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.

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).

Figure 1.1 The effects of ionic movement across the neuron cell membrane. The left side of the diagram illustrates the depolarising effect of sodium ion movement into the cell. The right side of the diagram illustrates the hyperpolarising effect of potassium movement out of the cell. The graphs illustrate the change in potential voltage inside the cell relative to outside the cell as the respective ions move across the membrane. Note the equilibrium potentials for sodium and potassium, +60 and −70 mV, respectively, are reached when the chemical and electrical forces for each ion become equal in magnitude.

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).

Figure 1.2 Anatomical characteristics of a healthy neuron. The central nucleus is maintained by microtubule and microfilament production which requires active protein synthesis. The myelin sheath is composed of oligodendrogliocytes in the central nervous system and Schwann cells in the peripheral nervous system. Note the different types of synaptic contacts illustrated from left to right: axodendritic, axosomatic, dendrodendritic, axohillonic, axoaxonic (presynaptic).

The concept of the CIS described above in relation to a single neuron can be loosely extrapolated to a functional group of neurons. Thus, the central integrative state of a functional unit or group of neurons can be defined as the total integrated input received by the group of neurons at any given moment and the probability that the group of neurons will produce action potential output based on the state of polarisation and the firing requirements of the group.

The concept of the central integrative state can be used to estimate the status of a variety of variables concerning the neuron or neuron system such as:

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).

Figure 1.3 Enzymes of oxidative phosphorylation. Electrons (e⁻) enter the mitochondrial electron transport chain from donors such as reduced nicotinamide adenine dinucleotide (NADH) and reduced flavin adenine dinucleotide (FADH₂). The electron donors leave as their oxidised forms, NAD⁺ and FAD⁺. Electrons move from complex I (I), complex II (II), and other donors to coenzyme Q₁₀ (Q). Coenzyme Q₁₀ transfers electrons to complex III (III). Cytochrome c (c) transfers electrons from complex III to complex IV (IV). Complexes I, III, and IV use the energy from electron transfer to pump protons (H⁺) out of the mitochondrial matrix, creating a chemical and electrical (δψ) gradient across the mitochondrial inner membrane. Complex V (V) uses this gradient to add a phosphate (P_i) to adenosine diphosphate (ADP), making adenosine triphosphate (ATP). Adenosine nucleotide transferase (ANT) moves ATP out of the matrix.

Source: From D. Wolf, with permission.

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).

Figure 1.4 Immediate early genes responses type I and type II. Following receptor activation the entry of calcium (Ca⁺) ions into the neuron activate both type I and type II response cascades. The type I cascade involves the activation of third-order messengers that modulate the activation or inhibition of DNA in the nucleus of the neuron. The type II cascade involves the activation of third-order messengers that modulate activation or inhibition of the mitochondrial DNA of the neuron.

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).

Figure 1.5 The progression of transneural degeneration in a neuron. (Top) A normal healthy neuron with a normal distribution of sodium (Na⁺) and potassium (K⁺) ions across its membrane, resulting in a normal resting membrane potential. Note the central nucleus. (Middle) The early stages of transneural degeneration. In this stage, the Na⁺ ion concentration in the cell increases because of loss of Na⁺/K⁺ pump activity and alterations in membrane permeability, resulting in a membrane potential more positive and closer to the threshold of firing of the neuron. A neuron in this state will fire action potentials when normally inadequate stimuli are received. This inappropriate firing is called physiological irritability. The neuron will only be able to maintain the frequency of firing for short periods because of the lack of sufficient enzymes and ATP supplies before it fatigues and fails to produce action potentials. (Bottom) The neuron in the late stages of transneural degeneration. Note the eccentric nucleus, which can no longer be maintained by the degraded state of the microfilaments and microtubules. The membrane has lost its ability to segregate ions, and calcium ions have entered the neuron in high concentrations, which will eventually result in cell death. The resting membrane potential has shifted away from firing threshold, resulting in the neuron requiring excessive stimulus in order to fire an action potential.

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.

The frequency of firing (FOF) of a neuron is quite simply the number of action potentials that it generates over a defined period of time. As a rule, the FOF is an important indicator of the central integrative state of a neuron. Neurons with high and regular FOF usually maintain high levels of energy and protein production that maintains the neuron in a good state of ‘health’. One exception to this rule is a neuron that is in the early stages of transneural degeneration, in which case it will produce high FOF but only for short durations.

