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Review 24 Lehrer, M. et al. (1988) Motion cues provide the bee’s visual world with a third dimension. Nature 332, 356–357 25 Zhang, S.W. et al (1995) Convergent processing in honeybee vision: multiple channels for the recognition of shape. Proc. NaH Acad. Sci. U. S. A. 92, 309–3031 26 Srinivasan, M.V. et al. (1990) Visual figure–ground discrimination in the honeybee: the role of motion parallax at boundaries. Proc. R. Soc. London Ser. B 238, 331–350 27 Wehner, R. (1972) Dorsoventral asymmetry in the visual field of the bee, Apis mellifica. J. Comp. Physiol. 77, 256–277 28 Hateren, J.H. van et al. (1990) Pattern recognition in bees: orientation discrimination. J.Comp.Physiol. (Ser. A) 167, 649–654 29 Giger, A.D. and Srinivasan, M.V. (1995) Pattern recognition in honeybees: eidetic imagery and orientation discrimination. J.Comp.Physiol. (Ser. A) 176, 791–795 30 Giurfa, M. et al. (1996) Symmetry perception in an insect. Nature 382, 458–461 31 Pearce, J.M. (1994) Discrimination and categorization. In Animal Learning and Cognition: Handbook of Perception and Cognition (Mackintosh, N.J., ed.), pp. 109–134, Academic Press 32 Yang, E.C. and Maddess, T. (1997) Orientationsensitive neurons in the brain of the honey bee (Apis mellifera). J. Insect Physiol. 43, 329–336 33 Menzel, R. et al. (2001) Cognition in insects: the honeybee as a study case. In Brain Evolution and Cognition (Roth, G. and Wullimann, M., eds), John Wiley & Sons

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34 Menzel, R. et al. (1998) Bees travel novel homeward routes by integrating separately acquired vector memories. Anim. Behav. 55, 139–152 35 Collet, T.S. et al. (1997) Places and patterns: a study of context learning in honeybees. J. Comp. Physiol. (Ser. A) 181, 343–353 36 Colborn, M. et al. (1999) Contextual modulation of visuomotor associations in bumble-bee (Bombus terrestris). Proc. R. Soc. London Ser. B 266, 2413–2418 37 Collett, T.S. et al. (1993) Sequence learning by honeybees. J. Comp. Physiol. (Ser. A) 172, 693–706 38 Collett, T.S. and Baron, J. (1995) Learnt sensory–motor mappings in honeybees: interpolation and its possible relevance to navigation. J. Comp. Physiol. (Ser. A) 177, 287–298 39 Srinivasan, M.V. et al. (1998) Honeybees link sights to smells. Nature 369, 637–638 40 Giurfa, M. et al. The concepts of sameness and difference in an insect. Nature (in press) 41 Collett, T.S. and Zeil, J. (1998) Places and landmarks: an arthropod perspective. In Spatial Representation in Animals (Healy, S., ed.), pp. 18–53, Oxford University Press 42 Menzel, R. et al. (2000) Two spatial memories for honeybee navigation. Proc. R. Soc. London Ser. B 267, 961–968 43 Giurfa, M. and Capaldi, E.A. (1999) Vectors, routes and maps: new discoveries about navigation in insects. Trends Neurosci. 22, 237–242

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44 Tolman, E.C. (1948) Cognitive maps in rats and men. Psychol. Rev. 55, 189–208 45 Riley, J.R. et al. (1996) Tracking bees with harmonic radar. Nature 379, 29–30 46 Menzel, R. (1999) Memory dynamics in the honeybee. J. Comp. Physiol. (Ser. A) 185, 323–340 47 Hammer, M. and Menzel, R. (1998) Multiple sites of associative odor learning as revealed by local brain microinjections of octopamine in honeybees. Learn. Mem. 5, 146–156 48 Faber, T. et al. (1999) Associative learning modifies neural representations of odors in the insect brain. Nat. Neurosci. 2, 74–78 49 Joerges, J. et al. (1997) Representation of odours and odour mixtures visualized in the honeybee brain. Nature 387, 285–288 50 Botzer, D. et al. (1998) Multiple memory processes following training that a food is inedible in Aplysia. Learn. Mem. 5, 204–219 51 Müller, U. and Carew, T.J. (1998) Serotonin induces temporally and mechanistically distinct phases of persistent PKA activity in Aplysia sensory neurons. Neuron 21, 1423–1434 52 Dubnau, J. and Tully, T. (1998) Gene discovery in Drosophila: new insights for learning and memory. Annu. Rev. Neurosci. 21, 407–444 53 Rose, S.P.R. (1991) How chicks make memories: the cellular cascade from c-fos to dendritic remodelling. Trends Neurosci. 14, 390–397

fMRI and cognitive dysfunction in schizophrenia Rachel L.C. Mitchell, Rebecca Elliott and Peter W.R. Woodruff Despite being one of the most prevalent psychiatric conditions, schizophrenia is still poorly understood, with no clear objective biological marker. The advent of neuroimaging has enabled in vivo investigations to complement older techniques, and has revealed important insights. fMRI provides a means to assess the neurobiological theory that schizophrenia is caused by abnormal fronto–temporal lobe connections. In studies of language abnormalities, fMRI can explicitly assess the hypothesis that the normal lateralization of language is reversed in schizophrenia. Longitudinal fMRI studies, and studies examining the effects of medication, suggest that the technique has further potential to advance our understanding of this complex disorder.

