Neurology: Anatomical and functional organization

Development of the nervous system

The first signs of nervous system development occur in the third week of gestation, under the influence of secreted factors from the notochord, with the formation of a neural plate along the dorsal aspect of the embryo. This plate broadens, folds (forming the neural groove) and fuses to form the neural tube, which ultimately gives rise to the brain at its rostral (i.e. towards the head) end and the spinal cord caudally (i.e. towards the feet/tail end). The fusion
begins approximately halfway along the neural groove at the level of the fourth somite and continues caudally and rostrally with the closure of the posterior/caudal and anterior/rostral neuropore during the fourth week of gestation.

The development of the spinal cord

The process of neural tube fusion isolates a group of cells termed the neural crest.

The neural crest gives rise to a range of cells including the dorsal root ganglia (DRG) and peripheral components of the autonomic nervous system.
The DRG contain the sensory cell bodies which send their developing axons into the evolving spinal cord and skin.
These growing neuronal processes or neurites have an advancing growth cone that finds its appropriate target in the periphery and central nervous system (CNS), using a number of cues including cell adhesion molecules and diffusible neurotrophic factors. The neural tube surrounds the neural canal, which forms the
central canal of the fully developed spinal cord.
The tube itself contains the neuroblasts (ependymal layer), which divide and migrate out to the mantle layer, where they differentiate into neurones to form the grey matter of the spinal cord.
The developing processes from the neuroblasts/neurones grow out into the marginal layer, which therefore ultimately forms the white matter of the spinal cord.
The dividing neuroblasts segregate into two discrete populations, the alar and basal plates, which in turn will create the dorsal and ventral horns of the spinal cord while a small lateral horn of visceral efferent neurones (part of the ANS) develops at their interface in the thoracic and upper lumbar cord.
This dorso-ventral patterning relies, at least in part, on factors secreted dorsally (bone morphogenic proteins (BMPs)) or ventrally from the notochord (sonic hedgehog (SHH)).

The development of the brain

Adult neurogenesis

Until recently it was believed that no new neurones could be born in the adult mammalian brain. However, it is now clear that neural progenitor cells can be found in the adult CNS, including in humans. These cells are predominantly found in the dentate gyrus of the hippocampus (see Chapter 45) and just next to the lateral ventricles in the subventricular zone (SVZ). They may also exist at other sites of the adult CNS but this is contentious. They respond to a number of signals and appear to give rise to functional neurones in the hippocampus and olfactory bulb, with the
latter cells migrating from the SVZ to the olfactory bulb via the rostral migratory stream (RMS). They may therefore fulfil a role in certain forms of memory and possibly in mediating the therapeutic effects of some drugs such as antidepressants.

Disorders of central nervous system embryogenesis

Anencephaly occurs when there is failure of fusion of the anterior rostral neuropore. The cerebral vesicles fail to develop and thus there is no brain formation. The vast majority of fetuses with this abnormality are spontaneously aborted.
Spina bifida refers to any defect at the lower end of the vertebral column and/or spinal cord. The most common form of spina bifida refers to a failure of fusion of the dorsal parts of the lower vertebrae (spina bifida occulta). This can be associated with defects in the meninges and neural tissue which may herniate through the defect to form a meningocoele and meningomyelocoele, respectively. The most serious form of spina bifida is when nervous tissue
is directly exposed as a result of a failure in the proper fusion of the posterior/caudal neuropore. Spina bifida is often associated with hydrocephalus. Occasionally, bony defects are found at the base of the skull with the formation of a meningocoele. However, unlike the situation at the lower spinal cord, these can often be repaired without any neurological deficit being accrued.
Cortical dysplasia refers to a spectrum of defects that are the result of the abnormal migration of developing cortical neurones. These defects are becoming increasingly recognized with improved imaging of the human CNS, and are now known to be an important cause of epilepsy.
Many intrauterine infections (such as rubella), as well as some environmental agents (e.g. radiation), cause major problems in the development of the nervous system. In addition, a large number of rare genetic conditions are associated with defects of CNS development, but these lie beyond the scope of this book.

Did you know?

The adult human brain continues to make new nerve cells throughout life and that this can be promoted by a whole range of activities including exercising, learning new skills and, for example, socializing.

Organization of the nervous system

The nervous system can be divided into three major parts: the autonomic (ANS), peripheral (PNS) and central (CNS) nervous systems. The PNS is defined as those nerves that lie outside the brain, brainstem or spinal cord, while the CNS embraces those cells that lie within these structures.

Autonomic nervous system

The ANS has both a central and peripheral component and is involved with the innervation of internal and glandular organs: it has an important role in the control of the endocrine and homoeostatic systems of the body. The peripheral component of the ANS is defined in terms of the enteric, sympathetic and parasympathetic systems.
The efferent fibres of the ANS originate either from the intermediate zone (or lateral column) of the spinal cord or specific cranial nerve and sacral nuclei, and synapse in a ganglion, the site of which is different for the sympathetic and parasympathetic systems. The afferent fibres from the organs innervated by the ANS pass via the dorsal root to the spinal cord.

Peripheral nervous system

The PNS consists of nerve trunks made up of both afferent fibres or axons conducting sensory information to the spinal cord and brainstem, and efferent fibres transmitting impulses primarily to the muscles.
Damage to an individual nerve leads to weakness of the muscles it innervates and sensory loss in the area from which it conveys sensory information.
The peripheral nerves occasionally form a dense network or plexus adjacent to the spinal cord (e.g. brachial plexus in the upper limb).
The peripheral nerves connect with the spinal cord through foramina between the bones (or vertebrae) of the spine (or vertebral column), or with the brain through foramina in the skull.

