Neurology: Consciousness and higher brain function

Neurology: Consciousness and higher brain function

Reticular formation and sleep

Sleep

Sleep is a characteristic of all mammals and is defined behaviourally as a reduced responsiveness to environmental stimuli, and electrophysiologically by specific changes in electroencephalographic (EEG) activity. In addition, there are a number of changes associated with autonomic nervous system (ANS) function.
Normal patterns of sleep are essential for human wellbeing, although it is still unclear why we need to dream.

EEG patterns during states of consciousness and slow-wave sleep

EEG recordings from normal awake subjects at rest show a characteristic high-frequency (13–30 Hz, β activity) low-voltage pattern. This desynchronized activity changes as the subject closes their eyes and becomes drowsy, with the new EEG pattern having a lower frequency (8–13 Hz, α activity) but slightly higher voltage. This pattern is said to be synchronized and results from the simultaneous firing of many cortical neurones following thalamocortical
activity.
EEG studies have revealed that sleep occurs in stages.

  1. As the subject falls asleep (stage 1), the EEG is similar to the awake EEG (low-voltage, fast activity).
  2. As sleep deepens through stages 2 and 3 to stage 4, the EEG amplitude progressively increases and its frequency falls. Stage 3 and 4 sleep is called collectively slow-wave sleep (SWS) or non-rapid eye movement (non-REM) sleep because the eyes are still.
  3. After about 90 minutes of sleep, the EEG changes back to a low-voltage, fast pattern that is indistinguishable from stage 1 non-REM sleep. However, during this phase of sleep there are rapid eye movements. This type of sleep is called rapid eye movement sleep (REM sleep), or paradoxical sleep because although the EEG is similar to that of an awake person, sleepers are difficult to arouse and muscle tone is absent. Most dreaming occurs during REM sleep, although that which takes place during non-REM sleep is said to have a higher emotional content with less detail.

Neural mechanisms of sleep

Sleep is an active process involving a number of neurotransmitter systems.

  • Cholinergic neurones in the ascending reticular activating system project via two pathways: a dorsal route through the medial thalamus and a ventral one through the lateral hypothalamus, basal ganglia and forebrain. Extensive thalamocortical projections provide the basis for widespread changes in cortical cell excitability.
    Activity in cholinergic neurones lead to an increase in arousal and cortical desynchrony. Activity in this system is also responsible for the pontine–geniculo–occipital (PGO) waves, at the onset of REM sleep.
  • Both noradrenergic neurones in the locus coeruleus and serotoninergic (5-hydroxytryptamine [5-HT]) neurones in the raphé nuclei are involved in controlling the balance between different sleep stages and sleep and arousal.
  • Neurones in the ventrolateral preoptic area (VLPA) send an inhibitory γ-aminobutyric acid (GABA)-mediated input to the locus coeruleus, raphé nuclei and tuberomammillary nucleus. The latter contains histaminergic neurones, which are likely to be the substrate for the sedative effects of antihistamine drugs.
  • Other brain regions implicated in sleep and arousal patterns include the suprachiasmatic nucleus of the hypothalamus.
  • A number of peptides have been identified as being associated with sleep states (e.g. orexins and delta sleep-inducing peptide [DSIP]) and appear to be involved in switching sleep–wake cycles.

Sleep disorders

Insomnia

Insomnia is the most common sleep disorder. It can be defined as the failure to obtain the required amount or quality of sleep to function normally during the day. Primary insomnia supposedly brought about by dysfunction of sleep mechanisms in the brain is rare, but these patients may require treatment with hypnotic drugs. Causes of secondary insomnia include psychiatric disease (especially depression and anxiety disorders), physical disorders, chronic
pain, drug misuse (e.g. excessive alcohol, caffeine), and old age.

Management of insomnia

Hypnotics are drugs that promote sleep. They include drugs acting at the benzodiazepine receptor (benzodiazepines and Z-drugs), chloral hydrate, chlormethiazole and barbiturates. Benzodiazepines and the more recent Z-drugs are by far the most widely used hypnotics. They also have anxiolytic, anticonvulsant, muscle relaxant and amnesic actions.

  • All the actions of benzodiazepines are believed to be caused by the enhancement of GABA-mediated inhibition in the CNS. GABAA receptors possess several ‘modulatory’ sites including one for benzodiazepines, which when activated causes a conformational change in the GABA receptor. This increases the affinity of GABA binding and enhances the actions of GABA on the Cl− conductance of the neuronal membrane. Any benzodiazepine given at night will induce sleep but a rapidly eliminated drug (e.g. temazepam) is usually preferred to avoid daytime sedation. Adverse effects of benzodiazepines include drowsiness, impaired alertness and ataxia as well as a low-grade dependence after a few weeks’ use. Suddenly stopping the drug may cause a physical withdrawal
    syndrome (anxiety, insomnia) that may last for weeks.
  • Some newer drugs do not have the benzodiazepine structure but are benzodiazepine-receptor agonists. These are the so-called Z-drugs, zopiclone, zolpidem and zaleplon. The Z-drugs have shorter half-lives than the benzodiazepines and are less likely to cause daytime sedation. They have a reduced propensity to tolerance
    and withdrawal and are becoming increasingly popular for the management of insomnia.