A century ago Kraepelin described a group of psychiatric disturbances, which he saw as a single disease entity, the common feature of which was a loss of the internal connections of the psychic personality1. He termed this disease ‘dementia praecox’ because of the apparent degradation in function over time, and the young age of onset. His observations were later refined by Bleuler2, who renamed the disease ‘schizophrenia’.

SCHIZOPHRENIA (see Glossary) is a PSYCHOTIC DISORDER in which hallucinations and delusions are hallmark features, and impaired judgement and loss of contact with reality typically occur. The disease is characterised by a range of symptoms, frequently classified into POSITIVE and NEGATIVE SYMPTOMS (see Box 1). Positive symptoms refer to behaviours and cognitions that are not normally present in the general population, whilst negative symptoms refer to behaviours and cognitions that are absent in schizophrenia, but are normally present in the general population. Schizophrenia is a heterogeneous disorder, and individual symptom profiles may vary considerably. Although the core symptoms are occasionally seen in other disorders, the disturbances of word usage and linguistic expression seen in formal thought disorder, are unique and specific to schizophrenia. Schizophrenia is relatively common, with a lifetime prevalence of approximately 1 in 100. Indeed,

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Glossary Symptoms/Cognitions Executive functions: Processes such as planning, strategy selection and monitoring of performance that are largely mediated by the frontal lobes. Classic tests include the Tower of Hanoi Test and the Wisconsin Card Sorting Test. Hypofrontality: A pattern of functional brain activity sometimes encountered in patients with schizophrenia, in which patients display reduced frontal lobe activation compared with controls. Negative symptoms: Behaviours and cognitions that are absent in patients with schizophrenia, but are normally present in the general population. PFC: Prefrontal cortex covers the most anterior portion of the frontal lobes. It subserves executive functions such as working memory, information processing, behavioural organisation, and attention. Converging evidence suggests structural and functional abnormalities of the PFC in schizophrenia. Positive symptoms: Behaviours and cognitions that are not normally present in the general population. Psychotic disorder: A severe mental disorder in which there is impaired judgement and loss of contact with reality. Retrograde amnesia: Memory loss for events occurring prior to the event that caused amnesia. Schizophrenia: A psychotic disorder including (a) deterioration from previous levels of social, cognitive and occupational functioning; (b) onset before midlife; (c) a duration of at least 6 months; and (d) psychotic symptoms including thought disturbances, delusions, hallucinations, a disturbed sense of self, and loss of reality testing.

fMRI Methodology/Paradigms Activation paradigm: A paradigm used in functional imaging studies, in which the neural response to a task of interest is compared to the brain’s functional activity during a period of rest or during a neutral condition matched for perceptuomotor components. Blocked design: An experimental design in which several stimuli are presented one after the other in blocks. Counting task: A control task used in functional imaging studies of word generation. Subjects are required to count from one until cued to stop. CPT: Continuous Performance Test. A random sequence of stimuli is presented over an extended period of time. Subjects are required to respond to a target by pressing a button. They are thus required to maintain their attention and performance over time.

Rachel L.C. Mitchell* Neuroscience and Psychiatry Unit, Stopford Building, University of Manchester, Oxford Road, Manchester, UK M13 9PT *e-mail: moe93rlm@ fs2.scg.man.ac.uk Rebecca Elliott Neuroscience and Psychiatry Unit, Stopford Building, University of Manchester, Oxford Road, Manchester, UK M13 9PT Peter W.R. Woodruff Academic Department of Psychiatry, University of Sheffield, The Longley Centre, Norwood Grange Drive, Sheffield, UK S5 7JT

