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To understand the effects of anesthesia and surgery on the nervous system, one needs to know basic cellular neurophysiology as well as organ-level physiologic function.
Cellular neurophysiology
The basic properties of neuronal excitability are due to a change in the membrane potential so that a threshold is reached and the neuron fires an action potential. This propagates to the axon terminal and releases a neurotransmitter that influences the membrane potential of a second neuron.
Membrane potentials are voltages measured across the cell membrane due to an unequal distribution of ions across that membrane. A combination of the equilibrium potential for a particular ion and the membrane's conductance (permeability) for that ion determines its contribution to the membrane potential.
The equilibrium potential (E) for an ion can be calculated using the Nernst equation if the intra- (for potassium, Ki) and extracellular (K0) concentrations of that ion are known. For an ion with a single positive charge, the equation simplifies to EK = -61 log [Ki/K0] at 37°C. Under normal conditions in the nervous system, the equilibrium potential for potassium (K) is approximately -90 mV and for sodium (Na) +45 mV.
(1) The relative conductance of the neuronal membrane to different ions determines the membrane potential. This conductance (g) for the different ions varies with conditions, input to the specific neuron, and time. The membrane potential of a neuron at any point in time can be described by the following equation:

Em = [gk(Ek)+gNa(ENa)+gx(Ex)]/ gK +gNa+gx

where gx is the conductance for ion x and Ex is the equilibrium potential for that ion. The resting membrane potential for a neuron is approximately -70 mV, which is closer to the Ek (-90 mV) than the ENa (+45 mV) because gK is much greater than gNa in resting (unexcited) neurons.
(2) There are concentration-dependent and electrical field-dependent forces acting on ions; the sum of these forces determines whether the net movement of a particular ion will be into or out of that neuron. This is referred to as the electrochemical gradient for that ion.
Action potentials are regenerative changes in a neuron's membrane potential due to excitation of the neuron so that its membrane potential depolarizes past a certain threshold. During an action potential, a rapid initial increase in the gNa is followed by a return to baseline and a slower increase in the gK. These conductance changes lead to a short and rapid depolarization followed by a repolarization. This is sometimes followed by a hyperpolarization after the action potential (Figure 1).
The Na conductance changes are due to the opening of a protein channel in the membrane that is selectively permeable to Na ions. This channel has one activation and one inactivation gate, both of which must be in the open configuration if the channel is to allow Na through it. The rapid opening and closing of this channel are in part responsible for the brief duration of the action potential.
At rest, more K than Na channels are open. With the action potential, more Na channels open so that the gNa is greater than the gK and the neurons depolarize. The depolarization causes a slow opening of K channels, increasing gK and leading to a repolarization (gK > gNa). In the period after the action potential, when the Na channels have become inactivated, the increased gK can actually cause a hyperpolarization below the resting potential; this so-called afterhyperpolarization is frequently found in neurons.
(3) Synaptic transmission is the process by which one neuron (presynaptic neuron) influences the membrane potential and thereby the action potential generation in a second neuron (postsynaptic neuron). The axon terminals of a neuron contain vesicles with neurotransmitter molecules in them. When a terminal is depolarized, voltage-sensitive calcium (Ca) channels open, increasing the Ca concentration in the terminal. This Ca increase causes the vesicles to release a neurotransmitter into the synaptic cleft. The transmitter diffuses across the synapse and binds to a specific receptor on the postsynaptic neuron. Its effect on the postsynaptic neuron depends on ion channels that are opened or biochemical processes that are altered by the activation of that receptor.



Figure 1. Changes in the membrane potential and the sodium and potassium conductances (gNa and gK) during an action potential. ENa and Ek are the sodium and potassium equilibrium potentials.

