Early life oxytocin treatment improves thermo-sensory reactivity and maternal behavior in neonates lacking the autism-associated gene Magel2.

Atypical responses to sensory stimuli are considered as a core aspect and early life marker of autism spectrum disorders (ASD). Although recent findings performed in mouse ASD genetic models report sensory deficits, these were explored exclusively during juvenile or adult period. Whether sensory dysfunctions might be present at the early life stage and rescued by therapeutic strategy are fairly uninvestigated. Here we found that under cool environment neonatal mice lacking the autism-associated gene Magel2 present pup calls hypo-reactivity and are retrieved with delay by their wild-type dam. This neonatal atypical sensory reactivity to cool stimuli was not associated with autonomic thermoregulatory alteration but with a deficit of the oxytocinergic system. Indeed, we show in control neonates that pharmacogenetic inactivation of hypothalamic oxytocin neurons mimicked atypical thermosensory reactivity found in Magel2 mutants. Furthermore, pharmacological intranasal administration of oxytocin to Magel2 neonates was able to rescue both the atypical thermosensory response and the maternal pup retrieval. This preclinical study establishes for the first-time early life impairments in thermosensory integration and suggest a therapeutic potential benefit of intranasal oxytocin treatment on neonatal atypical sensory reactivity for autism.

Onset hyperalgesia and offset analgesia: Transient increases or decreases of noxious thermal stimulus intensity robustly modulate subsequent perceived pain intensity.

Reported pain intensity depends not only on stimulus intensity but also on previously experienced pain. A painfully hot temperature applied to the skin evokes a lower subjective pain intensity if immediately preceded by a higher temperature, a phenomenon called offset analgesia. Previous work indicated that prior pain experience can also increase subsequent perceived pain intensity. Therefore, we examined whether a given noxious stimulus is experienced as more intense when it is preceded by an increase from a lower temperature. Using healthy volunteer subjects, we observed a disproportionate increase in pain intensity at a given stimulus intensity when this intensity is preceded by a rise from a lower intensity. This disproportionate increase is similar in magnitude to that of offset analgesia. We call this effect onset hyperalgesia. Control stimuli, in which a noxious temperature is held constant, demonstrate that onset hyperalgesia is distinct from receptor or central sensitization. The absolute magnitudes of offset analgesia and onset hyperalgesia correlate with each other but not with the noxious stimulus temperature. Finally, the magnitude of both offset analgesia and onset hyperalgesia depends on preceding temperature changes. Overall, this study demonstrates that the perceptual effect of a noxious thermal stimulus is influenced in a bidirectional manner depending upon both the intensity and direction of change of the immediately preceding thermal stimulus.

Deletion of Tsc2 in Nociceptors Reduces Target Innervation, Ion Channel Expression, and Sensitivity to Heat.

The mechanistic target of rapamycin complex 1 (mTORC1) is known to regulate cellular growth pathways, and its genetic activation is sufficient to enhance regenerative axon growth following injury to the central or peripheral nervous systems. However, excess mTORC1 activation may promote innervation defects, and mTORC1 activity mediates injury-induced hypersensitivity, reducing enthusiasm for the pathway as a therapeutic target. While mTORC1 activity is required for full expression of some pain modalities, the effects of pathway activation on nociceptor phenotypes and sensory behaviors are currently unknown. To address this, we genetically activated mTORC1 in mouse peripheral sensory neurons by conditional deletion of its negative regulator Tuberous Sclerosis Complex 2 (Tsc2). Consistent with the well-known role of mTORC1 in regulating cell size, soma size and axon diameter of C-nociceptors were increased in Tsc2-deleted mice. Glabrous skin and spinal cord innervation by C-fiber neurons were also disrupted. Transcriptional profiling of nociceptors enriched by fluorescence-associated cell sorting (FACS) revealed downregulation of multiple classes of ion channels as well as reduced expression of markers for peptidergic nociceptors in Tsc2-deleted mice. In addition to these changes in innervation and gene expression, Tsc2-deleted mice exhibited reduced noxious heat sensitivity and decreased injury-induced cold hypersensitivity, but normal baseline sensitivity to cold and mechanical stimuli. Together, these data show that excess mTORC1 activity in sensory neurons produces changes in gene expression, neuron morphology and sensory behavior.

Impact of collagen crosslinking on corneal sensitivity in keratoconus patients.

