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34

INTRODUCTION

Psychiatrists often bemoan the absence of biological markersfor the diseases they study and treat, and critics ofpsychiatry frequently cite this absence as evidence thatpsychiatric illness does not exist. Electroencephalographyhas been used to investigate psychiatric illness for more thanhalf a century but it has contributed little to ourunderstanding of such illness. However, the use ofincreasingly sophisticated structural and functionalneuroimaging, and indeed electrophysiological, techniquesoffers hope that we will soon more fully understand theneurophysiological correlates of psychiatric illness. Currentand potential future applications to psychiatry ofelectroencephalography and of structural and functionalneuroimaging will be discussed in this chapter.

ELECTROENCEPHALOGRAPHY IN PSYCHIATRY

The normal electroencephalogram

An electroencephalogram (EEG) is a recording of theelectrical potential of the brain made at the scalp surface. TheEEG α rhythm was first recorded with an Einthoven stringgalvanometer by Austrian psychiatrist Hans Berger in 1929,and until recently the EEG was the only non-invasive meansof assessing brain function (Berger 1931).

An EEG is a recording of the electrical potential producedby inhibitory and excitatory post-synaptic electricaldischarges from neuronal dendrites at the cortical surface.Such neurons constitute less than 5% of all neurons in thebrain. The voltage recorded on an EEG is only 10% of thatrecorded on an electrocardiograph because the electricalresistance of the skull is high. An individual’s EEG is largelygenetically determined and several investigations havereported that EEGs recorded from monozygotic twins werealmost identical (Dummermuth 1968). The EEG records

changes in the electrical potential of the brain, which aredetected as variations in voltage (10 to 100 microvolts) andfrequency (0.5 to 40 Hz).

When recording an EEG, electrodes (usually 21) areplaced on the scalp in a standard (or international) 10/20arrangement, in which the electrodes are placed at pointseither 10% or 20% of the total distance along an imaginaryline between two anatomical landmarks, for example thenasion and inion. Negative potentials cause an upwarddeflection on the EEG record, and either bipolar (betweentwo electrodes) or common (between any single electrodeand a fixed electrically neutral site such as the nose or earlobe) reference potentials may be recorded. The arrangementof recording electrodes in use at a given time is referred to asa montage.

EEG recordings may be made with the patient eitherlying still or ambulatory, and nasopharyngeal (inserted viathe nares) or sphenoidal (inserted inferior to the zygomaticarch) electrodes may be used to allow recordings from theinferior temporal lobe, especially prior to temporal lobesurgery. Depth electrodes are occasionally placed in thebrain via burr holes, and electrocorticography may beundertaken by placing electrodes directly on the brain intra-operatively. More recent technological advances allowcontinuous portable EEG recording for 24 hours or more,simultaneous videotape display and recording of a subject’sbehaviour and EEG and thus their potential correlation, andthe rapid computerized analysis of digitized EEG data. Thislatter facilitates brain mapping, in which EEG voltages oramplitudes are plotted on a map representing the brain andfor which extensive comparative data from both healthy andpsychiatric subjects are available (Fenwick 1992).

Normal EEG frequenciesThe normal EEG frequencies are as follows:

• δ rhythm = 0.1–3.9 Hz• θ rhythm = 4.0–7.9 Hz• α rhythm = 8.0–13.0 Hz• β rhythm = 13.0–40.0 Hz

Electroencephalography andneuroimagingPádraig Wright, Thordur Sigmundsson and James V Lucey

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The α rhythm (30–50 microvolts) is the normal rhythm seenin a subject who is awake with his eyes closed. It is maximalover the occipital and, to a lesser extent, the parietal regions,and is often less evident over the dominant hemisphere. Theβ rhythm is present over the remaining frontocentral areas ofthe scalp. If the subject opens his eyes or undertakes mentalactivity, the α rhythm blocks or attenuates and is replaced byβ rhythm all over the scalp. The β waves from different sitesare out of phase and are said to be desynchronized. The δand θ frequencies occur during sleep but are not presentduring wakefulness in adults, while τ and µ waves occurover the occipital and motor cortices respectively, and arecaused by minimal ocular (scanning) and limb movements.A hypnotized subject exhibits the same EEG as one who isawake and alert, and minor abnormalities are common inEEGs recorded from healthy individuals.

Age and the EEGAlthough EEG activity is evident from at least the secondtrimester of gestation (Eeg-Olofsson 1970), the EEG of anormal neonate reveals relatively little rhythmic electricalactivity. Desynchronized δ and θ waves are evident inrecordings from alert older infants. With increasing age,these are replaced by α rhythm from frontal, throughtemporal and parietal, and thence to occipital regions. Ingeneral, the EEG is dominated by δ rhythm until about theage of two years, by θ until about the age of five years, andby α activity thereafter until the adult EEG emerges.

The adult pattern of dominant α rhythm described abovebecomes evident in late adolescence and is referred to as themature EEG. Frontal θ and posterior temporal δ waves maypersist in some young adults (referred to as a maturationalEEG) and there is some evidence that these rhythms areassociated with personality disorder when they are presentin later adulthood (referred to as an immature EEG).

From the seventh decade of life onwards, α waves are oflower voltage and frequency, and low-frequency rhythmssuch as δ waves may reappear. These changes are moreevident in men than in women and may be accompanied byclinically insignificant temporal slow-wave foci (Obrist &Busse 1965).

