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Multisensory processing can be assessed by measuring susceptibility to crossmodal illusions such as the Sound-Induced Flash Illusion (SIFI). When a single flash is accompanied by two or more beeps, it is perceived as multiple flashes (fission illusion); conversely, a fusion illusion is experienced when more flashes are matched with a single beep, leading to the perception of a single flash. Such illusory perceptions are associated to crossmodal changes in visual cortical excitability. Indeed, increasing occipital cortical excitability, by means of transcranial electrical currents, disrupts the SIFI (i.e. fission illusion). Similarly, a reduced fission illusion was shown in patients with episodic migraine, especially during the attack, in agreement with the pathophysiological model of cortical hyperexcitability of this disease. If episodic migraine patients present with reduced SIFI especially during the attack, we hypothesize that chronic migraine patients should consistently report less illusory effects than healthy controls; drugs intake could also affect SIFI. On such a basis, we studied the proneness to SIFI in chronic migraine (CM) patients (n=63), including 52 patients with Medication Overuse Headache (MOH), compared to 24 healthy controls. All migraine patients showed reduced fission phenomena than controls (p<0.0001). Triptan MOH patients (n=23) presented significantly less fission effects than other chronic migraine groups (p=0.008). This exploratory study suggests that CM – both with and without medication overuse – is associated to a higher visual cortical responsiveness which causes deficit of multisensorial processing, as assessed by the SIFI. Perspective: This observational study shows reduced susceptibility to the sound-induced flash illusion in chronic migraine, confirming and extending previous results in episodic migraine. Medication overuse headache contributes to this phenomenon, especially in case of triptans.
Learn More >In the present study, we examined whether LDK1258, which produces strong CB receptor allosteric effects in in vitro assays, would elicit in vivo effects consistent with allosteric activity. In initial studies, LDK1258 reduced food consumption and elicited delayed antinociceptive effects in the chronic constrictive injury of the sciatic nerve (CCI) model of neuropathic pain, which unexpectedly emerged 4 h post-injection. UPLC-MS/MS analysis quantified significant levels of LDK1258 in both blood and brain tissue at 30 min post-administration that remained stable up to 4 h. The observation that LDK1258 also produced respective antinociceptive and anorectic effects in rimonabant-treated wild type mice and CB (-/-) mice suggests an off-target mechanism of action. Likewise, LDK1258 produced a partial array of common cannabimimetic effects in the tetrad assay, which were not CB receptor mediated. Additionally, LDK1258 did not substitute for the CB receptor orthosteric agonists CP55,940 or anandamide in the drug discrimination paradigm. In other in vivo assays sensitive to CB receptor allosteric modulators, LDK1258 failed to shift the dose-response curves of either CP55,940 or anandamide in producing thermal antinociception, catalepsy, or hypothermia, and did not alter the generalization curve of either drug in the drug discrimination assay. Thus, this battery of tests yielded results demonstrating that LDK1258 produces antinociceptive effects in the CCI model of neuropathic pain, anorectic effects, and other in vivo pharmacological effects in a manner inconsistent with CB receptor allosterism. More generally, this study offers a straightforward screening assay to determine whether newly synthesized CB receptor allosteric modulators translate to the whole animal.
Learn More >Why some people develop chronic pain following an acute episode of low back pain is unknown. Recent cross-sectional studies have suggested a relationship between aberrant sensorimotor cortex activity and pain persistence. The UPWaRD (Understanding persistent Pain Where it ResiDes) cohort study is the first prospective, longitudinal investigation of sensorimotor cortex activity in low back pain. This paper describes the development of a causal model and statistical analysis plan for investigating the causal effect of sensorimotor cortex activity on the development of chronic low back pain.
Learn More >Paclitaxel (PTX) is one of the most commonly used chemotherapeutic agents for various cancer diseases. Despite its advantages, PTX also causes behavioral deficits related to nervous-system dysfunction, such as neuropathic pain, depression, anxiety, and cognitive impairments. The prefrontal cortex (PFC) is one of the areas that is susceptible to adverse effects of chemotherapeutic agents. Therefore, the present study was designed to examine sex-biased behavioral deficits and whole-transcriptome changes in gene expression in the PFC of mice treated with vehicle or PTX. In this study, PTX (4mg/kg) was injected intraperitoneally four times in mice every other day. Three weeks later, both PTX-treated male and female mice developed mechanical pain hypersensitivities, as indicated by increased paw withdrawal responses to 0.16-g von Frey filaments. Additionally, PTX-treated mice exhibited depression-like symptoms, as they exhibited increased immobility times in the forced swim test. PTX also induced cognitive impairment, as demonstrated via results of a novel object recognition test and anxiety-like behavior in an elevated plus-maze test in male mice, but not in female mice. RNA sequencing and in-depth gene expression analysis of the PFC in paired vehicle and PTX-treated mice showed that PTX induced 1,755 differentially expressed genes in the PFCs of male and female mice. Quantitative real-time RT-PCR verified that some gene expressions in the medial PFC were related to neurotransmission. In conclusion, this study identified a sex-biased effect of PTX on PFC function and gene expression, which provides a foundation for future studies to explore the precise mechanisms of PTX-induced behavioral deficits.
