No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Dynamic synchronization of ongoing neuronal activity across spinal segments regulates sensory information flow: Neuronal synchronization and regulation of sensory information
Abstract
Previous studies on correlation between spontaneous cord dorsum potentials recorded in the lumbar spinal segments of anaesthetized cats suggested the operation of a population of dorsal horn neurones that modulates, in a differential manner, transmission along pathways mediating Ib non-reciprocal postsynaptic inhibition and pathways mediating primary afferent depolarization and presynaptic inhibition (Chávez et al., 2012). To have further insight on the possible neuronal mechanisms that underlie this process, we have now measured changes in the correlation between the spontaneous activity of individual dorsal horn neurones and the cord dorsum potentials associated with intermittent activation of these inhibitory pathways. We found that high levels of neuronal synchronization within the dorsal horn are associated with states of incremented activity along the pathways mediating presynaptic inhibition relative to pathways mediating Ib postsynaptic inhibition. It is suggested that ongoing changes in the patterns of functional connectivity within a distributed ensemble of dorsal horn neurones play a relevant role in the state-dependent modulation of impulse transmission along inhibitory pathways, among them those involved in the central control of sensory information. This feature would allow the same neuronal network to be involved in different functional tasks. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
... In previous work, we examined the functional relations between the ongoing activity of single dorsal horn neurons and the negative and negative-positive cord dorsum potentials (nCDPs and npCDPs, respectively; see Contreras-Hernández et al. 2015). We now examined the relations of the dIFPs with the ongoing nCDPs and npCDPs. ...
... We have shown in the previous section that the dIFPs increased their spontaneous firing during both nCDPs and npCDPs. In Contreras-Hernández et al. (2015) we suggested that the npCDPs are generated during a state of increased synchronization along a longitudinally distributed ensemble of dorsal horn neurons. It, thus, seemed of interest to examine the changes in the frequency of the dIFPs generated at different times before, during and after the nCDPs and npCDPs. ...
... Already in our 2000 paper, we reported that stimulation of the SU and SP nerves with relatively weak strengths (1.2xT) induced a pronounced inhibition of the ongoing CDPs lasting between 100 and 150 ms (see Fig. 10 in Manjarrez et al. 2000). Subsequent studies also indicated that the spinal potentials produced by skin stimulation with pulses of 3.2xT strength were also inhibited when preceded by spontaneous nCDPs or npCDPs (see Fig. 9 of Contreras-Hernández et al. 2015). This finding raised the question on whether the ongoing dIFPs would be similarly inhibited during SP stimulation with relatively low strengths. ...
In addition to the action potentials generated by the ongoing activation of single dorsal horn neurons in the anesthetized cat, we often recorded small negative field potentials with a fast-rising phase and a slow decay (dIFPs). These potentials could be separated in different classes, each with a specific and rather constant shape and amplitude. They were largest in spinal laminae III–V and gradually faded at deeper locations, without showing the polarity reversal displayed at these depths by the focal potentials produced by stimulation of muscle and cutaneous afferents. We propose that the dIFPs are postsynaptic field potentials generated by strongly coupled sets of dorsal horn neurons displaying a spatial orientation that generates closed field potentials in response to stimulation of high-threshold cutaneous and muscle afferents. These neuronal sets could form part of the spinal inhibitory circuitry that mediates presynaptic inhibition and Ib non-reciprocal postsynaptic inhibition and could be involved in the sensory–motor transformations activated by stimulation of high-threshold cutaneous afferents.
... Eccles took up the detailed study of presynaptic inhibition in late 1958 or early 1959, and this continued for a few years (see below). The work had immediate impact as emphasized by Pablo Rudomin [1934-] (for career, see Rudomin, 2013), who has now systematically studied presynaptic inhibition for over 50 years, i.e., Rudomin (1965Rudomin ( , 1967a to Contreras-Hernández et al. (2015) and Martin et al. (2015), and advanced the concept and mode of its investigation to a remarkable degree. In one of his several erudite reviews on the topic Rudomin (2009;p. ...
... These concerned the functional role of presynaptic inhibition and PAD during natural movements, and the nature and role of sensory processing in creating a higher coherence between cortically programmed and spinally executed movements. -Hernández, Chávez, and Rudomin (2015). This article examined in anesthetized cats the relationship between ongoing fluctuations of spinal cord dorsal horn neuronal activity (cord dorsal root potentials; CDPs) and the activation of various inhibitory reflex pathways. ...
... Focus was on using a machine learning methodology to explore the functional organization of a far larger number of CDPs in response to nociceptive stimulation, which can elicit presynaptic inhibition. The initial preliminary results showed that the new technique did indeed uncover several more types of CDP than reported by Contreras-Hernández et al. (2015). Prophetically, this suggested to Rudomin (personal communication) that "presynaptic inhibition is not only a mechanism for reducing transmitter release but it is also a mechanism for changing the level of neuronal synchronization in sensory pathways and thereby altering their information content." ...
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.
... To approach the first two questions we utilized Machine Learning procedures that use similarity criteria for the automatic selection and classification of the ongoing CDPs according to their shape and amplitude (see Béjar et al., 2015;Martin et al., 2015). We used this procedure to build dictionaries with CDPs selected under basal (control) conditions to estimate the changes produced during nociception and antinociception on the probabilities of occurrence of the different classes of CDPs, a task that would be otherwise difficult to achieve using predetermined template selection methods such as those employed in previous studies (see Chávez et al., 2012;Contreras-Hernández et al., 2015). ...
... As in previous studies ( Manjarrez et al., 2000Manjarrez et al., , 2003Chávez et al., 2012;Contreras-Hernández et al., 2015;Martin et al., 2017), we found that the ongoing potentials recorded in the dorsum of the lumbar spinal segments included a series of brief potentials (CDPs), some of which appeared synchronously in different segments ( Figure 1A). By 1 h after the nociceptive stimulation produced by the intradermal injection of capsaicin, the ongoing CDPs showed, in addition to the brief potentials, a series of slow synchronized oscillations ( Figure 1B) that were transiently suppressed after the systemic injection of lidocaine, leaving sequences of brief potentials that resembled those recorded before the injection of capsaicin ( Figure 1C). ...
... The finding that the shapes of the different classes of the CDPs selected in segment L5rL resembled rather closely those extracted from recordings made in segment L6rL (and in other lumbar segments as well) further supports our previous proposal that the different classes of CDPs are generated by the activation of a segmentally distributed ensemble of interconnected dorsal horn neurones ( Manjarrez et al., 2000Manjarrez et al., , 2003Chávez et al., 2012;Contreras-Hernández et al., 2015;Martin et al., 2017). ...
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 dorsal horn neuronal ensembles involved in the generation of these potentials. During the nociception induced by the intradermic injection of capsaicin, the patterns of segmental correlation between the spontaneous CDPs acquire other non-random configurations that are temporarily reversed to their pre-capsaicin state by the systemic injection of lidocaine, a procedure known to decrease the manifestation of neuropathic pain in both animals and humans. We have now extended these studies and utilized machine learning for the automatic extraction and selection of particular classes of CDPs according to their shapes and amplitudes. By using a Markovian analysis, we disclosed the transitions between the different kinds of CDPs induced by capsaicin and lidocaine and constructed a global model based on the changes in the behavior of the CDPs generated along the whole set of lumbar segments. This allowed the identification of the different states of functional connectivity within the whole ensemble of dorsal horn neurones attained during nociception and their transitory reversal by systemic administration of lidocaine in preparations with the intact neuroaxis and after spinalization. The present observations provide additional information on the state of self-organized criticality that leads to the adaptive behavior of the dorsal horn neuronal networks during nociception and antinociception both shaped by supraspinal descending influences.
... Previous studies in our laboratory have shown that the ongoing cord dorsum potentials (CDPs) recorded in the lumbosacral segments of the anesthetized cat are generated by the synchronous activity of a longitudinally distributed network of interconnected local and intersegmental sets of dorsal horn neurones ( Manjarrez et al., 2000and Chávez et al., 2012). A key finding was that depending on the level of neuronal synchronization, this ensemble could acquire specific configurations of neuronal connectivity, some leading to the preferential activation of the pathways mediating Ib non-reciprocal postsynaptic inhibition and others to the activation of the pathways mediating primary afferent depolarization and presynaptic inhibition ( Contreras-Hernández et al., 2015). ...
... CDPs located in more distant segments in the same and in opposite sides of the spinal cord ( Fig. 2 A2-A4). This distribution is consistent with the proposal of a longitudinally bilaterally distributed set of interconnected neuronal populations ( Chávez et al., 2012;Contreras-Hernández et al., 2015). Quite interestingly, 70-80 min after the injection of capsaicin there was a significant increase in the correlation between the crossed CDPs generated in nearby segments ( Fig. 2B1) and a concurrent reduction in the correlation between the more distant sets of CDPs ( Fig. 2 B2 and B3). ...
... Structured changes in synchronization between dorsal horn neurones appear to be an effective way to address information flow to specific neuronal networks (see also Abarbanel et al., 1996;Jiao, 2006;Womelsdorf et al., 2007). In fact, the recruitment of presynaptic inhibitory pathways during high levels of spontaneous dorsal horn neuronal synchronization described by Contreras-Hernández et al., (2015), could play a relevant role in the addressing of sensory information during secondary hyperalgesia and allodynia induced by nociceptive stimulation (see Cervero et al., 2003). The present study provides important evidence regarding the overall changes in neuronal correlation during nociceptive stimulation but rather limited information on the concurrent changes in the connectivity of specific, functionally identified neuronal populations. ...
Key points:
The state of central sensitization induced by the intradermic injection of capsaicin leads to structured (non-random) changes in functional connectivity between dorsal horn neuronal populations distributed along the spinal lumbar segments in anaesthetized cats. The capsaicin-induced changes in neuronal connectivity and the concurrent increase in secondary hyperalgesia are transiently reversed by the systemic administration of small doses of lidocaine, a clinically effective procedure to treat neuropathic pain. The effects of both capsaicin and lidocaine are greatly attenuated in spinalized preparations, showing that supraspinal influences play a significant role in the shaping of nociceptive-induced changes in dorsal horn functional neuronal connectivity. We conclude that changes in functional connectivity between segmental populations of dorsal horn neurones induced by capsaicin and lidocaine result from a cooperative adaptive interaction between supraspinal and spinal neuronal networks, a process that may have a relevant role in the pathogenesis of chronic pain and analgesia.