Activation of the EEGSuspected EEG abnormalities may not be evident during astandard recording. These may be revealed if the brain isstressed or otherwise activated in some way. The techniquesused to unmask abnormalities hidden in the resting EEGrecord include:

• hyperventilation, which induces cortical hypocapnia,cerebral vasoconstriction and hypoxia, and may allowepileptic foci to become evident

• photic stimulation, in which a strobe light flashing at8–15 Hz is used to capture the occipital α frequency, thatis the α frequency adjusts to match that of the strobe

light (photic driving). This may allow epileptic foci to beseen and may even induce epileptic seizures, as may aflickering television screen

• barbiturates and neuroleptics, which may both be usedto unmask epileptic foci.

The EEG and sleep

Sleep is similar to coma, in that it consists of inactivity andloss of awareness and responsivity. In contrast to thecomatose individual, however, the sleeping individual eitherawakens spontaneously or can be roused. The EEG has beenused extensively in the investigation of both the physiologyof sleep and sleep disorders. Indeed physiological sleep isdivided into five stages purely on the basis of changesobserved in EEG recordings taken from sleeping subjects.

During sleep, the rhythm recorded on an EEG changesfrom the β rhythm of wakefulness, through occipital αrhythm when the eyes are closed, to the sleep EEG. Stages I(transitional sleep), II, III and IV of the sleep EEG arereferred to as non-rapid eye movement (non-REM) ororthodox sleep, during which parasympathetic tone isincreased, while Stage V is referred to as rapid eyemovement (REM) or desynchronized sleep, during whichsympathetic tone is increased. Stages III and IV arecharacterized by slow waves and are therefore sometimesreferred to as slow wave sleep (SWS), or as synchronizedsleep. The principal EEG features of sleep stages I through IVare summarized in Box 34.1.

Stage V or REM sleep is also called paradoxical sleepbecause while deep unconsciousness and marked atoniaoccur, paradoxically the EEG resembles that recorded during

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Box 34.1 EEG features of sleep

Stage I

The α rhythm gradually disappears

Low-voltage desynchronized slow waves (δ and θ) appear

High-voltage sharp waves occur at the vertex

Stage II

Low voltages and δ and slower frequencies dominate the

recording

Sleep spindles occur (sinusoidal 12–14 Hz of 0.5 sec)

K complexes occur (high-amplitude sharp positive/negativedeflections)

Stage III

High-voltage slow waves all over the scalp

δ waves account for <50% of rhythm

Sleep spindles and K complexes diminish

Stage IV

High-voltage slow (δ) waves dominate the EEG

δ waves account for >50% of rhythm

Sleep spindles and K complexes are absent

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Stage I (transitional) sleep, or when a subject is awake withhis eyes closed. Thus low voltage, variable frequency wavesand occasional α rhythm are recorded. The eyes exhibitrapid conjugate movements and physiological arousal isevident as tachycardia, tachypnoea, systolic hypertension,increased oxygen consumption, dilated pupils, peniletumescence or vaginal lubrication, increased cerebralperfusion and occasional myoclonic jerks. Dreaming isreported (and is vividly recalled) by 60–80% of individualsawakened from REM sleep, as compared to about 20% ofsubjects awakened from non-REM sleep. REM accounts forover 50% of sleep in childhood, for 25% in adulthood and for10% of sleep in old age. REM changes on an EEG recordedduring the daytime suggest either sleep deprivation,withdrawal from alcohol or from drugs that suppress REM(barbiturates, benzodiazepines), or narcolepsy.

The cycle from Stage I to V takes about 1.5 hours and isrepeated 4 or 5 times per night (Fig. 34.1). Thus, sleep duringthe early part of the night is largely SWS, sleep during thelater part of the night is largely REM sleep, and overall mosttime is spent in Stage II sleep. The normal sleep/wake cycleis of 25 hours’ duration (not 24 hours) and if deprived ofsleep (or selectively of REM sleep) extra REM sleep, calledREM-rebound, occurs when normal sleep is again possible.However, the function of sleep in general, and of REM sleepin particular, is unknown. Both total sleep deprivation andselective REM deprivation have real but relatively modesteffects on formal tests of cognitive function, which canlargely be compensated for by increased effort, at least in theshort term. This cognitive deficit has been quantified asequivalent to that caused by a blood alcohol level of 0.05%(Falleti et al. 2003). However, performance on formal tests ofcognitive function are not good indicators of occupational orother performance and there is growing evidence that sleepdeprivation significantly impairs the working ability of, forexample, doctors (Samkoff & Jacques 1991). It is important tonote that sleep requirements vary greatly both betweenindividuals and within individuals at different times and

that 5 or 6 hours’ sleep is sufficient for many people. Inparticular, sleep requirements diminish with age.

The circadian rhythm of secretion that hormones such ascortisol, prolactin, growth hormone and insulin exhibit iswell known and some hormones exhibit a similar secretorypattern (which may be superimposed on the circadianpattern) during the sleep cycle. Thus growth hormone levelsare maximal during SWS, prolactin levels peak during earlyStage I and later Stage IV sleep, and testosterone levelsincrease continuously during sleep. There is also increasingevidence that seasonal and circadian patterns of hormonelevels and behaviour may be controlled by rhythmicsecretion of melatonin from the pineal gland. Melatoninlevels are low during REM sleep and may be controlled by aputative biological clock in the suprachiasmatic nucleus ofthe hypothalamus which responds to light falling on theretina. Melatonin is effective in alleviating jet lag (duringwhich the normal diurnal variation in body temperature andin cortisol and catecholamine secretion is disrupted) butthere is no evidence that phototherapy for seasonal affectivedisorder acts by increasing melatonin levels.