For many cases of insomnia, psychological strategies may be effective alternatives to drugs.

Hypersomnia (daytime sleepiness)

This is a serious but less common complaint than insomnia. Common causes of persistent daytime sleepiness include narcolepsy, obstructive sleep apnoea, drugs (e.g. benzodiazepines, alcohol) and depression (20% have hypersomnia rather than insomnia).

Narcolepsy

Narcolepsy is characterized by irresistible sleep episodes lasting 5–30 minutes during the day, often in association with cataplexy (loss of muscle tone and temporary paralysis) usually provoked by emotion, e.g. laughter, anger, as well as sleep paralysis and hallucinations at the time of going to or waking up from sleep. It has a very strong histocompatibility locus antigen (HLA) association (DR2/DQW1) and, while no pathological abnormalities have been detected in these patients, it is likely that there are abnormalities in the brainstem structures underlying sleep, as there
is evidence of short latency REM sleep during normal waking hours. In addition, deficiencies in hypocretins or orexins have recently been described in narcolepsy in some patients. The syndrome has a devastating effect on quality of life, which may be improved by long-term treatment with stimulants, e.g. dexamfetamine, methylphenidate and modafinil. Clomipramine is used to treat the cataplexy.

Obstructive sleep apnoea syndrome

This occurs if the upper airway at the back of the throat collapses when the patient breathes during sleep. This reduces the oxygen in the blood, which arouses the patient causing him or her to momentarily awake and prevents a normal sleep pattern. The patient, usually an overweight man, is often unaware of these awakenings, but the disruption to sleep results in daytime sleepiness and impaired daytime performance. It can be treated by weight loss,
positive ventilatory support at night and, occasionally, oropharyngeal surgery. If sleep apnoea is not treated it can lead to long-term cardiorespiratory problems such as pulmonary hypertension and right heart failure. It is also known that sleep apnoea can have a central nervous system origin.

Did you know?

Dolphins can put one hemisphere to sleep while keeping the other awake.

Consciousness and theory of mind

In this chapter we discuss what is meant by consciousness, and how this can be altered in certain pathological conditions. This ability to be aware of what we are doing, namely consciousness, is then discussed further in terms of how we can understand the thought processes of others, so-called theory of mind, disorders of which may underlie a range of conditions, especially autism.

Consciousness – what is it?

In thinking about consciousness, it is important to differentiate between the level and the content of conscious experience. The level of consciousness may also be referred to as the level of arousal while the contents of consciousness refers to the objects and occurrences of which we are aware. Of course, the contents of consciousness
will be affected greatly by the level of consciousness but these two phenomena are likely to be at least partly dissociable. For example, people in hyperaroused states may be less aware of surroundings than less-aroused individuals. Conversely, it has recently been shown that individuals in a vegetative state may actually show
neurophysiological patterns of activity (as measured by functional magnetic resonance imaging [fMRI], indicating a much richer level of awareness than their immobile unresponsive state would suggest.

In general, experimental and clinical access to the contents of consciousness relies on verbal report and certain behavioural indicators. We may ask a subject to tell us or to indicate whether they are aware of a stimulus in the periphery of their visual field. We may assess their memory by requiring them to indicate whether they have an awareness of a particular stimulus that was previously presented to them. We may also attempt to ascertain the
richness of their awareness through such measures; with respect to memory, for example, does the subject truly recollect a prior presentation or do they simply have a strong sense that it is familiar?

An important observation with respect to the contents of consciousness is that while our awareness obviously defines our experience of the world, the explanations that they provide for our behaviour is only partial and may be inaccurate. This was shown strikingly in an experiment by Libet and colleagues, who required volunteers to make periodic movements while simultaneously recording cerebral activity. They showed that subjective assessments of becoming aware of an intention to move actually occurred some 500 ms after there had been a brain response. This finding, subsequently replicated, suggests that our brain can indicate what we are about to do before we are aware of wanting to do it.

Further evidence of a discrepancy between what we are aware of and what we actually do comes from work by Castiello and colleagues. These authors showed that when subjects receive incorrect feedback about the trajectory of an arm movement that they are in the process of making, they will correct the movement without actually being aware of doing so, even when the correction made is relatively large. Furthermore, when asked to reproduce the movement that they have just made, subjects will reproduce the one that mirrors the incorrect feedback that they were given, further suggesting that they were unconscious of the control that they have exerted over the movement.