Ionotropic receptor activation opens membrane channels for certain ions that can either hyperpolarize or depolarize the postsynaptic neuron, making it less or more likely to fire an action potential.
Metabotropic receptors can activate second messengers that alter neuronal biochemical parameters. This can effect long-term changes in a neuron's activity.
(4) Glutamate is a major excitatory neurotransmitter in the central nervous system (CNS). Its activation depolarizes neurons, increasing the number of action potentials generated.
There are three major ionotropic glutamate receptors: alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), kainate, and N-methyl-D-aspartic acid (NMDA). The AMPA and kainate receptors are attached to ion channels that allow Na and K to pass through them; a small number of AMPA receptors are also permeable to Ca. The NMDA channels activated when neurons are already depolarized are permeable to Na, K, and Ca. Activation of NMDA channels has been associated with long-term changes in neuronal activity that may be cellular correlates of learning and memory. Overactivation of glutamate receptors has been associated with neuronal injury from epilepsy, trauma, and ischemia.
Metabotropic receptors are also activated by glutamate. These receptors act via guanosine-triphosphate (GTP)-binding proteins (G proteins) to affect ion channels or second-messenger pathways (e.g., 3'-5'-cyclic-adenosine monophosphate [cAMP], inositol 1,4,5-trisphosphate [IP3]), which in turn can alter ionic conductance, cell Ca levels, and a host of other biochemical changes. The effect of metabotropic receptor activation is longer in duration than that of inotropic receptor activation.
(5) Gamma-aminobutyric acid (GABA) and glycine are major inhibitory neurotransmitters in the CNS. Their activation hyperpolarizes neurons, decreasing the number of action potentials generated. Inhibition is important for the brain and spinal cord to function. When inhibition is substantially reduced, seizures can occur and lead to complete loss of function and permanent brain damage.
GABA is a major inhibitory transmitter in the brain and spinal cord. The GABAA receptor contains a chloride channel that is opened when GABA binds. This activity is augmented by benzodiazepines, volatile anesthetics, and barbiturates. The GABAB receptor acts via a second messenger to open K channels.
Glycine is a major inhibitory transmitter in the spinal cord. Strychnine blocks the action of glycine.
Active transport maintains the ionic concentrations required for neuronal function. There is a constant leak of ions down their electrochemical gradients. If not corrected, this leak leads to a loss of these ion gradients. Ion pumps use energy to maintain the ion concentrations necessary for neuronal viability. During ischemia, a decrease in energy production and a loss of ion gradients occurs (Figure-2).
Adenosine triphosphate (ATP), neuronal is a source of energy for many ion pumps. The Na/K ATPase pump maintains high intracellular K concentrations and low intracellular Na concentrations. The pump compensates for the leak of these ions in inactive neurons and the large changes in these ions during the action potential. If this pump is blocked, neurons quickly lose their ability to function. ATPase pumps in the plasma membrane and the endoplasmic reticulum maintain low cytosolic Ca concentrations in neurons.



Figure-2. Effect of ischemia on ion and metabolite levels in neurons. For clarity, ion channels are shown on the top membrane and ion pumps on the bottom membrane; their actual location can be on any membrane surface. Circles indicate energy-driven pumps; an x through the circle indicates that this pump is blocked or has reduced activity during ischemia. V indicates a voltage-dependent channel. NMDA, N-methyl-D-aspartic acid; ATP, adenosine triphosphate.

The Na gradient is a source of energy for ion pumps and amino acid transporters. These active transporters couple the energy of Na as it goes down its electrochemical gradient with the pumping of other ions and metabolites up their gradients. To maintain appropriate cellular levels of Ca and hydrogen (H), Na/Ca and Na/H exchangers are important transporters. The transport of glutamate and other amino acids from the extracellular to the intracellular compartment also uses the energy of the Na gradient. The gradient is maintained by the Na/K ATPase pump; thus, the ultimate energy for this ion exchanger comes from ATP used to power the Na/K pump.
When energy fails due to hypoxia or ischemia, the pumps can no longer maintain the gradients, intra- and extracellular ion concentrations change and the neurons depolarize, leading to a rapid and complete membrane depolarization and eventual cell death. This is illustrated in Figure-2.
Regional neurophysiology. Different regions of the brain subserve different and distinct functions.
(1) The primary somatosensory cortex located on the postcentral gyrus is the cortical locus where somatic sensations converge. Association areas that aid in the interpretation of these sensations are located posterior to this gyrus.
(2) The primary motor cortex is located on the precentral gyrus and has output to motor neurons in the spinal cord. Premotor association areas are located anterior to this gyrus and receive input from other important motor centers of the brain including the cerebellum, the basal ganglia, and the red nucleus. The reticular formation also has important motor functions.
The primary visual and visual association areas are located in the occipital lobe.
(4) The primary auditory and auditory association areas are located in the temporal lobe.
(5) Wernicke's area is located on the angular gyrus in the dominant hemisphere. It is a multimodal association area. Lesions in this area are devastating and can lead to the loss of comprehension of written and spoken words.
(6) The frontal association areas are important for controlling personality and directing intellectual activity through sequential steps toward a goal.
(7) The limbic areas of the brain, are located medially. Limbic system structures include the hypothalamus, the amygdala, the hippocampus, and the limbic cortex. These areas are associated with feelings of reward and punishment, emotional behavior, learning, and memory. The hippocampus is essential for the transformation of short-term to long-term memory. The hypothalamus controls many bodily vegetative functions (cardiovascular, temperature, and water regulation).
(8) The brain stem contains the reticular activating system, which is responsible for maintaining alertness. The vasomotor areas located in the brain stem are important for circulatory control. Lesions in the brain stem can lead to coma.
(9) The spinal cord is important as a pathway for information between the body and the brain as well as for the generation of certain reflexes. Input to the spinal cord comes via the dorsal root to the dorsal horn; output from motor neurons, which are located in the ventral horn, is via the ventral root. Input to the brain via the spinal cord can be modified before transmission to the brain via ascending tracts. Indeed, descending pathways can reduce pain input at the spinal level. These pathways are activated by periaqueductal and periventricular gray regions of the brain.

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