Abstract:
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.
... to populations restricted to one lumbar segment). It is also possible that some classes of CDPs are produced by a neuronal network distributed along several lumbar segments that acquires different configurations of functionally connectivity depending on the level of neuronal synchronization, as shown in Contreras-Hernández et al. (2015). In either case, the relations between the spontaneous CDPs may provide significant clues on the patterns of functional connectivity between the neuronal sets involved in their generation and on how these patterns change under different experimental situations. ...
... In this paper we used data from four experiments (see Table 1) to identify a class of Markov processes that describe the local interactions between the populations of dorsal horn neurones which generate the spontaneous CDPs examined by Contreras-Hernández et al. (2015) and Béjar et al. (2015). ...
... The functional implications of these findings are discussed in Section 7.2. Although, our results agree with the findings reported by Contreras-Hernández et al. (2015), the functional organization of the ensembles of neurons that produce this information has to be further investigated. To this end, and based on the idea that the studied processes are markovian (see Section 6), we introduced a method to predict the membership of a sequence C 100 l, * of the last 100 CDPs of a time step reds ∈ S (see Figure 7). ...
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.
... Recent studies aimed to disclose the neuronal populations involved in the generation of the spontaneous npCDPs and nCDPs were based on potentials selected from raw records using predetermined templates Contreras-Hernández et al., 2015). This procedure required continuous supervision and validation by visual inspection to extract only spontaneous nCDPs and npCDPs, which represent a small part of a wider repertory of spontaneous CDPs whose functional role remains to be established. ...
... Then one could use this count to define the configuration of functional interconnections between the neuronal populations involved in the generation of the CDPs in different spinal segments, giving detailed information on the temporal recurrence relations between identified patterns. This has the potential to identify functionally defined changes in the internal connectivity of the neuronal ensembles that generate the spontaneous CDPs during the performance of different tasks (Manjarrez et al., 2000;Contreras-Hernández et al., 2015). ...
... The problem addressed by the first phase of the methodology is similar to the analysis of neural spike activity made with Spike Sorting Methodology (SSM) (Lewicki, 1998). Nevertheless, we have to take into account that CDPs have amplitudes between 5 and 250 µV and durations between 20 and 300 ms, because these CDPs result from the activation of either the same or different neuronal ensembles (Contreras-Hernández et al., 2015). Henceforth, the possible patterns of these activations are quite different from those studied using SSM, meaning that a more general perspective has to be used to analyze such kind of signals. ...
Previous studies aimed to disclose the functional organization of the neuronal networks involved in the generation of the spontaneous cord dorsum potentials (CDPs) generated in the lumbosacral spinal segments 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 specific 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 present method is evaluated by analyzing the effects on the probabilities of generation of different classes of spontaneous CDPs induced by the intradermic injection of small amounts of capsaicin in the anesthetized cat, a procedure known to induce a state of central sensitization leading to allodynia and hyperalgesia. 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. These changes are considered as responses tending to adequate transmission of sensory information to specific functional requirements as part of homeostatic adjustments.
... Recent studies aimed to disclose the neuronal populations involved in the generation of the spontaneous npCDPs and nCDPs were based on potentials selected from raw records using predetermined templates (Chávez et al., 2012; Contreras- Hernández et al., 2015). This procedure required continuous supervision and validation by visual inspection to extract only spontaneous nCDPs and npCDPs, which represent a small part of a wider repertory of spontaneous CDPs whose functional role remains to be established. ...
... spinal segments , giving detailed information on the temporal recurrence relations between identified patterns . This has the potential to identify functionally defined changes in the internal connectivity of the neuronal ensembles that generate the spontaneous CDPs during the performance of different tasks ( Manjarrez et al . , 2000 ; Contreras - Hernández et al . , 2015 ) . ...
... lar to the analysis of neural spike activity made with Spike Sorting Methodology ( SSM ) ( Lewicki , 1998 ) . Nevertheless , we have to take into account that CDPs have amplitudes between 5 and 250 µV and durations between 20 and 300 ms , because these CDPs result from the activation of either the same or different neuronal ensembles ( Contreras - Hernández et al . , 2015 ) . Henceforth , the possible patterns of these activations are quite different from those studied using SSM , meaning that a more general perspective has to be used to analyze such kind of signals . ...
... The relation between discharge synchronization and wave amplitude in neuronal population is well known in other CNS areas like brain cortex, i.e., change from alpha rhythm (synchronized) to beta rhythm (desynchronized) induced by a sensory stimulation [31]. Recently, the presence of an additional control mechanism of sensory flow exerted by neuronal synchronization has been described in the SDH, which may explain part of the results of the present study [32]. This sensorial modulation at the SDH generates a decreased signal that will be projected to supraspinal structures. ...
... This kind of control appears to be exerted by a longitudinally, bilaterally distributed ensemble of functionally interconnected sets of neurons distributed along several spinal segments (and their respective sensory inputs). Increased synchronization between the spontaneous neuronal activity within this ensemble may lead to a state-dependent sensory modulation with preferential activation of the presynaptic inhibitory pathways that modulate the information transmitted by cutaneous afferents to other segmental and supraspinal networks [12,16,32,35]. ...
Most of the endogenous pain modulation (EPM) involves the spinal dorsal horn (SDH). EPM including diffuse noxious inhibitory controls have been extensively described in oligoneuronal electrophysiological recordings but less attention had been paid to responses of the SDH neuronal population to heterotopic noxious stimulation (HNS). Spinal somatosensory-evoked potentials (SEP) offer the possibility to evaluate the neuronal network behavior, reflecting the incoming afferent volleys along the entry root, SDH interneuron activities and the primary afferent depolarization. SEP from de lumbar cord dorsum were evaluated during mechanical heterotopic noxious stimuli. Sprague–Dawley rats (n = 12) were Laminectomized (T10-L3). The sural nerve of the left hind paw was electrically stimulated (5 mA, 0.5 ms, 0.05 Hz) to induce lumbar SEP. The HNS (mechanic clamp) was applied sequentially to the tail, right hind paw, right forepaw, muzzle and left forepaw during sural stimulation. N wave amplitude decreases (−16.6 %) compared to control conditions when HNS was applied to all areas of stimulation. This effect was more intense for muzzle stimulation (−23.5 %). N wave duration also decreased by −23.6 %. HNS did not change neither the amplitude nor the duration of the P wave but dramatically increases the dispersion of these two parameters. The results of the present study strongly suggest that a HNS applied to different parts of the body is able to reduce the integrated electrical response of the SDH, suggesting that not only wide dynamic range neurons but many others in the SDH are modulated by the EPM.
... Earlier studies were focused on spontaneous CDPs composed by a smooth negative wave (negative CDPs-nCDPs) or a negative wave followed by a slow positive phase (negative-positive CDPs-npCDPs) (e.g. blue traces 1 and 5 in Fig. 4, negativity upward), because these two types of CDPs are associated with the activation of non-reciprocal Ib inhibition of motoneurons and presynaptic inhibition of primary afferents, respectively (Chávez et al., 2012;Contreras-Hernández et al., 2015;Solodkin et al., 1984). Further analyses that employed machine learning methods extended the notion of nCDPs and npCDPs to CDPs with varied shapes composed of more intricate combinations of negative and positive waves (blue traces Nos. ...
Modules or modular organization are concepts widely used to describe anatomical and functional properties of neuronal circuits across the nervous system including the spinal cord. However, there is not a general consensus about the precise meaning of spinal module. In general terms they can be referred to discrete functional units or stable stereotyped neuronal configurations that integrate peripheral and central inputs in order to perform specific sensorimotor transformations. This review presents the features of five concepts of modular organization in the spinal cord: muscular synergistic modules, withdrawal reflex modules, discrete intraspinal field potentials, cord dorsum potentials and focal modules. Then it is proposed a general model that encompasses such levels of spinal modular organization embedded into a highly flexible network of dorsal horn interneurons that mutually interact to produce a range of motor outputs. The functional implications of this model as well as different open questions are discussed.
... Historically, studies of slow spinal potentials supported development of theories for pain manifestation and its control (Wall, 1958), including Gate Control Theory, and initial mechanistic hypotheses about SCS were tested through measurement of longer-latency "prolonged small fiber after discharge" (PSAD; Shealy et al., 1970). Slow spinal potentials may correlate with modulation of afferent input (e.g., primary afferent depolarization), interneuron activity, or dorsal horn excitability (Wall, 1958;Manjarrez et al., 2003;Contreras-Hernández et al., 2015 and may therefore provide more information about the spinal (pain) state than ECAPs alone. However, fundamental studies on slower potentials used electrodes not suitable for clinical applications. ...
Spinal cord stimulation (SCS) evokes fast epidural Evoked Compound Action Potential (ECAPs) that represent activity of dorsal column axons, but not necessarily a spinal circuit response. Using a multimodal approach, we identified and characterized a delayed and slower potential evoked by SCS that reflects synaptic activity within the spinal cord. Anesthetized female Sprague Dawley rats were implanted with an epidural SCS lead, epidural motor cortex stimulation electrodes, an epidural spinal cord recoding lead, an intraspinal penetrating recording electrode array, and intramuscular electromyography (EMG) electrodes in the hindlimb and back. We stimulated the motor cortex or the epidural spinal cord and recorded epidural, intraspinal, and EMG responses. SCS pulses produced characteristic propagating ECAPs (composed of P1, N1, and P2 waves with latencies <2 ms) and an additional wave (“S1”) starting after the N2. We verified the S1-wave was not a stimulation artifact and was not a reflection of hindlimb/back EMG. The S1-wave has a distinct stimulation-intensity dose response and spatial profile compared to ECAPs. CNQX (a selective competitive antagonist of AMPA receptors) significantly diminished the S1-wave, but not ECAPs. Furthermore, cortical stimulation, which did not evoke ECAPs, produced epidurally detectable and CNQX-sensitive responses at the same spinal sites, confirming epidural recording of an evoked synaptic response. Finally, applying 50 Hz SCS resulted in dampening of ESAPs, but not ECAPs. Therefore, we hypothesize that the S1-wave is synaptic in origin, and we term the S1-wave type responses: Evoked Synaptic Activity Potentials (ESAPs). The identification and characterization of epidurally recorded ESAPs from the dorsal horn may elucidate SCS mechanisms.
