By offering an unapologetically sceptical account of the research on ventricular enlargement, I do not mean to imply that structural imaging studies are always uninformative. As investigations have become progressively more sophisticated, subtler differences between the brains of psychotic patients and ordinary people have been reported.31 However, even if these findings – or any other observations of atypical brain structure – prove to be replicable, we should be cautious when making inferences about the aetiology of psychosis. Psychological changes are always accompanied by changes in the brain. Each new skill, or piece of information that we learn, is accompanied by the creation of new neural circuits that make new patterns of behaviour possible.32 These changes reflect the endless interaction between ourselves and the physical and social environment in which we live. Put crudely, our brains are constantly being rewired in response to our experiences.
This process can result in anatomical changes that are large enough to be detected by a scanner. For example, several studies have shown that the volume of the hippocampus (an area of the brain that plays an important role in memory) is reduced in people who experience post-traumatic stress following warfare or sexual assault.33 Other studies have shown that the corpus callosum and other anatomical structures are reduced in volume in children who have been victims of sexual or emotional abuse.34 Experience can also cause brain structures to increase in size. As I was completing this chapter, a research group at the Institute of Neurology in London published the results of a study of London taxi drivers. They reported that the posterior hippocampus becomes enlarged as taxi drivers struggle to acquire a detailed knowledge of the geography of London.35
Plainly, these findings do not imply that post-traumatic stress can be adequately understood as a disorder of the brain. It is better thought of as a psychological reaction to adverse events that manifests itself, at the biological level, as changes in brain structure. Perhaps some of the structural abnormalities observed in the brains of psychotic patients are similarly products of unfortunate experiences. (It is not difficult to believe, for example, that the richness of the early social environment affects cortical volume and thereby the size of the cerebral ventricles, a hypothesis that would be consistent with the lack of gliosis observed in neuropathological studies, and the suggestion that the loss of volume observed in some patients reflects changes in the synaptic connections between neurones rather than in their number.) Only research that focuses specifically on aetiological factors (which we will consider later in the book) can establish whether this is the case, or whether the abnormally shaped brains of psychotic patients are evidence of some kind of early biological insult.
The glimmer of enlightenment
The second type of biological investigation that we will consider involves measuring brain activity in the hope of discovering which regions are involved in different psychological functions. Surprisingly, perhaps, studies of this kind considerably predate the development of the new neuroimaging technologies. For example, Anglo Mosso, a nineteenth-century Italian physiologist, was able to observe blood pulsations in a peasant who had suffered damage to an area of the skull lying over the frontal lobes.36 Mosso asked his subject to perform mental calculations, observed an increase in the pulsations, and concluded that this was probably caused by increased blood flow to this region of the brain.
Hans Berger’s invention of the electroencephalogram at the beginning of the last century enabled regional brain activity to be quantified for the first time. Recall that neurones create electrical potentials, which are involved in the transmission of information within the cell. The synchrony or asynchrony of this activity in many cells results in gross electrical potentials that can be detected on the scalp. It is possible to use these potentials to gain some general indication of changes in activity in the underlying regions of the cerebral cortex. Often the results of these investigations are fairly uninformative. (When I worked in a high security hospital after qualifying as a clinical psychologist in the mid-1980s, EEGs were routinely taken from patients. The reports made by the electroencephalographer usually made vague reference to ‘possible’ and ‘non-specific’ abnormalities and were almost always useless for clinical purposes.) However, under well-controlled experimental conditions, EEGs can reveal quite specific information about brain functioning. One approach is to measure the evoked potentials that are detected in different brain regions when a stimulus is presented many times over. By averaging across the many presentations, it is possible to remove random noise from the EEG record, and thereby obtain a recording of the specific neural response evoked by the stimulus.
Functional imaging has been revolutionized by more recent developments in scanning technology. Two methods now widely used by researchers are positron emission tomography (PET)37 and functional magnetic resonance imaging (fMRI).38 In the case of PET, the volunteer is injected with a radioactive substance (for example, glucose that has been ‘radio-labelled’), which is drawn to those parts of the brain that use most energy. From there, the substance emits positrons, which almost immediately decay into two photons travelling in opposite directions. These are detected by a scanner surrounding the skull, which consists of a large number of crystals that scintillate when struck by the photons. By detecting which pairs of crystals scintillate together, the scanner is able to ‘see’ where the photons originated from, thereby identifying those brain regions to which the substance has been drawn. Although very precise, PET has several disadvantages. Because the radioactive isotopes employed by PET have very short half-lives, they have to be created on-site using expensive equipment. Also, of course, there are health hazards associated with introducing radioactive substances into the body, however short-lived.
