Early cortical GABAergic interneurons determine the projection patterns of L4 excitatory neurons.

During cerebral cortex development, excitatory pyramidal neurons (PNs) establish specific projection patterns while receiving inputs from GABAergic inhibitory interneurons (INs). Whether these inhibitory inputs can shape PNs' projection patterns is, however, unknown. While layer 4 (L4) PNs of the primary somatosensory (S1) cortex are all born as long-range callosal projection neurons (CPNs), most of them acquire local connectivity upon activity-dependent elimination of their interhemispheric axons during postnatal development. Here, we demonstrate that precise developmental regulation of inhibition is key for the retraction of S1L4 PNs' callosal projections. Ablation of somatostatin INs leads to premature inhibition from parvalbumin INs onto S1L4 PNs and prevents them from acquiring their barrel-restricted local connectivity pattern. As a result, adult S1L4 PNs retain interhemispheric projections responding to tactile stimuli, and the mice lose whisker-based texture discrimination. Overall, we show that temporally ordered IN activity during development is key to shaping local ipsilateral S1L4 PNs' projection pattern, which is required for fine somatosensory processing.

A nasal chemosensation-dependent critical window for somatosensory development.

Nasal chemosensation is considered the evolutionarily oldest mammalian sense and, together with somatosensation, is crucial for neonatal well-being before auditory and visual pathways start engaging the brain. Using anatomical and functional approaches in mice, we reveal that odor-driven activity propagates to a large part of the cortex during the first postnatal week and enhances whisker-evoked activation of primary whisker somatosensory cortex (wS1). This effect disappears in adult animals, in line with the loss of excitatory connectivity from olfactory cortex to wS1. By performing neonatal odor deprivation, followed by electrophysiological and behavioral work in adult animals, we identify a key transient regulation of nasal chemosensory information necessary for the development of wS1 sensory-driven dynamics and somatosensation. Our work uncovers a cross-modal critical window for nasal chemosensation-dependent somatosensory functional maturation.

Dynamic changes in somatosensory and cerebellar activity mediate temporal recalibration of self-touch.

An organism's ability to accurately anticipate the sensations caused by its own actions is crucial for a wide range of behavioral, perceptual, and cognitive functions. Notably, the sensorimotor expectations produced when touching one's own body attenuate such sensations, making them feel weaker and less ticklish and rendering them easily distinguishable from potentially harmful touches of external origin. How the brain learns and keeps these action-related sensory expectations updated is unclear. Here we employ psychophysics and functional magnetic resonance imaging to pinpoint the behavioral and neural substrates of dynamic recalibration of expected temporal delays in self-touch. Our psychophysical results reveal that self-touches are less attenuated after systematic exposure to delayed self-generated touches, while responses in the contralateral somatosensory cortex that normally distinguish between delayed and nondelayed self-generated touches become indistinguishable. During the exposure, the ipsilateral anterior cerebellum shows increased activity, supporting its proposed role in recalibrating sensorimotor predictions. Moreover, responses in the cingulate areas gradually increase, suggesting that as delay adaptation progresses, the nondelayed self-touches trigger activity related to cognitive conflict. Together, our results show that sensorimotor predictions in the simplest act of touching one's own body are upheld by a sophisticated and flexible neural mechanism that maintains them accurate in time.

Cortical cellular encoding of thermotactile integration.

Recent evidence suggests that primary sensory cortical regions play a role in the integration of information from multiple sensory modalities. How primary cortical neurons integrate different sources of sensory information is unclear, partly because non-primary sensory input to a cortical sensory region is often weak or modulatory. To address this question, we take advantage of the robust representation of thermal (cooling) and tactile stimuli in mouse forelimb primary somatosensory cortex (fS1). Using a thermotactile detection task, we show that the perception of threshold-level cool or tactile information is enhanced when they are presented simultaneously, compared with presentation alone. To investigate the cortical cellular correlates of thermotactile integration, we performed in vivo extracellular recordings from fS1 in awake resting and anesthetized mice during unimodal and bimodal stimulation of the forepaw. Unimodal stimulation evoked thermal- or tactile- specific excitatory and inhibitory responses of fS1 neurons. The most prominent features of combined thermotactile stimulation are the recruitment of unimodally silent fS1 neurons, non-linear integration features, and response dynamics that favor longer response durations with additional spikes. Together, we identify quantitative and qualitative changes in cortical encoding that may underlie the improvement in perception of thermotactile surfaces during haptic exploration.

