Keeping track of time: An interaction of mossy fibers and climbing fibers.

Precisely tracking time over second-long timescales is important for accurate anticipation and consequential actions, yet the neurobiological underpinnings remain unknown. In this issue of Neuron, Garcia-Garcia and colleagues1 show that computations in the cerebellum resulting from interactions between the mossy fiber and climbing fiber pathways contribute to long-interval learning during operant conditioning.

Effect of magnification error and axial length on circumpapillary capillary density and retinal nerve fiber layer thickness.

This study aimed to evaluate the effect of magnification error and axial length (AL) on circumpapillary capillary density (cpCD) and circumpapillary retinal nerve fiber layer thickness (cpRNFLT) in healthy eyes. Seventy-two healthy eyes of 72 subjects with AL 24.7 ± 1.5 mm (range: 20.9-28.0 mm) were enrolled in this retrospective cross-sectional study and underwent optical coherence tomography angiography scanning. Magnification corrected measurement areas were obtained using AL upon which corrected cpCD, cpRNFLT values were determined. Relationships between AL and the percentage difference between corrected and uncorrected values (ΔcpCD, ΔcpRNFLT) as well as the effect of AL on magnification corrected cpCD, cpRNFLT were evaluated. ΔcpCD significantly increased with AL in the global, inferior nasal and superior nasal sectors (all p < 0.001). ΔcpRNFLT significantly increased with AL in global and all sectors (all p < 0.001) and the correlations were significantly stronger than that of ΔcpCD-AL in all sectors (all p < 0.001). Corrected cpCD did not associate with AL while corrected cpRNFLT demonstrated a significant positive association with AL in the global (p = 0.005) and temporal sector (p < 0.001). Magnification error led to a significant underestimation of cpCD in eyes with longer AL although its underestimation and the effect of AL was smaller in comparison to that of cpRNFLT.

Highly efficient modeling and optimization of neural fiber responses to electrical stimulation.

Peripheral neuromodulation has emerged as a powerful modality for controlling physiological functions and treating a variety of medical conditions including chronic pain and organ dysfunction. The underlying complexity of the nonlinear responses to electrical stimulation make it challenging to design precise and effective neuromodulation protocols. Computational models have thus become indispensable in advancing our understanding and control of neural responses to electrical stimulation. However, existing approaches suffer from computational bottlenecks, rendering them unsuitable for real-time applications, large-scale parameter sweeps, or sophisticated optimization. In this work, we introduce an approach for massively parallel estimation and optimization of neural fiber responses to electrical stimulation using machine learning techniques. By leveraging advances in high-performance computing and parallel programming, we present a surrogate fiber model that generates spatiotemporal responses to a wide variety of cuff-based electrical peripheral nerve stimulation protocols. We used our surrogate fiber model to design stimulation parameters for selective stimulation of pig and human vagus nerves. Our approach yields a several-orders-of-magnitude improvement in computational efficiency while retaining generality and high predictive accuracy, demonstrating its robustness and potential to enhance the design and optimization of peripheral neuromodulation therapies.

Numerical simulation of neural excitation during brain tumor ablation by microsecond pulses.

Replacing monopolar pulse with bipolar pulses of the same energized time can minimize unnecessary neurological side effects during irreversible electroporation (IRE). An improved neural excitation model that considers dynamic conductivity and thermal effects during brain tumor IRE ablation was proposed for the first time in this study. Nerve fiber excitation during IRE ablation by applying a monopolar pulse (100 µs) and a burst of bipolar pulses (energized time of 100 µs with both the sub-pulse length and interphase delay of 1 µs) was investigated. Our results suggest that both thermal effects and dynamic conductivity change the onset time of action potential (AP), and dynamic conductivity also changes the hyperpolarization amplitude. Considering both thermal effects and dynamic conductivity, the hyperpolarization amplitude in nerve fibers located 2 cm from the tumor center was reduced by approximately 23.8 mV and the onset time of AP was delayed by approximately 17.5 µs when a 500 V monopolar pulse was applied. Moreover, bipolar pulses decreased the excitable volume of brain tissue by approximately 68.8 % compared to monopolar pulse. Finally, bipolar pulses cause local excitation with lesser damage to surrounding healthy tissue in complete tumor ablation, demonstrating the potential benefits of bipolar pulses in brain tissue ablation.

