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Multiple sclerosis (MS) is a chronic demyelinating and neuroinflammatory disease of the human central nervous system with complex pathoetiology, heterogeneous presentations and an unpredictable course of disease progression. There remains an urgent need to identify and validate a biomarker that can reliably predict the initiation and progression of MS as well as identify patient responses to disease-modifying treatments/therapies (DMTs). Studies exploring biomarkers in MS and other neurodegenerative diseases currently focus mainly on cerebrospinal fluid (CSF) analyses, which are invasive and impractical to perform on a repeated basis. Recent studies, replacing CSF with peripheral blood samples, have revealed that the elevation of serum neurofilament light chain (sNfL) in the clinical stages of MS is, potentially, an ideal prognostic biomarker for predicting disease progression and for possibly guiding treatment decisions. However, there are unresolved factors (the definition of abnormal values of sNfL concentration, the standardisation of measurement and the amount of change in sNfL concentration that is significant) that are preventing its use as a biomarker in routine clinical practice for MS. This updated review critiques these recent findings and highlights areas for focussed work to facilitate the use of sNfL as a prognostic biomarker in MS management.

Multiple Sclerosis (MS) is traditionally considered an autoimmune-mediated demyelinating disease, the pathoetiology of which is unknown. However, the key question remains whether autoimmunity is the initiator of the disease (outside-in) or the consequence of a slow and as yet uncharacterized cytodegeneration (oligodendrocytosis), which leads to a subsequent immune response (inside-out). Experimental autoimmune encephalomyelitis has been used to model the later stages of MS during which the autoimmune involvement predominates. In contrast, the cuprizone (CPZ) model is used to model early stages of the disease during which oligodendrocytosis and demyelination predominate and are hypothesized to precede subsequent immune involvement in MS. Recent studies combining a boost, or protection, to the immune system with disruption of the blood brain barrier have shown CPZ-induced oligodendrocytosis with a subsequent immune response. In this Perspective, we review these recent advances and discuss the likelihood of an inside-out vs. an outside-in pathoetiology of MS.

Among the various classes of fast-adapting (FA) tactile afferents found in hairy and glabrous skin, FA2 afferents, associated with Pacinian corpuscles (PC), preferentially signal high-frequency sinusoidal events corresponding with vibration percepts, in contrast to other classes associated with lower frequency flutter percepts. The FA2-PC complex is also uniquely sensitive to distant sources of vibration mechanically transmitted through anatomical structures. In the present study, we used a pulsatile waveform to assess the contribution of FA2 afferents to the perception of flutter-range frequency stimuli (~ 20 Hz) in combination with two methods to abolish local FA inputs and force a dependence on FA2 via transmission from adjacent structures. Firstly, we examined frequency discrimination and perception of vibration applied to the hairy skin overlying the ulnar styloid before and during the blockade of intradermal receptors by local anaesthesia. Secondly, we tested frequency discrimination on the digital glabrous skin before and during the blockade of myelinated fibres by ulnar nerve compression. Despite reliance on vibration transmission to activate remote PCs, we found that flutter-range frequency discrimination was unimpeded across both skin types. Comparisons with stimuli applied to the contralateral side also indicated that perceived frequency was unaffected. This confirms that flutter-range frequency perception can be encoded by the FA2-PC system. Our results demonstrate that input from receptors specialised for low-frequency signalling is not mandatory for flutter-range frequency perception. This explains how the constancy of frequency perception might be achieved across different skin regions, irrespective of the afferent type activated for transmitting these signals.

The established view is that vibrotactile stimuli evoke two qualitatively distinctive cutaneous sensations, flutter (frequencies < 60 Hz) and vibratory hum (frequencies > 60 Hz), subserved by two distinct receptor types (Meissner’s and Pacinian corpuscle, respectively), which may engage different neural processing pathways or channels and fulfil quite different biological roles. In psychological and physiological literature, those two systems have been labelled as Pacinian and non-Pacinian channels. However, we present evidence that low-frequency spike trains in Pacinian afferents can readily induce a vibratory percept with the same low frequency attributes as sinusoidal stimuli of the same frequency, thus demonstrating a universal frequency decoding system. We achieved this using brief low-amplitude pulsatile mechanical stimuli to selectively activate Pacinian afferents. This indicates that spiking pattern, regardless of receptor type, determines vibrotactile frequency perception. This mechanism may underlie the constancy of vibrotactile frequency perception across different skin regions innervated by distinct afferent types.

