Impact of transient acute hypoxia on the developing mouse EEG.

Hypoxemic events are common in sick preterm and term infants and represent the most common cause of seizures in the newborn period. Neonatal seizures often lack clinical correlates and are only recognized by electroencephalogram (EEG). The mechanisms leading from a hypoxic/ischemic insult to acute seizures in neonates remain poorly understood. Further, the effects of hypoxia on EEG at various developmental stages have not been fully characterized in neonatal animals, in part due to technical challenges. We evaluated the impact of hypoxia on neonatal mouse EEG to define periods of increased susceptibility to seizures during postnatal development. Hippocampal and cortical electrodes were implanted stereotaxically in C57BL/6 mice from postnatal age 3 (P3) to P15. Following recovery, EEG recordings were obtained during baseline, acute hypoxia (4% FiO2 for 4min) and reoxygenation. In baseline recordings, maturation of EEG was characterized by the appearance of a more continuous background pattern that replaced alternating high and low amplitude activity. Clinical seizures during hypoxia were observed more frequently in younger animals (100% P3-4, 87.5% P5-6, 93% P7-8, 83% P9-10, 33% P11-12, 17% P15, r(2)=0.81) and also occurred at higher FiO2 in younger animals (11.2±1.1% P3-P6 vs. 8.9±0.8% P7-12, p<0.05). Background attenuation followed the initial hypoxemic seizure; progressive return to baseline during reoxygenation was observed in survivors. Electrographic seizures without clinical manifestations were observed during reoxygenation, again more commonly in younger animals (83% P3-4, 86% P5-6, 75% P7-8, 71% P9-10, 20% P11-12, r(2)=0.82). All P15 animals died with this duration and degree of hypoxia. Post-ictal abnormalities included burst attenuation and post-anoxic myoclonus and were more commonly seen in older animals. In summary, neonatal mice exposed to brief and severe hypoxia followed by rapid reoxygenation reliably develop seizures and the response to hypoxia varies with postnatal age and maturation.

Gabapentin use in the neonatal intensive care unit and beyond: Single center report of 104 cases.

BACKGROUND: We aimed to describe our experience with gabapentin use in infants admitted to our neonatal intensive care unit (NICU), including neurodevelopmental follow-up after discharge. METHODS: We performed a retrospective medical record review of infants prescribed gabapentin during admission to the University of Virginia NICU from 01/01/2015 to 04/30/2021. We report clinical characteristics including gabapentin indication, dosing and side-effects while in the NICU, discharge data, and assessments in outpatient developmental follow-up clinic. RESULTS: Gabapentin was prescribed to 104 infants (median gestational age 29 weeks, median postmenstrual age at initiation 41 weeks). Sixty-one percent of infants were male. The primary indication was irritability in 86%, and 67% were receiving at least one other neurosedative medication. Median maximum dose was 25 mg/kg/day (IQR 15-35 mg/kg/day) and 84% were discharged home on gabapentin. The majority required equipment at discharge (64% gastrostomy or nasogastric tube feeds, 54% supplemental oxygen or mechanical ventilation, and 40% both). At the first neurodevelopmental follow-up appointment, at least one area of delay was identified in 93% of infants and by 2 years corrected age 66% had a diagnosis of global developmental delay. CONCLUSIONS: NICU patients treated with gabapentin often require complex post-discharge care and require close neurodevelopmental follow up.

Haploinsufficiency of X-linked intellectual disability gene CASK induces post-transcriptional changes in synaptic and cellular metabolic pathways.

Heterozygous mutations in the X-linked gene CASK are associated with intellectual disability, microcephaly, pontocerebellar hypoplasia, optic nerve hypoplasia and partially penetrant seizures in girls. The Cask+/- heterozygous knockout female mouse phenocopies the human disorder and exhibits postnatal microencephaly, cerebellar hypoplasia and optic nerve hypoplasia. It is not known if Cask+/- mice also display seizures, nor is known the molecular mechanism by which CASK haploinsufficiency produces the numerous documented phenotypes. 24-h video electroencephalography demonstrates that despite sporadic seizure activity, the overall electrographic patterns remain unaltered in Cask+/- mice. Additionally, seizure threshold to the commonly used kindling agent, pentylenetetrazol, remains unaltered in Cask+/- mice, indicating that even in mice the seizure phenotype is only partially penetrant and may have an indirect mechanism. RNA sequencing experiments on Cask+/- mouse brain uncovers a very limited number of changes, with most differences arising in the transcripts of extracellular matrix proteins and the transcripts of a group of nuclear proteins. In contrast to limited changes at the transcript level, quantitative whole-brain proteomics using iTRAQ quantitative mass-spectrometry reveals major changes in synaptic, metabolic/mitochondrial, cytoskeletal, and protein metabolic pathways. Unbiased protein-protein interaction mapping using affinity chromatography demonstrates that CASK may form complexes with proteins belonging to the same functional groups in which altered protein levels are observed. We discuss the mechanism of the observed changes in the context of known molecular function/s of CASK. Overall, our data indicate that the phenotypic spectrum of female Cask+/- mice includes sporadic seizures and thus closely parallels that of CASK haploinsufficient girls; the Cask+/- mouse is thus a face-validated model for CASK-related pathologies. We therefore surmise that CASK haploinsufficiency is likely to affect brain structure and function due to dysregulation of several cellular pathways including synaptic signaling and cellular metabolism.