Brain Slice Derived Nerve Fibers Grow along Microcontact Prints and are Stimulated by Beta-Amyloid(42).

BACKGROUND: Alzheimer's disease is characterized by extracellular beta-amyloid plaques, intraneuronal tau neurofibrillary tangles and excessive neurodegeneration. The mechanisms of neuron degeneration and the potential of these neurons to form new nerve fibers for compensation remain elusive. The present study aimed to evaluate the impact of beta-amyloid and tau on new formations of nerve fibers from mouse organotypic brain slices connected to collagen-based microcontact prints. METHODS: Organotypic brain slices of postnatal day 8-10 wild-type mice were connected to established collagen-based microcontact prints loaded with polyornithine to enhance nerve fiber outgrowth. Human beta-amyloid(42) or P301S mutated aggregated tau was co-loaded to the prints. Nerve fibers were immunohistochemically stained with neurofilament antibodies. The physiological activity of outgrown neurites was tested with neurotracer MiniRuby, voltage-sensitive dye FluoVolt, and calcium-sensitive dye Rhod-4. RESULTS: Immunohistochemical staining revealed newly formed nerve fibers extending along the prints derived from the brain slices. While collagen-only microcontact prints stimulated nerve fiber growth, those loaded with polyornithine significantly enhanced nerve fiber outgrowth. Beta-amyloid(42) significantly increased the neurofilament-positive nerve fibers, while tau had only a weak effect. MiniRuby crystals, retrogradely transported along these newly formed nerve fibers, reached the hippocampus, while FluoVolt and Rhod-4 monitored electrical activity in newly formed nerve fibers. CONCLUSIONS: Our data provide evidence that intact nerve fibers can form along collagen-based microcontact prints from mouse brain slices. The Alzheimer's peptide beta-amyloid(42) stimulates this growth, hinting at a neuroprotective function when physiologically active. This "brain-on-chip" model may offer a platform for screening bioactive factors or testing drug effects on nerve fiber growth.

A cerebellar granule cell-climbing fiber computation to learn to track long time intervals.

In classical cerebellar learning, Purkinje cells (PkCs) associate climbing fiber (CF) error signals with predictive granule cells (GrCs) that were active just prior (∼150 ms). The cerebellum also contributes to behaviors characterized by longer timescales. To investigate how GrC-CF-PkC circuits might learn seconds-long predictions, we imaged simultaneous GrC-CF activity over days of forelimb operant conditioning for delayed water reward. As mice learned reward timing, numerous GrCs developed anticipatory activity ramping at different rates until reward delivery, followed by widespread time-locked CF spiking. Relearning longer delays further lengthened GrC activations. We computed CF-dependent GrC→PkC plasticity rules, demonstrating that reward-evoked CF spikes sufficed to grade many GrC synapses by anticipatory timing. We predicted and confirmed that PkCs could thereby continuously ramp across seconds-long intervals from movement to reward. Learning thus leads to new GrC temporal bases linking predictors to remote CF reward signals-a strategy well suited for learning to track the long intervals common in cognitive domains.

Characterization, number, and spatial organization of nerve fibers in the human cervical vagus nerve and its superior cardiac branch.

BACKGROUND: Electrical stimulation of the vagus nerve (VN) is a therapy for epilepsy, obesity, depression, and heart diseases. However, whole nerve stimulation leads to side effects. We examined the neuroanatomy of the mid-cervical segment of the human VN and its superior cardiac branch to gain insight into the side effects of VN stimulation and aid in developing targeted stimulation strategies. METHODS: Nerve specimens were harvested from eight human body donors, then subjected to immunofluorescence and semiautomated quantification to determine the signature, quantity, and spatial distribution of different axonal categories. RESULTS: The right and left cervical VN (cVN) contained a total of 25,489 ± 2781 and 23,286 ± 3164 fibers, respectively. Two-thirds of the fibers were unmyelinated and one-third were myelinated. About three-quarters of the fibers in the right and left cVN were sensory (73.9 ± 7.5 % versus 72.4 ± 5.6 %), while 13.2 ± 1.8 % versus 13.3 ± 3.0 % were special visceromotor and parasympathetic, and 13 ± 5.9 % versus 14.3 ± 4.0 % were sympathetic. Special visceromotor and parasympathetic fibers formed clusters. The superior cardiac branches comprised parasympathetic, vagal sensory, and sympathetic fibers with the left cardiac branch containing more sympathetic fibers than the right (62.7 ± 5.4 % versus 19.8 ± 13.3 %), and 50 % of the left branch contained sensory and sympathetic fibers only. CONCLUSION: The study indicates that selective stimulation of vagal sensory and motor fibers is possible. However, it also highlights the potential risk of activating sympathetic fibers in the superior cardiac branch, especially on the left side.

