, distributing it, and having multiple teams of EHR analysts and clinical informaticists around the country independently reverse-engineer the list into a supertype-subtype rule-based form to gain its benefits of conciseness, maintainability, completeness, and understandability for their local EHR implementation. In lean terms, that extra work  and cannot be considered to represent national specialty society views. However, our experience demonstrates feasibility for a medical informaticist to build an initial candidate rule for defining a condition, then identify any clinical inclusion/exclusion questions for vetting with a clinician specializing in the condition . For mulThis study only covers 10 conditions and may not be representative of all and so should be considered merely as a deep dive into one set of conditions for CMS-designated eCQMs (as described in the Methods section). We took a conservative approach in matching intensional definitions to VSAC-downloaded extensional definitions, otherwise differences reported between intensional and extensional value set completeness would have been even greater. Specifically, for pregnancy we did not use our existing broad pregnancy intensional value set: instead we constructed a new, much more narrowly defined value set intended to match the scope of the VSAC-released pregnancy value set. Similarly, for pain related to prostate cancer, we lacked an existing intensional value set and constructed our new intensional value set closely mirroring the contents of the VSAC extensional value set. Both result in minimizing differences between the extensional and intensional approaches. Given the high percentage of missing concepts and clinical terms in conditions with large numbers of terms (hypertension), our prespecified use of medians instead of means (averages) also reduced the magnitude of the reported difference between intensional and extensional approaches.Although extensional lists of codes have long been used for ICD-based value sets, the use of extensional lists of SNOMED CT codes is suboptimal and fails to leverage the capabilities and clinical relevance of ontological relationships within SNOMED CT. Compared with SNOMED CT extensional (list) value sets, intensional (rule-based) value sets are far simpler to create, maintain, understand, and vet with specialist clinicians. For the 10 conditions studied here from the 2018 CMS high-value eCQMs for the MIPS program, intensional value sets also proved substantially more complete than their corresponding extensional list versions: a median 35% of diagnosis terms selectable in the EHR by clinicians were missing when using a downloaded extensional value set, with risk of failing to identify patients with a given clinical phenotype despite physician-entered discrete diagnoses in the EHR.Consequently, in the EHR era we believe defining conditions as computable clinical phenotypes preferentially should employ SNOMED CT concept hierarchy-based  value sets rather than extensional lists. By doing so, clinical guideline and eCQM authors can streamline broad EHR implementation of condition-specific decision support promoting guideline adherence and patient benefit.


Lymphoma presenting as a scalp mass is a rare but serious medical condition mandating aggressive treatment and neurosurgical intervention. We report a case of 53-year-old male who presented with a large right sided frontal scalp mass and a smaller mass located on the left frontal scalp. After discussion with the patient, it was decided to resect the larger mass for definitive diagnosis. After subtotal resection of the mass, biopsy revealed WHO grade 1 follicular lymphoma (FL), diffuse pattern stage IV. The patient was subsequently treated with 4 grays (Gy) of palliative radiotherapy over 2 fractions to the right frontal scalp and systemic chemo-immunotherapy (6 cycles) followed by rituximab maintenance. Lumbar puncture to obtain cerebrospinal fluid was done a month after therapy began and the results were negative for spread of malignant cells. Approximately 3 months after initiation of therapy, PET/CT showed no evidence of active malignancy and MRI revealed a complete internal resolution of the enlarged right frontal scalp mass. We use this case to provide a detailed discussion regarding disease pathophysiology, early diagnosis, and management Non-Hodgkin’s lymphoma (NHL) is a broad class of malignant neoplasms originating from B-cell progenitors, T-cell progenitors, mature B-cells, mature T-cells, and in rare cases natural killer cells (NK-cells) . The secOur patient is a 53-year-old male who worked as a coal miner. In spring of 2017, he noticed enlarging scalp nodules and right hip pain. He also complained of fatigue but was otherwise asymptomatic. Because of the hip pain and nodules, he came to the emergency department where a CT scan showed an enlarged right frontal scalp mass that measured about 4 cm . MRI alsIGH (immunoglobulin heavy chain locus)-Bcl-2 fusion. These findings support the definitive diagnosis of follicular lymphoma, WHO grade 1, diffuse pattern stage IV.He was taken to the operating room where a right frontal scalp incision was performed for subtotal resection of likely metastatic cancer. The mass was primarily located within the right frontal scalp but extended through the skull into the right frontal cortex. It did not however appear to be involved with the brain parenchyma. The resection consisted of removing scalp mass and taking a core biopsy from the specimen. Histopathology of the biopsy showed a diffuse and monotonous infiltrate composed of small cells with irregular nuclei, condensed chromatin and inconspicuous nucleoli . On immuAfter definitive diagnosis was made, the patient was then referred to radiation oncology for follow-up. By time of presentation to radiation oncology, the patient was showing symptoms of lower extremity numbness, personality changes, and some memory loss. The radiation oncologist discussed the diagnosis with the patient and his family and came up with a treatment plan to combat the unusual presentation of follicular lymphoma with the intracranial extension from the calvarium. The treatment plan consisted of repeat MRI’s; local  XRT (4 Grays over two fractions) and systemic chemo-immunotherapy (6 cycles) followed by rituximab maintenance. Lumbar puncture was done a month after resolution of vasogenic edema to assess leptomeningeal spread later proven negative for malignant cells. MRI showed complete resolution of the right scalp mass post-radiotherapy and after the patient had already underwent 3 cycles of chemo-immunotherapy. PET/CT done approximately 3 months since therapy initiation showed no suspicion for abnormal hypermetabolic activity, which suggested the absence of active malignancy.In the United States, FL represents 35% of all NHL diagnoses with the majority being sporadic . Other fIGH enhancer, causing constitutive expression of the antiapoptotic protein BCL2 [Our patient was unique in that he presented with a rare type of FL that had spread to the scalp by time of symptom onset. An extensive case series of FL patients showed that of 93 cases only one patient had metastatic spread to the neck with none to the scalp highlighting the rarity of our case . The reaein BCL2 . Dissemiein BCL2 . The keyein BCL2 .In summary, our patient had an aggressive metastatic FL that spread to his scalp. While initially asymptomatic he quickly progressed to B symptoms. Surgical resection, radiation, chemotherapy, and rituximab were used successfully to manage the FL. 3 months since therapy the patient is doing well. The key points going forward are related to the need for future study. First, understanding FL pathophysiology is critical for developing disease classification criteria. Second, prospective studies are needed to map survival once scalp metastasis has occurred. Finally, experimental immune modulator therapies should be explored further as adjuvant treatment options. With these three approaches improved management for patients with aggressively expanding FLs can be obtained.


