Inferior Olive Research Articles

Quenched disorder-induced chaotic resonance: Optimal stimulus response near the edge of chaos

We study the collective stimulus response in two classical nonlinear dynamical models, the globally coupled bistable oscillators and the excitable FitzHugh-Nagumo neurons, where the coupling strength among the units are randomly distributed with fixed mean and varying variance. We find theoretically and numerically that in both models the ensemble response to a weak periodic stimulus exhibits a bell-shaped amplification manifesting a different type of resonance mechanism, namely, coupling-disorder-induced resonance, as the quenched disorder of coupling increases. Of particular interest is that the optimal collective response emerges near the order-chaos transition point, i.e., at the edge of chaos. As a promising application, we discuss briefly the potential reasonability for exploiting such a type of chaotic resonance to explain the optimal mutual information in the realistic inferior olive. Our results provide explicitly a clue that the disorderly coupled elements may utilize the coupling-disorder-induced chaos to optimize their stimulus response. Published by the American Physical Society 2024

Radiological Hypertrophic Olivary Degeneration Following Posterior Fossa Tumor Surgery

Hypertrophic olivary degeneration is a rare form of transsynaptic degeneration, caused by injury to the Dentato-rubro-olivary pathway (DROP). Radiologically this manifests as T2 hyperintensity, with or without enlargement of the inferior olivary nucleus (ION). The purpose of the study was to evaluate the incidence, associated imaging characteristics, potential etiologies, latency period, and temporal progression of HOD in patients undergoing surgical resection of posterior fossa tumors (PFTs). A retrospective analysis of patients with PFTs and post-surgical MRI scans was conducted. HOD was diagnosed based on ION signal abnormalities and size changes. Demographics, tumor characteristics, time to HOD onset, involved DROP components, and clinical symptoms were recorded. HOD was seen in 40 (6.2%) patients following PFT surgery. 26 patients were aged 17 or less while the rest were older than 17 years. Medulloblastoma was the most frequently diagnosed tumor type (n=25), followed by pilocytic astrocytoma (n=8), ependymoma (n=6), and high grade glioma (n=1). No statistical association was found between the development of HOD and tumor grade (p=0.882). Ataxia was the most commonly reported clinical symptom (n=15). The time elapsed between surgery and the diagnosis of HOD varied, with median intervals of 1 month, 5 months, and 37 months for different stages. Dentate nucleus was the most commonly affected component of the DROP (n=36). HOD is a frequently overlooked postoperative complication following PFT resection. Increased recognition of HOD by neuroradiologists is essential for timely diagnosis and avoidance of unnecessary diagnostic procedures.

Neuropathologic Findings and Electrolyte Abnormalities in a Case of Lennox-Gastaut Syndrome (SCN2a- related) Encountered at Autopsy

Abstract Introduction/Objective Lennox-Gastaut syndrome is a severe form of childhood epilepsy which may be due to several conditions, including sodium channelopathies which alter neuronal firing patterns. We present a case of a 6-year-old female with Lennox-Gastaut syndrome (SCN2A-related) complicated by developmental delay, spastic quadriplegia, and gastrojejunostomy tube dependence who was referred for medicolegal autopsy due to death subsequent to becoming unresponsive during a supervised bath. Methods/Case Report A complete autopsy was performed, including gross and microscopic examination of all primary organ systems, formal neuropathologic examination, and postmortem microbiology, toxicology, and vitreous electrolyte studies. The decedent showed evidence of developmental delay and flexion contractures of the extremities. No significant traumatic injuries were identified. A postmortem nasopharyngeal swab was positive for Rhinovirus/Enterovirus and Influenza A H3. A postmortem vitreous electrolyte panel demonstrated a dehydration pattern, including markedly elevated sodium and chloride and elevated urea nitrogen. Gross examination of the brain showed a thin corpus callosum, small hippocampi, as well as abnormal cerebellar dentate and inferior olivary nuclei. Microscopic examination of the brain tissue supported the gross findings, including dentato-olivary dysplasia. The cause of death was certified as dehydration complicating Lennox-Gastaut syndrome (SCN2a-related). Rhinovirus/Enterovirus and Influenza A H3 infections were considered contributory to death. The manner of death remained undetermined, since it was unknown if the decedent’s natural diseases, issues following a scheduled gastrojejunostomy feeding regimen, neglect, or some combination thereof caused the dehydration. Results (if a Case Study enter NA) NA Conclusion This case highlights unique and rarely documented neuropathologic findings and electrolyte abnormalities that may be seen in Lennox-Gastaut syndrome associated with an SCN2A mutation in addition to demonstrating the challenges of cause and manner death certification in cases of severe developmental disorders of childhood related to sodium channelopathies.