Spinal cord

The spinal cord begins at the foramen magnum, which is the site at the base of the skull where the lower part of the brainstem (medulla) ends. The spinal cord terminates in the adult at the first lumbar vertebra, and gives rise to 30 pairs (or 31 if the coccygeal nerves are included) of spinal nerves, which exit the spinal cord between the vertebral bones of the spine.
The first eight spinal nerves originate from the cervical spinal cord with the first pair exiting above the first cervical vertebra and the next 12 spinal nerves originate from the thoracic or dorsal spinal cord. The remaining 10 pairs of spinal nerves originate from the lower cord, five from the lumbar and five from the sacral regions.
The spinal nerves consist of an anterior or ventral root that innervates the skeletal muscles, while the posterior or dorsal root carries sensation to the spinal cord from the skin that shared a common embryological origin with that part of the spinal cord. The dorsal root fibres have their cell bodies in the dorsal root ganglia which lie just outside the spinal canal.
The spinal cord itself consists of white matter, which contains the nerve fibres that form the ascending and descending pathways of the spinal cord, while the grey matter is located in the centre of the spinal cord and contains the cell bodies of the neurones.

Brainstem, cranial nerves and cerebellum

The spinal cord gives way to the brainstem, which lies at the base of the brain and is composed of the medulla, pons and midbrain (or mesencephalon as it is sometimes called, although this is strictly a term that should be reserved for this region of the brain in embryonic development) and contains discrete collections of neurones
or nuclei for 10 of the 12 cranial nerves, the exceptions being the first (olfactory) and second (optic) nerves.
The brainstem and the cerebellum constitute the structures of the posterior fossa.
The cerebellum is connected to the brainstem via three pairs of cerebellar peduncles, and is involved in the coordination of movement.

Cerebral hemispheres

The cerebral hemispheres are composed of four major lobes: occipital, parietal, temporal and frontal. On the medial part of the temporal lobe are a series of structures that form part of the limbic system.
The outer layer of the cerebral hemisphere is termed the cerebral cortex, and contains neurones that are organized in both horizontal layers and vertical columns.
The cerebral cortex is interconnected over long distances via pathways that run subcortically. These pathways, together with those that connect the cerebral cortex to the spinal cord, brainstem and nuclei deep within the cerebral hemisphere, constitute the white matter of the cerebral hemisphere. These deep nuclei include
structures such as basal ganglia and thalamus.

Meninges

The CNS is enclosed within the skull and vertebral column Separating these structures are a series of membranes referred to as the meninges.
The pia mater is separated from the delicate arachnoid membrane by the subarachnoid space (containing the cerebrospinal fluid), which in turn is separated from the dura mater by the subdural space.

Did you know?

Each hemisphere has a series of dominant functions, which one dominates in you?

Autonomic nervous system

Anatomy of the autonomic nervous system

The autonomic nervous system (ANS) includes those nerve cells and fibres that innervate internal and glandular organs. They subserve the regulation of processes that usually are not under voluntary influence.

The efferent conducting pathway from the central nervous system (CNS) to the innervated organ always consists of two succeeding neurones: a preganglionic and a postganglionic, with the former having its cell body in the CNS.
The ANS is subdivided into the enteric, sympathetic and parasympathetic nervous systems – the latter two commonly exert opposing influences on the structure they are innervating.
The sympathetic nervous system preganglionic neurones are found in the intermediate part (lateral horn) of the spinal cord from the upper thoracic to mid-lumbar cord (T1–L3).
The preganglionic parasympathetic neurones have their cell bodies in the brainstem and sacrum.
The postganglionic cell bodies are found in the vertebral and prevertebral ganglia in the sympathetic nervous system but in the parasympathetic system they are situated either adjacent to or in the walls of the organ they supply.
In addition to anatomical differences the sympathetic nervous system uses noradrenaline (norepinephrine; NA) as its postganglionic transmitter while the parasympathetic nervous system uses acetylcholine (ACh). Both systems use ACh at the level of the ganglia.

Central nervous system control of the autonomic nervous system

The CNS control of the ANS is complex, involving a number of brainstem structures as well as the hypothalamus. The main hypothalamic areas involved in the control of the ANS are the ventromedial hypothalamic area in the case of the sympathetic nervous system and the lateral hypothalamic area in the case of the parasympathetic nervous system. Controlling pathways are direct or indirect via a number of brainstem structures such as the
periaqueductal grey matter and parts of the reticular formation.

Clinical features of damage to the autonomic nervous system

Damage to the ANS can either be local to a given anatomical structure, or generalized when there is loss of the whole system caused by either a central or peripheral disease process.

Focal peripheral lesions: These are not uncommon and the deficiencies resulting from these lesions can be easily predicted. For example, loss of the sympathetic innervation to the eye results in pupillary constriction (miosis), drooping of the upper eyelid (ptosis) and loss of sweating around the eye (anhydrosis) – a triad of signs known as Horner’s syndrome. Other examples include the reflex sympathetic dystrophies where there is severe pain and autonomic changes confined to a single limb, often in response to some trivial injury. The exact role of the sympathetic nervous system in the genesis of these conditions is not known, as local sympathectomies
are not always effective treatments. However, in some instances these treatments can help which may relate to the fact that the nociceptors can start expressing receptors for NA.
More global damage to the ANS: This can occur because of degeneration of the central neurones either in isolation (e.g. pure autonomic failure) or as part of a more widespread degenerative process as is seen, for example, in multiple-system atrophy, where there may be additional cell loss in the basal ganglia and cerebellum.
Alternatively, the autonomic failure may result from a loss of the peripheral neurones, e.g. in diabetes mellitus, certain forms of amyloidosis, alcoholism and Guillain–Barré syndrome. Finally, abnormalities in the ANS can be seen with certain toxins as well as in Lambert–Eaton myasthenic syndrome.
In all these cases the patient presents with orthostatic and postprandial hypotension (syncopal or presyncopal symptoms on standing, exercising or eating a big meal) with a loss of variation in heart rate, bowel and bladder disturbances (urinary urgency, frequency and incontinence), impotence, loss of sweating and pupillary responses. The symptoms are often difficult to treat and a number of agents are used to try to improve the postural hypotension and sphincter abnormalities. Agents for postural hypotension include fludrocortisone, ephedrine, domperidone, midodrine and vasopressin analogues (all of which cause fluid retention).

Did you know?

Lie detectors reflect ANS responses.

