Michael Shoykhet

Coding of deflection velocity and amplitude by whisker primary afferent neurons: implications for higher level processing

Within the rat whisker-to-barrel pathway, local circuits in cortical layer IV are more sensitive to the initial timing of deflection-evoked thalamic responses than to the total number of spikes comprising them. Because thalamic response timing better reflects whisker deflection velocity than amplitude, cortical neurons are more responsive to the former than the latter. The aim of this study is to determine how deflection velocity and amplitude may be encoded by the primary afferent neurons innervating the vibrissae. Responses of 81 extracellularly recorded trigeminal ganglion neurons (60 slowly and 21 rapidly adapting) were studied using controlled whisker stimuli identical to those used previously to investigate the velocity and amplitude sensitivities of thalamic and cortical neurons. For either slowly (SA) or rapidly adapting (RA) neurons, velocity is reflected by both response magnitude, measured as the total number of evoked spikes/stimulus, and initial firing rate, measured as the number of spikes discharged during the first 2 ms of the response. Deflection amplitude, on the other hand, is represented only by the SA population in their response magnitudes. Thus, in both populations initial firing rates unambiguously reflect deflection velocity. Together with previous findings, results demonstrate that information about deflection velocity is preserved throughout the whisker-to-barrel pathway by central circuits sensitive to initial response timing.Within the rat whisker-to-barrel pathway, local circuits in cortical layer IV are more sensitive to the initial timing of deflection-evoked thalamic responses than to the total number of spikes comprising them. Because thalamic response timing better reflects whisker deflection velocity than amplitude, cortical neurons are more responsive to the former than the latter. The aim of this study is to determine how deflection velocity and amplitude may be encoded by the primary afferent neurons innervating the vibrissae. Responses of 81 extracellularly recorded trigeminal ganglion neurons (60 slowly and 21 rapidly adapting) were studied using controlled whisker stimuli identical to those used previously to investigate the velocity and amplitude sensitivities of thalamic and cortical neurons. For either slowly (SA) or rapidly adapting (RA) neurons, velocity is reflected by both response magnitude, measured as the total number of evoked spikes/stimulus, and initial firing rate, measured as the number of spikes discharged during the first 2 ms of the response. Deflection amplitude, on the other hand, is represented only by the SA population in their response magnitudes. Thus, in both populations initial firing rates unambiguously reflect deflection velocity. Together with previous findings, results demonstrate that information about deflection velocity is preserved throughout the whisker-to-barrel pathway by central circuits sensitive to initial response timing.

Neurological sequelae of 2009 influenza A (H1N1) in children: A case series observed during a pandemic

Objective: To outline a series of cases demonstrating neurologic complications in children with Influenza infection. The ongoing 2009 influenza A (H1N1) presents significant challenges to the field of pediatric critical care and requires increased awareness of new presentations and sequelae of infection. Since World Health Organization declared a H1N1 pandemic, much attention has been focused on its respiratory manifestations of the illness, but limited information regarding neurologic complications has been reported. Design: Case series. Setting: Pediatric intensive care unit of a tertiary care medical facility. Patients: Four children admitted to the pediatric intensive care unit between March and November 2009 at the Childrens Hospital of Pittsburgh with altered mental status and influenza infection. Interventions: None. Measurements and Main Results: The clinical course was extracted by chart review and is summarized. All children demonstrated a coryzal prodrome, fever, and altered level of consciousness at admission, and one child presented with clinical seizures. Diagnostic studies performed to establish a diagnosis are summarized. All children had abnormal electroencephalograms early in their intensive care unit course and 50% had abnormal imaging studies. All children survived but 50% had neurologic deficits at hospital discharge. Conclusion: We conclude that 2009 influenza A (H1N1) can cause significant acute and residual neurologic sequelae. Clinicians should consider Influenza within a comprehensive differential diagnosis in children with unexplained mental status changes during periods of pandemic influenza.

Emergency neurological life support: Intracranial hypertension and herniation

Sustained intracranial hypertension and acute brain herniation are “brain codes,” signifying catastrophic neurological events that require immediate recognition and treatment to prevent irreversible injury and death. As in cardiac arrest, a brain code mandates the organized implementation of a stepwise management algorithm. The goal of this emergency neurological life support protocol is to implement an evidence-based, standardized approach to the evaluation and management of patients with intracranial hypertension and/or herniation.

