Neuromuscular junction

The neuromuscular junction (NMJ) is one of the most widely studied examples of chemical synaptic transmission in the nervous system. The overall concept is deceivingly simple: An action potential at the presynaptic neuron releases a neurotransmitter that, in turn, activates ion channels on the muscle cell membrane, resulting in postsynaptic action potential. Yet every step in this process is exquisitely controlled and modulated in health and may be disrupted in disease. Our evolving understanding of the NMJ provides a critical window into synapse function and pathophysiology.

The NMJ consists of three distinct anatomic components: the presynaptic nerve terminal, the synaptic cleft containing the basement membrane, and the postsynaptic muscle fiber. The presynaptic nerve terminal originates from the myelinated axon of a motoneuron in the spinal cord. Lower motoneurons in the ventral gray matter of the spinal cord send their myelinated axons through the ventral root toward peripheral muscle targets. As the axon approaches the muscle fibers, it loses its myelin sheath and branches into a fine network of terminals, each approximately 2 µm in diameter. Each branch has several swellings along its course, termed presynaptic boutons , where the nerve makes synaptic contact with the muscle fiber. Presynaptic boutons are covered by terminal Schwann cells, which provide growth factors, recycle neurotransmitters, and may participate in recovery after nerve and muscle injury. Presynaptic boutons are positioned over specialized regions of the muscle cell membrane called the end plate regions. Underlying each bouton is a specialized invagination of the cell membrane that contains a high concentration of nicotinic acetylcholine (ACh) receptors and voltage-gated Na ⁺ channels. The presynaptic bouton and end plate are separated by a 100-nm-wide synaptic cleft containing the basement membrane and extracellular matrix. The basement membrane anchors a number of proteins, including acetylcholinesterase, the enzyme responsible for rapid hydrolysis of ACh in the synaptic cleft.

Several distinct functional steps occur during synaptic transmission at the NMJ. First, the action potential arriving from the motor axon depolarizes the membrane in the presynaptic boutons, causing Ca ²⁺ entry via voltage-gated Ca ²⁺ channels on the presynaptic membrane. Ca ²⁺ entry results in fusion of synaptic vesicles containing ACh with the presynaptic cell membrane and release of ACh into the synaptic cleft. ACh rapidly diffuses toward the postsynaptic membrane and binds to the nicotinic ACh receptor (nAChR); two ACh molecules are required to activate the nAChR. On activation, the nAChR opens and allows both Na ⁺ and K ⁺ to flow through the ion pore. The inward Na ⁺ current, however, dominates over the outward K ⁺ current, resulting in net depolarization of the muscle membrane at the end plate. This so-called end plate potential propagates a short distance before encountering voltage-gated Na ⁺ channels. These Na ⁺ channels open when membrane potential rises to a critical threshold value, allowing only Na ⁺ ions to flow into the cell and generating the all-or-none muscle action potential. Acetylcholinesterases in the synaptic cleft terminate the depolarizing action of ACh at the postsynaptic membrane by rapidly hydrolyzing ACh into acetate and choline.

A detailed understanding of diseases that affect synaptic transmission at the NMJ, as well as familiarity with clinical pharmacology as it applies to the NMJ, is essential in critical care. Specific diseases affecting the NMJ include toxin-mediated botulism and autoimmune disorders such as myasthenia gravis, Lambert-Eaton syndrome, and neuromyotonia. These are discussed in detail in Chapter 68 (see also Tseng-Ong and Mitchell and Lang and Vincent ). Among the pharmacotherapies targeted at the NMJ are some of the most commonly used drugs in the pediatric ICU (PICU): neuromuscular blockers. Furthermore, a number of toxins either decrease (anticholinergic agents) or increase (acetylcholinesterase inhibitors) the amount of ACh available at cholinergic synapses, resulting in corresponding toxidromes (see Chapter 126 ).

