692 e2 CH3 Choline L TyrosineCH3 CH3 N+ CH3 HO O Acetylcholine CH3 CH3 H3C HN A C D B N+ CH3 CoA SH CoA S O O O O H NH3 CC COO–[CH2]2 H2N O H NH3 C COO––OOC [CH2]2 NH3 –OOC [CH2]3 O C–OOC COO–[CH2]2 C[.]
692.e2 O Choline N+ HO O L-Tyrosine CH3 OH CH3 CoA S O2 Tetrahydrobiopterin CH3 AcetylCoA CoA chAT Acetylcholine N+ O A O HO CH3 O Tyrosine hydroxylase Dihydrobiopterin H2O SH H3C NH2 HO CH3 L-DOPA OH CH3 NH2 HO CH3 DOPA decarboxylase O L-Tryptophan OH NH2 HN HO Dopamine O2 Tetrahydrobiopterin Dihydrobiopterin H2O Tryptophan hydroxylase O2 Ascorbic acid HO OH OH HO NH2 HN Dopamine β-hydroxylase Dehydroascorbic acid H2O O 5-HTP NH2 HO Norepinephrine NH2 HO 5-HTP decarboxylase S-adenosylmethionine Phenylethanolamine N-methyltransferase HO Homocysteine OH Serotonin HO C HN Epinephrine NH2 N HO B H H O C [CH2]2 C COO– NH3 H2N Glutamine [CH2]2 C α-Ketoglutarate D • eFig 58.1 H –OOC C [CH2]2 NH3 O –OOC Glutamate COO– CH3 COO– Glutamic acid decarboxylase –OOC [CH2]3 GABA Neurotransmitter structure and synthesis (A) Acetylcholine (B) Catecholamines It should be noted that synthesis of norepinephrine and epinephrine requires dopamine as a precursor (C) Serotonin, an amine synthesized from tryptophan (D) Glutamate and g-aminobutyric acid, amino acid derivatives NH3 CHAPTER 58 Structure, Function, and Development of the Nervous System into epinephrine by an enzyme phentolamine N-methyltransferase, which is found only in adrenergic neurons Thus, all neurons that synthesize catecholamines contain TH and dopa decarboxylase, but only noradrenergic and adrenergic neurons contain the synthetic enzymes required to produce norepinephrine and epinephrine, respectively Catecholamine-using neurons reside primarily in the brainstem Dopaminergic neurons in humans are located in two mesencephalic nuclei: the substantia nigra and its medial neighbor, the ventral tegmental area Dopaminergic neurons in the substantia nigra project primarily to the basal ganglia, where they are involved with initiation of voluntary movement Ventral tegmental neurons send dopaminergic fibers to the amygdala and the cerebral cortex and participate in regulation of emotion, reward, and addiction Brainstem noradrenergic neurons are located in the locus ceruleus and in the reticular formation They project widely to the thalamus and cortex, as well as to the spinal cord, and play a significant role in arousal and vigilance Adrenergic CNS neurons are located in the ventrolateral medulla and participate in temperature regulation via their projections to the hypothalamus Unlike ACh, which is cleared from the synapse by hydrolysis, catecholamines are cleared from the synaptic cleft by reuptake into the axonal terminal Once inside the cell, catecholamines are either repackaged into vesicles or destroyed by monoamine oxidase (MAO) Pharmacologic manipulation of synaptic catecholamine concentrations plays a therapeutic role in the management of several disorders, such as depression and attention deficithyperactivity disorder (ADHD) Furthermore, recreational drugs affecting catecholamine concentrations at the synapse continue to gain popularity and to grow in number Therapeutic uses include treatment of severe depression with MAO inhibitors, which inhibit catecholamine breakdown, and treatment of ADHD with amphetamines, which interfere with dopamine transport and increase dopamine concentrations Recreational drugs include amphetamine and its analogs, along with cocaine, a selective norepinephrine transporter blocker Excess catecholamine levels at the synapse result in sensations of euphoria, increased energy levels, improved focus, anxiety, paranoia, and jitteriness Notably, hypertensive crises leading to myocardial infarction and stroke may occur with use of cocaine, amphetamines, and MAO inhibitors Serotonin Serotonin is an amine neurotransmitter synthesized from the amino acid tryptophan in a two-step process (eFig 58.1C) First, tryptophan is hydroxylated by tryptophan hydroxylase to form 5-hydroxytryptophan (5-HTP) 5-HTP is then decarboxylated by 5-HTP decarboxylase to form serotonin, also known as 5-hydroxytryptamine (5-HT) After 5-HT is released at the synapse, it is cleared by a specific serotonin reuptake transporter Serotonergic neurons are located in the rostral and caudal raphe nuclei in the brainstem Rostral raphe neurons innervate the cerebral cortex, including the limbic system, where serotonin levels help