Exploring alterations in sensory pathways in migraine

Background Migraine is a neurological disorder characterized by intense, debilitating headaches, often coupled with nausea, vomiting and sensitivity to light and sound. Whilst changes in sensory processes during a migraine attack have been well-described, there is growing evidence that even between migraine attacks, sensory abilities are disrupted in migraine. Brain imaging studies have investigated altered coupling between areas of the descending pain modulatory pathway but coupling between somatosensory processing regions between migraine attacks has not been properly studied. The aim of this study was to determine if ongoing functional connectivity between visual, auditory, olfactory, gustatory and somatosensory cortices are altered during the interictal phase of migraine. Methods To explore the neural mechanisms underpinning interictal changes in sensory processing, we used functional magnetic resonance imaging to compare resting brain activity patterns and connectivity in migraineurs between migraine attacks (n = 32) and in healthy controls (n = 71). Significant differences between groups were determined using two-sample random effects procedures (p < 0.05, corrected for multiple comparisons, minimum cluster size 10 contiguous voxels, age and gender included as nuisance variables). Results In the migraine group, increases in infra-slow oscillatory activity were detected in the right primary visual cortex (V1), secondary visual cortex (V2) and third visual complex (V3), and left V3. In addition, resting connectivity analysis revealed that migraineurs displayed significantly enhanced connectivity between V1 and V2 with other sensory cortices including the auditory, gustatory, motor and somatosensory cortices. Conclusions These data provide evidence for a dysfunctional sensory network in pain-free migraine patients which may be underlying altered sensory processing between migraine attacks.

Different Patterns of Attention Modulation in Early N140 and Late P300 sERPs Following Ipsilateral vs. Contralateral Stimulation at the Fingers and Cheeks

Intra-hemispheric interference has been often observed when body parts with neighboring representations within the same hemisphere are stimulated. However, patterns of interference in early and late somatosensory processing stages due to the stimulation of different body parts have not been explored. Here, we explore functional similarities and differences between attention modulation of the somatosensory N140 and P300 elicited at the fingers vs. cheeks. In an active oddball paradigm, 22 participants received vibrotactile intensity deviant stimulation either ipsilateral (within-hemisphere) or contralateral (between-hemisphere) at the fingers or cheeks. The ipsilateral deviant always covered a larger area of skin than the contralateral deviant. Overall, both N140 and P300 amplitudes were higher following stimulation at the cheek and N140 topographies differed between fingers and cheek stimulation. For the N140, results showed higher deviant ERP amplitudes following contralateral than ipsilateral stimulation, regardless of the stimulated body part. N140 peak latency differed between stimulated body parts with shorter latencies for the stimulation at the fingers. Regarding P300 amplitudes, contralateral deviant stimulation at the fingers replicated the N140 pattern, showing higher responses and shorter latencies than ipsilateral stimulation at the fingers. For the stimulation at the cheeks, ipsilateral deviants elicited higher P300 amplitudes and longer latencies than contralateral ones. These findings indicate that at the fingers ipsilateral deviant stimulation leads to intra-hemispheric interference, with significantly smaller ERP amplitudes than in contralateral stimulation, both at early and late processing stages. By contrast, at the cheeks, intra-hemispheric interference is selective for early processing stages. Therefore, the mechanisms of intra-hemispheric processing differ from inter-hemispheric ones and the pattern of intra-hemispheric interference in early and late processing stages is body-part specific.

Give me a pain that I am used to: distinct habituation patterns to painful and non-painful stimulation

Pain habituation is associated with a decrease of activation in brain areas related to pain perception. However, little is known about the specificity of these decreases to pain, as habituation has also been described for other responses like spinal reflexes and other sensory responses. Thus, it might be hypothesized that previously reported reductions in activation are not specifically related to pain habituation. For this reason, we performed a 3 T fMRI study using either painful or non-painful electrical stimulation via an electrode attached to the back of the left hand. Contrasting painful vs. non-painful stimulation revealed significant activation clusters in regions well-known to be related to pain processing, such as bilateral anterior and posterior insula, primary/secondary sensory cortices (S1/S2) and anterior midcingulate cortex (aMCC). Importantly, our results show distinct habituation patterns for painful (in aMCC) and non-painful (contralateral claustrum) stimulation, while similar habituation for both types of stimulation was identified in bilateral inferior frontal gyrus (IFG) and contralateral S2. Our findings thus distinguish a general habituation in somatosensory processing (S2) and reduced attention (IFG) from specific pain and non-pain related habituation effects where pain-specific habituation effects within the aMCC highlight a change in affective pain perception.