The time to activation (TTA) of a neuron is a measure of the time from which the neuron receives a stimulus to the time that an activation response can be detected. Obviously, in clinical practice the response of individual neurons cannot be measured but the response of neuron systems such as the pupil response to light can be. As a rule, the TTA will be less (faster) in situations where the neuron system has maintained a high level of integration and activity and greater (slower) in situations where the neuron has not maintained a high level of integration and activity or is in the late stages of transneural degeneration. Again, an exception to this rule can occur in situations where the neuron system is in the early stages of transneural degeneration and is irritable to stimulus and responds quickly. This response will be of short duration and cannot be maintained for more than a short period of time.

The time to fatigue (TTF) in a neuron is the length of time that a response can be maintained during a continuous stimulus to the neuron. The TTF effectively measures the ability of the neuron to sustain activation under continuous stimuli, which is a good indicator of the ATP and protein stores contained in the neuron. This in turn is a good indication of the state of health of the neuron. The TTF will be longer in neurons that have maintained high levels of integration and stimulus and shorter in neurons that have not. TTF can be very useful in determining whether a fast time to response (TTR) is due to a highly integrated neuron system or a neuron system that is in the early stages of transneural degeneration.

For example, in clinical practice we can compare the individual responses of two pupils to light. If both pupils respond very quickly to light stimulus (fast TTR), and they both maintain pupil contraction for 3–4 seconds (long TTF), this is a good indication that both neuronal circuits are in a good state of health. If, however, both pupils respond quickly (fast TTR) but the right pupil immediately dilates despite the continued presence of the light stimulus (short TTF), this may be an indication that the right neuronal system involved in pupil constriction may be in an early state of transneural degeneration and more detailed examination is necessary.

Diaschisis refers to the process of degeneration of a downstream neuronal system in response to a decrease in stimulus from an upstream neuronal system.

This reemphasises the point that neuronal systems do not exist in isolation but are involved in highly complicated and interactive networks. Interference or disruption in one part of the network can impact other parts of the network.

For example, injury or disease affecting the cerebellum invariably also affects the activity of the contralateral thalamus and cortex.

All multimodal integrated neuronal systems need to receive input from a constant stimulus pathway as well as appropriate oxygen and nutrient supply in order to maintain a healthy CIS.

Constant stimulus pathways are neural receptive systems that supply constant input into the neuraxis that are integrated throughout all multimodal systems to provide the stimulus necessary for the development and maintenance of the systems. Examples of constant stimulus pathways include receptors that detect the effects of gravity or constant motion, namely the joint and muscle position receptors of joint capsules and muscle spindles of the midline or axial structures including the ribs and spinal column. Certain aspects of the vestibulocerebellar system receive constant input and are constantly active. Several neural systems contain groups of neurons that exhibit innate pacemaker depolarisation mechanisms such as cardiac pacemaker cells, certain thalamic neurons, and selective neurons of the basal ganglia.

All other receptor systems are non-constant in nature, which means they are activated in bursts of activity that are not constantly maintained.

A few examples should illustrate this concept. One would think that the constant stimulus input to the cortical cells of vision would be the optic radiations from the lateral geniculate nucleus of the thalamus, which transmits the visual information received by the retinal cells to the cortex. Although it is true that most of the time these neurons are active when your eyes are open, these pathways are not active for large periods at a time, specifically about 7–8 hours per day while you sleep. These neurons are maintained in a healthy CIS by the activity generated in constant activation circuits of multimodal systems that include input via the thalamus from midline structures such as the vertebral and costal joint and muscle receptors.

Cortical neurons involved in memory may experience long periods of inactivity and only be activated to threshold when needed to supply appropriate memory information. These neurons are maintained in a high CIS by subthreshold activation supplied by complex multimodal neuron systems.

Finally, ventral horn neurons of small inactive muscles are only brought to activation occasionally when their motor units are called to action. These neurons are maintained in a high CIS by subthreshold stimulus from spinal and supraspinal multimodal neuron systems as well.

Neural plasticity results when changes in the physiological function of the neuraxis occur in response to changes in the internal or external milieu (Jacobson 1991). In other words, the development of synapses in the nervous system is very dependent on the activation stimulus that those synapses receive. The synapses that receive adequate stimulation will strengthen and those that do not receive adequate stimulation will weaken and eventually be eliminated (see Chapter 2).

The organisation of the synaptic structure in the neuraxis largely determines the stimulus patterns of the nervous system and hence the way in which the neuraxis functions.

Neural plasticity refers to the way in which the nervous system can respond to external stimuli and adjust future responses based on the outcome of the previously initiated responses. In essence, the ability of the nervous system to learn is dependent on neural plasticity.

The study of brain asymmetry or hemisphericity has a long history in the behavioral and biomedical sciences but is probably one of the most controversial concepts in functional neurology today.

