HIV peripheral neuropathy-related degeneration of white matter tracts to sensorimotor cortex.

Human immunodeficiency virus-associated distal sensory polyneuropathy (HIV-DSP) affects up to 50% of people with HIV and is associated with depression, unemployment, and generally worsened quality of life. Previous work on the cortical mechanism of HIV neuropathy found decreased gray matter volume in the bilateral midbrain, thalamus, and posterior cingulate cortex, but structural connectivity in this context remains under-studied. Here we examine alterations in white matter microstructure using diffusion imaging, hypothesizing that cortical white matter degeneration would be observed in continuation of the peripheral white matter atrophy previously observed in HIV-DSP. Male HIV seropositive patients (n = 57) experiencing varying degrees of HIV neuropathy underwent single-shell diffusion tensor imaging with 51 sampling directions. The scans were pooled using tractography and connectometry to create a quantitative map of white matter tract integrity, measured in generalized fractional anisotropy (GFA). The relationship between GFA and neuropathy severity was evaluated with linear regression. Correction for multiple comparisons was done using false discovery rate (FDR), a statistical method commonly used in genomics and imaging to minimize false positives when thousands of individual comparisons are made. Neuropathy severity was associated with decreased GFA along thalamocortical radiations leading along the lateral thalamus to sensorimotor cortex, with r = -0.405 (p < 0.001; FDR), as well as with the superior bilateral cingulum (r = -0.346 (p < 0.05; FDR)). Among a population of HIV neuropathy patients, greater neuropathy severity was correlated with lower white matter integrity running from midbrain to somatosensory cortex. This suggests ascending deafferentation extending from damaged peripheral nerves further downstream than seen previously, into the axons of third-order neurons. There is also evidence of cingulum degeneration, implying some more complex mechanism beyond the ascending atrophy observed here.

Distal neuropathic pain in HIV is associated with functional connectivity patterns in default mode and salience networks.

HIV-associated distal neuropathic pain (DNP) is one of the most prevalent, disabling, and treatment-resistant complications of HIV, but its biological underpinnings are incompletely understood. While data specific to mechanisms underlying HIV DNP are scarce, functional neuroimaging of chronic pain more broadly implicates the role of altered resting-state functional connectivity within and between salience network (SN) and default mode network (DMN) regions. However, it remains unclear the extent to which HIV DNP is associated with similar alterations in connectivity. The current study aimed to bridge this gap in the literature through examination of resting-state functional connectivity patterns within SN and DMN regions among people with HIV (PWH) with and without DNP. Resting state functional magnetic resonance imaging (rs-fMRI) scans were completed among 62 PWH with HIV-associated peripheral neuropathy, of whom 27 reported current DNP and 35 did not. Using subgrouping group iterative multiple estimation, we compared connectivity patterns in those with current DNP to those without. We observed weaker connectivity between the medial prefrontal cortex (MPFC) and posterior cingulate cortex (PCC) and stronger connectivity between the anterior cingulate cortex (ACC) and thalamus among those reporting DNP. Overall, these findings implicate altered within DMN (i.e., MPFC-PCC) and within SN (i.e., ACC-thalamus) connectivity as potential manifestations of adaptation to pain from neuropathy and/or mechanisms underlying the development/maintenance of DNP. Findings are discussed in the context of differential brain response to pain (i.e., mind wandering, pain aversion, pain facilitation/inhibition) and therapeutic implications.

Toward Composite Pain Biomarkers of Neuropathic Pain-Focus on Peripheral Neuropathic Pain.

Chronic pain affects ~10-20% of the U.S. population with an estimated annual cost of $600 billion, the most significant economic cost of any disease to-date. Neuropathic pain is a type of chronic pain that is particularly difficult to manage and leads to significant disability and poor quality of life. Pain biomarkers offer the possibility to develop objective pain-related indicators that may help diagnose, treat, and improve the understanding of neuropathic pain pathophysiology. We review neuropathic pain mechanisms related to opiates, inflammation, and endocannabinoids with the objective of identifying composite biomarkers of neuropathic pain. In the literature, pain biomarkers typically are divided into physiological non-imaging pain biomarkers and brain imaging pain biomarkers. We review both types of biomarker types with the goal of identifying composite pain biomarkers that may improve recognition and treatment of neuropathic pain.