Chemical synapses in the central nervous system

Chemical synapses in the CNS operate on basic principles similar to those governing synaptic transmission at the NMJ, although the cadre of neurotransmitters and postsynaptic receptors is significantly more diverse in the CNS. Importantly, a given neuron in the CNS may synthesize and store more than a single neurotransmitter, but it releases the same set of neurotransmitters at all of its synapses (the Dale principle). CNS synapses are generally divided into asymmetric (Gray type I) synapses and symmetric (Gray type II) synapses on the basis of their appearance under electron microscopy. Physiologically, these correspond to excitatory and inhibitory synapses, respectively. Each neuron synthesizes its own complement of neurotransmitters, which are delivered to all synaptic contact sites in the axon and packaged into synaptic vesicles. When an action potential reaches the axon, Ca ²⁺ currents cause the synaptic vesicles to fuse with the cell membrane, releasing neurotransmitters into the synaptic cleft. Neurotransmitters then act on their corresponding ionotropic and metabotropic receptors on the postsynaptic membrane. Ionotropic receptor activation leads to either a depolarizing, excitatory current or a hyperpolarizing, inhibitory current. These subthreshold currents are called excitatory postsynaptic potentials (EPSPs) and inhibitory postsynaptic potentials (IPSPs), respectively. Temporal and spatial summation of EPSPs in the dendritic tree of the postsynaptic neuron occasionally depolarizes the somatic membrane sufficiently to cross a threshold and generate an action potential. One of the distinguishing features of chemical synaptic transmission in the CNS, compared with the NMJ, is its lack of reliability on a single-cell level; an action potential in the presynaptic neuron does not necessarily cause a postsynaptic neuron to fire its own action potential. Such lack of determinism likely allows for individual differences in responses to the same stimuli. After interaction with the receptor, the neurotransmitter is cleared from the synapse by diffusion, active reuptake into the terminal, or enzymatic destruction, similar to ACh hydrolysis at the NMJ.

Acetylcholine

Acetylcholine is an amine that functions as a neurotransmitter at the NMJ and in the CNS. At the NMJ, its actions are quick and precise, whereas in the CNS, it functions as a slow, more global modulator of synaptic activity. Cholinergic CNS neurons include all motoneurons in the spinal cord and a number of cell nuclei in the brainstem reticular formation and basal forebrain. Cholinergic neurons synthesize ACh using choline acetyltransferase (ChAT), which transfers an acetyl group from acetyl coenzyme A (CoA) to choline ( eFig. 58.1 A). Choline concentration in the extracellular fluid is the rate-limiting step in the reaction. Cholinergic neurons also synthesize acetylcholinesterase (AChE), the enzyme that breaks down ACh. AChE is released with ACh into the synaptic cleft, where it rapidly hydrolyzes ACh into acetic acid and choline.

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 γ-aminobutyric acid, amino acid derivatives.

Low concentrations of choline in the CNS have been associated with neurologic impairment during fetal and postnatal life. Thus choline supplementation represents an attractive therapeutic strategy in neurologic disorders characterized by decreased CNS choline. Interestingly, patients receiving long-term parenteral nutrition (TPN) occasionally develop choline deficiency, which has been associated with TPN-related liver failure and possibly cognitive dysfunction. Hence, choline supplementation in TPN-dependent patients may ameliorate some neurologic deficits.

Catecholamines

Catecholamine neurotransmitters include dopamine, norepinephrine, and epinephrine. For all three, the initial starting point in biochemical synthesis is the amino acid tyrosine ( eFig. 58.1 B). Tyrosine is converted into an intermediate compound, called dopa, by tyrosine hydroxylase (TH). In dopaminergic neurons, dopa is converted into dopamine by dopa decarboxylase. Noradrenergic neurons, which use norepinephrine as a neurotransmitter, further convert dopamine into norepinephrine using dopamine β-hydroxylase. Finally, norepinephrine is converted 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 deficit-hyperactivity 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. 58.1 C). 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). 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 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, γ-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. 58.1 D). 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 GABA-ergic 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 α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA)–type and N -methyl- d -aspartate (NMDA)–type glutamate receptors and regulates cardiovascular function. Hydrogen sulfide is produced from the amino acid cysteine and may influence cellular redox state and glutamatergic transmission. Intriguingly, hydrogen sulfide induces a suspended animation-like state in animals and may be protective after resuscitation from cardiac arrest.