Intracortical microelectrodes are used both in basic research to increase our understanding of the nervous system and for rehabilitation purposes through brain-computer interfaces. Yet, challenges exist preventing the widespread clinical use of this technology. A prime challenge is with the neuroinflammatory response to intracortical microelectrodes. This mini-review details immunomodulatory strategies employed to decrease the inflammatory response to these devices. Over time, broad-spectrum anti-inflammatory approaches, such as dexamethasone and minocycline, evolved into more targeted treatments since the underlying biology of the neuroinflammation was elucidated. This review also presents studies which examine novel prospective targets for future immunomodulatory targeting. BMI technologies have shown great success in enabling locked-in patients to interact with computers, robotic limbs, and their own electrically driven limbs4. The recent advances have inspired worldwide enthusiasm resulting in billions of dollars of federal and industrial sponsorships to promote understanding the brain for rehabilitative and preventative medicine applications. Additionally, private philanthropists have also demonstrated excitement in the field by investing in the use of brain interfacing technologies as a means to human augmentation6. In the future, brain-dwelling microelectrodes could restore patterns of normal brain function in diseased or injured patients through therapeutic modulation of dysfunctional pathways. Thus, implantable microelectrodes in the future can be transformative in not only restoring sensorimotor abilities but also improving the treatment of brain disorders and augmenting human capabilities.Intracortical microelectrodes were created as a tool for basic neuroscience research to understand the normal and diseased physiology of the brain for the treatment of neurological disorders, and they have since expanded to become critical components for brain-machine interfacing (BMI)7. Notably, the increased time to complete fine motor tasks was correlated with persistent damage to the blood-brain barrier, as a result of the neuroinflammatory response.While the promise of these incredible technologies is real, caution must be taken as implications regarding optimal performance and unforeseen side effects following device implantation into the brain are not fully characterized. For example, we recently demonstrated that rats with intracortical microelectrodes implanted in the primary motor cortex exhibited a remarkable 527% increase in the time required to complete a fine motor task8 One of the primary causes for this failure is believed to originate from the perpetual inflammatory response following implantation10. Since the neurodegenerative progression of the disease and injured states are often associated with the progression of cognitive and motor-related disease symptoms, the relative contribution of implanting potentially restorative devices that could actually contribute to the perceived progression of disease-like symptoms remains unclear, and in most cases untested. Therefore, these critical questions need to be answered in respect to both understanding disease progression and the role of interfacing technologies in both treating and propagating disease-like symptoms of deteriorated cognitive and motor abilities.Despite the incredible enthusiasm for brain interfacing technologies, it is widely understood that microelectrodes for BMI technologies exhibit limited long-term viability where recordings typically fail 6 months to 1 year after implantation, due to multimodal failure mechanisms.11). Although significant progress has been made fabricating ultra-small implants, a universal approach to reduce inflammation regardless of the device decreases the need for design restrictions for successful tissue integration. For example, larger brain-dwelling electrodes are necessary to reach deep brain structures such as nucleus accumbens12. Additionally, in order to input/output more degrees of freedom from these neural prostheses, many electrode sites are needed resulting in designs with greater surface area13. Larger electrodes result in more foreign material in the brain disrupting tissue; the more invasive the implant, the more tissue is damaged during implantation. Ideally, lessons learned about the neuroinflammatory response to smaller intracortical microelectrodes can be applied to future applications of any brain-dwelling electrode, regardless of size or design. The factors that drive the inflammatory response must be targeted to reduce neuronal dysfunction and damage, to lead to improved signal for any application using implantable microelectrodes to ensure chronic, high-fidelity function.Fortunately, much work is being done surrounding microelectrode design to reduce the inflammatory response (for review see8). In this mini-review, however, we focus on only direct immunomodulatory approaches applied to reduce the inflammatory response and improve the function of implantable intracortical microelectrodes, and we provide our current vision of the leading prospects moving forward.An active immunomodulatory approach should afford the resolution of the damage caused during the implantation of the microelectrode, while also curtailing the chronic neurodegenerative aspects of the neuroinflammatory response to enhance the long-term function of the device. Furthermore, an immunomodulatory approach should also work in combination with innovative design strategies to combat the foreign body response, as no one solution can adapt as fast as the dynamic temporally facilitated biological response. In addition to modifications in the design of the probe to mitigate the inflammatory response, there are also biological and materials-based approaches undertaken to reduce neuroinflammation to chronically implanted intracortical microelectodes (reviewed inThe following sections will discuss leading active anti-inflammatory approaches to mitigate microelectrode-induced neuroinflammation.14.The first method to directly modulate the immune system after implantation of microelectrodes was the use of systemic injection of dexamethasone (DEX), commonly used for the treatment of multiple sclerosis in the clinic. DEX is a synthetic glucocorticoid that induces pleiotropic anti-inflammatory functions through cellular glucocorticoid receptors. Most cells, including microglia, express receptors for glucocorticoids such as dexamethasone15. However, the same systemic repeated administration of DEX at a lower dose (200 μg/kg) in rats, led to a “transient increase” in both microglial/macrophage responses and laminin deposition which was interpreted by the authors as a response to injury, repair, and/or angiogenesis16. Since high systemic delivery of steroids can have serious side effects, DEX has also been incorporated into different probe coatings: poly(ethyl-vinyl) acetate, nitrocellulose, carbon nanotubes, and poly(lactic-co-glycolic acid) nanoparticles within alginate hydrogel matrices18. Each of the studies delivering DEX locally examined different markers of neuroinflammation. Benefits common to all the studies included decreased astrocytic response, reduced microglial/macrophage activity, mitigated neuronal loss, and minimized chondroitin sulfate proteoglycan expression21.The first group to report the use of DEX to minimize neuroinflammation in response to intracortical microelectrodes peripherally injected DEX (200 mg/kg) in rats daily for six days beginning the day of surgery. The systemic administration of DEX led to decreased astrocytic response at 1 and 6 weeks post-implantation22. DEX incorporated into nanoparticle embedded coatings reduced impedance compared to no-drug controls by 25%, likely due to the demonstrated decreased tissue response23. Zhong and colleagues were able to release DEX from nitrocellulose coatings for 16 days in vitro. However, once the drug is depleted from the probe material, it is currently not possible to reload the material with the drug, Furthermore, acute strategies to mitigate the inflammatory response have not been completely successful at more chronic time points25. Currently, continuous local delivery of a drug such as DEX can be delivered in vitro on a 1.5 mm metal neural probe using microfluidic technology26. As the development of this technology progresses to incorporate a microfluidic delivery system into smaller, functional, neural probes, local continuous delivery of DEX can be a promising strategy in a larger multifaceted anti-inflammatory approach.DEX has also been shown to improve the functional recording performance of intracortical microelectrode. For example, DEX was loaded into electrospun biodegradable nano-fibers followed by an alginate hydrogel encapsulation to allow for long-term release. Poly  (PEDOT) was then electrochemically polymerized on the electrode sites within the scaffold. The composite coating with PEDOT elicited decreased impedance compared to non-PEDOT coated electrodes and allowed for higher applied charge density than traditional electrodes27. Rennekar and colleagues were the first group to use minocycline to improve neural recordings from intracortical microelectrodes. The team dissolved minocycline-HCl in the drinking water of experimental rats for 2 days prior to probe implantation through 5 days post-implantation. It was estimated that the rats received about 4 mg minocycline per day (13–20 mg kg−1), based on water consumption. After 6 days, the group receiving minocycline yielded significantly higher signal to noise ratios (SNR) and the percentage of active channels detecting neural activity was higher than the control group. Both metrics for improved recording quality were maintained through 4 weeks post-implantation (study completion). Additionally, glial