Effective connectivity: The influence one neural system exerts over another. Event-related design: An experimental design in which trains of single stimuli are presented. Event-related fMRI: An fMRI technique that can pinpoint the haemodynamic response to single stimuli. It models fMRI signal changes associated with single behavioural trials as opposed to blocks of behavioural trials. Haemodynamic response: The movements of the blood and the forces involved in regional blood circulation related to neural activity. Nitrous oxide technique: An early functional imaging technique that measured the differences between the arterial input and venous outflow of nitrous oxide, from which cellular uptake could be determined. Capable of determining global but not regional changes in blood flow. Paramagnetic: Paramagnetism is the ability of an otherwise nonmagnetic material to exhibit magnetic properties in the presence of a magnetic field. SPECT: Single Positron Emission Computed Tomography. Like PET, SPECT is a functional imaging technique that produces an image of the distribution in the brain of radionuclides. In contrast to PET, however, radionuclides are used that emit a single photon, of lower energy than the two emitted by PET radionuclides. Thus SPECT has lower detection sensitivity than PET. Structural equation modelling: Models data according to the variancecovariance structure rather than considering variables individually. Tower of Hanoi test: The goal of this test is to rearrange a tower of discs of decreasing size on a defined stick with the fewest moves. Subjects can only move one disc at a time, and cannot stack a bigger disc on top of a smaller one. This test assesses problem solving and planning. Two-back task: A version of the N-back working memory task. In this task, the numbers 1 to 4 are displayed randomly. In the no-back sensorimotor control condition, subjects press the button corresponding to the number seen on the screen, whereas in the two-back condition, they are required to press the button corresponding to the number seen two stimuli previously. Verbal fluency task: Activation task used in functional imaging studies of word generation. Subjects are required to generate as many words as possible beginning with a specified letter of the alphabet. WCST: Wisconsin Card Sorting Test. In the classic version of this test subjects are required to match a response card with one of four reference cards according to colour, number or shape, and to find the rule that governs correct matching. After an unpredictable number of trials the rule is changed. The test measures flexibility in thinking, the capacity to form abstract concepts, and the ability to shift or maintain attentional set.

schizophrenia is now recognised globally as the single most important cause of chronic psychiatric disability3. Schizophrenia is extremely distressing for sufferers and their relatives, and a major challenge for mental health professionals. Recent media attention to failures of care in the community have raised the profile of mental health issues. Developing a clear understanding of the pathology of schizophrenia is thus one of the most significant challenges in psychiatry. Cognitive dysfunction in schizophrenia

A key feature of the symptomatology of schizophrenia is pervasive cognitive impairment. Dysfunction has been reported in most cognitive domains, including attention, language, memory and EXECUTIVE FUNCTION. Many patients demonstrate cognitive impairment prior to manifestation of clinical symptoms4. Furthermore, recent studies of relatives of schizophrenic patients have found that many impairments can also be detected in attenuated form in non-schizophrenic relatives who have never been exposed to treatment5. These cognitive dysfunctions cannot, therefore, simply be correlates of chronic neuroleptic medication, but seem to be an inherent http://tics.trends.com

biological phenomenon. Cognitive deficits have a major impact, compromising many aspects of daily life, including social function, education and employment. One widely studied aspect of cognitive function is memory performance. Schizophrenic patients perform poorly on tests of verbal6 and visual7 memory. Levin et al.8 summarized the basic recall deficits in schizophrenia as similar to those associated with RETROGRADE AMNESIA (memory loss for events occurring prior to the event which caused amnesia), a common finding being that recall, but not recognition is deficient. Intact recognition is not, however, universally found. It has been argued that memory impairments and other cognitive deficits in schizophrenia, may be secondary to general intellectual decline, as measured by decreased IQ (Refs 9,10). In patients without significant IQ decline, pronounced cognitive deficits are still seen, particularly in that group of higher cognitive abilities known as executive functions. This term is used to define processes such as planning, strategy selection and monitoring of performance, thought to be largely mediated by frontal lobe function. Schizophrenic subjects are

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Box 1. Symptoms of schizophrenia DSM-IV* criteria for the diagnosis of schizophrenia (1) The presence of two or more characteristic symptoms during the active /acute phase (e.g. delusions and hallucinations) (2) Evidence of social or occupational dysfunction (3) Continuous signs of disturbance for at least six months (4) Exclusion of schizoaffective/mood disorders (5) Exclusion of cause by a substance or a medical condition (6) If there is also a history of pervasive developmental disorder, schizophrenia can only be diagnosed if prominent delusions or hallucinations are present for at least a month Positive symptoms • Hallucinations: sensory experiences in the absence of external stimulation. Three main characteristics: experienced as vividly as if real, experienced as if originating outside the body, are not corrected in the light of contrary information. May be auditory (hearing sounds that no one else hears) or visual (seeing things that aren’t actually present). Less common forms include somatic, tactile and olfactory hallucinations. • Delusions: false beliefs that persist despite the evidence against them. Types of delusions include persecution, jealousy, guilt/sin, special powers or abilities, religious, somatic, delusions of being controlled and mind reading, feeling that thoughts are broadcast aloud, inserted into your mind, and taken away from your mind. • Bizarre behaviour: unusual clothing and appearance, inappropriate social and sexual behaviour, aggressive and agitated behaviour, repetitive and stereotyped behaviour. • Positive formal thought disorder: abnormalities of speech including narrative moving off onto unrelated topics, replying to a question in an irrelevant manner, incoherence, speech being delayed in reaching its goal, speech rapid and difficult to interrupt, nearby stimuli interrupting train of speech, and sounds governing word choice. Negative symptoms • Affective flattening or bluntening: repressed or impaired emotions. Examples include unchanging facial expression, decreased spontaneous movement, few expressive gestures, poor eye contact, lack of emotion, and a monotone voice. • Alogia: impoverished thinking and cognition such as reduced spontaneous speech, adequate amount of speech but it conveys little real meaning, interruption of speech before train of thought completed, taking a long time to respond. • Avolition-apathy: indifference. Poor grooming and hygiene, impersistence at work or school, lack of energy. • Anhedonia-asociality: inability to experience pleasure. Few recreational interests and activities or an inability to enjoy them, decreased sexual interest and activity, inability to feel intimacy and closeness, few quality relationships with friends and peers. Attention: social inattentiveness and inattentiveness during cognitive tasks.

