Neurology: Sensory systems

Sensory systems: an overview

A sensory system is one in which information is conveyed to the spinal cord and brain from peripheral sensory receptors, which in themselves are either specialized neurones or nerve endings.

The specialized sensory receptor, afferent axon and cell body together with the synaptic contacts in the spinal cord are known as the primary afferent. The process by which stimuli from the external environment are converted into electrical signals for transmission through the nervous system is known as sensory transduction.
The signal produced by the sensory receptor is relayed to the central nervous system (CNS) via peripheral or cranial nerves and through a series of synapses eventually projects to a given area of cortex that is then capable of detailed analysis of that sensory input.

There are five main sensory systems in the mammalian nervous system:

touch/pressure, proprioception, temperature and pain or the somatosensory system;
vision;
hearing and balance;
taste;
smell or olfaction.

All but the somatosensory pathways are regarded as ‘special’ senses.

Sensory receptors

Sensory receptors transduce the sensory stimulus either by a process of direct ion channel activation (e.g. the auditory system) or indirectly via a secondary intracellular messenger network (e.g. the visual system). In both cases the sensory stimulus is converted into an electrical signal that can then be relayed to the CNS in the form of either graded depolarizations/hyperpolarizations leading on to action potentials (e.g. visual system) or the direct generation of action potentials at the level of the receptor.

The specificity or modality of a sensory system relies on the activation of specialized nerve cells or fibres which are highly specific for different forms of afferent stimuli.
The receptor will only respond to stimuli when they are applied within a given region around it (its receptive field). This area or receptive field from which the receptor can be activated is recognized by the CNS as corresponding to a specific site or position in the body or outside world. The receptor will only transmit electrical information to the CNS when it receives a stimulus of sufficient intensity to reach the firing threshold.

The incremental response to a change in stimulus intensity by the receptor gives the receptor its sensitivity. Many receptors have high sensitivity both to the absolute level of stimulus detection and to changes in stimulus intensity. This is because they are capable of both amplifying the original signal by the use of secondary messenger systems and adapting to the presence of a continuous unchanging stimulus).

Ascending sensory pathways in the spinal cord

With very sensitive receptors the intrinsic instability of the transduction process is termed the noise and the challenge for the nervous system is to detect a sensory stimulus response or signal over this background noise (termed the signal to noise ratio).

The strength of a sensory stimulus can be coded for at the level of the receptor and its first synapse, either in the form of action potentials or graded membrane potentials within the receptor. The afferent sensory nerve can code (among other things) for the strength of the stimulus, first by increasing the number of afferent fibres activated (recruitment or spatial coding) and, second, by increasing the number of action potentials generated in each axon per unit time (temporal or frequency coding). There is a complex relationship between the stimulus intensity and action potential firing frequency in the afferent nerve – this is defined by the Weber–Fechner law.

Sensory pathways

Each sensory pathway has its own unique input to the CNS, although ultimately most sensory pathways provide an input to the thalamus – the site of that projection being different for each sensory system. This in turn projects to the cortex, although the olfactory pathway primarily projects to limbic structures and the muscle spindle to the cerebellum.

Each sensory system has its own area of cortex that is primarily concerned with analysing the sensory information and this area of cortex – the primary sensory area – is connected to adjacent cortical areas that perform more complex sensory processing (secondary sensory areas). This in turn projects into the association areas (posterior parietal, prefrontal and temporal cortices) which then project to the motor and limbic systems. These latter areas are more involved in the processing of sensory information as a cue for moving and generating complex behavioural responses.

The primary sensory cortical areas project also subcortically to their thalamic (and/or brainstem) projecting nuclei. This may be important in augmenting the detection of significant ascending sensory signals. This augmentation probably involves at least two major processes: lateral inhibition and feature detection. Lateral inhibition is a process by which those cells and axons with the greatest activity are highlighted by the inhibition of adjacent less active ones, which produces greater contrast in the afferent information. Feature detection, on the other hand, corresponds to the
selective detection of given features of a sensory stimulus, which can occur at any level from the receptor to the cortex.

Did you know?

The first sense to develop while in utero is the sense of touch and it begins in the face at around 8 weeks of age.

Sensory transduction

Sensory transduction involves the conversion of a stimulus from the external or internal environment into an electrical signal for transmission through the nervous system. This process is performed by all sensory systems and in general involves either:

a chemical process in the retina, tongue or olfactory epithelium;
or
a mechanical process in the cochlea and somatosensory systems. These contrasting modes of transduction are best characterized in some of the special senses.

Phototransduction

Phototransduction is the process by which light energy in the form of photons is translated into electrical energy in the form of potential changes in the photoreceptors (rods and cones) in the retina.
The following sequence of events defines it:

Photons are captured in pigments in the photoreceptor outer segment.
This results in an amplification process using the G-protein, transducin and cyclic guanosine monophosphate (cGMP) as the secondary messenger.
This causes a reduction in cGMP concentrations which leads to channel closure.
The closure of these channels, which allows Na+ and Ca2+ to enter the photoreceptor in the dark, leads to a hyperpolarization response, the degree of which is graded according to the number of photons captured by the photoreceptor pigment.

The hyperpolarization response leads to reduced glutamate release by the photoreceptor on to bipolar and horizontal cells. The termination of the photoreceptor response to a continuous unvarying light stimulus is multifactorial, but changes in intracellular Ca2+ concentration are important. The light insensitive
Ca2+ pump in the outer segment coupled to the closure of the cation channel leads to a significant reduction in intracellular Ca2+ concentrations which is important in terminating the photoreceptor response as well as mediating light (or background) adaptation.

A number of rare congenital forms of night blindness have now been associated with specific deficits within the phototransduction pathway.

Olfactory transduction

Olfactory transduction is similarly a chemically mediated process. The olfactory receptor cells are bipolar neurones consisting of a dendrite with a knob on which are found the cilia, and an axonal part that projects as the olfactory nerve to the olfactory bulb on the underside of the frontal lobe. The presence of cilia, which contain the olfactory receptors, greatly increases the surface area of the olfactory neuroepithelium and so increases the probability of trapping odorant molecules. The following sequence of events defines it:

The binding of the odorant molecule to the receptor leads to the activation of Golf.
This activates adenylate cyclase type III which hydrolyses adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP).
cAMP then binds to and activates specific cation channels, thus allowing Na+ and Ca2+ to influx down their concentration gradients.
This not only partly depolarizes the receptor, but also leads to the activation of a Ca2+-dependent Cl− channel and the subsequent Cl− efflux then further depolarizes the olfactory receptor.
There are probably additional transduction processes present in the olfactory receptor using inositol triphosphate as the secondary messenger.
This can lead to the generation of action potentials at the cell body, which are then conducted down the olfactory nerve axons to the olfactory bulb.
The Ca2+ influx is also important in adaptation by resetting the transduction response.

Auditory transduction

In contrast to both phototransduction and olfactory transduction, the process of auditory transduction in the inner ear involves the mechanical displacement of stereocilia on the hair cells of the cochlea. The following sequence of events defines it:

The sensory stimulus, a sound wave, causes displacement of the stapedial foot process in the oval window which generates waves in the perilymphatic filled scala vestibuli and tympani of the cochlea.
This leads to displacement of the basilar membrane on which the hair cells are to be found in the organ of Corti. These cells transduce the sound waves into an electrical response by a process of mechanotransduction. The stereocilia at the apical end of the hair cell are linked by tip links, which are attached to ion channels.
The sound causes the stereocilia to be displaced in the direction of the largest stereocilia (or kinocilium) which creates tension within the tip links which then pull open an ion channel.
This ion channel then allows K+ (not Na+, as the endolymph within the scala media is rich in K+ and low in Na+) and Ca2+ to flow into the hair cell and by so doing depolarizes it.
This depolarization leads to the release of neurotransmitter at the base of the hair cell which activates the afferent fibres of the cochlear nerve.