The fact that the human brain is asymmetric has been fairly well established in the literature (Geschwind & Levitsky 1968; LeMay & Culebras 1972; Galaburda et al. 1978; Falk et al. 1991; Steinmetz et al. 1991). The exact relationship between this asymmetric design and the functional control exerted by each hemisphere remains controversial.

The concept of hemispheric asymmetry or lateralisation involves the assumption that the two hemispheres of the brain control different asymmetric aspects of a diverse array of functions and that the hemispheres can function at two different levels of activation. The level at which each hemisphere functions is dependent on the central integrative state of each hemisphere, which is determined to a large extent by the afferent stimulation it receives from the periphery as well as nutrient and oxygen supply. Afferent stimulation is gated through the brainstem and thalamus, both of which are asymmetric structures themselves, and indirectly modulated by their respective ipsilateral cortices (Savic et al. 1994).

Traditionally, the concepts of hemisphericity were only applied to the processing of language and visuospatial stimuli. Today, the concept of hemisphericity has developed into a more elaborate theory that involves cortical asymmetric modulation of such diverse constructs as approach versus withdrawal behaviour, maintenance versus interruption of ongoing activity, tonic versus phasic aspects of behaviour, positive versus negative emotional valence, asymmetric control of the autonomic nervous system, and asymmetric modulation of sensory perception, as well as cognitive, attentional, learning, and emotional processes (Davidson & Hugdahl 1995).

The cortical hemispheres are not the only right- and left-sided structures. The thalamus, amygdala, hippocampus, caudate, basal ganglia, substantia nigra, red nucleus, cerebellum, brainstem nuclei, and peripheral nervous system all exist as bilateral structures with the potential for asymmetric function.

Hemisphericity can result in dysfunction of major systems of the body including the spine. Some spinal signs of hemisphericity include:

In the application of functional neurology the concept of embryological homological relationships between neurons born at the same time frequently needs to be taken into consideration.

The term embryological homologues is used to describe the functional relationships that exist between neurons born at the same time in the cell proliferation phase of development. These cells born at the same time along the length of neuraxial ventricular area develop and retain synaptic contact with each other, many of which remain in the mature functional state. This cohort of cells that remain functionally connected after migration results in groups of neurons that may be unrelated in cell type or location but fire as a functional group when brought to threshold. Dorsal root ganglion cells detecting joint motion and muscle contraction and postsynaptic neurons in the sympathetic ganglia controlling blood flow to the joints and muscles illustrate the concept. Another example includes the motor column of the cranial nerves III, IV, VI, and XII in the brainstem which act functionally as a homologous column. This concept also applies to functional areas of the neuraxis that developed from the same embryological tissues. Neuron systems that have developed from the same embryological tissues usually maintain reciprocal connections throughout their life span. For example, in the mesencephalon there is an area of the neuraxis that develops in an undifferentiated fashion, all of the functional structures would be considered embryological homologues and as such be expected to maintain reciprocal connections throughout life. This would imply that the structures in the mesencephalon such as the red nucleus, the substantia nigra, the oculomotor nucleus, the Edinger–Westphal nucleus, and the reticular neurons all maintain close functional relationships. This is in fact the case. Another spin-off from this concept is that all neuron systems developing from the same tissue remain in close reciprocal contact even after further differentiation; for example, the cortex and the thalamus, which develop from prosencephalon but further differentiate to telencephalon and diencephalon respectively, would still be considered embryological homologues. These two structures do indeed retain reciprocal connectivity throughout life. Other examples include the structures that have developed from the rhombencephalon: the cerebellum, pons, and brainstem.

Excitation of a neuron moves the neuron membrane potential closer to threshold so that the probability of generating an action potential increases.

Inhibition of a neuron moves the membrane potential of the neuron away from its threshold potential and decreases the probability that the neuron will produce an action potential. These same concepts apply to neuron systems; however, in a neuron system several components are integrated to arrive at the final system output.

Components of a neuron system usually involve an input stimulus, a series of integration steps, and an output (Williams & Warwick 1980).

The input stimulus or output, as well as any steps in the integration portion, may be either excitatory or inhibitory in nature (Fig. 1.6).

Figure 1.6 The ‘integrate and fire’ model of the nervous system. The primary afferent neurons supply the sensory input to the system. The input is then integrated and modulated by the neurons of the central nervous system, which then produce the appropriate efferent or motor activation in response to the original input received.

Virtually all input from the primary afferent neurons of the peripheral nervous system and most cortical output is excitatory in nature. In order to modulate both the input to the integrator (central nervous system) and the output from the integrator the nervous system utilises a complex array of interneuronal inhibitory strategies.