regulate mood and attention Caudal raphe neurons project to the brainstem and spinal cord, where they are involved in regulation of general arousal and pain perception, respectively Importantly, dysfunction of the serotonergic pathways originating in the raphe nuclei has been linked with sudden infant death syndrome (SIDS).15 Additionally, serotonin levels play a key role in depression, giving rise to an entire class of drugs in clinical use called selective serotonin reuptake inhibitors (SSRIs) SSRI abuse or overdose is rare but may result in patients presenting with the 693 potentially life-threatening “serotonin syndrome,” characterized by hypertension, tachycardia, mental status changes, myoclonus, and severe hyperthermia The latter may lead to shock, rhabdomyolysis, renal failure, and death The serotonin syndrome is particularly likely to occur when SSRIs and MAO inhibitors, inadvertently or intentionally, are taken together Treatment includes serotonin antagonists, blood pressure control with either adrenergic antagonists or agonists as clinically indicated, and temperature control with benzodiazepines and neuromuscular blockade Amino Acids Neurotransmitters derived from common amino acids include glutamate, g-aminobutyric acid (GABA), and glycine These are among the most widely distributed neurotransmitters in the CNS Glutamate and glycine exist as amino acids in all cells, where they are used as protein building blocks Glutamatergic and glycinergic neurons have the additional capacity to package glutamate and glycine, respectively, into synaptic vesicles and release them at the synapse GABA must be synthesized from glutamate via an additional reaction catalyzed by an enzyme glutamic acid decarboxylase (GAD; eFig 58.1D) Only GABA-ergic neurons contain GAD Glutamate is generally an excitatory neurotransmitter, whereas GABA and glycine are inhibitory Excitatory glutamatergic neurons exert their influence both locally and over a long distance, depending on the shape of their axons Inhibitory neurons, on the other hand, tend to exert local inhibitory control over neuronal circuitry either in the brain (GABA) or spinal cord (glycine) A major exception is cerebellar Purkinje cells, which are GABAergic but project over long distances to the brainstem, thalamus, and cerebral cortex (see later discussion) Adenosine, Peptides, and Nitric Oxide In addition to the “classic” neurotransmitters described earlier, a number of substances have been documented to mediate or modulate information transfer between neurons These include ATP and adenosine, which, at the synapse, is a metabolite of ATP released in the synaptic vesicle ATP modulates neuronal excitability such that energy may be conserved during times of ATP depletion Adenosine functions as a neurotransmitter in the autonomic nervous system (ANS), in the basal ganglia, and at some cortical synapses It also modulates the respiratory rate, and adenosine antagonists, such as caffeine, are used to treat apnea and bradycardia of prematurity In addition to ATP and adenosine, a number of peptides can be released in synaptic vesicles, including substance P, vasoactive intestinal peptide (VIP), endogenous opioids, and endogenous cannabinoids These peptides are involved in pain sensation and perception (substance P and opioids), modulation of vascular tone (VIP), and as yet uncharacterized processes (cannabinoids) Finally, several gaseous molecules function as neurotransmitters These include nitric oxide (NO), carbon monoxide (CO), and possibly hydrogen sulfide NO, the most thoroughly studied of the gaseous neurotransmitters, is produced by brainstem neurons in the nucleus tractus solitarius, where it interacts with a-amino3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA)–type and N-methyl-d-aspartate (NMDA)–type glutamate receptors and regulates cardiovascular function.16 Hydrogen sulfide is produced from the amino acid cysteine and may influence cellular redox state and glutamatergic transmission.17 Intriguingly, hydrogen sulfide induces a suspended animation-like state in animals18 and may be protective after resuscitation from cardiac arrest.19 694 S E C T I O N V I Pediatric Critical Care: Neurologic Neurotransmitter Receptors Nicotinic Acetylcholine Receptors nAChRs are ligand-gated ion channels, related structurally and functionally to GABAA channels and a subset of serotonin receptors Five transmembrane subunits