Petra Schweinhardt

Allodynia limits the usefulness of intraspinal neural stem cell grafts; directed differentiation improves outcome

Several studies have reported functional improvement after transplantation of neural stem cells into injured spinal cord. We now provide evidence that grafting of adult neural stem cells into a rat thoracic spinal cord weight-drop injury improves motor recovery but also causes aberrant axonal sprouting associated with allodynia-like hypersensitivity of forepaws. Transduction of neural stem cells with neurogenin-2 before transplantation suppressed astrocytic differentiation of engrafted cells and prevented graft-induced sprouting and allodynia. Transduction with neurogenin-2 also improved the positive effects of engrafted stem cells, including increased amounts of myelin in the injured area, recovery of hindlimb locomotor function and hindlimb sensory responses, as determined by functional magnetic resonance imaging. These findings show that stem cell transplantation into injured spinal cord can cause severe side effects and call for caution in the consideration of clinical trials.

Accelerated Brain Gray Matter Loss in Fibromyalgia Patients: Premature Aging of the Brain?

Fibromyalgia is an intractable widespread pain disorder that is most frequently diagnosed in women. It has traditionally been classified as either a musculoskeletal disease or a psychological disorder. Accumulating evidence now suggests that fibromyalgia may be associated with CNS dysfunction. In this study, we investigate anatomical changes in the brain associated with fibromyalgia. Using voxel-based morphometric analysis of magnetic resonance brain images, we examined the brains of 10 female fibromyalgia patients and 10 healthy controls. We found that fibromyalgia patients had significantly less total gray matter volume and showed a 3.3 times greater age-associated decrease in gray matter than healthy controls. The longer the individuals had had fibromyalgia, the greater the gray matter loss, with each year of fibromyalgia being equivalent to 9.5 times the loss in normal aging. In addition, fibromyalgia patients demonstrated significantly less gray matter density than healthy controls in several brain regions, including the cingulate, insular and medial frontal cortices, and parahippocampal gyri. The neuroanatomical changes that we see in fibromyalgia patients contribute additional evidence of CNS involvement in fibromyalgia. In particular, fibromyalgia appears to be associated with an acceleration of age-related changes in the very substance of the brain. Moreover, the regions in which we demonstrate objective changes may be functionally linked to core features of the disorder including affective disturbances and chronic widespread pain.

Fibromyalgia patients show an abnormal dopamine response to pain

Fibromyalgia is characterized by chronic widespread pain and bodily tenderness and is often accompanied by affective disturbances. Accumulating evidence indicates that fibromyalgia may involve a dysfunction of modulatory systems in the brain. While brain dopamine is best known for its role in pleasure, motivation and motor control, recent evidence suggests that it is also involved in pain modulation. Because dopamine is implicated in both pain modulation and affective processing, we hypothesized that fibromyalgia may involve a disturbance of dopaminergic neurotransmission. Fibromyalgia patients and matched healthy control subjects were subjected to deep muscle pain produced by injection of hypertonic saline into the anterior tibialis muscle. In order to determine the endogenous release of dopamine in response to painful stimulation, we used positron emission tomography to examine binding of [11C]‐raclopride (D2/D3 ligand) in the brain during injection of painful hypertonic saline and nonpainful normal saline. Fibromyalgia patients experienced the hypertonic saline as more painful than healthy control subjects. Control subjects released dopamine in the basal ganglia during the painful stimulation, whereas fibromyalgia patients did not. In control subjects, the amount of dopamine release correlated with the amount of perceived pain but in fibromyalgia patients no such correlation was observed. These findings provide the first direct evidence that fibromyalgia patients have an abnormal dopamine response to pain. The disrupted dopaminergic reactivity in fibromyalgia patients could be a critical factor underlying the widespread pain and discomfort in fibromyalgia and suggests that the therapeutic effects of dopaminergic treatments for this intractable disorder should be explored.

An fMRI study of cerebral processing of brush-evoked allodynia in neuropathic pain patients.

Previous human imaging studies have revealed a network of brain regions involved in the processing of allodynic pain; this includes prefrontal areas, insula, cingulate cortex, primary and secondary somatosensory cortices and parietal association areas. In this study, the neural correlates of the perceived intensity of allodynic pain in neuropathic pain patients were investigated. In eight patients, dynamic mechanical allodynia was provoked and brain responses recorded using functional magnetic resonance imaging (fMRI). Voxels in which the magnitude of fMRI signal correlated linearly with the ratings of allodynic pain across the group were determined in a whole brain analysis using a general linear model. To ensure that activation reflected only allodynic pain ratings, a nuisance variable containing ratings of ongoing pain was included in the analysis. We found that the magnitude of activation in the caudal anterior insula (cAI) correlates with the perceived intensity of allodynic pain across subjects, independent of the level of ongoing pain. However, the peak of activation in the allodynic condition was located in the rostral portion (rAI). This matches the representation of other clinical pain syndromes, confirmed by a literature review. In contrast, experimental pain in healthy volunteers resides predominantly in the cAI, as shown by the same literature review. Taken together, our data and the literature review suggest a functional segregation of anterior insular cortex.

