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Neuropathic pain is pain caused by damage to the somatosensory nervous system. Both degenerating injured nerves and neighboring sprouting nerves can contribute to neuropathic pain. However, the mesoscale changes in cutaneous nerve fibers over time after the loss of the parent nerve has not been investigated in detail. In this study, we followed the changes in nerve fibers longitudinally in the toe tips of mice that had undergone spared nerve injury (SNI). Nav1.8-tdTomato, Thy1-GFP and MrgD-GFP mice were used to observe the small and large cutaneous nerve fibers. We found that peripheral nerve plexuses degenerated within 3 days of nerve injury, and free nerve endings in the epidermis degenerated within 2 days. The timing of degeneration paralleled the initiation of mechanical hypersensitivity. We also found that some of the Nav1.8-positive nerve plexuses and free nerve endings in the fifth toe survived, and sprouting occurred mostly from 7 to 28 days. The timing of the sprouting of nerve fibers in the fifth toe paralleled the maintenance phase of mechanical hypersensitivity. Our results support the hypotheses that both injured and intact nerve fibers participate in neuropathic pain, and that, specifically, nerve degeneration is related to the initiation of evoked pain and nerve sprouting is related to the maintenance of evoked pain.

Summary The Nyquist-Shannon criterion has never been realized in a laser-scanning mesoscopic multiphoton microscope (MPM) with a large field-of-view (FOV)-resolution ratio, especially when employing a high-frequency resonant-raster-scanning. With a high optical resolution nature, a current mesoscopic-MPM either neglects the criterion and degrades the digital resolution to twice the pixel size, or reduces the FOV and/or the raster-scanning speed to avoid aliasing. We introduce a Nyquist figure-of-merit (NFOM) parameter to characterize a laser-scanning MPM in terms of its optical-resolution retrieving ability. Based on NFOM, we define the maximum aliasing-free FOV, and subsequently, a cross-over excitation wavelength, below which the FOV becomes NFOM-constrained irrespective of an optimized optical design. We validate our idea in a custom-built mesoscopic-MPM with millimeter-scale FOV yielding an ultra-high FOV-resolution ratio of >3,000, while securing up-to a 1.6 mm Nyquist-satisfied aliasing-free FOV, a ∼400 nm lateral resolution, and a 70 M/s effective voxel-sampling rate, all at the same time., Graphical abstract, Highlights • Nyquist figure-of-merit is introduced to characterize laser-scanning MPM digitization • Maximum aliasing-free FOV and cross-over excitation wavelength are formulated • High repetition-rate laser can enable high-speed large-FOV high-resolution MPM imaging • Up-to 1.6 mm-wide non-aliased FOV and ∼400 nm digital resolution at 8 kHz line-rate, Data acquisition in bioinformatics; Materials science; Optical imaging

We have demonstrated a widely-tunable femtosecond fiber source between 770-1180 nm enabled by self-phase modulation, and the wide spectral coverage is suitable for most of two-photon fluorescence microscopy applications. Based on femtosecond Yb:fiber laser, we also compared spectral broadening in different dispersion regimes using different photonic crystal fibers. We managed to maximize the self-phase modulated feature from the broadened spectra while avoiding unwanted nonlinear temporal trapping. The optimization of fiber selection and laser input conditions led to a wide tunability down to below 800nm region, which is the most commonly used two-photon excitation wavelength for many intrinsic fluorescent labels in biological tissues. We believe this fiber-based femtosecond source can be a relatively cost-effective and robust solution for most of two-photon fluorescence microscopy applications.

Essential tremor (ET) is one of the most common movement disorders and the prototypical disorder for abnormal rhythmic movements. However, the pathophysiology of tremor generation in ET remains unclear. Here, we used autoptic cerebral tissue from patients with ET, clinical data, and mouse models to report that synaptic pruning deficits of climbing fiber (CF)-to-Purkinje cell (PC) synapses, which are related to glutamate receptor delta 2 (GluRδ2) protein insufficiency, cause excessive cerebellar oscillations and might be responsible for tremor. The CF-PC synaptic pruning deficits were correlated with the reduction in GluRδ2 expression in the postmortem ET cerebellum. Mice with GluRδ2 insufficiency and CF-PC synaptic pruning deficits develop ET-like tremor that can be suppressed with viral rescue of GluRδ2 protein. Step-by-step optogenetic or pharmacological inhibition of neuronal firing, axonal activity, or synaptic vesicle release confirmed that the activity of the excessive CF-to-PC synapses is required for tremor generation. In vivo electrophysiology in mice showed that excessive cerebellar oscillatory activity is CF dependent and necessary for tremor and optogenetic-driven PC synchronization was sufficient to generate tremor in wild-type animals. Human validation by cerebellar electroencephalography confirmed that excessive cerebellar oscillations also exist in patients with ET. Our findings identify a pathophysiologic contribution to tremor at molecular (GluRδ2), structural (CF-to-PC synapses), physiological (cerebellar oscillations), and behavioral levels (kinetic tremor) that might have clinical applications for treating ET.