Enteric nervous system

Structure of the enteric nervous system

The enteric nervous system is found in the wall of the gut, primarily the small and large intestine, and is involved with normal gastrointestinal motility and secretory function. It contains about 100 million nerve cell bodies. It is heavily innervated/regulated by the autonomic nervous system but is a separate entity with its own intrinsic circuitry and function. It has no major role in the oesophagus and it is less clear what role it fulfils in the stomach.
The enteric nervous system consists of two plexuses:

myenteric plexus or Auerbach’s plexus, which lies between the longitudinal and circular muscle layers;
submucosal plexus or Meissner’s plexus, which lies between the circular muscle and muscularis mucosa.
The plexuses consist of:
excitatory and some inhibitory motor neurones regulate muscle contraction;
inhibitory interneurones integrate responses;
intrinsic primary (1°) afferent neurones (IPAN) detect the chemical and mechanical state of the gut.
Multiple neurotransmitters and receptors are found in the different neuronal populations, the activities of which can therefore be modulated by a large number of drugs as well as by the ANS. Many of the neurones of the enteric nervous system contain more than one neurotransmitter.

Functions of the enteric nervous system

The enteric nervous system can function in isolation to coordinate contraction of the gut musculature.
It also regulates local food flow and the mucosal movement of ions/electrolytes.
It allows for changes in local gut behaviour in response to local stimuli – both mechanical and chemical – and this may also rely on the release of substances from non-neuronal cells, e.g. 5-hydroxytryptamine (5HT)/adenosine triphosphate (ATP) from entero-endocrine cells.
In addition there are ascending and descending neuronal networks that enable the sequential activation of muscles in the gut wall, which allows for the transport of luminal contents down the gut (peristalsis).

Disorders of the enteric nervous system

Congenital or developmental abnormalities such as Hirschs- prung’s disease – in which there is a localized absence of enteric nervous system in the colon, causing constipation at birth, and which can only be cured by surgery to remove the atonic bit of bowel.
Sporadic or acquired abnormalities, such as irritable bowel syn-drome or chronic constipation as is seen in Parkinson’s disease, where it is due to local degeneration of intrinsic neurones.
Secondary to a neuropathy from diabetes mellitus/Guillain– Barré syndrome.
Iatrogenic, e.g. laxative abuse/opioid medication.

Did you know?

Many neuroscientists refer to the network of neurones lining the gut as the ‘second brain’, as these neurones are capable of generating “feelings” such as butterflies in your stomach when you are anxious.

Meninges and cerebrospinal fluid

The brain is enclosed by three protective layers, which also extend
down the spinal cord.

The dura mater is a thick tough membrane lying close to the skull and vertebrae and innervated by afferent fibres of the trigeminal and upper cervical nerves.
Adjacent to the dura mater is the arachnoid mater, a thin membrane with thread-like processes that project into the subarachnoid space and making contact with the delicate pia mater.
The pia mater envelops the spinal cord and contours of the brain surface and dips into the sulci.
The subarachnoid space is filled with cerebrospinal fluid (CSF) and also accommodates major arteries, branches of which project down through the pia into the central nervous system (CNS). At specific sites the size of the subarachnoid space increases to form cisterns. These are particularly prevalent in the region of the brainstem
and the largest is the cisterna magna found between the cerebellum and medulla.
The meninges extend caudally enclosing the spinal cord. Here the dura is attached to the foramen magnum at its upper limit and projects down to the second sacral vertebrae.

Cerebrospinal fluid (CSF) production and circulation

CSF is secreted by the choroid plexuses, which are found primarily in the ventricles.
The rate of production varies between 300 and 500 mL/24 h and the ventricular volume is approximately 75 mL.
CSF is similar to blood plasma although it contains less albumin and glucose.
After production, CSF flows from the lateral ventricles into the third ventricle via the intraventricular foramina of Monro and then passes into the fourth ventricle through the central aqueduct of Sylvius and into the subarachnoid space via the foramina of Luschka and Magendie. From the subarachnoid space at the base of the brain, CSF flows rostrally over the cerebral hemispheres or down into the spinal cord.
CSF reabsorption occurs within the superior sagittal and related venous sinuses. Arachnoid granulations are minute pouches of the arachnoid membrane projecting through the dura into the venous sinuses. The exact mechanism by which CSF is reabsorbed is not clear but it does involve the movement of all CSF constituents into
the venous blood. As well as playing an important part in maintaining a constant intracerebral chemical environment (see below), the CSF also helps protect the brain from mechanical damage by buffering the effects of impact.

Blood–brain barrier

The blood–brain barrier (BBB) used to be thought of as a single physical barrier preventing the passage of molecules and cells into the brain. More recently, however, it has been shown to be made up of a series of different transport systems for facilitating or restricting the movement of molecules across the blood–CSF interface. A characteristic of cerebral capillary endothelial cells is the presence of tight junctions between such cells, which are induced and maintained by astrocytic foot processes (see Chapter 13). These unusually tight junctions reduce opportunities for the movement of large molecules and cells, and thus require the existence of specific transport systems for the passage of certain critical molecules into the brain.

Small molecules such as glucose pass readily into the CSF despite not being lipid soluble.
Larger protein molecules do not enter the brain, but there are a number of carrier mechanisms that enable the transport of other sugars and some amino acids.
The rôle of the barrier is to maintain a constant intracerebral chemical environment and protect against osmotic challenges, while granting the CNS relative immunological privilege by preventing cells from entering it (see Chapter 62). However, from a therapeutic point of view the barrier reduces or prevents the delivery of many large-molecular-weight drugs (e.g. antibiotics) into the brain and represents a major problem in the treatment of many
CNS disorders.