Increased gray matter density in young women with chronic vulvar pain

Abstract Provoked vestibulodynia (PVD) is a common form of chronic vulvar pain with unknown aetiology. Central pain regulatory mechanisms have been suggested to be disrupted in PVD, and consequently, PVD may be associated with anatomical changes in pain modulatory brain areas. Here, we compared total gray matter volumes and regional gray matter densities between 14 medication‐free young women with relatively short‐standing PVD (1 to 9 yrs) and 14 control subjects using whole brain voxel‐based morphometry (VBM). VBM revealed that PVD subjects had significantly higher gray matter densities in pain modulatory and stress‐related areas, i.e. the parahippocampal gyrus/hippocampus and basal ganglia (globus pallidus, caudate nucleus, and substantia nigra). In several of these regions, gray matter was related to clinical symptoms, namely lowered pain thresholds and increased pain catastrophizing scores. No region showed decreased gray matter density in the PVD group. These results point at the morphological alterations in supra‐spinal pain modulatory circuitry, which might contribute to the clinical symptoms of patients with PVD. Previous VBM studies in older subjects with a longstanding chronic pain condition have demonstrated gray matter decreases in similar areas. We therefore speculate that gray matter density might increase in young pain patients with short disease duration and decrease in older subjects with longstanding disease, similarly to some psychiatric conditions, in which bi‐directional changes of gray matter have been observed.

The Anatomy of the Mesolimbic Reward System: A Link between Personality and the Placebo Analgesic Response

The anticipation of clinical benefit, a crucial component of placebo analgesia, has been suggested to be a special case of reward anticipation. Since reward processing is closely linked to the ventral striatum and the neurotransmitter dopamine, we examined the relationships between brain gray matter, placebo analgesic response, and personality traits associated with dopaminergic neurotransmission. We report that dopamine-related traits predict a substantial portion of the pain relief an individual gains from a sham treatment. Voxel-based morphometry of magnetic resonance images shows that the magnitude of placebo analgesia is related to gray matter density (GMD) in several brain regions, including the ventral striatum, insula, and prefrontal cortex. Similarly, GMD in ventral striatum and prefrontal cortex is related to dopamine-related personality traits. Our findings highlight the relationship between placebo and reward and potentially offer ways of identifying subjects who are likely to show large placebo analgesic responses.

Pain imaging in health and disease — how far have we come?

Since modern brain imaging of pain began 20 years ago, networks in the brain related to pain processing and those related to different types of pain modulation, including placebo, have been identified. Functional and anatomical connectivity of these circuits has begun to be analyzed. Imaging in patients suggests that chronic pain is associated with altered function and structural abnormalities in pain modulatory circuits. Moreover, biochemical alterations associated with chronic pain are being identified that provide information on cellular correlates as well as potential mechanisms of structural changes. Data from these brain imaging studies reinforce the idea that chronic pain leads to brain changes that could have functional significance.

In vivo magnetic resonance tracking of olfactory ensheathing glia grafted into the rat spinal cord.

Engraftment of olfactory ensheathing cells (OEC), a unique type of glia required for olfactory nerve growth throughout life, has been shown to foster axonal regeneration in different types of CNS and PNS injuries. However, a lack of suitable markers of OEC has hindered studies assessing survival and function of OEC grafts following transplantation. The aim of this study was to examine the possible usefulness of superparamagnetic iron oxide nanoparticles (magnetodendrimers) as a label to allow in vivo tracking of grafted OEC by MR imaging and to determine temporal and spatial migration of OEC in normal and injured rat spinal cords, including the possibility of such cells to cross a complete spinal cord injury zone. We found that labeled OEC were readily detectable in vivo by MR imaging for at least 2 months. Labeled OEC migrated extensively in normal spinal cord as shown by MRI and histological markers. In contrast, OEC showed limited migration in transected spinal cord and were not able to cross the transection gap. Furthermore, iron-containing hemorrhage products confounded interpretation of MR contrast patterns in the injured spinal cord. We conclude that (1) MR imaging is useful for noninvasive observation of cell migration dynamics after grafting in vivo, although interpretation in severe injuries should be cautious, and that (2) OEC migratory and thus regeneration-enhancing ability is limited when confronted with the glial scar of a transected spinal cord.

Exogenously applied muscle metabolites synergistically evoke sensations of muscle fatigue and pain in human subjects

What is the central question of this study? Can physiological concentrations of metabolite combinations evoke sensations of fatigue and pain when injected into skeletal muscle? If so, what sensations are evoked? What is the main finding and its importance? Low concentrations of protons, lactate and ATP evoked sensations related to fatigue. Higher concentrations of these metabolites evoked pain. Single metabolites evoked no sensations. This suggests that the combination of an ASIC receptor and a purinergic P2X receptor is required for signalling fatigue and pain. The results also suggest that two types of sensory neurons encode metabolites; one detects low concentrations of metabolites and signals sensations of fatigue, whereas the other detects higher levels of metabolites and signals ache and hot.

Early life adversity as a risk factor for fibromyalgia in later life.

The impact of early life events is increasingly becoming apparent, as studies investigate how early childhood can shape long-term physiology and behaviour. Fibromyalgia (FM), which is characterised by increased pain sensitivity and a number of affective co-morbidities, has an unclear etiology. This paper discusses risk factors from early life that may increase the occurrence or severity of FM in later life: pain experience during neonatal life causes long-lasting changes in nociceptive circuitry and increases pain sensitivity in the older organism; premature birth and related stressor exposure cause lasting changes in stress responsivity; maternal deprivation affects anxiety-like behaviours that may be partially mediated by epigenetic modulation of the genome—all these adult phenotypes are strikingly similar to symptoms displayed by FM sufferers. In addition, childhood trauma and exposure to substances of abuse may cause lasting changes in developing neurotransmitter and endocrine circuits that are linked to anxiety and stress responses.