Reward-driven cerebellar climbing fiber activity influences both neural and behavioral learning.

The cerebellum plays a key role in motor coordination and learning. In contrast with classical supervised learning models, recent work has revealed that CFs can signal reward-predictive information in some behaviors. This raises the question of whether CFs may also operate according to principles similar to those described by reinforcement learning models. To test how CFs operate during reward-guided behavior, and evaluate the role of reward-related CF activity in learning, we have measured CF responses in Purkinje cells of the lateral cerebellum during a Pavlovian task using 2-photon calcium imaging. Specifically, we have performed multi-stimulus experiments to determine whether CF activity meets the requirements of a reward prediction error (rPE) signal for transfer from an unexpected reward to a reward-predictive cue. We find that once CF activity is transferred to a conditioned stimulus, and there is no longer a response to reward, CFs cannot generate learned responses to a second conditioned stimulus that carries the same reward prediction. In addition, by expressing the inhibitory opsin GtACR2 in neurons of the inferior olive, and optically inhibiting these neurons across behavioral training at the time of unexpected reward, we find that the transfer of CF signals to the conditioned stimulus is impaired. Moreover, this optogenetic inhibition also impairs learning, resulting in a deficit in anticipatory lick timing. Together, these results indicate that CF signals can exhibit several characteristics in common with rPEs during reinforcement learning, and that the cerebellum can harness these learning signals to generate accurately timed motor behavior.

Control of action potential afterdepolarizations in the inferior olive by inactivating A‐type currents through KV4 channels

Control of action potential afterdepolarizations in the inferior olive by inactivating A‐type currents through K_V4 channels

Early-onset palatal myoclonus in Wernekinck commissure syndrome secondary to caudal paramedian midbrain infarction: A case report and a mini review of the literature

IntroductionWernekinck commissure syndrome (WCS) is an extremely rare midbrain syndrome, which selectively destroys the decussation of the superior cerebellar peduncle and the central tegmental tract, which commonly presents with bilateral cerebellar ataxia, dysarthria, and internuclear ophthalmoplegia. Palatal myoclonus in Wernekinck commissure syndrome is uncommon and often occurs as a late phenomenon due to hypertrophic degeneration of bilateral inferior olivary nuclei. Material and methodA patient with WCS, admitted to our hospital from December 2023, was chosen for this study, and the syndrome's clinical manifestations, imaging features, and etiology were retrospectively analyzed based on the literature. A 68-year-old right-handed East Asian man presented with dizziness, slurred speech, difficulty with swallowing and walking, and rhythmic contractions of the soft palate. He had several risk factors for ischemic cerebrovascular diseases (age, sex, dyslipidemia, hypertension and smoking history). Brain magnetic resonance imaging showed hyperintensity of DWI and hypointensity of ADC at the caudal midbrain which was around the paramedian mesencephalic tegmentum anterior to the aqueduct of midbrain. ResultsHe was diagnosed with Wernekinck commissure syndrome (WCS) secondary to caudal paramedian midbrain infarction. He was started on dual antiplatelet therapy (aspirin and clopidogrel) and intensive statin therapy. Blood pressure and glucose were also adjusted. His symptoms improved rapidly, and he walked steadily and speak clearly after 7 days of treatment. ConclusionsPalatal myoclonus is known to occur as a late phenomenon due to hypertrophic degeneration of bilateral inferior olivary nuclei. However, Our case suggests that palatal myoclonus can occur in the early stages in WCS.

The Neuroanatomical Basis of the 5-HT Syndrome and Harmalineinduced Tremor.