Theta Phase Entrainment of Single-Cell Spiking in Rat Somatosensory Barrel Cortex and Secondary Visual Cortex Is Enhanced during Multisensory Discrimination Behavior.

Phase entrainment of cells by theta oscillations is thought to globally coordinate the activity of cell assemblies across different structures, such as the hippocampus and neocortex. This coordination is likely required for optimal processing of sensory input during recognition and decision-making processes. In quadruple-area ensemble recordings from male rats engaged in a multisensory discrimination task, we investigated phase entrainment of cells by theta oscillations in areas along the corticohippocampal hierarchy: somatosensory barrel cortex (S1BF), secondary visual cortex (V2L), perirhinal cortex (PER), and dorsal hippocampus (dHC). Rats discriminated between two 3D objects presented in tactile-only, visual-only, or both tactile and visual modalities. During task engagement, S1BF, V2L, PER, and dHC LFP signals showed coherent theta-band activity. We found phase entrainment of single-cell spiking activity to locally recorded as well as hippocampal theta activity in S1BF, V2L, PER, and dHC. While phase entrainment of hippocampal spikes to local theta oscillations occurred during sustained epochs of task trials and was nonselective for behavior and modality, somatosensory and visual cortical cells were only phase entrained during stimulus presentation, mainly in their preferred modality (S1BF, tactile; V2L, visual), with subsets of cells selectively phase-entrained during cross-modal stimulus presentation (S1BF: visual; V2L: tactile). This effect could not be explained by modulations of firing rate or theta amplitude. Thus, hippocampal cells are phase entrained during prolonged epochs, while sensory and perirhinal neurons are selectively entrained during sensory stimulus presentation, providing a brief time window for coordination of activity.

Network-neuron interactions underlying sensory responses of layer 5 pyramidal tract neurons in barrel cortex.

Neurons in the cerebral cortex receive thousands of synaptic inputs per second from thousands of presynaptic neurons. How the dendritic location of inputs, their timing, strength, and presynaptic origin, in conjunction with complex dendritic physiology, impact the transformation of synaptic input into action potential (AP) output remains generally unknown for in vivo conditions. Here, we introduce a computational approach to reveal which properties of the input causally underlie AP output, and how this neuronal input-output computation is influenced by the morphology and biophysical properties of the dendrites. We demonstrate that this approach allows dissecting of how different input populations drive in vivo observed APs. For this purpose, we focus on fast and broadly tuned responses that pyramidal tract neurons in layer 5 (L5PTs) of the rat barrel cortex elicit upon passive single whisker deflections. By reducing a multi-scale model that we reported previously, we show that three features are sufficient to predict with high accuracy the sensory responses and receptive fields of L5PTs under these specific in vivo conditions: the count of active excitatory versus inhibitory synapses preceding the response, their spatial distribution on the dendrites, and the AP history. Based on these three features, we derive an analytically tractable description of the input-output computation of L5PTs, which enabled us to dissect how synaptic input from thalamus and different cell types in barrel cortex contribute to these responses. We show that the input-output computation is preserved across L5PTs despite morphological and biophysical diversity of their dendrites. We found that trial-to-trial variability in L5PT responses, and cell-to-cell variability in their receptive fields, are sufficiently explained by variability in synaptic input from the network, whereas variability in biophysical and morphological properties have minor contributions. Our approach to derive analytically tractable models of input-output computations in L5PTs provides a roadmap to dissect network-neuron interactions underlying L5PT responses across different in vivo conditions and for other cell types.

Multi-scale analysis of acupuncture mechanisms for motor and sensory cortex activity based on SEEG data.

Acupuncture, a traditional Chinese therapy, is gaining attention for its impact on the brain. While existing electroencephalogram and functional magnetic resonance image research has made significant contributions, this paper utilizes stereo-electroencephalography data for a comprehensive exploration of neurophysiological effects. Employing a multi-scale approach, channel-level analysis reveals notable $\delta $-band activity changes during acupuncture. At the brain region level, acupuncture modulated connectivity between the paracentral lobule and the precentral gyrus. Whole-brain analysis indicates acupuncture's influence on network organization, and enhancing $E_{glob}$ and increased interaction between the motor and sensory cortex. Brain functional reorganization is an important basis for functional recovery or compensation after central nervous system injury. The use of acupuncture to stimulate peripheral nerve trunks, muscle motor points, acupoints, etc., in clinical practice may contribute to the reorganization of brain function. This multi-scale perspective provides diverse insights into acupuncture's effects. Remarkably, this paper pioneers the introduction of stereo-electroencephalography data, advancing our understanding of acupuncture's mechanisms and potential therapeutic benefits in clinical settings.