Climbing fibers provide essential instructive signals for associative learning.

Supervised learning depends on instructive signals that shape the output of neural circuits to support learned changes in behavior. Climbing fiber (CF) inputs to the cerebellar cortex represent one of the strongest candidates in the vertebrate brain for conveying neural instructive signals. However, recent studies have shown that Purkinje cell stimulation can also drive cerebellar learning and the relative importance of these two neuron types in providing instructive signals for cerebellum-dependent behaviors remains unresolved. In the present study we used cell-type-specific perturbations of various cerebellar circuit elements to systematically evaluate their contributions to delay eyeblink conditioning in mice. Our findings reveal that, although optogenetic stimulation of either CFs or Purkinje cells can drive learning under some conditions, even subtle reductions in CF signaling completely block learning to natural stimuli. We conclude that CFs and corresponding Purkinje cell complex spike events provide essential instructive signals for associative cerebellar learning.

Neuroscience of taste: unlocking the human taste code.

Since antiquity human taste has been divided into 4-5 taste qualities. We realized in the early 1970s that taste qualities vary between species and that the sense of taste in species closer to humans such as primates should show a higher fidelity to human taste qualities than non-primates (Brouwer et al. in J Physiol 337:240, 1983). Here we present summary results of behavioral and single taste fiber recordings from the distant South American marmoset, through the Old World rhesus monkey to chimpanzee, the phylogenetically closest species to humans. Our data show that in these species taste is transmitted in labelled-lines to the CNS, so that when receptors on taste bud cells are stimulated, the cell sends action potentials through single taste nerve fibers to the CNS where they create taste, whose quality depends on the cortical area stimulated. In human, the taste qualites include, but are perhaps not limited to sweet, sour, salty, bitter and umami. Stimulation of cortical taste areas combined with inputs from internal organs, olfaction, vision, memory etc. leads to a choice to accept or reject intake of a compound. The labelled-line organization of taste is another example of Müller's law of specific nerve energy, joining other somatic senses such as vision (Sperry in J Neurophysiol 8:15-28, 1945), olfaction (Ngai et al. in Cell 72:657-666, 1993), touch, temperature and pain to mention a few.

Cutaneous nerve biopsy in patients with symptoms of small fiber neuropathy: a retrospective study.

OBJECTIVES: We aimed to investigate to what extent small fiber tests were abnormal in an unselected retrospective patient material with symptoms suggesting that small fiber neuropathy (SFN) could be present, and to evaluate possible gender differences. METHODS: Nerve conduction studies (NCS), skin biopsy for determination of intraepidermal nerve fiber density (IENFD) and quantitative sensory testing (QST) were performed. Z-scores were calculated from reference materials to adjust for the effects of age and gender/height. RESULTS: Two hundred and three patients, 148 females and 55 males had normal NCS and were considered to have possible SFN. 45.3 % had reduced IENFD, 43.2 % of the females and 50.9 % of the males. Mean IENFD was 7.3 ± 2.6 fibers/mm in females and 6.1 ± 2.3 in males (p<0.001), but the difference was not significant when adopting Z-scores. Comparison of gender differences between those with normal and abnormal IENFD were not significant when Z-scores were applied. QST was abnormal in 50 % of the patients (48.9 % in females and 52.9 % in males). In the low IENFD group 45 cases out of 90 (50 %) were recorded with abnormal QST. In those with normal IENFD 51 of 102 (50 %) showed abnormal QST. CONCLUSIONS: Less than half of these patients had reduced IENFD, and 50 % had abnormal QST. There were no gender differences. A more strict selection of patients might have increased the sensitivity, but functional changes in unmyelinated nerve fibers are also known to occur with normal IENFD. Approval to collect data was given by the Norwegian data protection authority at University Hospital of North Norway (Project no. 02028).

Corneal stress‒strain index in relation to retinal nerve fibre layer thickness among healthy young adults.

