Distinct neural signaling characteristics between fibromyalgia and provoked vestibulodynia revealed by means of functional magnetic resonance imaging in the brainstem and spinal cord

IntroductionFibromyalgia and provoked vestibulodynia are two chronic pain conditions that disproportionately affect women. The mechanisms underlying the pain in these conditions are still poorly understood, but there is speculation that both may be linked to altered central sensitization and autonomic regulation. Neuroimaging studies of these conditions focusing on the brainstem and spinal cord to explore changes in pain regulation and autonomic regulation are emerging, but none to date have directly compared pain and autonomic regulation in these conditions. This study compares groups of women with fibromyalgia and provoked vestibulodynia to healthy controls using a threat/safety paradigm with a predictable noxious heat stimulus.MethodsFunctional magnetic resonance imaging data were acquired at 3 tesla in the cervical spinal cord and brainstem with previously established methods. Imaging data were analyzed with structural equation modeling and ANCOVA methods during: a period of noxious stimulation, and a period before the stimulation when participants were expecting the upcoming pain.ResultsThe results demonstrate several similarities and differences between brainstem/spinal cord connectivity related to autonomic and pain regulatory networks across the three groups in both time periods.DiscussionBased on the regions and connections involved in the differences, the altered pain processing in fibromyalgia appears to be related to changes in how autonomic and pain regulation networks are integrated, whereas altered pain processing in provoked vestibulodynia is linked in part to changes in arousal or salience networks as well as changes in affective components of pain regulation

Reliability of resting-state functional connectivity in the human spinal cord: Assessing the impact of distinct noise sources

The investigation of spontaneous fluctuations of the blood-oxygen-level-dependent (BOLD) signal has recently been extended from the brain to the spinal cord, where it has also generated initial interest from a clinical perspective. A number of resting-state functional magnetic resonance imaging (fMRI) studies have demonstrated robust functional connectivity between the time-series of BOLD fluctuations in bilateral dorsal horns and between those in bilateral ventral horns, in line with the functional neuroanatomy of the spinal cord. A necessary step prior to extension to clinical studies is assessing the reliability of such resting-state signals, which we aimed to do here in a group of 45 healthy young adults at the clinically prevalent field-strength of 3T. When investigating connectivity in the entire cervical spinal cord, we observed fair to good reliability for dorsal-dorsal and ventral-ventral connectivity, whereas reliability was poor for within- and between-hemicord dorsal-ventral connectivity. Considering how prone spinal cord fMRI is to noise, we extensively investigated the impact of distinct noise sources and made two crucial observations: removal of physiological noise led to a reduction in functional connectivity strength and reliability – due to the removal of stable and participant-specific noise patterns – whereas removal of thermal noise considerably increased the detectability of functional connectivity without a clear influence on reliability. Finally, we also assessed connectivity within spinal cord segments and observed that while the pattern of connectivity was similar to that of whole cervical cord, reliability at the level of single segments was consistently poor. Taken together, our results demonstrate the presence of reliable resting-state functional connectivity in the human spinal cord even after thoroughly accounting for physiological and thermal noise, but at the same time urge caution if focal changes in connectivity (e.g. due to segmental lesions) are to be studied, especially in a longitudinal manner

Infra-slow oscillations in chronic orofacial neuropathic pain and the effects of palmitoylethanolamide

For centuries, chronic pain was denied as being real by physicians, mainly because there was no evidence of tissue damage. The lack of understanding of the neural mechanisms underlying chronic pain, particular that arising from nervous system damage, has hindered treatment development which has led to the over-prescription of opioids. Whilst the brain circuitry responsible for the perception of acute painful stimuli have been mapped in both animal studies and studies using brain imaging in awake humans, the circuitry responsible for the initiation and maintenance of chronic pain remain unknown. Over the past few decades, many human brain imaging investigations have shown that neuropathic pain is associated with altered brain rhythms and in particular thalamocortical dysrhythmia. In addition, animal studies have shown that neuropathic pain is associated with altered non-neural function including microglial and astrocyte activation at the level of the primary afferent synapse. These results have led to theories that non-neuronal cells may be crucial for the initiation and maintenance of chronic pain, particularly chronic neuropathic pain. It has been a long held view that astrocytes mainly play the role of neural support in the central nervous system, however, these cells are also capable of controlling neural function. In fact, astrocytes have access to every neural synapse and animal models of chronic neuropathic pain have shown that targeting astrocytes can control pain intensity. As such, the focus of this thesis is to identify the role of astrocytes in modulating neural function in chronic neuropathic pain and to determine whether reducing astrocyte activity can reduce pain intensity. There are three main investigations that make up this thesis, the first describes an experimental procedure whereby on-going patterns of neural activity were assessed in patients with orofacial neuropathic pain using resting state functional magnetic resonance imaging. The second attempts to measure an anatomical marker of astrocyte activation. And the final investigation describes an experimental procedure whereby patients with orofacial neuropathic pain were administered an astrocyte modulator, palmitoylethanolamide (PEA) and neural activity was compared before and after treatment