PURPOSE: To evaluate changes in corneal sensitivity after corneal collagen crosslinking in patients having progressive keratoconus. METHODS: Thirty-six consecutive patients having progressive keratoconus were included in the study. The crosslinking surgery was performed in one eye of each patient (study group) and the opposite eye was used as control (control group). The following steps were done in the procedure: central cornea epithelial debridement, riboflavin solution dropping (1 drop every 5 minutes) for 30 minutes, and subsequently, corneal surface irradiation with Ultraviolet A for 30 minutes, keeping the riboflavin instillation while irradiating. The analysis of corneal tactile sensitivity in each patient was performed using the Cochet-Bonnet aesthesiometer at 5 time points: preoperative and 7, 30, 90, and 180 days after surgery. RESULTS: The study enrolled 72 eyes of 36 patients. Considering the eyes submitted to crosslinking, there was a significant statistical difference concerning the tactile corneal sensitivity at all 5 evaluated moments. The median sensitivity at each time point studied was: preoperative, 52.5 mm (range, 25-60 mm); 7 days, 20.0 mm (range, 5-60 mm); 30 days, 32.5 mm (range, 5-60 mm); 90 days, 40.0 mm (range, 10-60 mm) and 180 days, 45.0 mm (range, 25-60 mm) (P < 0.001). The control group showed no statistical difference among all 5 time points (P = 0.160). CONCLUSIONS: Corneal crosslinking performed in keratoconus patients induced a considerable decrease in corneal sensitivity. This decrease was more intense at the first week after the procedure, with a progressive recovery up to 6 months.

Significant head motion can cause either hypermetabolic or hypometabolic cerebral activity on 18F-FDG PET/CT.

We report 2 separate cases with significant head motion causing apparent hypometabolic and hypermetabolic cerebral activity on FDG PET/CT. Case 1 is a 57-year-old man with facial numbness status post chemotherapy for mantle cell lymphoma. Restaging attenuation-corrected PET showed increased left frontal region activity, whereas nonattenuation-corrected PET demonstrated evidence of patient motion with normal physiologic left frontal cortical activity. Case 2 is a 78-year-old man with history of malignant melanoma. Attenuation-corrected PET/CT demonstrated diffusely decreased activity in the left cerebral hemisphere, whereas nonattenuation-corrected PET showed significant head motion with intact cortical activity.

Decreased corneal sensitivity and abnormal corneal nerves in Fuchs endothelial dystrophy.

PURPOSE: To determine corneal sensitivity and evaluate corneal nerves before and after keratoplasty for Fuchs endothelial dystrophy. METHODS: Central corneal sensitivity, measured by using a Cochet-Bonnet esthesiometer in 69 eyes before and after different keratoplasty procedures for Fuchs dystrophy, was compared with that of 35 age-matched normal corneas. Corneal nerves were qualitatively examined by confocal microscopy in 42 eyes before and after Descemet stripping endothelial keratoplasty (DSEK). RESULTS: Corneal sensitivity in Fuchs dystrophy (4.61 ± 1.42 cm) was lower than that of age-matched controls (5.74 ± 0.48 cm, P < 0.001). Sensitivity decreased by 1 month after DSEK (2.98 ± 2.01 cm, P < 0.001), returned to preoperative sensitivity by 24 months (4.50 ± 1.63 cm, n = 33, P = 0.99), but remained lower than controls at 36 months (4.50 ± 1.48 cm, n = 15, P < 0.001). Sensitivity at 36 months after penetrating keratoplasty (1.46 ± 1.98 cm) remained decreased compared with preoperative sensitivity (P < 0.001). Subbasal nerves appeared sparse with abnormal branching before and through 36 months after DSEK. Sensitivity was lower in corneas without visible subbasal nerves by confocal microscopy at 12 months after DSEK (P < 0.005) than in corneas with visible nerves. Stromal nerves were frequently tortuous and formed loops in Fuchs dystrophy, and this appearance persisted in some eyes at 36 months after DSEK. CONCLUSION: Corneal sensitivity is decreased in Fuchs dystrophy compared with normal and remains subnormal even at 3 years after endothelial keratoplasty. Decreased sensitivity is likely to be related to loss of subbasal nerves and abnormal nerve morphology, which persist after endothelial keratoplasty.

A 45-year old male with left-sided hemihypesthesia.

A 45-year-old man presented with progressive brainstem and cerebellar dysfunction. Extensive immunological and radiological investigations were not able to differentiate between an intrinsic brain tumor and a demyelinating disease. Stereotactic biopsies of the brainstem were performed; the findings of abundant Rosenthal fibers, interjacent spindle-shaped and gemistocytic cells partially with dark and irregularly formed nuclei favored primarily the diagnosis of a malignant astrocytoma, although a demyelinating disease could not be definitely excluded. Facing the fulminant clinical course radio- and chemotherapy was initiated; however, the patient died of sepsis-associated multi-organ failure three and a half years after disease onset. Post mortem pathology finally revealed lesions with central amorphic necrosis surrounded by areas of significant demyelination, astrocytosis, microglia cells and macrophages typical for MS. Although criteria for establishing MS are well known, a correct diagnosis can be extremely challenging in small stereotactic specimens, where so-called pathological hallmarks are spared and unusual pathological findings are predominant.