The more recently developed fMRI approach, which capitalizes on the relationship between blood flow and brain activity first described by Mosso, is less hazardous than PET. As in structural MRI, a strong magnetic field is used to stimulate molecules in the body. However, fMRI makes use of the fact that oxygenated blood, which surges to different parts of the brain as they become active, responds with a stronger MRI signal than deoxygenated blood. It is therefore possible to use this blood-oxygen-level-dependent (BOLD) response to detect those brain regions that are most active at any point in time. In practice, the process of experimentation is rather similar to that for PET. Typically, a volunteer is asked to lie in a scanner and to perform a series of tasks in response to various cues and instructions. Outside the scanner, the researchers watch a video monitor and see an image of the volunteer’s brain, which is coloured to indicate which regions are most active.
PET and fMRI are such dazzling technologies that it is easy to regard them as a kind of magic. A person thinks and regions of her brain begin to glow. In fact, the successful conduct of this kind of experiment requires considerable forethought. Tasks must be chosen to reflect the kinds of psychological functions that are of special interest. Moreover, the brain activity measured when the volunteer performs the task must be compared with the activity observed when the brain is doing something else. (The choice of the ‘off-task’ can dramatically affect the observations made when the volunteer performs the ‘on-task’. The best kind of off-task is identical to the on-task except that the psychological function of interest is not involved.) In short, the success of functional imaging studies usually depends on having a reasonable understanding of the psychological processes that are being imaged. In the absence of such an understanding, functional neuroimaging research is somewhat reminiscent of the nineteenth-century pseudoscience of phrenology, which tried to locate mental functions in different regions of the brain by mapping bumps on the scalp.
Psychiatrists and psychologists have attempted to use these technologies to test theories about the role of abnormal brain activity in psychosis. One line of research has been driven by the observation that the left and right sides of the normal brain have different functions. This phenomenon, known as cerebral lateralization, was known to neur
ologists in the nineteenth century, and was enthusiastically researched by neuropsychologists throughout the 1970s and 1980s. (Roger Sperry, the only psychologist to receive the Nobel Prize for medicine, was responsible for many of the most important studies of lateralization carried out during this period.) Looking downwards from above the brain, the two cerebral hemispheres stand out as the most prominent anatomical structures. In most people, the left hemisphere is said to be dominant because language functions are located there (damage to the right side of the brain usually results in much less language impairment than damage to the left) and because most people are right-handed (each hemisphere controls the hand on the opposite side, so right-handedness implies left dominance). In 1969, a Canadian psychiatrist, Pierre Flor-Henry, suggested that epileptic patients who had schizophrenia symptoms usually had left hemisphere or bilateral damage to their brains, whereas those that had mood disorder usually had damage to the right. This led him to argue that cerebral lateralization might be abnormal in psychotic patients.39
The idea that atypical lateralization is implicated in psychosis is still favoured by some researchers. However, there is now a plethora of theories about how this leads to symptoms. Some have argued that dominance may be less marked or even reversed in psychotic people, so that the functions of the hemispheres are less clearly differentiated than in ordinary people. One version of this hypothesis suggests that schizophrenia patients hear voices when the left hemisphere detects speech emanating from the normally silent right.40 Another theory suggests that it is not the relative dominance of the hemispheres that is important, but the way in which they are connected and work together. Perhaps the boldest account of the relationship between lateralization and psychosis has been proposed by Tim Crow, who argues that schizophrenia is a price paid by humanity for the gift of language.41 According to Crow, the genes that are responsible for determining language specialization by one hemisphere (usually the left) are also responsible for schizophrenia. (Crow takes the much disputed WHO claim that the incidence of schizophrenia is constant across the world, which we considered in Chapter 6, to support his view that it is ‘a disease (perhaps the disease) of humanity’,42 and that the genetic mutation that leads to psychosis is as old as humanity itself.)
One observation that seems to be consistent with the abnormal lateralization hypothesis is a high rate of mixed-handedness in schizophrenia patients compared to ordinary people.43 Also consistent with Crow’s particular version of the theory is recent structural scanning study data indicating that the slight anatomical differences between the hemispheres seen in ordinary people are absent in some schizophrenia patients.44 However, studies using EEG have yielded complex findings that do not lead to any simple interpretation, so that, in the words of Raquel Gur of the University of Pennsylvania, ‘One may vacillate… between being overwhelmed by the amount of data that have converged on the issue of laterality in schizophrenia and feeling some exasperation at the paucity of solid answers for questions that seem quite rudimentary.’45
In an attempt to make sense of this evidence, including the results of his own research conducted over several decades, psychologist John Gruzelier of Imperial College London has suggested that different kinds of abnormal lateralization are related to different types of complaints.46 He has argued that active symptoms of psychosis (by which he means over-activity, pressure of speech, mania and paranoia) reflect the excessive dominance of the left-hemisphere functions, and an under-activation of the right. He attributes symptoms of social and emotional withdrawal, on the other hand, to the excessive dominance of right-hemisphere functions and an under-activation of the left hemisphere. Interestingly, Gruzelier’s analysis of the evidence led him to conclude that these abnormal patterns of activation are reduced when patients’ symptoms improve following drug treatment.