comprise the nAChR and form a central pore that allows ionic currents to pass There are two subunit classes, a and b, with multiple members in each class The nAChR is generally a heteromer, but homomer channels have been described Each nAChR binds two ACh molecules, with affinity for ACh and nicotine dependent on subunit composition The receptor exists in three distinct states: closed, open, and desensitized In the closed position, no ionic current passes through the central core When an agonist, such as ACh or nicotine, binds the nAChR, the receptor opens, becoming permeable to monovalent and divalent cations After a short period of time, the receptor spontaneously closes On continued exposure to an agonist, however, the nAChR assumes a permanently closed, or desensitized, conformation.20 As discussed earlier, nAChRs mediate neuromuscular coupling at the NMJ In addition, nAChRs are widely distributed in the CNS, where they perform a variety of functions depending on subunit composition and location In the CNS, unlike at the NMJ, nAChRs are permeable to both Na1 and Ca21 In neurons, however, nAChR-evoked Ca21 current exceeds the Na1 current twofold to tenfold The greater Ca21 permeability indicates that nAChRs mostly modulate synaptic transmission and release of other neurotransmitters Indeed, although direct nAChR-dependent responses have been observed in the hippocampus and developing visual cortex, overwhelming evidence points to nicotinic receptors playing the role of modulator in the CNS Their wide distribution in the CNS—with locations presynaptically, postsynaptically, and extrasynaptically—further supports that role Activation of presynaptic nAChRs enhances release of ACh, dopamine, glutamate, and GABA Coupling of enhanced glutamate release with nAChR-dependent increase in intracellular Ca21 suggests that nAChRs participate in synaptic plasticity during learning Postsynaptic and extrasynaptic nAChRs regulate excitability and signal propagation in neuronal circuits In the hippocampus, for example, nAChR activation leads to increased release of GABA from inhibitory interneurons, which decreases the excitability of hippocampal pyramidal neurons Nicotinic receptors also interact with the dopaminergic system in regulating neuronal circuitry in the basal ganglia and limbic system Thus, nicotinic receptors have been implicated in not only learning and memory but also regulation of addiction and reward Furthermore, loss of cholinergic neurons represents one of the distinguishing neuropathologic features of Alzheimer disease, and cholinesterase inhibitors are widely used to improve cognition and memory in Alzheimer patients.20 In pediatrics, a mutation in nAChR is responsible for a specific clinical epilepsy phenotype, called autosomal-dominant nocturnal frontal lobe epilepsy.21 Seizure onset usually occurs around 12 years of age in otherwise healthy children Seizures originate in the frontal lobe and occur predominantly during non-REM sleep.22 The mutant nAChR is more sensitive to ACh than the wild-type receptor, suggesting that cholinergic medications should be avoided in these patients Muscarinic Acetylcholine Receptors Muscarinic ACh receptors (mAChRs) comprise a group of metabotropic receptors that link ACh exposure at the surface with G protein activation inside the cell There are five distinct subtypes of mAChRs, designated M1 through M5 These subtypes are divided into two broad classes on the basis of the identity of the G protein with which they interact M2 and M4 mAChRs couple with Gi proteins, inhibit adenylyl cyclase activity, and reduce intracellular cAMP levels M1, M3, and M5 receptor subtypes couple with Gq proteins and increase intracellular Ca21 levels via activation of phospholipase C.23 In the CNS, the M1 mAChR is the most abundant subtype, located on neurons in the cortex, thalamus, and striatum.24 mAChRs are also present in the PNS in the sweat glands and organs of lacrimation and salivation, as well as in the heart, where they mediate the parasympathetic control of heart rate and contractility mAChRs thus mediate many of the systemic effects of organophosphate exposure and nerve gas poisoning.25 Glutamate Receptors Glutamate is the major excitatory neurotransmitter in the CNS In mammals, it depolarizes postsynaptic neurons by binding to three types of ionotropic glutamate receptor (iGluR), each of which is characterized by different affinities for