It is also the case that previously experienced events or objects may influence our ongoing actions and decisions without necessarily re-emerging into consciousness. The occurrence of basic processing outside our awareness would seem to be an efficient way of freeing our conscious processing to deal with more complex problems. However, it should be remembered that there are clear instances where the contents of consciousness may have a marked
impact on lower level processes. For example, Haggard and colleagues showed that subjects who have made a willed (conscious) movement are likely to link more closely in time that movement with an outcome than when the movement is not felt to be consciously initiated (if it is produced by application of a brief magnetic field over the motor cortex).

Thus, consciousness enables actions to gain greater prominence in our memory, but much of what we do routinely does not require this to happen. As to the precise neurobiological origin of consciousness, this is unknown, but the coordinated activity of the cortex and its reciprocal connections to the thalamus and diffusely projecting brainstem nuclei is important. This is best illustrated in patients in a vegetative state (see below) and blindsight (see Chapter
26). In this latter condition there is damage to the primary visual cortex such that individuals cannot consciously see but when tested it is clear that their visual system can detect stimuli of different forms including colour and motion. It is thought to arise from the intact extrastriate visual areas, which cannot feedback to the primary visual cortex, as a result of which conscious visual perception is lost.

Consciousness and theory of mind

As humans, we may be unique in being conscious of our consciousness. This “thinking about thinking” has been referred to as ‘meta-representation’ and it is perhaps the ability to represent our own mental states and those of others that facilitates and shapes our most complex social interactions. To be able to represent the mental states of others has been referred to as having a theory of mind. We use this theory of mind to interpret, explain and predict many of the actions and utterances of other people. If someone is being sarcastic or deceitful, they say and do precisely the opposite of what they feel. By understanding these possibilities their behaviour may become more logical and predictable to us.

What happens if we have difficulty with theory of mind processing? It has been suggested that the isolation and very limited social repertoire of individuals with autism may arise from the difficulty that they have in understanding the mental states of other people. There is also evidence that people with schizophrenia may have deficits in theory of mind abilities and in both cases the abnormality underlying this deficit is thought to reside in the prefrontal cortex.

Vegetative state

Some patients who have a major global brain injury (e.g. anoxia secondary to a cardiac or respiratory arrest) can end up in a state of unresponsive wakefulness or a vegetative state (which is said to be permanent if it continues for more than six months to a year depending on the nature of the original insult). In this state the patient clearly has periods of sleep and wakefulness, but during the latter time they are unable to respond to any stimuli as there is extensive damage above the level of the arousal systems in the brainstem. In some cases the responses to such stimuli are present, but inconsistently so, and such individuals are deemed to be in a minimally conscious state (MCS).

It is important that all individuals in a vegetative state or MCS are investigated thoroughly over time using a range of stimuli and functional imaging. This is because although some patients appear not to be able to respond there is evidence of cortical activation with sensory stimuli on functional imaging. In these cases, the patient may have had a more focal injury to the upper brainstem that prevents them from being able to make any clear motor responses to stimuli – the so-called locked-in syndrome. Once diagnosed, such patients may be able to communicate
through the use of eye movements and blinking.

Did you know?

Some patients with autism can show savantism (as was demonstrated by Dustin Hoffman in the film Rain Man), a condition in which the person shows a remarkable talent that is in striking contrast with their overall limitations. This is thought to relate to the way in which the person uses detail focused processing.

Limbic system and long-term potentiation

Anatomy of the limbic system

Many different definitions of the limbic system exist, and in this chapter we will be restricting our definition to structures that lie primarily along the medial aspect of the temporal lobe: cingulate gyrus, para hippocampal structures (post subiculum, para subiculum, pre subiculum and perirhinal cortex), entorhinal cortex, hippocampal complex (dentate gyrus, CA1–CA4 subfields and subiculum), septal nuclei and the amygdala. Additional structures closely associated with the limbic system include the mammillary bodies of the hypothalamus, the olfactory cortex and the nucleus accumbens.

The anatomical organization of the limbic system indicates that it performs some high level processing of sensory information, given its input from the associative cortical areas. The predominant outflow of the limbic system is to the prefrontal cortex and hypothalamus as well as to cortical areas involved with the planning of behaviour, including motor response. Thus, anatomically the limbic system appears to have a role in attaching a behavioural significance and response to a stimulus, especially with respect to its emotional content. The hippocampal complex has been shown to have both a high degree of susceptibility to hypoxia and yet a remarkable degree of plasticity, which helps explain why this structure is important in the generation of epileptic seizures as well as memory acquisition. It is also one of the major sites for neurogenesis in the adult brain, which may also be important in some forms of memory and mood functions.

