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Background Idiopathic cervical dystonia (CD) is a chronic movement disorder characterized by impressive clinical symptoms and the lack of clear pathological findings in clinical diagnostics and imaging. At present, the injection of botulinum toxin (BNT) in dystonic muscles is an effective therapy to control motor symptoms and pain in CD. Objectives We hypothesized that, although it is locally injected to dystonic muscles, BNT application leads to changes in brain and network activity towards normal brain function. Methods Using 3 T functional MR imaging along with advanced analysis techniques (functional connectivity, Granger causality, and regional homogeneity), we aimed to characterize brain activity in CD (17 CD patients vs. 17 controls) and to uncover the effects of BNT treatment (at 6 months). Results In CD, we observed an increased information flow within the basal ganglia, the thalamus, and the sensorimotor cortex. In parallel, some of these structures became less responsive to regulating inputs. Furthermore, our results suggested an altered somatosensory integration. Following BNT administration, we noted a shift towards normal brain function in the CD patients, especially within the motor cortex, the somatosensory cortex, and the basal ganglia. Conclusion The changes in brain function and network activity in CD can be interpreted as related to the underlying cause, the effort to compensate or a mixture of both. Although BNT is applied in the last stage of the cortico-neuromuscular pathway, brain patterns are shifted towards those of healthy controls., Highlights • we characterized brain activity in CD and the effects of BNT using 3T fMR imaging and network analysis techniques • following treatment with botulinum toxin (BNT), abnormal brain activity patterns in primary dystonia are attenuated • critical key regions for both the pathophysiology and BNT-induced improvement in cervical dystonia are the BG

Background Writer's cramp is a task-specific dystonia impairing writing and sometimes other fine motor tasks. Neuroimaging studies using manifold designs have shown varying results regarding the nature of changes in the disease. Objective To clarify and extend the knowledge of underlying changes by investigating functional connectivity (FC) in intrinsic connectivity networks with putative sensorimotor function at rest in an increased number of study subjects. Methods Resting-state functional magnetic resonance imaging with independent component analysis was performed in 26/27 writer's cramp patients/healthy controls, and FC within and between resting state networks with putative sensorimotor function was compared. Additionally, voxel-based morphometry was carried out on the subjects' structural images. Results Patients displayed increased left- and reduced right-hemispheric primary sensorimotor FC in the premotor-parietal network. Mostly bilaterally altered dorsal/ventral premotor FC, as well as altered parietal FC were observed within multiple sensorimotor networks and showed differing network-dependent directionality. Beyond within-network FC changes and reduced right cerebellar grey matter volume in the structural analysis, the positive between-network FC of the cerebellar network and the basal ganglia network was reduced. Conclusions Abnormal resting-state FC in multiple networks with putative sensorimotor function may act as basis of preexisting observations made during task-related neuroimaging. Further, altered connectivity between the cerebellar and basal ganglia network underlines the important role of these structures in the disease., Highlights • Investigation of FC changes in various sensorimotor ICNs at rest in writer's cramp. • We saw multiple, network-specific FC changes in primary/higher sensorimotor cortices. • This may act as basis of the varying nature of sensorimotor changes during task-fMRI. • Further, findings supporting disrupted cerebellar-basal ganglia interaction were made. • An additional morphometric analysis demonstrated structural cerebellar abnormality.

Background Migraine is a common episodic neurological disorder. Literature has shown that transcutaneous auricular vagus nerve stimulation (taVNS) at 1 Hz can significantly relieve migraine symptoms. However, its underlying mechanism remains unclear. This study aims to investigate the neural pathways associated with taVNS treatment of migraine. Methods Twenty-nine patients with migraine were recruited from outpatient neurology clinics. Each patient attended two magnetic resonance imaging/functional magnetic resonance imaging (MRI/fMRI) scan sessions separated by one week. Each session included a pre-stimulation resting state fMRI scan, fMRI scans during real or sham 1 Hz taVNS (with block design), and a post-stimulation resting state fMRI scan. Results Twenty-six patients were included in the final analyses. Real taVNS evoked fMRI signal decreases in brain areas belonging to the default mode network (DMN) and brain stem areas including the locus coeruleus (LC), raphe nuclei, parabrachial nucleus, and solitary nucleus. Sham taVNS evoked fMRI signal decreases in brain areas belonging to the DMN. Compared to sham taVNS, real taVNS produced greater deactivation at the bilateral LC. Resting state functional connectivity (rsFC) analysis showed that after taVNS, LC rsFC with the right temporoparietal junction and left secondary somatosensory cortex (S2) significantly increased compared to sham taVNS. The increased rsFC of the left LC-left S2 was significantly negatively associated with the frequency of migraine attacks during the preceding month. Conclusion Our results suggest that taVNS at 1 Hz can significantly modulate activity/connectivity of brain regions associated with the vagus nerve central pathway and pain modulation system, which may shed light on the neural mechanisms underlying taVNS treatment of migraine., Highlights • taVNS at l HZ evoked fMRI signal decrease in the locus coeruleus in migraine. • After taVNS, LC rsFC with TPJ, hippocampus and S2 increased in migraine. • The increased LC-S2 rsFC negatively associated with the frequency of migraine attacks.

The limited success of translating basic animal findings into effective clinical treatments of pain can be partly ascribed to the use of sub-optimal models. Murine models of pain often consist in recording (1) threshold responses (like the tail-flick reflex) elicited by (2) non-nociceptive specific inputs in (3) anaesthetized animals. The direct cortical recording of laser-evoked potentials (LEPs) elicited by stimuli of graded energies in freely-moving rodents avoids these three important pitfalls, and has thus the potential of improving such translation. Murine LEPs are classically reported to consist of two distinct components, reflecting the activity of Aδ- and C-fibre afferent pathways. However, we have recently demonstrated that the so-called “Aδ-LEPs” in fact reflect the activation of the auditory system by laser-generated ultrasounds. Here we used ongoing white noise to avoid the confound represented by the early auditory response, and thereby comprehensively characterized the physiological properties of C-fibre LEPs recorded directly from the exposed surface of the rat brain. Stimulus–response functions indicated that response amplitude is positively related to the stimulus energy, as well as to nocifensive behavioral score. When displayed using average reference, murine LEPs consist of three distinct deflections, whose polarity, order, and topography are surprisingly similar to human LEPs. The scalp topography of the early N1 wave is somatotopically-organized, likely reflecting the activity of the primary somatosensory cortex, while topographies of the later N2 and P2 waves are more centrally distributed. These results indicate that recording LEPs in freely-moving rats is a valid model to improve the translation of animal results to human physiology and pathophysiology., Highlights • We describe the physiological properties of LEPs in freely-moving rats, using ECoG. • Rat LEPs reflect the activation of C-fibre afferent pathways. • LEP amplitude reflects stimulus energy and rat nocifensive behavior. • Similar to their human counterpart, rat LEPs consist of three distinct deflections. • LEPs in freely-moving rats are a valid model for translational pain research.