Strangely, studies of brain lateralization in psychosis have rarely been conducted using the newer functional imaging techniques. These technologies have been associated with a quite different theory of abnormal brain function, known as the hypofrontality hypothesis. In a study published in 1974, Swedish researchers David Ingvar and Goran Franzen used an early version of PET to obtain crude measures of regional blood flow in the brains of a small group of chronically ill schizophrenia patients. Although the results from the patients were broadly normal, two important observations were noted. First, there seemed to be reduced blood flow to the anterior (front) portions of the brains of the schizophrenia patients in comparison with the healthy controls (hypofrontality). Second, the increase in blood flow to these regions detected when the controls were asked to perform certain mental tasks was not observed in the schizophrenia patients.47
The hypofrontality hypothesis has enjoyed mixed support since Ingvar and Franzen’s initial observations. In a recent review, Peter Liddle was able to find thirty-five studies in which blood flow had been measured while schizophrenia patients were resting, and found that hypofrontality was reported in only a minority of these.48 However, Ingvar and Franzen’s report of attenuated activation when schizophrenia patients engage in some kind of mental task has, to some extent, been supported by later investigations.
In an influential study by Daniel Weinberger and his colleagues at the National Institute for Mental Health in Washington, schizophrenia patients and normal controls were administered a psychological test, known as the Wisconsin Card Sort. This test requires participants to sort cards marked with complex shapes according to a rule known by the tester. The tester gives feedback as the test proceeds, allowing the participant gradually to formulate a hypothesis about the unknown rule. Consequently, their performance gradually improves. However, every so often, the tester changes the rule without informing the participant. The ability to shift to the new rule in these circumstances is thought to involve neural circuits located in the frontal cortex, as patients with damage to this area lack this kind of cognitive flexibility. Consistent with the hypofrontality hypothesis, the schizophrenia patients in Weinberger’s study performed poorly on the Wisconsin test and, in comparison with ordinary people, showed less increased activation of the frontal cortex as they attempted it.49 Other researchers have since reported similar findings, but have also demonstrated that hypofrontality is only present when patients are acutely ill, and is absent (or at least much reduced) when patients have recovered.50 It is not yet clear whether hypo frontality is restricted to schizophrenia patients, as adequate investigations have yet to be conducted with patients diagnosed as suffering from bipolar disorder.51
It would be foolish to underestimate the impact that functional neuroimaging is having on our understanding of the brain. As these technologies have become more routinely available, studies of abnormal neuroactivations in psychiatric patients have become more fashionable. Recent investigations have often focused on specific symptoms of psychosis rather than poorly defined diagnostic categories, and are therefore consistent with the approach that I am advocating in this book. (Although the main thrust of this book is psychological, in later chapters I will describe some of these experiments.) However, once again, caution is required when attempting to infer the causes of psychosis from the results of these experiments.
Most importantly – and this may seem an elementary point – the results of functional neuroimaging studies depend on how the participants attempt the prescribed psychological tasks. Abnormal activations in patients may simply reflect the fact that they are not cooperating, are poorly motivated, or are doing something else. In fact, as we will see in the next chapter, psychiatric patients often are poorly motivated when attempting psychological tests such as the Wisconsin Card Sort, and their performance can sometimes be dramatically improved by providing them with an incentive. Suspicion that this kind of problem can affect neuroimaging research is fuelled by the observation that hypofrontal patients sometimes show normal brain activations after a course of appropriate training on the relevant psychological tests.52
As in the case of structural abnormalities,
abnormal brain activity may, in the end, turn out to be a consequence of adverse experience rather than a product of some kind of biological insult or malfunction. Evidence that supports this supposition is available from studies of people who have suffered from early trauma. It has been found, for example, that survivors of sexual and emotional abuse show abnormal left-hemisphere activity as measured by EEG, and reduced activation of the left hemisphere compared to the right as measured by fMRI.53
The chemistry of madness
We turn finally to the chemical processes that underlie the changing neural activity detected in functional imaging experiments. For readers who are not already familiar with the basic facts of neurotransmission, the following is a brief summary (and see Figure 7.3).
We have already seen that neurones influence other neurones by means of chemicals known as neurotransmitters. These are secreted across the special junctions where one neurone meets another, known as synapses. At the receiving end of each synapse there are structures, known as receptors, which are proteins to which the neurotransmitter binds. Complex biochemical processes are then involved in the ‘reuptake’ of the neurotransmitter from the synaptic gap. When a post-synaptic neurone is stimulated by a neurotransmitter in this way, an electrical potential is created within the cell. These potentials, summating from several firings of a pre-synaptic neurone or of a number of pre-synaptic neurones, determine whether the post-synaptic neurone fires in turn, releasing neurotransmitters where it synapses with other neurones further along the circuit. It is the combined action of large numbers of neurones, working together in this way, which allows the brain to process input from the environment, integrate information, and command co-ordinated behaviour.
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