The effects of psychotropic drugs on theEEG

Almost all psychotropic drugs affect the EEG and recordingsfrom patients taking such drugs are effectively useless. Thespecific effects of the most frequently prescribed psycho-tropic drugs are presented in Box 34.2. It should also beremembered that barbiturates, benzodiazepines andantipsychotics all aggravate epileptic discharges.

The EEG and electroconvulsive therapy(ECT)

The EEG during an application of ECT is similar to that seenduring a tonic/clonic seizure. Between applications of ECT,irregular slow waves (θ and δ) occur. These are most evident

34ELECTROENCEPHALOGRAPHY AND NEUROIMAGING

519Figure 34.1 The cycle from sleep Stage I to V takes about 1.5 hours and is repeated four or five times per night.

Hours (asleep)

0 1 2 3 4 5 6 7

Stage V(REM)

Stage IV

Stage III

Stage II

Stage I

Awake

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over the dominant hemisphere, especially the frontal lobe,and they persist for increasingly longer periods of time aftereach successive administration of ECT. Very high voltageslow waves appear towards the end of a course of ECT, andthe α rhythm may disappear completely. The effects of ECTon the EEG gradually diminish following a course oftreatment and they are no longer evident after between oneand three months; prior to that, the EEG is impossible tointerpret.

The EEG and psychiatric illness

The EEG is helpful in the diagnosis and monitoring ofepilepsy and many other neuropsychiatric disorders, but isof more limited use when applied to psychotic, affective andanxiety disorders.

EpilepsyThe EEG is abnormal in about 15% of healthy subjects andnormal in about 20% of patients with epilepsy, althoughactivation procedures may reveal spikes (waveforms whichrise and fall rapidly) in many of the latter. Epilepsy istherefore a clinical diagnosis which may be supported by theEEG. Spikes and waves (waveforms which rise rapidly andfall slowly) occurring in the α, θ and δ ranges in the inter-ictal EEG record are the hallmark of epilepsy. These may befocal (for example, over the temporal recording leads intemporal lobe epilepsy), unilateral or bilateral, and may besynchronized or desynchronized. Spikes and waves maycombine to produce spike and wave complexes. Theseexhibit a high frequency in tonic/clonic epilepsy and afrequency of 3 Hz in classic absence epilepsy. Epilepsy isdiscussed in more detail in Chapter 26.

Acute organic psychosis and encephalitisMetabolic disorders such as hypoxia, hepatic encephalo-pathy, vitamin B12 deficiency and hypoglycaemia causediffuse slowing of the background rhythm and theoccurrence of triphasic waves (which must be differentiatedfrom triphasic sharp waves – see Creutzfeldt–Jakob diseasebelow). The exception is withdrawal from alcohol ordelirium tremens, in which the EEG may be normal andexhibit fast rhythms. Focal intracranial pathology, whethertumour, haemorrhage, abscess or infarct, may cause slowwaves and perhaps epileptiform rhythms to arise in theleads over the lesion. The degree of change on the EEGdepends on the site (cortical lesions are more easily detectedthan deeper lesions), size (a lesion <2 cm in diameter maycause no EEG changes) and rate of growth (a rapidlyenlarging lesion is more likely to cause EEG changes) of thelesion. EEGs from patients with encephalitis may exhibitdiffuse irregular slow waves and seizure patterns.

DementiaThere is a marked reduction in α waves and very lowamplitude background rhythm (referred to as a flattenedEEG) in Huntington’s disease. In Alzheimer’s dementia,there is accentuation of the normal changes that occur withageing, so α rhythm is reduced and a disorganized θ rhythmevolves. The EEG in vascular dementia is similar to that ofAlzheimer’s dementia but with the addition of focal featuresover infarcts or haemorrhages. In Creutzfeldt–Jakob disease(CJD) a reduced background rhythm with characteristictriphasic sharp wave complexes with a frequency of 1–2 Hzoccurs in up to 90% of patients. This may not be presentinitially and repeat recordings are necessary. These EEGchanges have not been reported in new variant CJD in whichneuropsychiatric symptoms, ataxia, myoclonus anddementia occur, nor in Gerstmann–Straussler–Scheinker(familial CJD) syndrome or iatrogenic CJD. The EEG is oftennormal in Pick’s disease.

Personality, affective and anxiety disordersAn immature EEG (see above) is present in about 50% ofpatients with personality disorder (and in 70% of prisonersconvicted of motiveless homicide) while EEGs from patientswith affective disorders reveal an excess of non-specificabnormalities. Excess generalized low-amplitude θ and βrhythms occur in a significant proportion of patients withanxiety disorders.

SchizophreniaOver 40% of schizophrenic patients have an abnormal EEG,the most frequent abnormality being the presence of low-amplitude epileptiform activity (especially with activationprocedures). This proportion is highest in catatonicschizophrenia, with low-amplitude slow waves (δ and θ)and a reduced α rhythm occurring in catatonic stupor.