*Diagnostic and Statistical Manual of Mental Disorders (1994) American Psychiatric Association

impaired on many standard tests assessing executive functions. For example, Goldberg et al.11 demonstrated profound impairments on the classic TOWER OF HANOI TEST of planning and goal-directed thought. Another prominent test of frontal lobe http://tics.trends.com

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function is the Wisconsin Card Sorting Test (WCST), and again, schizophrenic patients demonstrate deficits, even when unmedicated12. Furthermore, their performance correlates with both positive and negative symptoms, suggesting the dysfunction is present at the onset of the illness, and is not secondary to medication or length of illness12. In many instances, the cognitive dysfunctions of schizophrenia are inextricably linked to core clinical symptoms. For example, disordered language is a common clinical feature of schizophrenia, which particularly manifests itself in patients’ inability to convey their intended meaning13. Language dysfunctions in schizophrenia might relate to thought disorder, as many consider that language exists to encode thoughts. Thus, these deficits may not result from an expressive language deficit per se, but rather may be related to characteristically disordered and disrupted underlying thought processes. The role of functional imaging in the study of schizophrenia Functional imaging and cognition

Understanding the cognitive pathology of schizophrenia is central to understanding the disorder. Cognition is, by definition, a dynamic and evolving process that is best studied ‘on-line’ in a temporally flexible manner. Until the advent of functional imaging techniques, cognition was largely studied using neuropsychology. However, this only allows the abnormal outputs of processing to be assessed. Neural correlates can only be inferred by analogy to patients with circumscribed brain damage. Functional imaging provides a means to study the neural basis of cognition directly, and assess the abnormal neural circuitry underpinning cognitive dysfunction. It is therefore an ideal tool to characterise a disorder where functional deficits are paramount. Functional imaging and schizophrenia

It has long been suspected that schizophrenia is associated with abnormal neuronal activity. However, physical abnormalities have historically been harder to identify than in neurological disorders. Post-mortem brain analysis has established that physical abnormality can be observed14, but a crucial limitation of this technique is that any abnormality is potentially confounded by chemical changes that occur after death. In vivo neuroimaging overcomes this problem, and may ultimately provide a neurobiological diagnostic marker for schizophrenia. Early structural neuroimaging studies revealed important new insights. Computed tomography (CT) highlighted the importance of ventricular enlargement15, and structural magnetic resonance imaging demonstrated loss of temporal lobe volume16. A more recent meta-analysis by Wright et al.17 found consistent support for both ventricular enlargement and loss of temporal lobe matter (particularly the

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Box 2. Comparing PET and fMRI Advantages of PET • Quantitative models available • Can potentially image the whole brain, including deep and superficial brain structures • Can be used to image a wider range of brain processes, including studies of neuroreceptors Advantages of fMRI • Non-invasive • Widely available • The signal is the synthesis of many parameters, each of which can be manipulated so optimal information about the process being examined can be obtained • Relative robustness and reproducibility of results • High spatial resolution • Multiple scans can be obtained from a single subject, even within a single session • Relatively inexpensive • The repeatability of fMRI offers the unique potential for studying functional plasticity • Areas of activity can be localised in structural images obtained in the same scanning session • Superior temporal resolution to PET • Event-related fMRI • Use of magnetic contrast agents can increase sensitivity

amygdala, hippocampus and parahippocampus) in the brains of schizophrenic patients, and additionally reported reduced mean cerebral volume in schizophrenia. However, many of these structural abnormalities are relatively subtle, with pronounced individual variability. This means that the abnormalities cannot be used as a diagnostic marker (by contrast with, for example, Alzheimer’s disease). However, the core pathology of schizophrenia might be functional, with structural correlates only in certain cases. Functional neuroimaging provides a means to assess impaired functional neuroanatomy and is thus a crucial advance in the study of schizophrenia. Why fMRI?

