Chronic pain (CP) is a condition characterized by a wide spectrum of clinical signs and symptoms, missing a sound modelling at the neuronal network scale. Recently, we presented a general theory showing common electrophysiological traits in different CP rat models, i.e. a collapse of relevant functional connectivity network properties, such as modularity, in the somatosensory thalamo-cortical (TC) network. In this work, we preliminary investigated by an in silico accurate simulator of the six-layer mammalian cortical networks that evidenced the crucial collapse of network modularity in CP simulated conditions and the consequent reduction of network adaptive processes. On this track, in studies on CP experimental animals affected by sciatic nerve multiple ligature (Bennett-Xie model), by synchrotron-generated X-ray microbeam (MB) irradiations (7 parallel beams, 100um width), we targeted in vivo the CP involved hindlimb somatosensory projection cortex that, because of the doses radiation (360 Gy, peak at each beam), non-invasively produced fast and precise tissue destruction along the 7 beam projections. These parcellated the cortical tissue and restored the cortical network statistics related to modularity and information processing efficiency as evidenced from post irradiation in vivo electrophysiological recordings. In addition, by MB treatment there was an ensuing removal of behavioral signs of allodynia and hyperalgesia accompanied by recovered normal gait schemes yet preserving the normal sensory thresholds of the experimental rats up to three months after the MB irradiation. Finally, novel and unprecedented therapeutic appraisals for CP are devised. Significance StatementChronic pain (CP) is an excruciating condition with severe effects on patients' life. Apart from many clinical and experimental studies no current theory on CP is generally accepted. Recently, we proposed a general theory of CP in experimental animals as characterized by strong alteration of the connections among neurons in different brain regions. We show here on in silico simulations that specific connectivity changes in the somatosensory cortex recover the lost functional integrity. Concurrently, in experimental animals, we re-modulated, in vivo, some anatomical connections of the somatosensory cortex by extremely thin synchrotron generated X-ray microbeam irradiations. The resulting behavioral and electrophysiological signs of CP disappeared yet maintaining normal sensory responses. No adverse or pathological effects on blank animals were observable.The results report a multianalytic picture of the effects of high-dose sevenfold X-ray microbeams (MBs) irradiation through the intact skull on the somatosensory cortex of experimental rats in vivo anesthetized with a model of neuropathic Chronic Pain (CP, Figure 1A-F) and control (CR). Early computational inspectionsPreliminary, in silico exploratory analyses offered the possibility to evaluate the effects of guided connectivity interventions on functional and topological substrates of the c...
Chronic pain (CP) represents a complex pathology profoundly involving both neural and glial compartments of the central nervous system. While most CP studies have also investigated the macroscopic brain vascular system, its microstructural architecture still remains largely unexplored. Further, the adaptive modifications of the vascular microstructure as consequence of diseases or pathological insults did not receive adequate attention. Here we show microtomographic signs of diffuse and conspicuous microvascular neogenesis in somatosensory cortex of CP animal models already peaking at 15 days from the model instantiation.Progressive fading of this microvessel neogenesis then ensued in the next six months yet maintaining higher vascular density with a preserved small fraction of them. Due to the important consequences on the neuronglial-vessel arrangements and on the resulting metabolic and functional disorders of the local networks, novel additional scenarios of CP are thus conceivable with profound consequences of potential future CP diagnostic and therapeutic appraisals. Significance StatementChronic pain (CP) is an excruciating condition with various clinical presentations. Major signs are characterized by a rich repertoire of pain quality, intensity and length. While neuronal and glial anomalies have been associated to CP less attention has been granted to the micro-vessel and capillary compartments of the involved brain regions. Our research illustrates how the microvessel compartments of the somatosensory cortex in experimental animals present profound and long-lasting signs of extensive neogenesis (about fourfold) early within the first two weeks from the CP start, undergoing a slow and incomplete decline within six months. These results may change the CP clinical picture with potential novel therapeutic approaches to it. IntroductionAt the level of the central nervous system, Chronic Pain (CP) displays a cohort of signs and symptoms, where the percept of pain dominates within a complex morpho-functional background of anomalous neuronal and glial events. These appear variously combined and causative of a global, maladaptive condition. At large scales, brain regional anomalous activations in CP patients 1-3 , as shown by functional neuroimaging, are seemingly accompanied by metabolic dysfunctions and local macrostructural signs such as cortical thickness reductions or cortical laminar misalignments 4 . At lower cell-level scales, CP-related functional disorders have been described, in the past, mostly as gangliar, spinal or central neuronal dynamic irregularities 5-8 .These mainly included spontaneous hyper-or hypo-activities, hyper-responsiveness to non-noxious and noxious stimuli, anomalous spiking patterns, often accompanied by variable signs of local neuronal degeneration and by cortical somatotopic mapping readjustments of sensory projection fields. These signs appeared complementary and ascribed to perceptual conditions such as spontaneous pain, allodynia and hyperalgesia. A step forward was then envi...
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