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Box 34.2 Effects of psychotropic drugs on EEG recordings

Barbiturates

Increased β and θ rhythms

Reduced α rhythm

Occasional δ waves

Benzodiazepines

Increased β and θ rhythms

Reduced α rhythm

Tricyclic antidepressants

Increased δ, θ and β rhythms

Antipsychotics

Increased β (low to moderate dosage)

Increased δ and/or θ (high dosage)

Lithium carbonate

No or minimal effects (therapeutic levels)

Increased δ and/or θ (high and toxic levels)

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Schizophreniform psychosis associated with temporal lobeepilepsy is discussed in Chapter 18.

Evoked potentials

It has long been known that stimulation of peripheral senseorgans alters the EEG, and that a sound or light may evoke awave over the auditory or visual cortex respectively. Evokedwaves are usually hidden by background EEG activity butthey may be revealed by averaging, a computerizedmathematical technique which greatly reduces backgroundEEG ‘noise’. A positive evoked wave occurring 300milliseconds after a stimulus is conventionally referred to asthe P300. P300 abnormalities have been reported in patientswith dementia (delayed response and reduced amplitude)and in both schizophrenic patients (Muller et al. 2001) andtheir first-degree relatives (reduced amplitude) (Blackwood& Muir 1990).

Magnetoencephalography

Magnetoencephalography (MEG) utilizes modern super-conductor technology to record the minute magnetic fieldsgenerated by neuronal electrical activity. MEG thus has thesame range of applications in psychiatry as the EEG butcontrasts with electroencephalography in that it allows thedetection of electrical activity throughout the brain withoutthe need for intracerebral electrodes and it has greaterresolution. The science of magnetoencephalography and itsapplication to psychiatry is in its infancy and furtherdevelopments are awaited.

STRUCTURAL NEUROIMAGING IN PSYCHIATRY

Neuroimaging is conveniently divided into structural andfunctional neuroimaging. The two most commonly usedstructural imaging techniques are computed X-raytomography (CT) and magnetic resonance (MR) imaging.These have largely replaced the skull X-ray which will bebriefly described. Technical aspects of CT and MRneuroimaging will then be reviewed and the clinical andresearch applications of these imaging techniques topsychiatry will be discussed.

Skull X-ray

The skull X-ray is of very limited use in modern psychiatricpractice. Nonetheless, it allows detection of intracranialcalcifications, especially hypophyseal calcification which, ifpresent, enables radiologists to see any shift of midlinestructures caused by space-occupying lesions. Erosion ofbone, for example of the sella turcica by pituitary tumours orthe cranial vault by other brain tumours, can also be

visualized on skull X-ray, as can thickening of the skull inPaget’s disease. However, psychiatrists had recognized thelimitations of skull X-ray even prior to the introduction ofmodern neuroimaging techniques. One study found noabnormality in 53 ‘routine’ skull X-ray examinations andonly one abnormality – a skull fracture – in 30 clinicallyindicated skull X-ray examinations (Larkin et al. 1985). It isof interest to note that Jakobi and Winkler in 1927 describedventricular enlargement in patients with schizophreniaexamined with pneumoencephalography, a techniquedependent on X-ray and the introduction of (radiolucent) airinto the subarachnoid space via lumbar puncture.

Computed X-ray tomography (CT)

Like conventional X-ray, CT depends on measuring theamount of energy absorbed by tissues placed in front of anX-ray tube emitting high-energy photons, in order toproduce an image. X-ray photons are attenuated by atoms intissue, leading to the emission of an electron. X-rays aretherefore a form of ionizing radiation. The degree to whichtissues attenuate X-rays depends on their density, andattenuation values (CT values or Hounsfield units) havebeen calculated for various tissues relative to the attenuationvalue of water, arbitrarily set at 0 (Table 34.1). Photonspassing through tissue sensitize photographic film inconventional X-ray, but are detected by photon detectors inCT.

In cranial CT, the X-ray tube and photon detectors rotatearound the head in a transverse plane (usually theorbitomeatal plane through the orbits and the externalauditory meatus, in order to minimize radiation to the eyes).The signal from the photon detectors is then transformed(using Fourier transformation) by computer in order to builda two-dimensional picture of a slice of healthy or abnormalbrain (Fig. 34.2A) within a grid or matrix. Each square, orpixel (picture element) in this grid has a particular shade ofgrey determined by the attenuation value of the tissue. Theadvantages and disadvantages of CT and MR neuroimagingare presented in Box 34.3.

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Table 34.1 CT or Hounsfield values for a range of humantissues

Tissue CT/Hounsfield value

Cerebrospinal fluid +8

White matter +15

Grey matter +18

Bone +200-500

Air –500

Water 0

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Magnetic resonance imaging (MRI)

MR (or nuclear magnetic resonance, NMR) imaging dependson the detection of electromagnetic energy derived frominteractions between atoms and an external magnetic field,in order to produce an image. Protium (1H), the isotopeaccounting for 99.9% of hydrogen atoms, and the mostabundant element in most living tissues, is effectively anunpaired proton that behaves like a moving charge,spinning and generating a magnetic field along its axis of

spin. Protons may be thought of as bar magnets or magneticdipoles with a definite magnitude or vector and direction totheir axis of rotation. Individual protons in living tissue arearranged randomly and their net magnetization is 0. Whenplaced in an external magnetic field, protons align in thedirection of the field (the B0 axis) and their netmagnetization is no longer 0. They also ‘wobble’ likespinning tops along the axis of the magnetic field, aphenomenon called precession. The frequency of precession,or Lamour frequency, is measurable and is unique for each

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522

Figure 34.2 (A) CT of the head of a patient showing a bilateral white matter lesion involving the anterior limb of the internal capsule. (B),(C) and (D) are axial, sagittal and coronal MR images, respectively, of the same patient and are shown for comparison. Clinically, this lesionwas associated with a behavioural syndrome identical to frontal lobe syndrome, indicating that most of the afferent fibres from the frontallobe to the striatum were severed by the lesion.