The early functional imaging technique, NITROUS OXIDE TECHNIQUE, was restricted by its inability to assess regional brain activity. Studies using inert gas blood flow were invasive and relied on radioactive substances. PET shares these limitations but was superior to previous techniques in spatial resolution, and remains a widely used technique that has led to many advances (reviewed, for example, by Sedvall18). However, the most recently developed functional neuroimaging technique, fMRI, has certain advantages over PET (Box 2), and may well become the technique of choice in cognitive activation studies. Key advantages are that it is non-invasive, http://tics.trends.com

• •

High signal-to-noise ratio No exposure to ionising radiation

Disadvantages of PET • Low spatial resolution • Expensive • Requires on-site cyclotron and radiopharmaceutical team • Need to average data across multiple subjects • Involves exposure to radioactive agents, hence limited number of scans can be performed on a single subject • Experimental conditions must last a minute or more Disadvantages of fMRI • Relationship between fMRI signal and neuronal activation not fully elucidated • Not all areas of the brain can be imaged very well (e.g. areas near the frontal sinuses) • Susceptible to movement related artefacts • Relatively immature technique compared to PET • Excludes patients with metal implants and pacemakers • Temporal resolution constrained by the time course of the physiological processes generating the signal

better tolerated, cheaper and more widely available than PET, with better spatial and temporal resolution. Although the PET literature is more extensive at present, we believe that the potential of fMRI justifies a focused review. fMRI cognitive activation methodology

fMRI typically assesses differences between neural states, and is therefore ideal for studies of brain activation. Early functional imaging studies with PET often assessed resting brain activity. More recent studies employ ACTIVATION PARADIGMS to assess the brain’s response to a specified cognitive task. Neural response to a task of interest is compared to response during a period of rest or a neutral condition (matched for perceptuomotor components). Careful experimental design ensures that the subsequent difference between the active and control condition ‘reflects’ the brain’s response to the cognitive process of interest. The temporal resolution of the fMRI technique is such that both BLOCKED (several stimuli presented sequentially in blocks) and EVENT-RELATED (trains of single stimuli) experimental designs are possible. fMRI studies of cognitive functions in schizophrenia

Amongst the first successful uses of fMRI to detect neuronal activation in the human brain were Ogawa et al.19 in 1990 and Belliveau et al.20 a year later. As

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fMRI methodology has become more sophisticated, use of the technique to study cognitive function in schizophrenia has expanded rapidly. The literature is diverse, considering many aspects of function. In this review we focus on particular questions that serve as examples to illustrate important principles. Verbal memory and word generation

Main approaches to the study of schizophrenic language dysfunctions using fMRI, have assessed verbal recall of word lists and word production. Patients with schizophrenia fail to show the normal increase in frontal lobe activity associated with verbal recall of word lists under various conditions21,22. Specifically, these two studies demonstrated that normal sensitivity of auditory processing to manipulation of processing demands is lost in schizophrenic patients. In addition to frontal abnormalities during verbal recall, Yurgelun-Todd et al.21 demonstrated an augmentation of temporal lobe response which was lacking in controls. Baird et al.23 have demonstrated the reverse pattern. This discrepancy remains an unresolved issue. However, the findings of temporal lobe abnormalities are consistent with structural MRI abnormalities17,24, and functional evidence of temporal lobe dysfunction during verbal memory tasks25. Stevens et al.26 used fMRI to investigate the neural basis of the finding that learning and working memory deficits are specific to words, and do not extend to tones6. In both verbal and tone tasks patients consistently showed less temporal lobe activity than controls. Areas of the left inferior frontal cortex also showed reduced neural response specific to the verbal task in schizophrenics relative to controls. However, despite normal performance on the non-verbal tone task, patients failed to show normal HAEMODYNAMIC RESPONSE in the superior frontal gyrus. Unlike in the verbal task, the decreased response to tones could not be attributed to a performance deficit. Here, fMRI revealed more than could be inferred from neuropsychological investigations, by showing neural abnormality in the absence of performance deficits. The finding may reflect the adoption of a modified strategy by schizophrenic patients: to perform as well as controls, they may use different cognitive skills, and thus engage different brain regions. The neural response associated with word generation can be assessed by subtracting the response to a COUNTING TASK (‘count from one until cued to stop’) from the response to the VERBAL FLUENCY TASK (‘generate as many words as possible beginning with a specified letter’). Using this method, YurgelunTodd et al.27,28 showed abnormal patterns of neural response in the frontal and temporal lobes in schizophrenic subjects – a lower level of frontal response than controls, but greater left temporal response. Curtis et al.29 also demonstrated a similar pattern, but the difference in temporal lobe response http://tics.trends.com