scarring was reduced with minocycline administration at both of the time points in which histology was examined, 1 and 4 weeks post-implantation28. Unfortunately, no report of neuronal density, known to die back around the implants, was provided in Rennekar’s study.Another broad-spectrum drug that has been investigated to decrease neuroinflammation associated with microelectrode implantation is minocycline. Minocycline is a semi-synthetic tetracycline shown to be neuroprotective in brain and spinal cord injury30. Thus, Zhang et al. incorporated minocycline into thin film coatings on oxidized silicon, a common material for neural electrodes31. The thin film coatings allow for increased loading and local, sustained release of higher concentrations of minocycline (over 46 days). In preliminary in vitro testing, minocycline incorporated in thin film coatings were able to elicit neuroprotective activity similar to controls dispersed directly into the culture media. Although these studies were conducted in vitro, the results demonstrated promise for the extended delivery of minocycline via neural probes. Additionally, recent work showed that minocycline delivered through microfluidic channels fabricated within an implanted neural probe led to reductions in microglial reactions between 200–400 μm from the probe interface32. Such distances are unlikely to impact neural recording quality. Interestingly, minocycline delivery had no effect on astrocyte density, inconsistent with the original findings from Rennekar et al. Similarly, in concordance to the previously mentioned studies, Hayn et al. (2017) administered minocycline in a single local dose (20 μg/μL) via cannula implantation in the motor cortex of rats and found decreased neuronal death and anti-inflammatory effects with improved motor function33. Overall, these studies demonstrate promise for minocycline to mitigate the neuroinflammatory response around implanted microelectrodes.An earlier study had previously shown that to achieve neuroprotective effects, minocycline must be present by the neurons at much higher levels35. Minocycline possesses an increased chance of serious adverse events relative to other tetracyclines35. Thus, minocycline could be part of a multi-faceted approach to reduce initial neuroinflammation, but less risky alternative therapies are needed for chronic applications.However, long-term dosing of minocycline begets an increased risk of adverse events—including hyperpigmentation of the skin and other organsBecause of an increased understanding of the biological response to microelectrode implantation, more specific immunomodulatory approaches are being utilized to mitigate the inflammatory response and improve the chronic performance of these devices.36. Alpha-MSH has been shown to inhibit both nitric oxide and pro-inflammatory cytokines produced by activated microglia—both of which are detrimental to neuronal health37. In their study, the Bellamkonda group coupled the Alpha-MSH peptide to silicon single shank planar microprobes and implanted the probes into the motor cortex of rats. The astrocytic and activated microglial response was examined via histology at 1 and 4 weeks post-implantation. At both time points, the activated microglial response was significantly decreased compared to a non-coated control probe. There was no notable difference in astroglial scarring at 1 week, but at 4 weeks post-implantation significantly less scarring was present36.Both microglia and astrocytes contribute to the biological response affecting electrode function. Thus, an effective way to modulate the immune response would be to mitigate the glial response. The Bellamkonda group utilized alpha-melanocyte stimulating hormone (MSH) (an endogoneous tridecapetide) to target the microglial responseet al. administered flavopiridol to rats implanted with Michigan-style single shank silicon multi-channel intracortical electrodes38. Flavopiridol arrests progression into the cell cycle, yet, re-entry into the cell cycle has been demonstrated in glial activation as shown by upregulation of cell-cycle components39. Thus, flavopiridol was hypothesized to lead to decreased glial activation and improved intracortical microelectrode recording performance. However, Purcell et al. were unable to demonstrate improved neural recording or decreased presence of glial cells (astrocytes and microglia combined)38.Purcell 41. Neural probe coatings incorporated with IL-1Ra have been successfully used to improve neuronal survival and reduce glial scarring as long as four weeks post-implantation43. Unfortunately, no information has been reported to date about either chronic time points or the effects on recording performance.Another immunomodulatory approach that has been explored was to use a cytokine receptor antagonist to reduce neuroinflammation. Interleukin- 1 receptor antagonist (IL-1Ra) has been used in human clinical trials for rheumatoid arthritis treatment and is endogenously released by microglia to facilitate neuroprotection44. Kozai et al. used a knock-out mouse model to demonstrate caspase-1 as a promising immunomodulatory target for improving chronic single-unit recordings by intracortical microelectrodes implanted in the visual cortex of mice45. Data obtained by Kozai et al. suggested that pharmacologic interventions which target the components and downstream players of the inflammasome can yield more stable chronic neural recordings. Future studies could entail using a caspase inhibitor such as VX-765 or Ac-YVAD-cmk, both of which have demonstrated neuroprotection in various models48.Given the role of the inflammasome in brain injury models, targeting the players of this construct can be pivotal in reducing neuroinflammation following intracortical microelectrode implantation. The inflammasome is an innate immune protein complex. The inflammasome activates caspase-1, an enzyme which allows a pivotal pro-inflammatory cytokine, IL- β, to achieve its active form. IL-β has been shown to be significantly upregulated around intracortical probes and plays a role in blood-brain barrier (BBB) dysfunction50. Thus, a recently developed hypothesis is that immunomodulatory strategies that limit blood-derived immune cells from the area within the brain, surrounding the implanted neural electrodes, could mitigate the inflammatory response and concurrently improve recording performance. Targeting monocyte chemoattractant protein-1 (MCP-1) using a knock out mouse model was found to decrease the inflammatory response to intracortical microelectrode implantation51. MCP-1 is a chemoattractant which attracts monocytes to areas of inflammation, such as the response to a neural electrode in the brain. Although this study did not directly evaluate reductions to blood-derived cells, they found that MCP-1 knock-out mice reduced BBB leakage, microglia/macrophage response, and astrocytic response, all leading to an increased neuronal density at acute and chronic time points. Notably, the improved neuroinflammatory response was recapitulated with pharmacological inhibition of MCP-1 via daily intraperitoneal injections51. It will be critical for future studies to also investigate the impact on neural recordings.Blood-derived cells have been shown to be major contributors to the inflammatory response of brain-dwelling intracortical microelectrode, despite the perception of the immune privileged brain52. Thus, pattern recognition receptors are amenable targets to improve neural recording from brain-dwelling intracortical microelectrodes, yet appropriate dosing regimens for optimal wound healing and anti-inflammatory responses remains to be determined.Given the presence of blood and cellular damage present at the tissue-device interface after implantation, targeting cellular receptors that recognize damage and initialize the production of pro-inflammatory cytokines promises to reduce the inflammatory response and improve intracortical microelectrode performance. Pattern recognition receptors detect cellular damage and blood proteins and are found on microglia, neurons, astrocytes, and blood-derived macrophages present at the probe interface. Through the use of knock-out mouse models and a small-molecule inhibitor, we have previously shown that targeting the toll-like receptor (TLR)/cluster of differentiation 14 (CD14) pathways can improve both acute and chronic microelectrode performanceThe goal of our mini-review was to highlight key studies in the many parallel approaches to mitigating the neuroinflammatory response to brain-dwelling neural electrodes . The min