Background: The number and calibre of myelinated and unmyelinated fibres of the sacrococcygeal dorsal roots innervating the tail of rats were studied by means of light and electron microscopy. Materials and methods: There were an estimated total of 12,500 myelinated and 25,500 unmyelinated dorsal root fibres innervating the tail of a rat. Results: The results showed that from the second sacral (S2) to the fourth sacral (S4) segment, the fibre diameter spectrum of myelinated fibres within each dorsal root was bimodal with two peaks at 5 microns and 10 microns, respectively. The first sacral (S1) segment was composed of numerous smaller-size myelinated fibres, thus forming a right-skewed distribution. The coccygeal (Co) segments showed a unimodal distribution peaking at 10 microns for the first (Co1) segment and gradually shifting to 7 microns for the third (Co3) segment. Overall, there was a continuous relative increase of the larger vs. the smaller myelinated fibres from the sacral to coccygeal segments. The fibre diameter of unmyelinated fibres of all these roots was unimodal with a single peak at 0.5 microns. The ratio of unmy- elinated to myelinated fibre numbers was on average 2.83 for the S1–S2 roots, 1.66 for the S3–S4 roots, and 1.24 for the coccygeal roots. Conclusions: The comparison of the left- and right-side nerve fibres show that there was no significant difference, thus implying a symmetrical sensory innervation of the rat’s tail.

Primary somatosensory cortex (SI) is a key area in the processing of nociceptor inputs to our consciousness. To clarify the columnar and laminar organization of SI for pain processing, we compared spatiotemporal changes in neuronal activities of the primary sensorimotor cortex (SmI) of the rat in response to noxious laser heat stimulation applied to the mid-tail. Longitudinal and vertical array microelectrodes were chronically implanted in the cerebral cortex. Evoked neuronal activities, including intracortical local field potentials (LFP) and ensemble single-unit activity (SU) around SmI were simultaneously recorded. The effect of pentobarbital on the neuronal responses was evaluated in comparison with the neuronal responses in conscious animals to explore the potential substrate of nociceptive processing in the conscious state. The results from the experiment with longitudinal microelectrode arrays indicated that noxious stimulation induced a neuronal response which was spread widely around the SmI of the conscious rat, and the range of neuronal responses was limited to the tail region of the SmI under anesthesia. The results from the experiment with vertical microelectrode arrays showed the universal neuronal responses through all cortical layers of the SmI in conscious rats, and sodium pentobarbital suppressed these neuronal responses in the supragranular layers significantly relative to the deeper layers and basal activity. These results imply that a wider range of cortical activation, both in the horizontal or vertical dimension, might be important for nociceptive processing in the conscious state.

Tooth loss is common, and exploring the neuroplastic capacity of the face primary motor cortex (face-M1) and adjacent primary somatosensory cortex (face-S1) is crucial for understanding how subjects adapt to tooth loss and their prosthetic replacement. The aim was to test if functional reorganization of jaw and tongue motor representations in the rat face-M1 and face-S1 occurs following tooth extraction, and if subsequent dental implant placement can reverse this neuroplasticity. Rats (n = 22) had the right maxillary molar teeth extracted under local and general anesthesia. One month later, seven rats had dental implant placement into healed extraction sites. Naive rats (n = 8) received no surgical treatment. Intracortical microstimulation (ICMS) and recording of evoked jaw and tongue electromyographic responses were used to define jaw and tongue motor representations at 1 month (n = 8) or 2 months (n = 7) postextraction, 1 month postimplant placement, and at 1–2 months in naive rats. There were no significant differences across study groups in the onset latencies of the ICMS-evoked responses (P > 0.05), but in comparison with naive rats, tooth extraction caused a significant (P

