Markovian analysis of the sequential behavior of the spontaneous spinal cord dorsum potentials induced by acute nociceptive stimulation in the anesthetized cat

In a previous study we developed a Machine Learning procedure for the automatic identification and classification of spontaneous cord dorsum potentials (CDPs). This study further supported the proposal that in the anesthetized cat, the spontaneous CDPs recorded from different lumbar spinal segments are generated by a distributed network of dorsal horn neurons with structured (non-random) patterns of functional connectivity and that these configurations can be changed to other non-random and stable configurations after the noceptive stimulation produced by the intradermic injection of capsaicin in the anesthetized cat. Here we present a study showing that the sequence of identified forms of the spontaneous CDPs follows a Markov chain of at least order one. That is, the system has memory in the sense that the spontaneous activation of dorsal horn neuronal ensembles producing the CDPs is not independent of the most recent activity. We used this markovian property to build a procedure to identify portions of signals as belonging to a specific functional state of connectivity among the neuronal networks involved in the generation of the CDPs. We have tested this procedure during acute nociceptive stimulation produced by the intradermic injection of capsaicin in intact as well as spinalized preparations. Altogether, our results indicate that CDP sequences cannot be generated by a renewal stochastic process. Moreover, it is possible to describe some functional features of activity in the cord dorsum by modeling the CDP sequences as generated by a Markov order one stochastic process. Finally, these Markov models make possible to determine the functional state which produced a CDP sequence. The proposed identification procedures appear to be useful for the analysis of the sequential behavior of the ongoing CDPs recorded from different spinal segments in response to a variety of experimental procedures including the changes produced by acute nociceptive stimulation. They are envisaged as a useful tool to examine alterations of the patterns of functional connectivity between dorsal horn neurons under normal and different pathological conditions, an issue of potential clinical concern.Peer ReviewedPostprint (published version

Supraspinal shaping of adaptive transitions in the state of functional connectivity between segmentally distributed dorsal horn neuronal populations in response to nociception and antinociception

In the anesthetized cat the correlation between the ongoing cord dorsum potentials(CDPs) recorded from different lumbar spinal segments has a non-random structure,suggesting relatively stable patterns of functional connectivity between the dorsalhorn neuronal ensembles involved in the generation of these potentials. During thenociception induced by the intradermic injection of capsaicin, the patterns of segmentalcorrelation between the spontaneous CDPs acquire other non-random configurationsthat are temporarily reversed to their pre-capsaicin state by the systemic injectionof lidocaine, a procedure known to decrease the manifestation of neuropathic painin both animals and humans. We have now extended these studies and utilizedmachine learning for the automatic extraction and selection of particular classes ofCDPs according to their shapes and amplitudes. By using a Markovian analysis, wedisclosed the transitions between the different kinds of CDPs induced by capsaicinand lidocaine and constructed a global model based on the changes in the behaviorof the CDPs generated along the whole set of lumbar segments. This allowed theidentification of the different states of functional connectivity within the whole ensembleof dorsal horn neurones attained during nociception and their transitory reversal bysystemic administration of lidocaine in preparations with the intact neuroaxis and afterspinalization. The present observations provide additional information on the stateof self-organized criticality that leads to the adaptive behavior of the dorsal hornneuronal networks during nociception and antinociception both shaped by supraspinaldescending influencesPeer ReviewedPostprint (published version

Supraspinal modulation of neuronal synchronization by nociceptive stimulation induces an enduring reorganization of dorsal horn neuronal connectivity