Responsive regularity of neurons in the hindlimb region of primary somatosensory cortex to different temperature thermal needle stimulation of "Zusanli"(ST36) in mice. / å°é¼ åˆçº§ä½“æ„Ÿçš®å±‚åŽè‚¢åŒºç¥žç»å ƒå¯¹"足三里"不同温度热刺激的响应规律.

OBJECTIVES: To study the regularity of central response to thermal needle stimulation of "Zusanli" (ST36) at different temperature, and to analyze the temperature difference of central responses. METHODS: Six male C57BL/6j adult mice were used in the present study. For observing activities of neurons in the hindlimb region of left primary somatosensory cortex (S1HL, A/P=0.46 mm, M/L=1.32 mm, D/V=-0.14 mm) by using a fast high-resolution miniature two-photon microscopy (FHIRM-TPM), the mice were anesthetized with 3% isoflurane (inhalation), with its head fixed in a stereotaxic apparatus, then, adeno-associated virus (AAV-hSyn-GCaMP6f-WPRE-hGHpA, for showing intracellular calcium transients in neurons transfected) was injected into the left S1HL region using a micro-syringe after scalp surgical operation. The mice's right ST36 were stimulated using internal thermal needles with the temperature being 43 ℃, or 45 ℃, or 47 ℃, separately. Image J software and MATLAB 2020b software were used to process the image data of neuronal calcium activity (Ca2+ signaling) in the left S1HL region, including the instant maximum calcium peak value (ΔF/F) in 2 s, instant calcium spike frequency in 2 s, short-term calcium peak value (ΔF/F) in 3.5 min, short-term calcium spike frequency in 3.5 min, calcium peak duration in 3.5 min, maximum calcium peak value (ΔF/F) at the 1st , 2nd and 3rd min, and calcium spike frequency at the 1st, 2nd and 3rd min after thermal needle stimulation. RESULTS: In comparison with the normal temperature needle stimulation, the instant intracellular maximum calcium peak value, instant calcium spike frequency, short-term maximum calcium peak value, short-term calcium spike frequency, and calcium peak duration of S1HL neurons in response to 43 ℃, 45 ℃ and 47 ℃ internal thermal needle stimulation of ST36 were significantly increased (P<0.001, P<0.01). Comparison among the 43 ℃, 45 ℃ and 47 ℃ thermal needle stimulation showed that the 45 ℃ thermal needle stimulation was obviously superior to 43 ℃ and 47 ℃ thermal needle stimulation in increasing instant calcium spike frequency, short-term calcium spike frequency and calcium peak duration of S1HL neurons (P<0.001, P<0.01). The 47 ℃ thermal needle stimulation was stronger than 43 ℃ and 45 ℃ thermal needle stimulation in increasing the instant maximum calcium peak value (P<0.001). The maximum calcium peak value was apparently higher (P<0.001) at the 2nd min than that at the 1st and 3rd min after 43 ℃, 45 ℃ and 47 ℃ thermal needle stimulation. No significant differences were found in the short-term maximum calcium peak value among the 3 thermal needle stimulation and in the calcium spike frequency among the 3 time points after 43 ℃, 45 ℃ and 47 ℃ thermal needle stimulation. CONCLUSIONS: S1HL neurons respond to all 43 ℃, 45 ℃ and 47 ℃ thermal needle stimulation of ST36 in mice, while more actively to 45 ℃ thermal needle stimulation.

Tactile processing in mouse cortex depends on action context.

The brain receives constant tactile input, but only a subset guides ongoing behavior. Actions associated with tactile stimuli thus endow them with behavioral relevance. It remains unclear how the relevance of tactile stimuli affects processing in the somatosensory (S1) cortex. We developed a cross-modal selection task in which head-fixed mice switched between responding to tactile stimuli in the presence of visual distractors or to visual stimuli in the presence of tactile distractors using licking movements to the left or right side in different blocks of trials. S1 spiking encoded tactile stimuli, licking actions, and direction of licking in response to tactile but not visual stimuli. Bidirectional optogenetic manipulations showed that sensory-motor activity in S1 guided behavior when touch but not vision was relevant. Our results show that S1 activity and its impact on behavior depend on the actions associated with a tactile stimulus.