Nicotinic acetylcholine receptors

nAChRs are ligand-gated ion channels, related structurally and functionally to GABA _A 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, α and β, 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. 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 Na ⁺ and Ca ²⁺ . In neurons, however, nAChR-evoked Ca ²⁺ current exceeds the Na ⁺ current twofold to tenfold. The greater Ca ²⁺ 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 Ca ²⁺ 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. In pediatrics, a mutation in nAChR is responsible for a specific clinical epilepsy phenotype, called autosomal-dominant nocturnal frontal lobe epilepsy . 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. 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 M ₁ through M ₅ . These subtypes are divided into two broad classes on the basis of the identity of the G protein with which they interact. M ₂ and M ₄ mAChRs couple with G _i proteins, inhibit adenylyl cyclase activity, and reduce intracellular cAMP levels. M ₁ , M ₃ , and M ₅ receptor subtypes couple with G _q proteins and increase intracellular Ca ²⁺ levels via activation of phospholipase C. In the CNS, the M ₁ mAChR is the most abundant subtype, located on neurons in the cortex, thalamus, and striatum. 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.

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 Na ⁺ and K ⁺ ions. At the negative resting potential of the neuronal cell membrane, Na ⁺ , driven by the electrochemical gradient, flows into the cell and causes a large, fast depolarization. AMPA receptors are generally impermeable to Ca ²⁺ , although more recent findings indicate that Ca ²⁺ -permeable AMPA receptors do exist and may significantly contribute to pathology observed in amyotrophic lateral sclerosis (ALS) and stroke. In contrast, NMDA receptors are universally permeable to Ca ²⁺ , as well as to Na ⁺ and K ⁺ , 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 Mg ²⁺ 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 Mg ²⁺ block is relieved and Ca ²⁺ , as well as Na ⁺ , flows into the cell. Once inside the cell, Ca ²⁺ 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. Group I mGluRs (mGluR1 and mGluR5) are localized at the edge of the postsynaptic neuronal membrane and are positively coupled with phospholipase C (PLC) via the G _q 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 G _i 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 (IP ₃ )—from the membrane phospholipid phosphoinositol 1,4,5-bisphosphate (PIP ₂ ). DAG activates protein kinase C in the neuronal membrane, whereas PIP ₂ diffuses toward its receptor on the internal cell membrane and triggers a massive Ca ²⁺ release into the cytoplasm. Downstream events lead to (1) modulation of K ⁺ 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 activity-dependent 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 (G _i ) is activated. It then functions to decrease AC-mediated production of cAMP. A decrease in cAMP leads to lower Ca ²⁺ 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.

GABA _A and GABA _B receptors

GABA is the major inhibitory neurotransmitter in the brain. Like glutamate and ACh, it binds two distinct classes of GABA receptors; GABA _A receptors are ionotropic and GABA _B 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.

GABA _A receptors are chloride channels. At the normal resting membrane potential, opening of the GABA _A receptor allows chloride ions to flow into the cell down their electrochemical gradient. Influx of negatively charged Cl ⁻ 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 GABA _A receptor.

GABA _A 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 GABA _A receptor. Only 500 combinations are known to exist, and most receptors contain a varying complement of the α, β, and γ subunits. Most GABA _A receptors cluster at postsynaptic densities; such clustering appears to depend on the presence of the γ subunit. However, a subset of the GABA _A receptors—in particular, those containing the δ subunit—localize to extrasynaptic sites, mediate tonic levels of inhibition in the brain, and may underlie the pathophysiology of absence seizures.