We recently showed that C low-threshold mechanoreceptors (CLTMRs) contribute to touch-evoked pain (allodynia) during experimental muscle pain. Conversely, in absence of ongoing pain, the activation of CLTMRs has been shown to correlate with a diffuse sensation of pleasant touch. In this study, we evaluated (1) the primary afferent fibre types contributing to positive (pleasant) and negative (unpleasant) affective touch and (2) the effects of tactile stimuli on tonic muscle pain by varying affective attributes and frequency parameters. Psychophysical observations were made in 10 healthy participants. Two types of test stimuli were applied: stroking stimulus using velvet or sandpaper at speeds of 0.1, 1.0 and 10.0 cm/s; focal vibrotactile stimulus at low (20 Hz) or high (200 Hz) frequency. These stimuli were applied in the normal condition (i.e. no experimental pain) and following the induction of muscle pain by infusing hypertonic saline (5%) into the tibialis anterior muscle. These observations were repeated following the conduction block of myelinated fibres by compression of sciatic nerve. In absence of muscle pain, all participants reliably linked velvet-stroking to pleasantness and sandpaper-stroking to unpleasantness (no pain). Likewise, low-frequency vibration was linked to pleasantness and high-frequency vibration to unpleasantness. During muscle pain, the application of previously pleasant stimuli resulted in overall pain relief, whereas the application of previously unpleasant stimuli resulted in overall pain intensification. These effects were significant, reproducible and persisted following the blockade of myelinated fibres. Taken together, these findings suggest the role of low-threshold C fibres in affective and pain processing. Furthermore, these observations suggest that temporal coding need not be limited to discriminative aspects of tactile processing, but may contribute to affective attributes, which in turn predispose individual responses towards excitatory or inhibitory modulation of pain.

Cuprizone (CPZ)-feeding in mice induces atrophy of peripheral immune organs (thymus and spleen) and suppresses T-cell levels, thereby limiting its use as a model for studying the effects of the immune system in demyelinating diseases such as Multiple Sclerosis (MS). To investigate whether castration ( ) can protect the peripheral immune organs from CPZ-induced atrophy and enable T-cell recruitment into the central nervous system (CNS) following a breach of the blood-brain barrier (BBB), three related studies were carried out. In Study 1, prevented the dose-dependent reductions (0.1% < 0.2% CPZ) in thymic and splenic weight, size of the thymic medulla and splenic white pulp, and CD4 and CD8 (CD4/8) levels remained comparable to gonadally intact ( ) control males. Importantly, 0.1% and 0.2% CPZ were equipotent at inducing central demyelination and glial activation. In Study 2, combining with 0.1% CPZ-feeding and BBB disruption with pertussis toxin (PT) enhanced CD8 T-cell recruitment into the CNS. The increased CD8 T-cell level observed in the parenchyma of the cerebrum, cerebellum, brainstem and spinal cord were confirmed by flow cytometry and western blot analyses of CNS tissue. In Study 3, PT+0.1% CPZ-feeding to female mice resulted in similar effects on the peripheral immune organs, CNS demyelination, and gliosis comparable to males, indicating that testosterone levels alone were not responsible for the immune response seen in Study 2. The combination of +0.1% CPZ-feeding+PT indicates that CPZ-induced demyelination can trigger an immune response when the peripheral immune system is spared and may provide a better model to study the initiating events in demyelinating conditions such as MS.