A primary sensory cortical interareal feedforward inhibitory circuit for tacto-visual integration.

Tactile sensation and vision are often both utilized for the exploration of objects that are within reach though it is not known whether or how these two distinct sensory systems combine such information. Here in mice, we used a combination of stereo photogrammetry for 3D reconstruction of the whisker array, brain-wide anatomical tracing and functional connectivity analysis to explore the possibility of tacto-visual convergence in sensory space and within the circuitry of the primary visual cortex (VISp). Strikingly, we find that stimulation of the contralateral whisker array suppresses visually evoked activity in a tacto-visual sub-region of VISp whose visual space representation closely overlaps with the whisker search space. This suppression is mediated by local fast-spiking interneurons that receive a direct cortico-cortical input predominantly from layer 6 neurons located in the posterior primary somatosensory barrel cortex (SSp-bfd). These data demonstrate functional convergence within and between two primary sensory cortical areas for multisensory object detection and recognition.

Local contribution to the somatosensory evoked potentials in rat's thalamus.

Local Field Potential (LFP), despite its name, often reflects remote activity. Depending on the orientation and synchrony of their sources, both oscillations and more complex waves may passively spread in brain tissue over long distances and be falsely interpreted as local activity at such distant recording sites. Here we show that the whisker-evoked potentials in the thalamic nuclei are of local origin up to around 6 ms post stimulus, but the later (7-15 ms) wave is overshadowed by a negative component reaching from cortex. This component can be analytically removed and local thalamic LFP can be recovered reliably using Current Source Density analysis. We used model-based kernel CSD (kCSD) method which allowed us to study the contribution of local and distant currents to LFP from rat thalamic nuclei and barrel cortex recorded with multiple, non-linear and non-regular multichannel probes. Importantly, we verified that concurrent recordings from the cortex are not essential for reliable thalamic CSD estimation. The proposed framework can be used to analyze LFP from other brain areas and has consequences for general LFP interpretation and analysis.

Dynamic corticothalamic modulation of the somatosensory thalamocortical circuit during wakefulness.

The feedback projections from cortical layer 6 (L6CT) to the sensory thalamus have long been implicated in playing a primary role in gating sensory signaling but remain poorly understood. To causally elucidate the full range of effects of these projections, we targeted silicon probe recordings to the whisker thalamocortical circuit of awake mice selectively expressing Channelrhodopsin-2 in L6CT neurons. Through optogenetic manipulation of L6CT neurons, multi-site electrophysiological recordings, and modeling of L6CT circuitry, we establish L6CT neurons as dynamic modulators of ongoing spiking in the ventral posteromedial nucleus of the thalamus (VPm), either suppressing or enhancing VPm spiking depending on L6CT neurons' firing rate and synchrony. Differential effects across the cortical excitatory and inhibitory sub-populations point to an overall influence of L6CT feedback on cortical excitability that could have profound implications for regulating sensory signaling across a range of ethologically relevant conditions.

Evolutionarily conserved neural responses to affective touch in monkeys transcend consciousness and change with age.

Affective touch-a slow, gentle, and pleasant form of touch-activates a different neural network than which is activated during discriminative touch in humans. Affective touch perception is enabled by specialized low-threshold mechanoreceptors in the skin with unmyelinated fibers called C tactile (CT) afferents. These CT afferents are conserved across mammalian species, including macaque monkeys. However, it is unknown whether the neural representation of affective touch is the same across species and whether affective touch's capacity to activate the hubs of the brain that compute socioaffective information requires conscious perception. Here, we used functional MRI to assess the preferential activation of neural hubs by slow (affective) vs. fast (discriminative) touch in anesthetized rhesus monkeys (Macaca mulatta). The insula, anterior cingulate cortex (ACC), amygdala, and secondary somatosensory cortex were all significantly more active during slow touch relative to fast touch, suggesting homologous activation of the interoceptive-allostatic network across primate species during affective touch. Further, we found that neural responses to affective vs. discriminative touch in the insula and ACC (the primary cortical hubs for interoceptive processing) changed significantly with age. Insula and ACC in younger animals differentiated between slow and fast touch, while activity was comparable between conditions for aged monkeys (equivalent to >70 y in humans). These results, together with prior studies establishing conserved peripheral nervous system mechanisms of affective touch transduction, suggest that neural responses to affective touch are evolutionarily conserved in monkeys, significantly impacted in old age, and do not necessitate conscious experience of touch.