Functions of the limbic system

Hippocampal complex and para hippocampal structures

The original description in the 1950s by Scoville and Milner of patient HM with bilateral anterior temporal lobectomy and a resulting profound amnesic state suggested that this area of the brain had a major role in memory. Subsequently, the hippocampus proper and para hippocampal areas were shown to have a role in the acquisition of information about events, although the major role of the hippocampus itself probably relates more to spatial memory.

However, the long-term storage of memories occurs at a distant site, probably within the overlying cerebral cortex – as demonstrated by the pattern of memory loss seen in dementia of the Alzheimer type (DAT) namely well-preserved retrograde memory (for distant events such as childhood) in the face of severely impaired or absent anterograde memory (inability to remember what the patient has just done).

Amygdala

The amygdala is a small, almond-shaped structure made up of many nuclei that lies on the medial aspect of the temporal lobe. Damage to this structure experimentally leads to blunted emotional reactions to normally arousing stimuli, and can even prevent the acquisition of emotional behaviour. In humans with selective amygdala damage there appears to be a profound impairment in the ability to recognize facial expressions of fear. Conversely, stimulation of this structure produces a pattern of behaviour typical of fear with increased autonomic activity. This is sometimes
seen clinically in temporal lobe epilepsy, in which patients complain of brief episodes of fear.

Cingulate gyrus

The cingulate gyrus running around the medial aspect of the whole hemisphere has a number of functions, including a role in complex motor control, pain perception and social interactions. Damage to this structure can produce motor neglect, as well as reduced pain perception, reduced aggressiveness and vocalization, emotional blunting and altered
social behaviour which can result in a clinical state of akinetic mutism (not talking or moving). Stimulation of this area, either experimentally or during an epileptic seizure, produces alterations in the autonomic outflow and motor arrest, with vocalization and complex movements.

Long-term potentiation

Long-term potentiation (LTP) is defined as an increase in the strength of synaptic transmission with repetitive use that lasts for more than a few minutes, and in the hippocampus it can be triggered by less than 1 second of intense synaptic activity and lasts for hours or much longer. It can be induced at a number of CNS sites but especially the hippocampus, and it has therefore been postulated to be important in memory acquisition. However, different mechanisms may underlie LTP at different synapses within the hippocampal complex, and most of the work is based on the
excitatory glutamate synapse in the CA1 subfield of the hippocampal complex.

The current model of LTP is as follows:

Stage 1 (see figure): An afferent burst of activity leads to the release of glutamate from the presynaptic terminal.

Stages 2 and 3: The released glutamate then binds to both Nmethyl- D-aspartate (NMDA) and non-NMDA receptors in the postsynaptic membrane. These latter receptors lead to a Na+ influx (stage 2) which depolarizes the postsynaptic membrane (stage 3).

Stage 4: The depolarization of the postsynaptic membrane not only leads to an excitatory postsynaptic potential (EPSP), but also removes Mg2+ from the NMDA-associated ion channel.

Stage 5: The Mg2+ normally blocks the NMDA-R associated ion channel and thus its removal in response to postsynaptic depolarization allows further Na+ and Ca2+ influx into the postsynaptic cell.

Stage 6: The Ca2+ influx leads to the activation of a postsynaptic protein kinase, which is responsible for the initial induction of LTP – a postsynaptic event.

Stage 7: The maintenance of LTP, in addition to requiring a persistent activation of protein kinase activity, the insertion possibly of more postsynaptic glutamate receptors (stage 7a) and changes in gene transcription (stage 7c), may also require a modification of neurotransmitter release (stage 7b), i.e. an increase in transmitter release in response to a given afferent impulse. The presynaptic modification, if necessary in the maintenance of LTP, means that the postsynaptic cell must produce a diffusible secondary signal that can act on the presynaptic terminal such as permeant arachidonic acid metabolites, nitric oxide, carbon monoxide and platelet activating factor.

In some circumstances long-term depression (LTD) can be induced in the mossy fibre synapses in the CA3 subfield of the hippocampus. This, in contrast to LTP, is thought to be mediated by a presynaptic metabotropic glutamate receptor.

Did you know?

It has been reported that London taxi drivers have bigger hippocampi compared with other people because of the fact that they have to constantly remember complex maps and routes of the city.

Memory

The term memory is commonly used to refer to the ability to remember information but it is important to understand that there are several different types of memory that subserve different functions. In the first instance, there is a distinction between motor and non-motor memories – the former is a form of implicit memory and typically involves the cerebellum, motor cortical areas and basal ganglia and will not be discussed further in this chapter. The other forms of memory are more involved with the taking in, manipulating and storing of information for problem solving (working memory), events and factual knowledge (explicit memory).

