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Central post-stroke pain (CPSP) is a neuropathic pain syndrome that can occur after a cerebrovascular accident. This syndrome is characterised by pain and sensory abnormalities in the body parts that correspond to the brain territory that has been injured by the cerebrovascular lesion. The presence of sensory loss and signs of hypersensitivity in the painful area in patients with CPSP might indicate the dual combination of deafferentation and the subsequent development of neuronal hyperexcitability. The exact prevalence of CPSP is not known, partly owing to the difficulty in distinguishing this syndrome from other pain types that can occur after stroke (such as shoulder pain, painful spasticity, persistent headache, and other musculoskeletal pain conditions). Future prospective studies with clear diagnostic criteria are essential for the proper collection and processing of epidemiological data. Although treatment of CPSP is difficult, the most effective approaches are those that target the increased neuronal hyperexcitability.

The authors identify the midcingulate cortex as a region that gates nociceptive plasticity without modulating basal nociception or the affective component of acute pain in mice. They identify a novel pathway from the midcingulate cortex to the posterior insula that recruits descending serotonergic projections to facilitate nociception. The identity of cortical circuits mediating nociception and pain is largely unclear. The cingulate cortex is consistently activated during pain, but the functional specificity of cingulate divisions, the roles at distinct temporal phases of central plasticity and the underlying circuitry are unknown. Here we show in mice that the midcingulate division of the cingulate cortex (MCC) does not mediate acute pain sensation and pain affect, but gates sensory hypersensitivity by acting in a wide cortical and subcortical network. Within this complex network, we identified an afferent MCC–posterior insula pathway that can induce and maintain nociceptive hypersensitivity in the absence of conditioned peripheral noxious drive. This facilitation of nociception is brought about by recruitment of descending serotonergic facilitatory projections to the spinal cord. These results have implications for our understanding of neuronal mechanisms facilitating the transition from acute to long-lasting pain.

Key Points Locomotion is a complex motor act that, to a large degree, is controlled by neuronal circuits in the spinal cord. Using a systems neuroscience approach in several model systems of non-limbed and limbed animals, important advances have been made in revealing the functional organization of the spinal locomotor networks. The key circuit elements in the spinal locomotor networks are the rhythm-generating circuits and the pattern-generating circuits, which include circuits that control bilateral muscle activity, and circuits that control flexor–extensor muscles in limbed animals. Comparison of the network organization of the key circuit elements in limbed and non-limbed animals reveals both commonalities and differences in organization. The commonalities extend to the basic components of inhibitory left–right alternating circuits and excitatory neurons involved in rhythm generation. The differences include left–right alternating circuitries that have multiple components in legged animals compared with the control of axial muscles in fish where one component dominates, rhythm-generating neurons that originate from developmentally diverse progenitors in fish and mice, and elaborated reciprocal network circuits involved in the flexor–extensor coordination that is found in legged animals, which do not have direct counterparts in non-legged animals. Locomotor networks, whether they control swimming or over-ground locomotion, are built around modules of rhythm- and pattern-generating modules. Functional network reorganization occurs with changes in the speed of locomotion or changes in gait. This reconfiguration takes places both at the level of rhythm generation and at the level of pattern generation. The exact mechanisms of rhythm generation are not generally understood across phyla but seem to depend on an interplay between active membrane properties and network properties. Proprioception suggests an important role for phase switching during locomotion. The combination of electrophysiological and molecular genetic approaches has revealed details of the organization of large-scale spinal networks in limbed animals in considerably different ways than previous research has suggested and has allowed for comparison with network organization in leg-less animals with more limited numbers of cells in the spinal cord. Although these fundamental motor networks have begun to be decoded, there are still unresolved issues regarding their functional organization. In vertebrates, assemblies of neurons in the spinal cord generate the precise timing and patterning of locomotor movements. In this Review, Ole Kiehn examines the organization and operation of these spinal locomotor networks in limbed and non-limbed animals. Unravelling the functional operation of neuronal networks and linking cellular activity to specific behavioural outcomes are among the biggest challenges in neuroscience. In this broad field of research, substantial progress has been made in studies of the spinal networks that control locomotion. Through united efforts using electrophysiological and molecular genetic network approaches and behavioural studies in phylogenetically diverse experimental models, the organization of locomotor networks has begun to be decoded. The emergent themes from this research are that the locomotor networks have a modular organization with distinct transmitter and molecular codes and that their organization is reconfigured with changes to the speed of locomotion or changes in gait.