Hypothermia for pediatric refractory status epilepticus

Refractory status epilepticus (RSE) is a life‐threatening emergency, demonstrating, by definition, significant pharmacoresistance. We describe five cases of pediatric RSE treated with mild hypothermia.

Dysautonomia after pediatric brain injury

Aim  Dysautonomia after brain injury is a diagnosis based on fever, tachypnea, hypertension, tachycardia, diaphoresis, and/or dystonia. It occurs in 8 to 33% of adults with brain injury and is associated with poor outcome. We hypothesized that children with brain injury with dysautonomia have worse outcomes and prolonged rehabilitation, and sought to determine the prevalence of dysautonomia in children and to characterize its clinical features.

Thalamocortical Dysfunction and Thalamic Injury after Asphyxial Cardiac Arrest in Developing Rats

Global hypoxia-ischemia interrupts oxygen delivery and blood flow to the entire brain. Previous studies of global brain hypoxia-ischemia have primarily focused on injury to the cerebral cortex and to the hippocampus. Susceptible neuronal populations also include inhibitory neurons in the thalamic reticular nucleus. We therefore investigated the impact of global brain hypoxia-ischemia on the thalamic circuit function in the somatosensory system of young rats. We used single neuron recordings and controlled whisker deflections to examine responses of thalamocortical neurons to sensory stimulation in rat survivors of 9 min of asphyxial cardiac arrest incurred on postnatal day 17. We found that 48–72 h after cardiac arrest, thalamocortical neurons demonstrate significantly elevated firing rates both during spontaneous activity and in response to whisker deflections. The elevated evoked firing rates persist for at least 6–8 weeks after injury. Despite the overall increase in firing, by 6 weeks, thalamocortical neurons display degraded receptive fields, with decreased responses to adjacent whiskers. Nine minutes of asphyxial cardiac arrest was associated with extensive degeneration of neurites in the somatosensory nucleus as well as activation of microglia in the reticular nucleus. Global brain hypoxia-ischemia during cardiac arrest has a long-term impact on processing and transfer of sensory information by thalamic circuitry. Thalamic circuitry and normalization of its function may represent a distinct therapeutic target after cardiac arrest.

Severe Hypernatremia in a Hospitalized Child: Munchausen by Proxy

An 8-week-old infant presented to a referring institution with profuse diarrhea and infectious enteritis for 1 week. He was initially treated for suspected Salmonella spp. sepsis and meningitis, because the organism was found in the stool, but the childs illness progressed, manifested by paroxysmal profuse diarrhea and increased urine output. After several weeks, he suffered a sagittal venous thrombosis and intracranial hemorrhage. Subsequently the child was transferred to a tertiary center for intestinal evaluation. The patients diarrhea and excessive diuresis resolved, and his sodium normalized soon after transfer. Four days later, however, after his mother arrived, he immediately developed severe hypernatremia (serum sodium concentration [Na(+)] = 214 mEq/L), with resumption of diarrhea and excessive diuresis. A gastric aspirate during the crisis demonstrated an extremely high sodium content, [Na(+)] = 1416 mEq/L, consistent with salt intoxication. Surveillance of the mother revealed that she manipulated the indwelling nasogastric tube; confronted, she admitted to salt administration. This case describes one of the ways that Munchausen syndrome by proxy can manifest with profound neurologic sequelae, and highlights the need for close observation and swift intervention when sufficient cause is present.

Whisker plucking alters responses of rat trigeminal ganglion neurons

Whisker plucking in developing and adult rats provides a convenient method of temporarily altering tactile input for the purposes of studying experience-dependent plasticity in the somatosensory cortex. Yet, a comprehensive examination of the effect of whisker plucking on the response properties of whisker follicle-innervating trigeminal ganglion (NVg) neurons is lacking. We used extracellular single unit recordings to examine responses of NVg neurons to controlled whisker stimuli in three groups of animals: (1) rats whose whiskers were plucked from birth for 21 days; (2) rats whose whiskers were plucked once at 21 days of age; and (3) control animals. After at least 3 weeks of whisker re-growth, NVg neurons in plucked rats displayed normal, single whisker receptive fields and could be characterized as slowly (SA) or rapidly adapting (RA). The proportion of SA and RA neurons was unaffected by whisker plucking. Both SA and RA NVg neurons in plucked rats displayed normal response latencies and angular tuning but abnormally large responses to whisker movement onsets and offsets. SA neurons were affected to a greater extent than RA neurons. The effect of whisker plucking was more pronounced in animals whose whiskers were plucked repeatedly during development than in rats whose whiskers were plucked once. Individual neurons in plucked animals displayed abnormal periods of prolonged rhythmic firing following deflection onsets and aberrant bursts of activity during the plateau phase of the stimulus. These results indicate that whisker plucking exerts a long-term effect on responses of trigeminal ganglion neurons to peripheral stimulation.