TRPV1-lineage somatosensory fibers communicate with taste neurons in the mouse parabrachial nucleus

Trigeminal neurons supply somatosensation to craniofacial tissues. In mouse brain, ascending projections from medullary trigeminal neurons arrive at taste neurons in the autonomic parabrachial nucleus, suggesting taste neurons participate in somatosensory processing. However, the genetic cell types that support this convergence were undefined. Using Cre-directed optogenetics and in vivo neurophysiology in anesthetized mice of both sexes, here we studied whether TRPV1-lineage nociceptive and thermosensory fibers are primary neurons that drive trigeminal circuits reaching parabrachial taste cells. We monitored spiking activity in individual parabrachial neurons during photoexcitation of the terminals of TRPV1-lineage fibers that arrived at the dorsal spinal trigeminal nucleus pars caudalis, which relays orofacial somatosensory messages to the parabrachial area. Parabrachial neural responses to oral delivery of taste, chemesthetic, and thermal stimuli were also recorded. We found that optical excitation of TRPV1-lineage fibers frequently stimulated traditionally defined taste neurons in lateral parabrachial nuclei. The tuning of neurons across diverse tastes associated with their sensitivity to excitation of TRPV1-lineage fibers, which only sparingly engaged neurons oriented to preferred tastes like sucrose. Moreover, neurons that responded to photostimulation of TRPV1-lineage afferents showed strong responses to temperature including noxious heat, which predominantly excited parabrachial bitter taste cells. Multivariate analyses revealed the parabrachial confluence of TRPV1-lineage signals with taste captured sensory valence information shared across aversive gustatory, nociceptive, and thermal stimuli. Our results reveal that trigeminal fibers with defined roles in thermosensation and pain communicate with parabrachial taste neurons. This multisensory convergence supports dependencies between gustatory and somatosensory hedonic representations in the brain.

Exploring Alterations in Sensory Pathways in Migraine

BackgroundMigraine is a neurological disorder characterized by intense, debilitating headaches, often coupled with nausea, vomiting and sensitivity to light and sound. Whilst changes in sensory processes during a migraine attack have been well-described, there is growing evidence that even between migraine attacks, sensory abilities are disrupted in migraine. Brain imaging studies have investigated altered coupling between areas of the descending pain modulatory pathway but coupling between somatosensory processing regions between migraine attacks has not been properly studied. The aim of this study was to determine if ongoing functional connectivity between visual, auditory, olfactory, gustatory and somatosensory cortices are altered during the interictal phase of migraine. MethodsTo explore the neural mechanisms underpinning interictal changes in sensory processing, we used functional magnetic resonance imaging to compare resting brain activity patterns and connectivity in migraineurs between migraine attacks (n= 32) and in healthy controls (n=71). Significant differences between groups were determined using two-sample random effects procedures (p<0.05, corrected for multiple comparisons, minimum cluster size 10 contiguous voxels, age and gender included as nuisance variables). ResultsIn the migraine group, increases in infra-slow oscillatory activity were detected in the right primary visual cortex (V1), secondary visual cortex (V2) and third visual complex (V3), and left V3. In addition, resting connectivity analysis revealed that migraineurs displayed significantly enhanced connectivity between V1 and V2 with other sensory cortices including the auditory, gustatory, motor and somatosensory cortices. ConclusionsThese data provide evidence for a dysfunctional sensory network in pain-free migraine patients which may be underlying altered sensory processing between migraine attacks.

