Neurophysiology

Introduction to Neurophysiology

Neurons produce electrical signals as a way of conveying information from one place in the body to another place very quickly, at speeds up to 100 meters/second (200 miles per hour). These rapidly traveling electrical signals allow you to perceive sensory stimuli, like the sound of a passing fire truck blasting its siren. Electrical signals, travelling in different neural pathways, coordinate motor responses that allow you to move your car out of the way of the fire truck, withdraw your hand from a dangerously hot pan, and rhythmically contract your diaphragm to breathe. Electrical signals arise as a result of movement of ions back and forth across the cell membrane of neurons. As ions move down their electrochemical gradients, they carry their charge with them, creating very miniscule but physiologically important electrical currents. These ionic currents flowing across membranes are the basis for the propagating electrical signals that underlie all nervous system functions. In this section, we’ll explore how neurons generate these electrical signals.

Cell Membrane Voltage

All living, eukaryotic cells have a transmembrane potential (a difference in charges between the intracellular and extracellular fluid). While the cell is at rest (i.e., unstimulated), the transmembrane potential is stable and is called the resting membrane potential (RMP). Right at the cell membrane, there is a little excess negative charge on the inside of the cell membrane and a little excess of positive charge on the outside. Because separation of charges creates a voltage, a very small probe on a voltmeter can be used to measure the voltage across the cell membrane. By convention the voltage outside the cell is set to zero. In a typical cell, the voltage recorded across the membrane is between -60 and -90 millivolts(-.06 to -.09 volts) with the negative sign indicating that the inside of the cell is negative with respect to the outside. Some cells have the ability to transiently alter their transmembrane potential (excitable cells), while others do not (non-excitable cells).

Non-excitable cells (ex: intestinal epithelial cells) have a stable and unchanging RMP. Excitable cells, like neurons and muscle, have a membrane potential that can fluctuate under certain conditions, with each fluctuation representing a signal produced by the cell. These fluctuations may be small and local to a region of a cell membrane (often called local or graded potentials) or larger in magnitude and travel along the length of the cell. These latter potentials, called action potentials, always lead to some response by the cells. In a neuron, action potentials lead to neurotransmitter release.

Illustration of resting membrane potential (measured as a voltage) as an energy gradient across the cell membrane

The resting membrane potential (measured as a voltage) is an energy gradient across the cell membrane due to a slight separation of charge right along the cell membrane. This work by Cenveo is licensed under a Creative Commons Attribution 3.0 United States (http://creativecommons.org/licenses/by/3.0/us/).
 

Ion Concentrations

To understand the basis of the resting membrane potential, we must first investigate the composition of body fluids – intracellular fluid (ICF) and extracellular fluid (ECF). Recall that ICF and ECF are composed of salts like NaCl and KCl that dissociate into their ionic components when placed in aqueous solutions. These ions are the mobile charges in body fluids that move between compartments to generate electrical currents along cell membranes.

>NaCl (salt) dissociates in water to form Na+ and Cl- ions

NaCl dissociates in water to form ions, mobile charge carriers used to generate electrical currents in living organisms. This work by Cenveo is licensed under a Creative Commons Attribution 3.0 United States (http://creativecommons.org/licenses/by/3.0/us/).

The ECF and ICF have high concentrations of different salts, which leads to differing concentrations of individual ions in the ECF versus the ICF. Recall from your earlier studies that sodium (Na+), chloride (Cl), and calcium (Ca2+) are more highly concentrated in the ECF, while potassium (K+) and large anions (An) are more highly concentrated in the ICF.

This table does not include all the ions, but only those that are major contributors to the membrane potential and changes in the membrane potential.

Ion Extracellular Fluid (mM) Intracellular Fluid (mM)
K+ 5 150
Na+ 145 15
Cl 108 10
Ca2+ 1 0.0001

Neuron Resting Membrane Potential

The resting membrane potential arises due to the combined effects of three factors, which determine what ions move across the cell membrane in an unstimulated cell (at rest).

Ions are not evenly distributed between the inside and the outside of a cell. As we just learned, sodium is nearly 10 times more concentrated outside the cell than inside. Conversely, potassium is nearly 30 times more concentrated inside the cell than outside. The uneven distribution of ions leads to concentration gradients across the cell membrane. Given the opportunity, ions will move down their concentration gradient (i.e., from an area where they are highly concentrated to an area where they are less concentrated). So, given the chance, sodium ions would move into the cell and potassium ions would move out of the cell based on their respective concentration gradients.

The ionic composition of body fluids is tightly regulated. Small increases or decreases in ion concentrations can disrupt normal functions of the brain, heart, skeletal muscle or other organs. In many instances, you or one of your loved ones may need to receive treatment for an electrolyte imbalance. These situations might be as simple as that restoring blood lost in an accident, or receiving fluids to rehydrate you following a soccer tournament. The article below shows how critically important it is that people receive solutions with appropriate ion concentrations in their treatments.