Association of painful human immunodeficiency virus distal sensory polyneuropathy with aberrant expectation of pain relief: functional magnetic resonance imaging evidence.

Mechanisms underlying chronic neuropathic pain associated with HIV-associated distal sensory polyneuropathy are poorly understood, yet 40% of those with distal neuropathy (or 20% of all people with HIV) suffer from this debilitating condition. Central pain processing mechanisms are thought to contribute to the development of HIV neuropathic pain, yet studies investigating central mechanisms for HIV neuropathic pain are few. Considering the motivational nature of pain, we aimed to examine the degree to which expectation of pain onset and expectation of pain offset are altered in sixty-one male patients with HIV-related distal sensory polyneuropathy with (N = 30) and without (N = 31) chronic neuropathic pain. By contrasting painful (foot) and non-painful (hand) sites between those with and without neuropathic pain, we could identify unique neural structures that showed altered activation during expectation of pain offset or relief. Our results showed no evidence for peripheral mechanisms evidenced by lack of significant between group differences in thermo-sensation, subjective pain response or epidermal nerve fibre density. Likewise, we found no significant differences between groups in subjective or brain mechanisms underlying the expectation of pain onset. Conversely, we found significant interaction within right anterior insula during expectation of pain offset in our study in that individuals in the pain group compared to the no-pain group exhibited increased anterior insula activation on the painful compared to the non-painful site. Our findings are consistent with abnormal processing of expectation of pain offset or abnormal pain relief-related mechanisms potentially due to increased emotional distress regarding the experience of chronic endogenous pain.

Paresthesia Predicts Increased Risk of Distal Neuropathic Pain in Older People with HIV-Associated Sensory Polyneuropathy.

OBJECTIVE: Distal sensory polyneuropathy (DSP) is a disabling consequence of human immunodeficiency virus (HIV), leading to poor quality of life and more frequent falls in older age. Neuropathic pain and paresthesia are prevalent symptoms; however, there are currently no known curative treatments and the longitudinal course of pain in HIV-associated DSP is poorly characterized. METHODS: This was a prospective longitudinal study of 265 people with HIV (PWH) enrolled in the CNS HIV Antiretroviral Therapy Effects Research (CHARTER) study with baseline and 12-year follow-up evaluations. Since pain and paresthesia are highly correlated, statistical decomposition was used to separate the two symptoms at baseline. Multivariable logistic regression analyses of decomposed variables were used to determine the effects of neuropathy symptoms at baseline on presence and worsening of distal neuropathic pain at 12-year follow-up, adjusted for covariates. RESULTS: Mean age was 56 ± 8 years, and 21% were female at follow-up. Nearly the entire cohort (96%) was on antiretroviral therapy (ART), and 82% had suppressed (≤50 copies/mL) plasma viral loads at follow-up. Of those with pain at follow-up (n = 100), 23% had paresthesia at the initial visit. Decomposed paresthesia at baseline increased the risk of pain at follow-up (odds ratio [OR] 1.56; 95% confidence interval [CI] 1.18, 2.07), and decomposed pain at baseline predicted a higher frequency of pain at follow-up (OR 1.96 [95% CI 1.51, 2.58]). CONCLUSIONS: Paresthesias are a clinically significant predictor of incident pain at follow-up among aging PWH with DSP. Development of new therapies to encourage neuroregeneration might take advantage of this finding to choose individuals likely to benefit from treatment preventing incident pain.

Evidence for a novel subcortical mechanism for posterior cingulate cortex atrophy in HIV peripheral neuropathy.