Orthodontic tooth movement (OTM) causes transient pain and changes in the dental occlusion that may lead to altered somatosensory inputs and patterns of mastication. This study used intracortical microstimulation (ICMS) and electromyographic (EMG) recordings to test whether neuroplastic changes occur in the ICMS-defined motor representations of left and right anterior digastric (LAD, RAD), masseter, buccinator, and genioglossus (GG) muscles within the rat's face primary motor cortex (face-M1) and adjacent face primary somatosensory cortex (face-S1) during OTM. Analyses included any changes in the number of ICMS sites representing these muscles and in the onset latencies of ICMS-evoked responses in the muscles. Sprague-Dawley rats were divided into experimental (E), sham (S), and naive (N) groups; OTM was induced in the E group. Statistical analyses involved a mixed model repeated-measures analysis of variance (MMRM ANOVA). OTM resulted in significant neuroplastic changes in the number of positive sites in the E group for LAD, RAD, and GG muscles in face-M1 and face-S1 at days 1, 7, and 28 of continuous orthodontic force application, and in the number of sites in face-M1 from which ICMS could simultaneously evoke EMG responses in different combinations of LAD, RAD, and GG muscles. However, the onset latencies of ICMS-evoked responses were not significantly different between groups or between face-M1 and face-S1. The neuroplastic changes documented in this study may reflect adaptive sensorimotor changes in response to the altered environment in the oral cavity induced by OTM.

Study Objective:To test the hypothesis that the reflex and corticobulbar motor excitability of jaw muscles is reduced during sleep.Design:Polysomnographic recordings in the electrophysiological study.Setting:University sleep research laboratories.Participants and Interventions:The reflex and corticobulbar motor excitability of jaw muscles was determined during the quiet awake state (QW) and quiet sleep (QS) in monkeys (n = 4).Measurements and Results:During QS sleep, compared to QW periods, both tongue stimulation-evoked jaw-opening reflex peak and root mean square amplitudes were significantly decreased with stimulations at 2-3.5 × thresholds (P < 0.001). The jaw-opening reflex latency during sleep was also significantly longer than during QW. Intracortical microstimulation (ICMS) within the cortical masticatory area induced rhythmic jaw movements at a stable threshold (≤ 60 μA) during QW; but during QS, ICMS failed to induce any rhythmic jaw movements at the maximum ICMS intensity used, although sustained jaw-opening movements were evoked at significantly increased threshold (P < 0.001) in one of the monkeys. Similarly, during QW, ICMS within face primary motor cortex induced orofacial twitches at a stable threshold (≤ 35 μA), but the ICMS thresholds were elevated during QS. Soon after the animal awoke, rhythmic jaw movements and orofacial twitches could be evoked at thresholds similar to those before QS.Conclusions:The results suggest that the excitability of reflex and corticobulbar-evoked activity in the jaw motor system is depressed during QS.

This review describes evidence in subprimates and primates that the face primary somatosensory cortex (face SI) and primary motor cortex (face MI) are involved in sensorimotor integration and control of orofacial motor functions that include semiautomatic movements (e.g., chewing, swallowing) and voluntary movements (e.g., jaw-opening). The review also notes that the neuroplastic capabilities of the face SI and face MI have recently been documented, and may reflect or allow for functional adaptation (or maladaptation) of the orofacial sensorimotor system to an altered oral state or oral motor behaviour. They may contribute to the processes whereby patients undergoing oral rehabilitation can (or cannot) restore the lost orofacial sensorimotor functions. Such understanding is important since pain, injuries to the oral tissues, and alterations to the dental occlusion induced by tooth loss or attrition are common occurrences in humans that may sometimes be accompanied by impaired oral sensorimotor functions. Furthermore, impaired oral sensorimotor functions are common in many neurological disorders, sometimes making the most vital functions of eating, swallowing and speaking difficult and thereby reducing the patient's quality of life. It has also been well documented that such negative consequences can be improved following oral rehabilitation as patients adapt, for example, to a new dental prosthesis aimed at restoring function. Therefore, understanding the mechanisms and cortical neuroplastic processes underlying orofacial sensorimotor functions and adaptation is also important for the development of new therapeutic strategies to facilitate recovery of patients suffering from orofacial pain and sensorimotor disorders and improve their quality of life.

