Does conservative treatment change the brain in patients with chronic musculoskeletal pain? : a systematic review

Background: Chronic musculoskeletal pain is characterized by maladaptive central neuroplastic changes. Many observational studies have demonstrated that chronic pain states are associated with brain alterations regarding structure and/or function. Rehabilitation of patients with chronic musculoskeletal pain may include cognitive, exercise, or multimodal therapies. Objective: The current review aims to provide a constructive overview of the existing literature reporting neural correlates, based on brain magnetic resonance imaging (MRI) techniques, following conservative treatment in chronic musculoskeletal pain patients. Study Design: Systematic review of the literature. Methods: The current review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Literature was searched from 3 databases and screened for eligibility. Methodological quality across studies was assessed with Cochrane Collaboration's tool for assessing risk of bias and quality of evidence was determined applying the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) approach. Results: A total of 9 eligible studies were identified with a predominant high risk of bias. Cognitive behavioral therapy induced several structural and functional changes predominantly in prefrontal cortical regions and a shift from affective to sensory-discriminative brain activity after behavioral extinction training. Multidisciplinary treatment in pediatric complex regional pain syndrome facilitated normalization of functional connectivity of resting-state networks and the amygdala, and increased gray matter in prefrontal and specific subcortical areas. Exercise therapy led to specific for resting-state functional connectivity and a trend towards pressure-induced brain activity changes. Limitations: A very small number of studies was available, which furthermore exhibited small study samples. Moreover, only 2 of the included studies were randomized controlled trials. Conclusions: It is likely that conservative treatments may induce mainly functional and structural brain changes in prefrontal regions in patients with chronic musculoskeletal pain. Due to the relatively high risk of bias across the included studies, future studies with randomized designs are needed to confirm the current findings. In addition, more research evaluating

The neural mechanisms of mindfulness-based pain relief: a functional magnetic resonance imaging-based review and primer.

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 (ie, less than 10 hours of practice), mindfulness-based pain relief is associated with higher order (orbitofrontal cortex and rostral anterior cingulate cortex) regulation of low-level nociceptive neural targets (thalamus and primary somatosensory cortex), 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

Intrinsic brain connectivity in fibromyalgia is associated with chronic pain intensity

Objective Fibromyalgia (FM) is considered to be the prototypical central chronic pain syndrome and is associated with widespread pain that fluctuates spontaneously. Multiple studies have demonstrated altered brain activity in these patients. The objective of this study was to investigate the degree of connectivity between multiple brain networks in patients with FM, as well as how activity in these networks correlates with the level of spontaneous pain. Methods Resting-state functional magnetic resonance imaging (FMRI) data from 18 patients with FM and 18 age-matched healthy control subjects were analyzed using dual-regression independent components analysis, which is a data-driven approach for the identification of independent brain networks. Intrinsic, or resting-state, connectivity was evaluated in multiple brain networks: the default mode network (DMN), the executive attention network (EAN), and the medial visual network (MVN), with the MVN serving as a negative control. Spontaneous pain levels were also analyzed for covariance with intrinsic connectivity. Results Patients with FM had greater connectivity within the DMN and right EAN (corrected P [ P corr ] < 0.05 versus controls), and greater connectivity between the DMN and the insular cortex, which is a brain region known to process evoked pain. Furthermore, greater intensity of spontaneous pain at the time of the FMRI scan correlated with greater intrinsic connectivity between the insula and both the DMN and right EAN ( P corr < 0.05). Conclusion These findings indicate that resting brain activity within multiple networks is associated with spontaneous clinical pain in patients with FM. These findings may also have broader implications for how subjective experiences such as pain arise from a complex interplay among multiple brain networks.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/77979/1/27497_ftp.pd

An Examination of Brain Network Organization and the Analgesic Mechanisms of a Non-Pharmacological Treatment in Chronic Centralized Pain