synthetic analogs, different selectivity to ions, and different time course of the current that is permitted to pass through the cell membrane The three types of iGluR are the AMPA receptor, NMDA receptor, and kainate receptor All three channel types are widely present throughout the CNS, with AMPA and NMDA channels mediating the bulk of the excitatory transmission At present, the function of the kainate channel remains to be clearly defined AMPA and NMDA receptors differ from each other with respect to ion permeability and time course of ion flow through the channel On binding of glutamate, AMPA receptors open their pores, which are permeable to Na1 and K1 ions At the negative resting potential of the neuronal cell membrane, Na1, driven by the electrochemical gradient, flows into the cell and causes a large, fast depolarization AMPA receptors are generally impermeable to Ca21, although more recent findings indicate that Ca21-permeable AMPA receptors exist and may significantly contribute to pathology observed in amyotrophic lateral sclerosis (ALS) and stroke.26 In contrast, NMDA receptors are universally permeable to Ca21, as well as to Na1 and K1, generating a slow, inward depolarizing current NMDA receptors possess a unique property, however, that allows them to pass current only when the neuronal membrane is already depolarized This property, termed voltage dependence, stems from Mg21 ions blocking the entry pore of the NMDA channel at negative membrane potentials even in the presence of glutamate As the neuron depolarizes further, mostly due to current flow via the AMPA receptor, the Mg21 block is relieved and Ca21, as well as Na1, flows into the cell Once inside the cell, Ca21 ions mediate a multitude of effects, from modifying protein phosphorylation and gene expression to overt excitotoxicity and cell death Thus, NMDA receptors are thought to function as coincidence detectors, linking events at the cell membrane (e.g., AMPA receptor–mediated depolarization, with long-term changes in synaptic strength and gene expression in the neuron) In addition to directly modulating current flow via the ionotropic channels, glutamate modulates effector molecules within the neuron by binding to a diversity of G protein–linked metabotropic glutamate receptors (mGluRs) Eight mammalian subtypes of mGluR are divided into three categories on the basis of sequence homology and coupling to secondary effector systems.27 Group I mGluRs (mGluR1 and mGluR5) are localized at the edge of the postsynaptic neuronal membrane and are positively CHAPTER 58 Structure, Function, and Development of the Nervous System coupled with phospholipase C (PLC) via the Gq protein Group II and group III mGluRs are located on the edge of the presynaptic neuronal membrane and are negatively coupled with adenylyl cyclase (AC) via the Gi protein All three groups are activated only when excess glutamate spills out of the synaptic cleft and diffuses toward mGluRs located at the periphery of the synaptic membrane Differential secondary messenger coupling and synaptic localization of the three mGluR groups point to their divergent roles in regulating neuronal function Binding of glutamate to group I mGluRs leads to activation of PLC, which releases two secondary messengers—diacylglycerol (DAG) and inositol triphosphate (IP3)—from the membrane phospholipid phosphoinositol 1,4,5-bisphosphate (PIP2) DAG activates protein kinase C in the neuronal membrane, whereas PIP2 diffuses toward its receptor on the internal cell membrane and triggers a massive Ca21 release into the cytoplasm Downstream events lead to (1) modulation of K1 currents, resulting in increased neuronal excitability; and (2) potentiation of glutamate-dependent current at NMDA receptors specific to the synapses at which excess glutamate release has occurred Thus, group I mGluRs participate in activitydependent strengthening of synaptic connections and play a significant role in learning and memory In contrast, group III, and probably group II, mGluRs on presynaptic neurons provide a negative feedback loop by inhibiting glutamate release When glutamate binds to group III mGluRs, an inhibitory G protein (Gi) is activated It then functions to decrease AC-mediated production of cAMP A decrease in cAMP leads to lower Ca21 concentrations at the presynaptic neuronal membrane and decreased synaptic vesicle fusion The net effect is a decrease in the amount of