Central sensitization is a crucial process underlying the increased neuronal excitability of nociceptive pathways following peripheral tissue injury and inflammation. Our previous findings have suggested that extracellular adenosine 5'-triphosphate (ATP) molecules acting at purinergic receptors located on presynaptic terminals (e.g., P2X2/3, P2X3 subunits) and glial cells are involved in the glutamatergic-dependent central sensitization induced in medullary dorsal horn (MDH) nociceptive neurons by application to the tooth pulp of the inflammatory irritant mustard oil (MO). Since growing evidence indicates that activation of P2X7 receptors located on glia is involved in chronic inflammatory and neuropathic pain, the aim of the present study was to test in vivo for P2X7 receptor involvement in this acute inflammatory pain model. Experiments were carried out in anesthetized Sprague-Dawley male rats. Single unit recordings were made in MDH functionally identified nociceptive neurons for which mechanoreceptive field, mechanical activation threshold and responses to noxious stimuli were tested. We found that continuous intrathecal (i.t.) superfusion over MDH of the potent P2X7 receptor antagonists brilliant blue G and periodated oxidized ATP could each significantly attenuate the MO-induced MDH central sensitization. MDH central sensitization could also be produced by i.t. superfusion of ATP and even more effectively by the P2X7 receptor agonist benzoylbenzoyl ATP. Superfusion of the microglial blocker minocycline abolished the MO-induced MDH central sensitization, consistent with reports that dorsal horn P2X7 receptors are mostly expressed on microglia. In control experiments, superfusion over MDH of vehicle did not produce any significant changes. These novel findings suggest that activation of P2X7 receptors in vivo may be involved in the development of central sensitization in an acute inflammatory pain model.

Loss of teeth is associated with changes in somatosensory inputs and altered patterns of mastication, but it is unclear whether tooth loss is associated with changes in motor representations within face sensorimotor cortex of rats. We used intracortical microstimulation (ICMS) and recordings of cortically evoked muscle electromyographic (EMG) activities to test whether changes occur in the ICMS-defined motor representations of the left and right jaw muscles [masseter, anterior digastric (LAD, RAD)] and tongue muscle [genioglossus (GG)] within the cytoarchitectonically defined face primary motor cortex (face-M1) and adjacent face primary somatosensory cortex (face-S1) 1 week following extraction of the right mandibular incisor in anesthetized (ketamine-HCl) adult male Sprague-Dawley rats. Under local and general anesthesia, an “extraction” group (n = 8) received mucoalveolar bone surgery and extraction of the mandibular right incisor. A “sham-extraction” group (n = 6) received surgery with no extraction. A “naive” group (n = 6) had neither surgery nor extraction. Data were compared by using mixed-model repeated-measures ANOVA. Dental extraction was associated with a significantly increased number of sites within face-M1 and face-S1 from which ICMS evoked RAD EMG activities, a lateral shift of the RAD and LAD centers of gravity within face-M1, shorter onset latencies of ICMS-evoked GG activities within face-M1 and face-S1, and an increased number of sites within face-M1 from which ICMS simultaneously evoked RAD and GG activities. Our novel findings suggest that dental extraction may be associated with significant neuroplastic changes within the rat's face-M1 and adjacent face-S1 that may be related to the animal's ability to adapt to the altered oral state. J. Comp. Neurol. 518:1030–1045, 2010. © 2009 Wiley-Liss, Inc.

The mechanisms whereby orofacial pain affects motor function are poorly understood. The aims were to determine whether 1) lingual algesic chemical stimulation affected face primary motor cerebral cortex (face MI) excitability defined by intracortical microstimulation (ICMS); and 2) any such effects were limited to the motor efferent MI zones driving muscles in the vicinity of the noxious stimulus. Ketamine-anesthetized Sprague–Dawley male rats were implanted with electromyographic (EMG) electrodes into anterior digastric, masseter, and genioglossus muscles. In 38 rats, three microelectrodes were located in left face MI at ICMS-defined sites for evoking digastric and/or genioglossus responses. ICMS thresholds for evoking EMG activity from each site were determined every 15 min for 1 h, then the right anterior tongue was infused (20 μl, 120 μl/h) with glutamate (1.0 M, n = 18) or isotonic saline ( n = 7). Subsequently, ICMS thresholds were determined every 15 min for 4 h. In intact control rats ( n = 13), ICMS thresholds were recorded over 5 h. Only left and right genioglossus ICMS thresholds were significantly increased (≤350%) in the glutamate infusion group compared with intact and isotonic saline groups ( P < 0.05). These dramatic effects of glutamate on ICMS-evoked genioglossus activity contrast with its weak effects only on right genioglossus activity evoked from the internal capsule or hypoglossal nucleus. This is the first documentation that intraoral noxious stimulation results in prolonged neuroplastic changes manifested as a decrease in face MI excitability. These changes appear to occur predominantly in those parts of face MI that provide motor output to the orofacial region receiving the noxious stimulation.

