Learning about time within the spinal cord: evidence that spinal neurons can abstract and store an index of regularity

Prior studies have shown that intermittent noxious stimulation has divergent effects on spinal cord plasticity depending upon whether it occurs in a regular [fixed time (FT)] or irregular [variable time (VT)] manner: In spinally transected animals, VT stimulation to the tail or hind leg impaired spinal learning whereas an extended exposure to FT stimulation had a restorative/protective effect. These observations imply that lower level systems are sensitive to temporal relations. Using spinally transected rats, it is shown that the restorative effect of FT stimulation emerges after 540 shocks; fewer shocks generate a learning impairment. The transformative effect of FT stimulation is related to the number of shocks administered, not the duration of exposure. Administration of 360 FT shocks induces a learning deficit that lasts 24 hours. If a second bout of FT stimulation is given a day after the first, it restores the capacity to learn. This savings effect implies that the initial training episode had a lasting (memory-like) effect. Two bouts of shock had a transformative effect when applied at different locations or at difference frequencies, implying spinal systems abstract and store an index of regularity (rather than a specific interval). Implications of the results for step training and rehabilitation after injury are discussed

Impact of Behavioral Control on the Processing of Nociceptive Stimulation

How nociceptive signals are processed within the spinal cord, and whether these signals lead to behavioral signs of neuropathic pain, depends upon their relation to other events and behavior. Our work shows that these relations can have a lasting effect on spinal plasticity, inducing a form of learning that alters the effect of subsequent nociceptive stimuli. The capacity of lower spinal systems to adapt, in the absence of brain input, is examined in spinally transected rats that receive a nociceptive shock to the tibialis anterior muscle of one hind leg. If shock is delivered whenever the leg is extended (controllable stimulation), it induces an increase in flexion duration that minimizes net shock exposure. This learning is not observed in subjects that receive the same amount of shock independent of leg position (uncontrollable stimulation). These two forms of stimulation have a lasting, and divergent, effect on subsequent learning: controllable stimulation enables learning whereas uncontrollable stimulation disables it (learning deficit). Uncontrollable stimulation also enhances mechanical reactivity. We review evidence that training with controllable stimulation engages a brain-derived neurotrophic factor (BDNF)-dependent process that can both prevent and reverse the consequences of uncontrollable shock. We relate these effects to changes in BDNF protein and TrkB signaling. Controllable stimulation is also shown to counter the effects of peripheral inflammation (from intradermal capsaicin). A model is proposed that assumes nociceptive input is gated at an early sensory stage. This gate is sensitive to current environmental relations (between proprioceptive and nociceptive input), allowing stimulation to be classified as controllable or uncontrollable. We further propose that the status of this gate is affected by past experience and that a history of uncontrollable stimulation will promote the development of neuropathic pain

Maladaptive spinal plasticity opposes spinal learning and recovery in spinal cord injury

Synaptic plasticity within the spinal cord has great potential to facilitate recovery of function after spinal cord injury (SCI). Spinal plasticity can be induced in an activity-dependent manner even without input from the brain after complete SCI. A mechanistic basis for these effects is provided by research demonstrating that spinal synapses have many of the same plasticity mechanisms that are known to underlie learning and memory in the brain. In addition, the lumbar spinal cord can sustain several forms of learning and memory, including limb-position training. However, not all spinal plasticity promotes recovery of function. Central sensitization of nociceptive (pain) pathways in the spinal cord may emerge in response to various noxious inputs, demonstrating that plasticity within the spinal cord may contribute to maladaptive pain states. In this review we discuss interactions between adaptive and maladaptive forms of activity-dependent plasticity in the spinal cord below the level of SCI. The literature demonstrates that activity-dependent plasticity within the spinal cord must be carefully tuned to promote adaptive spinal training. Prior work from our group has shown that stimulation that is delivered in a limb position-dependent manner or on a fixed interval can induce adaptive plasticity that promotes future spinal cord learning and reduces nociceptive hyper-reactivity. On the other hand, stimulation that is delivered in an unsynchronized fashion, such as randomized electrical stimulation or peripheral skin injuries, can generate maladaptive spinal plasticity that undermines future spinal cord learning, reduces recovery of locomotor function, and promotes nociceptive hyper-reactivity after SCI. We review these basic phenomena, how these findings relate to the broader spinal plasticity literature, discuss the cellular and molecular mechanisms, and finally discuss implications of these and other findings for improved rehabilitative therapies after SCI

Metaplasticity and behavior: how training and inflammation affect plastic potential within the spinal cord and recovery after injury