Some examples of these inhibitory strategies utilised by the nervous system include direct inhibition, feedforward inhibition, feedback inhibition, disinhibition, feedback disinhibition, lateral inhibition, and surround inhibition.

Direct inhibition involves a hyperpolarising stimulus to the target neuron, which results in a decreased probability that the target neuron will be brought to threshold potential and fire and action potential per unit stimulus (Fig. 1.7).

Figure 1.7 Direct inhibition. The process of direct inhibition involves the inhibition of the downstream neuron by a neuron directly upstream, with no interneuron involvement.

Feedforward inhibition involves the linking of an inhibitory interneuron into a pathway that causes relative hyperpolarisation of the next neuron in the pathway, resulting in a decreased probability of output activation of that pathway (Fig. 1.8).

Figure 1.8 Feedforward inhibition. The process of feedforward inhibition involves the simultaneous activation of the target neuron and an inhibitory interneuron, which in turn inhibits the target neuron.

Feedback inhibition involves an inhibitory interneuron that receives stimulus from the neuron that it projects to and thus also inhibits (Fig. 1.9).

Figure 1.9 Feedback inhibition. Feedback inhibition involves the simultaneous stimulation of a downstream neuron and an inhibitory interneuron that in turn inhibits the original stimulating neuron.

Disinhibition (inhibition of inhibition) involves two inhibitory interneurons linked in series with each other so that stimulation of the first neuron results in inhibition of the second neuron, which in turn results in decreased inhibitory output of the second interneuron to the target. The overall effect of disinhibition is an increased probability that the effector will reach threshold potential per unit stimulus (Fig. 1.10).

Figure 1.10 Disinhibition. Disinhibition involves the inhibition of an inhibitory interneuron. The result of this process is a decrease inhibition of the target neuron or increased probability of firing in the target neuron.

Feedback disinhibition involves a series of inhibitory interneurons that receive their original stimulus from the neuron that they project to; however, in this case the net result is an increase in the probability that the target neuron will reach threshold per unit stimulus (Fig. 1.11).

Figure 1.11 Feedback disinhibition. Feedback disinhibition involves the stimulation of an inhibitory interneuron that in turn synapses on a primary inhibitory neuron of the target neuron. This system tends to result in a positive feedback stimulus of the target neuron and is rare in humans.

To illustrate these concepts the corticostriate-basal ganglio-thalamocortical neuron projection system in the neuraxis will be examined. (See Chapter 11 for more detailed descriptions.)

Selective pyramidal output neurons, in wide areas of cortex, project to the neostriatum (caudate and putamen) via the corticostriatal projection system. The cortical neurons are excitatory in nature to the neurons in the caudate and putamen. The neurons of the caudate and putamen project to neurons in both regions of the globus pallidus, the globus pallidus pars interna, and globus pallidus pars externa, and are inhibitory in nature. For the purposes of this example we will only consider the projections to the globus pallidus pars interna. This nucleus comprises the final output nucleus of the basal ganglia to the thalamus. (For a more complete description, see Chapter 11.)

Neurons in the globus pallidus pars interna project to neurons in the thalamus and are inhibitory in nature.

The neurons in the thalamus project back to neurons in the cortex and are excitatory in nature to the cortical neurons.

Following the flow of stimulus through the system (Fig. 1.12), it can be noted that the end result is a disinhibition of the thalamus and an increased likelihood of cortical activation by thalamic neurons.

Figure 1.12 The direct and indirect functional pathways of the basal ganglia. The input to the basal ganglia occurs via the neostriatum from the cortex. The output of the neostriatum projects to both areas of the globus pallidus, the globus pallidus pars internus (GPi) and externus (GPe). The stimulus received from the neostriatum is inhibitory on both the GPi and the GPe. The direct pathway involves the projections from the neostriatum to GPi, the projections from the GPi to the thalamus, and the projections from the thalamus to the cortex. The direct pathway results in inhibition of the inhibitory output of the GPi on the thalamus (inhibition of inhibition). This results in a gating pattern of disinhibition, or increased probability of firing of the thalamic neurons. The disinhibition of the thalamus results in increased activation of the cortical neurons. The indirect pathway involves the projections from the neostriatum to the GPe, the projections from the GPe to the subthalamic nuclei, the projections from the subthalamic nuclei to the GPi, the projections from the GPi to the thalamus, and the projections from the thalamus to the cortex. The projections from the neocortex to the GPe are inhibitory to the GPe. The projections from the GPe to the subthalamic nuclei are inhibitory to the subthalamic nuclei. Projections from the subthalamic nucleus to the GPi are excitatory and the projections from the GPi to the thalamus are inhibitory. The end result of stimulation of the indirect pathway is a gating mechanism that increases the inhibition on the thalamic neurons, which in turn results in decreased activation input from the thalamic neurons to the cortex. To summarise, stimulus of the direct pathway results in increased cortical stimulation and stimulus of the indirect pathway results in decreased cortical stimulation. The physiological impact of these pathways will be discussed in more detail in following chapters.