Clinical disorders

Hydrocephalus

Hydrocephalus is defined as dilatation of the ventricular system and so can be seen in cases of cerebral atrophy, e.g. dementia (compensatory hydrocephalus). However, hydrocephalus can also occur as a result of increased pressure within the ventricular system, secondary to an obstruction in the flow of CSF (obstructive hydrocephalus). This typically occurs at the outlets from the fourth ventricle into the subarachnoid space, where the obstruction may be linked to the presence of a tumour, congenital malformation or the sequelae of a previous infection (see below). Alternatively, the flow of CSF from the third to the fourth ventricle may be impaired as a result of the development of central aqueduct stenosis.
Hydrocephalus is also seen in rare conditions of oversecretion of CSF (e.g. tumours of the choroid plexus) as well as in the common situation of reduced absorption as is characteristically seen in spina bifida.
The symptomatology of hydrocephalus is varied but classically the patient presents with features of raised intracranial pressure (early morning headache, nausea, vomiting) and, in acute rises of pressure, altered levels of consciousness with brief periods of visual loss. Overall, probably the most common cause of raised intracranial pressure is a glioma tumour producing these effects by virtue of its mass. Such tumours in the posterior fossa can also directly cause hydrocephalus, which may contribute to the raised intracranial pressure.
In obstructive hydrocephalus the treatment focuses on draining excess CSF using a variety of shunts linking the ventricles to either the heart (atrium) or the peritoneal cavity.

Meningitis

Meningitis or inflammation within the meningeal membrane can be caused by a number of different organisms. In acute infection there is the rapid spread of inflammation throughout the entire subarachnoid space of the brain and spinal cord, which produces the symptoms of headache, pyrexia, vomiting, neck stiffness (meningism) and, in severe forms of the disease, reduced levels of consciousness. The early administration of antibiotics is essential although the type of antibiotic employed will depend on the nature of the organism responsible for the inflammation.
In other cases the infection or inflammation may follow a more subacute course, such as tuberculous meningitis or sarcoidosis. In such cases, secondary hydrocephalus may ensue as a result of meningeal thickening at the base of the brain obstructing CSF flow.
Rarely, tumours can spread up the meninges giving a malignant meningitis. This characteristically presents as an evolving cranial nerve or nerve root syndrome with pain. This is to be distinguished from primary tumours of the meninges – meningiomas – which are slow growing and benign, and typically present with epileptic seizures or deficits secondary to compression of neighbouring CNS structures.

Did you know?

The CSF contains many important substances that can be measured and that could potentially be used as biomarkers for chronic neurodegenerative disorders of the brain, eg. A and tau protein in Alzheimer’s disease (Chapter 60).

Blood supply to the central nervous system

Blood supply to the brain

The arterial blood supply to the brain comes from four vessels: both the right and left internal carotid as well as the vertebral arteries.

The vertebral arteries enter the skull through the foramen magnum and unite to supply blood to the brainstem (basilar artery) and posterior parts of the cerebral hemisphere (posterior cerebral arteries) – the whole network constituting the posterior circulation.
The internal carotid arteries (ICAs) traverse the skull in the carotid canal and the cavernous sinus before piercing the dura and entering the middle cranial fossa just lateral to the optic chiasm. They then divide and supply blood to the anterior and middle parts of the cerebral hemispheres (anterior [ACA] and middle [MCA] cerebral arteries). In addition, the posterior and anterior cerebral circulations anastomose at the base of the brain in the circle of
Willis, with the anterior and posterior communicating arteries offering the potential to maintain cerebral circulation in the event of a major arterial occlusion. The ICA prior to their terminal bifurcation supply branches to the pituitary (hypophysial arteries), the eye (ophthalmic artery), parts of the basal ganglia (globus pallidus) and limbic system (anterior choroidal artery) as well as providing the posterior communicating artery.
The MCA forms one of the two terminal branches of the ICA and supplies the sensorimotor strip surrounding the central sulcus (with the exception of its medial extension which is supplied by the ACA) as well as the auditory and language cortical areas in the dominant (usually left) hemisphere. Therefore, occlusion of the MCA causes a contralateral paralysis that affects the lower part of the face and arm especially, with contralateral sensory loss or
inattention and a loss of language if the dominant hemisphere is involved. In addition, there are a number of small penetrating branches of the MCA that supply subcortical structures such as the basal ganglia and internal capsule (see below).
The two ACAs, which form the other major terminal vessels of the ICAs, are connected via the anterior communicating artery and supply blood to the medial portions of the frontal and parietal lobes as well as the corpus callosum. Occlusion of an ACA characteristically gives paresis of the contralateral leg with sensory loss, and on occasions deficits in gait and micturition accompanied with mental impairment and dyspraxia.
The vertebral arteries, which arise from the subclavian artery, ascend to the brainstem via foramina in the transverse processes of the upper cervical vertebrae. At the level of the lower part of the pons the vertebral arteries unite to form the basilar artery, which then ascends before dividing into the two posterior cerebral arteries (PCAs) at the superior border of the pons. Each vertebral artery enroute to forming the basilar artery gives off a number of branches including the posterior spinal artery, the posterior inferior cerebellar artery (PICA) and the anterior spinal artery. These spinal arteries supply the upper cervical cord (see below), whereas the PICA supplies the lateral part of the medulla and cerebellum. Occlusion of this vessel gives rise to the lateral medullary syndrome of Wallenberg.
The PCAs supply blood to the posterior parietal cortex, the occipital lobe and inferior parts of the temporal lobe. Occlusion of these vessels causes a visual field defect (usually a homonymous hemianopia with macular sparing, as this cortical area receives some supply from the MCA; amnesic syndromes, disorders of language and, occasionally, complex visual perceptual abnormalities. The PCA has a number of central perforating or penetrating branches that supply the midbrain, thalamus, subthalamus, posterior internal capsule, optic radiation and cerebral peduncle, and these are commonly affected in hypertension, when occlusion of the PCA produces small lacunar infarcts. Apart from occlusion, haemorrhage from cerebral vessels may involve the brain substance (intracerebral), the subarachnoid space or both. Such haemorrhages usually occur in the context of either trauma, hypertension or rupture of congenital aneurysms in
the circle of Willis (berry aneurysms).