Although the effects of cannabis on perception are well documented, little is known about their neural basis or how these may contribute to the formation of psychotic symptoms. We used functional magnetic resonance imaging (fMRI) to assess the effects of Delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) during visual and auditory processing in healthy volunteers. In total, 14 healthy volunteers were scanned on three occasions. Identical 10 mg THC, 600 mg CBD, and placebo capsules were allocated in a balanced double-blinded pseudo-randomized crossover design. Plasma levels of each substance, physiological parameters, and measures of psychopathology were taken at baseline and at regular intervals following ingestion of substances. Volunteers listened passively to words read and viewed a radial visual checkerboard in alternating blocks during fMRI scanning. Administration of THC was associated with increases in anxiety, intoxication, and positive psychotic symptoms, whereas CBD had no significant symptomatic effects. THC decreased activation relative to placebo in bilateral temporal cortices during auditory processing, and increased and decreased activation in different visual areas during visual processing. CBD was associated with activation in right temporal cortex during auditory processing, and when contrasted, THC and CBD had opposite effects in the right posterior superior temporal gyrus, the right-sided homolog to Wernicke's area. Moreover, the attenuation of activation in this area (maximum 61, −15, −2) by THC during auditory processing was correlated with its acute effect on psychotic symptoms. Single doses of THC and CBD differently modulate brain function in areas that process auditory and visual stimuli and relate to induced psychotic symptoms.

•taVNS effects on brainstem activity are assessed during fMRI.•taVNS modulates activity in brainstem vagal afferent targets (including the NTS).•The signal dynamics over time indicates both acute, persistent and delayed effects of taVNS. Our increasing knowledge about gut-brain interaction is revolutionising the understanding of the links between digestion, mood, health, and even decision making in our everyday lives. In support of this interaction, the vagus nerve is a crucial pathway transmitting diverse gut-derived signals to the brain to monitor of metabolic status, digestive processes, or immune control to adapt behavioural and autonomic responses. Hence, neuromodulation methods targeting the vagus nerve are currently explored as a treatment option in a number of clinical disorders, including diabetes, chronic pain, and depression. The non-invasive variant of vagus nerve stimulation (VNS), transcutaneous auricular VNS (taVNS), has been implicated in both acute and long-lasting effects by modulating afferent vagus nerve target areas in the brain. The physiology of neither of those effects is, however, well understood, and evidence for neuronal response upon taVNS in vagal afferent projection regions in the brainstem and its downstream targets remain to be established. Therefore, to examine time-dependent effects of taVNS on brainstem neuronal responses in healthy human subjects, we applied taVNS during task-free fMRI in a single-blinded crossover design. During fMRI data acquisition, we either stimulated the left earlobe (sham), or the target zone of the auricular branch of the vagus nerve in the outer ear (cymba conchae, verum) for several minutes, both followed by a short ‘stimulation OFF’ period. Time-dependent effects were assessed by averaging the BOLD response for consecutive 1-minute periods in an ROI-based analysis of the brainstem. We found a significant response to acute taVNS stimulation, relative to the control condition, in downstream targets of vagal afferents, including the nucleus of the solitary tract, the substantia nigra, and the subthalamic nucleus. Most of these brainstem regions remarkably showed increased activity in response to taVNS, and these effect sustained during the post-stimulation period. These data demonstrate that taVNS activates key brainstem regions, and highlight the potential of this approach to modulate vagal afferent signalling. Furthermore, we show that carry-over effects need to be considered when interpreting fMRI data in the context of general vagal neurophysiology and its modulation by taVNS.