Occasionally, a system will experience ‘wind-up’, which results in the development of a hyperexcited state of activity. This is usually not ideal since the output from the system will be inappropriate per unit input. Chronic wind-up can also result in damage to individual neurons or the whole system in the following ways:

Wind-up usually occurs when either the neuron or system receives too much excitatory stimulus or normal levels of tonic inhibition malfunction. The following example will illustrate the concept.

The thalamus contains neurons that tonically generate innate excitatory potentials that project to the cortex and result in excitation of cortical neurons. Under normal conditions, modulation of this tonic excitation occurs via the inhibitory output of the globus pallidus pars interna (GPi) of the basal ganglionic circuits. However, in certain circumstances, such as an increased output of the neostriatum, which can occur with loss of inhibition from the substantia nigra pars compacta, the globus pallidus receives an increased inhibitory input from the neostriatum. This increased inhibition to the GPi reduces the inhibition received by the thalamus from the GPi. This results in an increase in the innate tonic excitation to the cortex from the thalamus, which in turn results in a hyperexcitation or wind-up of cortical neurons. This example demonstrates how inhibition of inhibition can result in hyperexcitation of a neuron system. The concept of inhibition of inhibition is very important clinically in understanding the symptoms produced in multimodal integrative systems and is encountered frequently in clinical practice.

Ablative lesions are lesions that result in the death or destruction of neural tissues. This type of lesion commonly occurs as the result of a vascular stroke when tissues experience critical levels of hypoxia or anoxia and die as a result. Direct or indirect trauma as in the ‘coup counter coup’ injuries in whiplash or head trauma can also result in ablation of tissues or function. Replacement of the damaged tissue is usually very slow, if it occurs at all, and restoration of function depends on the rerouting of nerve pathways or regrowth of new synaptic connections.

Physiological lesions are functional lesions that result from overstimulation, excessive inhibition, excessive disinhibition, or understimulation of a neuronal system. Often, chemical deficiencies or ischemic conditions may cause these lesions also. Correction of these functional lesions is dependent on restoring normal levels of activation, oxygenation, and supplementation to the involved systems. The results are usually apparent relatively quickly and can occur almost immediately in some cases.

Often the symptom presentation of these two types of lesions can be very similar so the possibility of an ablative lesion must be ruled out before the diagnosis of a physiological lesion is made.

For example, in Huntington’s disease (HD) the neurons in the neostriatum degenerate. The degeneration appears to be more pronounced in the output neostriatal neurons of the indirect pathway. This results in the disinhibition of the globus pallidus pars externa (GPe), which in turn results in an overinhibition of the subthalamic nucleus. The functional overinhibition of the subthalamic nucleus results in a situation that resembles an ablative lesion to the subthalamic nucleus and results in a hyperkinetic movement disorder. In this case the lesion is not purely physiological in nature because the neostriatal neurons have actually degenerated but the result is the physiological functional state of overinhibition of a neuron system.

In order to apply the neurophysiological concepts discussed thus far in a clinical setting an understanding of some of the basic fundamental functional projection systems utilised by the cortex to modulate activity in wide-ranging areas of the neuraxis is essential.

About 90% of the output axons of the cortex are involved in modulation of the neuraxis. About 10% of the cortical output axons of the cortex are involved in motor control and form the corticospinal tracts.

Of the 90% output dedicated to neuraxis modulation about 10% projects bilaterally to the reticular formation of the mesencephalon (MRF) and 90% projects ipsilaterally to the reticular formation of the pons and medulla or pontomedullary reticular formation (PMRF). The cortical projections to both the MRF and the PMRF are excitatory in nature. The neurons in the MRF and some of those in the PMRF project bilaterally to excite neurons in the intermediolateral (IML) cell columns located between T1 and L2 spinal cord levels in the grey matter of the spinal cord; however, the majority of the PMRF remain ipsilateral (Fig. 1.13) (Nyberg-Hansen 1965). These neurons in the IML form the presynaptic output neurons of the sympathetic nervous system, and project to inhibit neurons in the sacral spinal cord regions that form the pelvic or sacral output of the parasympathetic nervous system.

Figure 1.13 The relative distribution of neuron cell bodies and projection fibre tracts of the pontomedullary reticulospinal tracts (PMRF). Although both the neurons and the projection fibres occur bilaterally, the majority of neurons and projections are ipsilateral in nature.

