The Biology of Psychological Disorders

David Linden

• Publisher: Bloomsbury Academic
• Year: 2018
• Print ISBN:
  9781137610416
• Edition: 2
• eBook ISBN:
  9781350312463
• Topic: Psychology
• Subtopic: Experimental Psychology
• Index: Psychology

This textbook introduces the reader to some of the most common psychological disorders, from schizophrenia, depression and substance abuse to disorders of childhood, adolescence and ageing. Coverage of these disorders is combined with a comprehensive grounding in the fundamentals of neurobiology and the principles of psychopharmacology that underpin their treatment. Written by David Linden, Scientific Director at the School of Mental Health and Neuroscience at Maastricht University, The Biology of Psychological Disorders sits at the intersection psychology, psychiatry, biology and neuroscience. Aimed primarily at undergraduate psychology students, it is also of relevance to trainee psychiatrists and clinicians. New to this Edition:
- Two completely new chapters on the immune system and mental health, and on environmental influences on brain development
- Incorporates recent advances in genetics and psychopharmacology
- Updated chapters in accordance with the DSM-5
- Discusses biological aspects of psychological interventions and psychological disease models
- Suitable for neuroscience curriculum for trainee psychiatrists
- New 'controversies' feature that promotes critical thinking skills by exploring the validity of disease concepts and evidence bases

Part I

BASIC NEUROSCIENCE AND RESEARCH METHODS

1

NEUROANATOMY

PREVIEW

A solid knowledge of the structure of the brain at several levels of description is a key to understanding its functions and dysfunctions. This chapter will therefore deal with the anatomy of the brain from the level of single cells, the neurons and the non-neuronal cells of the brain (the glia), through that of groups of cells, for example small networks or cortical layers, to that of anatomically or functionally defined brain areas or pathways. For each level of anatomical description, we will also discuss the relevant tools of investigation, for example the different microscopic techniques (see Box 1.1), staining methods and neuroimaging techniques, and their relevance to the biology of specific mental disorders.

1.1THE NEURON IS THE BASIC BUILDING BLOCK OF THE NERVOUS SYSTEM

The basic building block of the nervous system is the nerve cell, or neuron. It is estimated that the human brain, which weighs on average 1.5 kg or 2% of body mass in an adult, contains about 80 billion (1 billion = 1,000,000,000) neurons and about the same number of glia cells. The cerebral cortex (with the underlying white matter) accounts for about 80% of brain mass but only about 20% of the number of neurons, whereas about 80% of neurons are in the cerebellum, which makes up only 10% of brain mass. The rest of the brain, including the basal ganglia and the brainstem, accounts for less than 10% of brain mass and less than 1% of brain neurons. This large difference between the proportions of brain mass and neurons found in different regions of the brain indicates that factors other than the sheer number of neurons influence brain size and weight. These include the ratio of glia cells to neurons, which varies across brain regions, and the size of the neurons, particularly their dendritic trees and axons. For example, the white matter contains mainly axons originating from cortical neurons and glia cells, but few neurons for its vast size (Azevedo et al., 2009). The human brain is the largest primate brain and, although several mammals (e.g. elephants and whales) have larger brains, they may actually have lower overall numbers of neurons (Herculano-Houzel, 2009). Thus, number of neurons, rather than brain size, may correlate most closely with intellectual abilities across species.

1.1.1Neurons share many features with other cells

Like all other eukaryotic cells, the neuron has a nucleus that contains the chromosomes and thus the genetic information coded in its DNA (see Chapter 5). The cell body (soma) also contains the mitochondria, which are the main site of the generation of adenosine triphosphate (ATP), the main energy storage molecule, through the metabolism of pyruvate, a product of the breakdown of glucose (glycolysis) in the Krebs cycle. Through glycolysis and the various steps of the Krebs cycle and cellular respiration one glucose molecule can yield up to 38 ATP molecules. This is the main source of energy for the signalling processes within and between neurons (see Chapter 2). Cellular respiration (also called oxidative metabolism) is the main oxygen-consuming process in the body. In this process glucose is oxidised to carbon dioxide and water. This oxidative (or aerobic) metabolism of glucose is far more efficient than the anaerobic pathway to lactate, which needs to be taken when oxygen supply is scarce but results in only two ATP molecules per glucose molecule. The brain, which normally receives about 20% of the body’s blood supply, is particularly vulnerable to even short drops of blood (and oxygen) supply, which can result in hypoxic brain damage. Because of their specific function and separate structure with their own membrane mitochondria are counted amongst the ‘organelles’ of the cell. Other organelles include:

•the rough endoplasmic reticulum (ER), which is covered with ribosomes, the sites of protein synthesis, but also hosts a variety of enzymatic processes, including the production of precursors of peptide neurotransmitters;

•the smooth ER, site of the synthesis of phospholipids, steroids and fatty acids and carbohydrate metabolism, and involved in membrane receptor trafficking;

•the Golgi apparatus, which plays an important part in the modification, transport and excretion of macromolecules such as proteins or lipids (Figure 1.1).