The idea of using the effector immune cells to specifically fight cancer has recently evolved into an exciting concept of adoptive cell therapies. Indeed, genetically engineered T cells expressing on their surface recombinant, cancer-targeted receptors have been shown to induce promising response in oncological patients. However, in addition to exogenous expression of such receptors, there is also a need for disruption of certain genes in the immune cells to achieve more potent disease-targeted actions, to produce universal chimeric antigen receptor-based therapies or to study the signaling pathways in detail. In this review, we present novel genetic engineering methods, mainly TALEN and CRISPR/Cas9 systems, that can be used for such purposes. These unique techniques may contribute to creating more successful immune therapies against cancer or prospectively other diseases as well. The fundamental concept of adoptive cell therapies (ACT) against cancer or viral diseases is that immune effector cells can be isolated, expanded and returned to the patient to achieve a potent and disease-targeted cytotoxic activity -mediated route , zinc-finger nucleases (ZFN), transcription activator-like effector nucleases (TALEN) and clustered regularly interspaced short palindromic repeats (CRISPR) complexes, with the substantial predominance of the last technique in recent years. The main advantages and shortcomings of gene editing methods are summarized in Table Meganucleases, also called homing endonucleases, are an engineered version of naturally occurring endonucleases, which are able to recognize and cleave considerably large DNA sequences (~ 14–40 bps) very rare in the most genomes Stoddard . RecogniFokI restriction enzyme. ZFN were the first reagents utilized to introduce targeted changes into the genome  . Unlike ZFN, a single TALE monomer binds to one nucleotide in the target sequence. The ability of TALEN method to recognize single bases is an unquestionable advantage in targeting desirable sequence in contrast to ZFN approach which recognizes nucleotide triplets. Each TALE monomer is composed of a series of 33–35 amino acid repeat domains. The two highly variable amino acid residues located at positions 12 and 13  are responsible for TALE specificity  and CD52 genes] CAR-T cells targeting CD19 in two HLA-mismatched infants with relapsed refractory B-cell acute lymphoblastic leukemia has been recently reported . PAM sequences are typically several nucleotides long and vary among different variants of the CRISPR/Cas system , that is a fusion of crRNA and tracrRNA  to recognize and cleave foreign DNA sequences. During the action of Cas9 the crRNA hybridizes with the tracrRNA forming duplex crRNA:tracrRNA, which in the next step associates with Cas9. The crRNA is complementary to the target DNA sequence, while tracrRNA shows homology towards PAM and possess a binding site for the Cas9 which is indispensable for interference step  and hence cut only one strand of DNA generating single-strand breaks. Repair of individual nicks in the genome occur with high fidelity, without inducing in/dels, therefore, introduction of paired nicking can reduce unwanted off-target activity by 50–1000-fold  to the length of less than 20 nucleotides (17–19) and this manipulation decreases undesired mutagenesis by 5000-fold without compromising the efficiency , that are able to recognize extended sequences and introduce modifications with high efficiencies. RFNs are created by fusing, wild-type FokI nuclease domain to catalytically inactive Cas9 (dCas9) protein. The FokI nuclease domain requires dimerization to perform DNA cleavage. Thus, it is highly unlikely that any mutagenesis could be introduced at partially mismatched, off-target half-sites. Indeed, no detectable mutations were found in known off-target sites within targeted sequences with the use of RFN approach —encoding the accessory chain of major histocompatibility complex (MHC) class I . They will combine the lentiviral delivery of anti-CD19 CAR and CRISPR RNA electroporation to disrupt endogenous TCR- and B2M-encoding genes simultaneously. Several other Chinese clinical trials are investigating the efficacy of CRISPR/Cas9-mediated PD-1 knock-out T cells in patients with malignancies such as: advanced esophageal carcinoma (NCT03081715), muscle-invasive bladder cancer (NCT02863913), metastatic renal cell carcinoma (NCT02867332) and others . A number of similar clinical trials conducted earlier, have revealed that ZFN approach is mostly safe for application in humans . Generally, infusion of ZFN-modified autologous T cells was associated with mild side effects and only one serious side effect was observed in relation to transfusion. During those studies, a significant increase of CD4+ T cells was observed. What is more, HIV DNA decreased in most patients and HIV RNA was undetectable in one of four evaluated patients (Tebas et al. FAH gene function in 6% of liver cells in a mouse model of tyrosinemia type I, which was enough to cure the disease. Thus, with emergence of easy, inexpensive and highly efficient CRISPR/Cas9-based methodology, more and more clinical trials are testing safety of this approach in treating various cancers or viral infections (see Table Gene therapy holds promise of an attractive and expectantly precise treatment of variety of diseases in the future. Enabling treating illnesses caused by gene mutations by replacing DNA fragments with a correct copy of the gene or inactivating improperly functioning genes are widely studied subjects. Despite various drawbacks and limitations of gene editing methods (see Table In the last several years, we have observed a revolution in ACT used in oncology due to the capabilities of new methods for retargeting the immune effector cells against the cancer cells. Most recently, it has been increasingly clear that the gene editing techniques, such as TALEN or CRISPR/Cas9, may further refine ACT or direct genetic therapies to become a successful, universal and cost-effective strategy against cancer and perhaps a range of other diseases as well.


The advent of neuroimaging methodologies, such as functional magnetic resonance imaging (fMRI), has significantly advanced our understanding of the neurophysiological processes supporting a wide spectrum of mind–body approaches to treat pain. A promising self-regulatory practice, mindfulness meditation, reliably alleviates experimentally induced and clinical pain. Yet, the neural mechanisms supporting mindfulness-based pain relief remain poorly characterized. The present review delineates evidence from a spectrum of fMRI studies showing that the neural mechanisms supporting mindfulness-induced pain attenuation differ across varying levels of meditative experience. After brief mindfulness-based mental training , mindfulness-based pain relief is associated with higher order  regulation of low-level nociceptive neural targets , suggesting an engagement of unique, reappraisal mechanisms. By contrast, mindfulness-based pain relief after extensive training (greater than 1000 hours of practice) is associated with deactivation of prefrontal and greater activation of somatosensory cortical regions, demonstrating an ability to reduce appraisals of arising sensory events. We also describe recent findings showing that higher levels of dispositional mindfulness, in meditation-naïve individuals, are associated with lower pain and greater deactivation of the posterior cingulate cortex, a neural mechanism implicated in self-referential processes. A brief fMRI primer is presented describing appropriate steps and considerations to conduct studies combining mindfulness, pain, and fMRI. We postulate that the identification of the active analgesic neural substrates involved in mindfulness can be used to inform the development and optimization of behavioral therapies to specifically target pain, an important consideration for the ongoing opioid and chronic pain epidemic. Mindfulness-based meditation practice is associated with promoting a wide-spectrum of health outcomes including anxiety, depression, and pain  and Vipassana (open monitoring).125Mindfulness is defined here as nonreactive awareness of the present moment experience. This construct can be developed and enhanced with mindfulness-based mental training. However, experience with mindfulness meditation is not a prerequisite to being mindful.125 the practitioner is taught to sustain attention on an automatic and dynamic stimulus, such as breath sensations, as an analogy for the qualitative aspects of the present moment. As attention drifts from the object of focus  to a distracting sensory event, the practitioner is taught to acknowledge the event without further reaction, to disengage from the discursive event, and then to return attention to the meditative object . Shamatha training increases in complexity  as individuals develop expertise at each step. Shamatha practices aim primarily at gaining mental control and stabilization of attention, thus they naturally transition in a relatively undefined manner to open monitoring meditation, or Vipassana practice.During focused attention practice, or Shamatha,137 Indeed, there is little to no concrete consensus concerning where Shamatha ends and Vipassana begins. Vipassana practices are associated with an awareness of the awareness 99 of arising sensory, affective, or cognitive events. The Vipassana practitioner is said to experience each moment without evaluation or elaborative interpretation.Vipassana meditation has been described as a state of nonappraisal and/or a nonelaborative mental stance.prerequisite to, open monitoring practice. The reason for this is likely that a greater capacity for attentional stability and mental control138 would allow more success in alleviating one's tendency to reflexively engage with, and appraise, ongoing experience. As the practitioner becomes more adept in meditation, he/she will be able to use a unique cognitive approach where consciously available sensory events can be simply “let go,” presumably leading to significant reductions in affective or cognitive appraisals/reactions to the event. Said another way, the practitioner “watches” experience as it unfolds over time without cognitive elaboration or emotional reactivity. As skills in mindfulness meditation continue to develop, the practitioner brings mindfulness more effortlessly into meditation and other aspects of everyday life.59 It is postulated that the state transitions to a trait as a function of practice frequency and neural plasticity. However, the cultivation of mindfulness does not exclusively require training in mindfulness meditation. Some individuals are simply more “mindful” than others, as evinced by higher scores on standardized measures of dispositional/trait mindfulness without any formal training in meditation.142Traditionally, focused attention is taught before, or as a 21 treatments that work in a highly focal fashion on one neurotransmitter system or on one brain region or pathway