Significance Statement
Spinal cord stimulation (SCS) is an established treatment for chronic pain and has applications to other disorders and neurorehabilitation. Notwithstanding decades of trials and research, questions remain about SCS mechanisms of action - and indicators thereof. Recent technological developments have enabled the detection of Evoked Compound Action Potential (ECAPs) – reflecting synchronous activity of the dorsal column axons activated by SCS. However, ECAP is not a direct measure of sensory processing in the dorsal horn. Here, we identify and characterize a novel electrophysiological signal that is evoked and detectable by epidural SCS electrodes and reflects spinal synaptic currents. This new signal, termed an Evoked Synaptic Activity Potential (ESAP), is thus a novel means with which to interrogate spinal gray matter circuits during SCS.
... Indeed, an ensemble of dorsal interneurons produces spontaneous rhythmic field potentials (cord dorsum potentials, CDPs; Cuellar et al., 2009) that are recorded as low frequency waveforms from the dorsal surface of the cord. These oscillations provide a pre-synaptic inhibition of concurring input from afferent stimulation (Rudomin and Dutton, 1967;Dutton, 1969a, 1969b;Rudomin and Madrid, 1972;Contreras-Hernández et al., 2015). Generally, the peak of each spontaneous CDP corresponds to the maximal modulation of motor reflex amplitude (Manjarrez et al., 2000). ...
The present review focuses on the physiological states of spinal networks, which are stochastically modulated by continuously changing ensembles of proprioceptive and supraspinal input resulting in highly redundant neural networks. Spinal epidural interfaces provide a platform for probing spinal network dynamics and connectivity among multiple motor pool-specific spinal networks post-injury under in vivo experimental conditions. Continuous epidural low-frequency pulses at low intensity can evoke motor responses of stochastically changing amplitudes and with an oscillatory pattern of modulation. The physiological significance of this oscillatory pattern, intrinsic to “resting” spinal networks and observed in both uninjured and injured locomotor circuits, is unclear. This neural variability among spinal networks appears to be a fundamental mechanism of the network's design and not a “noise” interfering with movement control. Data to date also suggest that the greater the level of stimulation above motor threshold, the greater the loss of modulation over the motor output that is physiologically provided by interneuronal networks, which integrate naturally occurring proprioceptive and cutaneous input generated during movement. Sub-motor threshold spinal electrical stimulation experiments demonstrate a range of functional improvements of multiple physiological systems when used in concert with sensorimotor training after spinal cord injury. Although our understanding of the systemic, cellular and molecular modulatory mechanisms that trigger these activity-dependent adaptive processes remain incomplete, some basic physiological principles have evolved, at least at the systemic and neural network levels and to some degree at the cellular level.
... A subclassification corresponds to neurons that respond to both noxious and nonnoxious inputs and participates in the antinociceptive effect exerted by acupuncture on somatic pain [11]. Another characteristic of a particular RF is that it shows a change in response owing to excitatory and/or inhibitory influences from segmental or descending pathways [14,32]. In addition, RF could be modified by experience or by injury to sensory nerves. ...
In Traditional Chinese Medicine, acupuncture points (APs) have been emphasized as key elements that generate the therapeutic effects of acupuncture. At the spinal cord or su-praspinal level, sensory neurons located in the dorsal horn receive an extensive supply of sensory information from skin and muscle receptors through peripheral afferent nerves. The stimulated skin area that influences the activity of a spinal sensory neuron is known as the peripheral receptive field (RF) of that neuron. By considering that a particular AP location involves the activation of one or various RFs, it can be assumed that several sensory central neurons are the site of convergence of the peripheral input generated by acupuncture stimulation. However, stimulation on nonacupoint sites could also activate skin areas with RFs that have been sensitized, and they could be involved in the generation of nonspecific effects of acupuncture, as seen in clinical practice. From the latter, it is suggested that effective APs, and even nonacupoints, are associated with a particular arrangement of RFs, and their study will be useful for understanding the intrinsic mechanisms of acupuncture and for the development and identification of more efficient sites and modes of acupuncture stimulation to evoke optimal therapeutic actions. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http:// creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
... Both burst firing and synchronicity are important elements of neuronal coding in the temporal dimension favoring space and time summation and providing for a reliable way to transmit synaptic information [30]. An intriguing possibility is that this conjunction of factors may provide for a strong source of synchronous excitation such as that required for the generation of primary afferent depolarization [17]. ...
The superficial dorsal horn contains large numbers of interneurons which process afferent and descending information to generate the spinal nociceptive message. Here, we set out to evaluate whether adjustments in patterns and/or temporal correlation of spontaneous discharges of these neurons are involved in the generation of central sensitization caused by peripheral nerve damage. Multielectrode arrays were used to record from discrete groups of such neurons in slices from control or nerve damaged mice. Whole-cell recordings of individual neurons were also obtained. A large proportion of neurons recorded extracellularly showed well-defined patterns of spontaneous firing. Clock-like neurons (CL) showed regular discharges at ∼6 Hz and represented 9 % of the sample in control animals. They showed a tonic-firing pattern to direct current injection and depolarized membrane potentials. Irregular fast-burst neurons (IFB) produced short-lasting high-frequency bursts (2–5 spikes at ∼100 Hz) at irregular intervals and represented 25 % of the sample. They showed bursting behavior upon direct current injection. Of the pairs of neurons recorded, 10 % showed correlated firing. Correlated pairs always included an IFB neuron. After nerve damage, the mean spontaneous firing frequency was unchanged, but the proportion of CL increased significantly (18 %) and many of these neurons appeared to acquire a novel low-threshold A-fiber input. Similarly, the percentage of IFB neurons was unaltered, but synchronous firing was increased to 22 % of the pairs studied. These changes may contribute to transform spinal processing of nociceptive inputs following peripheral nerve damage. The specific roles that these neurons may play are discussed.
Spinal cord stimulation (SCS) evokes fast epidural evoked compound action potential (ECAP) that represent activity of dorsal column axons, but not necessarily a spinal circuit response. Using a multimodal approach, we identified and characterized a delayed and slower potential evoked by SCS that reflects synaptic activity within the spinal cord. Anesthetized female Sprague Dawley rats were implanted with an epidural SCS lead, epidural motor cortex stimulation electrodes, an epidural spinal cord recording lead, an intraspinal penetrating recording electrode array, and intramuscular electromyography (EMG) electrodes in the hindlimb and trunk. We stimulated the motor cortex or the epidural spinal cord and recorded epidural, intraspinal, and EMG responses. SCS pulses produced characteristic propagating ECAPs (composed of P1, N1, and P2 waves with latencies <2 ms) and an additional wave (“S1”) starting after the N2. We verified the S1-wave was not a stimulation artifact and was not a reflection of hindlimb/trunk EMG. The S1-wave has a distinct stimulation-intensity dose response and spatial profile compared with ECAPs. 6-Cyano-7-nitroquinoxaline-2,3-dione (CNQX; a selective competitive antagonist of AMPA receptors (AMPARs)] significantly diminished the S1-wave, but not ECAPs. Furthermore, cortical stimulation, which did not evoke ECAPs, produced epidurally detectable and CNQX-sensitive responses at the same spinal sites, confirming epidural recording of an evoked synaptic response. Finally, applying 50-Hz SCS resulted in dampening of S1-wave but not ECAPs. Therefore, we hypothesize that the S1-wave is synaptic in origin, and we term the S1-wave type responses: evoked synaptic activity potentials (ESAPs). The identification and characterization of epidurally recorded ESAPs from the dorsal horn may elucidate SCS mechanisms.
Current medical care lacks an effective functional evaluation for the spinal cord. Magnetic resonance imaging and computed tomography mainly provide structural information of the spinal cord, while spinal somatosensory evoked potentials are limited by a low signal to noise ratio. We developed a non-invasive approach based on near-infrared spectroscopy in dual-wavelength (760 and 850 nm for deoxy- or oxyhemoglobin respectively) to record the neurovascular response (NVR) of the peri-spinal vascular network at the 7th cervical and 10th thoracic vertebral levels of the spinal cord, triggered by unilateral median nerve electrical stimulation (square pulse, 5-10 mA, 5 ms, 1 pulse every 4 minutes) at the wrist. Amplitude, rise-time, and duration of NVR were characterized in 20 healthy participants. A single, painless stimulus was able to elicit a high signal-to-noise ratio and multi-segmental NVR (mainly from Oxyhemoglobin) with a fast rise time of 6.18 [4.4-10.4] seconds (median [Percentile 25-75]) followed by a slow decay phase for about 30 seconds toward the baseline. Cervical NVR was earlier and larger than thoracic and no left/right asymmetry was detected. Stimulus intensity/NVR amplitude fitted to a 2nd order function. The characterization and feasibility of the peri-spinal NVR strongly support the potential clinical applications for a functional assessment of spinal cord lesions.
Presynaptic inhibition of the sensory input from the periphery to the spinal cord can be evaluated directly by intra-axonal recording of primary afferent depolarization (PAD) or indirectly by intraspinal microstimulation (excitability testing). Excitability testing is superior for use in normal behaving animals, as this methodology bypasses the technically challenging intra-axonal recording. However, use of excitability testing on the muscle or joint afferent in intact animals presents its own technical challenges. Because these afferents, in many cases, are mixed with motor axons in the peripheral nervous system, it is crucial to dissociate antidromic volleys in the primary afferents from orthodromic volleys in the motor axon, both of which are evoked by intraspinal microstimulation. Here, we demonstrated in rats that application of a paired stimulation protocol with a short interstimulus interval (ISI) successfully dissociated the antidromic volley in the nerve innervating the medial gastrocnemius muscle. Using a 2-ms ISI, the amplitude of the volleys evoked by the second stimulation was decreased in dorsal root-sectioned rats, but the amplitude did not change or slightly increased in ventral root-sectioned rats. Excitability testing in rats with intact spinal roots indicated that the putative antidromic volleys exhibited dominant primary afferent depolarization, which was reasonably induced from the more dorsal side of the spinal cord. We concluded that excitability testing using a paired pulse protocol can be used for studying presynaptic inhibition of somatosensory afferents in animals with intact spinal roots.