(Images courtesy of Neuroimaging Department, Maudsley Hospital, London.)

A

C D

B

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element. In MRI, short radio-frequency pulses are applied toprecessing tissue protons (at the precessing frequency andperpendicular to the external magnetic field) by atransmitter coil. This additional energy tips the protonsthrough 90o or 180o causing protons that were precessing atrandom to precess in unison. Such protons absorb energyfrom the radio-frequency pulses, recover slowly (relax) andthen release this energy such that it may be detected by areceiver coil. The strength of the signal detected by a receivercoil depends on the density of protons in the tissue beingexamined. Thus tissue differentiation is possible on MRimages because hydrogen in living tissue is mostly in theform of water, the concentration of which differs in differenttissues.

The relaxation time of protons is described by twodifferent, but simultaneous, processes. The T1 (longitudinalor spin-lattice) relaxation time reflects the return of the netmagnetization to the B0 axis, while the T2 (transverse or

spin-spin) relaxation time reflects the return of randomprecession (dephasing of the spin coherence). T1 and T2relaxation times differ by tissue, and radio-frequency pulsesmay be applied so that the differing T1 or T2 properties ofthe tissue are accentuated (T1 or T2 weighting). The spatialinformation required for an image is obtained by applyinggradients to the static external magnetic field, such thatprotons will precess at slightly different frequencies alongthe gradient. The application of three such gradients at rightangles to each other generates three ‘slices’ of tissue andallows for the construction of a three-dimensional image ofthe brain (Figs 34.2A, C and D; 34.3A and B; and Chapter 20,Fig 20.2). The thickness of each slice of tissue determines thesize of each volume element (voxel) sampled (which isslightly less than 1 cubic millimetre in modern MRIscanners). The image is then reconstructed by computer in asimilar manner to that described for CT, but with theimportant difference that images may be reconstructed inany plane.

Unlike ionizing radiation, there are no known biologicalhazards associated with magnetic fields or radiofrequencywaves. MRI therefore offers a uniquely safe opportunity tostudy the brain. MRI is also superior to CT in differentiatingbetween grey and white matter and, because images can beobtained in different planes and information sampled atdifferent relaxation times, in investigating tissuecharacteristics. This intrinsic property of MRI not onlyprovides structural information but also allows thecollection of information about brain function (see below).

The role of CT and MR structuralneuroimaging in psychiatry

Structural scans of the brain are undertaken for two reasonsby psychiatrists: clinical investigation and research. Thecommonest clinical indications for neuroimaging are theexclusion or confirmation of suspected pathologyresponsible for focal neurological signs or symptoms and theinvestigation of suspected dementia (cortical atrophysupports the diagnosis, and the site and nature of brainabnormalities can help distinguish between the dementias).The intial scarcity of neuroimaging facilities meant that strictcriteria (the presence of a focal neurological sign or atypicalpsychosis, for example) had to be met before imaging wasundertaken. CT and MRI are now more widely available andclinical neuroimaging is increasingly recognized as anessential component of the clinical investigation of manypsychiatric disorders (Box 34.4). However, it remainsimportant to undertake a neurological examination prior toimaging, in order to facilitate interpretation of the CT or MRscan. In particular, the clinical question must be clearlyformulated prior to MR because the image protocol andradio-frequency pulse sequences utilized by the radiologistare determined by the patient’s symptoms and the impliedbrain region under investigation.

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Box 34.3 Advantages and disadvantages of CT and MRneuroimaging

Advantages of CT

Widely available and relatively inexpensive

Examinations are rapid

Relatively safe

Can readily distinguish cerebrospinal fluid (CSF) from grey matter

Resolution may be enhanced by use of contrast agents

Superior to MRI in evaluating bony abnormalities and cerebralcalcifications

Invaluable when MRI is contraindicated (patients on life-supportsystems, for example)

Disadvantages of CT

Does not effectively differentiate between white and grey matter

Poor resolution

Allergies to contrast agents

Exposure to ionizing radiation

Advantages of MR

Safe

More sensitive than CT in distinguishing between grey and whitematter

Can identify ectopic grey matter

Can evaluate deep grey matter nuclei in the basal ganglia

Can evaluate white matter lesions (plaques in multiple sclerosis,infarcts)

Invaluable when examining brain regions near bone (temporal lobe,basal forebrain, cerebellum)

Allows imaging in three planes and reconstruction in any plane

Allows measurement of volumes

Disadvantages of MR

Relatively unavailable and expensive

Several absolute contraindications (aneurysm clips, pacemakers,paramagnetic metallic objects)

Some relative contraindications (pregnancy, claustrophobia)