are likely to be of limited efficacy. Treatments that can target multiple nodes within this distributed network are crucially needed. Mindfulness may have that ability because it uniquely enhances cognitive control,138 emotion regulation,73 acceptance ,116 and improves mood.36 There is also a great deal of insight from Buddhist contemplatives in the way that mindfulness-based mental training impacts the subjective experience of pain. The Sallatha Sutta, a Theravadin Buddhist scripture from the Pali Canon (translated as The Arrow or The Dart), explicitly states that there is a key difference in how mindfulness trained and “untrained” individuals experience pain.3 The Sutta analogizes the reaction to pain to being stung by an arrow and, in the case of untrained individuals, being struck immediately after by a second arrow. The 2 arrows are described as representing physical and mental pain, respectively. The first arrow could refer to the noxious sensation one initially feels, while the second dart could be described as the worry, distress, and pain-evoked suffering that follows. The claim of Buddhist contemplatives is that mindfully trained individuals, because they do not cling to sensory pleasure, also do not engage cognitive and affective appraisals of pain.Given that pain is instantiated by a highly distributed network of brain mechanisms,33 Despite treatment advances, the pervasiveness and burden of chronic pain has dramatically increased Medicare expenditures for steroid injections (↑629%) and opioid treatments (↑423%).31 The widespread use of opioids to alleviate chronic pain has led to the so-called “opioid epidemic”84 with an exponential rise in opioid misuse and addiction.98 These staggering statistics signify the importance of developing fast-acting nonpharmacologic approaches to treat acute exacerbations of chronic pain. To this extent, the need for effective nonpharmacological treatment options has spurred much interest in mind–body approaches toward mitigating chronic pain. Mindfulness meditation-based interventions improve chronic pain symptomology across a wide range of pain conditions, including fibromyalgia,48 headache disorders,130 chronic pelvic pain,38 irritable bowel syndrome,44 and chronic lower back pain83—the most prevalent and financially burdensome chronic pain disorder. Research suggests that mindfulness meditation improves chronic pain symptomatology through unique mechanisms, such as disengagement from pain-related threat,119 extinction of fear conditioning, acceptance-based coping strategies,81 and strengthening one's ability to self-regulate affective appraisals of nociceptive input.42Chronic pain affects more than 100 million Americans, 1.5 billion people worldwide, and costs the United States an estimated $635 billion per year in medical expenses and lost work productivity.57 Mindfulness-based stress reduction is a structuralized, group-based psychosocial intervention consisting of mindfulness meditation, yoga, and cognitive-behavioral therapy with the goal of integrating mindfulness into everyday life. In their seminal work, Kabat-Zinn et al.56 showed that a 10-week MBSR program reduced pain reports, pain-related behaviors and improved general vitality in chronic pain patients, effects that were maintained at 15-month follow-up.58 However, this initial work lacked a control group, and thus, while promising, subsequent research was warranted. A more recent study showed that MBSR produced greater reductions in pain catastrophizing in chronic low-back pain patients compared with cognitive-behavioral therapy (CBT) and standard of care.118 It is interesting that MBSR outperformed CBT given the explicit focus of CBT on controlling maladaptive thoughts and behaviors, suggesting that mindfulness training may uniquely buffer against future-oriented, catastrophic thinking. In fact, growing research suggests that the nonreactivity component of mindfulness is negatively related to pain catastrophizing.30 However, the long-term benefits of MBSR on pain catastrophizing are questionable because group differences were no longer significant at follow-up,118 implying that training should to be continued to facilitate lasting changes in the propensity to catastrophize. By contrast, in a seminal study, Cherkin et al.19 found that both MBSR and CBT significantly improved ratings of functional limitations, pain-related distress, and pain intensity in chronic lower back pain patients when compared with standard of care. In the same study, findings persisted for MBSR and CBT at 8-, 26-, and 52-week follow-up, demonstrating the durability of mindfulness on certain pain-related outcomes over time. Taken together, this growing body of work demonstrates that a few weeks of mindfulness training improves pain and health outcomes in people suffering from chronic pain, and with some evidence of persistent benefit. Yet, the precise neural mechanisms supporting pain relief by mindfulness meditation remains relatively uncharacterized.Much of the work on the efficacy of mindfulness-based interventions for the treatment of chronic pain has focused on outcomes associated with mindfulness-based stress reduction (MBSR) and its varieties.Electrophysiological (EEG) and brain imaging methods have provided an important avenue for elucidating the neural mechanisms supporting the modulation of pain by mindfulness meditation. Converging lines of evidence demonstrate that mindfulness-based analgesia engages distinct neural processes that vary across training level. Here, we will delineate the neural mechanisms supporting mindfulness-based pain modulation across no to brief to long-term training levels. We will focus primarily on studies using fMRI.Trait or dispositional mindfulness is the innate propensity to be aware of the present moment in a nonreactive manner.27 Trait mindfulness can also be developed and increased through mindfulness-based mental training. Individuals who are low on the trait mindfulness spectrum exhibit higher pain in a number of clinical pain populations.100 Two recent studies combined psychophysics, noxious heat stimulation, and distinct functional neuroimaging techniques to identify the neural mechanisms supporting the postulated relationship between trait mindfulness and pain sensitivity142 and pain threshold.52 Zeidan et al.142 used perfusion-based arterial spin labeling (ASL) fMRI to determine the significant relationship between higher dispositional mindfulness (as measured by the Freiburg Mindfulness Inventory) and lower pain ratings in response to noxious heat (49°C).142 As hypothesized, higher trait mindfulness was associated with greater deactivation of the posterior, midline nodes of the so-called default mode network. The default mode network is defined by oscillating activity within a group of distinct brain regions  and is associated with facilitating self-referential processes.107 Specifically, greater deactivation of the dorsal PCC and precuneus was associated with higher trait mindfulness, and greater activation of the dorsal PCC during noxious heat was associated with higher pain reports during noxious heat  signaling fMRI, Harrison et al.52 found that greater trait mindfulness (measured by the Five Facet Mindfulness Questionnaire) was associated with higher pain threshold values. Higher trait mindfulness was associated with weaker connectivity between the central nodes of the default mode network  and stronger connectivity between the precuneus and somatosensory cortices. These findings are remarkably consistent with the principles of mindfulness supporting the disposition to attend to immediate sensory aspects of experience and the ability to disengage from immediate appraisals and corresponding ruminations. Taken together, these 2 studies provide unique mechanistic insight that trait mindfulness is associated with lower pain and lower PCC/precuneus processing, suggesting that trait mindfulness is associated with a lower propensity to ruminate on65 and personalize4 the appraisal of arising noxious sensory events.142 Furthermore, individuals who exhibit higher trait mindfulness may have a greater ability to decouple noxious sensory discriminations from affective appraisals.142 This is important because even brief bouts of mindfulness training (less than a week) can significantly increase dispositional mindfulness on average by 13%.141 These findings could assist us to better develop and tailor adjunctive pain therapies to specifically target reductions in PCC/precuneus and increase trait mindfulness activity to treat pain.Individuals that have never practiced mindfulness meditation may still be highly mindful as a function of genetics, environment, psychosocial, and cultural factors. brief mental training regimens can provide insight into measuring explicit changes in behavioral and physiological pain responses. To this extent, it is now well established that mindfulness meditation significantly reduces pain after brief mental training (4 days > 4 weeks).141 In one of the first preliminary studies to examine the effects of mindfulness meditation on pain, Kingston et al.62 found that 6 hours of mindfulness-based mental training was associated with higher pain tolerance during the cold pressor test, when compared with an active, visual imagery-based  control condition. The authors reported no significant between-group differences in mindfulness (as measured by the Kentucky Inventory of Mindfulness Skills), blood pressure, or mood.62Longitudinal and carefully controlled studies examining the effects of 55 To better address this issue, Zeidan et al.,138 across 3 separate experiments, dissected the pain relieving effects of mindfulness meditation regimen (three 20-minute Shamatha + Vipassana training sessions) from a robust, math distraction and relaxation condition during