The continued displacement of the stereocilia in response to a sound is countered by a process of adaptation with a repositioning of the ion channel such that it is now shut in response to that degree of tip link tension. This is achieved by the influx of Ca2+ through the ion transduction channels which leads via actin– myosin in the stereocilia to a new repositioning of the ion channel.

A number of syndromes with congenital deafness have now been identified as being caused by abnormalities in the myosin found in hair cells.

Did you know?

In an experiment performed in 1942, it was established that on average, an individual rod was sensitive to a single photon!

Visual system I: the eye and retina

The visual system is responsible for converting all incident light energy into a visual image of the world. This information is coded for in the retina which lies at the back of the eye, and transmits that information to the visual cortical areas, the hypothalamus and upper brainstem.

Optical properties of the eye

On reaching the eye, light has to be precisely focused on to the retina, and this process of refraction is dependent on the curvature of the cornea and the axial length of the eye. Failure to do this accurately leads to an inability either to see clearly when reading (long-sightedness or hypermetropia), or to see distant objects clearly (short-sightedness or myopia), or both. In the latter case there is often an additional problem of astigmatism, in which the refraction
of the eye varies in different meridians.

In addition to the need to be refracted precisely on to the retina, light must also be transmitted without any loss of quality and this relies on the cornea, anterior and posterior chambers and lens all being clear. Injuries or disease of any of these components can lead to a reduced visual acuity (the ability to discriminate detail). The most common conditions affecting these parts of the eye are infections and damage to the cornea (keratitis) or opacification of the
lens (cataracts).

Retinal anatomy and function

Photoreceptors

The light on striking the retina is transduced into electrical signals by the photoreceptors that lie on the innermost layer of the retina, furthest from the vitreous humour. There are two main types of photoreceptors: rods and cones.

Rods: The rods are found in all areas of the retina, except the fovea; they are sensitive to low levels of light and are thus responsible for our vision at night (scotopic vision). Many rods relay their information to a single ganglion cell, and so this system is sensitive to absolute levels of illumination while not being capable of discriminating
fine visual detail and colour. Thus, at night we can detect objects but not in any detail or colour.
Cones: The cones are found at highest density in the fovea and contain one of three different photopigments. They are responsible for our daytime or photopic vision. This, coupled to the high density of these receptors at the fovea, where they have an almost one-to-one relationship with ganglion cells, means that they are the receptors responsible for visual acuity and colour vision. Alterations in the photopigments contained within these receptors leads to colour blindness. Diseases of the receptors leading to their death, such as retinitis pigmentosa, lead to a progressive loss of vision that typically affects the peripheral retina and rods in the early stages, resulting in night blindness and constricted visual fields, although with time the disease process can spread to affect the cones.

Horizontal cells

The photoreceptors make synapses with both horizontal and bipolar cells. The horizontal cells have two major roles: (i)
they create the centre surround organization of the receptive field of the bipolar cell; and (ii) they are responsible for shifting the spectral sensitivity of the bipolar cell to match the level of background illumination (part of the light adaptation response.

The centre surround receptive field means that a bipolar cell will respond to a small spot of light in the middle of its receptive field in one way (depolarization or hyperpolarization), while an annulus or ring of light around that central spot of light will produce an opposite response. The horizontal cells, by receiving inputs from many receptors and synapsing onto the photoreceptor bipolar cell, can provide the necessary information for this receptive field to be
generated. The mechanism by which they fulfil their other role in light adaptation is not fully understood.

Bipolar cells

The bipolar cells relay information from the photoreceptors to the ganglion cells and receive synapses from photoreceptors, horizontal and amacrine cells. They can be classified according to the receptor they receive from (cone only, rod only, or both) or their response to light. Bipolar cells that are hyperpolarized by a small spot of light in the centre of their receptive fields are termed off-centre (on-surround) while the converse is true for those bipolar cells that are depolarized by a small spot of light in the centre of their receptive field.

Ganglion cells

The ganglion cells are found closest to the vitreous humour; they receive information from both bipolar and amacrine cells and send their axons to the brain via the optic nerve. These nerve fibres course over the inner surface of the retina before leaving at a site which forms the optic disc and which is responsible for the blind spot as no receptors are located at this site. This blind spot is not usually apparent in normal vision. The ganglion cells can be classified in a number of different ways: according to their morphology; their response to light as for bipolar cells (‘on’ or ‘off’ centre);
or a combination of these properties (the XYW system in cats or the M and P channels in primates). The X ganglion cells, which make up 80% of the retinal ganglion cell population, are involved in the analysis of detail and colour while the Y ganglion cells are more involved in motion detection. The W ganglion cells, which make up the remaining 10% of the population, project to the brainstem, but as yet have no clearly defined function. The X and Y ganglion cell system defined initially in cats is equivalent to the P and M channel in primates, which is broadly responsible for ‘form’ and ‘movement’ coding, respectively. In addition, there is a small population of ganglion cells that contain a protein called
melanopsin, which allows them to detect light independently of photoreceptors. These ganglion cells project to multiple sites within the central nervous system, especially the suprachiasmatic nucleus of the hypothalamus.

Amacrine cells

The amacrine cells of the retina, which make up the final class of retinal cells, receive and relay signals from and to bipolar, other amacrine and ganglion cells. There are many different types of amacrine cells, some of which are exclusively related to rods and others to cones, and they contain a number of different transmitters. They tend to have complex responses to light stimuli and are important in generating many of the response properties of ganglion cells, including the detection and coding of moving objects and the onset and offset of illumination.

Did you know?

The octopus has no blind spot as its retina is everted such that the photoreceptors lie directly behind the lens.

Visual system II: the visual pathways and subcortical visual areas

The retina conveys its information from the ganglion cells to a number of different sites, including:

several cortical areas, via the lateral geniculate nucleus (LGN) of the thalamus to the primary visual cortex (V1 or Brodmann’s area 17). Other cortical areas (known collectively as the extrastriate areas) receive information from the LGN as well as the pulvinar region of the thalamus;
the hypothalamus;
the midbrain.

The projection from the retina to V1 maintains its retinotopic organization, such that a lesion along the course of the pathway produces a predictable visual field defect. Lesions in front of the optic chiasm typically produce uniocular field defects, while lesions of the chiasm (e.g. from pituitary tumours) cause a bitemporal
hemianopia. Lesions behind the chiasm typically produce similar field defects in both eyes, e.g. a homonymous hemianopia or quadrantanopia.

Lateral geniculate nucleus

The LGN consists of six layers in primates, with each layer receiving an input from either the ipsilateral or contralateral eye.
The inner two with their large neurones form the magnocellular laminae while the remaining four layers constitute the parvocellular laminae. The morphological distinction between the neurones in these two laminae is also evident electrophysiologically.
The parvocellular neurones display chromatic or colour sensitivity and sensitivity to high spatial frequency (detail) with sustained responses to visual stimuli. In contrast, the magnocellular neurones show no colour selectivity, respond best to low spatial frequencies and often have a transient response on being stimulated.
Thus, the magnocellular layer neurones have similar properties to the Y ganglion cells and the parvocellular neurones to the X ganglion cells, a similarity that is reflected in the retinogeniculate projection of these two classes of ganglion cells. The X ganglion cells and the parvocellular laminae neurones are responsible for the detection of colour and form (or Pattern) and constitute the P channel, while the M channel of the Y ganglion cells and the
magnocellular laminae of the LGN are responsible primarily for motion detection (or Movement).
The LGN mainly projects to V1, where the afferent fibres synapse in layer IV, and to a lesser extent layer VI, with the M and P channels having different synaptic targets within these laminae. In addition, there is a projection from cells that lie between the laminae of the LGN (intralaminar part of the LGN) directly to layers II and III of V1.