The pharmacology of the GABA _A 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 GABA _A receptor. GABA itself binds the receptor at the junction of the α and β subunits. Benzodiazepines bind the GABA _A receptor at a different site, classically between the α and γ ₂ 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 GABA _A channels independent of endogenous GABA release. Hence, barbiturates have a significantly narrower safety window compared with benzodiazepines.

Additional GABA _A receptor ligands of clinical importance include (1) general inhalational anesthetics, which are thought to modulate tonic inhibition via the δ 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.

GABA _A receptor mutations contribute to several known disease states in humans. Two different point mutations on chromosome 5, both affecting the γ ₂ subunit, are associated with development of febrile seizures and generalized epilepsy, as well as with a link between the two conditions. ^, In patients with temporal lobe epilepsy, GABA _A receptor expression is altered in hippocampal neurons and GABA-evoked responses actually depolarize, rather than hyperpolarize, neurons in excised tissue (see also the Developmental Processes section later in this chapter). GABA _A receptor dysfunction is also thought to contribute to anxiety, panic disorder, schizophrenia, and sleep disturbances. Thus, pharmacologic modulation of GABA _A receptor function represents an active area of research and novel drug development.

GABA _B receptors are heterodimeric proteins that activate G protein–coupled second messenger systems upon interaction with GABA at the membrane. The GABA _B1 subunit binds GABA at the cell membrane, while the GABA _B2 subunit interacts with the G protein on the cytosolic surface. GABA _B 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 GABA _B receptors allow G protein–coupled Ca ²⁺ influx into the cell and lead to feedback inhibition of transmitter release. Postsynaptic GABA _B receptors function as K ⁺ channels by allowing a slow, G protein–dependent K ⁺ current to leak out of the cell and lead to cell hyperpolarization (because positive ions have left the inside of the cell membrane).

Baclofen is the only pharmacologic GABA _B receptor ligand in current clinical use. It directly activates the GABA _B 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. Systemic side effects have been minimized with intrathecal administration via an indwelling catheter and pump. ^, 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. 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. Thus, baclofen withdrawal should be considered in the differential diagnosis of an agitated child with an indwelling baclofen pump.

Spinal cord

The spinal cord is organized into segments delineated by the exiting spinal nerves. In humans, there are 31 segments: 8 cervical, 12 thoracic, 5 lumbar, 5 sacral, and 1 coccygeal. 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. 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 Pa co ₂ 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.

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 the trochlear nerve (CN IV), where it transitions into the midbrain. The trigeminal nerve (CN V) exits from the lateral aspect of the pons approximately midway between the medulla and midbrain.

In addition to the cranial nerves, the pons contains several other important structures. Its eponymous bulb, called the basis pontis, is formed by bundles of corticopontine fibers that connect the cerebral cortex with ipsilateral pontine nuclei. Postsynaptic fibers originating in the pontine nuclei then cross the midline and form the middle cerebellar peduncle, which comprises one of the major input pathways into the cerebellum. Cerebellar output to the thalamus and other structures takes place via the superior cerebellar peduncle contained in the rostral pons. Additionally, the rostral pons contains the locus ceruleus (from the Latin, blue spot ). Locus ceruleus neurons use norepinephrine as a neurotransmitter, innervate wide-ranging areas of the brain, and likely regulate sleep and arousal.