noxious electrical stimulation. Mindfulness meditation during noxious electrical stimulation significantly reduced pain responses above and beyond analgesia observed during math distraction and relaxation. Surprisingly, mindfulness meditation training significantly increased pain threshold when compared with before the intervention and the control group.138 These findings provided credence that mindfulness-based pain relief may engage unique physiological mechanisms from other cognitive techniques to reduce pain.Others have postulated that mindfulness-induced pain relief engages mechanisms supporting divided attention, relaxation, and/or positive mood.141 examined the behavioral and neural mechanisms supporting state mindfulness-induced pain relief before and after a brief, mindfulness training regimen (four 20-minute sessions) during noxious heat (49°C) in healthy participants. In the pre- and post-fMRI sessions, participants were instructed to “begin meditating and to focus on the changing sensations of the breath” during noxious heat- and perfusion-based fMRI (ASL). Focusing on the breath before the intervention reduced pain unpleasantness ratings but not pain intensity ratings when compared with rest. After training, mindful attention to the breath significantly reduced pain intensity (↓40%) and pain unpleasantness (↓57%) ratings when compared with rest. Mindfulness meditation produced widespread activation of the (1) ACC extending from the dACC to the perigenual ACC (pgACC), (2) bilateral orbitofrontal cortex (OFC), (3) the primary somatosensory cortices (SI) corresponding to the face region, (4) bilateral ventral striatum, and (5) deactivation of the default mode network.141 In the presence of noxious heat, mindfulness significantly reduced SI activation corresponding to the stimulation site (right leg), suggesting that mindfulness reduces ascending nociceptive inputs to somatosensory cortical regions. Regression analyses revealed that greater pain relief was directly associated with greater activation of the pgACC, right anterior insula, and bilateral OFC. Greater mindfulness-based pain relief was also associated with significant extensive, bilateral deactivation of the thalamus, a critical node of ascending nociceptive information from the spinal cord  mechanisms supporting mindfulness-based pain relief are distinct from those engaged by different placebo conditions. Healthy, pain-free participants were randomly assigned to 1 of 4 (four 20-minute/session) training regimens: (1) a mindfulness meditation akin to one previously described, (2) a placebo cream conditioning, (3) a sham mindfulness meditation, and 4) a book-listening control. Participants in the placebo-conditioning group were led to believe that the effects of an experimental form of Lidocaine was being evaluated, in which the pain-relieving effects of the cream (petroleum jelly) progressively increased with repeated application. Participants were led to believe that the cream was analgesic by covertly reducing stimulus temperature after application of the cream in each conditioning session. The sham mindfulness regimen mirrored mindfulness meditation on all nonspecific and psychosocial factors , but without the explicit training on focusing on the changing sensations of the breath in a nonreactive fashion. Thus, this group  allowed us to disentangle the active mechanisms that were specific to mindfulness. All conditions significantly reduced pain intensity and pain unpleasantness ratings compared to the book-listening controls. Mindfulness meditation was more effective than placebo cream, placebo (sham) mindfulness, and control conditions at reducing pain ratings. The neural mechanisms supporting mindfulness-based pain relief were, again, found to be associated with greater activation in the OFC, pgACC, and right anterior insula.135 There was also significant deactivation of the PAG and thalamus, replicating and extending on the findings described in the previous ASL study.141 Placebo cream-induced pain relief was associated with significant reductions of contralateral, nociceptive somatosensory areas  and greater activation of the dorsolateral prefrontal cortex [DLPFC]), likely reflective of perceive controllability of pain102 and lower expectations for pain.64 This was the first ASL fMRI placebo experiment and largely replicated the findings supporting other pain-placebo–focused brain imaging studies.123 Regression analyses revealed that sham mindfulness induced pain relief was associated with lower respiration rate. These findings provide clear mechanistic distinctions between mindfulness and placebo. As described earlier, mindfulness engages multiple mechanisms supporting top-down regulation of pain. By contrast, sham mindfulness meditation likely employs bottom-up processes. Taken together, these findings provide robust evidence that the state effect of mindfulness meditation, after brief mental training, significantly reduces pain and recruits multiple, distinct neural processes from robust placebo conditions.Randomized, placebo-controlled studies are characterized as the “gold standard” to defining the effectiveness and active novel pain relieving treatments. Yet, placebo-controlled meditation studies have been very limited. This is problematic when considering that meditation is very susceptible to placebo responses and nonspecific effects such as slow breathing, demand characteristics, beliefs related to practicing meditation, conditioning, posture, among others. Thus, in the follow-up experiment, Zeidan et al.83 Grant and Rainville46 were the first to demonstrate that adept Zen practitioners (a mindfulness practice similar to Vipassana) required significantly higher noxious heat stimulation to report the same level of pain as age-matched controls. In a follow-up fMRI (BOLD) study using a functional connectivity analyses during noxious heat stimulation and overlapping participant sample, Zen practitioners exhibited a significant decoupling between brain regions supporting nociceptive processing  and sensory/affective appraisal  when compared with age-matched controls  in long-term Vipassana practitioners and demographically matched meditation naïve controls.40 Practicing mindfulness in response to 1-second noxious electric stimuli reduced pain unpleasantness (↓22%) and anticipatory anxiety (↓29%) ratings when compared with rest and control conditions. Surprisingly, mindfulness meditation did not significantly reduce pain intensity ratings when compared with controls. Mindfulness-based pain relief was associated with decreased activation in the lateral PFC and increased activation in the right posterior insula/SII.40 The authors postulated that this reflects “decreased cognitive control.” One could also take the perspective143 that mindfulness was associated with enhanced cognitive flexibility, potentially reflected by observed increases in rACC during meditation. Other groups114 have also postulated that it requires a significant degree of cognitive-affective control to reduce appraisals (↓PFC) of ascending noxious sensory events.Research employing individuals with extensive mindfulness meditation experience (>1000 hours of practice) has provided insight into the ability of adept practitioners to evoke more stabilized, state- and trait-level changes in nociceptive processing, and corresponding pain responses. There is reliable and growing evidence demonstrating that long-term mindfulness practice can lead to significant increases in pain threshold values and lower pain sensitivity even when participants are not explicitly practicing mindfulness.140 Lutz et al.71 tested this postulation by examining the influence of long-term mindfulness meditation  on psychophysical and neural responses to noxious heat stimulation. Control participants were nonmeditators that were instructed to practice mindfulness at home for 1 week. Surprisingly, both adept and novice meditators reduced pain intensity ratings during Shamatha practice and noxious heat, and there were no significant group differences. Vipassana-based meditation produced significant pain unpleasantness reductions in the adept meditators when compared with novices. The adept meditators exhibited less activation in the contralateral anterior insula and the rostral aspect of the midcingulate cortex during the prestimulus period when compared with controls. Furthermore, the greater the meditative experience, the greater the deactivation of said regions. Brown and Jones13 used electroencephalography (EEG) and pain-evoking laser stimulation to examine behavioral and EEG pain responses in adept meditators. Similar to Lutz et al., they found that lower pain responses were associated with significantly lower anticipatory event-related potentials in the inferior parietal and midcingulate cortex in the meditation but not control group.13 Greater meditative experience also predicted lower anticipatory EEG responses and greater pain relief. Remarkably, these effects were detected during a nonmeditative state and provided a clear scope of the trait-like pain modulatory changes that can occur with extensive mindfulness training.13 Finally, in a recent preliminary study, Taylor et al.115 recruited 11 adept meditators  and 51 control subjects to examine whether mindfulness reduces pain and anticipatory skin conductance reactions, specifically the nociceptive flexion reflex, in response to a fear condition task and noxious electrical stimulation. They found that the meditation group exhibited less pain sensitivity and reduced fear-induced pain facilitation than controls. Meditators and nonmeditators displayed comparable nociceptive flexion reflexes, suggesting that mindfulness does not (1) modulate nociceptive processes at the level of the spinal cord, (2) engage classical descending