The 5-HT syndrome in rats is composed of head weaving, body shaking, forepaw treading, flat body posture, hindlimb abduction, and Straub tail. The importance of the brainstem and spinal cord for the syndrome is underlined by findings of 5,7-dihydroxytryptamine (5,7-DHT)-induced denervation supersensitivity in response to 5-HT-stimulant drugs. For head weaving and Straub tail, supersensitivity occurred when the neurotoxin was injected into the cisterna magna or spinal cord, for forepaw treading in cisterna magna, and for hindlimb abduction in the spinal cord. Although 5,7- DHT-related body shaking increased in the spinal cord, the sign decreased when injected into the striatum, indicating the modulatory influence of the basal ganglia. Further details on body shaking are provided by its reduced response to harmaline after 5-HT depletion caused by intraventricular 5,7-DHT, electrolytic lesions of the medial or dorsal raphe, and lesions of the inferior olive caused by systemic injection of 3-acetylpyridine along with those found in Agtpbp1pcd or nr cerebellar mouse mutants. Yet the influence of the climbing fiber pathway on other signs of the 5-HT syndrome remains to be determined.

Molecular Organization of Autonomic, Respiratory, and Spinally-Projecting Neurons in the Mouse Ventrolateral Medulla.

The ventrolateral medulla (VLM) is a crucial region in the brain for visceral and somatic control, serving as a significant source of synaptic input to the spinal cord. Experimental studies have shown that gene expression in individual VLM neurons is predictive of their function. However, the molecular and cellular organization of the VLM has remained uncertain. This study aimed to create a comprehensive dataset of VLM cells using single-cell RNA sequencing in male and female mice. The dataset was enriched with targeted sequencing of spinally-projecting and adrenergic/noradrenergic VLM neurons. Based on differentially expressed genes, the resulting dataset of 114,805 VLM cells identifies 23 subtypes of neurons, excluding those in the inferior olive, and five subtypes of astrocytes. Spinally-projecting neurons were found to be abundant in seven subtypes of neurons, which were validated through in situ hybridization. These subtypes included adrenergic/noradrenergic neurons, serotonergic neurons, and neurons expressing gene markers associated with premotor neurons in the ventromedial medulla. Further analysis of adrenergic/noradrenergic neurons and serotonergic neurons identified nine and six subtypes, respectively, within each class of monoaminergic neurons. Marker genes that identify the neural network responsible for breathing were concentrated in two subtypes of neurons, delineated from each other by markers for excitatory and inhibitory neurons. These datasets are available for public download and for analysis with a user-friendly interface. Collectively, this study provides a fine-scale molecular identification of cells in the VLM, forming the foundation for a better understanding of the VLM's role in vital functions and motor control.

Microstructural Properties of the Cerebellar Peduncles in Children With Developmental Language Disorder.

Children with developmental language disorder (DLD) struggle to learn their native language for no apparent reason. While research on the neurobiological underpinnings of the disorder has focused on the role of corticostriatal systems, little is known about the role of the cerebellum in DLD. Corticocerebellar circuits might be involved in the disorder as they contribute to complex sensorimotor skill learning, including the acquisition of spoken language. Here, we used diffusion-weighted imaging data from 77 typically developing and 54 children with DLD and performed probabilistic tractography to identify the cerebellum's white matter tracts: the inferior, middle, and superior cerebellar peduncles. Children with DLD showed lower fractional anisotropy (FA) in the inferior cerebellar peduncles (ICP), fiber tracts that carry motor and sensory input via the inferior olive to the cerebellum. Lower FA in DLD was driven by lower axial diffusivity. Probing this further with more sophisticated modeling of diffusion data, we found higher orientation dispersion but no difference in neurite density in the ICP of children with DLD. Reduced FA is therefore unlikely to be reflecting microstructural differences in myelination, rather the organization of axons in these pathways is disrupted. ICP microstructure was not associated with language or motor coordination performance in our sample. We also found no differences in the middle and superior peduncles, the main pathways connecting the cerebellum with the cortex. To conclude, it is not corticocerebellar but atypical olivocerebellar white matter connections that characterize DLD and suggest the involvement of the olivocerebellar system in speech and language acquisition and development.