Tools for analysis and conditional deletion of subsets of sensory neurons

Background: Somatosensation depends on primary sensory neurons of the trigeminal and dorsal root ganglia (DRG). Transcriptional profiling of mouse DRG sensory neurons has defined at least 18 distinct neuronal cell types. Using an advillin promoter, we have generated a transgenic mouse line that only expresses diphtheria toxin A (DTA) in sensory neurons in the presence of Cre recombinase. This has allowed us to ablate specific neuronal subsets within the DRG using a range of established and novel Cre lines that encompass all sets of sensory neurons. Methods: A floxed-tdTomato-stop-DTA bacterial artificial chromosome (BAC) transgenic reporter line (AdvDTA) under the control of the mouse advillin DRG promoter was generated. The line was first validated using a Nav1.8Cre and then crossed to CGRPCreER (Calca), ThCreERT2, Tmem45bCre, Tmem233Cre, Ntng1Cre and TrkBCreER (Ntrk2) lines. Pain behavioural assays included Hargreaves’, hot plate, Randall-Selitto, cold plantar, partial sciatic nerve ligation and formalin tests. Results: Motor activity, as assessed by the rotarod test, was normal for all lines tested. Noxious mechanosensation was significantly reduced when either Nav1.8 positive neurons or Tmem45b positive neurons were ablated whilst acute heat pain was unaffected. In contrast, noxious mechanosensation was normal following ablation of CGRP-positive neurons but acute heat pain thresholds were significantly elevated and a reduction in nocifensive responses was observed in the second phase of the formalin test. Ablation of TrkB-positive neurons led to significant deficits in mechanical hypersensitivity in the partial sciatic nerve ligation neuropathic pain model. Conclusions: Ablation of specific DRG neuronal subsets using the AdvDTA line will be a useful resource for further functional characterization of somatosensory processing, neuro-immune interactions and chronic pain disorders.

Ipsilateral stimulus encoding in primary and secondary somatosensory cortex of awake mice

Lateralization is a hallmark of somatosensory processing in the mammalian brain. However, in addition to their contralateral representation, unilateral tactile stimuli also modulate neuronal activity in somatosensory cortices of the ipsilateral hemisphere. The cellular organization and functional role of these ipsilateral stimulus responses in awake somatosensory cortices, especially regarding stimulus coding, are unknown. Here, we targeted silicon probe recordings to the vibrissa region of primary (S1) and secondary (S2) somatosensory cortex of awake head-fixed male and female mice while delivering ipsilateral and contralateral whisker stimuli. Ipsilateral stimuli drove larger and more reliable responses in S2 than in S1, and activated a larger fraction of stimulus-responsive neurons. Ipsilateral stimulus-responsive neurons were rare in layer 4 of S1, but were located in equal proportion across all layers in S2. Linear classifier analyses further revealed that decoding of the ipsilateral stimulus was more accurate in S2 than S1, while S1 decoded contralateral stimuli most accurately. These results reveal substantial encoding of ipsilateral stimuli in S1 and especially S2, consistent with the hypothesis that higher cortical areas may integrate tactile inputs across larger portions of space, spanning both sides of the body.

Human Somatosensory Processing and Artificial Somatosensation

In the past few years, we have gained a better understanding of the information processing mechanism in the human brain, which has led to advances in artificial intelligence and humanoid robots. However, among the various sensory systems, studying the somatosensory system presents the greatest challenge. Here, we provide a comprehensive review of the human somatosensory system and its corresponding applications in artificial systems. Due to the uniqueness of the human hand in integrating receptor and actuator functions, we focused on the role of the somatosensory system in object recognition and action guidance. First, the low-threshold mechanoreceptors in the human skin and somatotopic organization principles along the ascending pathway, which are fundamental to artificial skin, were summarized. Second, we discuss high-level brain areas, which interacted with each other in the haptic object recognition. Based on this close-loop route, we used prosthetic upper limbs as an example to highlight the importance of somatosensory information. Finally, we present prospective research directions for human haptic perception, which could guide the development of artificial somatosensory systems.