In clinical practice it is not uncommon for patients and their families to complain about disorders of memory when they are referring to a range of different cognitive problems such as a deficit in language, attention or perception. In this chapter we discuss the different types of memory, their neurobiological basis, and disorders that affect these different
systems and their clinical manifestations. In particular it is useful to distinguish between long-term and working memory (which is often erroneously referred to as short-term memory). While this distinction relates to the duration of a memory, it primarily refers to whether material is maintained in consciousness (working memory) or whether it is stored unconsciously and then retrieved into consciousness (long-term memory).

Working memory

Definition

Working memory is the limited capacity (around seven items or chunks of information) to store information in consciousness that rapidly disappears when attention is diverted. A distinction is typically made between processes required for maintaining material and the control (‘executive’) processes required for manipulation of that material. Maintenance processes would typically be engaged by reciting a list of digits and requiring a subject to repeat them
immediately (digit span). Executive control processes might be tested by requiring the subject to repeat the digits in reverse order.

Neurobiological basis and disorders of working memory

Studies in humans and monkeys have unequivocally demonstrated the importance of the lateral prefrontal cortex in working memory processes. It has been suggested that different parts of the prefrontal cortex are important for the maintenance and control processes that constitute working memory. Other brain regions are clearly implicated in working memory processes in a modality-dependent way. Working memory for visuospatial material may rely on occipitotemporal regions (when remembering, for example, the visual properties of an object) or occipitoparietal
regions (when remembering spatial properties). On the other hand, holding verbal or phonological material in working memory seems to require the lateral temporal cortex. Whatever the domain, it appears that the efficient flexible use of working memory processes depends upon coordinated interactivity of frontal control processes and modality-dependent ‘slave’ systems.

Abnormalities in this system typically occur with damage in the sites listed above, especially the prefrontal cortex, as well as in some disorders of the basal ganglia (e.g. Huntington’s and Parkin- son’s disease) where there is disruption of corticostriatal circuits. In these patients there is a difficulty in taking in information and as such the individuals have difficulty solving problems that require the ongoing manipulation of data.

Long-term memory

Long-term memory is the store of practically unlimited capacity and the memories within this system may persist over a lifetime. Long-term memory is primarily divided in to explicit and implicit components.

  • Explicit memory refers to memories that are accessible to consciousness. It is divided into episodic memory (memory for episodes or events; typically, memory with an autobiographical content) and semantic memory (knowledge of facts; memory that is not characterized by an autobiographical content). Thus, an episodic
    memory of Paris might comprise the memory of a visit there, while a semantic memory is that Paris is the capital of France, situated on the Seine, etc.
  • Implicit memory refers to memory that is not accessible to consciousness and typically refers to motor memory; it encompasses the acquisition of motor skills, conditioning (e.g. Pavlov’s dogs salivating when hearing a bell), as well as priming. This latter process is defined as the subject’s ability to provide answers to general questions (e.g. the word ‘Paris’ when asked to name a city), even when they do not remember this prior exposure.

Neuroanatomical basis and disorders of long-term memory

The famous case of HM, in whom both medial temporal cortices were removed for intractable epilepsy, provided the first clear evidence that the episodic memory system depends on medial regions of the temporal lobe. In addition, his case also highlighted the difference between explicit and implicit memories and that different systems underlie episodic and semantic memory at the neuroanatomical level. Subsequent to his operation, HM was unable to learn or recall new episodes or experiences in his life. However, his ability to learn new motor skills was preserved as was his factual knowledge. While there is a great deal of evidence underpinning the importance of medial temporal structures, especially the hippocampus, in episodic memory processes, it is clear that, as with working memory processes, distributed brain systems, frequently requiring pre-frontally mediated control, are necessary for optimum
autobiographical memory processes. In this respect, patients with certain forms of neurodegenerative disorders
with relatively widespread pathology may have profound disorders of long-term memory, as for example in Alzheimer’s disease. In this condition there is pathology within the hippocampus and related structures as well as temporal and parietal cortices, and patients develop problems of anterograde memory (i.e. the laying down of new memories) followed by progressive problems with retrograde memory (the retrieval of preformed established memories). This distinction in anterograde and retrograde memories is thought to have a basis in transferring information from hippocampal structures to the overlying cortex and thus as the pathology spreads out so the memory processes are affected in a similar fashion. While in Alzheimer’s disease the initial memory problem is more of an episodic nature, in some people there are problems within the semantic memory system. These cases of semantic dementia, wherein individuals begin to lose their knowledge of the meanings of words, depends on damage to the inferior and lateral temporal cortices and is seen in some patients with frontotemporal dementia (FTD).

Did you know?

Henry Gustav Molaison better known as HM, died in 2008 aged 82. He had been studied by neuroscientists for 55 years.

