Javeria A. Hashmi

Pain and the brain: Specificity and plasticity of the brain in clinical chronic pain

We review recent advances in brain imaging in humans, concentrating on advances in our understanding of the human brain in clinical chronic pain. Understanding regarding anatomical and functional reorganization of the brain in chronic pain is emphasized. We conclude by proposing a brain model for the transition of the human from acute to chronic pain.

Shape shifting pain: chronification of back pain shifts brain representation from nociceptive to emotional circuits

Chronic pain conditions are associated with abnormalities in brain structure and function. Moreover, some studies indicate that brain activity related to the subjective perception of chronic pain may be distinct from activity for acute pain. However, the latter are based on observations from cross-sectional studies. How brain activity reorganizes with transition from acute to chronic pain has remained unexplored. Here we study this transition by examining brain activity for rating fluctuations of back pain magnitude. First we compared back pain-related brain activity between subjects who have had the condition for ∼2 months with no prior history of back pain for 1 year (early, acute/subacute back pain group, n = 94), to subjects who have lived with back pain for >10 years (chronic back pain group, n = 59). In a subset of subacute back pain patients, we followed brain activity for back pain longitudinally over a 1-year period, and compared brain activity between those who recover (recovered acute/sub-acute back pain group, n = 19) and those in which the back pain persists (persistent acute/sub-acute back pain group, n = 20; based on a 20% decrease in intensity of back pain in 1 year). We report results in relation to meta-analytic probabilistic maps related to the terms pain, emotion, and reward (each map is based on >200 brain imaging studies, derived from neurosynth.org). We observed that brain activity for back pain in the early, acute/subacute back pain group is limited to regions involved in acute pain, whereas in the chronic back pain group, activity is confined to emotion-related circuitry. Reward circuitry was equally represented in both groups. In the recovered acute/subacute back pain group, brain activity diminished in time, whereas in the persistent acute/subacute back pain group, activity diminished in acute pain regions, increased in emotion-related circuitry, and remained unchanged in reward circuitry. The results demonstrate that brain representation for a constant percept, back pain, can undergo large-scale shifts in brain activity with the transition to chronic pain. These observations challenge long-standing theoretical concepts regarding brain and mind relationships, as well as provide important novel insights regarding definitions and mechanisms of chronic pain.

Brain networks predicting placebo analgesia in a clinical trial for chronic back pain

Summary Chronic back pain patients possess brain functional connectivity pattern differences before the initiation of treatment that can reliably predict interindividual differences in placebo response. ABSTRACT A fundamental question for placebo research is whether such responses are a predisposition, quantifiable by brain characteristics. We examine this issue in chronic back pain (CBP) patients who participated in a double‐blind brain imaging (functional magnetic resonance imaging) clinical trial. We recently reported that when the 30 CBP participants were treated, for 2 weeks, with topical analgesic or no drug patches, pain and brain activity decreased independently of treatment type and thus were attributed to placebo responses. Here we examine in the same group brain markers for predicting placebo responses—that is, for differentiating between posttreatment persistent CBP (CBPp) and decreasing CBP (CBPd) groups. At baseline, pain and brain activity for rating spontaneous fluctuations of back pain were not different between the 2 groups. However, on the basis of brain activity differences after treatment, we identified that at baseline the extent of information shared (functional connectivity) between left medial prefrontal cortex and bilateral insula accurately (0.8) predicted posttreatment groups. This was validated in an independent cohort. Additionally, by means of frequency domain contrasts, we observe that at baseline, left dorsolateral prefrontal cortex high‐frequency oscillations also predicted treatment outcomes and identified an additional set of functional connections distinguishing treatment outcomes. Combining medial and lateral prefrontal functional connections, we observe a statistically higher accuracy (0.9) for predicting posttreatment groups. These findings indicate that placebo response can be identified a priori at least in CBP, and that neuronal population interactions between prefrontal cognitive and pain processing regions predetermine the probability of placebo response in the clinical setting.

Altered Onset Response Dynamics in Somatosensory Processing in Autism Spectrum Disorder

Abnormalities in cortical connectivity and evoked responses have been extensively documented in autism spectrum disorder (ASD). However, specific signatures of these cortical abnormalities remain elusive, with data pointing toward abnormal patterns of both increased and reduced response amplitudes and functional connectivity. We have previously proposed, using magnetoencephalography (MEG) data, that apparent inconsistencies in prior studies could be reconciled if functional connectivity in ASD was reduced in the feedback (top-down) direction, but increased in the feedforward (bottom-up) direction. Here, we continue this line of investigation by assessing abnormalities restricted to the onset, feedforward inputs driven, component of the response to vibrotactile stimuli in somatosensory cortex in ASD. Using a novel method that measures the spatio-temporal divergence of cortical activation, we found that relative to typically developing participants, the ASD group was characterized by an increase in the initial onset component of the cortical response, and a faster spread of local activity. Given the early time window, the results could be interpreted as increased thalamocortical feedforward connectivity in ASD, and offer a plausible mechanism for the previously observed increased response variability in ASD, as well as for the commonly observed behaviorally measured tactile processing abnormalities associated with the disorder.