Implementation of a 'Hypothermia for HIE' program: 2-year experience in a single NICU.

Hypothermia has been shown to be neuroprotective in some newborns with moderate-to-severe perinatal hypoxic-ischemic encephalopathy (HIE). In 2006, the American Academy of Pediatrics recommended that institutions that choose to use therapeutic hypothermia do so in the context of a rigorous protocol, with systematic collection of patient data including neurodevelopmental follow-up. In this report, we describe our experience with implementation of a 'Hypothermia for HIE' program in a single tertiary care Neonatal Intensive Care Unit (NICU). Important components of the program include detailed protocols, staff and outreach education, early initiation of cooling in both inborn and outborn patients, maintaining stable hypothermia during neonatal transport, and comprehensive neurologic evaluation including serial EEGs, brain MRI and neurodevelopmental follow-up. In the first 2 years of the program, we have used hypothermia therapy in 21 patients, 18 with perinatal and 3 with early postnatal events leading to HIE. Eleven of fifteen outborn patients were cooled prior to and during transport, resulting in initiation of therapy 3 h sooner than if therapy had been delayed until arrival at our center. While lowering the body temperature of encephalopathic newborns is not difficult, addressing the complex medical problems of this vulnerable group of patients requires an experienced multidisciplinary team in regional referral centers.

Factors associated with treatment delays in pediatric refractory convulsive status epilepticus.

OBJECTIVE: To identify factors associated with treatment delays in pediatric patients with convulsive refractory status epilepticus (rSE). METHODS: This prospective, observational study was performed from June 2011 to March 2017 on pediatric patients (1 month to 21 years of age) with rSE. We evaluated potential factors associated with increased treatment delays in a Cox proportional hazards model. RESULTS: We studied 219 patients (53% males) with a median (25th-75th percentiles [p25-p75]) age of 3.9 (1.2-9.5) years in whom rSE started out of hospital (141 [64.4%]) or in hospital (78 [35.6%]). The median (p25-p75) time from seizure onset to treatment was 16 (5-45) minutes to first benzodiazepine (BZD), 63 (33-146) minutes to first non-BZD antiepileptic drug (AED), and 170 (107-539) minutes to first continuous infusion. Factors associated with more delays to administration of the first BZD were intermittent rSE (hazard ratio [HR] 1.54, 95% confidence interval [CI] 1.14-2.09; p = 0.0467) and out-of-hospital rSE onset (HR 1.5, 95% CI 1.11-2.04; p = 0.0467). Factors associated with more delays to administration of the first non-BZD AED were intermittent rSE (HR 1.78, 95% CI 1.32-2.4; p = 0.001) and out-of-hospital rSE onset (HR 2.25, 95% CI 1.67-3.02; p < 0.0001). None of the studied factors were associated with a delayed administration of continuous infusion. CONCLUSION: Intermittent rSE and out-of-hospital rSE onset are independently associated with longer delays to administration of the first BZD and the first non-BZD AED in pediatric rSE. These factors identify potential targets for intervention to reduce time to treatment.

Preserved simple and impaired compound movement after infarction in the territory of the superior cerebellar artery.

A patient with an infarct in the distribution of the right superior cerebellar artery was studied with regard to his ability to make simple movements (visually triggered, self-terminated ballistic wrist movements), and compound movements (reaching to a visual target and precision pinch of a seen object). Movements on the right side of the body alone were affected. Control movements were made by the normal left upper extremity. Wrist movement on the right side was normal in reaction time, direction, peak velocity, and end-point position control as compared to the left. By contrast, both reaching and pinching movements on the right were impaired. Reaching movements showed marked decomposition of the compound elbow-shoulder movement into seriatim simple movements made alternately at elbow and shoulder. Pinching movements were not made, and instead winkling movements (a movement of index alone) were substituted. These results are compared to similar results of controlled inactivation of the cerebellar dentate nucleus in monkeys. We conclude that one function of the cerebellum may be to combine elements in the movement repertoires of downstream movement generators. When that ability is lost, a strategy may be voluntarily adopted of using the preserved simple movements in place of the impaired compound movements.