Let’s review a tragic case where simple calculations to double check a dose of CaCl2 given to a baby to restore body fluids, might have saved her life.

Baby dies at Seattle Children’s hospital after overdose

An infant in the intensive-care unit of Seattle Children’s hospital died after she was administered 10 times the dose of a medication, calcium chloride, by a hospital nurse, according to a notice sent by hospital CEO Tom Hansen to the staff.

By Carol M. Ostrom, Seattle Times health reporter

Eight-month-old Kaia Zautner was in the intensive-care unit of Seattle Children’s hospital, battling back from serious heart problems and surgeries, when a hospital nurse gave her 10 times the proper dose of a medication, calcium chloride.

Five days later, on Sept. 19, after suffering a brain hemorrhage, the baby died.

Tom Hansen, hospital CEO, in a notice to staff on Sept. 22, said the hospital has offered “heartfelt apologies” to the family, without naming them. “This was a catastrophic outcome for the patient and the family, and caused serious distress for staff members as well,” Hansen said.

In a family blog, Kaia’s parents, Jared and Alana Zautner, of Puyallup, had described their baby’s fight to overcome the heart problem she’d had since her birth on Jan. 12 and then, just days after her “8th month birthday,” the “horrible turn of events” that gave them “one of the scariest days of our lives.”

The overdose was an accidental miscalculation, Alana Zautner wrote on the blog, thanking friends for their continued prayers.

“I have seen such strength in my daughter these last few hours and I have faith that she will pull through this,” she wrote. “I just pray for a miracle and that she will be completely touched and healed.”

A memorial for Kaia was held Saturday at Lighthouse Christian Center (Alana wrote that all doctors and nurses were welcome), and a “Hawaii Lei Ceremony and Scattering of the Ashes” is planned for Oct. 2 on Maui, Hawaii.

The hospital, as required, reported the overdose to the state Department of Health, which collects statistics on “adverse events” in hospitals.

The hospital reviewed the clinical record after the overdose and began a detailed analysis of why the usual safety checks had not prevented it, Hansen said in the letter to staff.

“Perhaps the best tribute we can pay to this family is by doing everything we can to prevent future medical errors in our system,” Hansen said in the letter. “An important way we can make medicine safer is if we admit that mistakes occur and openly investigate them. We must learn from these events and work together to evaluate our processes and to error-proof our care processes.”

Hansen said it is personally important to him that all staff and faculty feel safe to report mistakes.

While the investigation is under way, he said, the hospital will allow only pharmacists and anesthesiologists to fill needles with calcium chloride in nonemergency situations, but the drug can still be accessed by medical or nursing staff if needed in an emergency.

Hansen did not say whether the nurse who administered the overdose was disciplined by the hospital.

The state’s Nursing Care Quality Assurance Commission has also opened an investigation, according to Department of Health spokesman Tim Church.

“We don’t even have a name yet,” he said. “The nursing commission is opening (the investigation) because it’s aware of the situation — not under any particular name.”

The hospital will have 45 days to complete a “root cause” analysis of the event, Church said, but that report will not be publicly available.

In 2009, a 15-year-old Kent boy died after using a painkilling patch prescribed by his dentist at Children’s. The boy, Michael Blankenship, had four teeth extracted at the hospital and was sent home with the pain patch containing Fentanyl, prescribed by his dentist at the hospital. The teen was found dead the next morning.

The teen was autistic and could not tolerate pills or liquid medicine.

The hospital’s medical director said the highly potent narcotics patch should not have been prescribed.

His family filed a lawsuit against the hospital last September.

Update, 11:32a.m., Sept. 29: The family reached a settlement earlier this year, but didn’t disclose the terms.

Source: https://www.seattletimes.com/seattle-news/baby-dies-at-seattle-childrens-hospital-after-overdose/ 

However, the cell membrane is not freely permeable to ions. Ions cannot freely cross the plasma membrane because of its structure. The lipid core of the cell membrane is hydrophobic and does not allow charged molecules to pass through it. Rather the cell membrane is selectively permeable, meaning it allows certain ions to pass. You know that the ions do not pass directly through the cell membrane, but rather pass through ion channels. The membrane is permeable to a specific ion if there are open channels for that ion. Recall that ion channels open and close based on the presence of electrical or chemical stimuli. Voltage-gated channels open at specific membrane potentials and are either inactivated (while the stimulus persists) or close when the membrane potential changes. Ligand-gated channels open when they bind chemicals and close when the chemical is no longer bound.