Venous drainage of the brain

The brainstem and cerebellum directly drains into the dural venous sinuses adjacent to the posterior cranial fossa. The cerebral hemispheres, in contrast, have internal and external veins – the external cerebral veins drain the cortex and empty into the superior sagittal sinus. This sinus drains into the transverse sinus, then the lateral sinus, before emptying into the internal jugular vein. The internal cerebral veins drain the deep structures of the cerebral hemisphere to the great vein of Galen and thence into the straight sinus. Occlusion of either of these venous systems can occur, causing raised intracranial pressure with or without focal deficits.

Blood supply to the spinal cord

The blood supply to the spinal cord comes in the form of a single anterior spinal artery and paired posterior spinal arteries. The anterior spinal artery arises from the vertebral arteries and extends from the level of the lower brainstem to the tip of the conus medullaris. The posterior spinal arteries take their origin from the vertebral arteries. At certain sites along the spinal cord there are a number of reinforcing inputs from other arteries (see figure).
Vascular insults to the spinal cord occur most commonly at the watershed areas in the cord, namely the lower cervical and lower thoracic cord. Occlusion of the anterior spinal artery produces a loss of power and spinothalamic sensory deficit with preservation of the dorsal column sensory modalities (joint position sense and vibration perception).

Did you know?

There are over 100 000 miles of blood vessels in your brain.

Cranial nerves

Olfactory nerve

The receptors for olfaction are found within the nasal mucosa, and their axons project through the cribriform plate to the olfactory bulb on the undersurface of the frontal lobe. This cranial nerve therefore does not originate or pass through the brainstem and conveys information on smell.

Damage to this nerve occurs most commonly with head trauma and shearing of the olfactory axons as they pass through the cribriform plate causing anosmia.

Optic nerve

The photoreceptors in the eye project onto bipolar cells to ganglion cells and then to the CNS via the optic nerve. The nerve passes through the optic canal at the back of the orbit into the brain and unites with the optic nerve from the other eye to form the optic chiasm. The fibres from here pass ultimately to the visual cortex as
well as to a number of subcortical sites.

Damage to this nerve will affect vision, although the extent and type of this visual loss depends on the site of injury.

Oculomotor nerve

This originates in the midbrain at the level of the superior colliculus and supplies all the extraocular muscles apart from the lateral rectus, and superior oblique. It also carries the parasympathetic innervation to the eye and provides the major innervation of levator palpebrae superioris.

A complete third nerve palsy causes the eye to lie ‘down and out’ with a fixed dilated unresponsive pupil and ptosis (droopy eyelid). Cranial nerves Anatomical and functional organization 23 Common causes of this are a posterior communicating artery aneurysm or a microvascular insult to the nerve itself as occurs in diabetes mellitus, for example.

Trochlear nerve

This nerve originates in the midbrain at the level of the inferior colliculus, and exits out of the brainstem dorsally. It supplies the superior oblique muscle.

Damage to this nerve causes double vision (diplopia) when looking down. A common cause of fourth cranial nerve palsy is head trauma.

Fifth cranial or trigeminal nerve

The trigeminal nerve has both a motor and sensory function. The motor nucleus is situated at the mid-pontine level, medial to the main sensory nucleus of the trigeminal nerve, and receives an input from the motor cortex. It supplies the muscles of mastication. Sensation from the whole face (including the cornea) passes to the brainstem in the trigeminal nerve, and synapses in three major nuclear complexes: the nucleus of the spinal tract and the main sensory nucleus of the trigeminal nerve; and the mesencephalic nucleus. Sensation from the face is relayed
via three branches: the ophthalmic division that supplies the forehead; the maxillary division that innervates the cheek; and the mandibular branch from the jaw – with the more rostral fibres (ophthalmic branch fibres) passing to the lowest part of the nucleus of the spinal tract in the upper cervical cord. These brainstem trigeminal nuclei in turn project to the thalamus as part of the somatosensory and pain systems.

Damage to the trigeminal nerve results in weak jaw opening and chewing, coupled to facial sensory loss and an absent corneal reflex.

Sixth cranial or abducens nerve

This originates from the dorsal lower portion of the pons and supplies the lateral rectus muscle.

Damage to this nerve results in horizontal diplopia when looking to the lesioned side and can be caused by local brainstem pathology or can be a false localizing sign in raised intracranial pressure.

Seventh cranial or facial nerve

This is predominantly a motor nerve, although it does carry parasympathetic fibres to the lacrimal and salivary glands (the greater superficial petrosal nerve and chorda tympani) as well as sensation from the anterior two-thirds of the tongue (the chorda tympani). The motor nucleus for the facial nerve originates in the pons, and supplies all the muscles of the face except for those involved in mastication.

A lesion of this nerve produces a lower facial nerve palsy with weakness of all the facial muscles ipsilateral to the side of the lesion. In addition, there is a loss of taste on the anterior two-thirds of the tongue if the lesion occurs proximal to the origin of the chorda tympani. This is most commonly seen in Bell’s palsy. In contrast, damage to the descending motor input to the facial nucleus from the cortex (an upper motor neurone facial palsy) causes weakness of the lower part of the contralateral face only, as the musculature of the upper part of the face has upper motor neurone innervation from the motor cortex of both hemispheres.

Eighth cranial or vestibulocochlear nerve

This conveys information from the cochlea (the auditory or cochlear nerve) as well as the semicircular canals and otolith organs (the vestibular nerve).

Damage to this nerve (e.g. in acoustic neuromas) causes disturbances in balance with deafness and tinnitus (a ringing noise).

Ninth cranial or glossopharyngeal nerve

The glossopharyngeal nerve contains motor, sensory and parasympathetic fibres. The motor fibres originate from the rostral nucleus ambiguus and supply the stylopharyngeus muscle, while the sensory fibres synapse in the tractus solitarius (or nucleus of the solitary tract) and provide taste and sensation from the posterior tongue and pharynx. The parasympathetic fibres originate in the inferior salivatory nucleus and provide an input to the parotid gland.

Damage to this nerve usually occurs in conjunction with the vagus nerve (see below).