Cuprizone (CPZ) preferentially affects oligodendrocytes (OLG), resulting in demyelination. To investigate whether central oligodendrocytosis and gliosis triggered an adaptive immune response, the impact of combining a standard (0.2%) or low (0.1%) dose of ingested CPZ with disruption of the blood brain barrier (BBB), using pertussis toxin (PT), was assessed in mice. 0.2% CPZ(±PT) for 5 weeks produced oligodendrocytosis, demyelination and gliosis plus marked splenic atrophy (37%) and reduced levels of CD4 (44%) and CD8 (61%). Conversely, 0.1% CPZ(±PT) produced a similar oligodendrocytosis, demyelination and gliosis but a smaller reduction in splenic CD4 (11%) and CD8 (14%) levels and no splenic atrophy. Long-term feeding of 0.1% CPZ(±PT) for 12 weeks produced similar reductions in CD4 (27%) and CD8 (43%), as well as splenic atrophy (33%), as seen with 0.2% CPZ(±PT) for 5 weeks. Collectively, these results suggest that 0.1% CPZ for 5 weeks may be a more promising model to study the ‘inside-out’ theory of Multiple Sclerosis (MS). However, neither CD4 nor CD8 were detected in the brain in CPZ±PT groups, indicating that CPZ-mediated suppression of peripheral immune organs is a major impediment to studying the ‘inside-out’ role of the adaptive immune system in this model over long time periods. Notably, CPZ(±PT)-feeding induced changes in the brain proteome related to the suppression of immune function, cellular metabolism, synaptic function and cellular structure/organization, indicating that demyelinating conditions, such as MS, can be initiated in the absence of adaptive immune system involvement.

Oxaliplatin-induced neuropathic pain limits treatment compliance. However, the variability of neuropathic pain symptoms in each cycle for individual patients and the impacts on treatment compliance remain untested. Data from 322 adult patients who received oxaliplatin-based chemotherapy were extracted based on pattern of chemotherapy, adverse events, and patient survival. Cox regression and survival analyses were employed. Seventy-eight percent of patients developed neuropathic pain that oscillated between a complete absence and presence on a cycle-by-cycle basis. Consequently, the presence of neuropathy in one cycle did not predict the incidence of neuropathy in subsequent cycles. This implies that neuropathic pain need not be a sufficient criterion to reduce, delay, or cease chemotherapy. In the case of multiple system adverse events during combined drug treatment, the responsible cause for dose reduction was not identified. Cox regression analysis revealed that middle age (61–78 years old, P=0.003) and oxaliplatin cumulative dose <850 mg/m2 (P=0.002) were associated with patient mortality. Completion of chemotherapy (8 cycles) and cumulative dose >850 mg/m2 of oxaliplatin prolonged the median survival time by 8 and 5 months, respectively. As oxaliplatin-induced neuropathic pain fluctuates across cycles in a manner that varies from patient-to-patient, current assumptions on the predictive nature of the emergence of neuropathy (and its impact on treatment compliance) need to be reconsidered. Detailed patient-by-patient analysis of adverse events should be applied to future studies in order to determine the efficacy of current treatments (and future interventions) and whether neuropathic pain should be retained as a criterion to vary the treatment. Additionally, when two or more system toxicities occurred in cases of combined drug treatment, the causes for drug reduction should be separately recorded.

Despite the widespread use of experimental acute pain models, little exploration has been undertaken on the acute pain proteome in humans. We resolved to explore molecular alterations evoked by hypertonic saline (HS)-induced acute muscle pain and to map the spread of mechanical hyperalgesia. This study used a two-cohort design in healthy participants. Cohort one ( = 16) underwent intermittent blood sampling prior to, during, and following intramuscular HS (5%) infusion to allow for the discovery of the proteomic and cytokine profile of acute muscle pain. Cohort two ( = 10) underwent bilateral sensory testing during HS infusion, to map the spread of mechanical hyperalgesia. Molecular analysis in cohort one revealed a broad array of proteins and cytokines showing altered expression in response to acute muscle pain. Particularly, these alterations were linked to metabolism and immune response pathways suggestive of systemic effects of acute pain. Cohort two revealed a significant mechanical hyperalgesia which emerged in a distributed pattern over the ipsilateral limb to HS infusion. However, despite systemic molecular alterations, no such mechanical hyperalgesia was observed in the contralateral limb. This study demonstrates systemic molecular alterations resultant from acute HS-induced muscle pain, accompanied by spatially constrained sensory interactions. This dissociation implies that, at least in acute sensitization, widespread molecular changes may not necessarily translate into a correspondingly widespread sensory phenotype.

Neuropathic pain is abnormal,persistent pain that is caused by injury to the somatosensory system.It commonly involves damage to the peripheral nerves as a result of physical trauma,metabolic diseases such as diabetes,infections such as HIV or shingles,or toxicity induced neuropathies as a result of cancer treatments.