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did not reach statistical significance. It is possible that the discrepancy between these findings is due to methodological differences, specifically a difference between covert and overt speech. Covert performance requires a high level of subject cooperation, and speaking aloud typically causes significant head movement. Furthermore, in healthy subjects, temporal lobe activity is suppressed during overt speech30, perhaps owing to processing the sound of their own voice. Enhanced temporal lobe response in schizophrenics, in Yurgelun-Todd’s overt speech condition may actually represent a failure of the normal temporal lobe suppression, which would not be seen in Curtis’ covert task. In further fMRI studies of verbal fluency, Curtis et al.31 re-demonstrated HYPOFRONTALITY, and also showed increased activation of the right fusiform gyrus of schizophrenic subjects. Since both structures are part of a network mediating language processing, the authors suggested that the results might reflect a possible neurodevelopmental reorganisation within this network. Functional imaging allows such networks to be identified and fMRI has the advantage that repeated studies in individuals could develop our understanding of how these networks function under different conditions, and over time. Ultimately this could allow us to address Kraepelin’s original ideas, and assess the theory of schizophrenia as a progressive disorder. Higher cognitive functions in schizophrenia

Various higher cognitive functions in schizophrenia have been investigated using fMRI, but many studies have focused on the prefrontal substrates of working memory. Although these studies have largely just confirmed what was already known from PET studies, fMRI has helped to substantiate these findings in a modality which can offer significant practical and theoretical advantages (see Box 2). Kotrla et al.32 first demonstrated a use for fMRI in the study of schizophrenic subjects performing the classic WCST, a card-matching task that assesses flexibility in thinking, abstract concept formation, and the ability to shift or maintain attentional set. Volz et al.33 observed a lack of prefrontal activation in schizophrenic subjects compared with controls, and a trend towards increased left temporal activation. Another classic test of higher cognition is the TWOBACK TASK (a version of the N-back working memory task). The numbers 1 to 4 are displayed in random sequence. In the no-back (sensorimotor) control condition, subjects press the button corresponding to the number seen on the screen, whereas in the twoback condition, they press the button corresponding to the number seen two stimuli previously. Using fMRI, Weinberger et al.34 found that most patients performing this task, failed to show normal activation in the prefrontal cortex (PFC), a finding confirmed by Callicott et al.35. In addition to reduced frontal activation, Liddle et al.36 found that schizophrenic subjects failed to show the normal suppression of left

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Fig. 1. Lateral and midsaggital views of the normal brain, showing regions implicated in studies of schizophrenia. fMRI evidence suggests that there may be some functional reorganisation of brain areas in schizophrenic patients.

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SMA

SMA

DLPFC

AC IPL

IFG

STG

STG MTG

FG

AC = Anterior cingulate DLPFC = Dorsolateral prefrontal cortex FG = Fusiform gyrus

Lateral view

IFG = Inferior frontal gyrus IPL = Inferior parietal lobule

Mid-saggital section

MTG = Middle temporal gyrus SMA = Supplementary motor area STG = Superior temporal gyrus TRENDS in Cognitive Sciences

temporal response, and argue that this suggests abnormal coordination of activity between the frontal and left temporal cortices. fMRI studies37, have also confirmed histopathological38 evidence of schizophrenic abnormalities in the anterior cingulate. The anterior cingulate in controls is implicated in processes such as inhibition, and evaluation of the success of a particular strategy39. Using an EVENT-RELATED fMRI design, Belger et al.37 found that impairments of behavioural inhibition in schizophrenics were associated with attenuated neural response in the anterior cingulate and inferior frontal/insular regions. The event-related fMRI methodology is a means of obtaining information about responses to single trials which is inaccessible to PET. Abnormal activity in the anterior cingulate of the schizophrenic brain, is consistent with post-mortem evidence of altered microciruitry in this region14. Attenuated anterior cingulate response in schizophrenia has been shown during monitoring of performance using the Continuous Performance Test (CPT) (Ref. 40). This test involves presentation of a random sequence of stimuli over an extended period of time which subjects monitor for targets. They are therefore required to maintain their attention and performance over time. A first-episode patient study by Barch et al.41 demonstrated that failure to activate the prefrontal cortex (PFC) in a working memory task based on the CPT, occurred despite normal stimulus-driven activation of motor and visual regions, consistent with a role for the PFC in a higher, control level of processing. In the studies discussed above, neural abnormalities occur in the context of impaired performance. This raises the question of whether the http://tics.trends.com

impaired performance is a consequence of neural abnormality or vice versa. Ramsey et al.42 demonstrated reduced left frontal cortex activity in schizophrenics in the absence of deficits on a set-shifting task, implying that patients are able to complete the task adequately using different brain areas from control subjects. Similarly, Goodman et al.43, showed that there was no difference in performance between first-episode schizophrenics and controls on the two-back working memory task. However, fMRI showed that this apparently normal performance was achieved using abnormal brain regions: schizophrenics showed reduced activation in the dorsolateral PFC (DLPFC), but greater activation in inferior and medial frontal regions. Thus, fMRI has shown functional abnormalities associated with apparently normal task performance, implying an even more striking extent of abnormality than had been demonstrated in neuropsychological studies. This may suggest some functional reorganisation during brain development in patients with schizophrenia (see Fig. 1 for location of brain regions). Auditory hallucinations in schizophrenia