Tenth cranial or vagus nerve

This nerve provides a motor input to the soft palate, pharynx and larynx, which originates in the dorsal motor nucleus of the vagus and nucleus ambiguus. It also has a minor sensory role, conveying taste from the epiglottis and sensation from the pinna, but has a significant parasympathetic role.

Damage to the vagus nerve causes dysphagia and articulation disturbances and, as with glossopharyngeal nerve lesions, there may be a loss of the gag reflex.

Eleventh cranial or spinal accessory nerve

This is purely motor in nature and originates from the nucleus ambiguus in the medulla and the accessory nucleus in the upper cervical spinal cord. It supplies the sternocleidomastoid and trapezius muscles.

Damage to the eleventh nerve causes weakness in these muscles.

Twelfth cranial or hypoglossal nerve

The hypoglossal nerve provides the motor innervation of the tongue. Its fibres originate from the hypoglossal nucleus in the posterior part of the medulla.

Damage to this nerve causes wasting and weakness in the tongue, which leads to problems of swallowing and speech, and is most commonly seen in motor neurone disease. Isolated damage of this nerve is rare and it is more commonly affected with other lower cranial nerves (e.g. the ninth, tenth and eleventh
cranial nerves) and in such cases the patient may present with a bulbar palsy. A pseudobulbar palsy, in contrast, refers to a loss of the descending cortical input to these cranial nerve nuclei.

Did you know?

Some people with damage to their facial nerve cry when they eat – these are called crocodile tears.

Anatomy of the brainstem

The brainstem begins at the foramen magnum and extends to the cerebral peduncles and thalamus. It consists of the medulla, pons and midbrain and is located anterior to the cerebellum to which it is connected by three cerebellar peduncles. It contains the following:

nuclei for 10 of the 12 pairs of cranial nerves, the exceptions being the olfactory and optic nerves;
networks of neurones for controlling eye movements, which includes the third, fourth and sixth cranial nerves;
monoaminergic nuclei that project widely throughout the central nervous system;
areas that are vital in the control of respiration and the cardiovascular system, as well as the autonomic nervous system;
areas important in the control of consciousness including sleep and associated monoaminergic nuclei;
ascending and descending pathways linking the spinal cord to supraspinal structures, such as the cerebral cortex and cerebellum, some of which take their origin from the brainstem.

Important structures in the brainstem

The dorsal column nuclei represent the primary site of termination of the fibres conveyed in the dorsal columns (DCs), responsible for light touch, vibration perception and joint position sense. The relay neurones in this structure send axons that decussate in the lower medulla to form the medial lemniscus, which synapses within the thalamus.
The pyramid which represents the descending corticospinal tract (CoST) in the medulla, a pathway that decussates at the lower border of this structure.
The tractus solitarius and nucleus ambiguus are associated with taste and the motor innervation of the pharynx by the glossopharyngeal and vagus nerves.
The inferior olive in the medulla receives inputs from a number of sources and provides the climbing fibre input to the cerebellum.
The cerebellar peduncles convey information to and from the cerebellum.
The medial longitudinal fasciculus originates in the vestibular nucleus and projects rostrally connecting some of the oculomotor nuclei (third and sixth cranial nerves) as well as caudally to form part of the vestibulospinal tract.
The vestibular nucleus has important connections from the balance organs within the inner ear and projects to the spinal cord and cerebellum as well as other brainstem structures.
The substantia nigra in the midbrain contains both dopamine and -aminobutyric acid (GABA) neurones, forms part of the basal ganglia and is involved in the control of movement. The loss of its dopaminergic neurones is the major pathological event in Parkinson’s disease.
The red nucleus in the midbrain is intimately associated with the cerebellum, and is the site of origin for the rubrospinal tract which, with the CoST, forms the lateral descending pathway of motor control.
The periaqueductal grey matter of the mesencephalon is an area rich in endogenous opioids and thus is important in the supraspinal modulation of nociception.
The central aqueduct of Sylvius running through the midbrain connects the third to the fourth ventricle, and narrowing of it (stenosis) can cause hydrocephalus.
The cerebral peduncles contain the descending motor pathways from the cerebral cortex to the spinal cord and brainstem, especially the pons.
The inferior colliculi in the midbrain are part of the auditory system while the superior colliculi are more involved with visual processing and eye movement control.
Thus, damage to the brainstem can have devastating consequences, although small lesions can often be localized with great accuracy because of the number of structures located within this small area of the brain. The most common causes of lesions in this part of the brain are either inflammatory (e.g. multiple sclerosis😉 or vascular in nature. However, disorders of the brainstem can also be seen with tumours and a host of other conditions, and if damage is severe and extensive then it can be fatal. Testing specifically for brainstem functions is undertaken to assess if an individual with extensive brain injury (e.g. massive
stroke or head injury) is brain dead, which has implications for further interventional therapy and organ donation. This assessment involves looking at reflex eye movements to head movement, eye movement responses to stimulation of the vestibular system and spontaneous respiration.

Did you know?

It has been reported that brainstem damage can cause colourful, vivid hallucinations of small little people and animals.

Organization of the spinal cord

Overall structure

The spinal cord lies within the vertebral canal and extends from the foramen magnum to the lower border of the first lumbar vertebra.

It is enlarged at two sites (cervical and lumbar regions) corresponding to the innervations of the upper and lower limbs.
The lower part of the vertebral canal (below L1) contains the lower lumbar and sacral nerves and is known as the cauda equina.
Sensory nerve fibres enter the spinal cord via the dorsal (posterior) roots and their accompanying cell bodies are located in the dorsal root ganglia, while the motor and preganglionic autonomic fibres exit via the ventral (or anterior) root, together with some mostly unmyelinated afferent fibres.
The motor cell bodies (or motor neurones [MNs]) are found in the ventral horn of the spinal cord, while the preganglionic cell bodies of the sympathetic nervous system are found in the intermediolateral column of the spinal cord.
The neuronal cell bodies that make up the central grey matter of the cord are organized into a series of laminae (of Rexed). The white matter surrounding this is composed of myelinated and unmyelinated axons constituting the ascending and descending spinal tracts.