inhibition of pain mechanisms, and (3) reduce anticipatory responses corresponding to conditioned pain-focused fear response, but rather direct expectations of impending stimuli, a finding consistent with previous work.71 The authors further speculated that reductions in fear-conditioned pain learning might be a mechanism by which mindfulness reduces the progression of acute to chronic pain. Taken together, these mechanistic findings115 show that attenuating the expectations of impending sensory events by sustaining attention in the present moment are directly associated with facilitating mindfulness-based pain relief.To this extent, one of the defining features of mindfulness meditation is the emphasis on nonevaluative awareness of present moment experience. It can reasonably be construed, then, that this experiential acceptance should reduce expectations of impending noxious stimuli that could exacerbate the pain experience.127 To date, the endogenous opioidergic system is characterized as the primary endogenous pain modulatory system.127 Higher order brain regions  project to the PAG, the rostral ventral medulla, and the dorsal horn of the spinal cord to reduce the elaboration of spinal and supraspinal nociceptive processing through the release of endogenous opioids78 that largely bind with mu, delta, and kappa receptors.69 Pain relief produced by placebo,147 acupuncture,51 conditioned pain modulation,61 distraction,108 and hypnosis110 is meditated, in part, by endogenous opioidergic systems.A plethora of endogenous neurotransmitters, including the cannabinoid, serotonergic, dopaminergic, and opioidergic systems, at least, are partially engaged in the cognitive modulation of pain.124 However, mindfulness meditation also deactivates the PAG, a central node in opioidergically mediated descending inhibition of pain.7 To bridge this exploratory gap, Zeidan et al.134 conducted a double-blinded, randomized study of healthy, meditation-naïve participants to determine whether mindfulness pain relief engages endogenous opioids in response to intravenous administration (IV) of placebo saline and high-dose naloxone, the opioid antagonist, when compared with a book-listening control. In brief, mindfulness, after brief mental training, effectively reduced behavioral responses in the presence of opioid blockade and saline, demonstrating that mindfulness-based analgesia is not mediated by endogenous opioids. As a supplementary query, one could postulate that mindfulness-based pain relief, after extensive mindfulness training, could engage endogenous opioidergic systems due to progressive development of opioidergically driven processes such as conditioning, expectations, and other placebo-type mechanisms. Using a double-blinded, cross-sectional design, May et al. (2018) assessed the role of endogenous opioids in mindfulness-based pain relief in adept mindfulness practitioners with extensive training . Surprisingly, when compared with saline and the control group, high-dose IV naloxone infusion produced greater pain relief in the meditation group, providing further evidence that mindfulness across training levels produces analgesia independent of endogenous opioids.79 We postulated that expert meditators may have exerted more effort in the presence of naloxone to counteract the effect of naloxone, and that other nonopioidergic systems10 may have been engaged to compensate for opioid blockade.89 By contrast, another group used a randomized, crossover design and reported that mindfulness-based pain relief was reversed by naloxone105 in response to a brief (10 seconds) noxious cold stimulus. In our rebutting commentary of this study, we postulated that the authors' interpretations were not justified because of the significant decrease in pain  during mindfulness and naloxone infusion and the comparable reductions during meditation and saline infusion .133 Importantly, the authors did not directly statistically compare the differences in pain between the saline and naloxone conditions, which begs the question on why they used the elegant crossover-controlled design. The authors go on to say in their rebuttal to our commentary104 that “experience seems to be a crucial factor in opioid involvement in mindfulness meditation.” Our recent study demonstrating that mindfulness-based analgesia is more pronounced during naloxone in long-term meditators (mean experience >4000 hours of meditation practice) potentially invalidates this interpretation.79 Taken together, these findings are important because they provide supplementary evidence that mindfulness engages unique mechanisms to reduce pain that are distinct from those mediated by placebo analgesia . Because opioid and nonopioid processes synergistically interact with reduce pain, these findings suggest that mindfulness could be used in conjunction with traditional pain therapies to optimize analgesia, an important finding for the millions of chronic pain patients seeking effective, self-regulatory pain therapy.Mindfulness-based analgesia, after brief mental training, is associated with greater activation of the rACC, OFC, and insular cortices, brain regions that contain high concentrations of opioid receptors.The widespread employment of functional neuroimaging methodologies and identification of the health promoting mechanisms supporting meditation is credited with the explosive proliferation of mindfulness-based research. Functional magnetic resonance imaging, positron emission tomography (PET), and ASL fMRI have provided means to collect direct  and indirect  measures of cerebral blood flow (CBF), which provide higher spatial resolution , although this comes at a tradeoff, with poorer temporal resolution (2–5 seconds) than EEG/event-related potential. Here, we will provide very brief suggestions on how to best conduct mindfulness-pain research in combination with fMRI.state mindfulness meditation when compared with BOLD fMRI. Arterial spin labeling fMRI provides a fully quantifiable and direct measurement of CBF (mL/100 g of tissue/min). By contrast, BOLD is an indirect surrogate of CBF that assesses blood oxygen in arbitrary units. When compared with BOLD fMRI, ASL is less sensitive to low-frequency drifts in signal intensity that can occur as an individual's body relaxes as a function of time or as the scanner heats up over the course of an imaging series.126 Accordingly, BOLD fMRI is not well suited to appropriately image task-related brain activation longer than 30 seconds.1 Furthermore, when compared with BOLD, ASL fMRI can reliably assess rostral neural regions, such as the OFC,126 a brain area repeatedly implicated in mindfulness meditation,141 but suffering from substantial susceptibility artifacts. Nevertheless, BOLD fMRI does enjoy higher signal-to-noise ratio when compared with ASL.87 Thus, the utility of ASL vs BOLD comes down to the primary aims of the study.Both ASL and BOLD fMRI examine CBF to make inferences about neural activity. There are a number of reasons that we propose that perfusion-based, ASL fMRI method is more appropriate for examining the effects of 93 This is an important caveat because state mindfulness meditation reliably (1) reduces respiration rate and, in parallel, decreases CBF due to lower arterial levels of carbon dioxide131 and (2) alters chest movements that cause magnetic field changes, rendering a physiological artifact.112 This is problematic because meditation-induced changes in breathing are directly task-specific and can dramatically misconstrue the interpretation of findings. The changes in breathing are meditation-specific, and the brain (de) activations could be interpreted as meditation-related mechanisms, when they are potentially due to physiological noise.96 In our laboratory, we have seen (unpublished findings) significantly greater white-matter activation when compared with gray matter during meditation practice. One can make the mistake of regressing out each individual's respiration rate from his or her respective fMRI analysis. However, that would likely remove neuronal activation that directly corresponds to mindfulness-based breath focus, as opposed to controlling for physiological noise. Furthermore, the employment of perfusion fMRI may not directly correct for physiological artifacts, although it is better suited to identify if CBF deviations occurred . Thus, it is critical that researchers evaluate and correct for this issue by (1) collecting respiration data, (2) visually inspecting data for significantly greater white-matter activation when compared with gray matter, (3) segmenting and comparing white-matter and gray-matter brain, and (4) inputting segmented white values as covariates of no interest in the statistical analyses using a component-based noise correction method .8As fMRI scanners increase their respective field strengths, physiological noise has become a significant confound reducing the applicability and generalization of functional neuroimaging findings.connectivity analyses to measure stabilized changes in neural functioning because ASL fMRI is not yet optimized for connectivity studies.Functional neuroimaging experiments use “ON/OFF” block designs to identify brain activation corresponding to any specific event . For example, a traditional BOLD-based fMRI experimental paradigm may be designed to contrast brain activation in response to 10-second plateaus of noxious, 49°C and innocuous 35°C heat, respectively. The 49° stimulus is generally characterized as the “on” and 35°C as the “off” condition, respectively. Because this hypothetical experimental paradigm controls for contact of the thermal probe and change in stimulus temperature, significant brain activation could be interpreted as brain activity corresponding to 49°C when compared with 35°C, and vice versa. However, this on–off