To the layperson, auditory hallucinations are perhaps the most typical symptom of schizophrenia. Improved understanding of the neural basis of auditory hallucinations, which are not readily accessible to neuropsychological study, could be an important step towards generating more effective treatments for this debilitating symptom. Neuroimaging has allowed the neural basis of the phenomenon to be studied. McGuire et al.44 used SPECT, and Silbersweig et al.45 used PET to describe a neural basis for auditory hallucinations. Neuroimaging has subsequently been

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Box 3. Fronto–temporal connectivity in schizophrenia There are multiple connections between the DLPFC and the hippocampusa. PET studies by Frith et al.b,c, have demonstrated that in normal subjects, internal generation of words is associated with increased activity of the left DLPFC and decreased activity in bilateral auditory cortices. Frith et al. suggested that the absence of external stimulation (e.g. listening to words) in their study accounted for this decreased temporal activity, not seen in previous studiesd. Additionally, Friston et al.e have shown that the left DLPFC is responsible for modulating the responsivity of a neural system in the STG and is the probable mediator of changes in attentional and intentional states that underlie the intrinsic generation of words. In schizophrenic subjects Frith et al.f have shown that verbal fluency is associated with a failure to show the normal decrease in left STG blood flow, even when groups were matched for magnitude of frontal activation. The characteristic temporal lobe pathology of schizophrenia would not immediately suggest an increase in activation in this region, as this region tends to be smaller in size. It is likely that the mechanism for the observed increases in temporal lobe rCBF is disinhibitiong. Coordination of activity between the frontal and temporal lobes in schizophrenia may thus be abnormal, with disinhibition of temporal lobe activity mediated by fronto–limbic connections. In normal subjects, the frontal lobe would suppress temporal lobe activity during intrinsic word generation. It is possible that failure of this inhibition mechanism causes patients to misattribute inner speech as originating externally. Such a mechanism could account for the generation of

applied to understanding the relationship between auditory hallucinations and the normal perception of internal and external speech. Woodruff et al.46,47 have used fMRI to demonstrate that, whilst listening passively to externally presented speech, schizophrenic patients showed relatively less activation than controls in the left superior temporal gyrus (STG), and relatively more activation than controls in the right middle temporal gyrus (MTG). The normal left-lateralized response to speech was thus reversed in schizophrenia. Furthermore, when patients actively hallucinating were presented with external speech, the extent and intensity of response in temporal cortex (right MTG) was less than in the same patients during hallucination-free periods. The authors concluded that auditory verbal hallucinations and exogenously presented speech compete for the same neural resources within the temporal cortex, particularly in the right MTG (Ref. 46). Lennox et al. have also used fMRI to demonstrate right-lateralized activation of the STG during the hallucinatory state48. Activation by auditory http://tics.trends.com

auditory hallucinations. These initial functional studies are consistent with structural brain findingsh,i. For instance Woodruff et al.h have shown that healthy controls demonstrate large positive correlations between prefrontal and temporal lobe volumes, whereas schizophrenic patients exhibited a dissociation between prefrontal and STG volumes. These findings, they argue, can be explained by a relative lack of fronto–temporal connections (and hence reduced trophic influences) during brain development in patients with schizophrenia. References a Roberts, G.W. (1991) Schizophrenia: a neuropathological perspective. Br. J. Psychiatry 158, 8–17 b Frith, C.D. et al. (1991) Willed action and the prefrontal cortex in man: a study with PET. Proc. R. Soc. London Ser. B 244, 241–246 c Frith, C.D. et al. (1991) A PET study of word finding. Neuropsychologia 29, 1137–1148 d Petersen, S.E. et al. (1988) Positron emission tomographic studies of the cortical anatomy of single word processing. Nature 331, 585–589 e Friston, K.J. et al. (1991) Investigating a network model of word generation with positron emission tomography. Proc. R. Soc. London Ser. B 244, 101–106 f Frith, C.D. et al. (1995) Regional brain activity in chronic schizophrenic patients during the performance of a verbal fluency task. Br. J. Psychiatry 167, 343–349 g Friston, K.J. et al. (1992) The left medial temporal region and schizophrenia. Brain 115, 367–382 h Woodruff, P.W. et al. (1997) Structural brain abnormalities in male schizophrenics reflect fronto–temporal dissociation. Psychol. Med. 27, 1257–1266 i Goldberg, T.E. et al. (1994) Relations between neuropsychological performance and brain morphological and physiological measures in monozygotic twins discordant for schizophrenia. Psychiatry Res. 55, 51–61

hallucinations in schizophrenia has additionally been demonstrated in Heschl’s (transverse temporal) gyrus49. Noting additional activation of the left DLPFC in all schizophrenic subjects, Lennox et al. have suggested that their findings of abnormal frontal and temporal activity support a theory of failure to monitor internally generated stimuli (see Box 3). In normal subjects, the frontal lobe suppresses temporal lobe activity during intrinsic word generation. Failure of this inhibition mechanism may cause patients with schizophrenia to misattribute internal auditory stimulation as originating externally. David et al. reported attenuation of response to external speech input during auditory hallucinations only when the exogenous stimulation was in the auditory modality50. fMRI has therefore facilitated the study of a specific symptom of schizophrenia, and allowed greater insight into the processes underlying auditory hallucinations. Practical applications of fMRI in studying schizophrenia

