Apkar Vania Apkarian

• BS EE, MS BME, PHD
• Professor (Full) at Northwestern University

Placebo analgesia in chronic pain is a widely studied clinical phenomenon, where expectations about the effectiveness of a treatment can result in substantial pain relief when using an inert treatment agent. While placebos offer an opportunity for non-pharmacological treatment in chronic pain, not everyone demonstrates an analgesic response. Prior...

How does the human brain generate coherent, subjective perceptions—transforming yellow and oblong visual sensory information into the perception of an edible banana? This is a hard problem. According to the standard viewpoint, processing in groups of dedicated regions—identified as active “blobs” when using functional magnetic resonance imaging (fM...

Background Total knee replacement (TKR) is the gold standard treatment for end‐stage chronic osteoarthritis pain, yet many patients report chronic postoperative pain after TKR. The search for preoperative predictors for chronic postoperative pain following TKR has been studied with inconsistent findings. Methods This study investigates the predict...

Chronic pain is commonly treated with long-term opioids, but the neuropsychological outcomes associated with stable long-duration opioid use remain unclear. Here, we contrasted the psychological profiles, brain activity, and brain structure of 70 chronic back pain patients on opioids (CBP+O, average opioid exposure 6.2 years) with 70 patients manag...

Total knee replacement (TKR) is the gold-standard treatment for end-stage chronic osteoarthritis pain, yet many patients report chronic postoperative pain after TKR. The search for preoperative predictors for chronic postoperative pain following TKR has been studied with inconsistent findings. This study investigates the predictive value of quantit...

The chronic pain and opioid addiction epidemics interact with each other, potentially exacerbating each respective condition. Despite having modest efficacy, millions of chronic pain patients in the USA continue to use opioids as their primary source of pain management. The Centers for Disease Control recommends opioid tapering to diminish the risk...

This book sheds light on the translation of current mechanistic research on placebo effects to develop comprehensive and adequate strategies for better symptom management and treatment. This book identifies three core aspects to bridge state-of-the-art concepts with day-to-day clinical practice. First, lessons from mechanistic placebo research indi...

The neural mechanisms for the persistence of pain after a technically successful arthroplasty in osteoarthritis (OA) remain minimally studied, and direct evidence of the brain as a predisposing factor for pain chronicity in this setting has not been investigated. We undertook this study as a first effort to identify presurgical brain and clinical m...

Exercise is associated with lower prevalence and severity of pain, and is widely recommended for pain management. However, the mechanisms the exercise effect on pain remain unclear. In this study, we examined the association of exercise with pain and aimed to identify its neurobiological mediators. We utilized a baseline data of a clinical trial fo...

Microglia are important mediators of neuroinflammation, which underlies neuropathic pain. However, the molecular checkpoints controlling microglial reactivity are not well-understood. Here, we investigated the role of Orai1 channels for microglia-mediated neuroinflammation following nerve injury and find that deletion of Orai1 in microglia attenuat...

Microglia are important mediators of neuroinflammation that underlies neuropathic pain. However, the molecular checkpoints controlling microglial reactivity are not well-understood. We investigated the role of Orai1 channels for microglia-mediated neuroinflammation following nerve injury and find that deletion of Orai1 in microglia attenuates Ca2+...

IntroductionThe opiate epidemic has severe medical and social consequences. Opioids are commonly prescribed in patients with chronic pain, and are a main contributor to the opiate epidemic. The adverse effects of long-term opioid usage have been studied primarily in dependence/addiction disorders, but not in chronic pain. Here, we examine the added...

Accumulating evidence suggests hippocampal impairment under chronic pain phenotype. However, it is unknown whether neuropathic behaviors are related to dysfunction of the hippocampal circuitry. Here we enhanced hippocampal activity by pharmacological, opto- and chemo-genetic techniques to determine hippocampal influence on neuropathic pain behavior...