Following the stimulus flow through the functional system, it can be seen that high cortical output results in high PMRF output, which results in strong inhibition of the IML, which in turn results in disinhibition of the sacral parasympathetic output. The bilateral excitatory output of the MRF is overshadowed by the powerful stimulus from the cortex to the PMRF (Fig. 1.14).

Figure 1.14 A simplified schematic of the cortical projection system to the sympathetic (SNS) and parasympathetic nervous systems (PNS). All outputs of the cortex in this system are excitatory to both the mesencephalon (MES) and the pontomedullary reticular formation (PMRF); however, 90% of the cortical projections are to the PMRF and 10% to the MES. Bilateral, excitatory projections from the MES to the intermediolateral (IML) cell column neurons result in activation of the sympathetic preganglionic neurons. Ipsilateral inhibitory projections from the PMRF to the IML result in inhibition of the sympathetic preganglionic neurons. Because of the distribution of projection fibres, cortical activation will result in an ipsilateral inhibition of the IML or SNS and an ipsilateral activation of the PNS. These functional loops will be discussed in much more detail later in the text.

To further illustrate the impact that an asymmetric cortical output (hemisphericity) could potentially have clinically, consider the affects of an asymmetric cortical output on the activity levels of the sympathetic and parasympathetic systems on each side of the body. Autonomic asymmetries are an important indicator of cortical asymmetry as this reflects on fuel delivery to the brain (sympathetic system) and the integrity of excitatory and inhibitory influences on sympathetic and parasympathetic function throughout the rest of the body.

The PMRF has other modulatory effects in addition to modulation of the IML neurons. All of the modulatory interactions of the PMRF have clinical relevance and include:

A sense of the clinical impact that asymmetric stimulation of the PMRF can produce symptomatically in the patient becomes apparent when it is considered that all of the following can result:

Clinical presentation of ipsilateral flexor angulation of the upper limb and extensor angulation of the lower limb is known as pyramidal paresis, and is an important clinical finding in many patients with asymmetric cortical function.

The fundamental projection systems (see Fig. 1.14) presented above are simplified for the purposes of introduction and will be discussed more thoroughly throughout the rest of the text.

Lesions may occur at one or more points along a nerve pathway. Identifying the level at which the lesion has occurred is usually accomplished by taking a thorough history and performing a thorough physical examination of the patient. A nerve pathway may become dysfunctional at one or more of the following:

Lesions at the receptor level may be ablative, may be caused by states of habituation, or may be due to a decreased environmental stimulus. Often, the sensitivity of a receptor is cortically mediated and cortical hyper- or hyposensitivity states may be confused with a receptor lesion. The level of response of a receptor is often measured through the response of an effector organ and this may also result in confusion between a receptor lesion and an effector dysfunction.

Effector or end organ lesions may be hyper- or hypofunctional in nature. In skeletal muscle hypofunctional disorders can be caused by myopathies, neurotransmitter or neuroreceptor dysfunction, oxidative phosphorylation disorders, or lack of use. Hyperfunctional disorders can be caused by metabolic and ionic imbalances. Often, disinhibition of VHCs can result in a hyperfunctional state, such as rigidity and spasms of the end organ. This is actually a spinal cord (corticospinal tract lesion) or supraspinal (upper motor neuron) level of involvement which could be confused with an end organ dysfunction.

Peripheral nerve lesions usually involve both motor and sensory functional disturbances. The distributions of the peripheral nerves have been anatomically and functionally mapped fairly accurately and these distributions can be used to identify the location of a specific peripheral nerve dysfunction. Often, the end organs such as a muscle will show specific forms of activity (flaccid paralysis) or neurologically induced atrophy (muscle wasting) when a peripheral nerve is involved.

Spinal cord lesions may exhibit disassociation of sensory and motor symptoms depending on the specific areas of involvement of the spinal cord. Specific tract lesions may demonstrate classic symptoms (dorsal column lesions and loss of proprioception) and when specific areas of the cord are involved the patient may exhibit classic symptoms of a well-defined syndrome (posterior lateral medullary infarcts and symptoms of Wallenberg’s syndrome).

Lesions of the brainstem and cerebellum often result in widespread seemingly unrelated symptoms (cerebellar degeneration and changes in cognitive function, or dysautonomia with brainstem dysfunction). These can be one of the most challenging levels of lesion to treat, due to the involvement of both upstream and downstream neuronal systems which experience altered function concomitantly.

Basal ganglionic and thalamic levels usually result in movement disorders and disorders of sensory reception including pain disorders. Basal ganglionic disorders have also been implicated in a variety of cognitive function disorders as well.