Despite a profusion of information on the molecular and cellular mechanisms involved in the central sensitization produced by intense nociceptive stimulation, the changes in the patterns of functional connectivity between spinal neurones associated with the development of secondary hyperalgesia and allodynia remain largely unknown. Here we show that the state of central sensitization produced by the intradermal injection of capsaicin is associated with structured transformations in neuronal synchronization that lead to an enduring reorganization of the functional connectivity within a segmentally distributed ensemble of dorsal horn neurones. These changes are transiently reversed by the systemic administration of small doses of lidocaine, a clinically effective procedure to treat neuropathic pain. Lidocaine also reduces the capsaicin-induced facilitation of the spinal responses evoked by weak mechanical stimulation of the skin in the region of secondary but not primary hyperalgesia. The effects of both intradermic capsaicin and systemic lidocaine on the segmental correlation and coherence between ongoing cord dorsum potentials and on the responses evoked by tactile stimulation in the region of secondary hyperalgesia are greatly attenuated in spinalized preparations, showing that supraspinal influences are involved in the reorganization of the nociceptive-induced structured patterns of dorsal horn neuronal connectivity. We conclude that the structured reorganization of the functional connectivity between the dorsal horn neurones induced by capsaicin nociceptive stimulation results from cooperative interactions between supraspinal and spinal networks, a process that may have a relevant role in the shaping of the spinal state in the pathogenesis of chronic pain and analgesia.Peer ReviewedPostprint (author's final draft

Pioneers in CNS inhibition: 2. Charles Sherrington and John Eccles on inhibition in spinal and supraspinal structures

This article reviews the contributions of the English neurophysiologist, Charles Scott Sherrington [1857–1952], and his Australian PhD trainee and collaborator, John Carew Eccles [1903–1997], to the concept of central inhibition in the spinal cord and brain. Both were awarded Nobel Prizes; Sherrington in 1932 for “discoveries regarding the function of neurons,” and Eccles in 1963 for “discoveries concerning the ionic mechanisms involved in excitation and inhibition in central portions of the nerve cell membrane.” Both spoke about central inhibition at their Nobel Prize Award Ceremonies. The subsequent publications of their talks were entitled “Inhibition as a coordinative factor” and “The ionic mechanism of postsynaptic inhibition”, respectively. Sherrington's work on central inhibition spanned 41 years (1893–1934), and for Eccles 49 years (1928–1977). Sherrington first studied central inhibition by observing hind limb muscle responses to electrical (peripheral nerve) and mechanical (muscle) stimulation. He used muscle length and force measurements until the early 1900s and electromyography in the late 1920s. Eccles used these techniques while working with Sherrington, but later employed extracellular microelectrode recording in the spinal cord followed in 1951 by intracellular recording from spinal motoneurons. This considerably advanced our understanding of central inhibition. Sherrington's health was poor during his retirement years but he nonetheless made a small number of largely humanities contributions up to 1951, one year before his death at the age of 94. In contrast, Eccles retained his health and vigor until 3 years before his death and published prolifically on many subjects during his 22 years of official retirement. His last neuroscience article appeared in 1994 when he was 91. Despite poor health he continued thinking about his life-long interest, the mind-brain problem, and was attempting to complete his autobiography in the last years of his life

A machine learning methodology for the selection and classification of spontaneous spinal cord dorsum potentials allows disclosure of structured (non-random) changes in neuronal connectivity induced by nociceptive stimulation

Fractal analysis of spontaneous cord dorsum potentials (CDPs) generated in the lumbosacral spinal segments has revealed that these potentials are generated by ongoing structured (non-random) neuronal activity. Studies aimed to disclose the changes produced by nociceptive stimulation on the functional organization of the neuronal networks generating these potentials used predetermined templates to select specific classes of spontaneous CDPs. Since this procedure was time consuming and required continuous supervision, it was limited to the analysis of two types of CDPs (negative CDPs and negative positive CDPs), thus excluding potentials that may reflect activation of other neuronal networks of presumed functional relevance. We now present a novel procedure based in machine learning that allows the efficient and unbiased selection of a variety of spontaneous CDPs with different shapes and amplitudes. The reliability and performance of the method is evaluated by analyzing the effects on the probabilities of generation of different types of spontaneous CDPs induced by the intradermic injection of small amounts of capsaicin in the anesthetized cat.The results obtained with the selection method presently described allowed detection of spontaneous CDPs with specific shapes and amplitudes that are assumed to represent the activation of functionally coupled sets of dorsal horn neurones that acquire different, structured configurations in response to nociceptive stimuli