Research has shown that spinal circuits have the capacity to adapt in response to training, nociceptive stimulation and peripheral inflammation. These changes in neural function are mediated by physiological and neurochemical systems analogous to those that support plasticity within the hippocampus (e.g., long-term potentiation and the NMDA receptor). As observed in the hippocampus, engaging spinal circuits can have a lasting impact on plastic potential, enabling or inhibiting the capacity to learn. These effects are related to the concept of metaplasticity. Behavioral paradigms are described that induce metaplastic effects within the spinal cord. Uncontrollable/unpredictable stimulation, and peripheral inflammation, induce a form of maladaptive plasticity that inhibits spinal learning. Conversely, exposure to controllable or predictable stimulation engages a form of adaptive plasticity that counters these maladaptive effects and enables learning. Adaptive plasticity is tied to an up-regulation of brain derived neurotrophic factor (BDNF). Maladaptive plasticity is linked to processes that involve kappa opioids, the metabotropic glutamate (mGlu) receptor, glia, and the cytokine tumor necrosis factor (TNF). Uncontrollable nociceptive stimulation also impairs recovery after a spinal contusion injury and fosters the development of pain (allodynia). These adverse effects are related to an up-regulation of TNF and a down-regulation of BDNF and its receptor (TrkB). In the absence of injury, brain systems quell the sensitization of spinal circuits through descending serotonergic fibers and the serotonin 1A (5HT 1A) receptor. This protective effect is blocked by surgical anesthesia. Disconnected from the brain, intracellular Cl- concentrations increase (due to a down-regulation of the cotransporter KCC2), which causes GABA to have an excitatory effect. It is suggested that BDNF has a restorative effect because it up-regulates KCC2 and re-establishes GABA-mediated inhibition

Glial Tumor Necrosis Factor Alpha (TNFα) Generates Metaplastic Inhibition of Spinal Learning

Injury-induced overexpression of tumor necrosis factor alpha (TNFα) in the spinal cord can induce chronic neuroinflammation and excitotoxicity that ultimately undermines functional recovery. Here we investigate how TNFα might also act to upset spinal function by modulating spinal plasticity. Using a model of instrumental learning in the injured spinal cord, we have previously shown that peripheral intermittent stimulation can produce a plastic change in spinal plasticity (metaplasticity), resulting in the prolonged inhibition of spinal learning. We hypothesized that spinal metaplasticity may be mediated by TNFα. We found that intermittent stimulation increased protein levels in the spinal cord. Using intrathecal pharmacological manipulations, we showed TNFα to be both necessary and sufficient for the long-term inhibition of a spinal instrumental learning task. These effects were found to be dependent on glial production of TNFα and involved downstream alterations in calcium-permeable AMPA receptors. These findings suggest a crucial role for glial TNFα in undermining spinal learning, and demonstrate the therapeutic potential of inhibiting TNFα activity to rescue and restore adaptive spinal plasticity to the injured spinal cord. TNFα modulation represents a novel therapeutic target for improving rehabilitation after spinal cord injury

Hemodynamic responses to speech and music in preverbal infants.

Numerous studies have provided clues about the ontogeny of lateralization of auditory processing in humans, but most have employed specific subtypes of stimuli and/or have assessed responses in discrete temporal windows. The present study used near-infrared spectroscopy (NIRS) to establish changes in hemodynamic activity in the neocortex of preverbal infants (aged 4-11 months) while they were exposed to two distinct types of complex auditory stimuli (full sentences and musical phrases). Measurements were taken from bilateral temporal regions, including both anterior and posterior superior temporal gyri. When the infant sample was treated as a homogenous group, no significant effects emerged for stimulus type. However, when infants' hemodynamic responses were categorized according to their overall changes in volume, two very clear neurophysiological patterns emerged. A high-responder group showed a pattern of early and increasing activation, primarily in the left hemisphere, similar to that observed in comparable studies with adults. In contrast, a low-responder group showed a pattern of gradual decreases in activation over time. Although age did track with responder type, no significant differences between these groups emerged for stimulus type, suggesting that the high- versus low-responder characterization generalizes across classes of auditory stimuli. These results highlight a new way to conceptualize the variable cortical blood flow patterns that are frequently observed across infants and stimuli, with hemodynamic response volumes potentially serving as an early indicator of developmental changes in auditory-processing sensitivity

Hemodynamic responses to speech and music in preverbal infants.

Numerous studies have provided clues about the ontogeny of lateralization of auditory processing in humans, but most have employed specific subtypes of stimuli and/or have assessed responses in discrete temporal windows. The present study used near-infrared spectroscopy (NIRS) to establish changes in hemodynamic activity in the neocortex of preverbal infants (aged 4-11 months) while they were exposed to two distinct types of complex auditory stimuli (full sentences and musical phrases). Measurements were taken from bilateral temporal regions, including both anterior and posterior superior temporal gyri. When the infant sample was treated as a homogenous group, no significant effects emerged for stimulus type. However, when infants' hemodynamic responses were categorized according to their overall changes in volume, two very clear neurophysiological patterns emerged. A high-responder group showed a pattern of early and increasing activation, primarily in the left hemisphere, similar to that observed in comparable studies with adults. In contrast, a low-responder group showed a pattern of gradual decreases in activation over time. Although age did track with responder type, no significant differences between these groups emerged for stimulus type, suggesting that the high- versus low-responder characterization generalizes across classes of auditory stimuli. These results highlight a new way to conceptualize the variable cortical blood flow patterns that are frequently observed across infants and stimuli, with hemodynamic response volumes potentially serving as an early indicator of developmental changes in auditory-processing sensitivity

Neurobiological Consequences of Early Painful Experience: Basic Science Findings and Implications for Evidence-Based Practice

As healthcare teams have worked to improve infant survival rates, the management of painful events experienced by these hospitalized neonates has increased and yet pain management remains highly variable between healthcare institutions. At the same time, emerging evidence suggests that these early painful experiences may alter the trajectory of development for pain-processing pathways both peripherally and centrally. This concise review highlights findings from both the basic and clinical science literature supporting the hypothesis that early painful experiences can have long-lasting negative effects on biological, psychological, and socioemotional functions. Implications for pain management in neonates and considerations for evidence-based practice change are discussed