paradigm cannot be used to measure state mindfulness. That is, directing subjects to meditate for 10 seconds (ON) and rest (OFF) for 10 seconds will lead to contamination of the “OFF” period because the cognitive state of mindfulness meditation cannot be “turned off and on” like a thermal stimulus. There are carryover effects from mindfulness meditation that can last minutes to days. Thus, we propose starting the experiment with rest  for the first half of the experiment and instructing subjects to meditate in the second half of the study. This paradigm is weakened by obvious order effects, but using a paralleling nonmanipulation group/condition can easily control this for experimental confound. It is important to note that these recommendations are explicit to state mindfulness meditation activation studies. It is perfectly acceptable to use BOLD fMRI-based resting state functional 113 Mindfulness-based pain relief is believed to be associated with a spectrum of nonspecific factors such as distraction, slow breathing, placebo, conditioning, facilitator attention, social support, body posture, relaxation, and demand characteristics. This is a limitation in fostering the validity of this practice to relieve pain. We suggest that mindfulness-pain neuroimaging studies should use comparison conditions that most closely resemble mindfulness practices and suited to disentangle the mechanisms that are postulated to be engaged by mindfulness. To better address this issue, we recently developed and validated a sham-mindfulness meditation comparison condition.139 Sham-mindfulness meditation  was designed, so that the primary difference between the mindfulness and sham-mindfulness practice was the explicit instructions corresponding to the nonreactive attention to the breath sensations used in the mindfulness meditation. Participants were first instructed that they were randomly assigned to the mindfulness meditation group, and that mindfulness training was secular. In each of the training sessions, subjects were instructed to close their eyes, and to take a deep breath “as we sit here in meditation” every 2 to 3 minutes.139 All other aspects of the sham-mindfulness meditation intervention  matched the mindfulness meditation-training regimen. We also paralleled the fMRI-session's experimental directives (“begin practicing mindfulness meditation until the end of the experiment”) across the mindfulness and sham-mindfulness groups.The neural mechanisms supporting mindfulness-based practices still remain poorly characterized.136 relaxation conditions,136 cognitive-behavioral therapies, and techniques that may share mechanisms that may be engaged by mindfulness . Some recent studies have successfully disentangled the active mechanisms supporting mindfulness-based health promotion. Creswell et al.23 compared behavioral, inflammatory stress  and neural mechanisms supporting an intensive 3-day mindfulness meditation and 3-day health enhancement relaxation program in unemployed and clinically stressed adults. All aspects of the relaxation program were matched to the mindfulness regimen intervention (including time of the interventions held on the same weekends and even the location of the intervention). Mindfulness-induced stress reductions were associated with stronger functional connectivity between the PCC and dlPFC, mechanisms supporting executive-level control of emotions. By contrast, the relaxation group exhibited higher IL-6 responses after the intervention. Another group used a health enhancement program (HEP) to disentangle the mechanisms supporting mindfulness.95 The HEP controlled for facilitator allegiance, social support, and other components related to participating in a mindfulness program. Although the HEP and mindfulness conditions were effective at improving mood, stress, and cognition, they did not significantly differ. However, the mindfulness program was more effective at reducing inflammatory markers in response to a social stress test95 and pain.74 Taken together, these findings demonstrate that some mindfulness techniques are not more beneficial than active controls on some health outcomes (stress and cognition) but superior on other outcomes (pain). Nevertheless, they demonstrate that mindfulness engages unique health-promoting mechanisms that are important to better optimize the development and tailoring of said interventions for different patient populations.Other appropriate fMRI controls for mindfulness include divided attention tasks,66 have conducted mindfulness training while subjects are lying down and during an audio recording of the scanner sounds. We initially begin our mindfulness training regimens while subjects are in a more traditional pose  and then instruct individuals to lie in the supine to practice with the sounds of the scanner . We also recommend conducting mindfulness training in a “mock scanner” or a similar environment to better control for claustrophobic individuals and to better prepare subjects to meditate in the scanner.In light of the ongoing opioid epidemic, nonpharmacological pain therapies such as mindfulness-based approaches will continue to be examined by combining subjective reports and functional neuroimaging methodologies. We have provided a number of supplementary suggestions that may aid in conducting mindfulness-pain fMRI studies. Practicing mindfulness meditation is quite difficult to perform in a quiet room. Mindfulness practice difficulty is exacerbated in the fMRI environment. The scanner (1) is very loud, (2) confines the individual, and (3) renders the participant unable to practice mindfulness in an upright, seated position. To address this, we and others80 we propose that the observed relationship between mindfulness-based pain relief and thalamic deactivation reflects a remote tuning mechanism that is facilitated by feedback connections between excitatory, glutamatergic OFC innervations on the thalamus and subsequently the inhibitory, GABAergic thalamic reticular nuclei (TRN).146 Coincidently, these neuroanatomical projections (OFC > TRN) reflect a gating mechanism of ascending sensory information that selectively modulates, through higher order cognitive control processes , sensory and emotional salience of said sensory events to significantly reduce the thalamic transmission to early somatosensory cortices . This mechanism is critically involved in integrating real-time sensory and affective information,129 assessing value,49 and regulating “passage to the cortex”.146 Unfortunately, ASL fMRI does not provide optimized means to directly test this hypothesis using functional connectivity analyses, due to low signal-to-noise resolution. Nevertheless, these findings demonstrate that mindfulness-based pain relief engages multiple brain mechanisms that are relatively distinct from other cognitive manipulations. Importantly, the Zeidan et al. (2011) study lacked a matched and active control group, and thus, it was difficult to explicitly ascertain whether mindfulness reduces pain through brain mechanisms that are reflective of placebo analgesia.Here, we show that mindfulness meditation-based pain relief does not engage one particular brain mechanism to reduce pain, but rather a combination of processes that are reflective of effortful, reappraisal processes. In light of Francis Crick's “speculative…searchlight hypothesis,”and noxious sensory events. Mindfulness meditation, across all reported pain focused studies, impacted the affective dimension of pain more so than sensory pain. However, more brain imaging research is needed to clearly extrapolate the mechanisms that mindfulness impacts chronic pain, as the large proportion of said fMRI-mindfulness studies were conducted in healthy individuals. To this extent, it will no doubt be fruitful to incorporate PET studies to better identify neurochemical-based interactions supporting mindfulness-based analgesia. This line of research would, if properly designed, provide a clear understanding of the different classes of neurotransmitters involved in mindfulness and provide another means of testing our working hypothesis on the role of the TRN in modulating pain. Mindfulness is susceptible to nonspecific effects, thus we highly recommend appropriate placebo-based comparisons to better isolate genuine mindfulness mechanisms. We also need to better characterize the neural mechanisms supporting mindfulness-based pain relief in specific chronic pain populations. For instance, the neural processes supporting pain relief in chronic low-back pain may differ from those found to be effective at treating migraine pain. We also need to appreciate how long the effects of meditation last and how much training is required. Nevertheless, it is clear that mindfulness effectively reduces pain and does so by engaging processes that reflect changes in one's relationship with respective pain. This is important for those seeking ways to reduce the impact of developing chronic pain and the common comorbidities (anxiety and depression) that exacerbate the pain experience. We predict that the mechanisms supporting mindfulness-based pain relief become more robust with more practice, a distinction from traditional pain therapies that exhibit increasing tolerance and plateaus in efficacy. When considering the ongoing chronic pain and opioid epidemic, the utility of mindfulness meditation may prove to be an important tool to teach individuals to self-regulate pain directly with a present-centered and acceptance-based strategy.The postulated mechanisms supporting mindfulness-based pain relief may not explicitly relate to eradicating the intensity of pain but suggest that mindfulness alters the contextual evaluation of innocuous The authors have no conflict of interest to declare.


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