Superior colliculi

The superior colliculus in the midbrain is a multilayered structure, wherein the superficial layers are involved in mapping the visual field and the deep layers with complex sensory integration involving visual, auditory and somatosensory stimuli. The intermediate layers are involved in saccadic eye movements and receive connections
from the occipitoparietal cortex, the frontal eye fields and the substantia nigra. The saccadic eye movements are mapped in the superior colliculus to the visual field representation. So stimulation in this structure will cause a saccadic eye movement that brings the point of fixation to that point in the visual field that is represented in the more superficial layers of this structure. In the superior colliculus all the different sensorimotor representations lie in register. In other words, a vertical descent through this structure encounters, in the following order:

neurones that respond to visual stimuli in a given part of the visual field;
neurones that cause saccadic eye movements that bring the fovea to bear onto that same part of the visual scene;
auditory and somatosensory neurones that are maximally activated by sounds that originate from that part of the visual environment and by areas of skin that would most likely be activated by a physical contact with an object located in that part of the extra-personal space. This latter feature accounts for the fact that in the superior colliculus the somatosensory representation is primarily skewed towards the nose and face.

Thus, the superior colliculus not only codes for saccades, but tends to code specifically for those saccades that are triggered by stimuli of immediate behavioural significance as well as having a more widespread function in orienting responses. This role for the superior colliculus is reflected in its efferent connections to a number of brainstem structures as well as the spinal cord (tectospinal tract). Clinically, damage is rarely confined to this structure, but when it is, there is a profound loss of saccadic eye movements with neglect.

Pretectal structures and the pupillary response to light

There is a projection from the optic tract to the pretectal nuclei of the midbrain which in turn projects bilaterally to the Edinger– Westphal nucleus, which provides the parasympathetic input to the pupil allowing it to constrict.

Light shone in one eye will cause constriction of both pupils (direct and consensual response).
Damage to one of the optic nerves will cause a reduced direct and consensual response but that same eye will constrict normally to light shone in the unaffected eye, producing a relative afferent pupillary defect.

Suprachiasmatic nucleus of the hypothalamus

This nucleus receives a direct retinal input and is important in the generation and coordination of circadian rhythms.

Did you know?

Palinopsia is a rare condition which refers to the delayed persistence of a visual image in the absence of its original stimulus and is usually associated with a lesion in the visual cortical association areas.

Visual system III: visual cortical areas

Primary visual cortex (V1 or Brodmann’s area 17)

The primary visual cortex (V1) lies along the calcarine fissure of the occipital lobe and receives its major input from the lateral geniculate nucleus (LGN).

These connections are organized retinotopically so that adjacent areas of the retina project up the visual pathway via neighbouring axons. However, this retinal projection is not a simple map, as the critical factor is the relationship of the photoreceptors to the projecting ganglion cell of the retina. This means that the centre of vision (especially the fovea) dominates the retinal projection to V1 because of the near one-to-one relationship of photoreceptor to
ganglion cell at the fovea in contrast to the peripheral retina.
The LGN projection to V1 is mainly to layer IV and is different for the M and P channels, while the projection from the intralaminar part of the LGN is to layers II and III of V1 (see below).
The LGN input to layer IV of V1 is so large that this cortical layer is further subdivided into IVa, IVb, IVc and IVc”, with each subdivision having slightly different connections. In general, however, the cortical neurones in layer IVc of V1 have centre surround or circular symmetrical receptive field organization. These layer IVc neurones then project to other adjacent neurones within the cortex, in such a way that several neurones of this type converge onto a single neurone, whose receptive field is now more complex in terms of the optimal activating stimulus.
These cells respond most effectively to a line or bar of illumination of a given orientation and are termed simple cells. These cells in turn project in a convergent fashion onto other neurones (complex cells), which are predominantly found in layers II and III, and which are maximally activated by stimuli of a given orientation
moving in a particular direction. This direction is often orthogonal to the line orientation.
The complex cells project to the hypercomplex or end-stopped cells, which respond to a line of a given orientation and length. This series of cells originally described by Hubel and Wiesel is thus organized in a hierarchical fashion, with each cell deriving its receptive field from the cells immediately beneath it in the hierarchy.

The Hubel and Wiesel model

Hubel and Wiesel further discovered that these neurones were organized into columns of cells with similar properties; the two properties that they originally studied being the eye that provides the dominant input to that neurone (giving ocular dominance columns) and the orientation of the line needed to activate neurones maximally (giving orientation selective columns).

They represented these two sets of columns as running orthogonally to each other, with the area of cortex containing an ocular dominance column from each eye with a complete set of orientation selective columns being termed the hypercolumn.

This hypercolumn, which is 1 mm2 in size, is capable of analysing a given section of the visual field that is defined by the corresponding retinal inputs from both eyes. In the case of the fovea, where there is near unity of photoreceptors to ganglion cells, this visual field is very small, while the converse is true for more peripheral retinal inputs. Therefore a shift of 1 mm in the cortex from one hypercolumn to another leads to a shift in the location of the visual field being analysed, with most of these being concerned with foveal vision (see below).

However, there are two main complicating factors with this model:

the accommodation of the M and P channels;
the discovery of cytochrome oxidase (a marker of metabolic activity) – rich areas in layers II, III and IVb (and, to a lesser extent, layers V and VI), which show no orientation selectivity but colour and high spatial frequency sensitivity.

These cytochrome oxidase-rich areas in layers II and III are grouped together to form blobs, at least one of which is associated with each ocular dominance column, with the areas between them being termed interblobs. Both the blobs and interblobs, together with the cytochrome-rich layer IVb, have distinct projections to V2 and other extrastriate areas – projections that correlate well with the M and P channels. This arrangement of channels and connections suggests that visual information is processed not so much in a hierarchical fashion, but by a series of parallel pathways.

Functions of V1

The major function of V1, apart from being the first site of binocular interactions, is to deconstruct the visual field into small line segments of various orientation as well as segregating and integrating components of the visual image, which can then be relayed to more specialised visual areas. These areas perform more complex visual analysis but rely on their interaction with V1 for the conscious perception of the whole visual image. This occasionally presents itself clinically in patients with bilateral damage to V1, in which they deny being able to see any visual stimulus even though
on formal testing they are capable of localizing visual targets accurately (a phenomenon known as blindsight).

Visual association or extrastriate areas

The extrastriate areas are those cortical areas outside V1 that are primarily involved in visual processing. The number of such areas varies from species to species, with the greatest number being found in humans. These areas are found within Brodmann’s areas 18 and 19 and the inferotemporal cortex. They are involved in more complex visual processing than V1, with one aspect of the visual scene tending to be dominant in terms of the analysis undertaken by that cortical area (e.g. colour or motion detection). In general, damage to these areas tends to produce complex visual deficits, such as the ability to recognize objects visually (visual agnosia) or selective attributes of the image such as colour (central
achromatopsia) or motion. In addition, a number of other parts of the central nervous system are associated with the visual system including the posterior parietal cortex; the frontal cortex and frontal eye fields; and the subcortical structures of the hypothalamus and upper brainstem.

Often these projections are grouped together into a ventral stream which passes through the temporal lobe and is important in object recognition and a dorsal stream passing through the parietal lobe that is more concerned with object location.

Did you know?

People born blind have a large amount of inborn visual data stored in their brains. Depth perception is a good example of this, as an image from a single eye carries plenty of three-dimensional information about the objects contained within it.