Decreased corneal sensitivity and tear production in fibromyalgia.

PURPOSE: To investigate corneal sensitivity to selective mechanical, chemical, heat, and cold stimulation in patients with fibromyalgia (FM). METHODS: Twenty patients with FM (18 women, 2 men; 51.9 +/- 2.3 years old) and 18 control subjects (16 women, 2 men; 51.7 +/- 2.4 years) participated voluntarily in the study. Subjective symptoms of ocular dryness were explored and a Schirmer I test was performed. The response to selective stimulation of the central cornea with the Belmonte gas esthesiometer was measured. RESULTS: The majority (18/20) of patients with FM reported dry eye symptoms, with the ocular dryness score significantly higher in affected subjects than in healthy ones (2.3 +/- 0.1 vs. 0.05 +/- 0.02; P < 0.001). The Schirmer test results were significantly lower in patients with FM than in those in the control group (10.5 +/- 2.2 and 30.6 +/- 1.6 mm, respectively; P < 0.001). Mean corneal threshold sensitivity values to chemical stimulation (31.16% +/- 2.04% CO(2) FM; 15.72% +/- 0.67% CO(2) control), heat (1.87 +/- 0.11 degrees C FM; 0.99 +/- 0.05 degrees C control), and cold (-2.53 +/- 0.11 degrees C FM; -0.76 +/- 0.05 degrees C control) were increased in patients with FM, whereas threshold responses to mechanical stimulation did not vary significantly (123.0 +/- 8.0 mL/min FM; 107.8 +/- 4.4 mL/min control). CONCLUSIONS: The reduced corneal sensitivity of patients with fibromyalgia is attributable to a moderate decrease in corneal polymodal and cold nociceptor sensitivity, which may be the consequence or the cause of the chronic reduction in tear secretion also observed in these patients.

Continuous intra-arterial application of substance P induces signs and symptoms of experimental complex regional pain syndrome (CRPS) such as edema, inflammation and mechanical pain but no thermal pain.

Substance P is involved in nociception in both the peripheral nervous system and the CNS and has been documented to play a crucial role in the complex regional pain syndrome (CRPS). So far, however, most experimental animal models are restricted to the effect of neurokinin-1 receptor blockers to inhibit substance P and do not directly evaluate its action. Thus, this study was conducted to test the hypothesis that local application of substance P causes signs and symptoms of CRPS. For this purpose rats received a continuous infusion of either substance P or saline over 24 h delivered by a mini-osmotic pump connected to an intrafemoral catheter. Animals were analyzed at either day 1 (n=6, each group) or day 4 (n=5, each group) after start of infusion. Substance P application caused a significant and long-lasting decrease in paw withdrawal thresholds upon mechanical stimulation, while animals did not present with thermal allodynia at days 1 and 4 after onset of infusion. In addition, severe s.c. edema was observed in all animals receiving substance P. In vivo fluorescence microscopy of the extensor digitorum longus muscle of the affected hind paw revealed enhanced leukocyte-endothelial cell interaction with a significant rise in the number of leukocytes both rolling along and firmly adhering to the wall of postcapillary venules, while saline-exposed animals were free of this local inflammatory response. Muscle cell apoptosis, as assessed by in vivo bisbenzimide staining, terminal deoxynucleotidyl transferase nick end labeling analysis and caspase 3-cleavage, could not be observed in either of the animals. In summary, the present study indicates that substance P is responsible for neurogenic inflammation, including local cell response, edema formation and mechanical pain, while it seems not to contribute to the generation of thermal allodynia.

Changes in fiber integrity, diffusivity, and metabolism of the pyramidal tract adjacent to gliomas: a quantitative diffusion tensor fiber tracking and MR spectroscopic imaging study.