We previously reported that neuropathic pain was associated with smaller posterior cingulate cortical (PCC) volumes, suggesting that a smaller/dysfunctional PCC may contribute to development of pain via impaired mind wandering. A gap in our previous report was lack of evidence for a mechanism for the genesis of PCC atrophy in HIV peripheral neuropathy. Here we investigate if volumetric differences in the subcortex for those with neuropathic paresthesia may contribute to smaller PCC volumes, potentially through deafferentation of ascending white matter tracts resulting from peripheral nerve damage in HIV neuropathy. Since neuropathic pain and paresthesia are highly correlated, statistical decomposition was used to separate pain and paresthesia symptoms to determine which regions of brain atrophy are associated with both pain and paresthesia and which are associated separately with pain or paresthesia. HIV+ individuals (N = 233) with and without paresthesia in a multisite study underwent structural brain magnetic resonance imaging. Voxel-based morphometry and a segmentation/registration tool were used to investigate regional brain volume changes associated with paresthesia. Analysis of decomposed variables found that smaller midbrain and thalamus volumes were associated with paresthesia rather than pain. However, atrophy in the PCC was related to both pain and paresthesia. Peak thalamic atrophy (p = 0.004; MNI x = - 14, y = - 24, z = - 2) for more severe paresthesia was in a region with reciprocal connections with the PCC. This provides initial evidence that smaller PCC volumes in HIV peripheral neuropathy are related to ascending white matter deafferentation caused by small fiber damage observed in HIV peripheral neuropathy.

Chronic Distal Sensory Polyneuropathy Is a Major Contributor to Balance Disturbances in Persons Living With HIV.

BACKGROUND: Medical comorbidities accumulate in older persons living with HIV (PLWH), causing disability and reduced quality of life. Sensory neuropathy and polypharmacy may contribute to balance difficulties and falls. The contribution of neuropathy is understudied. OBJECTIVE: To evaluate the contribution of chronic distal sensory polyneuropathy (cDSPN) to balance disturbances among PLWH. METHODS: Ambulatory PLWH and HIV- adults (N = 3379) were prospectively studied. All participants underwent a neurologic examination to document objective abnormality diagnostic of cDSPN and reported neuropathy symptoms including pain, paresthesias, and numbness. Participants provided detailed information regarding balance disturbance and falls over the previous 10 years. Balance disturbances were coded as minimal or none and mild-to-moderate. Covariates included age, HIV disease, and treatment characteristics and medications (sedatives, opioids, and antihypertensives). RESULTS: Eleven percent of participants reported balance disturbances at some time during the last 10 years; the rate in PLWH participants exceeding that for HIV- [odds ratio 2.59, 95% confidence interval: 1.85 to 3.64]. Fifty-two percent met criteria for cDSPN. Balance problems were more common in those with cDSPN [odds ratio = 3.3 (2.6-4.3)]. Adjusting for relevant covariates, balance disturbances attributable to cDSPN were more frequent among HIV+ than HIV- (interaction P = 0.001). Among individuals with cDSPN, older participants were much more likely to report balance disturbances than younger ones. CONCLUSIONS: cDSPN contributes to balance problems in PLWH. Assessments of cDSPN in older PLWH should be a clinical priority to identify those at risk and to aid in fall prevention and the ensuing consequences, including bone fractures, subdural hematoma, hospital admissions, and fatal injury.

HIV Distal Neuropathic Pain Is Associated with Smaller Ventral Posterior Cingulate Cortex.