The conventional interpretation of spikes is from the perspective of an external observer with knowledge of a neuron's inputs and outputs who is ignorant of the contents of the "black box" that is the neuron. Here we consider a neuron to be an observer and we interpret spikes from the neuron's perspective. We propose both a descriptive hypothesis based on physics and logic, and a prescriptive hypothesis based on biological optimality. Our descriptive hypothesis is that a neuron's membrane excitability is "known" and the amplitude of a future excitatory postsynaptic conductance (EPSG) is "unknown". Therefore excitability is an expectation of EPSG amplitude and a spike is generated only when EPSG amplitude exceeds its expectation ("prediction error"). Our prescriptive hypothesis is that a diversity of synaptic inputs and voltage-regulated ion channels implement "predictive homeostasis", working to insure that the expectation is accurate. The homeostatic ideal and optimal expectation would be achieved when an EPSP reaches precisely to spike threshold, so that spike output is exquisitely sensitive to small variations in EPSG input. To an external observer who knows neither EPSG amplitude nor membrane excitability, spikes would appear random if the neuron is making accurate predictions. We review experimental evidence that spike probabilities are indeed maintained near an average of 0.5 under natural conditions, and we suggest that the same principles may also explain why synaptic vesicle release appears to be "stochastic". Whereas the present hypothesis accords with principles of efficient coding dating back to Barlow (1961), it contradicts decades of assertions that neural activity is substantially "random" or "noisy". The apparent randomness is by design, and like many other examples of apparent randomness, it corresponds to the ignorance of external macroscopic observers about the detailed inner workings of a microscopic system.
The precision of skilled movement depends on sensory feedback and its refinement by local inhibitory microcircuits. One specialized set of spinal GABAergic interneurons forms axo-axonic contacts with the central terminals of sensory afferents, exerting presynaptic inhibitory control over sensory-motor transmission. The inability to achieve selective access to the GABAergic neurons responsible for this unorthodox inhibitory mechanism has left unresolved the contribution of presynaptic inhibition to motor behaviour. We used Gad2 as a genetic entry point to manipulate the interneurons that contact sensory terminals, and show that activation of these interneurons in mice elicits the defining physiological characteristics of presynaptic inhibition. Selective genetic ablation of Gad2-expressing interneurons severely perturbs goal-directed reaching movements, uncovering a pronounced and stereotypic forelimb motor oscillation, the core features of which are captured by modelling the consequences of sensory feedback at high gain. Our findings define the neural substrate of a genetically hardwired gain control system crucial for the smooth execution of movement.
Inhibitory microcircuits are wired with a precision that underlies their complex regulatory roles in neural information processing. In the spinal cord, one specialized class of GABAergic interneurons (GABApre) mediates presynaptic inhibitory control of sensory-motor synapses. The synaptic targeting of these GABAergic neurons exhibits an absolute dependence on proprioceptive sensory terminals, yet the molecular underpinnings of this specialized axoaxonic organization remain unclear. Here, we show that sensory expression of an NB2 (Contactin5)/Caspr4 coreceptor complex, together with spinal interneuron expression of NrCAM/CHL1, directs the high-density accumulation of GABAergic boutons on sensory terminals. Moreover, genetic elimination of NB2 results in a disproportionate stripping of inhibitory boutons from high-density GABApre-sensory synapses, suggesting that the preterminal axons of GABApre neurons compete for access to individual sensory terminals. Our findings define a recognition complex that contributes to the assembly and organization of a specialized GABAergic microcircuit.
Significance
Delta oscillations have been largely associated with slow-wave sleep and anesthesia, when no conscious functions take place during these states. However, our study demonstrates that coherent delta-band oscillations reflect the linkage between distant parietal and frontal cortical circuits during decision making. Thus, these findings open an avenue for investigating whether the activity between distant cortical circuits oscillates in the delta frequency range during other cognitive functions.
In order to understand how nociceptive information is processed in the spinal dorsal horn we need to unravel the complex synaptic circuits involving interneurons, which constitute the vast majority of the neurons in laminae I-III. The main limitation has been the difficulty in defining functional populations among these cells. We have recently identified four non-overlapping classes of inhibitory interneuron, defined by expression of galanin, neuropeptide Y (NPY), neuronal nitric oxide synthase (nNOS) and parvalbumin, in the rat spinal cord. Here we show that these form distinct functional populations that differ in terms of sst2A receptor expression and in their responses to painful stimulation. The sst2A receptor was expressed by nearly all of the nNOS- and galanin-containing inhibitory interneurons, but by few of those with NPY and none of the parvalbumin cells. Many galanin- and NPY-containing cells showed phosphorylated extracellular signal-regulated kinases (pERK) after mechanical, thermal or chemical noxious stimuli, but very few nNOS-containing cells expressed pERK after any of these stimuli. However, many nNOS-positive inhibitory interneurons up-regulated Fos following noxious thermal stimulation or injection of formalin, but not after capsaicin injection. Parvalbumin cells did not express either activity-dependent marker following any of these stimuli. These results suggest that interneurons belonging to the NPY, nNOS and galanin populations are involved in attenuating pain, and for NPY and nNOS cells this is likely to result from direct inhibition of nociceptive projection neurons. They also suggest that the nociceptive inputs to the nNOS cells differ from those to the galanin and NPY populations.
The relation between large-scale brain structure and function is an outstanding open problem in neuroscience. We approach this problem by studying the dynamical regime under which realistic spatiotemporal patterns of brain activity emerge from the empirically derived network of human brain neuroanatomical connections. The results show that critical dynamics unfolding on the structural connectivity of the human brain allow the recovery of many key experimental findings obtained from functional magnetic resonance imaging, such as divergence of the correlation length, the anomalous scaling of correlation fluctuations, and the emergence of large-scale resting state networks.
Callosal axon projections are among the major long-range axonal projections in the mammalian brain. They are formed during the prenatal and early postnatal periods in the mouse, and their development relies on both activity-independent and -dependent mechanisms. In this paper, we review recent findings about the roles of neuronal activity in callosal axon projections. In addition to the well-documented role of sensory-driven neuronal activity, recent studies using in utero electroporation demonstrated an essential role of spontaneous neuronal activity generated in neonatal cortical circuits. Both presynaptic and postsynaptic neuronal activities are critically involved in the axon development. Studies have begun to reveal intracellular signaling pathway which works downstream of neuronal activity. We also review several distinct patterns of neuronal activity observed in the developing cerebral cortex, which might play roles in activity-dependent circuit construction. Such neuronal activity during the neonatal period can be disrupted by genetic factors, such as mutations in ion channels. It has been speculated that abnormal activity caused by such factors may affect activity-dependent circuit construction, leading to some developmental disorders. We discuss a possibility that genetic mutation in ion channels may impair callosal axon projections through an activity-dependent mechanism.
In the spinal cord of the anesthetized cat, spontaneous cord dorsum potentials (CDPs) appear synchronously along the lumbo-sacral segments. These CDPs have different shapes and magnitudes. Previous work has indicated that some CDPs appear to be specially associated with the activation of spinal pathways that lead to primary afferent depolarization and presynaptic inhibition. Visual detection and classification of these CDPs provides relevant information on the functional organization of the neural networks involved in the control of sensory information and allows the characterization of the changes produced by acute nerve and spinal lesions. We now present a novel feature extraction approach for signal classification, applied to CDP detection. The method is based on an intuitive procedure. We first remove by convolution the noise from the CDPs recorded in each given spinal segment. Then, we assign a coefficient for each main local maximum of the signal using its amplitude and distance to the most important maximum of the signal. These coefficients will be the input for the subsequent classification algorithm. In particular, we employ gradient boosting classification trees. This combination of approaches allows a faster and more accurate discrimination of CDPs than is obtained by other methods.
Key points
Perception of normal bodily sensations relies on the precise regulation of sensory information entering the dorsal horn of the spinal cord.
Inhibitory, axoaxonic, synapses provide a mechanism for this regulation, but the source of these important inhibitory connections remains to be elucidated.
This study shows that a subpopulation of spinal interneurons that expresses parvalbumin and have specific morphological, connectivity and functional characteristics are a likely source of the inhibitory inputs that selectivity regulate non‐noxious tactile input in the spinal cord.
Our findings suggest that a loss of normal function in parvalbumin positive dorsal horn neurons may result in the development of tactile allodynia, where non‐painful stimuli gain the capacity to evoke the sensation of pain.
Abstract Axo‐axonic synapses on the central terminals of primary afferent fibres modulate sensory input and are the anatomical correlate of presynaptic inhibition. Although several classes of primary afferents are under such inhibitory control, the origin of these presynaptic inputs in the dorsal horn is unknown. Here, we characterize the neurochemical, anatomical and electrophysiological properties of parvalbumin (PV)‐expressing cells in wild‐type and transgenic mice where enhanced green fluorescent protein (eGFP) is expressed under the PV promoter. We show that most PV cells have either islet or central cell‐like morphology, receive inputs from myelinated primary afferent fibres and are concentrated in laminae II inner and III. We also show that inhibitory PV terminals in lamina II inner selectively target the central terminals of myelinated afferents (∼80% of 935 PVeGFP boutons) and form axo‐axonic synapses (∼75% of 71 synapses from PV boutons). Targeted whole‐cell patch‐clamp recordings from PVeGFP positive cells in laminae II and III showed action potential discharge was restricted to the tonic firing and initial bursting patterns (67% and 33% respectively; n = 18), and virtually all express I h subthreshold voltage‐gated currents (94%; n = 18). These neurons show higher rheobase current than non‐eGFP cells but respond with high frequency action potential discharge upon activation. Together, our findings show that PV neurons in laminae II and III are a likely source of inhibitory presynaptic input on to myelinated primary afferents. Consequently PV cells are ideally placed to play an important role in the development of central sensitization and tactile allodynia.