Organization of sensory afferent fibres entering the spinal cord

Sensory information from the peripheral receptors is relayed by primary afferent nerve fibres which terminate in layers I–V of the dorsal horn, the site for termination being different for different receptors. However, in reality, many afferent fibres divide (into an ascending and a descending branch) as they enter the spinal cord so that synaptic contact can be made both with many interneurones in the dorsal horn, and up and down the cord through Lissauer’s tract.

Sensory processing in the dorsal horn

Typically, a number of primary afferents make synaptic contact with a single dorsal horn neurone.
This convergence of input has the effect of reducing the acuity (accuracy) of stimulus location, but the process of lateral inhibition helps minimize this loss of acuity by promoting the inhibition of submaximally activated fibre inputs and thus increasing spatial contrast in the sensory input.
The dorsal horn receives a number of descending inputs from supraspinal structures that are important in modulating the processing of sensory information through the spinal cord.

Ascending sensory pathways in spinal cord

The major ascending pathways of the spinal cord are:

spinothalamic tract (STT), also known as the anterolateral system;
spinocerebellar tracts;
dorsal columns (DCs; sometimes called the dorsal column-medial lemniscus system).

Each tract relays specific information in a topographical fashion, i.e. the sensory information from different parts of the body is conserved in the organization of the ascending pathways. Inputs from the more rostral parts of the body (arm as opposed to leg) supply fibres that lie more laterally in the ascending pathway.
Both the DC and STT decussate (fibres cross the midline) and therefore the sensory information they relay is ultimately processed in the contralateral cerebral hemisphere. However, the site at which this decussation occurs is different for the two pathways, with the anterolateral system crossing the midline in the spinal cord while the DCs decussate in the lower medulla after synapsing in the DC nuclei and forming the medial lemniscus.

Spinal motor neurones

– and “-MNs are both found in the ventral (anterior) horn.
The -MNs are some the largest neurones found in the nervous system and innervate skeletal muscle fibres, while the “-MNs innervate the intrafusal muscle fibres of the muscle spindle.
The cervical cord MNs innervate the arm muscles while the lumbar and sacral MNs innervate the leg musculature.
The MNs are arranged somatotopically across the ventral horn such that the more medially placed MNs innervate proximal muscles, while those located more laterally innervate distal muscles.

Descending motor tracts

There are a number of descending motor pathways that are defined by their site of origin within the brain:

corticospinal (CoST) or pyramidal tract originates in the cerebral cortex;
rubrospinal tract originates from the red nucleus in the midbrain and along with the CoST innervates the laterally placed MNs that supply the distal musculature;
The vestibulospinal, reticulospinal and tectospinal tracts – known as the extrapyramidal tracts – innervate the more ventromedially placed MNs that control the axial musculature.

Clinical features of spinal cord damage

A knowledge of the organizational anatomy of the spinal cord allows one to predict the pattern of deficits with damage, which is of great value in clinical neurology.

Did you know?

Two million people worldwide live with a spinal cord injury.

Organization of the cerebral cortex and thalamus

The organization of the outer layer of the cerebral cortex (neocortex) can be considered in various ways. One way uses cyto-architectural maps such as Brodmann’s areas – which equates to some extent with the functional organization of this structure into motor, sensory and associative areas, as evidenced by the laminar organization of the cortex. An area of cortex that is predominantly sensory in character has a prominent layer IV, while cortical motor areas have a prominent layer V.
An alternative approach is to view the cortex as being organized vertically. This vertical organization has become known as the columnar hypothesis and proposes that the ‘column’ of cortex is the basic unit of cortical processing.

Anatomical organization of the cerebral cortex

The neocortex is classically described as consisting of six layers, although in certain areas of the cerebral cortex further subdivisions are used, e.g. the primary visual cortex.

The thalamic afferent fibres, relaying sensory information, project to layer IV often with a smaller input to layer VI. They terminate in discrete patches.
This input then synapses onto interneurones within the cortex which in turn project vertically to neurones in layers II, III and V, and from there project to other cortical and subcortical sites, respectively.

Thus, the weight of synaptic relations within the cerebral cortex is in the vertical direction. This arrangement of synaptic connections is well seen in the somatosensory and visual cortices. In many cortical areas with a motor function, the motor output from that cortical area is such that it is directed back at the motor neurones controlling the muscles that move the sensory receptors which ultimately project to that same area of cortex – so-called
input–output coupling.

Developmental organization of the cerebral cortex

In the mammalian CNS the entire population of cortical neurones is produced by a process of migration from the proliferative zones that are situated around the cavities of the cerebral ventricles. The radial glial fibres, which guide and may even give rise to the migrating neurones, span the fetal cerebral wall and direct the neurones to their correct cortical location in the developing cortical plate from the ventricular and subventricular zones. Thus, developmentally, the cortex forms in a vertical fashion.

Neurophysiological organization of the cerebral cortex

Neurophysiologically, if a recording electrode is passed at right angles through the cortex, it encounters cells with similar properties. However, if the electrode is passed tangentially then cells shift their response characteristics. This has been shown in many cortical areas.
This columnar organization of the cortex ensures that topography can be maintained and that the reorganization of the cortex in the event of a change in the peripheral input is relatively straightforward.

Functional organization of the cerebral cortex

Serial processing models

The original models proposed that information processing was performed in a serial fashion, such that the cortical cells form a series of hierarchal levels. Thus, one set of cells performs a relatively straightforward analysis, which then converges on another population of neurones that perform a more complex analysis. The ultimate prediction of these hierarchical models is that one neurone at the top of the hierarchy will register the percept – the ‘grandmother’ cell.

Parallel processing models

The discovery of the X, Y and W classes of ganglion cells in the retina led to the development of a competing theory that proposed that information is analysed by a series of parallel pathways, with each pathway analysing one specific aspect of the sensory stimulus (e.g. colour or motion with visual stimuli. This theory does not exclude hierarchical processing but relegates it to the mode of analysis within separate parallel pathways. In practice, the cortex employs both modes of analysis.