    Emotion, motivation and drug addiction

    Emotion

    Initial attempts to understand the brain bases of emotions focused on the limbic system, with the amygdala as the key component in the system thought to be central to emotional processing. The evidence to support such an association has already been discussed in part, but it is also worth mentioning the Klüver–Bucy syndrome. This condition is seen with bilateral amygdala damage and is characterized by, among other phenomena, an apparent absence of the normal fear response and by marked placidity.

    In addition, functional neuroimaging studies in humans have been consistent with animal studies, implicating the amygdala in the processing of emotional stimuli and, notably, in fear conditioning (wherein a previously neutral stimulus can, through association with an unpleasant outcome, produce a fear response when presented alone). It is proposed that the amygdala is the critical site in which: the necessary associations between the stimuli are
    formed using a process akin to the long-term potentiation (LTP) seen in the hippocampus; and the origin of the broad series of phenomena that constitute a fear response through its efferent projections.

    Motivation

    Emotions are potentially useful in that they are allied with, and perhaps consist of, behavioural responses. They may be critical in helping us choose between competing behavioural possibilities and to guide behaviours that maximize rewarding and minimize punishing outcomes. The relationship between emotion and motivation is therefore an important one. In this respect, the dopamine systems, most notably the mesolimbic system, which has connections with the amygdala, appear critical.

    A series of hypotheses have been put forward concerning the dopaminergic contribution to motivation.

    • Hedonia hypothesis: whilst dopamine has been thought to be critical to the experience of pleasure. There is increasing evidence against this view.
    • Learning hypothesis: dopamine is critical to learning the relationship between stimuli and rewards. Dopamine acts as a ‘teaching signal’ for stimuli that predict rewards and thus is the origin of behaviour that makes the reward manifest.
    • Activation hypothesis: dopamine is required for the actual engagement in work that must be done to obtain the reward. It is important for both the attentional and the locomotor components of the work involved in reward-seeking and consumption.
    • Incentive salience: dopamine is important in imbuing certain stimuli with motivational or incentive properties.

    It would be simplistic to express motivational processes solely in terms of the input of the mesolimbic dopamine system to the amygdala but it is nevertheless a useful model by which to explain drug addiction.

    In addition to the motivational properties of specific stimuli, in many circumstances we must consider motivational states that appear stimulus independent. Feeding behaviours, for example, arise not solely from the motivational properties of foods (sight, smell, taste) but also from a drive state (hunger) dependent on a number of homeostatic factors, for example endocrine signals (levels of insulin, and of the hormones leptin and ghrelin which, respectively, reduce and promote feeding behaviour) acting predominantly through the hypothalamus. A comprehensive description of a motivational state would require several levels of description together with an understanding of the interactions inherent in the state; for example, the extent to which motivational properties of stimuli themselves influence, and/or are influenced by, the drive state of the individual. An additional, important concern is when individuals are motivated towards behaviours that are at odds with their homeostatic requirements and consequently detrimental to health, as is the case with addictive behaviours.

    Drug addiction

    Using some recreational drugs can be rewarding, but the evidence is that addictive behaviours (and associated withdrawal phenomena) are determined by how the brain adapts in response to repeated drug administration rather than as a direct result of the fact that drugs may be intensely pleasurable. Conversely, although the reward properties of the drug are insufficient to explain addictive behaviours, it is simplistic, too, to consider addiction solely as
    behaviours aimed towards avoiding withdrawal symptoms. In addition to considering addiction in terms of the pursuit of pleasurable states (drug-induced euphoria) or the avoidance of withdrawal states (an array of physical and psychological symptoms which may actually be produced simply by a stimulus or environment that has become associated with previous withdrawal), we must also take into account what may be considered a markedly
    augmented state of motivation to taking the drug – referred to as craving. Important in this respect is the fact that a craving may be precipitated by a drug-related stimulus or environment long after the individual has recovered from the withdrawal symptoms.

    Other important phenomena that need to be explained are tolerance (a requirement for increased frequency and/or dose of the drug with repeated usage) and sensitization (in contrast to tolerance effects, some of the consequences of the drug may actually increase with repeated ingestion). Interestingly, neither tolerance nor sensitization are explicable in purely pharmacological terms because both phenomena also show certain features suggesting that they are conditioned responses. One view that has been put forward to account for the simultaneous occurrence of tolerance
    and sensitization is that while the pleasurable effects of the drug diminish with repeated administration (leading to tolerance), the drug and related environments and paraphernalia become, over time, more likely to capture attention and to precipitate the associated behaviours (sensitization).

    While the neurobiological basis of drug addiction is still not fully understood, there is increasing evidence that it involves mesolimbic dopamine systems and genetic susceptibilities, which may in turn affect the normal functioning of this pharmacological system. An example of this is the recent recognition that some patients with Parkinson’s disease develop abnormal behaviours with their dopaminergic therapies – the so-called dopamine dysregulation syndrome which can involve pathological gambling and hypersexuality.

    Did you know?