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Structural neuroimaging has been used extensively inpsychiatric research, especially in the psychoses anddementias, since Johnstone et al. (1976) first reportedventricular dilatation in patients with schizophrenia, usingCT. Increasingly sophisticated neuroimaging techniqueshave been focused on identifying brain regions that differbetween patients and comparison populations. Early workdepended on manual measurement of the area of relativelylarge brain structures (ventricles) in cross-sections on CTscans. MRI subsequently provided the opportunity toexamine both smaller structures poorly visible on CT(temporal lobe, cerebellum) and images of the brain in

different planes. MRI also provided excellent separationbetween white and grey matter, which allowedsegmentation of the brain into three components – whiteand grey matter, and cerebrospinal fluid (CSF). It is usualto refer to specific brain regions being investigated withCT or MRI as regions of interest (ROI), the volumes ofROIs being compared between groups either manually (bytracing them on a computer monitor and multiplying thearea by the slice thickness to get the volume for each slice,the cumulative volume of ROIs on all slices providing anestimate of the volume of the structures being examined)or automatically (by using computer programs capable ofsegmenting the brain into grey and white matter and CSFand of calculating the volume of each componentseparately). More recently, it has become possible toanalyse structural imaging data using methods firstdeveloped for analysing functional neuroimaging data (therecording of images with a template image in stereotacticspace and the analysis of differences in grey or whitematter intensities on a voxel (volume element) by voxelbasis). In addition to the search for brain abnormalitiesspecific to individual neuropsychiatric disorders, structuralneuroimaging has also been used to monitor diseaseprogress in patients with degenerative brain disorders (Foxet al. 1996), examine the effects of pharmacologicaltreatments such as increased basal ganglia volume inpatients treated with antipsychotic drugs (Chakos et al.1995), and to co-register structural and functionalneuroimaging data, for example PET with MRI.

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Figure 34.3 (A) and (B) are proton density and T2-weighted axial MRI images respectively taken from the same anatomical location in thehead of a patient at the level of the basal ganglia.

(Images courtesy of Neuroimaging Department, Maudsley Hospital, London.)

Box 34.4 Clinical indications for structural brain scans

Dementia

Delirium

Catatonia

Movement disorder

Acute change in personality

First onset of psychosis

History of head trauma

History of seizures

Eating disorder

Electroencephalographic abnormalities

Focal neurological abnormalities

First onset of psychiatric symptoms after age 50 years

Atypical symptoms or course of illness

A B

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FUNCTIONAL NEUROIMAGING IN PSYCHIATRY

Four functional neuroimaging techniques have establishedthemselves in psychiatric research and their clinicalapplications are becoming increasingly important. Singlephoton emission tomography (SPET) and positron emissiontomography (PET) depend on the administration ofradioactive isotopes and the subsequent detection of gammaphotons and positrons respectively. Functional MRI (fMRI)and MR spectroscopy (MRS) utilize MRI technology asdescribed above.

Positron emission tomography (PET)

PET is the benchmark technique for functional imaging ofmetabolic processes such as regional cerebral blood flow(rCBF) or regional cerebral metabolism of glucose (rCMG). Itinvolves the combination of two technologies, tracer kineticassay (TKA) and CT. TKA involves the use of a radio-labelled, biologically active compound (the radionuclidetracer) and a mathematical model of its kinetics as itparticipates in a biological process. The PET scannermeasures the tissue concentration of the tracer and producesa three-dimensional image of the anatomical distribution ofthe biological process being investigated.

The radionuclide tracers used during PET imaging arenatural substrates or their analogues, combined withradioactive forms of natural elements (labels) such as 11C,13N, 15O and 18F. These radiolabels emit radiation in the formof positrons that pass through the body and are detectedexternally, but that do not alter the biological process beinginvestigated. Positrons are positively charged electrons thatare emitted from the nucleus of some radioisotopes becausethey have an excess of protons and a positive charge, and arethus unstable. An emitted positron collides with electronsuntil it comes to rest and then combines with an electron tobecome a positronium. Since the positron is an anti-electron,the positron and electron annihilate each other and theirmasses are converted into electromagnetic energy. The massof the electron and positron are equal, and equivalent to 511kiloelectronvolts (keV) of energy. In a collision referred to asa true coincidence, the annihilation produces two 511 keVphotons 180o apart. The scanner detects this energy. This isannihilation coincidence detection (ACD). Only truecoincidences produce valid spatial information, so scannerdesigns try to maximize true coincidences and minimizescatter coincidences that produce ‘noise’.

PET imaging (Fig. 34.4) requires a charged particleaccelerator or cyclotron to produce positron-emittingisotopes and over 500 such isotopes have been produced bylabelling with 15O, 13N, 11C or 18F. Compounds used with PETinclude H2O

15 for rCBF measurement and 18F deoxyglucose(DG) for rCMG. PET imaging benefits from a low radiation

exposure time:imaging time ratio, because PETradionuclides have short half-lives (15O = 2 minutes, 18F = 110minutes). Dosimetry (here, used to ascertain the relationshipbetween the radiation dose administered to the subject andthe quality of the image detected) is determined by effects onorgans throughout the body and not only by effects on theorgan under investigation. In 18F-DG PET imaging, 77% ofthe radiation dose is accounted for by photons of emittedionization and only 23% by annihilation of positrons.

The CT technique in PET uses rigorous mathematicalalgorithms to produce tomographic images of projectionsfrom an object. PET scintillation detectors produce lightwhen struck by radiation and image resolution depends onboth detector resolution and the radiation cut-off frequencyused. The signal to noise ratio is high and the tomographicplanes are usually perpendicular to the long axis of the body.Early tomographic systems used ROI (regions of interest)analysis relying on manual placement of templates uponreconstructed images (see above). These were prone to inter-rater and intra-rater variability because anatomicallocalization was relatively unreliable. Modern PET imagingdepends on computerized and automated systems for PETdata analysis such as the Statistical Parametric Mapping orSPM system. Moreover, simultaneous anatomical localiza-tion of PET data using MRI – a process known as MRI co-registration – is increasingly available.