Injury to pontine structures is of significant relevance in the PICU. First, increased intracranial pressure (ICP) from any cause may result in compression of the medially located small abducens nerve (CN VI), leading to paralysis of the lateral rectus eye muscle and associated turning in of the affected eye. Abducens nerve palsy due to increased ICP may precede the notorious fixed and dilated pupil phenomenon observed when CN III is compressed during impending uncal herniation (see later discussion). Second, damage to the rostral pons (or lower midbrain) results in decerebrate posturing, characterized by extension of both upper and lower extremities on painful stimulation. Importantly, decerebrate posturing corresponds to the motor score of 2 on the Glasgow Coma Scale (GCS) score. Finally, infarction of the basis pontis with sparing of the more dorsal pontine structures results in the locked-in syndrome. The locked-in state is characterized by complete paralysis of all voluntary muscles except the muscles of ocular movement and by complete cognitive awareness. Because the locked-in patient can communicate only via eye gaze, recognition of the locked-in state by the physician requires extreme diligence in patients with brainstem lesions lest the patient be misdiagnosed as comatose, with potentially dire consequences.

Midbrain

The midbrain is the most rostral and smallest of the brainstem structures. It is characterized by the presence of the bilateral inferior and superior colliculi on its dorsal surface. Additionally, the oculomotor nerve (CN III) emerges from its ventral surface, immediately below the temporal lobe of the cerebral hemisphere. The midbrain contains structures important for hearing, sound localization, and generation of saccadic eye movements. Furthermore, the substantia nigra in the midbrain contains neurons that use dopamine as their neurotransmitter. These dopaminergic neurons project to the basal ganglia, where dopamine release participates in initiation of voluntary movements, to the limbic system in the cerebral cortex, where dopamine plays a role in reward and emotion, and to the frontal and temporal cortices, indicating that dopamine affects thought and memory. Destruction of dopaminergic substantia nigra neurons underlies the pathology of idiopathic Parkinson disease in older individuals and of parkinsonian symptoms in drug abusers exposed to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, sometimes a contaminant in heroin preparations.

Two clinical phenomena of significant importance in pediatric critical care medicine arise from damage to midbrain structures. First, global injury to the midbrain results in decorticate posturing, characterized by flexion of upper extremities and extension of lower extremities in response to painful stimulation. Decorticate posturing corresponds to a motor score of 3 on the GCS. Second, the “blown” pupil universally recognized as a sign of increased ICP and impending transtentorial brain herniation results from compression of the oculomotor nerve (CN III) as it exits the midbrain. Pupillary dilation results from compression and inactivation of the parasympathetic fibers that run on the outer surface of CN III and which are actually responsible for pupillary constriction. When these fibers are damaged, unopposed sympathetic stimulation arising from the cervical sympathetic ganglia results in a constitutively dilated pupil that cannot constrict in response to light stimulation or, in other words, is fixed . Unilateral fixed and dilated pupil is an emergency that requires immediate medical and/or surgical intervention.

Reticular formation

The brainstem reticular formation is not a separate anatomic structure but is instead distributed throughout the core of the brainstem from the medulla into the midbrain. It plays a fundamental role in arousal and consciousness, control of movement and sensation, and in regulation of visceral functions. A subset of the reticular formation neurons sends fibers to the intralaminar thalamic nuclei, which, in turn, project widely throughout the cerebral cortex. Damage to these ascending brainstem fibers, collectively called the ascending reticular activating system , results in loss of consciousness and coma, even in the absence of any damage to the cerebral hemispheres. Thus, the cerebral cortex requires input from the brainstem to maintain awareness and arousal. In addition, the reticular formation contains neuronal circuits responsible for regulation of respiration, cardiovascular responses to blood pressure and oxygen level modulations, and coordination of swallowing and other oromotor functions. Finally, complex reflexes, such as walking and maintenance of body orientation with respect to gravity, are coordinated by the brainstem reticular formation and may occur in the absence of input from higher brain regions. Immaturity of the brainstem reticular formation, in particular of its serotonergic component, has been implicated in the etiology of SIDS.