At rest, the cell membrane is most permeable to potassium because there are more open potassium channels at the resting membrane potential than channels for any other ion. As a result, potassium “leaks” out of the resting cell. The resting membrane is less permeable to sodium, and, at rest, a small amount of sodium “leaks” into the cell.

If these were the only things happening in the resting cell, the resting membrane potential would not be stable, but rather the net movement of potassium ions would cause the membrane potential to change. Ions move not only based on their individual concentration gradients, but they also move based on charge attraction and repulsion. Ions move away from like charges (ex. sodium and potassium ions move away from each other) and move towards opposite charges (ex. potassium ions would move toward chloride ions). The net movement of a particular ion is influenced by its electrochemical gradient (the balance of its concentration gradient and any charge attraction or repulsion).

Let’s consider how the electrochemical gradient affects a potassium ion. You’ve already learned that the RMP ranges from -60 mV to -90 mV in living cells. The negative sign indicates that the inside of the cell is negatively charged with respect to the outside. You also know that potassium is 30 times more concentrated on the inside of the cell than the outside. So, the concentration gradient causes potassium ions to leave the cell (through open ion channels), but the electrical gradient causes the positively charged potassium ion to be attracted to re-enter the cell. As a result, potassium ions not only leave the cell at rest (due to the concentration gradient), but they also re-enter the cell (due to the electrical gradient). The overall movement of the ion depends on the strength of each of the two gradients. The concentration gradients are stronger in a resting cell; therefore, more ions will move in the direction favored by the concentration gradient than will move based on the electrical gradient.

One final factor also plays a role in determining the RMP. The sodium potassium pump operates continually in living cells. At maximum capacity, it pumps 3 sodium ions out of the cell and 2 potassium ions into the cell, and hydrolyzes 1 ATP to provide the energy for the ion transport.

Both ions are moved against their electrochemical gradients, so the transport requires hydrolysis of 1 ATP. Because an unequal number of charges are transported across the cell membrane, there is a net negative charge on the inside of the membrane due to the operation of the sodium potassium pump.

The sodium potassium pump transports 3 Na+ to the ECF and 2 K+ to the ICF. By Mariana Ruiz Villarreal (http://upload.wikimedia.org/wikipedia/commons/thumb/a/a5/scheme_sodium-potassium_pump-en.svg/300px-scheme_sodium-potassium_pump-en.svg.png) Public Domain.

The sodium potassium pump is electrogenic (there are an uneven number of charges transported into and out of the cell resulting in a net charge associated with each exchange cycle). Since 3 sodium ions leave the cell and only 2 potassium ions enter the cell, there is a net negative charge on the inside of the cell due to the sodium potassium pump.

Neuron Electrical Response

Neurons can be excited by various stimuli such as light, chemicals, heat or pressure. These stimuli, which are typically received at the dendrites, cause small, localized changes in membrane voltage. The stimuli open ion channels in the membrane, which allows specific ions to flow in or out of the cell. This ion movement produces a change in the membrane voltage around the area of the open channels. These local shifts in membrane potential are called local (or graded) potentials. Local potentials have the following characteristics:

They are graded, which means the change in membrane voltage that occurs is proportional to the size of the stimulus. A stronger stimulus can open more ion channels. A stimulus that lasts for a long time can either open more ion channels or keep channels open for a longer time. In either case, more ions are able to cross the cell membrane, which produces a larger change in membrane voltage.

They are decremental, meaning that the signal grows weaker as it moves farther from the site of stimulation. Ion channels are opened at the site of stimulation and that is where ions move across the cell membrane. As a result, there is a high concentration of ions right around the ion channels. Once the ions cross the membrane, they diffuse away from the channel and there are fewer and fewer ions as they move away from the open channels. Fewer ions results in a smaller change in membrane potential.

They are reversible. If the stimulus comes to an end, the ion channels close and resting membrane potential is re-established before the signal travels very far.

They can either excite the cell or inhibit the cell depending on what type of ion channel is opened. If the stimulus opens a sodium channel, sodium enters the cell and deporlarizes (make the membrane potential less negative) the membrane around the open channels. If the stimulus opens a chloride channel, chloride ions enter the cell and make the local membrane potential more negative than the RMP (hyperpolarizes the cell). Depolarization excites the cell and makes it more likely to send a signal to other cells. Hyperpolarization inhibits the cell and makes it less likely to send a signal to other cells.

A stimulus can also affect potassium channels. If the stimulus causes potassium channels to open, the effect will be hyperpolarization of that area of cell membrane. Potassium leaves the cell through the open channels, which removes positive charges from the ICF making the inside of the cell more negative. If the stimulus closes potassium channels, the membrane will depolarize around the closed channels because fewer potassium ions are leaving the cell.