Learn More >Small fiber neuropathy (SFN) is a common condition affecting thinly myelinated Aδ and unmyelinated C fibers, often resulting in excruciating pain and dysautonomia. SFN has been associated with several conditions, but a significant number of cases have no discernible cause. Recent genetic studies have identified potentially pathogenic gain-of-function mutations in several the pore-forming voltage-gated sodium channel α subunits (Nas) in a subset of patients with SFN, but the auxiliary sodium channel β subunits have been less implicated in the development of the disease. β subunits modulate Na trafficking and gating, and several mutations have been linked to epilepsy and cardiac dysfunction. Recently, we provided the first evidence for the contribution of a mutation in the β2-subunit to pain in human painful diabetic neuropathy. Here, we provide the first evidence for the involvement of a sodium channel β subunit mutation in the pathogenesis of SFN with no other known causes. We show, through current-clamp analysis, that the newly-identified Y69H variant of the β2 subunit induces neuronal hyperexcitability in dorsal root ganglion neurons, lowering the threshold for action potential firing and allowing for increased repetitive action potential spiking. Underlying the hyperexcitability induced by the β2-Y69H variant, we demonstrate an upregulation in tetrodotoxin-sensitive, but not tetrodotoxin-resistant sodium currents. This provides the first evidence for the involvement of β2 subunits in SFN and strengthens the link between sodium channel β subunits and the development of neuropathic pain in humans.
Learn More >There is growing literature supporting cannabinoids as a potential therapeutic for pain conditions. The development of chronic pain has been associated with reduced concentrations of the endogenous cannabinoid anandamide (AEA) in the midbrain dorsal periaqueductal gray (dPAG), and microinjections of synthetic cannabinoids into the dPAG are antinociceptive. Therefore, the goal of this study was to examine the role of the dPAG in cannabinoid-mediated sensory inhibition. Given that cannabinoids in the dPAG also elicit sympathoexcitation, a secondary goal was to assess coordination between sympathetic and antinociceptive responses. AEA was microinjected into the dPAG while recording single unit activity of wide dynamic range (WDR) dorsal horn neurons (DHNs) evoked by high intensity mechanical stimulation of the hindpaw, concurrently with renal sympathetic nerve activity (RSNA), in anesthetized male rats. AEA microinjected into the dPAG decreased evoked DHN activity (n = 24 units), for half of which AEA also elicited sympathoexcitation. AEA actions were mediated by cannabinoid 1 receptors as confirmed by local pretreatment with the cannabinoid receptor antagonist AM281. dPAG microinjection of the synaptic excitant DL-homocysteic acid (DLH) also decreased evoked DHN activity (n = 27 units), but in all cases this was accompanied by sympathoexcitation. Thus, sensory inhibition elicited from the dPAG is not exclusively linked with sympathoexcitation, suggesting discrete neuronal circuits. The rostrocaudal location of sites may affect evoked responses as AEA produced sensory inhibition without sympathetic effects at 86 % of caudal compared to 25 % of rostral sites, supporting anatomically distinct neurocircuits. These data indicate that spatially selective manipulation of cannabinoid signaling could provide analgesia without potentially harmful autonomic activation.
Learn More >Offset analgesia describes the effect of a slightly reduced nociceptive stimulus, resulting in a disproportionate large reduction in the pain perception. This effect may be associated with descending pain inhibition, but parameters influencing this phenomenon are poorly understood.
Learn More >Cervical radiofrequency neurotomy is a safe and relatively low-risk procedure commonly used to treat facet joint-mediated axial neck pain. Severe complications are extremely rare and can be avoided with proper technique and appropriate imaging guidance. This article describes the development and subsequent management of a case of dropped head syndrome after cervical radiofrequency neurotomy.
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