Like all animal cells, the neuron has as its outer boundary a lipid bilayer membrane, which separates the cytoplasm from the extracellular environment. The bilayer structure results from the composition of the membrane out of phospholipid molecules that are hydrophilic at one end and hydrophobic at the other. The hydrophobic tails pair with each other, while the hydrophilic heads point to the watery extra- and intracellular environments (which are essentially solutions of electrolytes and proteins). Interspersed in this phospholipid bilayer are intra- and transmembrane proteins, which can serve as receptors for neurotransmitters or ion channels (or both, in the case of ionotropic receptors). The cell membrane is largely impermeable to electrically charged molecules, meaning that electrolytes, amino acids and polar macromolecules such as proteins will pass only through the dedicated channels or other passive or active transport mechanisms (Figure 1.2).

Figure 1.1

Structural elements of neurons

This schematic drawing shows the basic structure of a neuron (light grey) and its main elements, whose functions are explained in Section 1.1.1. Neurons have many dendrites, which relay input from other neurons (e.g. from the dark grey axon in the upper half of the figure), but normally only one output path (the axon), which branches out into multiple terminals.

Figure 1.2

The cell membrane

The membranes of neurons and other cells (and of intracellular structures such as the nucleus and vesicles) consist of a lipid bilayer. The lipid molecules are drawn schematically with a head and tails. The head is hydrophilic (water-loving) and points outwards (to the extracellular fluid space, above, or the intracellular fluid, below), whereas the hydrophobic (water-avoiding) tails point inwards. Interspersed are transmembrane proteins, for example ion channels (shown in open conformation, left, and in closed conformation, right), for the transport of polar molecules (ions shown as black balls).

1.1.2Dendrites and axons are the specific projections of neurons

The two prominent specific structural elements of the neuron are its processes, the dendrites and the axon (there is normally only one). These projections are supported by the cytoskeleton, which is formed by three main protein-based structures: the microtubules, neurofilaments and microfilaments. The dendrites (derived from déndron, the Greek word for tree) form tree-like patterns, branching out from the cell soma in all directions, with tapering diameter and ever finer ramifications whose number per cell can go into the thousands. They receive input from other neurons through synapses formed with the synaptic terminals of the axons of those ‘presynaptic neurons’. The dendritic membrane is then called ‘postsynaptic’. The main function of dendrites is to generate and integrate postsynaptic potentials and intracellular signalling cascades, which are discussed in more detail in Chapter 2. The axon (Greek for axle) is a single projection which can vary in length between micrometres (µm) (for local intracortical projections) and over 1 metre (for motor or sensory neurons in large animals). It grows out of the axon hillock and then maintains an equal diameter across its length, branching out at the end into the synaptic terminals that form the synapses with further – ‘postsynaptic’ – neurons. Many vertebrate axons are coated in sheaths of myelin, an insulating substance consisting of lipids and proteins and formed by Schwann cells in the peripheral nervous system (PNS) and oligodendrocytes (a type of glia) in the central nervous system (CNS). The myelin sheath is interrupted by gaps called ‘Ranvier nodes’. These 1–2 µm-long myelin-free segments allow for the exchange of ions between the axon and the extracellular milieu. Myelination increases the resistance of the axonal membrane and speeds up the conductance of neuronal currents. Most neurons of the CNS become myelinated at some point during development, although CNS myelination is fairly sparse at birth. All lower motor neurons of the PNS and most classes of sensory neurons (except the C-fibres from temperature and pain receptors) are myelinated, as are the preganglionic neurons of the autonomic nervous system (ANS). The main functions of the axon are the propagation of action potentials and the transport of neurotransmitters or their precursors along the cytoskeleton.

1.1.3Neurons are classified according to their projections, shape and functions Neurons can be classified structurally according to the number and position of projections.

Unipolar neurons have only one process, from which both the axon and the dendrite emerge. They are found in the dorsal root ganglion of the PNS and convey signals from sensory receptors to the dorsal horn of the spinal cord. The dendrite is structurally and functionally akin to an axon, and thus these cells can be conceived as having a single axon projecting from the periphery into the spinal cord. Bipolar neurons have two processes. One example is the retinal bipolar cell, which conveys inputs from rods or cones to the ganglion cells. Most brain cells are multipolar, integrating information from a great number of dendrites, with a single axonal output path. Although the dendritic tree is normally confined to the local area, the length of the axon can vary widely, with the pyramidal cells of the cerebral cortex, the Purkinje cells of the cerebellum and the lower motor neurons in the anterior horn of the spinal cord all having long-ranging projections. Conversely, interneurons are multipolar neurons that project locally in the spinal cord, cerebellum (e.g. granule, stellate or basket cells) or the cerebral cortex.