Lesions at the cortical level can manifest as dysfunction at any other level in the neuraxis and as such are often very difficult to pinpoint. Many of the cortical functions, if not all cortical functions, are highly integrated over diffuse areas of cortex, which once again makes targeting specific neuron circuits difficult.

The neuraxis utilises a number of types of synaptic connections including monosynaptic and polysynaptic relays.

Monosynaptic connections between two structures suggest an important functional relationship between the two structures in question. Polysynaptic connections may be important as well but are not as well understood. For example, the existence of monosynaptic connections between the hypothalamus and the preganglionic sympathetic neurons in the IML suggests an important functional relationship between the output of the sympathetic nervous system and the CIS of the hypothalamus.

An area of singularity is a neuronal circuit or system that has one or very few input pathways that can modulate its activities. For example, the globus pallidus is a very difficult area of the neuraxis to influence clinically because the area can only be accessed via projections from neurons in the neostriatum, whereas ventral horn neurons in the spinal cord can be influenced by modulating a multitude of different pathways.

A visual image inverts and reverses as it passes through the lens of the eye and forms an image on the retina. Image from the upper visual field is projected on the lower retina and from the lower visual field on the upper retina. The left visual field is projected to the right hemiretina of each eye in such a fashion that the right nasal hemiretina of the left eye and the temporal hemiretina of the right eye receive the image. The central image or focal point of the visual field falls on the fovea of the retina, which is the portion of the retina with the highest density of retinal cells and as such produces the highest visual acuity. The fovea receives the corresponding image of the central 1°–2° of the total visual field but represents about 50% of the axons in the optic nerve and projects to about 50% of the neurons in the visual cortex. The macula comprises the space surrounding the fovea and also has a relatively high visual acuity. The optic disc is located about 15° medially or towards the nose on each retina and is the convergence point for the axons of retinal cells as they leave the retina and form the optic nerve. This area, although functionally important, has no photoreceptors. This creates a blind spot in each eye about 15° temporally from a central fixation point. When both eyes are functioning, open, and focused on a central fixation point, the blind spots do not overlap so all of the visual field is represented in the cortex and one is not aware of the blind spot in one’s visual experience. The area of the visual striate cortex which is the primary visual area of the occipital lobe, representing the blind spot and the monocular crescent which are both in the temporal field, does not contain alternating independent ocular dominance columns. This means that these areas only receive information from one eye. If you close that eye, the area representing the blind spot of the eye that remains open will not be activated due to the lack of receptor activation at the retina.

It would be expected that when one eye is closed the visual field should now have an area not represented by visual input and one should be aware of the absence of vision over the area of the blind spot. However, this does not occur. The cortical neurons responsible for the area of the blind spot must receive stimulus from other neurons that create the illusion that the blind spot is not there. This is indeed the case and is accomplished by a series of horizontal projection neurons located in the visual striate cortex that allow for neighbouring hypercolumns to activate one another. The horizontal connections between these hypercolumns allow for perceptual completion or ‘fill in’ to occur (Gilbert & Wiesel 1989; McGuire et al. 1991).

The blind spot is therefore not strictly monocular, but it is dependent on the FOF of horizontal connections from neighbouring neurons. These may be activated via receptors and pathways from either eye.

Perceptual completion refers to the process whereby the brain fills in the region of the visual field that corresponds to a lack of visual receptors. This explains why one generally is not aware of the blind spot in everyday experience. The size and shape of the blind spots can be mapped utilising simple procedures as outlined in Chapter 4.

The size and shape of the blind spots is dependent to some extent on the CIS of the horizontal neurons of the cortex that supply the stimulus for the act of completion to occur. The integrative state of the horizontal neurons is determined to some extent by the activity levels of the neurons in the striate cortex in general. Several factors can contribute to the CIS of striate cortical neurons; however, a major source of stimulus results from thalamocortical activation via the reciprocal thalamocortical optic radiation pathways involving the lateral geniculate nucleus (LGN) of the thalamus. Only 10–20% of the projections arriving in the LGN nucleus are derived directly from the retina. The remaining projections arise from the brainstem reticular formation, the pulvinar, and reciprocal projections from the striate cortex.

It is clear from the above that the majority of the projection fibres reaching the LGN are not from retinal cells. This strongly suggests that the LGN acts as a multimodal sensory integration convergence point that in turn activates neurons in the striate cortex appropriately. The level of activation of the LGN is temporally and spatially dependent on the activity levels of all the multimodal projections that it receives.

In 1997, Professor Frederick Carrick discovered that asymmetrically altering the afferent input to the thalamus resulted in an asymmetrical effect on the size of the blind spot in each eye. The blind spot was found to decrease on the side of increased afferent stimulus. This was attributed to an increase in brain function on the contralateral side due to changes in thalamocortical activation that occurred because of multimodal sensory integration in the thalamus.