glutamate released at the synapse and a reduction in synaptic transmission Recently, mGluRs have emerged as a major therapeutic target due to the multitude of effects that they exert on synaptic transmission Their extrasynaptic location presumably will allow newly developed pharmaceutical agents to maximize therapeutic value and minimize unwanted side effects.28 GABAA and GABAB Receptors GABA is the major inhibitory neurotransmitter in the brain Like glutamate and ACh, it binds two distinct classes of GABA receptors; GABAA receptors are ionotropic and GABAB receptors are metabotropic Both receptor classes are involved in regulation of physiologic and pathologic states, and pharmacologic manipulation of GABA receptors plays a major role in the management of pediatric critical illness GABAA receptors are chloride channels At the normal resting membrane potential, opening of the GABAA receptor allows chloride ions to flow into the cell down their electrochemical gradient Influx of negatively charged Cl2 ions results in hyperpolarization of the cell membrane In neurons, membrane hyperpolarization decreases the probability that the neuron will reach threshold and fire an action potential Thus, on an individual cell level, GABA decreases neuronal activity via the GABAA receptor GABAA receptors are heteropentamers, similar in structure to the nAChRs At least eight subunit classes exist in mammals, including humans Each class consists of several members, allowing for a staggering 150,000 possible subunit combinations to create one functional GABAA receptor Only 500 combinations are known to exist, and most receptors contain a varying complement of the a, b, and g subunits.29 Most GABAA receptors cluster at postsynaptic densities; such clustering appears to depend on the presence of the g subunit However, a subset of the GABAA 695 receptors—in particular, those containing the d subunit—localize to extrasynaptic sites, mediate tonic levels of inhibition in the brain, and may underlie the pathophysiology of absence seizures.30 The pharmacology of the GABAA receptor is of particular relevance in critical care because the two classes of first-line anticonvulsants and anxiolytics in clinical practice—the benzodiazepines and barbiturates—allosterically modulate the GABAA receptor GABA itself binds the receptor at the junction of the a and b subunits Benzodiazepines bind the GABAA receptor at a different site, classically between the a and g2 subunits, and, in the presence of GABA, increase the frequency with which the chloride channel opens Barbiturates, in contrast, bind at yet a different site and increase the duration of the open state in the presence of GABA Thus, both benzodiazepines and barbiturates increase the efficacy of endogenous GABA in hyperpolarizing the cell membrane A major difference between the two drug classes is that at increasing concentrations, barbiturates, but not benzodiazepines, become direct GABA agonists and can open GABAA channels independent of endogenous GABA release Hence, barbiturates have a significantly narrower safety window compared with benzodiazepines Additional GABAA receptor ligands of clinical importance include (1) general inhalational anesthetics, which are thought to modulate tonic inhibition via the d subunit–containing receptors; (2) alcohol, although its mechanistic action is poorly understood; and (3) flumazenil, a competitive benzodiazepine antagonist used clinically to reverse benzodiazepine overdose GABAA receptor mutations contribute to several known disease states in humans Two different point mutations on chromosome 5, both affecting the g2 subunit, are associated with development of febrile seizures and generalized epilepsy, as well as with a link between the two conditions.31,32 In patients with temporal lobe epilepsy, GABAA receptor expression is altered in hippocampal neurons33 and GABA-evoked responses actually depolarize, rather than hyperpolarize, neurons in excised tissue (see also the Developmental Processes section later in this chapter).34 GABAA receptor dysfunction is also thought to contribute to anxiety, panic disorder, schizophrenia, and sleep disturbances.35 Thus, pharmacologic modulation of GABAA receptor function represents an active area of research and novel drug development GABAB receptors are heterodimeric proteins that activate G protein–coupled second messenger systems upon interaction with GABA at the