Journal of neurophysiology
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Gain-of-function variants in voltage-gated sodium channel NaV1.7 that increase firing frequency and spontaneous firing of dorsal root ganglion (DRG) neurons have recently been identified in 5-10% of patients with idiopathic small fiber neuropathy (I-SFN). Our previous in vitro observations suggest that enhanced sodium channel activity can contribute to a decrease in length of peripheral sensory axons. We have hypothesized that sustained sodium influx due to the expression of SFN-associated sodium channel variants may trigger an energetic deficit in neurons that contributes to degeneration and loss of nerve fibers in SFN. ⋯ We demonstrate reduced steady-state ATP levels, faster depolarization-evoked ATP decay, and reduced mitochondrial density and size in cultured DRG neurons expressing SFN-associated variant NaV1.7 I228M. Dexpramipexole, which improves mitochondrial energy metabolism, has a protective effect. Because gain-of-function NaV1.7 variants can compromise bioenergetics, therapeutic strategies that target bioenergetic burden and mitochondrial damage merit study in SFN.
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Spinal cord stimulation (SCS) is used clinically to limit chronic pain, but fundamental questions remain on the identity of axonal populations recruited. We developed an ex vivo adult mouse spinal cord preparation to assess recruitment following delivery of clinically analogous stimuli determined by downscaling a finite element model of clinical SCS. Analogous electric field distributions were generated with 300-µm × 300-µm electrodes positioned 200 µm above the dorsal column (DC) with stimulation between 50 and 200 µA. ⋯ To identify axonal populations recruited, finite element modeling identified scaling parameters to deliver clinically analogous SCS in an ex vivo adult mouse spinal cord preparation. Results showed that SCS first recruited an axonal population in the dorsal column at a threshold severalfold lower than primary afferents. These putative postsynaptic dorsal column tract cells may represent a previously unconsidered population responsible for SCS-induced paresthesias necessary for analgesia.
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Heightened pain sensitivity, the amount of pain experienced in response to a noxious event, is a known risk factor for development of chronic pain. We have previously reported that pain-free, sensorimotor peak alpha frequency (PAF) is a reliable biomarker of pain sensitivity for thermal, prolonged pains lasting tens of minutes. To test whether PAF can provide information about pain sensitivity occurring over clinically relevant timescales (i.e., weeks), EEG was recorded before and while participants experienced a long-lasting pain model, repeated intramuscular injection of nerve growth factor (NGF), that produces progressively developing muscle pain for up to 21 days. ⋯ NEW & NOTEWORTHY Pain sensitivity, the intensity of pain experienced after injury, has been identified as an important risk factor in the development of chronic pain. Biomarkers of pain sensitivity have the potential to ease chronic pain burdens by preventing disease emergence. In the current study, we demonstrate that the speed of pain-free, sensorimotor peak alpha frequency recorded during resting-state EEG predicts pain sensitivity to a clinically-relevant, human model of prolonged pain that persists for weeks.
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Neural stimulation leads to increases in cerebral blood flow (CBF), but simultaneous changes in covariates, such as arterial blood pressure (BP) and P a C O 2 , rule out the use of CBF changes as a reliable marker of neurovascular coupling (NVC) integrity. Healthy subjects performed repetitive (1 Hz) passive elbow flexion with their dominant arm for 60 s. CBF velocity (CBFV) was recorded bilaterally in the middle cerebral artery with transcranial Doppler, BP with the Finometer device, and end-tidal CO2 (EtCO2) with capnography. ⋯ NEW & NOTEWORTHY A new approach was proposed to identify the separate contributions of stimulation, arterial blood pressure (BP), and arterial CO2 ( P a C O 2 ) to the cerebral blood flow (CBF) response observed in neurovascular coupling (NVC) studies in humans. Instead of adopting an empirical gate function to represent the stimulation input, a model-generated function is derived as part of the modeling process, providing a representation of the NVC response, independent of the contributions of BP or P a C O 2. This new marker of NVC, together with the model-predicted outputs for the contributions of BP, P a C O 2 and stimulation, has considerable potential to both quantify and simultaneously integrate the separate mechanisms involved in CBF regulation, namely, cerebral autoregulation, CO2 reactivity and other contributions.
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Offset analgesia (OA) is the disproportionate decrease in pain experience following a slight decrease in noxious heat stimulus intensity. We tested whether sequential offsets would allow noxious temperatures to be reached with little or no perception of pain. Forty-eight participants continuously rated their pain experience during trials containing trains of heat stimuli delivered by Peltier thermode. ⋯ We tested whether sequential offsets would allow noxious temperatures to be reached with little or no perception of pain. We found little evidence of such overall analgesia. In contrast, we observed analgesic effects after each offset with long-duration stimuli, even with relatively low-temperature noxious stimuli.