Chronic pain is a global public health challenge, affecting nearly one third of adults worldwide. Current treatments are inadequate, especially since some of the mainstay therapies (e.g. opioids, NSAIDs) are often ineffective and/or associated with significant toxicity. The solution to these problems requires an improved understanding of chronic pain pathology, particularly the role that the brain plays in causing or amplifying pain perception, and how analgesic intervention might target these brain-based mechanisms. This dissertation aims to identify brain network alterations in fibromyalgia (FM), a common and canonical chronic pain condition with presumed CNS pathology, and determine how non-invasive brain stimulation may target aberrant brain network connectivity to promote analgesia. Across a wide range of diverse neurological disorders, hubs (i.e. highly connected brain regions) appear to be disrupted and the character of this disruption can yield insights into the pathophysiology of these disorders. In Chapter 2, we describe the application of a brain network based approach to examine hub topology in FM patients compared to healthy volunteers. We identified significant disruptions in hub rank order in FM patients. In FM, but not controls, the anterior insula was a hub with significantly higher inter-modular connectivity and membership in the rich club (a functional backbone of connectivity formed by highly interconnected hubs). Among FM patients, rich club membership varied with the intensity of clinical pain: the posterior insula, primary somatosensory and motor cortices belonged to the rich club only in FM patients with the highest pain. Further, we found that the eigenvector centrality (a measure of how connected a brain region is to other highly connected regions) of the posterior insula positively correlated with clinical pain, and mediated the relationship between levels of glutamate + glutamine within this structure and the patient’s subjective clinical pain report. Together, these findings demonstrate an altered hub topology in FM and are the first to suggest that disruptions in the excitatory tone within the insula could alter the strength of the insula as a hub and subsequently lead to increased clinical pain. Transcranial direct current stimulation (tDCS) has emerged as an attractive noninvasive treatment for pain, given its ability to target specific cortical regions with relatively few side effects. Motor cortex (M1) tDCS relieves pain in FM, but the analgesic mechanism remains unknown. In Chapter 3, we measured changes in resting state functional connectivity after sham and real M1 tDCS in twelve FM patients and examined if these changes were related to subsequent analgesia. M1 tDCS (compared to sham) reduced pro-nociceptive functional connectivity, specifically between the motor and sensory nuclei of the thalamus and multiple cortical regions, including primary motor and somatosensory areas. Interestingly, decreased connectivity between the thalamus and posterior insula, M1 and somatosensory cortices correlated with reductions in clinical pain after both sham and active treatment. These results suggest that while there may be a placebo response common to both sham and real tDCS, repetitive M1 tDCS causes distinct changes in functional connectivity that last beyond the stimulation period and may produce analgesia by inhibiting pro-nociceptive thalamic connectivity. This research offers new insight into the neurobiology of chronic centralized pain conditions and contributes to the understanding of how non-invasive brain stimulation causes analgesia. This knowledge could lead to more informed stimulation sites and personalized treatment based on network connectivity in each individual patient.PHDNeuroscienceUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttps://deepblue.lib.umich.edu/bitstream/2027.42/143930/1/chelsmar_1.pd

Spinal cord stimulation in chronic pain: evidence and theory for mechanisms of action.

Well-established in the field of bioelectronic medicine, Spinal Cord Stimulation (SCS) offers an implantable, non-pharmacologic treatment for patients with intractable chronic pain conditions. Chronic pain is a widely heterogenous syndrome with regard to both pathophysiology and the resultant phenotype. Despite advances in our understanding of SCS-mediated antinociception, there still exists limited evidence clarifying the pathways recruited when patterned electric pulses are applied to the epidural space. The rapid clinical implementation of novel SCS methods including burst, high frequency and dorsal root ganglion SCS has provided the clinician with multiple options to treat refractory chronic pain. While compelling evidence for safety and efficacy exists in support of these novel paradigms, our understanding of their mechanisms of action (MOA) dramatically lags behind clinical data. In this review, we reconstruct the available basic science and clinical literature that offers support for mechanisms of both paresthesia spinal cord stimulation (P-SCS) and paresthesia-free spinal cord stimulation (PF-SCS). While P-SCS has been heavily examined since its inception, PF-SCS paradigms have recently been clinically approved with the support of limited preclinical research. Thus, wide knowledge gaps exist between their clinical efficacy and MOA. To close this gap, many rich investigative avenues for both P-SCS and PF-SCS are underway, which will further open the door for paradigm optimization, adjunctive therapies and new indications for SCS. As our understanding of these mechanisms evolves, clinicians will be empowered with the possibility of improving patient care using SCS to selectively target specific pathophysiological processes in chronic pain

Advances in functional neuroimaging in dementias and potential pitfalls

Neuroimaging is continuously advancing at a rapid rate and has progressed from excluding relatively uncommon secondary causes (stroke, tumor) to assisting with early diagnosis and subtype of dementia. Structural imaging has given way to functional, metabolic and receptor imaging