Cerebellum

The cerebellum overlies the majority of the brainstem and is separated from the cerebral cortex by a sheetlike reflection of the dura mater, called the tentorium cerebelli . Hence, the brainstem and cerebellum are referred to as infratentorial structures while the cerebral cortex and the diencephalon are referred to as supratentorial structures . The cerebellum consists of a midline vermis and two large cerebellar hemispheres. The outer surface of the cerebellum consists of a three-layered cortex, which includes the outer molecular layer, Purkinje cell layer, and granular layer. The molecular layer contains mostly axons and dendrites. The Purkinje cell layer contains the eponymous large GABA-ergic neurons that constitute the sole cerebellar output. Finally, the granular layer contains small granule cells that interact with other granule cells and with Purkinje neurons. In addition to the cerebellar cortex, each cerebellar hemisphere also contains a set of deep nuclei. From lateral to medial, these are the dentate, interposed, and fastigial nuclei.

Cerebellar function has traditionally been confined to regulation and coordination of movement of the eyes, head, and body in space. However, evidence from neuroanatomic and functional neuroimaging studies has suggested that the cerebellum—in particular, the dentate nucleus—plays a significant role in cognition, memory, and language. ^, Consequently, lesions in the cerebellum are characterized by ataxia, ipsilateral dysmetria, and intention tremor, as well as by scanning speech, in which each syllable is produced slowly and separately, and by disorders of memory and executive function. In the PICU, cerebellar lesions are seen most frequently in the setting of infratentorial tumors but also occasionally in cerebellar strokes and in viral cerebellitis.

Diencephalon

The diencephalon consists of four major structures: the thalamus, hypothalamus, subthalamus, and epithalamus. Of these, only the thalamus and hypothalamus are discussed in detail, as they serve crucial functions relevant to pediatric critical care medicine. The thalamus is the major relay station for all sensory information except olfaction as it travels from peripheral sensory organs to the cerebral cortex. For example, optic nerve neurons carrying visual information synapse onto neurons in the lateral geniculate nucleus in the thalamus, which process and transmit the signal to the primary visual cortex in the occipital lobe. Furthermore, the thalamus participates in coordination of motor activity via multiple neuronal loops that connect the cerebellum with the basal ganglia and cerebral cortex. Last, inhibitory thalamic nuclei, such as the reticular nucleus (distinct from the brainstem reticular formation) are thought to participate in gating of attention and consciousness.

Injury to the thalamus occurs frequently in both term and preterm neonates exposed to hypoxia-ischemia at birth. Additionally, thalamic necrosis is observed in infectious encephalitis, particularly that associated with the influenza virus ^, and Mycoplasma pneumoniae . Vascular diseases, such as occlusion of the basilar artery or systemic lupus erythematosus, can result in thalamic injury that can occasionally be reversible. Apparent life-threatening events have been rarely associated with thalamic lesions. Thalamic damage is associated with a wide range of symptoms, including pure sensory loss due to destruction of sensory relay nuclei, acute abnormalities in mental status, labile emotions, and motor dysfunction.

The hypothalamus is located inferior to the thalamus and plays a major role in regulation of emotion, homeostasis, circadian rhythms, and ANS function. Most important, it controls hormone release in the pituitary gland via two separate pathways. Large hypothalamic neurons in the supraoptic and paraventricular nuclei project their axons via the pituitary stalk into the posterior pituitary lobe (neurohypophysis), where they release antidiuretic hormone (ADH) and oxytocin directly into the bloodstream. ADH promotes water reabsorption in the kidney, whereas oxytocin participates in parturition and milk secretion. Damage to the posterior pituitary produces diabetes insipidus. Hypothalamic projections into the anterior pituitary (adenohypophysis) also travel down the pituitary stalk and release a multitude of release-promoting or release-inhibiting factors into the pituitary portal vein. These factors then control the release of all anterior pituitary hormones, including adrenocorticotropic hormone, thyroid-stimulating hormone, growth hormone, prolactin, and luteinizing/follicle-stimulating hormone. Of these, only prolactin release is constitutively inhibited by the hypothalamus, while the release of all remaining pituitary hormones is under positive control. Thus, transection of the pituitary stalk, as can occur during skull base and pituitary surgery, results in panhypopituitary syndrome characterized by diabetes insipidus, hypothyroidism, cortisol deficiency, and hyperprolactinemia.