IMG-01. LONGITUDINAL SIGNAL CHANGES IN THE DENTATE AND INFERIOR OLIVARY NUCLEI IN PATIENTS WITH CEREBELLAR MUTISM SYNDROME

Abstract BACKGROUND Cerebellar mutism syndrome (CMS) is a complication of posterior fossa surgery with an acute impairment in speech, and long-term neurocognitive deficits. Lesion mapping studies suggest the cognitive symptoms are associated with dentatorubrolivary damage1. We hypothesize that CMS patients will demonstrate more longitudinal MRI signal abnormalities in the dentate and inferior olivary nuclei as compared to non-CMS patients. METHODS MRI brains on 40 pediatric medulloblastoma patients between 2013-2015 were retrospectively reviewed by a neuroradiologist blinded to the diagnosis at pre-operative and immediate, 6-month, 12 month and most recent post-operative time points. The dentate and inferior olivary nuclei were scored for restricted diffusion, T1 and T2 hypo-and hyperintensity. A linear regression with different scores on CMS status (YES vs NO) was applied, after adjusting for age. RESULTS In the dentate nuclei, there was significantly higher T2 hypointensity in the CMS group on immediate (difference is 0.4084, p=0.0467) and most recent (difference is 0.7190, p=0.0386) post-operative MRIs. The CMS group had significantly higher T1 hyperintensity on the 1-year (difference is 0.9254, p=0.0108) and most recent (difference is 1.3291, p<0.001) post-operative MRIs. In the inferior olivary nuclei, there was significantly higher T2 hyperintensity on the 6-month (difference is 0.71, p=0.0045) and 1-year (difference is 0.6356, p=0.0162) post-operative MRIs. CONCLUSION The immediate post-operative findings are suggestive of a hemorrhagic, rather than an ischemic process in the dentate nuclei. On long-term follow up, the signal changes in the dentate and the inferior olivary nuclei represent dystrophic mineralization and hypertrophic degeneration, due to inflammation and axonal degeneration within the dentatorubroolivary tract2

Hypertrophic olivary degeneration following head injury: a case report

BackgroundHypertrophic olivary degeneration (HOD) is a unique type of neuronal degeneration presenting as hypertrophy, in contrast to atrophy as seen in most cases. It presents with classical characteristic clinical features due to involvement of dentate-rubral-olivary pathway, also described as triangle of Guillain and Mollaret formed in midbrain, pons and cerebellum. It can be idiopathic or secondary to infarction, bleeding, tumours, trauma or demyelination. However, the mechanism is still unclear. Herein, we present a case of HOD that had developed after post-traumatic pontine and midbrain haemorrhagic contusion.Case presentationA young male patient presented with progressively increasing tremors of both hands, inability to walk and multiple cranial nerve palsy. Magnetic resonance imaging demonstrated bilateral inferior olivary nucleus enlargement and signal changes seen as T2 and T2-FLAIR hyperintensities and non-enhancing T1 iso-intensities. Based on these features, diagnosis of HOD was made. Patient was kept on conservative management and his condition improved.ConclusionsHypertrophic olivary degeneration is a unique neuronal degeneration with typical clinical manifestations and distinct imaging features. Proper and early recognition and multidisciplinary treatment approach can result in the best outcomes for the patient.

Tricking AI chips into simulating the human brain: A detailed performance analysis

In recent years, significant strides in Artificial Intelligence (AI) have led to various practical applications, primarily centered around training and deployment of deep neural networks (DNNs). These applications, however, require considerable computational resources, predominantly reliant on modern Graphics-Processing Units (GPUs). Yet, the quest for larger and faster DNNs has spurred the creation of specialized AI chips and efficient Machine-Learning (ML) software tools like TensorFlow and PyTorch have been developed for striking a balance between usability and performance. Simultaneously, the field of computational neuroscience shares a similar quest for increased computational power to simulate more extensive and detailed brain models, while also keeping usability high. Although GPUs have also entered this field, programming complexity remains high, resulting in cumbersome simulations. Inspired by AI progress, we introduce a workflow for easily accelerating brain simulations using TensorFlow and evaluate the performance of various, cutting-edge AI chips – including the Graphcore Intelligence-Processing Unit (IPU), GroqChip, Nvidia GPU with Tensor Cores, and Google Tensor-Processing Unit (TPU) – when simulating a biologically detailed as well as simpler brain models. Our model simulations explore the architectural tradeoffs of a modern-day CPU and these four AI platforms by varying computational density, memory requirements and floating-point numerical accuracy. Results show that the GroqChip achieves the best performance for small networks, yet is unable to simulate large-scale networks. At the scale of mammalian brains, the GPU, IPU and TPU achieve speedups ranging from 29x to 1,208x times over CPU runtimes. Remarkably, the TPU sets a new record for the largest, real-time simulation of the inferior-olivary nucleus in the brain. Reduced-accuracy floating-point implementations make some simulation results unreliable for brain research, notably for the GroqChip. Consequently, this work underscores the potential of ML libraries for accelerating brain simulations as well as the critical role of AI-chip numerical accuracy for biophysically realistic brain models.