Distributed processing models

It should be stressed that cortical columns are not to be viewed as a static mosaic structure, as one column may be a member of a number of different pathways of analysis. This organization has been termed the distributed system theory and describes the brain as a complex of widely and reciprocally interconnected systems, with the dynamic interplay of neural activity within and between these systems as the very essence of brain function. Consequently,
one column may be a member of many distributed systems, because each distributed system is specific for one feature of a stimulus and one column may code for several features of the stimulus.

Anatomical and functional organization of the thalamus

The thalamus is made up of a number of discrete nuclei and is more than a simple relay station as it receives extensive connections from the cortex and brainstem structures and is also critically involved in levels of arousal. The main nuclei of the thalamus are:

The anterior nucleus – which is associated with the limbic system and prefrontal cortex.
The ventroanterior and ventrolateral nuclei – which are associated with motor systems.
The ventroposterior nuclei – which are associated with somatosensory systems.
The pulvinar – which is associated with posterior parietal cortex.
The medial geniculate nucleus – which is associated with the auditory pathways.
The lateral geniculate nucleus – which is associated with the visual system.
The intralaminar nuclei – which is associated with pain pathways and basal ganglia.
The reticular nucleus – which is associated with levels of arousal and some forms of epilepsy.

Did you know?

Korbinian Brodmann was the first to define the distinct cortical areas back in 1909. He proposed 50 distinct areas with the last one called Area 52!

Hypothalamus

The hypothalamus lies on either side of the third ventricle, below the thalamus and between the optic chiasm and the midbrain. It receives a significant input from limbic system structures as well as from the retina. It contains a large number of neurones that are sensitive to changes in hormone levels, electrolytes and temperature.
It has an efferent output to the autonomic nervous system (ANS), as well as a critical role in the control of pituitary endocrine function (a detailed discussion on the endocrinology of the hypothalamic–pituitary system is beyond the scope of this book). Thus, the hypothalamus, while being important in the control of the ANS, has a much greater role in the homoeostasis of many physiological systems (e.g. thirst, hunger, sodium and water balance, temperature regulation), the control of circadian and endocrine functions, the ability to form anterograde memories (in
conjunction with the limbic system) and the translation of the response to emotional stimuli into endocrinological and autonomic responses.
The hypothalamus performs a number of other functions, all of which can be lost or deranged in the disease state. The most common cause is as a side-effect of surgical removal of pituitary tumours.

Functions of the hypothalamus

The hypothalamus controls the ANS and damage to it can cause autonomic instability. The ventromedial part of the hypothalamus has a major role in controlling the sympathetic nervous system while the lateral hypothalamic area controls the parasympathetic nervous system.
It controls the endocrine functions of the pituitary by the production of releasing and inhibiting hormones as well as producing antidiuretic hormone (ADH, also known as vasopressin) and oxytocin. Hypothalamic damage can have profound systemic effects because of the endocrinological disturbances associated with it, of which perhaps the most common example is neurogenic diabetes insipidus, in which there is a loss of the production of ADH from
the hypothalamus. In this condition the patient passes many litres of urine each day, which needs to be compensated for by increased fluid intake. This is to be distinguished from nephrogenic diabetes insipidus, where the problem lies within the ADH receptor in the kidney.
It has a major role in coordinating autonomic and endocrinological responses, both under physiological conditions, and in the expression of emotional states as coded for by the limbic system. In cases of hypovolaemia or extreme anxiety, for example, the hypothalamus mediates not only increased sympathetic activity, but also enhanced cortisol production via the stimulated release of adrenocorticotrophic hormone (ACTH) from the anterior pituitary.
This is termed the stress response, which is defined by the rise in cortisol.
It has an important role in thermoregulation. Lesions to the anterior hypothalamic area cause hyperthermia, while stimulation of this same area lowers body temperature via the ANS, in contrast to the posterior hypothalamic area, which behaves in an opposite fashion. It may also mediate some of the more long-term responses
seen with prolonged changes in ambient temperature, such as increased thyrotrophin-releasing hormone (TRH) production in patients exposed to a chronically cold environment. Damage to the hypothalamus can lead to profound changes in the central control of temperature. In septic states, the production of some cytokines
(e.g. interleukin-1) may reset the thermostat in the hypothalamus to a higher than normal temperature, accounting for the paradoxical situation of a fever with physiological evidence of mechanisms designed to conserve or generate heat (e.g. shivering).
It has a role in the control of feeding. In simple terms, the ventromedial hypothalamus is often called the satiety centre, in that damage to it causes excessive eating (hyperphagia) and weight gain, while damage to the lateral hypothalamic (or hunger) area produces aphagia (no eating at all). The control of these centres involves a number of hormones, including insulin and the more recently described leptins.
It has a role in the control of thirst and water balance by virtue of its osmoreceptors; the afferent input from a host of peripheral sensory receptors (e.g. atrial stretch receptors in the heart, arterial baroreceptors); the activation of hypothalamic hormone receptors (e.g. angiotensin II receptors); and its efferent output via the ANS to the heart and kidney as well as the production of ADH.
It has a role in the control of circadian rhythms via the retinal input to the suprachiasmatic nucleus. This nucleus appears to be critical in setting the circadian rhythm as lesion and transplant experiments have shown. Although the exact mechanism by which these rhythms are mediated is not known, it may involve the production
of melatonin by the pineal gland.
It has a role with the limbic system in memory. Damage to the mammillary bodies, which receive a significant input from the hippocampal complex as occurs in chronic alcoholism with thiamine deficiency, produces a profound amnesia (Korsakoff’s syndrome) of both an anterograde (inability to lay down new memories) and retrograde (inability to recover old memories) nature. The latter feature distinguishes these patients from those who have hippocampal damage and may explain why patients with Korsakoff’s syndrome tend to invent missing information (confabulation).
The hypothalamus may also have a role in sexual and emotional behaviour independent of its endocrinological influences.

Did you know?

The hypothalamus is not only different in men and women but has been said to differ in homo- and heterosexual individuals.