Developmental dyslexia occurs across languages and has a major impact on the lives of affected individuals. Here, Usha Goswami considers the evidence for several prominent 'sensory' theories of dyslexia and outlines the key challenges for research in this area. Recent years have seen the publication of a range of new theories suggesting that the basis of dyslexia might be sensory dysfunction. In this Opinion article, the evidence for and against several prominent sensory theories of dyslexia is closely scrutinized. Contrary to the causal claims being made, my analysis suggests that many proposed sensory deficits might result from the effects of reduced reading experience on the dyslexic brain. I therefore suggest that longitudinal studies of sensory processing, beginning in infancy, are required to successfully identify the neural basis of developmental dyslexia. Such studies could have a powerful impact on remediation.

Key Points Brainstem vagovagal neurocircuits modulate the functions of the upper gastrointestinal tract Neuronal communications between vagal sensory (nucleus tractus solitarius, NTS) and motor (dorsal motor nucleus of the vagus, DMV) nuclei are highly specialized and probably specific for function and target organ NTS–DMV synaptic contacts are not static but undergo plastic changes to ensure that vagally regulated gastrointestinal functions respond appropriately to ever-changing physiological conditions or derangements Gastrointestinal peptides influence vagovagal circuits via actions on both vagal afferent fibres and brainstem nuclei Neurodegenerative alterations of the vagal neurocircuitry induce marked impairments of gastrointestinal functions Upper gastrointestinal tract function is regulated by vagovagal neurocircuits, comprising brainstem nuclei that integrate visceral sensory information and provide vagal motor output. Here, Travagli and Anselmi describe the organization of these neurocircuits and their plasticity in response to stressors. The influence of gastrointestinal peptides on vagovagal neurons is also discussed. A large body of research has been dedicated to the effects of gastrointestinal peptides on vagal afferent fibres, yet multiple lines of evidence indicate that gastrointestinal peptides also modulate brainstem vagal neurocircuitry, and that this modulation has a fundamental role in the physiology and pathophysiology of the upper gastrointestinal tract. In fact, brainstem vagovagal neurocircuits comprise highly plastic neurons and synapses connecting afferent vagal fibres, second order neurons of the nucleus tractus solitarius (NTS), and efferent fibres originating in the dorsal motor nucleus of the vagus (DMV). Neuronal communication between the NTS and DMV is regulated by the presence of a variety of inputs, both from within the brainstem itself as well as from higher centres, which utilize an array of neurotransmitters and neuromodulators. Because of the circumventricular nature of these brainstem areas, circulating hormones can also modulate the vagal output to the upper gastrointestinal tract. This Review summarizes the organization and function of vagovagal reflex control of the upper gastrointestinal tract, presents data on the plasticity within these neurocircuits after stress, and discusses the gastrointestinal dysfunctions observed in Parkinson disease as examples of physiological adjustment and maladaptation of these reflexes.