Hypertrophy of the inferior olivary nucleus in corticobasal degeneration: A neuropathological study.

Corticobasal degeneration (CBD) is a rare neurodegenerative disorder. The status of the inferior olivary nucleus (ION) in CBD has been inadequately investigated. In this study, we conducted a pathological investigation of the ION in CBD. We reviewed the data of Japanese patients with pathologically confirmed CBD who underwent consecutive autopsies between 1985 and 2020 at our institute. We retrospectively examined clinical data from medical records and clinicopathological conferences and semi-quantitatively assessed the ION, central tegmental tract, superior cerebellar peduncle, and dentate nucleus. Of the 32 patients included, 14 (43.8%) had hypertrophy of the ION (HION), of whom 6 showed laterality. In the 14 HION cases, with or without laterality, except in 1 unevaluable case, atrophy/myelin pallor of the central tegmental tract was observed on the same side as the hypertrophy. Ten patients with HION, with or without laterality, had atrophy/myelin pallor of the superior cerebellar peduncle on the contralateral side to the hypertrophy. The ION presents with hypertrophic changes in CBD. The lesion is a primary degeneration in CBD and is related to the degeneration of the Guillain-Mollaret triangle. This finding contributes to the elucidation of the specific pathological characteristics of CBD.

The olivary input to the cerebellum dissociates sensory events from movement plans

Neurons in the inferior olive are thought to anatomically organize the Purkinje cells (P-cells) of the cerebellum into computational modules, but what is computed by each module? Here, we designed a saccade task in marmosets that dissociated sensory events from motor events and then recorded the complex and simple spikes of hundreds of P-cells. We found that when a visual target was presented at a random location, the olive reported the direction of that sensory event to one group of P-cells, but not to a second group. However, just before movement onset, it reported the direction of the planned movement to both groups, even if that movement was not toward the target. At the end of the movement if the subject experienced an error but chose to withhold the corrective movement, only the first group received information about the sensory prediction error. We organized the P-cells based on the information content of their olivary input and found that in the group that received sensory information, the simple spikes were suppressed during fixation, then produced a burst before saccade onset in a direction consistent with assisting the movement. In the second group, the simple spikes were not suppressed during fixation but burst near saccade deceleration in a direction consistent with stopping the movement. Thus, the olive differentiated the P-cells based on whether they would receive sensory or motor information, and this defined their contributions to control of movements as well as holding still.

ExaFlexHH: an exascale-ready, flexible multi-FPGA library for biologically plausible brain simulations.

In-silico simulations are a powerful tool in modern neuroscience for enhancing our understanding of complex brain systems at various physiological levels. To model biologically realistic and detailed systems, an ideal simulation platform must possess: (1) high performance and performance scalability, (2) flexibility, and (3) ease of use for non-technical users. However, most existing platforms and libraries do not meet all three criteria, particularly for complex models such as the Hodgkin-Huxley (HH) model or for complex neuron-connectivity modeling such as gap junctions. This work introduces ExaFlexHH, an exascale-ready, flexible library for simulating HH models on multi-FPGA platforms. Utilizing FPGA-based Data-Flow Engines (DFEs) and the dataflow programming paradigm, ExaFlexHH addresses all three requirements. The library is also parameterizable and compliant with NeuroML, a prominent brain-description language in computational neuroscience. We demonstrate the performance scalability of the platform by implementing a highly demanding extended-Hodgkin-Huxley (eHH) model of the Inferior Olive using ExaFlexHH. Model simulation results show linear scalability for unconnected networks and near-linear scalability for networks with complex synaptic plasticity, with a 1.99 × performance increase using two FPGAs compared to a single FPGA simulation, and 7.96 × when using eight FPGAs in a scalable ring topology. Notably, our results also reveal consistent performance efficiency in GFLOPS per watt, further facilitating exascale-ready computing speeds and pushing the boundaries of future brain-simulation platforms. The ExaFlexHH library shows superior resource efficiency, quantified in FLOPS per hardware resources, benchmarked against other competitive FPGA-based brain simulation implementations.