1.2GLIA CELLS ARE THE NON-NEURONAL CELLS OF THE NERVOUS SYSTEM

The non-neuronal cells of the nervous system are summarily called ‘glia’ (from Greek glía = glue). They have mainly structural, immunological and metabolic functions, although recent evidence suggests that they may be involved in signal transmission as well. A basic distinction according to size divides the glia cells into micro- and macroglia.

1.2.1Microglia mediates the brain’s immune response

The microglia cells are part of the immune system and have the capability to ingest solid material, for example bacteria, dead cells or protein plaques, through a process called phagocytosis. Because the brain is separated from the rest of the body by the ‘blood–brain barrier’ (the endothelial cells of the cerebral vessels) relatively few infectious agents can reach the brain, which gives it a natural protection from systemic infections. However, the blood–brain barrier is also an obstacle to large proteins like antibodies, which gives the microglia a particular importance as first line of the immune defence of the brain. Microglia is are also activated when large amounts of debris are produced by the brain as a consequence of a neurodegenerative disorder, for example Alzheimer’s disease (AD), where it disposes of the amyloid plaques. Activated microglia can be detected in vivo with positron-emission-tomography (PET), and hotspots of microglia activation are correlated with progressive loss of brain volume (Cagnin et al., 2001). Whether brain inflammation in AD is one of the processes that trigger loss of neurons, rather than just a reaction to the consequences of brain degeneration, will be discussed in more detail in Chapter 4.

Another type of glia are the ependymal cells, epithelial cells that line the ventricles and the spinal canal. The ependyma does not constitute a barrier to fluid exchange between the brain and the ventricles and spinal canal, which is why investigations of cerebrospinal fluid (CSF), for example through a spinal tap, can provide good estimates of neurochemical processes (e.g. inflammation, neurotransmitter metabolism) in the brain. The CSF is produced in the choroid plexus of the ventricles, a convolution of capillaries and ependymal cells shielded against the ventricles by tight junctions, a kind of seal produced by neighbouring stretches of cell membrane, thus restricting the exchange of molecules and acting as the ‘blood–CSF barrier’.

1.2.2Astrocytes have structural and metabolic roles and regulate blood supply

We have already encountered two types of macroglia: the oligodendrocytes, which are the most abundant glia in the brain and make up about 75% of neocortical glia (Pelvig et al., 2008), and Schwann cells, the most important glia cell in the PNS. In the CNS, astrocytes are the second most common type of glia. They surround the neurons and link them to supplying vessels. Beyond this structural role, the astrocytes are also involved in the regulation of blood supply through the release of vasoactive substances, in the removal and metabolism of excess neurotransmitters and in the supply of nutrients to the neurons. The main source of energy for the body is the glucose that is taken up with food (or obtained from food carbohydrates through enzymatic breakdown). A traditional model assumes that glucose is extracted from blood by astrocytes, which maintain a glucose pool and supply the neurons as needed. The neuron then metabolises it through mainly aerobic processes; however, depending on the availability of oxygen, there would always be some anaerobic processing as well, resulting in the production of lactate, which is transported back into the astrocyte. According to an alternative model, the astrocytes produce lactate and supply it to the neurons, which then derive their ATP from oxidative metabolism of lactate (astrocyte-to-neuron-lactate-shuttle hypothesis (Pellerin and Magistretti, 2012)). In either scenario, it is interesting to note that the glucose pool would last for only 150 seconds of brain activity in the event of a stop of the glucose supply, with the lactate pool providing another 75 s and the glycogen stored in astrocytes another 500 s (Barros and Deitmer, 2010). Because the brain, unlike the liver, lacks the enzymes required for glucose synthesis, the glycogen would enter the ATP production pathway in the form of lactate. Areas with high resting state activity are especially vulnerable to this limited energy supply, which is the reason why the hippocampus is particularly affected by prolonged hypoglycaemia, for example after accidental or suicidal overdosing with insulin.

Astrocytes have their own electrochemical communication system through gap junctions (direct communication points between cell...

Table of contents

• Cover
• Half Title
• Title Page
• Copyright
• Brief Contents
• Detailed Contents
• List of Figures
• List of Tables
• About the Author
• Publisher’s Acknowledgements
• Preface
• Introduction
• PART I BASIC NEUROSCIENCE AND RESEARCH METHODS
• PART II PSYCHOPHARMACOLOGY AND FOUNDATIONS OF TREATMENT
• PART III CLINICAL DISORDERS
• Afterword: The Future of Biological Psychiatry
• Glossary: Biological and Neuroanatomical Terms and Methods
• References
• Index