Damage to hypothalamic nuclei, in addition to disrupting control of the pituitary gland, also results in emotional lability, aggression, and extreme overeating or anorexia leading to rapid weight gain or loss, respectively. Thus, overwhelming aggression combined with acute weight changes should raise suspicion for a hypothalamic tumor in a child.

Basal ganglia

The basal ganglia are a set of deep nuclei that reside below the surface of the cerebral cortex and surround the thalamus. They are composed of the caudate, putamen, globus pallidus, substantia nigra, and subthalamic nucleus. The caudate receives most of its input from the prefrontal cortex and projects via the globus pallidus and thalamus back to the prefrontal cortex. Thus, it is involved with cognitive function and tends to be one of the nuclei that degenerates slowly over time after a hypoxic-ischemic insult to the cortex. The putamen receives most of its input from the somatosensory and motor cortices and, like the caudate, projects back to these cortices via the globus pallidus and thalamus. The putamen plays a major role in coordination of motor function. The globus pallidus serves as an inhibitory modulator in the cortex–basal ganglia–thalamus–cortex loop. Hence, deep brain stimulation in the globus pallidus in patients with Parkinson disease results in resolution of motor symptoms attributable to hyperactivity in the loop, such as tremor and rigidity. The substantia nigra contains dopaminergic neurons that project to the other nuclei in the basal ganglia and participate in initiation and coordination of voluntary movement.

The basal ganglia are the site of injury in multiple processes in pediatrics. They are often injured by hypoxia and hypoglycemia due to interruption of energy supply. Similarly, carbon monoxide poisoning effectively prevents oxygen delivery to the basal ganglia, resulting in characteristic neuroradiologic findings. A number of metabolic diseases, including methylmalonic acidemia, Leigh disease, maple syrup urine disease, and glutaric acidemia type II, also result in degeneration in the basal ganglia. The basal ganglia accumulate iron and copper and, consequently, can be injured by iron overload or in Wilson disease. Finally, a juvenile form of Huntington disease presents with characteristic degeneration in the caudate nucleus. Clinical signs of injury to the basal ganglia are often nonspecific: lethargy, irritability, and decreased mental status. Movement disorders such as dystonia or chorea can be seen early in the course of injury but are relatively uncommon, being more likely to emerge with chronic deterioration in basal ganglia function.

Cerebral hemispheres

The cerebral hemispheres are the most rostral part of the CNS, and in humans and some other mammals, they are characterized by extensive folding of the cerebral cortex. The folding greatly expands the area of the cerebral cortex that can fit into the cranial vault. In humans, the cortical sheet has an area of 2.5 square feet when all the folds are flattened, yet the surface area of the adult skull is closer to 0.5 square feet. The folds consist of ridges termed gyri (singular, gyrus ) and spaces separating the ridges termed sulci (singular, sulcus ). Although the detailed organization of each gyrus and sulcus is quite individualized, the larger organizational features are common to all mammals.

Each cerebral hemisphere is divided into four lobes: frontal, parietal, temporal, and occipital ( eFig. 58.3 ). The frontal lobe extends caudally from the rostral pole of the brain to the central sulcus and inferolaterally to the lateral sulcus. The parietal lobe begins at the central sulcus and extends caudally to the parietooccipital sulcus. Inferolaterally, the parietal lobe is bounded by the lateral sulcus and imaginary line connecting the extension of the lateral sulcus with the parietooccipital sulcus. The temporal lobe is delineated primarily by the lateral sulcus. Finally, the occipital lobe resides posteriorly to the parietooccipital sulcus. Each of the four lobes performs dedicated functions, some of which are symmetric, occurring in both hemispheres, whereas others are lateralized, specific to either the right or left cerebral hemisphere.

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