The analysis of the interaction and synchronization of relatively large ensembles of neurons is fundamental for the understanding of complex functions of the nervous system. It is known that the temporal synchronization of neural ensembles is involved in the generation of specific motor, sensory or cognitive processes. Also, the intersegmental coherence of spinal spontaneous activity may indicate the existence of synaptic neural pathways between different pairs of lumbar segments. In this study we present a multichannel version of the detrended fluctuation analysis method (mDFA) to analyze the correlation dynamics of spontaneous spinal activity (SSA) from time series analysis. This method together with the classical detrended fluctuation analysis (DFA) were used to find out whether the SSA recorded in one or several segments in the spinal cord of the anesthetized cat occurs either in a random or in an organized manner. Our results are consistent with a non-random organization of the sets of neurons involved in the generation of spontaneous cord dorsum potentials (CDPs) recorded either from one lumbar segment (DFA-α mean = 1.04[Formula: see text]0.09) or simultaneously from several lumbar segments (mDFA-α mean = 1.01[Formula: see text]0.06), where α = 0.5 indicates randomness while α = 0.5 indicates long-term correlations. To test the sensitivity of the mDFA method we also examined the effects of small spinal lesions aimed to partially interrupt connectivity between neighboring lumbosacral segments. We found that the synchronization and correlation between the CDPs recorded from the L5 and L6 segments in both sides of the spinal cord were reduced when a lesion comprising the left dorsal quadrant was performed between the segments L5 and L6 (mDFA-[Formula: see text] = 0.992 as compared to initial conditions mDFA-α = 1.186). The synchronization and correlation were reduced even further after a similar additional right spinal lesion (mDFA-α = 0.924). In contrast to the classical methods, such as correlation and coherence quantification that define a relation between two sets of data, the mDFA method properly reveals the synchronization of multiple groups of neurons in several segments of the spinal cord. This method is envisaged as a useful tool to characterize the structure of higher order ensembles of cord dorsum spontaneous potentials after spinal cord or peripheral nerve lesions.
Although it is widely recognized that adaptive behavior emerges from the ongoing interactions among the nervous system, the body, and the environment, it has only become possible in recent years to experimentally study and to simulate these interacting systems. We briefly review work on molluscan feeding, maintenance of postural control in cats and humans, simulations of locomotion in lamprey, insect, cat and salamander, and active vibrissal sensing in rats to illustrate the insights that can be derived from studies of neural control and sensing within a biomechanical context. These studies illustrate that control may be shared between the nervous system and the periphery, that neural activity organizes degrees of freedom into biomechanically meaningful subsets, that mechanics alone may play crucial roles in enforcing gait patterns, and that mechanics of sensors is crucial for their function.
Latencies of presynaptic depolarization of group I muscle afferents and cutaneous afferents have been reinvestigated in an attempt to define the minimal number of interneurons interposed in the pathways of the presynaptic depolarization. Intra-axonal records from individual afferents, records of dorsal root potentials, and measurements of changes in excitability of individual afferents were used for this purpose. Some of the animals were treated with 4-aminopyridine to facilitate transmission via neuronal pathways. The minimal segmental latencies were measured relative to afferent volleys evoked by single electrical stimuli applied to peripheral nerves and to the second of a pair of stimuli. Due to subthreshold facilitatory effects of the first stimulus, the responses to the second stimulus appeared at a reduced latency. The minimal latencies of primary afferent depolarization found in this way were 1.7-2.0 ms. They were similar for group I and cutaneous afferents and in both cases compatible with a trisynaptic pathway (two interposed interneurons). Primary afferent depolarization was also evoked by local intraspinal stimuli applied in the dorsal horn, in the intermediate zone, and in the ventral horn to define the location of the last-order interneurons mediating depolarization group I and cutaneous afferents. Lowest threshold responses appearing with the shortest latencies (about 0.8 ms) and attributed to activation of the last-order interneurons were found when stimulating fairly restricted areas: within laminae V-VI for group I afferents and within laminae III-IV for cutaneous afferents. Both areas corresponded to the regions where the largest monosynaptic field potentials were evoked by fibers receiving the presynaptic depolarization. It is thus proposed that both the first- and last-order interneurons of the pathways may be located within these areas.
The detection of neural spike activity is a technical challenge that is a prerequisite for studying many types of brain function. Measuring the activity of individual neurons accurately can be difficult due to large amounts of background noise and the difficulty in distinguishing the action potentials of one neuron from those of others in the local area. This article reviews algorithms and methods for detecting and classifying action potentials, a problem commonly referred to as spike sorting. The article first discusses the challenges of measuring neural activity and the basic issues of signal detection and classification. It reviews and illustrates algorithms and techniques that have been applied to many of the problems in spike sorting and discusses the advantages and limitations of each and the applicability of these methods for different types of experimental demands. The article is written both for the physiologist wanting to use simple methods that will improve experimental yield and minimize the selection biases of traditional techniques and for those who want to apply or extend more sophisticated algorithms to meet new experimental challenges.
Extracellular recordings of neuronal activity made in the lumbosacral spinal segments of the anesthetized cat have disclosed the existence of a set of neurons in Rexed's laminae III-VI that discharged in a highly synchronized manner during the occurrence of spontaneous negative cord dorsum potentials (nCDPs) and responded to stimulation of low-threshold cutaneous fibers (<1.5x T) with mono- and polysynaptic latencies. The cross-correlation between the spontaneous discharges of pairs of synchronic neurons was highest when they were close to each other, and decreased with increasing longitudinal separation. Simultaneous recordings of nCDPs from several segments in preparations with the peripheral nerves intact have disclosed the existence of synchronized spontaneous nCDPs in segments S1-L4. These potentials lasted between 25 and 70 ms and were usually larger in segments L7-L5, where they attained amplitudes between 50 and 150 micro V. The transection of the intact ipsilateral hindlimb cutaneous and muscle nerves, or the section of the dorsal columns between the L5 and L6, or between the L6 and L7 segments in preparations with already transected nerves, had very small effects on the intersegmental synchronization of the spontaneous nCDPs and on the power spectra of the cord dorsum potentials recorded in the lumbosacral enlargement. In contrast, sectioning the ipsilateral dorsal horn and the dorsolateral funiculus at these segmental levels strongly decoupled the spontaneous nCDPs generated rostrally from those generated caudally to the lesion and reduced the magnitude of the power spectra throughout the whole frequency range. These results indicate that the lumbosacral intersegmental synchronization between the spontaneous nCDPs does not require sensory inputs and is most likely mediated by intra- and intersegmental connections. It is suggested that the occurrence of spontaneous synchronized nCDPs is due to the activation of tightly coupled arrays of neurons, each comprising one or several spinal segments. This system of neurons could be involved in the modulation of the information transmitted by cutaneous and muscle afferents to functionally related, but rostrocaudally distributed spinal interneurons and motoneurons, as well as in the selection of sensory inputs during the execution of voluntary movements or during locomotion.
Single-unit exploration of the dorsal horn of segments L4-S2 of unanesthetized cats with the neuraxis transected at lower thoracic levels reveals a somototopic organization in the horizontal plane. The dorsal horn dermatomes correspond closely to the dermatomes of the corresponding dorsal roots, and the ML gradient is equally well described by two different projection schemes: a distoproximal gradient and a ventrodorsal one (5, 33). There is no evidence of segmental discontinuity of the map. As is the case in other nuclear regions of the CNS, the relative area devoted to projections from the foot is disproportionately large relative to the area devoted to skin regions of similar size which are located more proximally on the limb. From our data, and from the close correspondence to anatomical data obtained by others, we suggest that at least some cutaneous afferent fibers from a given skin area project directly to any dorsal horn region where that skin area is represented. This assumption, together with the organization of the dorsal horn map, yields a model which predicts a precise somatotopic organization of presynaptic neuropil in the substantia gelatinosa.
Transmission of information is an important function of cortical neurons, so it is conceivable that they have evolved to transmit information efficiently, with low noise and high temporal precision. Such precision is consistent with the output generated by various working models that mimick neuronal activity, from simple integrate-and-fire models to elaborate numerical simulations of realistic-looking neurons. But our current inability to match this data with neurons' detailed spike-generating mechanisms in vivo allows us a wide latitude in interpreting the significance of the various components of their spike code. One extreme hypothesis, the 'simple' model, is that each neuron is noisy and slow, performing a simple computation and transmitting a small amount of information. A competing hypothesis, the 'efficient' model, postulates that a neuron transmits large amounts of information through precise, complex, single-spike computations. Both hypotheses are broadly consistent with the available data. The conflict may only be resolved with the development of new measurement techniques that will allow one to investigate directly the properties that make a neuron efficient--that is, to be able to measure highly transient, localized events inside the thinnest dendrites, which are currently experimentally inaccessible.
The detection of neural spike activity is a technical challenge that is a prerequisite for studying many types of brain function. Measuring the activity of individual neurons accurately can be difficult due to large amounts of background noise and the difficulty in distinguishing the action potentials of one neuron from those of others in the local area. This article reviews algorithms and methods for detecting and classifying action potentials, a problem commonly referred to as spike sorting. The article first discusses the challenges of measuring neural activity and the basic issues of signal detection and classification. It reviews and illustrates algorithms and techniques that have been applied to many of the problems in spike sorting and discusses the advantages and limitations of each and the applicability of these methods for different types of experimental demands. The article is written both for the physiologist wanting to use simple methods that will improve experimental yield and minimize the selection biases of traditional techniques and for those who want to apply or extend more sophisticated algorithms to meet new experimental challenges.
Recent advances in techniques, especially the intraneuronal injection of the enzyme horseradish peroxidase, have led to a new era in our understanding of spinal cord structure and function. Input to the cord is precisely organized: the primary afferent fibres from different types of receptors distribute their anatomically specific collaterals to particular parts of the dorsal horn, afferent fibres from the skin lay down a precise somatotopic map, input to the dorsal horn from descending systems is also distributed in a localized way. The neurones of the dorsal horn are varied in both structure and function, even so some quite specific cell types can be identified and the dendritic trees may respect laminar boundaries as determined cytoarchitectonically (although the majority of neurones have dendrites that cut across these boundaries). The output pathways from the dorsal horn are many and various, but again they arise from cells in definite parts of the dorsal horn. The dorsal horn must be considered as a well-organized, and complex, part of the central nervous system. It cannot be considered as a structural or functional unit but is made up of many interacting parts that process input from the primary afferent fibres, from other levels of the spinal cord and from many descending pathways from the brain.