Auditory system I: the ear and cochlea

The auditory system is responsible for sound perception. The receptive end-organ is the cochlea of the inner ear, which converts sound waves into electrical signals by mechanotransduction. The electrical signal generated in response to a sound is passed (together with information from the vestibular system, via the eighth cranial nerve (vestibulocochlear nerve) to the brainstem where it synapses in the cochlear nuclear complex.

Although the auditory system as a whole performs many functions, the primary site responsible for frequency discrimination is at the level of the cochlea.

Properties of sound waves

A sound wave is characterized by:

amplitude or loudness (measured in decibels [dB]);
frequency or pitch (measured in hertz [Hz]);
waveform;
phase and
quality or timbre.

The intensity of sound can vary enormously but in general we can discriminate changes in intensity of around 1–2 dB. The arrival of a sound at the head creates phase and intensity differences between the two ears unless the sound originates from the midline. The degree of delay and intensity change between the two ears as a result of their physical separation is useful but probably not necessary for the localization of sounds.

External and middle ear

On reaching the ear the sound passes down the external auditory meatus to the tympanic membrane or eardrum, which vibrates at a frequency and strength determined by the impinging sound. This causes the three ear ossicles in the middle ear to move, displacing fluid within the cochlea as the stapedial foot process moves within the oval window of the cochlea. This process is essential in reducing the acoustic impedance of the system and in enhancing the
response to sound, because a sound hitting a fluid directly is largely reflected.

There are two small muscles associated with the ear ossicles, which protect them from damage by loud noises as well as modifying the movement of the stapedial foot process in the oval window. Damage to the ear ossicles (e.g. otosclerosis), middle ear (e.g. infection or otitis media) or external auditory meatus (e.g. blockage by wax) all lead to a reduction in hearing or deafness that is conductive in nature.

Inner ear and cochlea

The displacement of the stapedial foot process in the oval window generates waves in the perilymph-filled scala vestibuli and tympani of the cochlea. These two scalae are in communication at the apical end of the cochlea, the helicotrema, but are separated for the rest of their length by the scala media, which contains the transduction
apparatus in the organ of Corti.

The organ of Corti sits on the floor of the scala media on a structure known as the basilar membrane (BM), the width of which increases with distance from the stapedial end. This increase in width coupled to a decrease in stiffness of the BM means that sounds of high frequency maximally displace the BM at the stapedial end of the cochlea while low-frequency sounds maximally activate the apical end of the BM. Thus, frequency tuning is, in part, a function of the BM although it is greatly enhanced and made more selective by the hair cells of the organ of Corti that lie on this membrane.

The organ of Corti is a complex structure that contains the cells of auditory transduction, the hair cells, which are of two types in this structure:

a single row of inner hair cells (IHCs) – which provide most of the signal in the eighth cranial nerve;
3–4 rows of outer hair cells (OHCs) – which have a role in modulating the response of IHCs to a given sound.
These two types of hair cell are morphologically and electrophysi-ologically distinct:
While the IHCs receive little input from the brainstem, the OHCs do so from the superior olivary complex, which has the effect of modifying the shape and response properties of these cells.
Some of the OHCs make direct contact with the overlying tectorial membrane (TM) in the organ of Corti which may be important in modifying the response of the IHCs to sound, as these cells do not contact the TM but provide 93% of the afferent input of the cochlear nerve.
One afferent fibre receives from many OHCs, but a single IHC is associated with many afferent fibres.
In addition to these differences between OHCs and IHCs, there are subtle alterations in the hair cells themselves with distance along the scala media. These alterations in shape modify their tuning characteristics, which adds a degree of refinement to frequency tuning beyond that imparted by the resonance properties of the BM.

Deafness

Damage to the cochlea, hair cells or cochlear part of the vestibulocochlear nerve leads to deafness that is described as being sensorineural in nature. Trauma, ischaemia and tumours of the eighth cranial nerve can lead to this. Certain hereditary causes of deafness have been associated recently with defects in the proteins found in the stereocilia of hair cells.

Did you know?

Eating too much can actually reduce your ability to hear.

Auditory system II: auditory pathways and language

The vestibulocochlear or eighth cranial nerve transmits information from both the cochlea and vestibular apparatus. Each fibre of the cochlear nerve is selectively tuned to a characteristic frequency, which is determined by its site of origin within the cochlea. These fibres are then arranged according to the location of their innervating hair cells along the basilar membrane (BM), and this tonotopic organization is maintained throughout the auditory pathway.

On entering the brainstem the cochlear nerve synapses in the cochlear nuclear complex of the medulla.

Auditory pathways

The cochlear nucleus is divided into a ventral (VCN) and dorsal (DCN) part. The VCN projects to the superior olivary complex (SOC) bilaterally. The DCN projects via the dorsal acoustic striae to the contralateral nucleus of the lateral lemniscus and inferior colliculus.
The SOC contains spindle-shaped neurones with a lateral and medial dendrite, which receive an input from each ear. It is the first site of binaural interactions and so is important in sound localization. In the medial part of the SOC this input is excitatory from each ear (EE cells) whereas in the lateral SOC the neurones have an excitatory input from one ear and an inhibitory input from the other (EI cells).
The EE cells by virtue of their input are important in the localization of sounds of low frequency (<1.4 kHz) where the critical factor is the delay (Δt) in the sound reaching one and then the other ear. One possible arrangement relies on the differential localization of the synaptic inputs to a single SOC neurone from the two ears.
The EI cells are important in the localization of higher frequency sounds where the difference in intensity (ΔI) of sound between the two ears is important (ΔI being generated as a result of the head acting as a shield). Sounds of frequencies greater than 1.4 kHz (in the case of humans) rely on ΔI for localization. In the case of sounds originating in the midline, there will be no Δt and no ΔI, and there is some confusion in localization which can be overcome to some extent by moving the head or using other sensory cues.
The localization of sound within the vertical plane is dependent in some way on the pinna.
The SOC not only projects rostrally to the inferior colliculus (IC), but also has an important input to the cochlea where it primarily controls the OHCs and by so doing the response properties of the organ of Corti (see Chapter 27). The projection to the IC is tonotopic, and this structure also receives an input from the primary auditory cortex (A1) and other sensory modalities. In this respect it interacts with the superior colliculus and is involved in the orienting response to novel audiovisual stimuli.
The IC projects to the medial geniculate nucleus of the thalamus (MGN), which projects to the A1 in the superior temporal gyrus. This area corresponds to Brodmann’s areas 41 and 42, with the thalamic afferent input synapsing in layers III and IV of the cortex. The columnar organization of A1 is poorly defined, but the tonotopic map is maintained so that low-frequency sounds are located posteriorly and high-frequency sounds anteriorly.

Language

Language is organized in the dominant, typically left hemisphere and is best developed and most studied in the human brain.

The localization and network subserving language is controversial as much of the early work used lesion studies, which of late has been refined using functional imaging studies.
Language dysfunction typically occurs in the context of stroke but can be affected in isolation in some neurodegenerative conditions – such as primary progressive aphasia.
Developmentally abnormalities in language can occur in isolation or be part of a more widespread problem such as autism, learning disabilities, and importantly can also be seen with hearing problems.

Did you know?

Children who learn two languages before the age of 5 years have altered brain structure while adults who do this have more dense grey matter.

Vestibular system

The vestibular system is concerned with balance, postural reflexes and eye movements, and is one of the oldest systems of the brain. It consists of a peripheral transducer component which projects to the brainstem (including the oculomotor nuclei), and from there to the thalamus and sensory cortex as well as to the cerebellum and spinal cord. Disruption to the system (e.g., vestibular neuronitis/labyrinthitis) results in the symptoms of dizziness, vertigo,
nausea with or without blurred vision with signs of eye movement abnormalities (typically nystagmus) and unsteadiness. In the comatose patient, clinical testing of the vestibular system can provide useful information on the integrity of the brainstem, as it is associated with a number of primitive brainstem reflexes.