Cortico-spinal imaging to study pain

ABSTRACT: Functional magnetic resonance imaging of the brain has helped to reveal mechanisms of pain perception in health and disease. Recently, imaging approaches have been developed that allow recording neural activity simultaneously in the brain and in the spinal cord. These approaches offer the possibility to examine pain perception in the entire central pain system and in addition, to investigate cortico-spinal interactions during pain processing. Although cortico-spinal imaging is a promising technique, it bears challenges concerning data acquisition and data analysis strategies. In this review, we discuss studies that applied simultaneous imaging of the brain and spinal cord to explore central pain processing. Furthermore, we describe different MR-related acquisition techniques, summarize advantages and disadvantages of approaches that have been implemented so far and present software that has been specifically developed for the analysis of spinal fMRI data to address challenges of spinal data analysis

Advanced neuroimaging methods and biomarkers applied to preclinical models of multiple sclerosis and amyothropic lateral sclerosis

New paradigms are developed in magnetic resonance imaging for the advanced diagnosis of neurodegenerative diseases. In particular, multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS) preclinical research poorly focuses on functional connectivity in brain. Available animal models of MS and ALS are extensively used for analysis such drug testing and discovery of underlying mechanisms of pathogenesis. These diseases present, since neuronal lesions formation and neuroinflammation, a multilevel heterogeneity in mechanism of neurodegeneration and brain connectivity still not well understood. Moreover, they play a key role in pharmacological research, from the identification of a therapy target to the in vivo validation of the efficacy. More recently alterations in synchronized brain activity at rest in MS patients have been reported. At the best of our knowledge, functional imaging has not been applied yet in the assessment of new therapies in the preclinical models for MS and ALS. In this study, we aim to develop an innovative platform based on functional MRI in the resting state (rsfMRI), for the pre-clinical evaluation of new markers in MS and ALS. Moreover, the advancing in MRI techniques could assess new criteria of sensitivity and specificity in diagnosis; an additional analysis on diffusion MRI outcomes in MS preclinical models is added to this study

Investigating the Cortical, Metabolic and Behavioral Effects of Transcranial Direct Current Stimulation in Preparation for Combined Rehabilitation

The goal of this thesis was to determine the cortical reorganization that occurs in patients with cervical spondylotic myelopathy (CSM) after surgical decompression and to implement this knowledge into a new rehabilitation strategy. Transcranial direct current stimulation (tDCS) is a non-invasive technique to modulate human behavior. Due to the novel electrode montage used, it was first pertinent that we determine how tDCS would modulate cortical, metabolic and motor behavior in healthy individuals. We observed the longitudinal functional adaptations that occur in patients with CSM using functional MRI. Enhanced excitation of supplementary motor area (SMA) was observed following surgical decompression and associated with increased function following surgery. This novel finding of enhanced excitation of motivated us to use a bihemispheric tDCS protocol, exciting bilateral motor areas to provide optimal motor enhancement. This novel tDCS electrode montage, targeting the SMA and primary motor cortex (M1) was implemented in healthy older adults to determine its effects on enhancing manual dexterity. Furthermore, to determine the frequency with which to apply tDCS, a single and tri session protocol was used. We observed a differential pattern of action with anti-phase and in-phase motor tasks during multisession tDCS. We used ultra-high field (7T) MRI to examined the metabolic changes that occur following tDCS. After the stimulation period we observed no significant metabolite modulation. A trend towards an increase in the NAA/tCr ratio, with a concomitant decrease in the absolute concentration of tCr was observed. Finally, we examined the functional connectivity before, during and after tDCS with the use of resting-state fMRI at 7T. We observed enhanced connectivity within right sensorimotor area after stimulation compared to during stimulation. This result confirmed that cortical modulations differ during versus after tDCS, signifying that optimal modulation of behaviour may be after the stimulation period. Furthermore, we observed an enhanced correlation between motor regions and the caudate, both during and after stimulation. In conclusion, we observed novel cortical adaptations in CSM patients after surgical decompression, which led us to believe that bihemispheric tDCS of M1-SMA network would result in optimal motor enhancement and warrants further investigation in CSM and other neurological disorders

Cortical mapping of the neuronal circuits modulating the muscle tone. Introduction to the electrophysiological treatment of the spastic hand