membrane.36 The GABAB1 subunit binds GABA at the cell membrane, while the GABAB2 subunit interacts with the G protein on the cytosolic surface GABAB receptors are widely distributed throughout the CNS but are particularly abundant in the thalamus, cerebellum, and hippocampus They can be located both presynaptically and postsynaptically Presynaptic GABAB receptors allow G protein–coupled Ca21 influx into the cell and lead to feedback inhibition of transmitter release Postsynaptic GABAB receptors function as K1 channels by allowing a slow, G protein–dependent K1 current to leak out of the cell and lead to cell hyperpolarization (because positive ions have left the inside of the cell membrane).37 Baclofen is the only pharmacologic GABAB receptor ligand in current clinical use It directly activates the GABAB receptor and, through its action in the spinal cord, leads to reduction in muscle tone Thus, it is used primarily to relieve spasticity after CNS injury When administered systemically, it has a significant side-effect profile, including hypotension and bradycardia.36 Systemic side effects have been minimized with intrathecal administration 696 S E C T I O N V I Pediatric Critical Care: Neurologic via an indwelling catheter and pump.38,39 Indeed, intrathecal baclofen infusion has emerged as an alternative to the more invasive dorsal rhizotomy in the treatment of spasticity refractory to medical therapy in pediatric patients.40 Although intrathecal baclofen delivery systems are effective, they have a 10% to 20% failure rate over time When an intrathecal baclofen pump fails, patients can develop baclofen withdrawal symptoms characterized by agitation, increasing spasticity and dystonia, hypertension, tachycardia, hyperthermia, and potentially death.40 Thus, baclofen withdrawal should be considered in the differential diagnosis of an agitated child with an indwelling baclofen pump Major Anatomic Organization of the Nervous System The nervous system in mammals is organized along an evolutionarily conserved axis It can be divided anatomically and functionally into the central and peripheral nervous systems Broadly speaking, the CNS consists of the spinal cord and brain inside the skull All other components, such as nerves after they leave the spinal canal or exit the brain, as well as autonomic ganglia in the body, comprise the PNS The general subdivisions are shown in eFig 58.2 The following sections focus on well-defined functions of these subdivisions as well as on their clinical relevance in pediatric critical care medicine Central Nervous System Spinal Cord The spinal cord is organized into segments delineated by the exiting spinal nerves In humans, there are 31 segments: cervical, 12 thoracic, lumbar, sacral, and coccygeal.41 The first seven cervical nerves exit the spinal canal above the corresponding vertebra, that is, the C1 nerve exits between the occiput and the C1 vertebra (the atlas) Because in humans there are only seven cervical vertebrae and eight cervical nerves, the last cervical nerve, C8, exits the spinal canal between C7 and T1 From T1 on, each corresponding spinal nerve exits the spinal cord below its corresponding vertebra, that is, the T12 nerve exits between T12 and L1 Early in fetal life, the spinal cord extends throughout the entire length of the spinal canal Beginning in gestation week 12, the growth rate of the vertebrae exceeds that of the spinal cord, such that by birth in humans, the spinal cord ends at L3 During postnatal development, further differential growth occurs; in adults, the spinal cord ends more rostrally, between L1 and L2 The nerve roots continue to exit the spinal canal through their corresponding foramina, such that the caudal spinal roots extend past the end of the spinal cord toward their exit points and form the cauda equina The end of the spinal cord forms an important landmark during development because the lumbar puncture must be performed below the spinal cord in order to avoid severe injury Hence, in infants, the preferred location of the lumbar puncture is between L4 and L5 vertebrae, with an alternate site between L3 and L4 In adults, it is safe to perform the lumbar puncture between L3 and L4, with both the L2–L3 and the L4–L5 intervertebral spaces as alternative sites Spinal cord lesions result in two general subsets of neurologic deficits: those caused by interruption of ascending information flow toward the