Vestibular transduction

The peripheral transducer component consists of the: labyrinth, which is made up of two otolith organs (the utricle and the sacculus) together with the ampullae located in the three semicircular canals. The otolith organs are primarily concerned with static head position and linear acceleration while the semicircular canals are more concerned with rotational (angular) acceleration of the head.

Hair cells are found in both the otolith organs and the ampullae and are similar in structure to those found in the cochlea. As in the cochlea, deflection of the stereocilia towards the kinocilium depolarizes the cell and allows transmitter to be released from the hair cell, leading to activation of the associated afferent fibre. The converse is true if the stereocilia are deflected in the opposite direction.

Movement of the cilia is associated with rotational movement of the head (ampullae receptors in the semicircular canals) and acceleration or tilting of the head (otolith organs in utricle), as although head movement causes the endolymph bathing the hair cells to move, it ‘lags behind’ and so distorts the stereocilia.

Spontaneous activity in the afferent fibres is high, reflecting the spontaneous leakage of transmitter from the cell at the synapse. Hyperpolarization of the hair cell therefore results in a reduced afferent discharge, while depolarization is associated with an increase in firing. Efferent fibres from the brainstem terminating on the hair cells can change the sensitivity of the receptor end-organ.

Peripheral disorders of the vestibular system

Damage to the peripheral vestibular system is not uncommon. Examples include:

Benign paroxysmal positional vertigo (BPPV) commonly occurs after trauma or infection of the vestibular apparatus with the deposition of debris (e.g. otolith crystals or otoconia) typically in the posterior semicircular canal. This condition, which is characterized by paroxysms of vertigo, nausea and ataxia induced by turning the head into certain positions (such as lying down or rolling over in bed), is therefore the consequence of distortion of
endolymph flow in this canal secondary to the debris. It is diagnosed using Hallpike’s manoeuvre, which seeks to manipulate the head in such a way as to provoke the episode of vertigo. Treatment and cure can be effective by undertaking a series of head manoeuvres (classically Epley’s manoeuvre), which allows the debris to fall out of the semicircular canal and into the ampullae.
Viral infections of the vestibular apparatus are common (labyrinthitis) and can be severely disabling with profound dizziness and vomiting without any head movement. Such infections are usually self-limiting.
Bilateral failure of the vestibular apparatus can result in oscillopsia, a symptom describing an inability to visually fixate on objects especially with head movements. In contrast, powerful excitation of the vestibular system, such as that encountered during motion sickness produces dizziness, vomiting, sweating and tachycardia, caused by discrepancies between vestibular and visual information.

Vestibular function can be tested by introducing water into the external meatus (caloric testing).
When warm water is applied to a seated subject whose head is tilted back by about 60°, nystagmus towards the treated side is observed.

Cold water produces nystagmus towards the opposite side. These effects reflect the changes in the temperature of the endolymph and an effect resembling head rotation away from the irrigated side.

Central vestibular system and vestibular reflexes

Afferent vestibular fibres in the eighth cranial nerve have their cell bodies in the vestibular (Scarpa’s) ganglion and terminate in one of the four vestibular nuclei in the medulla, which also receive inputs from neck muscle receptors and the visual system.

The vestibular nuclei project to:

the spinal cord;
the contralateral vestibular nuclei;
the cerebellum;
the oculomotor nuclei;
and the ipsilateral and contralateral thalamus.

Some of these structures are important in reflex eye movements, such as the ability to maintain visual fixation while moving the head – the vestibulo-ocular reflex (VOR). Other projections of the vestibular nuclei are important in maintaining posture and gait. The cortical termination of the vestibular input to the CNS is the primary somatosensory cortex (SmI) and the posterior parietal cortex. Very rarely, epileptic seizures can originate in this area and give symptoms of vestibular disturbance.

Disorders of central vestibular pathways

Caloric testing of the vestibular system examines the integrity of the vestibular apparatus and its brainstem connections. Therefore, it can be useful in comatosed patients when the degree of brainstem function needs to be ascertained. Less severe central damage to the vestibular apparatus can occur in a number of conditions
including multiple sclerosis and vascular insults. In most cases other structures are involved and so there are other symptoms and signs on examination.

Did you know?

The vestibular system in man can detect changes in head orientation of as little as of 0.5° from the upright.

Olfaction and taste

The olfactory or first cranial nerve contains more fibres than any other sensory nerve projecting to the CNS, while taste is relayed via the seventh, ninth and tenth cranial nerves.

Olfaction

The olfactory system as a whole is able to discriminate a great diversity of different chemical stimuli or odours, and this is made possible through thousands of different olfactory receptors. These receptors are located in the apical dendrite of the olfactory receptor cell and the axon of this cell projects directly into the central nervous system (CNS) via the cribriform plate at the top of the nose to the olfactory bulb.

The olfactory stimulus or odour, on binding to the olfactory receptor, depolarizes it (see Chapter 23) which, if sufficient, leads to the generation of action potentials at the cell body which are then conducted down the olfactory nerve axons to the olfactory bulb.

The olfactory nerve passes through the roof of the nose through a bone known as the cribriform plate. Damage to this structure (e.g. head trauma) can shear the olfactory nerve axons causing a loss of smell or anosmia, although the most common cause of a loss of smell is local trouble within the nose, usually infection and inflammation. The olfactory receptor axons then synapse in the olfactory bulb that lies at the base of the frontal lobe. Damage to this structure, as occurs in frontal meningiomas, produces anosmia that can be unilateral.

The olfactory bulb contains a complex arrangement of cells. The axons from the olfactory nerve synapse on the apical dendrites of mitral and, to a lesser extent, tufted cells, both of which project out of the olfactory bulb as the olfactory tract. The olfactory bulb contains a number of inhibitory interneurones (granule and periglomerular cells), which are important in modifying the flow of olfactory information through the bulb. Some of these neurones are replaced throughout life, with the neural precursor cells for them originating in the subventricular zone and then migrating to
the olfactory bulb via the rostral migratory stream, a structure that has been shown to exist in the adult mammalian brains including in humans. This system may be important in olfactory learning.

The olfactory tract projects to the temporal lobe where it synapses in the piriform cortex and limbic system, which projects to the hypothalamus. This projection is important in the behavioural effects of olfaction, which are perhaps more evident in other species. In humans, lesions in these structures rarely produce a pure anosmia, but activation of this area of the CNS as occurs in temporal lobe epilepsy is associated with the abnormal perception of smells (e.g. olfactory hallucinations).
The projection of the olfactory system to the thalamus is small and is mediated via the olfactory tubercle to the mediodorsal nucleus, which projects to the prefrontal cortex. The role of this pathway is not clear.

Taste

The taste or gustatory receptors are located in the tongue. They are clustered together in fungiform papillae with supportive stem cells; the latter dividing to replace damaged gustatory receptors. The apical surface of the gustatory receptor contains microvilli covered in mucus, which is generated by the neighbouring goblet cells. Any ingested compound can therefore reach the gustatory receptor; hydrophilic substances are dissolved in saliva while
lipophilic substances are dissolved in the mucus. Taste is traditionally classified according to four modalities – salt, sour, sweet and bitter – which correlate well with the different transduction processes that are now known to exist for these different tastes. A fifth taste (umami) has also recently been described.