Women experience greater heat pain adaptation and habituation than men

ABSTRACT It is not clear how males and females cope with pain over time and how sensory and emotional qualities fluctuate from moment to moment, although studies of pain at discrete time points suggest that women are more pain sensitive than men. Therefore, we developed a new broader‐based pain model that incorporates a temporally continuous assessment of multiple pain dimensions across sensory and affective dimensions, and normalized peak pain intensity to unmask sex differences that may otherwise be confounded by inter‐individual variability in pain sensitivity. We obtained continuous ratings of pain, burning, sharp, stinging, cutting, and annoyance evoked by repeated prolonged noxious heat stimuli in 32 subjects. Strikingly, females reported more pain than males at the outset of the first exposure to pain, but then experienced less pain and annoyance than males as a painful stimulus was sustained and with repeated stimulation. Patterns of pain and annoyance attenuation in women resembled the attenuation of sharp, stinging and cutting sensations, whereas patterns of pain and annoyance in men resembled burning sensations. Taken together, these data demonstrate a prominent sex difference in the time course of pain. Notably only females demonstrate adaptation and habituation that allow them to experience less pain over time. These findings suggest a sexual dichotomy in mechanisms underlying pain intensity and annoyance that could involve specific quality‐linked mechanisms. Importantly, temporal processing of pain differs between males and females when adjusted for sex differences in pain sensitivity. Our findings provide insight into sex differences in tonic and possibly chronic pains.

Deconstructing sex differences in pain sensitivity

1. IntroductionAristotle erroneously believed that women had fewer teeththan men, even though this preconceived notion could easily betested with a simple measurement [2]. Today, women are pro-claimed ‘‘pain sensitive’’. But despite several investigations andbest intentions, this view is too simplistic given the myriad metricsthat comprise ‘‘sensitivity’’. Although there may be a relationshipbetween lower pain thresholds and a greater incidence and preva-lence of many debilitating chronic pain conditions in women, thedata are not definitive and there certainly are several chronic painconditions more prevalent in men [5,15,19,42]. From a socio-cul-tural perspective, ascribing higher pain sensitivity to any groupcan lead to incorrect assumptions such as disposition to ‘‘height-ened somatic tendencies’’ [6,10]. This disparity has importantsociological consequences with a strong link to occupational sexinequities [3,31]. Moreover, women are often undertreated fortheir pain [30,41].In this review, we explore the fundamental questions as towhether men and women (1) experience pain similarly, and (2)are similarly sensitive to noxious stimuli. The answers to thesequestions are essential to our understanding of mechanisms thatunderlie sex differences in acute and chronic pain, and effectivetreatment for both sexes. Yet, studies of these fundamental issueshave been riddled with variability owing, in part, to the lack ofstandardized measures, poor control of context, and other experi-mental variables. Therefore, to understand sex differences in acuteand chronic pains, we revisit the factors that should be used to des-ignate ‘‘sensitivity’’ and suggest a paradigm shift towards a mech-anistic understanding of sex differences in pain.2. The evolution of the ‘‘pain sensitivity’’ conceptHistorically, assumptions about pain-sensitive individuals havebeen groundedin ideas about physicalor moral strength.High painsensitivity has been traditionally viewed as a weakness, and peoplewho were stoic or less pain sensitive were thought to be strong.Many cultural beliefs hold that men are less sensitive to pain thanwomen [9,10]. These impressions have lingered, despite evidenceof great intersubject variability, cultural differences, and complex-ity in assessing pain sensitivity. In a 1940 psychophysical study ofsex differences in metabolic responses to temperature, Hardy andDu Bois [21] noted the dearth of psychophysical studies that tookinto account sex differences, with most measuring pain responsesonly in men, assuming that findings could be generalized to bothsexes. In 1997, a thought-provoking review by Berkley [5] under-scored the importance of sex differences in pain research. She re-ported the major discrepancies in the literature where sex wasconstrued as a covariant of no interest or ‘‘irritant variable’’. Shealso highlighted that most studies either did not report the sex oftheir subjects or studied men exclusively. This landmark reviewby Berkley [5] and a 2007 consensus report on studying sex andgender differences in pain clearly stated that ‘‘we recommend thatall pain researchers consider testing their hypotheses in bothsexes’’, and provided a variety of measures to be used for such test-ing [19]. However, these recommendations have not been imple-mented widely (partly owing to practical issues) and thus moststudies of sex differences of pain simply rely on threshold testingto capture pain ‘‘sensitivity’’.3. Are women truly ‘‘pain sensitive’’?There is now growing interest and research activity on sex dif-ferences in pain [35,39,40]. In general, many studies have reportedlower pain thresholds, less pain tolerance, and greater evoked painin women compared with men [15,42]. However, there is signifi-cant variability between studies, results are riddled with small ef-fect sizes [5,50], and despite much effort, pain sensitivity measuresand chronic pain conditions among women have not been clearlyand consistently linked [5,27]. Despite heterogeneous findings inthese studies, the predominant view that still persists is that wo-men are the pain-sensitive sex. A recent systemic review of 172pain and sex studiesbring moreclarityto this issue bydemonstrat-ing that sex differences are highly variable and only exist for sometypes of pain measures. Whereas lower pressure pain thresholdsand thermal/pressure pain tolerance in women is variable betweenstudies, only a small percentage of studies showed sex differencesfor cold/muscle/ischemic pain thresholds, or for chemical or