We have carried out a series of studies to address the role of the face primary motor area (MI) in the cerebral cortex in trained or semi-automatic orofacial motor behaviours and in behavioural adaptations to an altered oral environment. These studies have utilized intracortical microstimulation (ICMS), reversible cold block or single neurone recordings in face MI. Our studies in monkeys have revealed that face MI plays a strategic role in elemental and learned motor behaviours and in certain aspects of chewing and swallowing. Furthermore, successful training of awake monkeys in a novel tongue-protrusion task is associated with significant neuroplastic changes in face MI. These findings in monkeys are supported by correlated findings in humans which have revealed significantly enhanced corticomotoneuronal excitability when humans learn the novel tongue-protrusion task. Our related ICMS studies in rats reveal that trimming or extraction of the rat's lower incisors or damage to the rat's lingual nerve can result in significant changes in the MI representations of the tongue or jaw muscles. These various findings suggest that the face MI is important in orofacial motor skill acquisition and adaptation to an altered occlusion or loss of teeth or lingual sensory function, and that it reflects dynamic and modifiable constructs that are modelled by behaviourally significant experiences and that are critical to learning and adaptive processes.

Modification to the dental occlusion may alter oral sensorimotor functions. Restorative treatments aim to restore sensorimotor functions; however, it is unclear why some patients fail to adapt to the restoration and remain with sensorimotor complaints. The face primary motor cortex (face-M1) is involved in the generation and control of orofacial movements. Altered sensory inputs or motor function can induce face-M1 neuroplasticity. We took advantage of the continuous eruption of the incisors in Sprague-Dawley rats and used intracortical microstimulation (ICMS) to map the jaw and tongue motor representations in face-M1. Specifically, we tested the hypothesis that multiple trimming of the right mandibular incisor, to keep it out of occlusal contacts for 7 d, and subsequent incisor eruption and restoration of occlusal contacts, can alter the ICMS-defined features of jaw and tongue motor representations (i.e., neuroplasticity). On days 1, 3, 5, and 7, the trim and trim-recovered groups had 1 to 2 mm of incisal trimming of the incisor; a sham trim group had buccal surface trimming with no occlusal changes; and a naive group had no treatment. Systematic mapping was performed on day 8 in the naive, trim, and sham trim groups and on day 14 in the trim-recovered group. In the trim group, the tongue onset latency was shorter in the left face-M1 than in the right face-M1 ( P < .001). In the trim-recovered group, the number of tongue sites and jaw/tongue overlapping sites was greater in the left face-M1 than in the right face-M1 ( P = 0.0032, 0.0016, respectively), and the center of gravity was deeper in the left than in the right face-M1 ( P = 0.026). Therefore, incisor trimming and subsequent restoration of occlusal contacts induced face-M1 neuroplasticity, reflected in significant disparities between the left and right face-M1 in some ICMS-defined features of the tongue motor representations. Such neuroplasticity may reflect or contribute to subjects’ ability to adapt their oral sensorimotor functions to an altered dental occlusion.