brain and those caused by interruption of descending brain control of the spinal cord circuitry and the PNS Thus, complete spinal cord transection leads to loss of sensation and muscular paralysis below the level of the lesion due to injury to the ascending sensory pathways and descending motor pathways, respectively Immediately after the transection, paralysis is flaccid, with loss of deep tendon reflexes, characteristic of spinal shock (not to be confused with neurogenic shock; see later discussion) After a period of time, paralysis becomes spastic, with increased muscle tone and hyperactive deep tendon reflexes due to disrupted inhibitory control of spinal cord circuitry by the brain’s motor centers Medulla The medulla extends rostrally from the spinal cord in the rough shape of an ice cream scoop.41 The closed “handle” portion contains an enclosed central canal contiguous with that in the spinal cord The open “scoop” portion is located rostrally where the central canal opens into the fourth ventricle The medulla gives origin to four cranial nerves (CN): the glossopharyngeal (CN IX), vagus (CN X), accessory (CN XI), and hypoglossal (CN XII) It also contains decussations (crossings) of two major fiber tracts The postsynaptic fibers from the nuclei gracilis and cuneatus, which carry tactile information from the lower and upper parts of the body, respectively, cross the midline in the caudal medulla, giving rise to the sensory decussation The pyramidal tracts, which contain fibers descending from the motor cortex into the spinal cord, decussate slightly more rostrally, giving rise to the pyramidal or motor decussation These decussations are responsible for the fact that the left half of the brain controls and senses the right half of the body and vice versa Thus, in general, damage to brain structures above the decussation gives rise to contralateral symptoms, whereas damage below the decussation results in ipsilateral symptoms (except for the cerebellum, as discussed later) Finally, the medulla contains the brain’s respiratory control center, which is of paramount importance in determining brain death (see later discussion) In the absence of neuromuscular blockade, complete apnea in response to rising Paco2 results only when the medulla has been extensively injured Although extensive damage to the medullary structures is often quickly fatal due to ensuing apnea, more localized injury produces a number of recognizable syndromes Wallenberg, or lateral medullary, syndrome occurs when the territory supplied by posterior inferior cerebellar artery has been compromised and consists of loss of temperature and pain sensation on the contralateral side of the body and ipsilateral side of the face Additionally, Horner syndrome and varying degrees of vertigo, dysphagia, and dysarthria can be present The medial medullary syndrome (Dejerine, or inferior alternating, syndrome) results from injury to the territory supplied by the anterior spinal artery or, occasionally, the vertebral artery It is characterized by weakness or complete hemiplegia and loss of tactile and vibratory perception on the contralateral side of the body, together with preservation of temperature and pain sensation in the body and full sensation in the face Medullary injury also occurs as a life-threatening, albeit rare, complication of tonsillectomy and adenoidectomy.42 Pons The pons extends from the medulla to the midbrain and is readily recognized by the massive, bulbous structure with horizontally oriented fibers on its ventral surface that gives rise to its name (from the Latin, bridge) The pons begins at the pontine-medullary junction, characterized by a groove from which the abducens (CN VI), facial (CN VII), and vestibulocochlear (CN VIII) nerves emerge It extends rostrally to the point of emergence of ... however, that allows them to pass current only when the neuronal membrane is already depolarized This property, termed voltage dependence, stems from Mg21 ions blocking the entry pore of the NMDA... directly modulating current flow via the ionotropic channels, glutamate modulates effector molecules within the neuron by binding to a diversity of G protein–linked metabotropic glutamate receptors (mGluRs)... hyperpolarize, neurons in excised tissue (see also the Developmental Processes section later in this chapter).34 GABAA receptor dysfunction is also thought to contribute to anxiety, panic disorder,