BACKGROUND/OBJECTIVES: To determine the relationship between corneal stress-strain index (SSI) and retinal nerve fibre layer (RNFL) thickness. SUBJECTS/METHODS: 1645 healthy university students from a university-based study contributed to the analysis. The RNFL thickness was measured by high-definition optical coherence tomography (HD-OCT), axial length (AL) was measured by IOL Master, and corneal biomechanics including SSI, biomechanical corrected intraocular pressure (bIOP), and central corneal thickness (CCT) were measured by Corvis ST. Multivariate linear regression was performed to evaluate the relationship between the SSI and RNFL thickness after adjusting for potential covariates. RESULTS: The mean age of the participants was 19.0 ± 0.9 years, and 1132 (68.8%) were women. Lower SSI was significantly associated with thinner RNFL thickness ( ß =8.601, 95% confidence interval [CI] 2.999-14.203, P = 0.003) after adjusting for age, CCT, bIOP, and AL. No significant association between SSI and RNFL was found in men, while the association was significant in women in the fully adjusted model. The association was significant in the nonhigh myopic group ( P for trend = 0.021) but not in the highly myopic group. Eyes with greater bIOP and lower SSI had significantly thinner RNFL thickness. CONCLUSIONS: Eyes with lower SSI had thinner RNFL thickness after adjusting for potential covariates, especially those with higher bIOP. Our findings add novel evidence of the relationship between corneal biomechanics and retinal ganglion cell damage.

Evaluation of Quantitative and Selective Sensory Fiber Dysfunction in Patients with Cirrhosis.

BACKGROUND: Chronic liver disease has been reported to be associated with peripheral neuropathy. However, which sensory fibers are affected remains unknown. The objective of this study was to examine the function of sensory nerve fibers in patients with cirrhosis using the current perception threshold (CPT) test, as well as the correlation between blood biochemical indicators related to cirrhosis and CPT values. METHODS: We recruited 44 patients with liver cirrhosis and 37 healthy controls of the same age and gender. The Neurometer® system for the CPT test was used to stimulate the median nerve on the right index finger, as well as the deep and superficial peroneal nerves on the right hallux, using three distinct parameters (2000 Hz, 250 Hz, and 5 Hz). Comparative analysis was performed on the CPT values of the sensory nerves. Additionally, the correlation between CPT values and biochemical blood indicators in the study participants was analyzed. RESULTS: Under 2000 Hz electrical stimulation, there was a significant difference between the cirrhosis and healthy control groups in the median nerve as well as the deep and superficial peroneal nerves (p < 0.05). In addition, the median nerve CPT value of the cirrhosis group was significantly higher than that of the control group at an electrical stimulation frequency of 250 Hz (p = 0.005). There was no correlation between CPT values and blood biochemical indicators. CONCLUSION: According to the results, the sensory peripheral neuropathy in liver cirrhosis is mainly manifested as Aß fiber neuropathy.

Correlation between a commercial electrophysiological test of sudomotor function and intraepidermal nerve fiber density in hereditary transthyretin amyloidosis.

INTRODUCTION/AIMS: In the early stage, hereditary transthyretin (ATTRv) amyloidosis predominantly affects small nerve fibers, resulting in autonomic dysfunction and impaired sensation of pain and temperature. Evaluation of small fiber neuropathy (SFN) is therefore important for early diagnosis and treatment of ATTRv amyloidosis. Herein, we aimed to investigate the accuracy of a quick and non-invasive commercial sudomotor function test (SFT) for the assessment of SFN in ATTRv amyloidosis. METHODS: We performed the SFT in 39 Japanese adults with ATTRv amyloidosis, and we analyzed the correlations between electrochemical skin conductance (ESC) values obtained via the SFT and the parameters of other neuropathy assessment methods. RESULTS: ESC in the feet demonstrated significant, moderate correlations with intraepidermal nerve fiber density (IENFD) results (Spearman's rank correlation coefficient [rs ], 0.58; p < .002) and other neuropathy assessment methods including the sensory nerve action potential amplitude in the nerve conduction studies (rs , 0.52; p < .001), the Neuropathy Impairment Score (rs , -0.45; p < .01), the heat-pain detection threshold (rs , -0.62; p < .0001), and the autonomic section of the Kumamoto ATTRv clinical score (rs , -0.53; p < .0001). DISCUSSION: In this study, we found that ESC values in the feet via the SFT demonstrated significant, moderate correlations with IENFD and other SFN assessment methods in patients with ATTRv amyloidosis, suggesting that the SFT appears to be an appropriate method for assessment of SFN in this disease.