Tooth loss is common, and exploring the neuroplastic capacity of the face primary motor cortex (face-M1) and adjacent primary somatosensory cortex (face-S1) is crucial for understanding how subjects adapt to tooth loss and their prosthetic replacement. The aim was to test if functional reorganization of jaw and tongue motor representations in the rat face-M1 and face-S1 occurs following tooth extraction, and if subsequent dental implant placement can reverse this neuroplasticity. Rats (n = 22) had the right maxillary molar teeth extracted under local and general anesthesia. One month later, seven rats had dental implant placement into healed extraction sites. Naive rats (n = 8) received no surgical treatment. Intracortical microstimulation (ICMS) and recording of evoked jaw and tongue electromyographic responses were used to define jaw and tongue motor representations at 1 month (n = 8) or 2 months (n = 7) postextraction, 1 month postimplant placement, and at 1-2 months in naive rats. There were no significant differences across study groups in the onset latencies of the ICMS-evoked responses (P 0.05), but in comparison with naive rats, tooth extraction caused a significant (P 0.05) and sustained (1-2 months) decreased number of ICMS-defined jaw and tongue sites within face-M1 and -S1, and increased thresholds of ICMS-evoked responses in these sites. Furthermore, dental implant placement reversed the extraction-induced changes in face-S1, and in face-M1 the number of jaw sites even increased as compared to naive rats. These novel findings suggest that face-M1 and adjacent face-S1 may play a role in adaptive mechanisms related to tooth loss and their replacement with dental implants.

The orofacial sensorimotor cortex is known to play a role in motor learning. However, how motor learning changes the dynamics of neuronal activity and whether these changes differ between orofacial primary motor (MIo) and somatosensory (SIo) cortices remain unknown. To address these questions, we used chronically implanted microelectrode arrays to track learning-induced changes in the activity of simultaneously recorded neurons in MIo and SIo as two naive monkeys (Macaca mulatta) were trained in a novel tongue-protrusion task. Over a period of 8–12 d, the monkeys showed behavioral improvements in task performance that were accompanied by rapid and long-lasting changes in neuronal responses in MIo and SIo occurring in parallel: (1) increases in the proportion of task-modulated neurons, (2) increases in the mutual information between tongue-protrusive force and spiking activity, (3) reductions in the across-trial firing rate variability, and (4) transient increases in coherent firing of neuronal pairs. More importantly, the time-resolved mutual information in MIo and SIo exhibited temporal alignment. While showing parallel changes, MIo neurons exhibited a bimodal distribution of peak correlation lag times between spiking activity and force, whereas SIo neurons showed a unimodal distribution. Moreover, coherent activity between pairs of MIo neurons was higher and centered around force onset compared with pairwise coherence of SIo neurons. Overall, the results suggest that the neuroplasticity in MIo and SIo occurring in parallel serves as a substrate for linking sensation and movement during sensorimotor learning, whereas the differing dynamic organizations reflect specific ways to control movement parameters as learning progresses.

BACKGROUND Mutations in Fibroblastic Growth Factor Receptors (FGFR) have been associated with human craniosynostotic birth defects like Crouzon syndrome. Several anecdotes and case reports have indicated higher incidence of gastrointestinal tract disorders in FGFR-associated craniosynostotic birth defects. Our objective was to characterize esophageal defects in a mouse model of human Crouzon syndrome, with a mutation in codon 290 of FGFR2. METHODS Dissected esophagi of Fgfr2W290R postnatal heterozygous (HET) and wild-type mice were analyzed by histological staining, immunohistochemically with cell proliferation marker, and functionally by strain gauge measures of electrically evoked contractile force. RESULTS The esophagi of HETs were noticeably smaller but with wider lumen than those of wild-type littermates. The HET esophagi showed a decrease in proliferation and an increase in expression of Sonic Hedgehog as compared to wild-type esophagi. Histological investigations revealed reduced amounts and disorganization of collagen in muscle layers. Functional analysis revealed altered contractile properties in HET with reduced peak amplitude and prolonged duration of evoked contractile force response and lower stimulation threshold. CONCLUSION The defects observed in the esophagus of the mutant may explain some of the clinical symptoms observed in humans, for example, recurrent vomiting, gastroesophageal reflux, and esophageal strictures. Taken together, our results provide evidence for the importance of Fibroblastic Growth Factor signaling in the growth and patterning of the esophagus, providing a possible scientific basis for the gastrointestinal tract clinical findings in craniosynostotic patients. Furthermore, the findings also provide a sound scientific rationale for any changes in the clinical management of gastrointestinal tract problems in patients with craniosynostotic defects. Birth Defects Research (Part A) 97:578–586, 2013. © 2013 Wiley Periodicals, Inc.