Title: Characterization of dorsal horn neuronal ensembles generating different patterns of spontaneous cord dorsum potentials in the cat spinal cord. We examined in the anesthetized cat the organization of dorsal horn neurons generating spontaneous cord dorsum potentials bilaterally in the lumbosacral segments. Predetermined templates were used to select, from segments L5 or L6, spontaneous negative cord dorsum potentials lasting 45-50 ms (nCDP's), negative potentials followed by positive waves lasting 60-100 (npCDP's), or slow positive potentials lasting 40-60 ms (pCDP's). These potentials were used as reference to disclose spontaneous CDP´s appearing in synchrony in other lumbosacral segments. Analysis of the associated intraspinal field potentials (IFP's) showed that the reference CDP's were generated within the dorsal horn. Spontaneous dorsal root potentials (DRP's) appeared synchronized with the reference npCDP's, but not with the reference nCDP's or pCDP's. The IFP's and the DRP's produced by activation of low-threshold cutaneous afferents were facilitated during nCDP's and the negative phase of the npCDP's. They were inhibited during the positive phase of the npCDP's and during the pCDP's. Spontaneous CDP's recorded from neighboring segments in the same side were partially decoupled by an interposed lesion of the ipsilateral dorsolateral quadrant, and entirely by a similar contralateral lesion. It is suggested that the spontaneous nCDP's are generated by activation of first order dorsal horn neurons. The spontaneous npCDP's would be probably due to activation of other sets of dorsal horn neurons connected to the PAD-mediating interneurons, and the pCDP's to inhibitory neurons acting on first order interneurons in the cutaneous pathway. We are now investigating the features of individual dorsal horn neurons that are excited (or inhibited) in synchrony with different types of CDP's to determine if these neurons are part of a distributed system or if they are grouped in discrete, moderately coupled aggregates.
P values, the 'gold standard' of statistical validity, are not as reliable as many scientists assume.
We describe here an automatic selection method
to retrieve spontaneous cord dorsum potentials from the spinal
cord in the anesthetized cat. Previous studies have indicated
that some of these potentials appear synchronized in several
spinal segments and are generated by the activation of specific
sets of dorsal horn neurons. Since their synchronization is
affected in a characteristic manner by acute peripheral nerve
and spinal lesions, as well as during capsaicin-induced skin
inflammation, they can be used to describe the patterns of
functional interconnectivity between specific sets of dorsal horn
neurons, which makes them of potential clinical interest.
Key points
We investigated, in the anaesthetized cat, the effects of acute section of the saphenous and superficial peroneal nerves on the synaptic effectiveness of the sural nerve afferents.
We found that acute section of these nerves produced a long‐lasting increase of the sural‐evoked field potentials. At the same time, sural afferents ending within Rexed's laminae III–IV showed a reduced tonic primary afferent depolarization, while sural afferents projecting deeper into the dorsal horn (Rexed's laminae V–VI) instead showed increased tonic primary afferent depolarization.
It is suggested that a differential control of the synaptic effectiveness of the low‐threshold cutaneous afferents according to their sites of termination within the dorsal horn provides means for a selective processing of sensory information in response to tactile and nociceptive stimulation or during the execution of different motor tasks.
Abstract In the anaesthetized cat, the acute section of the saphenous (Saph) and/or the superficial peroneal (SP) nerves was found to produce a long‐lasting increase of the field potentials generated in the dorsal horn by stimulation of the medial branch of the sural (mSU) nerve. This facilitation was associated with changes in the level of the tonic primary afferent depolarization (PAD) of the mSU intraspinal terminals. The mSU afferent fibres projecting into Rexed's laminae III–IV were subjected to a tonic PAD that was reduced by the acute section of the SP and/or the Saph nerves. The mSU afferents projecting deeper into the dorsal horn (Rexed's laminae V–VI) were instead subjected to a tonic PAD that was increased after Saph and SP acute nerve section. A differential control of the synaptic effectiveness of the low‐threshold cutaneous afferents according to their sites of termination within the dorsal horn is envisaged as a mechanism that allows selective processing of sensory information in response to tactile and nociceptive stimulation or during the execution of different motor tasks.
Experimental biologists, their reviewers and their publishers must grasp
basic statistics, urges David L. Vaux, or sloppy science will continue
to grow.
In acute rat spinal cord slices, the application of capsaicin (5 μm, 90 s), an agonist of transient receptor potential vanilloid 1 receptors expressed by a subset of nociceptors that project to laminae I-II of the spinal cord dorsal horn, induced an increase in the frequency of spontaneous excitatory and spontaneous inhibitory postsynaptic currents in about half of the neurons in laminae II, III-IV and V. In the presence of tetrodotoxin, which blocks action potential generation and polysynaptic transmission, capsaicin increased the frequency of miniature excitatory postsynaptic currents in only 30% of lamina II neurons and had no effect on the frequency of miniature excitatory postsynaptic currents in laminae III-V or on the frequency of miniature inhibitory postsynaptic currents in laminae II-V. When the communication between lamina V and more superficial laminae was interrupted by performing a mechanical section between laminae IV and V, capsaicin induced an increase in spontaneous excitatory postsynaptic current frequency in laminae II-IV and an increase in spontaneous inhibitory postsynaptic current frequency in lamina II that were similar to those observed in intact slices. However, in laminae III-IV of transected slices, the increase in spontaneous inhibitory postsynaptic current frequency was virtually abolished. Our results indicate that nociceptive information conveyed by transient receptor potential vanilloid 1-expressing nociceptors is transmitted from lamina II to deeper laminae essentially by an excitatory pathway and that deep laminae exert a 'feedback' control over neurons in laminae III-IV by increasing inhibitory synaptic transmission in these laminae. Moreover, we provide evidence that laminae III-IV might play an important role in the processing of nociceptive information in the dorsal horn.
Key points
We have examined the functional organization of the neuronal ensembles involved in the generation of spontaneous cord dorsum potentials in the lumbo‐sacral spinal cord of the anaesthetized cat.
These potentials appear synchronously along several spinal segments and are generated by a longitudinally distributed network of bilaterally interconnected sets of dorsal horn neurones.
Low levels of synchronization of spontaneous neuronal activity within this network appear associated with activation of spinal pathways mediating glycinergic non‐reciprocal postsynaptic inhibition of motoneurones.
During states of spontaneous increased synchronization, or after the acute section of cutaneous nerves, there is a preferential activation of the GABAergic pathways producing primary afferent depolarization and presynaptic inhibition of muscle and cutaneous afferents.
It is suggested that modulation of the temporal synchronization of spontaneous activity of dorsal horn neurones might provide means for selection of alternatively operating inhibitory spinal pathways during different sensory and motor behaviours.
Glickfeld and colleagues (2009) suggested that single hippocampal interneurones generate field potentials at monosynaptic latencies. We pursued this observation in simultaneous intracellular and multiple extracellular records from the CA3 region of rat hippocampal slices. We confirmed that interneurones evoked field potentials at monosynaptic latencies. Pyramidal cells initiated disynaptic inhibitory field potentials, but did not initiate detectable monosynaptic excitatory fields. We confirmed that inhibitory fields were GABAergic in nature and showed they were suppressed at low external Cl(-), suggesting they originate at postsynaptic sites. Field potentials generated by a single interneuron were detected at multiple sites over distances of more than 800 mum along the stratum pyramidale of the CA3 region. We used arrays of extracellular electrodes to examine amplitude distributions of spontaneous inhibitory fields recorded at sites orthogonal to or along the CA3 stratum pyramidale. Cluster analysis of spatially distributed inhibitory field events let us separate events generated by interneurones terminating on distinct zones of somato-dendritic axis. Events generated at dendritic sites had similar amplitudes but occurred less frequently and had somewhat slower kinetics than perisomatic events generated near the stratum pyramidale. In records from multiple sites in the CA3 stratum pyramidale, we distinguished inhibitory fields that seemed to be initiated by interneurones with spatially distinct axonal arborisations.
Reporting of ethical matters in The Journal is very important. To advise and assist authors, particularly those who may be less familiar with the legislation in the UK, this article sets out the basic principles and methods that should be used and provides many key web sources of information. It addresses the structure of regulations, and introduces the concept of research governance. The UK law is summarized. Advice is given on the format and description of experiments, and common problems addressed. Aspects of human studies are addressed. Ethical considerations of publication such as authorship and originality, and problems such as plagiarism and fabrication are described. Updates will be published regularly.
The aim of the present study was to compare properties of excitatory and inhibitory spinal intermediate zone interneurons in pathways from group I and II muscle afferents in the cat. Interneurons were labelled intracellularly and their transmitter phenotypes were defined by using immunocytochemistry. In total 14 glutamatergic, 22 glycinergic and 2 GABAergic/glycinergic interneurons were retrieved. All interneurons were located in laminae V-VII of the L3-L7 segments. No consistent differences were found in the location, the soma sizes or the extent of the dendritic trees of excitatory and inhibitory interneurons. However, major differences were found in their axonal projections; excitatory interneurons projected either ipsilaterally, bilaterally or contralaterally, while inhibitory interneurons projected exclusively ipsilaterally. Terminal projections of glycinergic and glutamatergic cells were found within motor nuclei as well as other regions of the grey matter which include the intermediate region, laminae VII and VIII. Cells containing GABA/glycine had more restricted projections, principally within the intermediate zone where they formed appositions with glutamatergic axon terminals and unidentified cells and therefore are likely to be involved in presynaptic as well as postsynaptic inhibition. The majority of excitatory and inhibitory interneurons were found to be coexcited by group I and II afferents (monosynaptically) and by reticulospinal neurons (mono- or disynaptically) and to integrate information from several muscles. Taken together the morphological and electrophysiological data show that individual excitatory and inhibitory intermediate zone interneurons may operate in a highly differentiated way and thereby contribute to a variety of motor synergies.