Sweat gland nerve fiber density and association with sudomotor function, symptoms, and risk factors in adolescents with type 1 diabetes.

PURPOSE: To quantify sweat gland nerve fiber density in adolescents with diabetes. Additionally, to investigate associations between sudomotor innervation, sweat responses, and possible risk factors for sudomotor neuropathy. METHODS: Cross-sectional study where 60 adolescents with type 1 diabetes (duration > 5 years) and 23 control subjects were included. Clinical data, quantitative sudomotor axon reflex test, and skin biopsies were obtained. Skin tissue was immunostained and imaged by confocal microscopy. Quantification of the sweat gland volume and three-dimensional reconstruction of the nerve fibers was performed using a design-unbiased technique. RESULTS: Adolescents with diabetes had a significant reduction of maximum and mean values of nerve fiber length and nerve fiber density in sweat glands compared to controls (p values < 0.05). No association between nerve fiber density and sweat responses was found (p = 0.21). In cases with reduced sweat gland nerve fiber length, nerve fiber density, and volume, the sweat response was reduced or absent. Height, systolic blood pressure, time in hypoglycemia, and total daily and basal/total insulin dose were positively correlated to sweat response, while low-density lipoprotein, and HbA1c were negatively correlated with sweat response (p values < 0.05). Other microvascular complications and high cholesterol levels increased the relative risk for reduced sweat gland nerve fiber density. CONCLUSION: Our findings of reduced sweat gland innervation in a selected group of adolescents add new knowledge about the structural changes that occur in autonomic nerves due to diabetes. Evaluating both the sweat gland innervation and sweat gland volume was important for understanding the association with sweat responses. Further research is needed to understand its clinical relevance.

Cochlear aging disrupts the correlation between spontaneous rate- and sound-level coding in auditory nerve fibers.

The spiking activity of auditory nerve fibers (ANFs) transmits information about the acoustic environment from the cochlea to the central auditory system. Increasing age leads to degeneration of cochlear tissues, including the sensory hair cells and stria vascularis. Here, we aim to identify the functional effects of such age-related cochlear pathologies of ANFs. Rate-level functions (RLFs) were recorded from single-unit ANFs of young adult (n = 52, 3-12 months) and quiet-aged (n = 24, >36 months) Mongolian gerbils of either sex. RLFs were used to determine sensitivity and spontaneous rates (SRs) and were classified into flat-saturating, sloping-saturating, and straight categories, as previously established. A physiologically based cochlear model, adapted for the gerbil, was used to simulate the effects of cochlear degeneration on ANF physiology. In ANFs tuned to low frequencies (<3.5 kHz), SR was lower in those of aged gerbils, while an age-related loss of low-SR fibers was evident in ANFs tuned to high frequencies. These changes in SR distribution did not affect the typical SR versus sensitivity correlation. The distribution of RLF types among low-SR fibers, however, shifted toward that of high-SR fibers, specifically showing more fast-saturating and fewer sloping-saturating RLFs. A modeled striatal degeneration, which affects the combined inner hair cell and synaptic output, reduced SR but left RLF type unchanged. An additional reduced basilar membrane gain, which decreased sensitivity, explained the changed RLF types. Overall, the data indicated age-related changes in the characteristics of single ANFs that blurred the established relationships between SR and RLF types.NEW & NOTEWORTHY Auditory nerve fibers, which connect the cochlea to the central auditory system, change their encoding of sound level in aged gerbils. In addition to a general shift to higher levels, indicative of decreased sensitivity, level coding was also differentially affected in fibers with low- and high-spontaneous rates. Loss of low-spontaneous rate fibers, combined with a general decrease of spontaneous rate, further blurs the categorization of auditory nerve fiber types in the aged gerbil.

A Continuum of Response Properties across the Population of Unipolar Brush Cells in the Dorsal Cochlear Nucleus.