Salt stimuli cause a direct depolarization of the gustatory receptors by virtue of the fact that Na+ passes through an amiloride-sensitive apical membrane channel. The depolarization leads to the release of neurotransmitter from the basal part of the cell which activates the afferent fibres in the relevant cranial nerve.
Sour stimuli, in contrast, probably achieve a similar effect by blocking apical voltage-dependent H+ channels.
Sweet stimuli bind to a receptor that activates the G protein, gustducin, which then through adenylate cyclase leads to cyclic adenosine monophosphate (cAMP) production. The rise in cAMP activates a protein kinase that phosphorylates and closes basolateral K+ channels and by so doing depolarizes the receptor.
Bitter stimuli similarly rely on receptor binding and G-protein activation. One pathway involves gustducin but, in this instance, it leads to activation of a cAMP phosphodiesterase, which reduces the level of cAMP (and so the phosphorylating protein kinase) leading to opening of the basolateral Ca2+ channels and so transmitter
release. An alternative pathway for both sweet and bitter tastes involves the activation of a phospholipase C and the production of inositol triphosphate (IP3) and diacylglycerol (DAG), which can release Ca2+ from internal stores within the receptor. The increased Ca2+ concentration promotes neurotransmitter release.

The receptors relay their information via the chorda tympani (anterior two-thirds of the tongue) and glossopharyngeal nerve (posterior third of the tongue) to the nucleus of the solitary tract in the medulla. The structure projects rostrally via the thalamus to the primary somatosensory cortex (SmI) and the insular cortex, with a possible additional projection to the hypothalamus and amygdala. Some patients with temporal lobe epilepsy have an aura of an abnormal taste in the mouth which may relate to ictal electrical activity within the temporal lobe.

Did you know?

It is possible for the human nose to identify and discriminate more than 50 000 smells.

Somatosensory system

The somatosensory system is the part of the nervous system that is involved in the processes of touch, pressure, proprioception (or joint position sense, pain and temperature perception.

Sensory receptors

The receptors for touch are specialized nerve endings located in the skin with their cell bodies in the dorsal root ganglia. They are found at particularly high density in the fingertips, while those for proprioception are found not only in the skin but also in the muscle and joints.

Skin receptors can best be characterized by their structure, location, receptive fields and speed of adaptation.

Type I receptors with very small, sharply demarcated receptive fields (Meissner’s corpuscles and Merkel’s discs) are packed in high density at the fingertips. In particular, Meissner’s corpuscles convey information about objects slipping or moving across the skin, while Merkel’s discs are more involved with fine touch (i.e. sensory detail).
In contrast, the rapidly adapting (RA) Pacinian corpuscles convey vibration perception as they quickly stop firing to continuous sensory stimulus.
The more slowly adapting (SA) Ruffini endings sense the magnitude, direction and rate of change of tension in the skin and deeper tissues (i.e. skin stretch).

Dorsal column–medial lemniscal pathway

The sensory receptors are specialized nerve endings and the fast conducting, large diameter axons associated with them are found in peripheral nerves and project into the dorsal horn of the spinal cord. The trigeminal sensory system for the face has a similar organization.

Each class of receptor has a specific pattern of passage through the dorsal horn, but all ultimately end up in the dorsal column (with the exception of the trigeminal system), where they are organized according to receptor type and body location (somatotopy). They then project ipsilaterally up to the dorsal column nuclei at the cervicomedullary junction (consisting of the gracile and cuneate nuclei), where they make their first synapse, although it should be understood that many dorsal column axons synapse at other spinal sites.

The dorsal column nuclei (DCN) are a complex series of structures that lie at the cervicomedullary junction and send axons which immediately decussate to form the medial lemniscus, which projects to the thalamus. The DCN also project to other brainstem structures, as well as receiving input from the primary somatosensory
cortex (SmI).
The medial lemniscus projects to the ventroposterior (VP) nucleus of the thalamus, connecting with the trigeminal system as it ascends. This latter projection synapses in the medial part of the VP nucleus (VPM) with the remainder of the tract terminating in the lateral nucleus (VPL). This medial lemniscal termination is in the form of an anteroposterior thalamic rod, where all the cells within the rod have a similar modality and peripheral location (e.g. index finger, RA type I receptors). The thalamic rod subsequently projects to layer IV of the SmI and forms the basis of the cortical column.
The SmI consists of four different areas (Brodmann’s areas 3a, 3b, 1 and 2), each of which has a separate representation of the contralateral body surface, with the tongue being represented laterally and the feet medially. The cortical representation is proportional to the receptor density in the skin so, for example, the hand has a much greater representation than the trunk (the sensory homunculus).

Primary and secondary sensory cortices

Each cortical area within SmI has slightly different response properties with respect to the neurones found in these areas. As one moves towards the posterior parietal cortex the response properties of the neurones become more complex, implying a higher level of cortical analysis. SmI projects not only back to the dorsal column nuclei but to the posterior parietal cortex and second somatosensory area (SmII). This latter area is found in the lateral wall of the Sylvian sulcus and is important in tactile object recognition, while the posterior parietal cortex input from SmI is
important in the attribution of significance to a sensory stimulus.

The primary somatosensory pathway has developed during evolution with the corticospinal tract (CoST), which has a selective role in the control of fine finger movements. These two systems act together in the process of ‘active touch’ by which we explore our environment. Both systems display a degree of plasticity even in adult life. This is in part made possible by somatotopic organization of the sensory pathway: adjacent areas of skin are represented in neighbouring parts of the sensory system, at least as far as SmI.

Clinical disorders of the somatosensory system

Damage to the receptors and their afferent fibres can occur in a large number of peripheral neuropathies. Patients typically complain of both paraesthesiae and numbness, often in association with alterations in proprioception especially if the dorsal root ganglion is involved.

Damage to the somatosensory pathway above the level of the DCN produces a contralateral sensory loss that will involve the face if the lesion lies at or above the level of the upper brainstem.

Did you know?

Tickling involves both pain and touch fibres. You tickle mostly because of surprise. Even if you know you are about to be tickled, you do not necessarily know where, so you react by being ticklish. When you try to tickle yourself, it usually does not work because your brain already knows how you are going to do it. In other words, you cannot tickle yourself because you cannot surprise yourself.

Pain systems I: nociceptors and nociceptive pathways

Pain is defined as an unpleasant sensory or emotional experience associated with actual or potential tissue damage. Much of what is known about pain mechanisms has derived from animal-based research where the affective component is unclear. For this reason neuroscientists prefer to use the term nociception, which defines the
processing of information about damaging stimuli up to the point where perception occurs. This is an important distinction because tissue damage is not inevitably linked to pain and vice versa.

Nociceptors

Nociceptors are found in the skin, visceral organs, skeletal and cardiac muscle and in association with blood vessels. They conduct information about noxious events to the dorsal horn of the spinal cord where the primary afferents synapse.

There are basically two types of nociceptor, distinguished by the diameter of the afferent fibre and the stimulus required to activate it.

The high-threshold mechanoreceptor (HTM) is activated by intense mechanical stimulation and innervated by thinly myelinated Aδ fibres conducting at 5–30 m/s.
Polymodal nociceptors (PMN) respond to intense mechanical stimulation, temperatures in excess of about 42 °C and irritant chemicals. These receptors are innervated by unmyelinated C fibres conducting at 0.5–2 m/s.

Sharply localized pain is thought to be conducted in the faster conducting fibres whereas poorly localized pain is conducted in the C fibres.

Although nociceptors are histologically simple free nerve endings, the process of transduction at the receptor ending is complex and is associated with some of the chemical mediators of inflammation and tissue damage. Thus, adenosine triphosphate (ATP), bradykinin, histamine and prostaglandins all either activate or sensitize the receptor ending. Indeed, some of the transmitters in the nociceptive pathway are themselves released peripherally (e.g. substance P) to produce further sensitization of the receptor ending. Nociceptor receptor sensitization helps explain the perception of heightened pain (primary hyperalgesia) in areas of tissue damage and is essentially a peripheral phenomenon usually of relatively short duration.