Dorsal horn neurons responding to tactile input were recorded in segments L3-S2 of unanesthetized, low-spinal cats. Single units were characterized with regard to receptive field (RF) location, RF size and shape, spontaneous discharge rate, central delay, and convergence of four tactile afferent types. 1. RF size increased from the toes to the calf region. 2. Length-width ratio increased from the toes to the calf and declined from the calf to the hip. 3. The relation between RF size and position on the limb was independent of segmental and laminar location of the neurons. 4. RF size was positively correlated with spontaneous discharge rate. 5. The relation between RF size and shape and RF position can be interpreted in terms of regional variations in the magnitude of the gradient of representation in the dorsal horn somatotopic map. 6. Central delay was negatively correlated with both RF size and rate of ongoing discharge. 7. There were no statistically significant differences among the laminae with respect to central delay, RF size or shape, ongoing discharge, or convergence combinations of the four tactile afferent systems. 8. Data presented were at variance with Wall's laminar cascading model for laminae IV-VI. Our results suggest that the model should be modified, at least to emphasize monosynaptic tactile input to all three of these laminae.
Single-unit exploration of the dorsal horn of segments L4-S2 of unanesthetized cats with the neuraxis transected at lower thoracic levels reveals a somototopic organization in the horizontal plane. The dorsal horn dermatomes correspond closely to the dermatomes of the corresponding dorsal roots, and the ML gradient is equally well described by two different projection schemes: a distoproximal gradient and a ventrodorsal one (5, 33). There is no evidence of segmental discontinuity of the map. As is the case in other nuclear regions of the CNS, the relative area devoted to projections from the foot is disproportionately large relative to the area devoted to skin regions of similar size which are located more proximally on the limb. From our data, and from the close correspondence to anatomical data obtained by others, we suggest that at least some cutaneous afferent fibers from a given skin area project directly to any dorsal horn region where that skin area is represented. This assumption, together with the organization of the dorsal horn map, yields a model which predicts a precise somatotopic organization of presynaptic neuropil in the substantia gelatinosa.
1. The aim of this study was to investigate the effects of drugs blocking glycinergic and GABAergic transmission on the postsynaptic inhibition of hindlimb motoneurons produced by activation of last-order laminae V-VI interneurons, which are coexcited by muscle and cutaneous afferents and have axonal branches projecting to the Clarke's column. 2. In anesthetized cats with right spinal cord hemisected and both dorsal columns cut between L4 and L5 segments, stimulation of the Clarke's column (CC) at L3-L4 level produced a short-latency, presumably monosynaptic, inhibitory potential that could be recorded either from L7 or S1 ventral rootlets by means of the sucrose-gap technique (iVRP) or intracellularly from hindlimb motoneurons (IPSP). These potentials have been attributed to antidromic activation of a population of last-order interneurons mediating nonreciprocal inhibition of motoneurons. 3. The early iVRP and IPSP produced by CC stimulation was practically abolished 10-20 s after the intravenous injection of strychnine (0.1 mg/kg) and replaced by an excitatory synaptic potential followed by delayed, slow, strychnine-resistant inhibitory potential. 4. Monosynaptic reflexes (MSR) elicited by stimulation of group I gastrocnemius (GS) afferents were inhibited during the occurrence of the CC-iVRP. This inhibition was significantly reduced after intravenous strychnine. On the other hand, the inhibition of the GS-MSR, produced by conditioning stimulation of the posterior biceps and semitendinosus (PBSt) nerve with trains of pulses applied 25-35 ms before the test stimulus, was practically unchanged after the intravenous injection of strychnine. 5. The CC-iVRP and the associated inhibition of GS-MSRs were not significantly affected after the intravenous injection of 0.1 mg/kg of picrotoxin, which clearly reduced the dorsal root potentials (DRP), the late component of the iVRP, and the inhibition of MSRs produced by PBSt volleys. 6. The effect of strychnine and picrotoxin was tested on the monosynaptic iVRP elicited by single intermediate nucleus interneurons that were antidromically activated from the CC and responded both to low-threshold cutaneous fibers and to group I or group II afferents. In three experiments where the interneuronal activity could be kept after the drug injection, it was possible to show that strychnine abolished the interneuronally elicited iVRP, which was replaced by an excitatory synaptic potential with onset preceding the interneuronal activity. In another experiment, it was possible to show that the interneuronally elicited iVRP was not affected by an intra-aortic injection of picrotoxin (0.5 mg/kg) that reduced to one-half the DRP and the iVRP produced by group I PBSt volleys.(ABSTRACT TRUNCATED AT 400 WORDS)
Spike-triggered averaging of dorsal and ventral root potentials was used in anesthetized cats to disclose possible synaptic connections of spinal interneurons in the intermediate nucleus with afferent fibers and/or motoneurons. With this method we have been able to document the existence of a distinct group of interneurons whose activity was associated with the recording of inhibitory potentials in the ventral roots (iVRPs), but not with negative dorsal root potentials (nDRPs). The iVRPs had mean durations of 60.8 +/- 22.1 ms and latencies between 1.7 and 5.1 ms relative to the onset of the interneuronal spikes. Within this group of neurons it was possible to characterize two categories depending on their responses to segmental inputs. Most type A interneurons were mono- or disynaptically activated by group I muscle afferents and polysynaptically by low threshold (1.08-1.69 X T) cutaneous fibers. Type B interneurons were instead polysynaptically activated by group II muscle and by cutaneous fibers with thresholds ranging from 1.02 to 3.1 X T. Whenever tested, both type A and B interneurons could be antidromically activated from Clarke's columns. There was a second group of interneurons whose activity was associated with the generation of both iVRPs and nDRPs. These potentials had mean durations of 107.5 +/- 35.6 and 131.5 +/- 32 ms, respectively, and onset latencies between 1.7 and 6.1 ms. The interneurons belonging to this group, which appear not to send axonal projections to Clarke's column, could be classified in three categories depending on their responses to peripheral inputs. Type C interneurons responded mono- or disynaptically to group I muscle volleys and polysynaptically to intermediate threshold (1.22-2.7 X T) cutaneous afferents. Type D interneurons were polysynaptically activated by group II muscle afferents (2.3-8.5 X T) and by intermediate threshold (1.4-3 X T) cutaneous fibers and type E interneurons only by group I muscle afferents with mono- or disynaptic latencies. A third group of interneurons produced nDRPs without iVRPs. The nDRPs had onset latencies varying from 1.9 to 6.2 ms and mean durations of 130.0 +/- 34.6 ms. These neurons (type F) showed spontaneous and evoked bursts of activity and were not antidromically activated from Clarke's column. They responded to stimulation of low- and intermediate-threshold cutaneous fibers (1.04-2.9 X T) with mono- and polysynaptic latencies, but not by group I muscle fibers. Type F interneurons appear to be located in more superficial layers than all the other interneurons.(ABSTRACT TRUNCATED AT 400 WORDS)
Single-unit recordings from 312 units of lamina I-VII of the lumbar spinal cord of unanesthetized, decerebrate, T8 spinal cats were used to determine the somatotopic and laminar organization of spinal neurons responding to cutaneous stimulation of the hindlimb. Properties of cells confined to different Rexed laminae (I-VII) were shown to differ in several respects, including responses to variations in stimulus intensity, receptive-field areas, spontaneous frequencies, and central delays. Spinal cord neurons with similarly localized cutaneous receptive fields were found to be organized in sagittally oriented rectangular columns. These columns were 7 to at least 20 mm long (rostral-caudal axis), 0.5-1.0 mm wide, and could encompass laminae I-VII in depth. Touch, pressure, and pinch were effective excitatory inputs into each column subserving a given receptive-field location. A map of the somatotopic organization of units in the horizontal plane is presented, which in general confirms previous reports and in particular deals with the organization of units with receptive fields on the plantar cushion and individual toes.
Recent advances in techniques, especially the intraneuronal injection of the enzyme horseradish peroxidase, have led to a new ear in our understanding of spinal cord structure and function. Input to the cord is precisely organized: the primary afferent fibres from different types of receptors distribute their anatomically specific collaterals to particular parts of the dorsal horn, afferent fibres from the skin lay down a precise somatotopic map, input to the dorsal horn from descending systems is also distributed in a localized way. The neurones of the dorsal horn are varied in both structure and function, even so some quite specific cell types can be identified and the dendritic trees may respect laminar boundaries as determined cytoarchitectonically (although the majority of neurones have dendrites that cut across these boundaries). The output pathways from the dorsal horn are many and various, but again they arise from cells in definite parts of the dorsal horn. The dorsal horn must be considered as a well-organized, and complex, part of the central nervous system. It cannot be considered as a structural or functional unit but is made up of many interacting parts that process input from the primary afferent fibres, from other levels of the spinal cord and from many descending pathways from the brain.
Current knowledge of spinal processing of sensory information is largely based on single-cell recordings; however, temporal correlation of multiple cell discharges may play an important role in sensory encoding, and single electrode recordings of several neurons may provide insights into the functions of a neuronal network. The technique was applied to the lumbar spinal dorsal horn of pentobarbital-anaesthetized rats during background activity, steady-state noxious heat stimulation (48 degrees C, 100 s), cold block spinalization or radiant heat-induced inflammation of the skin, and the recordings were evaluated by means of auto-correlation, autospectral and cross-correlation analysis. Background patterns obtained by these three methods were extremely stable in time. Autocorrelation with short lag peaks was observed in 72.2% of neurons (n = 223). Background correlated discharges were found in 83.6% of the neuron pairs (n = 134). Cross-correlation with a central peak, suggestive of common input to the recorded cells, was the most common pattern observed in almost all laminae and was associated with high incidence (91.8%) of overlapping receptive fields and with neurons with initial peak autocorrelation pattern. Cross-correlations with central trough were associated with increase autocorrelation patterns. Bilateral peaks in cross-correlation, suggestive of reverberating circuitry, were observed only for pairs of neurons located in laminae IV and V and were associated with rhythmic discharges in one or in both simultaneously-recorded neurons. Lagged peaks or troughs were observed in 4.6% and 2.2% of neuronal pairs, respectively. Long-lasting skin heating induced qualitative changes (pattern changes) in the cross-correlation of 21.6% of the neuron pairs and quantitative changes in 85.7% of them. During skin inflammation qualitative changes in the cross-correlation pattern were observed in 30.8% of the neuron pairs, and quantitative changes (strength and/or synchronization time) in about 57.7% of them. Spinalization induced quantitative changes in cross-correlation in the vast majority of neuron pairs. The results of the present study suggest that discharges of neighbouring spinal dorsal horn neurons are strongly synchronized probably by propriospinal and primary afferent sources. The existence of functional reverberating circuitry was also evidenced. Finally, the functional synchronicity in the spinal dorsal horn presents stimulus-induced plasticity which consists mainly of changes on the strength and/or time of the synchronization and rarely of activation of new connectivities.