Unipolar brush cells (UBCs) in the cerebellum and dorsal cochlear nucleus (DCN) perform temporal transformations by converting brief mossy fiber bursts into long-lasting responses. In the cerebellar UBC population, mixing inhibition with graded mGluR1-dependent excitation leads to a continuum of temporal responses. In the DCN, it has been thought that mGluR1 contributes little to mossy fiber responses and that there are distinct excitatory and inhibitory UBC subtypes. Here, we investigate UBC response properties using noninvasive cell-attached recordings in the DCN of mice of either sex. We find a continuum of responses to mossy fiber bursts ranging from 100 ms excitation to initial inhibition followed by several seconds of excitation to inhibition lasting for hundreds of milliseconds. Pharmacological interrogation reveals excitatory responses are primarily mediated by mGluR1 Thus, UBCs in both the DCN and cerebellum rely on mGluR1 and have a continuum of response durations. The continuum of responses in the DCN may allow more flexible and efficient temporal processing than can be achieved with distinct excitatory and inhibitory populations.SIGNIFICANCE STATEMENT UBCs are specialized excitatory interneurons in cerebellar-like structures that greatly prolong the temporal responses of mossy fiber inputs. They are thought to help cancel out self-generated signals. In the DCN, the prevailing view was that there are two distinct ON and OFF subtypes of UBCs. Here, we show that instead the UBC population has a continuum of response properties. Many cells show suppression and excitation consecutively, and the response durations vary considerably. mGluR1s are crucial in generating a continuum of responses. To understand how UBCs contribute to temporal processing, it is essential to consider the continuous variations of UBC responses, which have advantages over just having opposing ON/OFF subtypes of UBCs.

Compare of optic coherence tomography parameters in recreational synthetic tetrahydrocannabinol use and healthy control.

PURPOSE: To evaluate retinal thickness (RT), retinal nerve fiber layer thickness (RNFLT), and choroidal thickness (CT) changes in synthetic cannabinoid (SC) users. METHODS: This prospective study evaluated the RT, RNFLT, and CT values of 56 SC users and 58 healthy controls. The individuals using SCs were referred to us by our hospital's forensic medicine department. Retinal and choroidal images were obtained using spectral-domain optical coherence tomography (OCT). Measurements (one subfoveal, three temporals, three nasal) were taken at 500 µm intervals up to 1500 µm using the caliper system. Only the right eye was used for subsequent analysis. RESULTS: Mean ages were 27.7 ± 5.7 years in the SC-user group and 25.4 ± 6.7 in the control group. Subfoveal Global RNFLT was in the SCs group 102.3 ± 10.5 µm and 105.6 ± 20.2 µm in the control group (p = 0.271). Subfoveal CT was in the SC group mean of 316.1 ± 100.2 µm and in the control group mean 346.4 ± 81.8 µm (p = 0.065). RT, T500 (283.3 ± 36.7 µm, 296.6 ± 20.5 µm, p = 0.011) and N1500 (355.1 ± 14.3 µm, 349.3 ± 18.1 µm, p = 0.049) were significantly higher in the SC group than in the control group, respectively. CONCLUSION: Analysis of OCT findings of individuals who had been using SC for more than one year revealed no statistically significant difference between RNFLT and CT, although N1500 was significantly higher in RT. Further studies in the field of OCT are important to explore the pathology of SC.

Corneal Confocal Microscopy Abnormalities in Children and Adolescents With Type 1 Diabetes.

OBJECTIVE: Utility of corneal confocal microscopy (CCM) in children and adolescents with type 1 diabetes mellitus (T1DM) without neuropathic symptoms or signs and minimal abnormality in large and small nerve fiber function tests remains largely undetermined. This study aimed to evaluate the performance of CCM in comparison to thermal detection thresholds (TDT) testing and nerve conduction studies (NCS) for detecting neuropathy in children with T1DM. METHODS: A cohort of children and adolescents with T1DM (n = 51) and healthy controls (n = 50) underwent evaluation for symptoms and signs of neurological deficits, including warm detection threshold, cold detection threshold, vibration perception threshold, NCS, and CCM. RESULTS: Children with T1DM had no or very minimal neuropathic symptoms and deficits based on the Toronto Clinical Neuropathy Score, yet NCS abnormalities were present in 18 (35%), small fiber dysfunction defined by an abnormal TDT was found in 13 (25.5%) and CCM abnormalities were present in 25 (49%). CCM was abnormal in a majority of T1DM children with abnormal TDT (12/13, 92%) and abnormal NCS (16/18, 88%). CCM additionally was able to detect small fiber abnormalities in 13/38 (34%) in T1DM with a normal TDT and in 9/33 (27%) with normal NCS. CONCLUSION: CCM was able to detect corneal nerve loss in children with and without abnormalities in TDT and NCS.