Neurons generally receive multiple stimuli at the same time – some may be excitatory and others inhibitory. The overall response of the neuron will depend on the net effect of all the stimuli. In some cases, the neuron will produce a signal that will travel to other cells. In other cases, no signal will be sent from the neuron.

Action Potentials

If there is adequate excitatory stimulation of a neuron, a signal called an action potential is generated. An action potential is a transient and marked shift in membrane potential that occurs when voltage-gated ion channels in the membrane open. A series of action potentials can rapidly carry information from the neural soma along the axon to the axon terminal. A sufficient number of voltage-gated channels must be present in the cell membrane to initiate an action potential. The dendrites and most of the soma lack enough voltage-gated ion channels for this. However, at the trigger zone, where the soma interfaces with the axon, there is a high concentration of voltage-gated channels. To create an action potential in a neuron, an excitatory local potential must reach the trigger zone and depolarize (a shift in membrane potential making it less negative or even positive) it to the threshold voltage needed to open the ion channels.

Two types of voltage-gated channel are responsible for the propagating action potentials in most neurons – a fast Na+ channel (a voltage-gated Na+ channel that opens quickly when stimulated) and a slow K+ channel (a voltage-gated K+ channel that opens slowly when stimulated) . Let’s take a closer look at the specific events of an action potential.

Excitatory local potentials reach the trigger zone and depolarize it. If the local potentials depolarize the membrane to threshold (the membrane voltage at which the voltage-gated channels are stimulated to open), these voltage-gated channels begin to open. The fast Na+ channel opens quickly, increasing the permeability of the membrane to Na+ that flows into the cell down its electrochemical gradient leading to further depolarization. This causes more fast Na+ channels to open, further depolarizing the membrane. As the membrane potential reaches 0 mV, the fast Na+ channels become “inactivated.” A second gate that works like a timer closes the channel. By the time all the fast Na+ channels are inactivated the membrane voltage has reached its peak.

As the fast Na+ channels are being inactivated, the slow K+ channels are finally opening. This increases the permeability of the membrane to K+. Potassium ions leave the cell moving down their electrochemical gradient, and the efflux of positive charge causes the membrane voltage to return toward the resting membrane potential (repolarization).

Slow K+ channels stay open longer than fast Na+ channels, so more K+ leaves the cell than Na+ entered. The removal of excess potassium ions causes the membrane potential to become more negative than the resting membrane potential. When this happens, we say the membrane is hyperpolarized.

The changes in membrane permeability and their relationship to the membrane potential can be seen in the following figure.

Action Potential Refractory Period

The duration of time that the membrane is hyperpolarized following an action potential is termed its refractory period. The refractory period is an interval of time during which that part of the membrane cannot be excited (to produce another action potential) or requires a larger than normal stimulus to be excited. The refractory period is divided into two parts based on whether or not the membrane can be stimulated to produce an action potential. During the absolute refractory period, the membrane cannot be stimulated to produce another action potential regardless of the strength of the stimulus. During the relative refractory period, the membrane can be stimulated to produce an action potential, but a stronger than normal stimulus is required.

The absolute refractory period lasts from the beginning of the action potential (when the membrane reaches the threshold voltage) until the fast Na+ channels reset to their resting state. As long as the Na+ channels are open or inactivated, a new action potential cannot be generated.

The relative refractory period continues from the end of the absolute refractory period until the membrane is no longer hyperpolarized (returns to the resting membrane potential). During hyperpolarization, slow K+ channels are still open, but are in the process of closing. In order to stimulate an action potential during this time, a very strong stimulus is needed to overcome the effect of potassium flowing out of the cell and depolarize the cell.

Previously, we considered the characteristics of local potentials. They are graded, decremental, reversible, and can either excite or inhibit the membrane. In contrast, action potentials are all-or-none, nondecremental, irreversible and always excitatory.

Action potentials within a particular cell are all identical regardless of stimulus strength. If the membrane at the trigger zone reaches the threshold voltage or a voltage above the threshold, a maximal action potential will be generated. If the threshold voltage is not attained, no action potential is generated (no signal is propagated). In this way, action potentials are all-or-none – a cell either fires a full action potential or no action potential at all.

The action potential at the axon terminal looks exactly like the action potential that was initially generated at the trigger zone. Since the signal does not change as it travels the length of the axon it is nondecremental. It should be noted that the action potential at the axon terminal is not the same one that originated at the trigger zone. Rather, a series of identical action potentials are generated as the signal travels toward the axon terminal.

If the membrane reaches threshold, an action potential will be initiated and the signal will be propagated down the entire axon. Once the events are set in motion there is no stopping them. The process is irreversible.

In contrast to local potentials, which can either excite or inhibit the membrane, action potentials are all excitatory (cause an initial depolarization of the membrane).