Introduction: Lumbar disc herniation (LDH) is a common back disorder that evokes back and/or leg pain. Percutaneous endoscopic lumbar discectomy (PELD) is a minimally invasive surgery for patients with LDH. However, there is little evidence of effectiveness of PELD compared with conservative treatments. Objective: The goal of this study was to q...

Although placebo effect sizes in clinical trials of chronic pain treatments have been increasing, it remains unknown if characteristics of individuals' thoughts or prior experiences can reliably infer placebo pill responses. Research using language to investigate emotional and cognitive processes has recently gained momentum. Here, we quantified pl...

High-profile studies claim to assess mental states across individuals using multi-voxel decoders of brain activity. The fixed, fine-grained, multi-voxel patterns in these "optimized" decoders are purportedly necessary for discriminating between, and accurately identifying, mental states. Here, we present compelling evidence that the efficacy of the...

The judgement of human ability is ubiquitous, from school admissions to job performance reviews. The exact make-up of ability traits, however, is often narrowly defined and lacks a comprehensive basis. We attempt to simplify the spectrum of human ability, similar to how five personality traits are widely believed to describe most personalities. Fin...

Osteoarthritis (OA) manifests with chronic pain, motor impairment, and proprioceptive changes. However, the role of the brain in the disease is largely unknown. Here, we studied brain networks using the mathematical properties of graphs in a large sample of knee and hip OA (KOA, n = 91; HOA, n = 23) patients. We used a robust validation strategy by...

Sex differences in the quality and prevalence of chronic pain are manifold, with women generally presenting higher incidence and severity. Uncovering chronic pain-related sex differences inform neural mechanisms and may lead to novel treatment routes. In a multicenter morphological study (total n = 374), we investigated whether the shape of subcort...

Head motion is a major confounding factor impairing the quality of functional magnetic resonance imaging (fMRI) data. In particular, head motion can reduce analytical efficiency, and its effects are still present even after preprocessing. To examine the validity of motion removal and to evaluate the remaining effects of motion on the quality of the...

The nucleus accumbens (NAc) and the ventral tegmental area (VTA) are critical hubs in the brain circuitry controlling chronic pain. Yet, how these two regions interact to shape the chronic pain state is poorly understood. Our studies show that in mice spared nerve injury (SNI) induced alterations in the functional connectome of D2-receptor expressi...

More than 75% of major limb amputees experience chronic pain; however, data on severity and experience of pain are inconsistent. Without a benchmark using quantitative patient-reported outcomes, it is difficult to critically assess the efficacy of novel treatment strategies. Our primary objective is to report quantitative pain parameters for a larg...

The interaction between osteoarthritis (OA) pain and brain properties remains minimally understood, although anatomical and functional neuroimaging studies suggest that OA, similar to other chronic pain conditions, may impact as well as partly be determined by brain properties. Here, we studied brain grey matter (GM) properties in OA patients sched...

Importance Opioid prescriptions for treatment of pain in emergency departments (EDs) are associated with long-term opioid use. The temporal pattern of opioid prescribing in the context of the opioid epidemic remains unknown. Objective To examine the temporal pattern of opioid prescribing within an ED for varying pain conditions between 2009 and 20...

The positive or negative value (valence) of past experiences is normally integrated into neuronal circuits that encode episodic memories and plays an important role in guiding behavior. Here, we show, using mouse behavioral models, that glutamatergic afferents from the ventral tegmental area to the dorsal hippocampus (VTA→DH) signal negative valenc...

A significant proportion of osteoarthritis (OA) patients continue to experience moderate to severe pain after total joint replacement (TJR). Preoperative factors related to pain persistence are mainly studied using individual predictor variables and distinct pain outcomes, thus leading to a lack of consensus regarding the influence of preoperative...

Coronary heart disease is the leading cause of death throughout the developed world, yet the symptoms that patients experience as a result of coronary disease are often not specific. Determining who are the minority of patients with myocardial ischemia necessitating revascularization is a major activity of many medical centers. This task has tradit...