    Oestrogens have been shown to promote memory functions.

    Neural plasticity and neurotrophic factors I: the peripheral nervous system

    The peripheral nervous system (PNS) is capable of significant repair, to some extent independent of the age at which damage occurs. In contrast, the central nervous system (CNS) has always been thought of as being unable to repair itself, although there is now mounting evidence for considerable plasticity within it even in the adult state and that most, if not all areas of the CNS, are capable of some degree of reorganization.

    Repair in the peripheral nervous system

    Injury to a peripheral nerve if severe enough will cause permanent damage with loss of sensation, loss of muscle bulk and weakness. However, in many cases the nerve is able to repair itself, as the peripheral axon can regrow under the influence of the favourable environment of the Schwann cells. This is in contrast to the CNS where the neuroglial cells (astrocytes and oligodendrocytes) are generally inhibitory to axonal growth, even though most CNS neurones are capable of growing new axons.

    When a peripheral nerve is damaged, the distal aspect of the axon is lost by the process of wallerian degeneration. Wallerian degeneration leads to the removal and recycling of both axonal and myelin-derived material, but leaves in place dividing Schwann cells inside the basal lamina tube that surrounds all nerve fibres. These columns of Schwann cells surrounded by basal lamina are known as endoneurial tubes, and provide the favourable substrate for axonal growth.

    Following injury, the degenerating nerve fibre elicits an initial macrophage invasion and this in turn provides the mitogenic input to the Schwann cell. The regenerating axon starts to sprout within hours of injury and contacts the Schwann cell basal laminae on one side, and the Schwann cell membrane on the other. The Schwann cell basal lamina is especially important in the process of axonal sprouting as it contains a number of molecules that are powerful promoters of axonal outgrowth in vitro (e.g. laminin and fibronectin).

    In addition to providing a substrate for axonal growth, Schwann cells also produce a number of neurotrophic factors, including nerve growth factor (NGF; see below). Thus, the Schwann cell provides a substrate along which the regenerating axon can grow, as well as providing a favourable humoral neurotrophic environment. It also helps direct the regenerating axon back to its appropriate target, by means of the endoneurial tube. Occasionally, the regrowth of the axons is inaccurate or incomplete so, for example, following damage to the third cranial nerve one can have aberrant regeneration such that there is elevation of the eyelid on looking down.

    In contrast to axonal damage, the loss of the cell body (in the ventral horn or dorsal root ganglia) leads to an irreversible and permanent loss of axons in the peripheral nerve. Examples of such disorders include poliomyelitis and motor neurone disease (MND) with respect to the -MN, and a number of inflammatory and paraneoplastic syndromes in the case of the dorsal root ganglia. In all these cases the loss of axons is secondary to the loss of the cell body and so no regeneration is possible. Attempts to rescue dying -MN in MND via the peripheral delivery of neurotrophic factors have been made without much success to date.

    Neurotrophic factors

    The number of identified neurotrophic factors has expanded greatly since the original description of the first of these, NGF. These factors, many of which are also found to influence nonneural populations of cells, form discrete families that act through specific types of receptors. Many of these receptors are composed of subunits, one or some of which form common binding domains for a family of neurotrophic factors. For example, the neuro-trophin family of neurotrophic factors and the trk receptors use a range of cytoplasmic tyrosine kinases as part of their signalling
    mechanism.

    Many populations of neurones respond to neurotrophic factors experimentally both in vitro and in the lesioned animal. However, despite these encouraging results, administration of neurotrophic factors to patients in clinical trials of neurodegenerative disorders and neuropathies has met with only limited success. This argues against these disorders being the result of specific neurotrophic factor deficiencies. More recently, greater success has been achieved with the direct infusion of neurotrophic factors into the brain parenchyma rather than using the cerebrospinal fluid (CSF) or periphery, e.g. glial cell line derived neurotrophic factor (GDNF) in Parkinson’s disease.

    Did you know?

    Salamanders can regrow their complete limbs over the course of a few weeks.

    Neural plasticity and neurotrophic factors II: the central nervous system

    There is now mounting evidence that regeneration and reorganization can occur in the adult central nervous system (CNS). However, plasticity in the CNS is probably not due to a major production of new neurones, as most neurones in the mature CNS are postmitotic, but to their ability to extend branching new axons. The time at which this is most florid is in the early postnatal period when the systems of the brain are developing, and it is during this time that major modifications can be made.

    The mechanisms underlying this plasticity are not fully known, but the production and uptake of factors promoting neuronal growth and survival (neurotrophic factors) are important.

    Plasticity in the developing visual system

    In their pioneering studies, Hubel and Wiesel demonstrated that at birth the input to lamina IV of the primary visual cortex (V1) is diffuse, and that it is only during the critical period of development (in cats this is up to 3–14 weeks of postnatal life while in humans it may be several years) that these inputs segregate and form the basis of ocular dominance columns.