The stimulus utilised by Professor Carrick in his study was a manipulation of the upper cervical spine which is known to increase the FOF of multimodal neurons in areas of the thalamus and brainstem that project to the visual striate cortex. These reciprocal connections lower the threshold for activation of neurons in the visual cortex. By decreasing the threshold for firing of neurons in the visual cortex the blind spot became smaller because the area surrounding the permanent geometric blind spot zone is more likely to reach threshold and respond to the receptor activation that occurs immediately adjacent to the optic disc on the contralateral side. The size and shape of the blind spot will also be associated with the degree of activation of neurons associated with receptors adjacent to the optic disc. The receptors surrounding the optic disc underlie the neurons that form the optic nerve exiting by way of the optic disc. The amplitude of receptor potentials adjacent to the optic disc may therefore also be decreased due to interference of light transmission through the overlying fibres even though they should have lost their myelin coating during development; otherwise, interference would be even greater. This interference results in a decreased receptor amplitude, which in turn results in decreased FOF of the corresponding primary afferent nerve. This may result in a blind spot physiologically larger than the true anatomical size of the blind spot.

This led to the understanding that the size and shape of the blind spots could be used as a measure of the CIS of areas of the thalamus and cortex due to the fact that the amplitude of somatosensory receptor potentials received by the thalamus will influence the FOF of cerebellothalamocortical loops that have been shown to maintain a CIS of the cortex.

Therefore, muscle stretch and joint mechanoreceptor potentials will alter the FOF of primary afferents that may have an effect on visual neurons associated with the cortical receptive field of the blind spot when visual afferents are in a steady state of firing. Professor Carrick proposed that ‘A change in the frequency of firing of one receptor-based neural system should effect the central integration of neurons that share synaptic relationships between other environmental modalities, resulting in an increase or decrease of cortical neuronal expression that is generally associated with a single modality’ (Carrick 1997).

Care should be taken not to base too much clinical significance on the blind spot sizes until any pathological or other underlying cause that may have resulted in the changes in blind spot size are ruled out. The blind spot has been found to increase in size due to the following conditions:

An ophthalmoscopical examination is therefore an important component of the functional neurological examination. There are several other valuable ophthalmoscopic findings discussed in Chapter 4 that can assist with estimating the CIS of various neuronal pools.

The concept of a group of upper motor neuron pools versus groups of lower motor neuron pools can be of great value when localising lesions in the neuraxis in the clinical setting. Upper motor neurons are considered all of the neuron pools which project directly or indirectly to the final common path motor neurons. Lower motor neurons are the neurons that supply the final common projection to the skeletal muscles. Some examples will illustrate the concepts.

The pyramidal neurons in the motor cortex project via the corticospinal tracts to the ventral grey area of the spinal cord where they synapse on the VHCs. The ventral horn neurons are the final common pathway to the skeletal muscles and as such are considered lower motor neurons. The cortical neurons and their projections in the corticospinal tracts are considered the upper motor neurons.

The same concept applies to the cortical neurons that modulate the motor output of cranial nerves. The cortical neurons in the motor strip that project their axons via the corticobulbar tracts to the motor nuclei of the cranial nerves in the brainstem are considered upper motor neurons. The cranial nerve motor neurons in the brainstem are considered the final common pathway to the muscles that they supply and are considered the lower motor neurons of this system.

The functional effects of upper and lower motor neuron dysfunction are distinct and important clinically.

Lower motor neuron lesions will produce flaccid muscle weakness, muscular atrophy, fasciculations, and hyporeflexia. Upper motor neuron lesions will produce spastic muscle weakness, and hyperreflexia. Upper motor neuron dysfunction involving the corticospinal tracts usually produces a classic reflex sign referred to as Babinski’s sign or reflex. Under normal conditions, stroking the plantar aspect of the foot will produce a reflex flexion of the toes. In cases of corticospinal tract dysfunction, stroking the plantar surface of the foot produces an ‘up-going’ or extended big toe and fanning action of the rest of the toes. This is referred to as a positive or present Babinski sign or up-going plantar reflex. Other reflex signs of upper motor neuron dysfunction will be discussed in Chapter 4. Initially, in the acute stages, the signs of upper motor neuron dysfunction may mimic lower motor neuron dysfunction exhibiting flaccid muscle weakness and hyporeflexia. These signs change progressively over hours or days to the true signs of upper motor neuron dysfunction. In the case of long-standing upper motor neuron dysfunction, the involved muscles may atrophy due to disuse and give the appearance of a lower motor neuron involvement.