Background and Purpose Myoclonus dystonia due to a pathogenic variant in SGCE (MYC/DYT‐SGCE) is a rare condition involving a motor phenotype associating myoclonus and dystonia. Dysfunction within the networks relying on the cortex, cerebellum, and basal ganglia was presumed to underpin the clinical manifestations. However, the microarchitectural abnormalities within these structures and related pathways are unknown. Here, we investigated the microarchitectural brain abnormalities related to the motor phenotype in MYC/DYT‐SGCE. Methods We used neurite orientation dispersion and density imaging, a multicompartment tissue model of diffusion neuroimaging, to compare microarchitectural neurite organization in MYC/DYT‐SGCE patients and healthy volunteers (HVs). Neurite density index (NDI), orientation dispersion index (ODI), and isotropic volume fraction (ISOVF) were derived and correlated with the severity of motor symptoms. Fractional anisotropy (FA) and mean diffusivity (MD) derived from the diffusion tensor approach were also analyzed. In addition, we studied the pathways that correlated with motor symptom severity using tractography analysis. Results Eighteen MYC/DYT‐SGCE patients and 24 HVs were analyzed. MYC/DYT‐SGCE patients showed an increase of ODI and a decrease of FA within their motor cerebellum. More severe dystonia was associated with lower ODI and NDI and higher FA within motor cerebellar cortex, as well as with lower NDI and higher ISOVF and MD within the corticopontocerebellar and spinocerebellar pathways. No association was found between myoclonus severity and diffusion parameters. Conclusions In MYC/DYT‐SGCE, we found microstructural reorganization of the motor cerebellum. Structural change in the cerebellar afferent pathways that relay inputs from the spinal cord and the cerebral cortex were specifically associated with the severity of dystonia. In this work, we investigated microstructural abnormalities in patients with myoclonus dystonia using neurite orientation dispersion and density imaging applied to diffusion magnetic resonance imaging. We showed abnormalities in the motor cerebellum of patients compared to controls. Moreover, structural change in the cerebellar afferent pathways that relay inputs from the spinal cord and the cerebral cortex was associated with the severity of dystonia.

Study design: A randomized, double-blind, placebo-controlled, crossover, multicenter trial. A 1-week baseline period was followed by two treatment periods of 5 weeks duration with levetiracetam increased from 500 mg b.i.d. to a maximum of 1500 mg b.i.d. separated by a 1-week washout period. Objectives: The objective of the study was primarily to evaluate the efficacy of the anticonvulsant levetiracetam in patients with spinal cord injury (SCI) at- and below-level pain and secondarily to evaluate the effect on spasm severity. Setting: Outpatients at two spinal cord units and a pain center. Methods: Patients were allowed to continue their usual pain treatment at a constant dose. The primary outcome measure was the change in median daily pain score (on a 0–10 point numeric rating scale) from 1-week baseline period to the last week of each treatment period. Secondary outcome measures included pain relief of at- and below-level pain, allodynia, spasms and spasticity. Results: A total of 36 patients with SCI at- and or below-level pain were enrolled. Of these, 24 patients completed the trial. We found no effect of levetiracetam on the primary ( P =0.46) or any of the secondary outcome measures. Only two patients continued levetiracetam treatment following the trial, and one patient was still in levetiracetam treatment at the 6-month follow-up. Levetiracetam was generally well tolerated with no serious adverse events. Conclusions: Levetiracetam does not relieve neuropathic pain or spasm severity following spinal cord injury.

The authors find that long-range axons from primary motor cortex (vM1) preferentially recruit vasointestinal peptide (VIP)-expressing interneurons in somatosensory cortex (S1). VIP neurons in turn inhibit somatostatin-expressing interneurons that target the distal dendrites of pyramidal cells in S1. This dis-inhibitory circuit is active during voluntary movement, suggesting that it participates in the modulation of primary cortical sensory processing by motor cortex. The influence of motor activity on sensory processing is crucial for perception and motor execution. However, the underlying circuits are not known. To unravel the circuit by which activity in the primary vibrissal motor cortex (vM1) modulates sensory processing in the primary somatosensory barrel cortex (S1), we used optogenetics to examine the long-range inputs from vM1 to the various neuronal elements in S1. We found that S1-projecting vM1 pyramidal neurons strongly recruited vasointestinal peptide (VIP)-expressing GABAergic interneurons, a subset of serotonin receptor–expressing interneurons. These VIP interneurons preferentially inhibited somatostatin-expressing interneurons, neurons that target the distal dendrites of pyramidal cells. Consistent with this vM1-mediated disinhibitory circuit, the activity of VIP interneurons in vivo increased and that of somatostatin interneurons decreased during whisking. These changes in firing rates during whisking depended on vM1 activity. Our results suggest previously unknown circuitry by which inputs from motor cortex influence sensory processing in sensory cortex.