    The segregation of input is dependent on the amount and type of activity within the afferent pathway from each eye; the greater this is, the more likely it is that the afferent input will gain control over those cortical neurones. Thus, ocular dominance (OD) columns will form in the absence of competition between the input from the two eyes but will not develop when there is no afferent input from either eye.

    Hubel and Wiesel experimentally manipulated the inputs by initially depriving one eye of an input by suturing it shut (monocular deprivation) and then reversing the procedure in later experiments (‘reverse suturing’). Monocular deprivation created an expansion of the thalamic influence from the unsutured eye in layer IV with a subsequent shift in OD columns so that more cortical cells were under the control of the open eye. This pattern could be rapidly changed by ‘reverse suturing’ during the critical period, which implies that the initial shift in thalamic influence on cortical
    cells is caused by the activation of synapses that were present but functionally suppressed as there is not enough time for any axonal outgrowth. However, in time, the initially suppressed synapses from the uncompetitive eye would be physically lost as the active thalamic input takes over the control of cortical cells.

    The correct segregation of the ocular inputs into V1 as OD columns is important for the generation of many of the other visual functions in V1. However, once outside the critical period the ability to modify the visual cortex in such a fashion is reduced, but not lost.

    Plasticity in the adult state

    Somatosensory system and the vestibulo-ocular reflex

    It is now known that the somatosensory system is capable of being remodelled in the face of alterations in the input from the peripheral receptors. Thus, the loss of input from a digit (e.g. by amputation) does not lead to a permanently silent area of cortex, but instead the adjacent cortical areas with sensory inputs from adjacent digits would sprout axons and exert influence over this initially silent cortical area.

    Conversely, increased afferent information in a sensory pathway results in an expansion of the cortical area receiving that input. Simplistically, it can be imagined that the activity in a given afferent induces the production of a neurotrophic factor in the postsynaptic cell, which then binds to the appropriate receptor in the active presynaptic terminal, promoting its growth and survival. In this way the CNS is constantly remodelling itself based on the
    amount and type of ongoing afferent information.

    Subsequently, it was discovered that major sensory deficits, such as the deafferentation of a whole limb, produces similar results, which implies that the reclaiming of cortical areas by adjacent inputs is not solely achieved by the local sprouting of axons in the cortex.

    Occasionally, this plasticity may go awry in certain situations, such as in dystonia. In this condition, abnormal plasticity in the primary motor and sensory cortices is thought to cause abnormal activation of muscles, and this results in abnormal posturing of a body. A further example of the plasticity of the mature CNS is seen with the vestibulo-ocular reflex. The vestibular system provides a signal to the CNS on head velocity and this is relayed to the cerebellum via mossy fibres. However, the other input to the cerebellum – the climbing fibre – can provide information on the degree to which the image is slipping across the retina (the degree to which eye movements are compensating or not for head movement). This input from the climbing fibre is not only important in providing a signal on the degree to which the reflex is working or not (i.e. provides an error signal), but also gives a critical input to correct it. Thus, if one alters the relationship between ocular and head movements by having the patient wear prisms, for example, the reflex adapts with time to compensate for the new relationship and this adaptation is possible because the climbing fibre input can modify the parallel fibre (and so indirectly mossy fibre) input to the Purkinje cell. The basis for this latter modification at the level of the Purkinje cell is an intracellular process and is termed long-term depression (LTD).

    Neural stem cells

    In many adult tissues, cell loss occurring through natural attrition or injury is balanced by the proliferation and subsequent differentiation of stem cells. In the adult CNS this was thought not to be the case, but recent evidence has shown that neural precursor cells are to be found in the mature CNS of mammals including humans. These cells are mainly found in the hippocampus and around the ventricles (in the subventricular zone) and appear to be able to form functionally active neurones. However, their role in plasticity and repair is unknown, but in the dentate gyrus of the
    hippocampus these cells may have a role in memory and mediating the effects of various hormones (e.g. cortisol/corticosterone) and drugs (e.g. antidepressants) on CNS function.

    Limits on the regenerative capacity of the adult central nervous system

    The regenerative capacity of the CNS is limited by:

    • neurones are postmitotic in the mature CNS, and the stem cell population is small and localized to certain sites;
    • glial cells in the CNS are generally inhibitory to axonal outgrowth.

    Astrocytes produce signals that stop axons growing and oligodendrocytes produce a number of factors that repel axons or even cause the approaching axonal growth cone to collapse. Attempts to overcome these inhibitory signals are now entering early clinical trial in patients with spinal cord damage.

    Did you know?

    Rita Levi Montalcini, who won the Nobel Prize for her co-discovery of neurotrophic factors, did much of her early experimental work in this area in a laboratory she set up in her apartment.