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Figure 34.4 PET images of 11C raclopride, a dopamine D2receptor ligand. The images are darkest in the striatum where thehighest levels of 11C raclopride occurs. Subject study 4 hadplacebo, and subject studies 1-3 and 5-8 had increasing doses ofziprasidone (2, 5, 10, 15, 20, 40 and 60 mg). The images showdecreasing binding of 11C raclopride due to ziprasidone’sincreasing occupancy of the dopamine D2 receptor.

(Image courtesy of Dr C. Bench, MRC Cyclotron Unit,Hammersmith Hospital, London.)

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Single photon emission tomography (SPET)

SPET refers to a computerized emission tomographic systemthat depends on isotopes that emit single photons (asdistinct from positrons in PET). Single photons are detectedsingly rather than in coincident pairs (as in PET).Collimation – the trapping of emitted photons and theirdirection towards the detector – is required because singlephotons are scattered randomly, and this means that mostphotons are absorbed by collimators and thus goundetected. Thus only a fraction of emitted photons arecounted by SPET detector systems and SPET resolution isachieved at the expense of SPET sensitivity. The sensitivity ofSPET is the degree to which the system responds to anincoming signal measured as counts per second (CPS) perslice (megaBequerel per litre or MBq/L). The mostfrequently used detector systems in clinical practice arerotating gamma cameras.

Once acquired, SPET data are organized as slices, andreconstructed separately from projections spaced over a 360o

arc of rotation about the subject. The SPET detector systembehind the collimator is made of sodium iodide crystals withphotomultiplier tubes (PMTs) and SPET detector systemsmay have one large detector covered with many PMTs, ormultiple detectors capable of higher count-rate detection andsuitable for dynamic studies. Brain-dedicated SPET detectorsystems view the head from several angles simultaneouslywith separate scintillation detectors, while convergingcollimators increase the crystal surface area utilized for agiven slice and thus maximize sensitivity. Reconstruction intransverse, coronal and sagittal planes is possible (Fig. 34.5).SPET images are collected over a much longer period of timeand depend on many fewer photons than standard CT. ThusSPET images have more noise and less resolution than CTimages. As with PET, ROI data analysis is still commonlyused in SPET. However, SPM (see above) has recently beenadapted for SPET. Ideal anatomical localization with SPETwould require MRI co-registration as with PET, but incontrast to PET, this is difficult to achieve with SPET.

The role of PET and SPET in psychiatry

PET imaging techniques may be adapted to study metabolicprocesses such as the cerebral metabolic rate for glucose(with 18F-DG) or cerebral protein synthesis (with 11C-L-leucine). PET may also be utilized to investigate bothpresynaptic and post-synaptic receptor systems via differentligands, e.g. 18F-fluoroethylspiperone for dopamine D2receptors. Multiple PET images may be overlapped in orderto investigate simultaneous disease processes such asParkinson’s disease with or without Alzheimer’s dementia.

SPET uses in neuropsychiatry include the examination ofrCBF using 133xenon (inhalation technique) or technetium99m HMPAO, in the study of dementia, cerebral vasculardisease and epilepsy. SPET receptor ligands include

123iodine epidepride (which has been used extensively toinvestigate the dopaminergic system in schizophrenia), thesubstituted benzamide IBZM (which has also been used toinvestigate the dopaminergic system in schizophrenia) and123iodine Iomazenil (which has been used to examine theGABA receptor system in schizophrenia, alcoholism andanxiety)

For rCBF imaging, SPET represents a technique that isreadily available and relatively inexpensive when comparedto PET. Resolution similar to that achieved with second-generation PET is possible and, in contrast to PET, there is noneed for an on-site cyclotron, and no need for arterialcannulation (essential with PET in order to achieve absolutelevels of quantification). The disadvantages of SPET arenonetheless considerable. SPET techniques requirecollimation, the tissue volume sampled in each scan issubstantially reduced, and SPET scans are generated by farfewer photons and must be collected over much greaterperiods of time than with PET scans. SPET ligands musttherefore have a much longer half-life than PET ligands, sothe capacity of SPET for repeated examinations is limited(this represents perhaps the greatest limitation of SPET). Incontrast, PET may be used to repeatedly study serial brainstates in the same individual. Regional CMG studies are notpossible with SPET, nor is absolute quantification.

However, and despite the above, SPET presents realadvantages to psychiatrists over and above those of costand availability. These depend on technetium Tc 99mHMPAO, the ubiquitous SPET rCBF radionuclide, whichhas largely replaced 133xenon inhalation in SPET rCBFstudies. Xenon studies provided poor resolution and littleinformation about deep cerebral structures. However, Tc99m HMPAO is lipophilic and its uptake is proportional toblood flow for about five minutes after administration,following which it becomes hydrophilic and is no longertaken up by tissues. Thus a patient may receive an injectionof the ligand some time prior to scanning, and SPETimaging at a later time (allowing for loss due to radiationdecay) will reflect the rCBF during the five minutesfollowing injection. This facilitates the study of patientswith psychiatric disorders because the ligand may beinjected in a calm environment, thus minimizing theinfluence of anxiety or hyperventilation on rCBF. Moreover,the specific anxiogenic potential of the SPET scanner is nowmuch less of a problem.