What does the mean mean? A simple test for neuroscience.

Trial-averaged metrics, e.g. tuning curves or population response vectors, are a ubiquitous way of characterizing neuronal activity. But how relevant are such trial-averaged responses to neuronal computation itself? Here we present a simple test to estimate whether average responses reflect aspects of neuronal activity that contribute to neuronal processing. The test probes two assumptions implicitly made whenever average metrics are treated as meaningful representations of neuronal activity: Reliability: Neuronal responses repeat consistently enough across trials that they convey a recognizable reflection of the average response to downstream regions.Behavioural relevance: If a single-trial response is more similar to the average template, it is more likely to evoke correct behavioural responses. We apply this test to two data sets: (1) Two-photon recordings in primary somatosensory cortices (S1 and S2) of mice trained to detect optogenetic stimulation in S1; and (2) Electrophysiological recordings from 71 brain areas in mice performing a contrast discrimination task. Under the highly controlled settings of Data set 1, both assumptions were largely fulfilled. In contrast, the less restrictive paradigm of Data set 2 met neither assumption. Simulations predict that the larger diversity of neuronal response preferences, rather than higher cross-trial reliability, drives the better performance of Data set 1. We conclude that when behaviour is less tightly restricted, average responses do not seem particularly relevant to neuronal computation, potentially because information is encoded more dynamically. Most importantly, we encourage researchers to apply this simple test of computational relevance whenever using trial-averaged neuronal metrics, in order to gauge how representative cross-trial averages are in a given context.

The Anterolateral Barrel Subfield Differs from the Posteromedial Barrel Subfield in the Morphology and Cell Density of Parvalbumin-Positive GABAergic Interneurons.

Layer 4 of the rodent somatosensory cortex has unitary structures called barrels that receive tactile information from individual vibrissae. Barrels in the anterolateral barrel subfield (ALBSF) are much smaller and have gained less attention than larger barrels in the posteromedial barrel subfield (PMBSF), though the former outnumber the latter. We compared the morphological features of barrels between the ALBSF and PMBSF in male mice using deformation-free tangential sections and confocal optical slice-based, precise reconstructions of barrels. The average volume of a single barrel in the ALBSF was 34.7% of that in the PMBSF, but the numerical density of parvalbumin (PV)-positive interneurons in the former was 1.49 times higher than that in the latter. Moreover, PV neuron density in septa was 2.08 times higher in the ALBSF than that in the PMBSF. The proportions of PV neuron number to both all neuron number and all GABAergic neuron number in the ALBSF were also higher than those in the PMBSF. Somata of PV neurons in barrels and septa in the ALBSF received 1.64 and 1.50 times more vesicular glutamate transporter Type 2-labeled boutons than those in the PMBSF, suggesting more potent feedforward inhibitory circuits in the ALBSF. The mode of connectivity through dendritic gap junctions among PV neurons also differed between the ALBSF and PMBSF. Clusters of smaller unitary structures containing a higher density of representative GABAergic interneurons with differential morphological features in the ALBSF suggest a division of functional roles in the two vibrissa-barrel systems, as has been demonstrated by behavioral studies.

Modulation of somatosensory signal transmission in the primate cuneate nucleus during voluntary hand movement.

Primate hands house an array of mechanoreceptors and proprioceptors, which are essential for tactile and kinematic information crucial for daily motor action. While the regulation of these somatosensory signals is essential for hand movements, the specific central nervous system (CNS) location and mechanism remain unclear. Our study demonstrates the attenuation of somatosensory signals in the cuneate nucleus during voluntary movement, suggesting significant modulation at this initial relay station in the CNS. The attenuation is comparable to the cerebral cortex but more pronounced than in the spinal cord, indicating the cuneate nuclei's role in somatosensory perception modulation during movement. Moreover, our findings suggest that the descending motor tract may regulate somatosensory transmission in the cuneate nucleus, enhancing relevant signals and suppressing unnecessary ones for the regulation of movement. This process of recurrent somatosensory modulation between cortical and subcortical areas could be a basic mechanism for modulating somatosensory signals to achieve active perception.