Objective: . Despite modern antiretroviral therapy, HIV-associated neuropathy is one of the most prevalent, disabling and treatment-resistant complications of HIV disease. The presence and intensity of distal neuropathic pain is not fully explained by the degree of peripheral nerve damage. A better understanding of brain structure in HIV distal neuropathic pain may help explain why some patients with HIV neuropathy report pain while the majority does not. Previously, we reported that more intense distal neuropathic pain was associated with smaller total cerebral cortical gray matter volumes. The objective of this study was to determine which parts of the cortex are smaller. Methods: . HIV positive individuals with and without distal neuropathic pain enrolled in the multisite (N = 233) CNS HIV Antiretroviral Treatment Effects (CHARTER) study underwent structural brain magnetic resonance imaging. Voxel-based morphometry was used to investigate regional brain volumes in these structural brain images. Results: . Left ventral posterior cingulate cortex was smaller for HIV positive individuals with versus without distal neuropathic pain (peak P = 0.017; peak t = 5.15; MNI coordinates x = -6, y = -54, z = 20). Regional brain volumes within cortical gray matter structures typically associated with pain processing were also smaller for HIV positive individuals having higher intensity ratings of distal neuropathic pain. Conclusions: . The posterior cingulate is thought to be involved in inhibiting the perception of painful stimuli. Mechanistically a smaller posterior cingulate cortex structure may be related to reduced anti-nociception contributing to increased distal neuropathic pain.

HIV-associated distal neuropathic pain is associated with smaller total cerebral cortical gray matter.

Despite modern antiretroviral therapy, HIV-associated sensory neuropathy affects over 50 % of HIV patients. The clinical expression of HIV neuropathy is highly variable: many individuals report few symptoms, but about half report distal neuropathic pain (DNP), making it one of the most prevalent, disabling, and treatment-resistant complications of HIV disease. The presence and intensity of pain is not fully explained by the degree of peripheral nerve damage, making it unclear why some patients do, and others do not, report pain. To better understand central nervous system contributions to HIV DNP, we performed a cross-sectional analysis of structural magnetic resonance imaging volumes in 241 HIV-infected participants from an observational multi-site cohort study at five US sites (CNS HIV Anti-Retroviral Treatment Effects Research Study, CHARTER). The association between DNP and the structural imaging outcomes was investigated using both linear and nonlinear (Gaussian Kernel support vector) multivariable regression, controlling for key demographic and clinical variables. Severity of DNP symptoms was correlated with smaller total cerebral cortical gray matter volume (r = -0.24; p = 0.004). Understanding the mechanisms for this association between smaller total cortical volumes and DNP may provide insight into HIV DNP chronicity and treatment-resistance.

Health-related quality of life 'well-being' in HIV distal neuropathic pain is more strongly associated with depression severity than with pain intensity.

BACKGROUND: Despite modern antiretroviral treatment, HIV-associated distal neuropathic pain (DNP) remains one of the most prevalent and debilitating complications of HIV disease. Neuropathic pain is often accompanied by depressed mood, and both pain and depression have been associated with decreased health-related quality of life (HRQOL) well-being. The relative contribution of depression and pain to worse life quality has not been addressed, however, even though a better understanding might sharpen intervention strategies. METHODS: We used the Medical Outcomes Study HIV (MOS-HIV) Health Survey and the Beck depression inventory-II and linear regression models to investigate HRQOL well-being in HIV-infected patients with DNP (n = 397) participating in an observational cohort study at six U.S. sites (CNS HIV Antiretroviral Treatment Effects Research Study, CHARTER). RESULTS: For this sample of patients with HIV DNP, severity of depressed mood was more highly correlated with HRQOL well-being than was pain intensity. CONCLUSIONS: These results suggest that interventions to improve HRQOL well-being in individuals with HIV-associated DNP may need to address not only pain intensity but mood state as well.

Psychophysical and functional imaging evidence supporting the presence of central sensitization in a cohort of osteoarthritis patients.