Preventing transition to chronic back pain (CBP) is an ideal strategy that would rescue patients from years to a lifetime of suffering with pain. Recent studies suggest involvement of sexually-dimorphic dopaminergic-motivational circuits in the transition to chronic pain (tCBP), and hints the combination of carbidopa/levodopa and naproxen (LDP+NPX)...

A significant proportion of osteoarthritis (OA) patients continue to experience moderate to severe pain after total joint replacement (TJR). Preoperative factors related to pain persistence are mainly studied using individual predictor variables and distinct pain outcomes, thus leading to a lack of consensus regarding the influence of preoperative...

Psychological and personality factors, socioeconomic status, and brain properties all contribute to chronic pain but have essentially been studied independently. Here, we administered a broad battery of questionnaires to patients with chronic back pain (CBP) and collected repeated sessions of resting-state functional magnetic resonance imaging (fMR...

Brain functional network properties are globally disrupted in multiple musculoskeletal chronic pain conditions. Back pain with lumbar disc herniation is highly prevalent and a major route for progression to chronic back pain. However, brain functional network properties remain unknown in such patients. Here, we examined resting-state fMRI-based fun...

This review expounds on types and properties of biomarkers for chronic pain, given a mechanistic model of processes underlying development of chronic pain. It covers advances in the field of developing biomarkers for chronic pain, while outlining the general principles of categorizing types of biomarkers driven by specific hypotheses regarding unde...

This overview covers advances in mechanisms of chronic pain and their consequent clinical opportunities. Our research field is fractured into two separate camps: “peripheralists” and “centralists”. While the strong position of the first group is the contention that mechanisms of chronic pain can be understood within the limits of afferent inputs an...

The terminology used in pain research has strong implications regarding conducted science as well as how scientists, clinicians and society interpret our findings. This article goes over the standard definitions and their nuanced modifications recently proposed. Then, evidence and interpretation pitfalls are expounded, concluding with a plea to kee...

Objective: To compare targeted muscle reinnervation (TMR) to "standard treatment" of neuroma excision and burying into muscle for postamputation pain. Summary background data: To date, no intervention is consistently effective for neuroma-related residual limb or phantom limb pain (PLP). TMR is a nerve transfer procedure developed for prosthesis...

Psychological and personality factors, socioeconomic status, and brain properties all contribute to chronic pain but have essentially been studied independently. Here, we administered a broad battery of questionnaires to patients with chronic back pain (CBP). Clustering and network analyses revealed four orthogonal dimensions accounting for 60% of...

The placebo response is universally observed in clinical trials of pain treatments, yet the individual characteristics rendering a patient a 'placebo responder' remain unclear. Here, in chronic back pain patients, we demonstrate using MRI and fMRI that the response to placebo 'analgesic' pills depends on brain structure and function. Subcortical li...

This focus article addresses the issue of the proper use of terminology in pain research. A review and some revisions of the definitions of pain and nociception in relation to consciousness are presented. From a behavioral viewpoint, it is argued that pain is a conscious assessment of the failure of the organism to protect the body from injury (act...

Accumulating evidence suggests the hippocampus being involved in, and modified with, chronic neuropathic pain. However, it is still not clear whether hippocampal activity has direct control over neuropathic behaviors. Here we show that activation of the dorsal, but not ventral, hippocampus, by glutamate microinjection or by chemogenetically increas...

A thirty-year quest, from genes to pain-signaling neurons to people with a rare genetic disorder that makes them feel they are on fire. Two soldiers, both with wounds injuring the same nerve, show very different responses: one is disabled by neuropathic pain, unable to touch the injured limb because even the lightest contact triggers excruciating d...

Development and maintenance of chronic pain is associated with structural and functional brain reorganization. However, few studies have explored the impact of drug treatments on such changes. The extent to which long-term analgesia is related to brain adaptations and its effects on the reversibility of brain reorganization remain unclear. In a ran...