BACKGROUND AND PURPOSE: The underlying changes in the neuronal connectivity adjacent to brain tumors cannot always be depicted by conventional MR imaging. The hypothesis of this study was that preoperative sensorimotor deficits are associated with impairment in pyramidal fiber bundles. Hence, we investigated the potential of combined quantitative diffusion tensor (DT) fiber tracking and MR spectroscopic imaging (MRSI) to determine changes in the pyramidal tract adjacent to gliomas. MATERIALS AND METHODS: Quantitative DT fiber tracking and proton MRSI were performed in 20 patients with gliomas with WHO grades II-IV. Eight patients experienced preoperative sensorimotor deficits. Mean diffusivity (MD), fractional anisotropy (FA), and number of fibers per voxel (FpV) were calculated for the pyramidal tract of the ipsilateral and contralateral hemisphere. Metabolite concentrations for choline-containing compounds (Cho), creatine (Cr), and N-acetylaspartate (NAA) were computed, using LCModel, for all voxels located at the pyramidal tracts. RESULTS: For the whole pyramidal tract, quantitative DT fiber tracking resulted in significantly lower FpV and FA values (P < .001), but not MD values, for the ipsilateral hemisphere. For the section of the fiber bundle closest to the lesion, we found significantly decreased FpV and FA (P < .001) and increased MD (P = .002). MRSI showed, for the same volumes of interest, significantly decreased NAA (P = .001), increased Cho (P = .034) and Cho/NAA (P = .001) for the ipsilateral pyramidal tract. In patients suffering sensorimotor deficits, we found significantly lower FA (P = .022) and higher MD values (P = .026) and a strongly negative correlation between FA and MD (R = -0.710, P = .024) but no correlation in patients without deficits (R = 0.078, ns). CONCLUSION: Quantitative DTI was able to show significant differences in diffusivity of the pyramidal tract in patients with sensorimotor deficits in relation to patients without them. The additional use of proton MRSI may be helpful to discern whether these diffusivity changes in fiber tracts are caused by tumor infiltration or peritumoral edema.

Ocular surface changes in laser in situ keratomileusis-induced neurotrophic epitheliopathy.

PURPOSE: To evaluate the ocular surface changes in patients with laser in situ keratomileusis (LASIK)-induced neurotrophic epitheliopathy. METHODS: Seven consecutive patients with LASIK-induced neurotrophic epitheliopathy were studied prospectively and compared to a control group (seven consecutive patients who had LASIK- but without neurotrophic epitheliopathy). Bilateral sequential LASIK was performed at a 1-week interval; the first operated eye of each patient was considered for statistical analysis. Blinking, corneal sensitivity, tear break-up time, tear secretion and clearance were measured preoperatively (T0) and postoperatively at 1 week after surgery on the first eye (T1), and 1 week (T2), 1 month (T3), and 3 months (T4) after surgery was performed on the second eye. RESULTS: Laser in situ keratomileusis-induced neurotrophic epitheliopathy occurred bilaterally in all patients. During follow-up, patients with LASIK-induced neurotrophic epitheliopathy showed a significant decrease in blinking (P = .0002), which was not observed in cases without LASIK-induced neurotrophic epitheliopathy [corrected] Compared to eyes without LASIK-induced neurotrophic epitheliopathy, those with LASIK-induced neurotrophic epitheliopathy revealed lower values of sensitivity in the central cornea preoperatively and early postoperatively (T0, P = .004; T1, P = .003; T2, P = .003). A trend towards reduced sensitivity was also detected in the central cornea in late follow-up and in the superior, temporal, and nasal sectors of the flap at all examinations. No significant differences were observed in break-up time, tear secretion, or clearance within or between the two groups. CONCLUSION: Decreased blinking seems to be involved in the pathogenesis of LASIK-induced neurotrophic epitheliopathy. The reduction probably depends on the lower levels of corneal sensitivity and induces the epitheliopathy by increasing the ocular surface exposure.

Descending serotonergic facilitation mediated through rat spinal 5HT3 receptors is unaltered following carrageenan inflammation.

A descending facilitatory drive originating from superficial dorsal horn NK1-expressing neurones and relaying through parabrachial and rostroventral medial medulla to act on deep dorsal horn neurones, mediated through spinal 5HT3 receptors, was recently documented. To determine if this pathway plays a role in the pathophysiology of inflammation, we investigated the effects of spinally administered ondansetron (a selective 5HT3 receptor antagonist) on deep dorsal horn neuronal responses in carrageenan inflamed and naïve animals using in vivo electrophysiology. The mechanical and thermal evoked responses of spinal neurones were dose dependently attenuated by ondansetron to a similar degree in both groups. In contrast, the electrically evoked responses (Abeta-, Adelta-, C-fibre evoked response and post-discharge) remained unaltered in both groups. Thus 5HT3 receptor mediated descending facilitation remains unaltered at this stage after tissue injury.

Substance P in human tears.