Neurons in the arm and orofacial regions of the sensorimotor cortex in behaving monkeys display directional tuning of their activity during arm reaching and tongue protrusion, respectively. While studies on population activity abound for the arm motor cortex, how populations of neurons from the orofacial sensorimotor cortex represent direction has never been described. We therefore examined and compared the directional information contained in the spiking activity of populations of single neurons recorded simultaneously from chronically implanted microelectrode arrays in the orofacial primary motor (MIo, N = 345) and somatosensory (SIo, N = 336) cortices of monkeys ( Macaca mulatta) as they protruded their tongue in different directions. Differential modulation to the direction of tongue protrusion was found in >60% of task-modulated neurons in MIo and SIo and was stronger in SIo ( P < 0.05). Moreover, mutual information between direction and spiking was significantly higher in SIo compared with MIo at force onset and force offset ( P < 0.01). Finally, the direction of tongue protrusion was accurately predicted on a trial-by-trial basis from the spiking activity of populations of MIo or SIo neurons by using a discrete decoder ( P < 0.01). The highly reliable decoding was comparable between MIo and SIo neurons. However, the temporal evolution of the decoding performance differed between these two areas: MIo showed late-onset, fast-rising, and phasic performance, whereas SIo exhibited early-onset, slow-rising, and sustained performance. Overall, the results suggest that both MIo and SIo are highly involved in representing the direction of tongue protrusion but they differ in the amplitude and temporal processing of the directional information distributed across populations of neurons.

Mutations in Fibroblastic Growth Factor Receptors (FGFR) have been associated with human craniosynostotic birth defects like Crouzon syndrome. Several anecdotes and case reports have indicated higher incidence of gastrointestinal tract disorders in FGFR-associated craniosynostotic birth defects. Our objective was to characterize esophageal defects in a mouse model of human Crouzon syndrome, with a mutation in codon 290 of FGFR2.Dissected esophagi of Fgfr2(W290R) postnatal heterozygous (HET) and wild-type mice were analyzed by histological staining, immunohistochemically with cell proliferation marker, and functionally by strain gauge measures of electrically evoked contractile force.The esophagi of HETs were noticeably smaller but with wider lumen than those of wild-type littermates. The HET esophagi showed a decrease in proliferation and an increase in expression of Sonic Hedgehog as compared to wild-type esophagi. Histological investigations revealed reduced amounts and disorganization of collagen in muscle layers. Functional analysis revealed altered contractile properties in HET with reduced peak amplitude and prolonged duration of evoked contractile force response and lower stimulation threshold.The defects observed in the esophagus of the mutant may explain some of the clinical symptoms observed in humans, for example, recurrent vomiting, gastroesophageal reflux, and esophageal strictures. Taken together, our results provide evidence for the importance of Fibroblastic Growth Factor signaling in the growth and patterning of the esophagus, providing a possible scientific basis for the gastrointestinal tract clinical findings in craniosynostotic patients. Furthermore, the findings also provide a sound scientific rationale for any changes in the clinical management of gastrointestinal tract problems in patients with craniosynostotic defects.

Loss of teeth or dental attrition is a common clinical occurrence associated with altered somatosensation and impaired oral motor behavior (e.g., mastication, deglutition, phonation). Oral rehabilitation aims at restoring these sensorimotor functions to improve patients' quality of life. Recent studies have implicated neuroplastic changes within the primary motor cortex (M1) in the control of limb motor behaviors following manipulations of sensory inputs to or motor outputs from the central nervous system as well as in learning and adaptation processes. However, limited data are available of the neuroplastic capabilities of face-M1 in relation to orofacial motor functions. The overall objective of our series of studies was to use intracortical microstimulation (ICMS) and recordings of evoked muscle electromyographic activity to test if neuroplastic changes occur in the ICMS-defined motor representations of the tongue-protrusive (genioglossus, GG) and jaw-opening (anterior digastric, AD) muscles within the rat face-M1 and adjacent face primary somatosensory cortex (face-S1) following several different types of intraoral manipulations. We found that a change in diet consistency was not associated with statistically significant changes in AD and GG motor representations. However, incisor extraction resulted, one week later, in a significantly increased AD representation within the contralateral face-M1 and face-S1, and incisor trimming produced time-dependent changes in the AD motor representation. These novel findings underscore the neuroplastic capabilities of the face sensorimotor cortex and point to its possible role in adaptation to an altered peripheral state or altered sensorimotor behavior. Further insights into the neuroplastic capabilities of the face sensorimotor cortex promise to improve therapeutic strategies aimed at the restoration of oral functions, particularly in patients suffering from orofacial sensorimotor deficits or pain.