Zona incerta modulation of the inferior olive and the pontine nuclei.

The zona incerta (ZI) is a subthalamic structure that has been implicated in locomotion, fear, and anxiety. Recently interest has grown in its therapeutic efficacy in deep brain stimulation in movement disorders. This efficacy might be due to the ZI's functional projections to the other brain regions. Notwithstanding some evidence of anatomical connections between the ZI and the inferior olive (IO) and the pontine nuclei (PN), how the ZI modulates the neuronal activity in these regions remains to be determined. We first tested this by monitoring responses of single neurons in the PN and IO to optogenetic activation of channelrhodopsin-expressing ZI axons in wild-type mice, using an in vivo awake preparation. Stimulation of short, single pulses and trains of stimuli at 20 Hz elicited rapid responses in the majority of recorded cells in the PN and IO. Furthermore, the excitatory response of PN neurons scaled with the strength of ZI activation. Next, we used in vitro electrophysiology to study synaptic transmission at ZI-IO synapses. Optogenetic activation of ZI axons evoked a strong excitatory postsynaptic response in IO neurons, which remained robust with repeated stimulation at 20 Hz. Overall, our results demonstrate a functional connection within ZI-PN and ZI-IO pathways.

179 Stem Progenitor Cell Proliferation in the Brainstem After Spinal Cord Injury: A Potential Target for Therapeutic Intervention Distant From the Site of Injury

INTRODUCTION: Though there has been an increasing number of clinical trials focused on modulating stem/progenitor cell proliferation in the spinal cord after spinal cord injury (SCI), little is known about the acute response of stem/progenitor cells in supraspinal structures. We hypothesized that the signals stimulating stem/progenitor cell proliferation in the spinal cord after SCI activate similar responses in supraspinal regions because pathways injured in the spinal cord have their targets or sources in the brain. METHODS: We employed a mouse model of SCI, bromodeoxyuridine (BrdU) labeling of cells in S-phase, and co-labeling of markers of astrocytes, microglia, glial/oligodendrocyte precursor cells, and neuronal lineages to characterize the proliferative response within the brainstem of C57BL/6J mice 96 hours after a thoracic SCI. The extent of SCI and white matter (WM) spared was quantified by labeling of beta amyloid precursor protein and eriochrome cyanine R staining, respectively. RESULTS: Compared to sham-operated mice, there was a significant increase (3-fold; p < 0.01) in BrdU-labeled cells in the ventral-caudal medulla of injured mice. This response was consistent with the extent of SCI and primarily in WM tracts (57%) and the inferior olive (41%; IO). Co-labeling with cell-specific markers indicated that this response is glial (i.e., NG-2+ glial/oligodendrocyte precursor cells and GFAP+ astrocytes) with the largest increase in the number of BrdU-labeled cells occurring in the IO (6-fold increase; p < 0.01). Notably, there were no BrdU-labeled cells that co-labeled with markers of microglia or neuronal lineages. CONCLUSIONS: Our results demonstrate a stem/progenitor cell response within days of SCI that occurs distant from the injury site, notably in brainstem structures involved in motor learning and coordination. These findings highlight an acute response of glial/oligodendrocyte precursor cells in the brainstem as a potential target for future studies and therapeutic intervention after SCI.