Chronic and referred pain

Pain that lasts many months is known as chronic pain. It is often disabling and resistant to treatment. It may arise following damage to either the peripheral or central nervous system or chronic inflammatory states (e.g. osteoarthritis). Changes in peripheral nociceptor sensitivity does not explain secondary hyperalgesia, in which light touch outside the immediate area of cutaneous damage can lead to pain.

A more serious problem associated with peripheral or central nerve damage is allodynia. In this condition light stroking of the skin can give rise to severe pain. Disturbed patterns of sensory input to the dorsal horn (e.g. following compression or sectioning of a peripheral nerve trunk) can lead to long-term changes in the processing of noxious information in the dorsal horn. At these sites, the arrival of axonally conducted substance P in the superficial
layers of the dorsal horn leads to both an increase in receptive field sizes and the sensitivity of some dorsal horn neurones. These functional changes are mediated in part by the synaptic release of glutamate acting on postsynaptic N-methyl-D-aspartate (NMDA) receptors and may contribute to some chronic pain states.

In addition, allodynia and secondary hyperalgesia are linked to increased activity in microglia and astrocytes, and the release of a number of agents (interleukin-1 and -6, tumour necrosis factor [TNF], nitric oxide [NO], ATP and prostaglandins).

Damage to peripheral nerve trunks can lead to complex regional pain syndrome (CPRS). One form is associated with disturbances to the sympathetic nervous system (SNS) (CRPS-1, of which reflex sympathetic dystrophy is an example). Severing a peripheral nerve trunk leads to the formation of a neuroma which acts as a generator of ectopic action potentials (ectopic foci) sending barrages of action potentials to the spinal cord. This activity is thought to explain the development of phantom limb pain with the neuroma being sensitive to both mechanical stimulation and SNS activity
(i.e. noradrenaline).

Visceral nociceptors project into the spinal cord via the small-diameter myelinated and unmyelinated fibres of the autonomic nervous system (ANS), and synapse at the spinal level of their embryological origin. The development of pain in an internal organ can therefore produce the perception of a painful stimulus in the skin rather than the organ itself, at least in the early stages of inflammation – a phenomenon known as referred pain. For example, inflammation of the appendix initially leads to pain being perceived at the umbilicus.

Nociceptive pathways

The majority of nociceptors and thermoreceptors project into the spinal cord via the dorsal root, although some pass through the ventral horn. On reaching the spinal cord these sensory nerves synapse in a complex fashion in the dorsal horn.

The postsynaptic cell conveying nociceptive information projects up the spinal cord as the spinothalamic, spinoreticulothalamic and spinomesencephalic tracts (latter not shown on figure), with the axons crossing at the spinal level by passing around the central canal of the cord. This crossing of fibres often occurs a few levels
above where the nociceptive fibres enter the cord, and thus damage in the region of the central canal as seen in syringomyelia results in a loss of pain and temperature sensibility.
The postsynaptic cell and presynaptic nociceptive nerve terminal receive synapses from other peripherally projecting somatosensory systems, descending projections from the brainstem and interneurones
intrinsic to the dorsal horn. Many of these interneurones contain endogenous opioid substances known as enkephalins and endorphins which activate opioid receptors of which there are three main subtypes (μ, κ, δ). There is therefore enormous potential for modifying the transfer of nociceptive information at the level of the dorsal horn.
The ascending nociceptive pathways synapse in a number of different central nervous system (CNS) sites. Information concerning noxious events ascends in either the spinothalamic tract (providing accurate localization) or the spinoreticulothalamic system (transmitting information concerning the affective components of pain).
However, some of the nuclei in the brainstem to which these pathways project (e.g. the raphé nucleus and locus coeruleus) in turn send axons back down the spinal cord to the dorsal horn, and can be exploited in the control of chronic pain syndromes.
The thalamic termination of the spinothalamic pathway is in the ventroposterior and intralaminar nuclei (IL) (including the posterior group), which in turn project to multiple cortical areas but especially the primary and secondary somatosensory area (SmI and SmII) and the anterior cingulate cortex. Lesions to any of these sites alter the perception of pain but do not produce a true and complete loss of pain or analgesia, and indeed may even
produce a chronic pain syndrome. Such syndromes are not uncommonly seen with small thalamic cerebrovascular accidents.

The thermoreceptors, and to a lesser extent the nociceptors, also project to the hypothalamus, which has an important role in thermoregulation and the autonomic response to a painful stimulus.

Did you know?

Men and women react differently to pain, which may explain why the two sexes discuss pain differently.

Pain systems II: pharmacology and management

The development of pain is a common experience and the treatment for it is important, not only where it is caused by injury or inflammation, but also in cases where the nerves themselves are damaged. In these latter cases the pain can arise from a site of previous injury (e.g. allodynia) or may develop for more obscure reasons, now renamed complex regional pain syndrome. In all cases, pain is both disabling and depressing, and a multidisciplinary approach to management is often needed. However, it should also be realized that some patients with affective disorders, such
as depression and anxiety, may complain of pain in the absence of any obvious tissue damage.

Management of pain

Pain relief or analgesia can be approached using a number of different strategies.

Site I

Many analgesic therapies work by reducing the peripheral inflammatory response, which is also responsible for receptor sensitization (site I on figure). Non-steroidal anti-inflammatory drugs (NSAIDs) are the most widely used analgesics. These drugs have analgesic, antipyretic and, at higher doses, anti-inflammatory actions. Aspirin was the first NSAID but has been largely replaced by drugs that are less toxic to the gastrointestinal tract, e.g. paracetamol,
ibuprofen, naproxen. NSAIDs produce their effects by inhibiting cyclo-oxygenase (COX), a key enzyme in the production
of prostaglandins (PGs). PGs are one of the mediators released at sites of inflammation. They do not themselves cause pain but they potentiate the pain caused by other mediators, e.g. bradykinin, 5-hydroxytryptamine (5-HT), histamine (site I on figure).

NSAIDs are not effective in the treatment of visceral pain, which usually requires opioid analgesics.

Site II

The interruption of peripheral nerve conduction by injection of local anaesthetics can be helpful in some pain states, but lesioning of the peripheral nerve is usually without effect in ameliorating neuropathic pain (site II), unless it is to remove a neuroma.

Site III

This site involves blocking aberrant sympathetic innervation/activation of peripheral nociceptors as occurs in some patients in response to nerve/limb injury (see below).

Sites IV–VII

The organization of the nociceptive input to the dorsal horn has been explored clinically in pain management. For example, stimulation of non-nociceptive receptors can inhibit the transmission of nociceptive information in the dorsal horn, which means that painful stimuli can be ‘gated’ out by counter-irritation using nonpainful stimuli. This is the basis of the gate theory of Wall and Melzack and is exploited clinically in the use of transcutaneous nerve stimulation (TENS) in areas of pain (site VI), as well as the stimulation of the dorsal columns themselves in some cases of chronic pain (site V).

Similarly, the supraspinal input can also gate out noxious stimuli when activated (site VII), as occurs in stressful situations, when attending to a painful stimulus would not necessarily be useful (e.g. war injuries). These supraspinal nuclei can also be manipulated pharmacologically, with the administration of drugs that are usually used in the treatment of depression. These antidepressant drugs with a presumed action at the noradrenergic and serotoninergic synapses have been used to treat pain states, irrespective of any antidepressant action they might have (site VII). The most commonly used agents are amine uptake inhibitors, such as imipramine and amitriptyline (tricyclic antidepressants). These agents appear to alter the pain threshold but are not without side effects.

Furthermore, the recognition that one of the major transmitters in the nociceptive pathway is substance P (SP) has led to the development of other analgesic medications. For example, capsaicin (the active ingredient of red chilli), which initially releases SP from nociceptors and subsequently inactivates the SP-containing C fibres, can be used topically in some pain syndromes such as postherpetic neuralgia. However, perhaps the most common exploitation of this system is the manipulation of the enkephalinergic interneurone and opioid receptors by the exogenous administration of morphine and its analogues to control pain (site IV).

