Fundamental concepts in functional neurology

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1 Fundamental concepts in functional neurology

Introduction

Much of the understanding that we have today of how human neurons function was based on the ‘integrate and fire’ concept formed by Eccles in the 1950s which was developed based on studies of spinal motor neurons (Brock et al. 1952). In this model, spinal motor neurons integrate synaptic activity, and when a threshold is reached, they fire an action potential. The firing of this action potential is followed by a period of hyperpolarisation or refraction to further stimulus in the neuron. This early integrate and fire model was then extrapolated to other areas of the nervous system including the cortex and central nervous system which strongly influenced the development of theories relating to neuron and nervous system function (Eccles 1951).

Early in the 1970s, studies that revealed the existence of neurons that operated under much more complex intrinsic firing properties started to emerge. The functional output of these neurons and neuron systems could not be explained by the existing model of integrate and fire for neuron function (Connor & Stevens 1971).

Since the discoveries of these complex firing patterns many other forms of neural interaction and modulation have also been discovered. It is now known that in addition to complex firing patterns neurons also interact via a variety of forms of chemical synaptic transmission, electrical coupling through gap junctions, and interactions through electric and magnetic fields, and can be modulated by neurohormones and neuromodulators such as dopamine and serotonin.

With this fundamental change in the understanding of neuron function came new understanding of the functional interconnectivity of neuron systems, new methods of investigation, and new functional approaches to treatment of nervous system dysfunction.

With the emergence of any clinical science it is essential that the fundamental concepts and definitions are clearly understood. Throughout the textbook the following concepts and terms will be referred to and discussed frequently so it is essential that a good understanding of these concepts be established in the reader’s mind before moving on to the rest of the text.

This chapter will constitute an introduction to the concepts below, which will be covered in more elaborate detail later in the text.

Central integrative state (CIS) of a neuron

The central integrative state (CIS) of a neuron is the total integrated input received by the neuron at any given moment and the probability that the neuron will produce an action potential based on the state of polarisation and the firing requirements of the neuron to produce an action potential at one or more of its axons.

The physical state of polarisation existing in the cell at any given moment is determined by the temporal and spatial summation of all the excitatory and inhibitory stimuli it has processed at that moment. The complexity of this process can be put into perspective when you consider that a pyramidal neuron in the adult visual cortex may have up to 12 000 synaptic connections, and certain neurons in the prefrontal cortex can have up to 80 000 different synapses firing at any given moment (Cragg 1975; Huttenlocher 1994).

The firing requirements of the neuron are usually genetically determined but environmentally established and can demand the occurrence of complex arrays of stimulatory patterns before a neuron will discharge an action potential. Some examples of different stimulus patterns that exist in neurons include the ‘and/or’ gated neurons located in the association motor areas of cortex and the complex rebound burst patterns observed in thalamic relay cells.

‘And’ pattern neurons only fire an action potential if two or more specific conditions are met. ‘Or’ pattern neurons only fire an action potential when one or the other specific condition is present (Brooks 1984).

The thalamic relay cells exhibit complex firing patterns. They relay information to the cortex in the usual integrate and fire pattern unless they have recently undergone a period of inhibition. Following a period of inhibition stimulus, in certain circumstances, they can produce bursts of low-threshold spike action potentials referred to as post-inhibitory rebound bursts. This activity seems to be generated endogenously and may be responsible for production of a portion of the activation of the thalamocortical loop pathways thought to be detected in encephalographic recordings of cortical activity captured by electroencephalograms (EEG) (Destexhe & Sejnowski 2003).

The neuron may be in a state of relative depolarisation, which implies the membrane potential of the cell has shifted towards the firing threshold of the neuron. This gener­ally implies that the neuron has become more positive on the inside and the potential difference across the membrane has become smaller. Alternatively, the neuron may be in a state of relative hyperpolarisation, which implies the membrane potential of the cell has moved away from the firing threshold. This implies that the inside of the cell has become more negative in relation to the outside environment and the potential difference across the membrane has become greater (Ganong 1983) (Fig. 1.1).

The membrane potential is established and maintained across the membrane of the neuron by the flux of ions; usually sodium (Na), potassium (K), and chloride (Cl) ions are the most involved although other ions such as calcium can be involved with modulation of permeability. The movement of these ions across the neuron membrane is determined by changes in the permeability or ease at which each ion can move through selective channels in the membrane.