Loss of teeth or dental attrition is a common clinical occurrence associated with altered somatosensation and impaired oral motor behavior (e.g., mastication, deglutition, phonation). Oral rehabilitation aims at restoring these sensorimotor functions to improve patients' quality of life. Recent studies have implicated neuroplastic changes within the primary motor cortex (M1) in the control of limb motor behaviors following manipulations of sensory inputs to or motor outputs from the central nervous system as well as in learning and adaptation processes. However, limited data are available of the neuroplastic capabilities of face-M1 in relation to orofacial motor functions. The overall objective of our series of studies was to use intracortical microstimulation (ICMS) and recordings of evoked muscle electromyographic activity to test if neuroplastic changes occur in the ICMS-defined motor representations of the tongue-protrusive (genioglossus, GG) and jaw-opening (anterior digastric, AD) muscles within the rat face-M1 and adjacent face primary somatosensory cortex (face-S1) following several different types of intraoral manipulations. We found that a change in diet consistency was not associated with statistically significant changes in AD and GG motor representations. However, incisor extraction resulted, one week later, in a significantly increased AD representation within the contralateral face-M1 and face-S1, and incisor trimming produced time-dependent changes in the AD motor representation. These novel findings underscore the neuroplastic capabilities of the face sensorimotor cortex and point to its possible role in adaptation to an altered peripheral state or altered sensorimotor behavior. Further insights into the neuroplastic capabilities of the face sensorimotor cortex promise to improve therapeutic strategies aimed at the restoration of oral functions, particularly in patients suffering from orofacial sensorimotor deficits or pain.

Jaw and tongue motor alterations may occur following changes in food consistency, but whether such changes are associated with re-organization of motor representations within the facial sensorimotor cortex is unclear. We used intracortical microstimulation (ICMS) and recordings of evoked electromyographic responses to determine jaw (anterior digastric) and tongue (genioglossus) motor representations within the histologically defined face primary motor cortex (face-M1) and adjacent somatosensory cortex (face-S1) of rats fed hard (N = 6) or soft (N = 6) diet for 2 to 3 weeks. ICMS evoked jaw and tongue responses from an extensive area within the face-M1 and a smaller area within the face-S1. A significant contralateral predominance was reflected in the number and latency of ICMS-evoked jaw responses (p < 0.05). There were no significant differences between the hard- and soft-diet groups in jaw and tongue motor representations, suggesting that the rat’s ability to adapt to changes in diet consistency may not be associated with significant neuroplasticity of sensorimotor cortex motor outputs.

The aim of this study was to determine if lingual nerve trauma affects the features of face primary motor cortex (MI) defined by intracortical microstimulation (ICMS). The left lingual nerve was transected in adult male rats by an oral surgical procedure; sham rats (oral surgery but no nerve transection) as well as naive intact rats served as control groups. ICMS was applied at post-operative days 0, 7, 14, 21, and 28 to map the jaw and tongue motor representations in face MI by analyzing ICMS-evoked movements and electromyographic activity recorded in the genioglossus (GG) and anterior digastric (AD) muscles. There were no statistically significant effects of acute (day 0) nerve transection or sham procedure (p0.05). The surgery in the sham animals was associated with limited post-operative change; this was reflected in a significant (p0.05) increase in the number of GG sites in left MI at post-operative day 14 compared to day 0. However, nerve transection was associated with significant increases in the total number of AD and GG sites in left or right MI or specifically the number of GG sites in rats at post-operative days 21 or 28 compared to earlier time periods. There were also significant differences between nerve-transected and sham groups at post-operative days 7, 14, or 21. These findings suggest that lingual nerve transection is associated with significant time-dependent neuroplastic changes in the tongue motor representations in face MI.

1. The lateral pericentral region of the cerebral cortex has been well documented in primates to be important in sensorimotor integration and control and in the learning of new motor skills. 2. The present article provides, first, an overview of limb sensorimotor cortical mechanisms and, second, outlines recent evidence pointing to an important role for the face sensorimotor cortex in semi-automatic, as well as trained, orofacial motor behaviour and to its propensity for neuroplastic changes in association with orofacial motor skill acquisition or an altered oral environment.