L'objectiu d'aquest estudi es investigar l'organització cortical junt amb la connectivitat còrtico-subcortical en subjectes sans, com a estudi preliminar. Els mapes corticals s'han fet per TMS navegada, i els punts motors obtinguts s'han exportant per estudi tractogràfic i anàlisi de las seves connexions. El coneixement precís de la localització de l'àrea cortical motora primària i les seves connexions es la base per ser utilitzada en estudis posteriors de la reorganització cortical i sub-cortical en pacients amb infart cerebral. Aquesta reorganització es deguda a la neuroplasticitat i pot ser influenciada per els efectes neuromoduladors de la estimulació cerebral no invasiva.The purpose of this study is to investigate the motor cortex organisation together with the cortico-subcortical connectivity in healthy subjects, as a preliminary study. Cortical maps have been performed by navigated TMS and the motor points have been exported to DTI to study their subcortical connectivity. The precise knowledge of localization of the primary motor cortex area and its connectivity is the base to be used in later studies of cortical and subcortical re-organisation in stroke patients. This re-organisation is due to the neuroplascity and can be influenced by the neuromodulation effects of the non-invasive cerebral stimulation therapy by TMS

Functional connectome of arousal and motor brainstem nuclei in living humans by 7 Tesla resting-state fMRI

Brainstem nuclei play a pivotal role in many functions, such as arousal and motor control. Nevertheless, the connectivity of arousal and motor brainstem nuclei is understudied in living humans due to the limited sensitivity and spatial resolution of conventional imaging, and to the lack of atlases of these deep tiny regions of the brain. For a holistic comprehension of sleep, arousal and associated motor processes, we investigated in 20 healthy subjects the resting-state functional connectivity of 18 arousal and motor brainstem nuclei in living humans. To do so, we used high spatial-resolution 7 Tesla resting-state fMRI, as well as a recently developed in-vivo probabilistic atlas of these nuclei in stereotactic space. Further, we verified the translatability of our brainstem connectome approach to conventional (e.g. 3 Tesla) fMRI. Arousal brainstem nuclei displayed high interconnectivity, as well as connectivity to the thalamus, hypothalamus, basal forebrain and frontal cortex, in line with animal studies and as expected for arousal regions. Motor brainstem nuclei showed expected connectivity to the cerebellum, basal ganglia and motor cortex, as well as high interconnectivity. Comparison of 3 Tesla to 7 Tesla connectivity results indicated good translatability of our brainstem connectome approach to conventional fMRI, especially for cortical and subcortical (non-brainstem) targets and to a lesser extent for brainstem targets. The functional connectome of 18 arousal and motor brainstem nuclei with the rest of the brain might provide a better understanding of arousal, sleep and accompanying motor functions in living humans in health and disease

Investigating the Effects of Custom Made Orthotics on Brain Forms: A Pilot Study

OBJECTIVES: To determine (1) the feasibility of this novel approach and technique of recording brain activity, wirelessly and continuously, during human gait, and (2) if custom made orthotics will alter the brain activity patterns recorded. METHODS: Gait trials were performed on 16 participants walking with and without orthotic devices in their shoes while simultaneously collecting EEG data through the Emotiv wireless neuroheadset. RESULTS: The Emotiv neuroheadset was capable of detecting changes in brain activity between the two gait trials. The differences in brain activity identified between conditions were not statistically significant. CONCLUSION: The findings suggest the Emotiv EEG device is sensitive enough to detect changes in brain activation patterns during human gait. Further research is required before definite conclusions can be made about this novel device, or about what effects, if any, orthotics have on brain activation patterns during gait

The role of endogenous opioid neuropeptides in neurostimulation-driven analgesia

Due to the prevalence of chronic pain worldwide, there is an urgent need to improve pain management strategies. While opioid drugs have long been used to treat chronic pain, their use is severely limited by adverse effects and abuse liability. Neurostimulation techniques have emerged as a promising option for chronic pain that is refractory to other treatments. While different neurostimulation strategies have been applied to many neural structures implicated in pain processing, there is variability in efficacy between patients, underscoring the need to optimize neurostimulation techniques for use in pain management. This optimization requires a deeper understanding of the mechanisms underlying neurostimulation-induced pain relief. Here, we discuss the most commonly used neurostimulation techniques for treating chronic pain. We present evidence that neurostimulation-induced analgesia is in part driven by the release of endogenous opioids and that this endogenous opioid release is a common endpoint between different methods of neurostimulation. Finally, we introduce technological and clinical innovations that are being explored to optimize neurostimulation techniques for the treatment of pain, including multidisciplinary efforts between neuroscience research and clinical treatment that may refine the efficacy of neurostimulation based on its underlying mechanisms