Separation of bimodal fMRI responses in mouse somatosensory areas into V1 and non-V1 contributions.

Multisensory integration is necessary for the animal to survive in the real world. While conventional methods have been extensively used to investigate the multisensory integration process in various brain areas, its long-range interactions remain less explored. In this study, our goal was to investigate interactions between visual and somatosensory networks on a whole-brain scale using 15.2-T BOLD fMRI. We compared unimodal to bimodal BOLD fMRI responses and dissected potential cross-modal pathways with silencing of primary visual cortex (V1) by optogenetic stimulation of local GABAergic neurons. Our data showed that the influence of visual stimulus on whisker activity is higher than the influence of whisker stimulus on visual activity. Optogenetic silencing of V1 revealed that visual information is conveyed to whisker processing via both V1 and non-V1 pathways. The first-order ventral posteromedial thalamic nucleus (VPM) was functionally affected by non-V1 sources, while the higher-order posterior medial thalamic nucleus (POm) was predominantly modulated by V1 but not non-V1 inputs. The primary somatosensory barrel field (S1BF) was influenced by both V1 and non-V1 inputs. These observations provide valuable insights for into the integration of whisker and visual sensory information.

Involvement of primary somatosensory cortex in motor learning and task execution.

The primary somatosensory cortex (S1) is responsible for processing information related to tactile stimulation, motor learning and control. Despite its significance, the connection between S1 and the primary motor cortex (M1), as well as its role in motor learning, remains a topic of ongoing exploration. In the present study, we silenced S1 by the GABA receptor agonist muscimol to study the potential roles of S1 in motor learning and task execution. Our results show that the inhibition of S1 leads to an immediate impairment in performance during the training session and also a substantial reduction in performance improvement during post-test session on the subsequent day. To understand the underlying mechanism, we used intravital two-photon imaging to investigate the dynamics of dendritic spines of layer V pyramidal neurons and the calcium activities of pyramidal neurons in M1 after inhibition of S1. Notably, S1 inhibition reduces motor training-induced spine formation and facilitates the elimination of existing spines of layer V pyramidal neurons in M1. The calcium activities in M1 exhibit a significant decrease during both resting and running periods following S1 inhibition. Furthermore, inhibition of S1, but not M1, significantly impairs the execution of the acquired motor task in the well-trained animals. Together, these findings reveal that S1 plays important roles in motor learning and task execution.

Ocular surface information seen from the somatosensory thalamus and cortex.

Ocular Surface (OS) somatosensory innervation detects external stimuli producing perceptions, such as pain or dryness, the most relevant symptoms in many OS pathologies. Nevertheless, little is known about the central nervous system circuits involved in these perceptions, and how they integrate multimodal inputs in general. Here, we aim to describe the thalamic and cortical activity in response to OS stimulation of different modalities. Electrophysiological extracellular recordings in anaesthetized rats were used to record neural activity, while saline drops at different temperatures were applied to stimulate the OS. Neurons were recorded in the ophthalmic branch of the trigeminal ganglion (TG, 49 units), the thalamic VPM-POm nuclei representing the face (Th, 69 units) and the primary somatosensory cortex (S1, 101 units). The precise locations for Th and S1 neurons receiving OS information are reported here for the first time. Interestingly, all recorded nuclei encode modality both at the single neuron and population levels, with noxious stimulation producing a qualitatively different activity profile from other modalities. Moreover, neurons responding to new combinations of stimulus modalities not present in the peripheral TG subsequently appear in Th and S1, being organized in space through the formation of clusters. Besides, neurons that present higher multimodality display higher spontaneous activity. These results constitute the first anatomical and functional characterization of the thalamocortical representation of the OS. Furthermore, they provide insight into how information from different modalities gets integrated from the peripheral nervous system into the complex cortical networks of the brain. KEY POINTS: Anatomical location of thalamic and cortical ocular surface representation. Thalamic and cortical neuronal responses to multimodal stimulation of the ocular surface. Increasing functional complexity along trigeminal neuroaxis. Proposal of a new perspective on how peripheral activity shapes central nervous system function.