Objective Pain catastrophizing is linked to many aspects of pain perception and defines a unique dimension in predicting pain intensity and physical disability. Pain Catastrophizing Scale (PCS) is an effective, validated,self-report measure, commonly used in clinical trials. Here, we present a Simplified Chinese PCS (SC-PCS) version developed in Ch...

Placebo response is universally observed in randomized controlled trials (RCTs), yet these effects are commonly dismissed as consequences of uncontrollable confounds. In this prospective neuroimaging-based RCT performed in chronic back pain patients, we demonstrate that the intensity, but not quality, of pain is diminished with placebo pill ingesti...

It was recently suggested that in brain disorders neuronal alterations does not occur randomly, but tend to form patterns that resemble those of cerebral connectivity. Following this hypothesis, we studied the network formed by co-altered brain regions in patients with chronic pain. We used a meta-analytical network approach in order to: i) find ou...

The autonomic nervous system (ANS) is a brain body interface which serves to maintain homeostasis by influencing a plethora of physiological processes, including metabolism, cardiorespiratory regulation and nociception. Accumulating evidence suggests that ANS function is disturbed in numerous prevalent clinical disorders, including irritable bowel...

The autonomic nervous system (ANS) is a brain body interface which serves to maintain homeostasis by influencing a plethora of physiological processes, including metabolism, cardiorespiratory regulation and nociception. Accumulating evidence suggests that ANS function is disturbed in numerous prevalent clinical disorders, including irritable bowel...

The autonomic nervous system (ANS) is a brain body interface which serves to maintain homeostasis by influencing a plethora of physiological processes, including metabolism, cardiorespiratory regulation and nociception. Accumulating evidence suggests that ANS function is disturbed in numerous prevalent clinical disorders, including irritable bowel...

The autonomic nervous system (ANS) is a brain body interface which serves to maintain homeostasis by influencing a plethora of physiological processes, including metabolism, cardiorespiratory regulation and nociception. Accumulating evidence suggests that ANS function is disturbed in numerous prevalent clinical disorders, including irritable bowel...

Experiences and memories are often mismatched. While multiple studies have investigated psychological underpinnings of recall error with respect to emotional events, the neurobiological mechanisms underlying the divergence between experiences and memories remain relatively unexplored in the domain of chronic pain. Here we examined the discrepancy b...

Pain perception temporarily exaggerates abrupt thermal stimulus changes revealing a mechanism for nociceptive temporal contrast enhancement (TCE). Although the mechanism is unknown, a non-linear model with perceptual feedback accurately simulates the phenomenon. Here we test if a mechanism in the central nervous system underlies thermal TCE. Our mo...

Chronic pain is often measured with a severity score that overlooks its spatial distribution across the body. This widespread pain is thought to be a marker of centralization, a central nervous system process that decouples pain perception from nociceptive input. Here, we investigated whether centralization is manifested at the level of the brain u...

Chronic pain symptoms often change over time, even in individuals who have had symptoms for years. Studying biological factors that predict trends in symptom change in chronic pain may uncover novel pathophysiological mechanisms and potential therapeutic targets. In this study, we investigated whether brain functional connectivity measures obtained...

Tactile allodynia, a condition in which innocuous mechanical stimuli are perceived as painful, is a common feature of chronic pain. However, how the brain reorganizes in relation to the emergence of tactile allodynia is still largely unknown. This may stem from the fact that experiments in humans are cross-sectional in nature, whereas animal brain...

Background Few effective pharmacological treatment options exist for chronic back pain, the leading cause of disability in the US, and all are associated with significant adverse effects. Objective To determine the efficacy and safety of D-cycloserine, a partial agonist to the N-methyl-D-aspartate receptor, in the treatment of chronic low back pai...

Placebo response in the clinical trial setting is poorly understood and alleged to be driven by statistical confounds, and its biological underpinnings are questioned. Here we identified and validated that clinical placebo response is predictable from resting-state functional magnetic-resonance-imaging (fMRI) brain connectivity. This also led to di...