When Na ions move across the neuron membrane into the neuron, the potential across the membrane decreases or depolarises due to the positive nature of the Na ions, which increases the relative positive charge inside the neuron compared to outside the neuron. When Cl ions move into the neuron, the neuron the membrane potential becomes greater or hyperpolarises due to the negative nature of the Cl ions, which increase the relative negative charge inside the neuron compared to outside the neuron. The same is true when K ions move out of the neuron due to the relative loss of positive charge that the K ions possess.

The firing threshold of the neuron is the membrane potential that triggers the activation of specialised voltage gated channels, usually concentrated in the area of the neuron known as the axon hillock or activation zone, that allow the rapid influx of Na into the axon hillock area, resulting in the generation of an action potential in the axon (Stevens 1979) (Fig. 1.2).

Transneural degeneration

The central integrative state of a neuron or neuron system is modulated by three basic fundamental activities present and necessary in all neurons.

These activities include:

Although other activities of neuron function require certain components of oxygen or nutritional supplies, the major necessity of adequate gaseous exchange and adequate nutritional intake into the neuron is to supply the mitochondrial production of adenosine triphosphate (ATP).

The mitochondria utilise a process called chemiosmotic coupling to harness energy from the food obtained from the environment for use in metabolic and cellular processes. The energy obtained from the tightly controlled slow chemical oxidation of food is used by membrane-bound proton pumps in the mitochondrial membrane that transfer H ions from one side to the other, creating an electrochemical proton gradient across the membrane. A variety of enzymes utilise this proton gradient to power their activities including the enzyme ATPase that utilises the potential electrochemical energy created by the proton gradient to drive the production of ATP via the phosphorylation of adenosine diphosphate (ADP) (Alberts et al. 1994). Other proteins produced in the mitochondria utilise the proton gradient to couple transport metabolites in, out of, and around the mitochondria (Fig. 1.3).

The proteins required to support neuron function, including the proteins necessary for mitochondrial function and thus ATP production described above, are produced in response to environmental signals that reach the neuron via receptor and hormonal stimulation that it receives. Thus, the types and amounts of protein present in the neuron at any given moment are determined by the amounts of oxygen and nutrients available and the amount and type of stimulation it has most recently received.

The mechanisms by which extracellular signals communicate their message across the neuron membrane to alter the protein production are discussed in Chapter 3. Here it will suffice to say that special transmission proteins called immediate early genes (IEG) are activated by a variety of second messenger systems in the neuron in response to membrane stimulus (Mitchell & Tjian 1989). Type 1 IEG responses are specific for the genes in the nucleus of the neuron and type 2 IEG responses are specific for mitochondrial DNA (Fig. 1.4).

Proteins have a multitude of functions in the neuron, some of which include cytoskeletal structure formation of microtubules and microfilaments, neurotransmitter production, intracellular signalling, formation of membrane receptors, formation of membrane channels, structural support of membranes, and enzyme production.

If the cell does not produce enough protein the cell cannot perform the necessary functions to the extent required for optimal performance and/or to sustain its very life.

In situations where the neuron has not had adequate supplies of oxygen, nutrients, or stimulus, the manufacturing of protein is down-regulated. This process of degeneration of function is referred to as transneural degeneration.

Initially, the neuron response to this down-regulation is to increase its sensitivity to stimulus so that less stimulus is required to stimulate protein production. This essentially means that the neuron alters its membrane potential so that it is closer to its threshold potential; in other words, it becomes more depolarised and becomes more irritable to any stimulus it may receive.

After a period of time if the neuron does not receive the deficient component in sufficient amounts, it can no longer sustain its state of depolarisation and starts to drastically downgrade the production of protein as a last ditch effort to conserve energy and maintain survival. At this stage, the neuron will still respond to stimulus but only for short periods as it consumes its available protein and ATP stores very quickly. In this state the neuron is vulnerable to overstimulation that may further exhaust and damage the neuron (Fig. 1.5).

The process of transneural degeneration may be one approach that determines the survival or death of neurons during embryological development where it has become quite clear that neurons that do not receive adequate stimulus do not usually survive (see Chapter 2).

The concept of transneural degeneration can also apply to systems or groups of neurons that will respond in a similar pattern to that described above when they do not receive the appropriate stimulus or nutrients that they require.