Cerebellar nuclei: rapid alternating movement, motor somatotopy, and a mechanism for the control of muscle synergy.

Monkeys were trained to make rapid alternating flexion and extension movements seriatim at each of five body parts--foot (toe grasp and release), shoulder, elbow, wrist, and thumb. "Facial movements"--mouth, tongue, jaw and pharynx--were also made to drink the fruit juice reward. Movement at a given joint could be performed simply by alternate activation of the prime mover muscle groups, and EMG analysis indicated that these primary muscles were active during movement of that joint. No muscle within any one large body part (leg or arm) was strongly active in relation to movement of another body part. Yet, within a body part (arm), synergist muscles were often more active than the primaries during movement of a given joint, only to become less active during movement of the joint at which their action was primary. Neurons in dentate and interpositus discharged in relation to these movements. In the antero-posterior dimension of both dentate and interposed nuclei, there was a significant tendency for neural modulation to be somatotopically arranged according to the preferred movement: hindlimb anteriormost, forelimb in the middle, and head posteriorly. In the medio-lateral dimension, no such localization was seen for the different movements of the upper limb. Like muscle activity, neural discharge modulation usually occurred in strong relation to a number of movements in a single body part (arm), but not to the movements of different body parts (leg, face). Lesion of the middle third of dentate and of a portion of lateral interpositus had little effect upon the movements at the single joints, and thus upon the prime movers. However, the pattern of activity of agonist, antagonist, and synergist muscles was changed. These results are consistent with the view that the dentate controls muscle synergy and movement coordination more than the prime movers per se.

Salmonella berta meningitis in a term neonate.

We report the case of a 37-week male infant born via spontaneous vaginal delivery who developed Salmonella berta sepsis and meningitis. The infant was born to a mother with active diarrhea and stool cultures growing S. berta. On day 3, the infant developed poor feeding, lethargy, apnea and bradycardia prompting a sepsis evaluation. Blood, stool and cerebrospinal fluid cultures were positive for S. berta. An electroencephalogram performed for posturing revealed neonatal status epilepticus. Extensive bilateral periventricular venous hemorrhagic infarctions with multiple herniations were seen on brain magnetic resonance imaging. The infant's condition continued to deteriorate despite maximal support and care was redirected towards comfort measures.

Cerebellar control of constrained and unconstrained movements. I. Nuclear inactivation.

The aim of this study was to determine in monkeys if inactivation of dentate and lateral interposed deep cerebellar nuclei preferentially impairs certain movements relative to others. Constrained movements of the digits were trained with digits, hand, and elbow constrained in a cast. Simple movements were flexion of Thumb or Index. A compound movement was simultaneous flexion of Thumb+Index. An unconstrained movement consisted of a reach to, pinch of, and retrieval of a small food reward (Reach+Pinch). In two monkeys we mapped the dentate and interpositus with 66 injections of muscimol (3 microl of 5 microg/microl). Thirty-two percent of the injections resulted in increased reaction times of Thumb, Index, and Thumb+Index (mean = 24, 24, 28 + 26, respectively). Fifty percent of the injections impaired Reach+Pinch, producing target overshoot, curved reach trajectory, missed target (X and Y errors), and clumsy pinch with dropped fruit bits. Inactivation impaired each and all of Thumb, Index, Thumb+Index, and Reach+Pinch in 27%, only Reach+Pinch in 23%, and only Thumb, Index, Thumb+Index in 5% of injections. In sum, all types of movement were impaired. Thumb+Index was no more impaired than Thumb or Index alone, suggesting that the lateral cerebellar nuclei are not specifically required for combining movements of the two digits when constrained. Reach+Pinch appeared so greatly impaired and Thumb, Index, Thumb+Index so little as to be consistent with the hypothesis that a principal role of the cerebellum is to control those interactions that occur between body segments in natural unconstrained movements. However, the fact that all movements were impaired shows that the cerebellum contributes to the control of all movements.

Cerebellar control of constrained and unconstrained movements. II. EMG and nuclear activity.