483 Radiographic Changes in the Auditory Pathway to Predict Outcomes of Children with Hearing Loss

OBJECTIVES/GOALS: Early diagnosis of congenital sensorineural hearing loss (SNHL) is of paramount importance in preventing speech and language impairment.Diffusion tensor imaging (DTI) MRI can identify brain microstructural changes that may potentially contribute towards prognosticating rehabilitation. METHODS/STUDY POPULATION: We retrospectively reviewed pediatric patients with SNHL who obtained DTI MRI between 2011 and 2019, identifying 16 pediatric patients (age <18 years) with at least moderate asymmetric/bilateral SNHL., and gender-matched controlswithout neurological, developmental, or MRI-based brain macrostructural abnormalities. The following brainstem regions and tracts of the auditory pathway were assessed: superior olivary nucleus (SON), inferior colliculus (IC), ipsilateral tracts between the inferior colliculus and superior olivary nucleus (IC-SON). Diffusion values for bilateral regions and tracts were generated, then averaged to calculate a mean value for fractional anisotropy (FA) and mean diffusivity (MD) for each subject. RESULTS/ANTICIPATED RESULTS: Significant differences were identified in FA values of the SON between the SNHL cohort and controls (0.377±0.056 vs 0.422±0.052; p=0.009). No other FA or MD values were significantly different. In children £5 years, MD was significantly decreased in the SNHL cohort compared to controls in the IC (0.918±0.051 vs 1.120±0.142; p<0.001). In children >5 years, there were no significant differences in MD (1.124±0.198 vs 0.997±0.103; p = 0.119). There were no significant differences in MD or FA in the white matter fibers of the IC-SON tract [applewebdata%3A//720AAF0C-C4CF-459C-A42A-6BAA56C4E4CA#_msocom_2]. DISCUSSION/SIGNIFICANCE: This is the first study to assess microstructural changes in brainstem auditory pathway regions among children with SNHL. Longitudinal studies are warranted to assess the predictive value of DTI imaging for long-term outcomes and prognosticating intervention.

The Effect of Nucleo-Olivary Stimulation on Climbing Fiber EPSPs in Purkinje Cells

Climbing fibers, connecting the inferior olive and Purkinje cells, form the nervous system's strongest neural connection. These fibers activate after critical events like motor errors or anticipation of rewards, leading to bursts of excitatory postsynaptic potentials (EPSPs) in Purkinje cells. The number of EPSPs is a crucial variable when the brain is learning a new motor skill. Yet, we do not know what determines the number of EPSPs. Here, we measured the effect of nucleo-olivary stimulation on periorbital elicited climbing fiber responses through in-vivo intracellular Purkinje cell recordings in decerebrated ferrets. The results show that while nucleo-olivary stimulation decreased the probability of a response occurring at all, it did not reduce the number of EPSPs. The results suggest that nucleo-olivary stimulation does not influence the number of EPSPs in climbing fiber bursts.

Marked IDO2 expression and activity related to autophagy and apoptosis in brain tissue of fatal tuberculous meningitis

In about 1% of tuberculosis (TB) patients, Mycobacterium tuberculosis (M. tuberculosis) can disseminate to the meninges, causing tuberculous meningitis (TBM) with mortality rate up to 60%.Chronic granulomatous inflammation (non-necrotizing and necrotizing) in the brain is the histological hallmark of TBM. The tryptophan-catabolizing enzyme indoleamine 2,3-dioxygenase 1 (IDO1) and the generated kynurenine metabolites exert major effector functions relevant to TB granuloma functioning. Here we have assessed immunohistochemically IDO1 expression and activity and its effector function and that of its isoform, IDO2, in post-mortem brain tissue of patients that demised with neurotuberculosis. We also related these findings to brain tissue of fatal/severe COVID-19. In this study, IDO1 and IDO2 were abundantly expressed and active in tuberculoid granulomas and were associated with the presence of M. tuberculosis as well as markers of autophagy and apoptosis. Like in fatal/severe COVID-19, IDO2 was also prominent in specific brain regions, such as the inferior olivary nucleus of medulla oblongata and cerebellum, but not associated with granulomas or with M. tuberculosis. Spatially associated apoptosis was observed in TBM, whereas in fatal COVID-19 autophagy dominated. Together, our findings highlight IDO2 as a potentially relevant effector enzyme in TBM, which may relate to the symptomology of TBM.