PURPOSE: To determine the levels and biochemical characteristics of substance P-like immunoreactivity (SPLI) in human tears and ascertain whether substance P (SP) concentrations in tears reflect the condition of the ocular surface. METHODS: Unstimulated tears were collected with a micropipette. Tear samples were partially purified using C-18 cartridges. Levels of SPLI in purified samples were measured using an enzyme immunoassay (EIA). For biochemical characterization of SPLI, tear extracts were fractionated using high-performance liquid chromatography (HPLC); each fraction was then subjected to EIA. To determine the catabolism of SP in tears, synthetic SP was incubated in medium containing pooled tears and then analyzed using HPLC. RESULTS: The concentration of SPLI in normal human tears was 306.0 +/- 96.5 pg/mL (mean +/- SD, range 148-555 pg/mL). Levels of SPLI did not vary significantly by age or gender. Concentrations of SPLI in tears from eyes with unilateral corneal hypesthesia were lower than those in tears from contralateral healthy eyes. Diclofenac sodium eye drops reduced concentrations of prostaglandin E2 and SPLI in tears. Analysis using HPLC indicated that five different substances contributed to SPLI in tears and that SP was broken down into several fragments, including SP(8-11), by enzymes present in tears. CONCLUSIONS: Substance P is a normal component of human tears. Levels of SPLI in tears might reflect the denervated status of the ocular surface. Substance P is catabolized by degradative enzymes in tears to maintain the ocular surface by exerting the trophic effects of SP while avoiding undesirable effects.

Effects of laser in situ keratomileusis on tear production, clearance, and the ocular surface.

PURPOSE: To evaluate components of the integrated ocular surface/lacrimal gland unit in a series of patients before and after undergoing bilateral laser in situ keratomileusis (LASIK). DESIGN: Prospective, noncomparative case series. PARTICIPANTS: Forty-eight eyes of 14 men and 34 women (age range, 26-54; mean, 39.2 years) who underwent bilateral LASIK for myopia or myopic astigmatism. METHODS: LASIK was performed using a VISX Star Excimer Laser (Santa Clara, CA). Patients completed a questionnaire containing 11 questions that evaluated the character and severity of ocular irritation symptoms. Snellen visual acuity, tear fluorescein clearance, corneal fluorescein staining, aqueous tear production by the Schirmer 1 test, and corneal and conjunctival sensitivity were measured in each eye. Corneal surface regularity (SRI) was evaluated with the Tomey TMS-1 (Tomey, Cambridge, MA) topography instrument. Each randomly chosen eye was evaluated 1 to 2 days (T0) before LASIK and 7 days (T1), 1 (T2), 2 (T3), 6 (T4), 12 (T5), and 16 (T6) months postoperatively. A Wilcoxon test, two-tailed paired t test, Friedman test, or analysis of variance were used for statistical comparisons. MAIN OUTCOME MEASURES: Components of the integrated ocular surface/lacrimal gland unit. RESULTS: Both corneal and conjunctival sensitivity were noted to be significantly decreased from preoperative levels at 1week, 1 month, 12 months, and 16 months postoperatively (P < 0.0002 at each time point). Symptom severity scores were significantly increased at 1 week, 12 months, and 16 months postoperatively (P < 0.007 at all time points). The mean Schirmer 1 test scores were 24 +/- 14 mm preoperatively, and they decreased to 18 +/- 14 mm by 1 month postoperatively (P < 0.001). Tear fluorescein clearance showed a linear increase postoperatively and was significantly greater than baseline (P < 0.001) at each time point. There was a significant increase in punctate corneal fluorescein staining at 1 week postoperatively (P < 0.0001), but staining returned to baseline by 12 months. There was a statistically significant increase in SRI 1 week postoperatively (P < 0.007) with return to baseline levels by 6 months. CONCLUSIONS: Sensory denervation of the ocular surface after bilateral LASIK disrupts ocular surface tear dynamics and causes irritation symptoms. Patients undergoing LASIK should be informed of these risks.

Decreased substance P concentrations in tears from patients with corneal hypesthesia.

PURPOSE: To determine whether substance P concentrations in tears reflect corneal hypesthesia. METHODS: Sixteen patients with unilateral corneal hypesthesia participated in this study. Unstimulated tears were collected from each eye of all subjects. Substance P concentrations in tears were measured by an enzyme immunoassay system. RESULTS: Substance P concentrations in tears from the affected eye were lower than those in tears from the unaffected eye in all subjects. The mean concentration of substance P in tears from affected eyes was 197.7 +/- 69.5 pg/mL, markedly lower than those from unaffected eyes (333.2 +/- 74.6 pg/mL). CONCLUSION: Substance P concentrations in tears, which are thought to reflect the neuropeptides levels in ocular tissues, can be used as an indicator of corneal denervation.