The aim of this study was to see in monkeys if neurons in dentate and lateral interposed deep cerebellar nuclei are preferentially active in relation to certain movements relative to others. Simple and compound digit movements were trained with digits, hand, and elbow constrained in a cast. The constrained simple movement was flexion of Thumb or Index; the constrained compound movement, flexion of Thumb+Index. An unconstrained compound movement consisted of a reach to, pinch of, and retrieval of a small food reward (Reach+Pinch). Electromyographic (EMG) recording showed that many muscles in the upper extremity, shoulder girdle, and trunk were active in all movements. EMG/muscle stimulation during the constrained digit movements showed that the digit prime movers were active during, sufficient for, and necessary for performance of these digit tasks. By contrast, EMG/muscle stimulation showed that the proximal muscles (though co-active during the tasks) were neither sufficient nor necessary for performance of the digit tasks. A fraction of those neurons that were active during both the constrained and the unconstrained movements fired at a higher frequency during the unconstrained task. Some neurons were active during Reach+Pinch only; a few others were active during one or more of Thumb, Index, Thumb+Index only. There was no distinct preferential discharge relationship to the compound Thumb+Index as compared with the simple Thumb or Index. These correlational data are consistent with an interpretation that the cerebellar discharge influenced all of these movements-simple and compound, constrained, and unconstrained-no one type seemingly more than any other.

The cerebellum and the adaptive coordination of movement.

Based on a review of cerebellar anatomy, neural discharge in relation to behavior, and focal ablation syndromes, we propose a model of cerebellar function that we believe is both comprehensive as to the available information (at these levels) and unique in several respects. The unique features are the inclusion of new information on (a) cerebellar output--its replicative representation of body maps in each of the deep nuclei, each coding a different type and context of movement, and each appearing to control movement of multiple body parts more than of single body parts; and (b) the newly assessed long length of the parallel fiber. The parallel fiber, by virtue of its connection through Purkinje cells to the deep nuclei, appears optimally designed to combine the actions at several joints and to link the modes of adjacent nuclei into more complex coordinated acts. We review the old question of whether the cerebellum is responsible for the coordination of body parts as opposed to the tuning of downstream executive centers, and conclude that it is both, through mechanisms that have been described in the cerebellar cortex. We argue that such a mechanism would require an adaptive capacity, and support the evidence and interpretation that it has one. We point out that many parts of the motor system may be involved in different types of motor learning for different purposes, and that the presence of the many does not exclude an existence of the one in the cerebellar cortex. The adaptive role of the cerebellar cortex would appear to be specialized for combining simpler elements of movement into more complex synergies, and also in enabling simple, stereotyped reflex apparatus to respond differently, specifically, and appropriately under different task conditions. Speed of learning and magnitude of memory for both novel synergies and task-specific performance modifications are other attributes of the cerebellar cortex.

Throwing while looking through prisms. I. Focal olivocerebellar lesions impair adaptation.

Normal human subjects and patients with lesions of the olivocerebellar system threw balls of clay at a visual target while wearing wedge prism spectacles. Normal subjects initially threw in the direction of prism-bent gaze, but with repeated throws adapted to hit the target. Patients with generalized cerebellar atrophy, inferior olive hypertrophy, or focal infarcts in the distribution of the posterior inferior cerebellar artery, in the ipsilateral inferior peduncle, in the contralateral basal pons or in the ipsilateral middle cerebellar peduncle had impaired or absent prism adaptation. Patients with infarcts in the distribution of the posterior inferior cerebellar artery usually had impaired or absent adaptation but little or no ataxia. By contrast, patients with damage in the distribution of the superior cerebellar artery or in cerebellar thalamus usually had ataxia but preserved adaptation. These results implicate climbing fibres from the contralateral inferior olive via the ipsilateral inferior cerebellar peduncle, mossy fibres from the contralateral pontocerebellar nuclei via the ipsilateral middle cerebellar peduncle, and posterior inferior cerebellar artery territory cortex as being critical for this adaptation. The dentatothalamic projection and the superior cerebellar artery territory cortex are not necessary for this adaptation.

Throwing while looking through prisms. II. Specificity and storage of multiple gaze-throw calibrations.

Human subjects threw balls of clay at a visual target while looking through wedge prism spectacles. In studies of short-term adjustment, subjects threw in the direction of their prism-bent gaze, missing the target to that side. Within 10-30 throws, they gradually adapted with a wider gaze-throw angle and hit the target. Immediately after removal of the prisms the wide gaze-throw angle persisted and throws missed the target to the opposite side, the so-called 'negative after effect'. Repeated throws were required to adapt back to the normal gaze-throw angle and hit the target. The adaptation was specific both to the body parts trained and the type of throw trained: training with the right hand did not generalize to throwing with the left; overhand training seldom generalized to underhand throwing. In a study of long-term adjustment, two subjects threw with the same hand (right) and the same type of throw (overhand) alternately, with and without prisms, over a period of 6 weeks. They gradually learned to hit the target on the first throw, with and without prisms. The two gaze-throw calibrations (prism and no-prism) were retained for > 27 months. The long-term adjustment was shown to consist of a coordinated relationship of eye-in-head, head-on-trunk and trunk-on-arm angles.