Minoxidil improves vascular compliance, restores cerebral blood flow, and alters extracellular matrix gene expression in a model of chronic vascular stiffness

Increased vascular stiffness correlates with a higher risk of cardiovascular complications in aging adults. Elastin (ELN) insufficiency, as observed in patients with Williams-Beuren syndrome or with familial supravalvular aortic stenosis, also increases vascular stiffness and leads to arterial narrowing. We used Eln+/- mice to test the hypothesis that pathologically increased vascular stiffness with concomitant arterial narrowing leads to decreased blood flow to end organs such as the brain. We also hypothesized that drugs that remodel arteries and increase lumen diameter would improve flow. To test these hypotheses, we compared carotid blood flow using ultrasound and cerebral blood flow using MRI-based arterial spin labeling in wild-type (WT) and Eln+/- mice. We then studied how minoxidil, an ATP-sensitive K+ channel opener and vasodilator, affects vessel mechanics, blood flow, and gene expression. Both carotid and cerebral blood flows were lower in Eln+/- mice than in WT mice. Treatment of Eln+/- mice with minoxidil lowered blood pressure and reduced functional arterial stiffness to WT levels. Minoxidil also improved arterial diameter and restored carotid and cerebral blood flows in Eln+/- mice. The beneficial effects persisted for weeks after drug removal. RNA-Seq analysis revealed differential expression of 127 extracellular matrix-related genes among the treatment groups. These results indicate that ELN insufficiency impairs end-organ perfusion, which may contribute to the increased cardiovascular risk. Minoxidil, despite lowering blood pressure, improves end-organ perfusion. Changes in matrix gene expression and persistence of treatment effects after drug withdrawal suggest arterial remodeling. Such remodeling may benefit patients with genetic or age-dependent ELN insufficiency. NEW & NOTEWORTHY Our work with a model of chronic vascular stiffness, the elastin ( Eln)+/- mouse, shows reduced brain perfusion as measured by carotid ultrasound and MRI arterial spin labeling. Vessel caliber, functional stiffness, and blood flow improved with minoxidil. The ATP-sensitive K+ channel opener increased Eln gene expression and altered 126 other matrix-associated genes.

Long-term increase in coherence between the basal ganglia and motor cortex after asphyxial cardiac arrest and resuscitation in developing rats

Background:The basal ganglia are vulnerable to injury during cardiac arrest. Movement disorders are a common morbidity in survivors. Yet, neuronal motor network changes post-arrest remain poorly understood.Methods:We compared function of the motor network in adult rats that, during postnatal week 3, underwent 9.5 min of asphyxial cardiac arrest (n = 9) or sham intervention (n = 8). Six months after injury, we simultaneously recorded local field potentials (LFP) from the primary motor cortex (MCx) and single neuron firing and LFP from the rat entopeduncular nucleus (EPN), which corresponds to the primate globus pallidus pars interna. Data were analyzed for firing rates, power, and coherence between MCx and EPN spike and LFP activity.Results:Cardiac arrest survivors display chronic motor deficits. EPN firing rate is lower in cardiac arrest survivors (19.5 ± 2.4 Hz) compared with controls (27.4 ± 2.7 Hz; P < 0.05). Cardiac arrest survivors also demonstrate greater coherence between EPN single neurons and MCx LFP (3—100 Hz; P < 0.001).Conclusions:This increased coherence indicates abnormal synchrony in the neuronal motor network after cardiac arrest. Increased motor network synchrony is thought to be antikinetic in primary movement disorders. Characterization of motor network synchrony after cardiac arrest may help guide management of post-hypoxic movement disorders.