Opioid analgesics are drugs that mimic endogenous opioid peptides by causing a prolonged activation of opioid receptors (usually μ-receptors). This reduces pain transmission at synapses in the dorsal horn of the spinal cord by an inhibitory action on the relay neurones. Opioids also stimulate noradrenergic, serotoninergic and enkephalinergic neurones in the brainstem that descend in the spinal cord and further inhibit the relay neurones of the spinothalamic
tract. Opioid analgesics are widely used to relieve dull, poorly localized (visceral) pain. Repeated doses can cause dependence so that the sudden termination of opioid analgesics may precipitate a withdrawal syndrome.

Morphine is the most widely used analgesic in severe pain but, like all strong opioids, may cause nausea and vomiting.
Diamorphine (heroin) is more lipid soluble than morphine and therefore has a more rapid onset of action when given by injection and is widely used for postoperative pain.
Fentanyl can be given transdermally in patients with chronic stabilized pain. The patches are very useful in patients with intractable nausea or vomiting when taking oral opioids.
Methadone has a long duration of action and is less sedative than morphine. It is given orally for the maintenance treatment of heroin or morphine addicts. The methadone prevents the ‘buzz’ of intravenous drugs and so reduces the point of taking them.
Buprenorphine is a partial agonist at the μ-receptors. It has a slow onset of action. It has a much longer duration of action than morphine (6–8 hours), but may cause prolonged vomiting.
Tramadol is a weak μ-agonist and its analgesic action is mainly a result of enhanced serotoninergic neurotransmission.
Codeine and dextropropoxyphene are weaker drugs used in mild to moderate pain.
Naloxone is an antagonist at opioid receptors and is used to reverse the effects of opioid overdose.

Although pain typically arises from tissue damage, it can also occur with damage to the peripheral and central nervous systems. One such example is trigeminal neuralgia. It can be treated surgically by lesioning of the appropriate nerve root, although most patients respond to the antiepileptic agent carbamazepine or gabapentin.

More recently there has been interest in using deep brain stimulation for managing some patients with chronic pain. Whether this works or not is currently unresolved. The main targets for the stimulator are motor cortical areas for reasons that are not clear.

Did you know?

Young people with aggressive behaviours that include inflicting pain on others demonstrate abnormal patterns of activation on functional magnetic resonance imaging (fMRI) when viewing others in pain.

Association cortices: the posterior parietal and prefrontal cortex

The association cortices are parts of the cerebral cortex that do not have a primary motor or sensory role, but instead are involved in the higher order processing of sensory information necessary for perception and movement initiation. These association areas include:

the posterior parietal cortex (PPC; defined in monkeys as corresponding to Brodmann’s areas 5 and 7, and in humans including areas 39 and 40);
the prefrontal cortex (corresponding to Brodmann’s areas 9–12 and 44–47);
the temporal cortex (corresponding to Brodmann’s areas 21, 22, 37 and 41–43). The temporal cortex is involved in audition and language, complex visual processing (such as face recognition) and memory (discussed in Chapters 26–28, 45–47).

Posterior parietal cortex

This area has developed greatly during evolution and relates to specific forms of human behaviour, such as the extensive use of tools, collaborative strategic planning and the development of language. It has two main subdivisions:

one involved mainly with somatosensory information (centred on area 5);
the other with visual stimuli (centred on area 7).

Neurophysiologically, area 5 contains many units with a complex sensory input often with a convergence of different sensory modalities, such as proprioceptive and cutaneous stimuli. These units with such a dual input are probably involved in the sensory control of posture and movements. Other units with multiple cutaneous inputs are probably more involved in object recognition. However, in addition to having these complex sensory inputs, units in this area are often only maximally activated when the sensory stimulus is of interest or behavioural significance. Clinical features of lesions in area 5 of the posterior parietal cortex include:

a contralateral sensory loss that is often subtle, e.g. a failure to recognize objects on tactile manipulation (astereognosis).
an inattention to stimuli received on the contralateral side of the body. This can be so severe that the patient denies the existence of that part of his or her body, which can then interfere with the actions of the normal non-neglected side (intermanual conflict or alien limb). More commonly, the patient fails to perceive sensory stimuli contralaterally when stimuli are simultaneously applied to both sides of the body (extinction).

In contrast, area 7 is more involved in complex visual processing, with many of the units in this area responding to stimuli of interest or behavioural significance (e.g. food). Many different units are found in this cortical area some of which maximally respond to the visual fixation and tracking, while others are more involved in the process of switching attention from one visual object of interest to another (light sensitive or visual space neurones).
There are individual neurones in area 7 that respond to both sensory and visual stimuli. Some of these neurones are maximally activated when a stimulus is moved towards the neurone’s cutaneous receptive field from extrapersonal (distant) space, while others are maximally activated during visual fixation of a desired object in which there is concomitant movement of the arm towards that object.

Clinical features of lesions in area 7 of the posterior parietal cortex include:

a neglect of visual stimuli in the contralateral hemifield;
defects in eye movement and the visual control of movement. In some patients, more striking deficits occur in the realm of complex visual processing such as route finding, the construction of complex shapes and the copying of motor actions/gestures (dyspraxia).

Finally, in humans, and to a lesser extent in other primates and animals, some units in the posterior parietal cortex are maximally activated by vestibular and auditory inputs. Therefore damage to this area in humans can lead to complex difficulties in vision and visually guided movements, balance and language processing, including arithmetic skills. This includes an inability to write (agraphia), to read (alexia) and calculate simple sums (acalculia).

Prefrontal cortex

This cortical area has increased in size with phylogenetic development and has its greatest representation in humans. It is involved in the purposeful behaviour of an organism and thus is intimately involved in the planning of responses to stimuli that include a motor component. Within this structure are specialized cortical areas such as the frontal eye fields (FEF) and Broca’s area. Although the prefrontal cortex is treated as a functional whole, this is a gross simplification.

Many different types of units are encountered neurophysiologically in this area of cortex, but they generally respond to complex sensory stimuli of behavioural relevance, which can then be translated into a cue for movement.

Damage to this site in animals leads to increased distractibility with corresponding deficits in working memory (the ability to retain information for more than a few seconds) and a change in locomotor activity and emotional responsiveness. A patient with frontal lobe damage anterior to the motor areas has a characteristic
syndrome without insight (as occurs in frontal variant frontotemporal dementia (FTD)).

The patient:

is often disinhibited, which results in him or her behaving in an atypical, often childish fashion;
has very poor attention and is easily distractible, cannot retain information and is sometimes unable to form new memories, with a tendency to perseverate (the repetition of words or phrases and actions) and pursue old patterns of behaviour even in the face of environmental change;
is unable to formulate and pursue goals and plans, to generalize and deduce, and may have difficulties in judging risk;
displays a marked reduction in verbal output, which is also reflected in motor behaviour as evidenced by a lack of spontaneous movement;
has a change in food preference, typically favouring sweet over savoury foods;
can become apathetic with severe blunting of his or her emotional responses, although in some cases the converse is true with the patient becoming aggressive;
show overall changes in their personality and it is typically others who bring the patient to medical attention, as the patient usually denies there is any problem (no insight).

The reliance on the clinical symptomatology to describe the function of the prefrontal cortex relates to the fact that this part of the cortex is most developed in humans. However, extensive damage of the frontal lobes can also affect the cortical motor areas, eye movements, the ability to talk (an expressive dysphasia) and the control of micturition.

Did you know?

There is some evidence that permanent traumatic damage to the frontal lobes can occur in footballers through repeated heading of the old leather footballs.