OBJECTIVE: The groin pain experienced by patients with hip osteoarthritis (OA) is often accompanied by areas of referred pain and changes in skin sensitivity. We aimed to identify the supraspinal influences that underlie these clinical manifestations that we consider indicative of possible central sensitization. METHODS: Twenty patients with hip OA awaiting joint replacement and displaying signs of referred pain were recruited into the study, together with age-matched controls. All subjects completed pain psychology questionnaires and underwent quantitative sensory testing (QST) in their area of referred pain. Twelve of 20 patients and their age- and sex-matched controls underwent functional magnetic resonance imaging (MRI) while the areas of referred pain were stimulated using cold stimuli (12 degrees C) and punctate stimuli (256 mN). The remaining 8 of 20 patients underwent punctate stimulation only. RESULTS: Patients were found to have significantly lower threshold perception to punctate stimuli and were hyperalgesic to the noxious punctate stimulus in their areas of referred pain. Functional brain imaging illustrated significantly greater activation in the brainstem of OA patients in response to punctate stimulation of their referred pain areas compared with healthy controls, and the magnitude of this activation positively correlated with the extent of neuropathic-like elements to the patient's pain, as indicated by the PainDETECT score. DISCUSSION: Using psychophysical (QST) and brain imaging methods (functional MRI), we have identified increased activity with the periaqueductal grey matter associated with stimulation of the skin in referred pain areas of patients with hip OA. This offers a central target for analgesia aimed at improving the treatment of this largely peripheral disease.

Meta-analysis of neuroimaging data: a comparison of image-based and coordinate-based pooling of studies.

With the rapid growth of neuroimaging research and accumulation of neuroinformatic databases the synthesis of consensus findings using meta-analysis is becoming increasingly important. Meta-analyses pool data across many studies to identify reliable experimental effects and characterize the degree of agreement across studies. Coordinate-based meta-analysis (CBMA) methods are the standard approach, where each study entered into the meta-analysis has been summarized using only the (x, y, z) locations of peak activations (with or without activation magnitude) reported in published reports. Image-based meta-analysis (IBMA) methods use the full statistic images, and allow the use of hierarchical mixed effects models that account for differing intra-study variance and modeling of random inter-study variation. The purpose of this work is to compare image-based and coordinate-based meta-analysis methods applied to the same dataset, a group of 15 fMRI studies of pain, and to quantify the information lost by working only with the coordinates of peak activations instead of the full statistic images. We apply a 3-level IBMA mixed model for a "mega-analysis", and highlight important considerations in the specification of each model and contrast. We compare the IBMA result to three CBMA methods: ALE (activation likelihood estimation), KDA (kernel density analysis) and MKDA (multi-level kernel density analysis), for various CBMA smoothing parameters. For the datasets considered, we find that ALE at sigma=15 mm, KDA at rho=25-30 mm and MKDA at rho=15 mm give the greatest similarity to the IBMA result, and that ALE was the most similar for this particular dataset, though only with a Dice similarity coefficient of 0.45 (Dice measure ranges from 0 to 1). Based on this poor similarity, and the greater modeling flexibility afforded by hierarchical mixed models, we suggest that IBMA is preferred over CBMA. To make IBMA analyses practical, however, the neuroimaging field needs to develop an effective mechanism for sharing image data, including whole-brain images of both effect estimates and their standard errors.

Isolating the modulatory effect of expectation on pain transmission: a functional magnetic resonance imaging study.

We use a novel balanced experimental design to specifically investigate brain mechanisms underlying the modulating effect of expected pain intensity on afferent nociceptive processing and pain perception. We used two visual cues, each conditioned to one of two noxious thermal stimuli [ approximately 48 degrees C (high) or 47 degrees C (low)]. The visual cues were presented just before and during application of the noxious thermal stimulus. Subjects reported significantly higher pain when the noxious stimulus was preceded by the high-intensity visual cue. To control for expectancy effects, for one-half of the runs, the noxious thermal stimuli were accompanied by the cue conditioned to the other stimulus. Comparing functional magnetic resonance imaging blood oxygenation level-dependent activations produced by the high and low thermal stimulus intensities presented with the high-intensity visual cue showed significant activations in nociceptive regions of the thalamus, second somatosensory cortex, and insular cortex. To isolate the effect of expectancy, we compared activations produced by the two visual cues presented with the high-intensity noxious thermal stimulus; this showed significant differences in the ipsilateral caudal anterior cingulate cortex, the head of the caudate, cerebellum, and the contralateral nucleus cuneiformis (nCF). We propose that pain intensity expectancy modulates activations produced by noxious stimuli through a distinct modulatory network that converges with afferent nociceptive input in the nCF.