Dorsal root potentials (DRPs) and dorsal cord potentials (DCPs) were recorded from the lumbar spinal cord in anaesthetised rats. With the spinal cord intact, low-voltage low-frequency spontaneous DRPs were recorded in synchrony on all lumbar dorsal roots. When the cord was cut at T12, spontaneous large-voltage approximately 10 Hz DRPs appeared immediately in synchrony on all dorsal roots. Section of the dorsolateral funiculus (DLF) was necessary to release these 10 Hz waves. They persisted unchanged for at least 2 h and were not affected by section of all lumbar, sacral and coccygeal dorsal roots. Selective transverse lesions were made to locate the fibres responsible for the synchrony of the oscillations of DRPs recorded on L1 and L6 dorsal roots. Synchrony was maintained with lesions of the entire cord medial to the Lissauer tract but disappeared when the lesion was extended to include the Lissauer tract. We conclude that the isolated cord contains a synchronous oscillatory mechanism inhibited by impulses descending in the DLF and synchronised by way of intrinsic axons in the Lissauer tract.
Simultaneous recordings of 135 pairs of units, located respectively in the superficial (I-IIo) and deep (V) laminae of the dorsal horn of the lumbar spinal cord of anaesthetized and paralysed animals, were performed both from normal (62 pairs) and from peripherally injured (chronically constricted sciatic nerve) rats (73 pairs). In each pair, one neuron was classified as nociceptive, responding only to noxious stimuli, and the other as a wide dynamic range neuron, responding to both non-noxious and noxious stimuli. To understand if some interaction was present between diverse neurons modulated by noxious inputs, we used cross-correlation techniques. The responses of simultaneously recorded pairs of units to suprathreshold (5 mA, 0.5 ms) electrical stimuli were used. A clearly delayed peak in the cross-correlograms of recordings from normal animals was present, indicating connectivity of superficial and deep-layer cells. This feature was not present in the cross-correlograms obtained from nerve-injured animals. Even if a specific pathway cannot be explicitly assigned to support these functional results, an overall connection between superficial and deep layers of the spinal cord is suggested. These connections are supposed to be either inactive or rearranged in the nerve-injured rats, thus suppressing a well timed coordinated connectivity. This anomaly could underlie a reduced degree of functional coherence in the modulation of nociceptive spinal inputs in cases of chronic pain.
Peaks in spike train correlograms are usually taken as indicative of spike timing synchronization between neurons. Strictly speaking, however, a peak merely indicates that the two spike trains were not independent. Two biologically plausible ways of departing from independence that are capable of generating peaks very similar to spike timing peaks are described here: covariations over trials in response latency and covariations over trials in neuronal excitability. Since peaks due to these interactions can be similar to spike timing peaks, interpreting a correlogram may be a problem with ambiguous solutions. What peak shapes do latency or excitability interactions generate? When are they similar to spike timing peaks? When can they be ruled out from having caused an observed correlogram peak? These are the questions addressed here. The previous article in this issue proposes quantitative methods to tell cases apart when latency or excitability covariations cannot be ruled out.
This review examines the proposition that state-dependent modulation of transmission through spinal reflex pathways can be used as an investigative tool to reveal details about the organization of spinal interneurons into functional circuits. The first set of examples includes the use of spinal and supraspinal lesions, as well as the administration of the drug l-dihydroxyphenylalanine (l-DOPA), to produce different, relatively stable "states" of the central nervous system (CNS), revealing previously unsuspected spinal pathways activated by the flexor reflex afferents (FRA). The second set of examples deals with the use of fictive locomotion and scratching to investigate the organization of oligosynaptic excitatory and inhibitory reflex pathways from cutaneous and muscle afferents. As in the first set of examples, several hitherto unknown reflex pathways have been found only during the flexion or extension phases of rhythmic locomotion, which are regarded as different CNS states. Differences in the patterns of control can be used to infer the existence of distinct sets of reflex pathway interneurons that have remarkably precise input/output relations.
We examined, in the anaesthetised cat, the influence of the neuronal ensembles producing spontaneous negative cord dorsum potentials (nCDPs) on segmental pathways mediating primary afferent depolarisation (PAD) of cutaneous and group I muscle afferents and on Ia monosynaptic activation of spinal motoneurones. The intraspinal distribution of the field potentials associated with the spontaneous nCDPs indicated that the neuronal ensembles involved in the generation of these potentials were located in the dorsal horn of lumbar segments, in the same region of termination of low-threshold cutaneous afferents. During the occurrence of spontaneous nCDPs, transmission from low-threshold cutaneous afferents to second order neurones in laminae III-VI, as well as transmission along pathways mediating PAD of cutaneous and Ib afferents, was facilitated. PAD of Ia afferents was instead inhibited. Monosynaptic reflexes of flexors and extensors were facilitated during the spontaneous nCDPs. The magnitude of the facilitation was proportional to the amplitude of the 'conditioning' spontaneous nCDPs. This led to a high positive correlation between amplitude fluctuations of spontaneous nCDPs and fluctuations of monosynaptic reflexes. Stimulation of low-threshold cutaneous afferents transiently reduced the probability of occurrence of spontaneous nCDPs as well as the fluctuations of monosynaptic reflexes. It is concluded that the spontaneous nCDPs were produced by the activation of a population of dorsal horn neurones that shared the same functional pathways and involved the same set of neurones as those responding monosynaptically to stimulation of large cutaneous afferents. The spontaneous activity of these neurones was probably the main cause of the fluctuations of the monosynaptic reflexes observed under anaesthesia and could provide a dynamic linkage between segmental sensory and motor pathways.
By tradition - and for historical reasons - reflex pathways and interneurones have been named by their dominating sensory input. Later studies have demonstrated that each individual interneurone, as a rule, receives a broad convergence from a large variety of sensory modalities, as well as inputs from one or more descending tracts. It is thus possible that the traditional nomenclature inadvertently has served as a 'straightjacket' for conceptual development in this field. Indeed, there is now much evidence in favour of the view that the many classes of spinal interneurones may be seen as 'functional units' representing different levels of muscle synergies, parts of movements, or even more integrated motor behaviour. Such 'functional units' may be used by (different) descending pathways to mediate the motor commands from the brain and integrate the appropriate (multimodal) sensory feedback into the central command. A given sensory stimulus would then be able to affect the motor output through a number of parallel, or alternative, segmental pathways belonging to different 'functional units'. If this were correct it would indeed be predicted, rather than coming as a surprise, that a given sensory stimulus can result in different outputs - even with a different sign - depending on the preceding selection of active 'functional units', i.e. the type of motor activity initiated by the brain.
Clinical examination of joint position sense and vibration sense can provide important information concerning specific cutaneous sensory receptors, peripheral nerves, dorsal roots, and central nervous system pathways and should be included as a regular component of the neurological examination. Although these sensory modalities share a spinal cord and brainstem pathway, they arise in different receptors and terminate in separate distributions within the thalamus and cerebral cortex. Consequently, both modalities should be tested as part of the neurological examination. Clinical testing of these modalities requires simultaneous stimulation of tactile receptors; hence this review will include information about the receptors and pathways responsible for tactile sensation.
L undberg , A. and O. O scarsson . Three ascending spinal pathways in the dorsal part of the lateral funiculus.
Three pathways with axons ascending in the dorsal part of the lateral funicle have been identified as not belonging to the dorsal spino‐cerebellar tract because the axons could be activated on stimulation of the lateral funicle in L5 below the caudal level of Clarke's column but not antidromically from the anterior cerebellar lobe cortex. One of these pathways is located medial to the dorsal spino‐cerebellar tract and is activated exclusively by tactile stimuli from small skin fields.
It has been established that there is a strong functional link between sensory neural circuits on the two sides of the spinal cord. In one of our recent studies we provided a morphological confirmation of this functional phenomenon, presenting evidence for the presence of a direct commissural connection between the lateral aspects of the dorsal horn on the two sides of the lumbar spinal cord. By using a combination of neural tracing and immunocytochemical detection of neural markers like vesicular glutamate transporters, glutamic acid decarboxylase, glycine transporter, and met-enkephalin (which are characteristic of various subsets of excitatory and inhibitory neurons), we investigated here the distribution, synaptic relations, and neurochemical characteristics of the commissural axon terminals. We found that the cells of origin of commissural fibers in the lateral aspect of the dorsal horn were confined to laminae III-IV and projected to the corresponding area of the contralateral gray matter. Most of the commissural axon terminals established synaptic contacts with dendrites. Axospinous or axosomatic synaptic contacts were found in limited numbers. We demonstrated that interactions among commissural neurons also exist. More than three-fourths of the labeled axon terminals were immunostained for glutamic acid decarboxylase and/or glycine transporter, but none of them showed positive immunoreaction for met-enkephalin and vesicular glutamate transporters. The results indicate that there is a substantial reciprocal commissural synaptic interaction between the lateral aspects of laminae III-IV on the two sides of the lumbar spinal cord and that this pathway may transmit both inhibitory and excitatory signals to their postsynaptic targets.
At any one moment, many neuronal groups in our brain are active. Microelectrode recordings have characterized the activation of single neurons and fMRI has unveiled brain-wide activation patterns. Now it is time to understand how the many active neuronal groups interact with each other and how their communication is flexibly modulated to bring about our cognitive dynamics. I hypothesize that neuronal communication is mechanistically subserved by neuronal coherence. Activated neuronal groups oscillate and thereby undergo rhythmic excitability fluctuations that produce temporal windows for communication. Only coherently oscillating neuronal groups can interact effectively, because their communication windows for input and for output are open at the same times. Thus, a flexible pattern of coherence defines a flexible communication structure, which subserves our cognitive flexibility.