Functional Network Architecture Predicts Psychologically Mediated Analgesia Related to Treatment in Chronic Knee Pain Patients

Placebo analgesia is an indicator of how efficiently the brain translates psychological signals conveyed by a treatment procedure into pain relief. It has been demonstrated that functional connectivity between distributed brain regions predicts placebo analgesia in chronic back pain patients. Greater network efficiency in baseline brain networks may allow better information transfer and facilitate adaptive physiological responses to psychological aspects of treatment. Here, we theorized that topological network alignments in resting state scans predict psychologically conditioned analgesic responses to acupuncture treatment in chronic knee osteoarthritis pain patients (n = 45). Analgesia was induced by building positive expectations toward acupuncture treatment with verbal suggestion and heat pain conditioning on a test site of the arm. This procedure induced significantly more analgesia after sham or real acupuncture on the test site than in a control site. The psychologically conditioned analgesia was invariant to sham versus real treatment. Efficiency of information transfer within local networks calculated with graph-theoretic measures (local efficiency and clustering coefficients) significantly predicted conditioned analgesia. Clustering coefficients in regions associated with memory, motivation, and pain modulation were closely involved in predicting analgesia. Moreover, women showed higher clustering coefficients and marginally greater pain reduction than men. Overall, analgesic response to placebo cues can be predicted from a priori resting state data by observing local network topology. Such low-cost synchronizations may represent preparatory resources that facilitate subsequent performance of brain circuits in responding to adaptive environmental cues. This suggests a potential utility of network measures in predicting placebo response for clinical use.

Predictive Dynamics of Human Pain Perception

While the static magnitude of thermal pain perception has been shown to follow a power-law function of the temperature, its dynamical features have been largely overlooked. Due to the slow temporal experience of pain, multiple studies now show that the time evolution of its magnitude can be captured with continuous online ratings. Here we use such ratings to model quantitatively the temporal dynamics of thermal pain perception. We show that a differential equation captures the details of the temporal evolution in pain ratings in individual subjects for different stimulus pattern complexities, and also demonstrates strong predictive power to infer pain ratings, including readouts based only on brain functional images.

Effects of temperature on heat pain adaptation and habituation in men and women

&NA; We recently reported that women report greater pain adaptation and habituation to moderately painful heat stimuli than men (Hashmi and Davis [16]); but slightly lower temperatures were needed to evoke moderate pain in the women. Hardy et al (1962) and LaMotte (1979) suggested that pain adaptation is most prominent at modest noxious heat temperatures and may occur at temperatures close to pain thresholds. Thus, as a follow‐up to our previous study, we examined the role of absolute temperature in pain adaptation and habituation in men and women and assessed whether pain threshold impacts these findings. We hypothesised that pain adaptation and habituation would be more prominent at low and moderate temperatures, and that higher temperatures would induce pain adaptation and habituation in women but not in men. We further hypothesized that pain adaptation would not be correlated with pain thresholds. To test this, we obtained continuous ratings of pain evoked by 44.5–47.5°C stimuli applied to the dorsal foot of men and women. Each run consisted of three 30 s stimuli at the same temperature with a 60 s inter‐stimulus interval. Women showed within‐stimulus adaptation of total pain at all temperatures, but men showed significant adaptation to temperatures less than 47 °C. There were no sex differences in inter‐stimulus habituation and both men and women reported habituation to temperatures less than 46 °C. Pain thresholds did not correlate with pain adaptation. These data highlight the temperature‐sensitivity and sex differences of pain adaptation and habituation.

A Longitudinal Study of the Reliability of Acupuncture Deqi Sensations in Knee Osteoarthritis

Deqi is one of the core concepts in acupuncture theory and encompasses a range of sensations. In this study, we used the MGH Acupuncture Sensation Scale (MASS) to measure and assess the reliability of the sensations evoked by acupuncture needle stimulation in a longitudinal clinical trial on knee osteoarthritis (OA) patients. The Knee injury and Osteoarthritis Outcome Score (KOOS) was used as the clinical outcome. Thirty OA patients were randomized into one of three groups (high dose, low dose, and sham acupuncture) for 4 weeks. We found that, compared with sham acupuncture, real acupuncture (combining high and low doses) produced significant improvement in knee pain (P = .025) and function in sport (P = .049). Intraclass correlation analysis showed that patients reliably rated 11 of the 12 acupuncture sensations listed on the MASS and that heaviness was rated most consistently. Overall perceived sensation (MASS Index) (P = .014), ratings of soreness (P = .002), and aching (P = .002) differed significantly across acupuncture groups. Compared to sham acupuncture, real acupuncture reliably evoked stronger deqi sensations and led to better clinical outcomes when measured in a chronic pain population. Our findings highlight the MASS as a useful tool for measuring deqi in acupuncture research.