Transparent Reporting of Evaluations with Nonrandomized Designs (TREND) checklist of information to include when reporting a nonrandomized trial following www.cdc.gov/trendstatement/ requirements. (PDF)

Raw data used in all figures. (XLSX)

Full Northwestern University protocol for study 3. (PDF)

Demographics and pain scores for participants in study 3. Values are shown as mean and 1 SE (in parenthesis). Duration = duration of OA knee pain, which was only available in 50% of participants; VAS = knee OA pain. (DOCX)

Complete list of inclusion and exclusion criteria. (DOCX)

Consolidated Standards of Reporting Trials (CONSORT) 2010 checklist of information to include when reporting a randomized trial following www.consort-statement.org requirements. (PDF)

Knee pain variation in the observational group, study 3, over time. Knee pain profile over time for the observational no-treatment group (study 3). To assess regression to the mean and other statistical effects on knee pain over time, an independent OA cohort (n = 53) was followed for a 3-mo period without any intervention. Participants’ knee pain...

Relationship between knee pain and the brain placebo predictor, r-MFG degree counts, before and after placebo treatment. The degree counts from the r-MFG region extracted from scans for study 1 and study 2 (placebo-treated groups) were correlated with the knee pain values (VAS and WOMAC) obtained before and after the placebo treatment. No correlati...

Full Northwestern University protocol for study 1 and 2. (PDF)

Demographics for participants in study 1 and study 2 and healthy controls. Values are shown as mean and 1 SE (in parenthesis). Duration = duration of OA knee pain, in years; MQS, Medication Quantification Scale = medication use at time of entry into study. (DOCX)

Chronic pain remains poorly understood; yet it is associated with the reorganization of the nervous system. Here, we demonstrate that a unitary global measure of functional connectivity, defined as the extent of degree rank order disruption, kD, identifies the chronic pain state. In contrast, local degree disruption differentiates between chronic p...

Introduction:. Recent advances regarding mechanisms of chronic pain emphasize the role of corticolimbic circuitry in predicting risk for chronic pain, independently from the site of injury-related parameters. These results compel revisiting the role of peripheral nociceptive signaling in chronic pain. We address this issue by examining what informa...

Clinical phenotyping of urological chronic pelvic pain syndromes (UCPPSs) in men and women have focused on end organ abnormalities to identify putative clinical subtypes. Initial evidence of abnormal brain function and structure in male pelvic pain has necessitated large-scale, multisite investigations into potential UCPPS brain biomarkers. We pres...

View largeDownload slide See Tracey (doi: 10.1093/brain/aww147 ) for a scientific commentary on this article. Why some individuals progress from acute to chronic pain is unclear. Vachon-Presseau et al . monitor patients with subacute pain for three years, and show that pre-existing structural and functional connectivity within dorsal mPFC-amygdala...

Importance: There is a need for more effective pharmacotherapy for chronic pain, including pain in inherited erythromelalgia (IEM) in which gain-of-function mutations of sodium channel NaV1.7 make dorsal root ganglion (DRG) neurons hyperexcitable. Objective: To determine whether pain in IEM can be attenuated via pharmacotherapy guided by genomic...

Functional magnetic resonance imaging (fMRI) in rodents holds great promise for advancing our knowledge about human brain function. However, the use of anesthetics to immobilize rodents during fMRI experiments has restricted the type of questions that can be addressed using this technique. Here we describe an innovative procedure to confine rodents...

Human neuroimaging studies and complementary animal experiments now identify the gross elements of the brain involved in the chronification of pain. We briefly review these advances in relation to somatic and orofacial persistent pain conditions. First, we emphasize the importance of reverse translational research for understanding chronic pain—tha...

The Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network is an ongoing multi-center collaborative research group established to conduct integrated studies in participants with urologic chronic pelvic pain syndrome (UCPPS). The goal of these investigations is to provide new insights into the etiology, natural histor...