Functional MRI (fMRI)

Increased neuronal activity raises the demand for metabolicenergy and leads to an increase in regional cerebral bloodflow. Local oxygen utilization changes the ratio ofoxygenated to deoxygenated haemoglobin in blood. This inturn alters the MR signal from nearby hydrogen nucleibecause deoxygenated haemoglobin is paramagnetic. This

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Figure 34.5 Single photon emission tomograms (SPET) of the brain using 123I-5-I-R91150, a ligand that binds selectively and reversiblywith serotonin 5HT2A receptors. Binding of the ligand to the receptor (yellow and orange areas) is demonstrated in (A) a healthy volunteer atthe level of the temporal cortex and cerebellum (upper image) and at the level of the frontal, parietal and occipital cortices (lower image). (B)displays binding at the same levels in the brain of a patient with schizophrenia treated with clozapine 450 mg per day while (C) displaysbinding at these levels in the brain of a patient with schizophrenia treated with risperidone 6 mg per day. These SPET scans indicate thatboth clozapine and risperidone bind to the 5HT2A receptor in vivo.

(Image courtesy of Dr. M. J. Travis, Institute of Psychiatry, London.)

Figure 34.6 Functional MR imaging of brain activation during sampling of auditory hallucinations in schizophrenia. The five transversesections are relative to the AC–PC plane, the numbers below the sections indicating their level with respect to this plane. The right side ofthe patient’s brain is represented on the left side of each image and vice versa. The red to yellow colour scale illustrates regions active inphase with auditory hallucinations with the areas of greatest significance in yellow. The grey scale template was calculated by voxel-by-voxelaveraging of the individual EPI images of 6 patients, following transformation into Talairach space. The main activations are in the rightinferior colliculus (A), the right and left insulae (B and C), the right superior temporal gyrus (D), the left paraphippocampal gyrus (E) and theright thalamus (F). Similar activations are present in the middle frontal (G) and the anterior cingulate (H) gyri bilaterally, and in the right inferiorparietal lobule extending into the superior lobule (I).

(Image courtesy of Dr S. Shergill, Institute of Psychiatry, London.)

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change in signal intensity is referred to as the bloodoxygenation level dependent (BOLD) effect. Using recentlydeveloped techniques that allow the rapid acquisition of MRimages (such as echoplanar imaging) data from numerousslices through the brain may be collected from an individualat rest or performing control or test procedures. Theresulting fMR images may then be compared, areas ofaltered signal intensity identified and the underlying

regional brain structures involved in a particular taskdetermined (Fig. 34.6).

The excellent temporal and spatial resolution of the MRtechnology, its lack of ionizing radiation and its ease of use isrevolutionizing neuroimaging and our understanding of thebrain. It appears likely that this functional imagingtechnique will soon take its place in clinical psychiatricpractice.

Figure 34.7 Magnetic resonancespectroscopy (MRS). (A) shows the locationwithin the brain using coronal and sagittalmagnetic resonance images of spectroscopicvoxels from which a processed proton MRSspectrum may be derived. (B) displays a typicalprocessed proton MRS spectrum from thefrontal lobe in a healthy volunteer. The majormetabolite peaks, N-acetyl aspartate (NAA) - anamino acid found only in neurons and thereforeused as a neuronal marker, choline (Cho) andcreatine and phosphocreatine (Cr1PCr), areindicated.

(Images courtesy of Neuroimaging Department,Maudsley Hospital, London.)

A

B

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MR spectroscopy (MRS)

MRS is an MR dependent neuroimaging technique thatallows quantification of brain neurochemistry. Radio-frequency pulses applied at the Lamour frequency causeprotons to absorb, and later emit, energy (see above).However, the Lamour frequency of protons is modified bythe electrons of nearby atoms which shield the protons froman external magnetic field. The extent of shielding dependson the atoms in the molecule in which the protons areincorporated. Thus protons in water molecules have adifferent Lamour frequency to protons in creatinine. Thisphenomenon, or chemical shift, may be presentedgraphically as points on the x-axis, each point representingthe Lamour frequency of protons in different molecules. Ifquantitative data about the concentration of protons inspecific voxels is then presented on the y-axis, an MRspectrum may be generated (Fig. 34.7).

The three metabolites detected most easily by MRS are N-acetyl aspartate (NAA), creatine1phosphocreatine (Cr1PCr)and choline (Cho). NAA is one of the most abundant aminoacids in the brain. Its role is not yet fully understood but it isfound only in neurons and may therefore be used as aneuronal marker (Maier 1995). MRS depended initially ondetecting proton signals from relatively large single voxels(single voxel imaging). More recently, it has become possibleto simultaneously detect signals from multiple voxels andthus to generate metabolite maps of the brain (chemical shiftimaging) (Lim et al. 1998). In addition to protium (1H), otherisotopes that possess nuclear spin include fluorine (19F),sodium (23Na), phosphorus (31P) and lithium (7Li). Thisallows MRS detection in the brain of molecules thatincorporate these isotopes, and phosphorus and proton MRShave been used extensively to investigate brain energymetabolism. Furthermore, the preliminary use of MRS in theevaluation of psychopharmacological compounds hasalready been reported (Maier 1995). It therefore appearslikely that MRS, like fMRI, will soon have a place in clinicalpsychiatric practice (Malhi et al. 2002).

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