The studies discussed above have extended our theoretical knowledge of schizophrenia. Other fMRI studies have focused on the impact of treatment

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Box 4. Hypofrontality in schizophrenia The concept of hypofrontality in schizophrenia first came to the fore in the pioneering studies of Ingvar and Franzena. They highlighted the shift in blood flow distribution from frontal to more posterior regions, with their demonstration that schizophrenic patients display reduced frontal activation compared with controls. Subsequent studies have questioned the extent to which this phenomenon is generally found. For example, Mathew et al.b found that reduction in regional CBF was global, whereas Ariel et al.c did report the presence of hypofrontality (in the left hemisphere). Several methodological factors have been proposed to account for the inconsistent results of studies of hypofrontality, such as lack of adequate control for age and sex differences, clinical symptomatology, medication status and scanning conditions under which the measurement was takend. Other groups have attempted to measure rCBF in the brain when a subject is engaged in performing a cognitive task rather than solely ‘at rest’. Administration of the Wisconsin Card-Sorting Task (believed to assess DLPFC function) showed a clear difference in areas of the brain activated by the task, between the normal control and schizophrenic group. Normal control subjects showed a task-related increase in rCBF of the DLPFC, not detected in schizophrenic patientse. PET studies have continued the controversy surrounding whether or not hypofrontality exists in schizophrenia. Farkas et al.f reported a relative metabolic hypofunction of the frontal lobe in one never-medicated schizophrenic at rest; a finding replicated in a 18FDG PET study of 8 unmedicated schizophrenics and 6 agematched controlsg. At rest, the antero-posterior gradient in metabolic rate was greater in controls than schizophrenics. Buchsbaum et al.h used 16 schizophrenic subjects, 19 normal subjects and also included 11 patients with affective disorder (to evaluate diagnostic specificity). Although this study demonstrated hypofrontality in schizophrenics, the degree of hypofrontality was similar to that observed in the affective patient group. In contrast to their first studyg, hypofrontality in schizophrenics was confined to the right hemisphere. Farkas et al.i also followed up their preliminary report, with a comparison of the FDG PET scans of 13 schizophrenics and 11 normal controls in the resting state. Their analysis showed that the absolute parietal and whole slice glucose metabolic rates showed no difference between the two groups,

but that the frontal to parietal ratio was lower in the schizophrenic group than the controls. Thus, although there were no differences between schizophrenics and controls in whole brain glucose utilisation, relative hypofrontality was demonstrated. Two of the major PET studies inconsistent with the findings of Buchsbaum et al.g,h used a different nuclide from 18F (Refs j,k). Sheppard et al.j scanned with 15O-labelled CO2, and computed O2 uptake and C B F. Some 50% of patients were on neuroleptic medication, and scans were done in an open room without rigorous sensory or neuropsychological control. Although Sheppard et al.j tried several statistical approaches in the analysis of their data, all of them failed to confirm the hypofrontality hypothesis. Many of the discrepancies between PET studies of hypofrontality may be caused by factors other than the functional demands placed on the brain being imaged. Examples include the patient’s specific symptom profile, their chronicity, and medication. References a Ingvar, D.H. and Franzen, G. (1974) Distribution of cerebral activity in chronic schizophrenics. Lancet 7895, 1484–1486 b Mathew, R.J. et al. (1982) A study of regional cerebral blood low in schizophrenia. Arch Gen. Psychiatry 39, 1121–1124 c Ariel, R.N. et al. (1983) Regional cerebral blood flow in schizophrenics. Arch. Gen. Psychiatry 40, 258–263 d Berman, K.F. and Weinberger, D.R. (1986) Cerebral blood flow studies in schizophrenia. In Handbook of Schizophrenia (Vol. I) (Nasrallah, H.A. and Weinberger, D.R., eds), Elsevier e Weinberger, D.R. et al. (1986) Physiological dysfunction of dorsolateral prefrontal cortex in schizophrenia: I. Regional cerebral blood flow evidence. Arch. Gen. Psychiatry 43, 114–125 f Farkas, T. et al. (1980) The application of 18F-2-fluro-D-glucose and positron emission tomography in the study of psychiatric condition. In Cerebral Metabolism and Neural Function (Passonean, J.V. et al., eds), pp. 403–408, Williams & Wilkins g Buchsbaum, M.S. et al. (1982) Cerebral glucography with positron emission tomography: use in normal subjects and in patients with schizophrenia. Arch. Gen. Psychiatry 39, 251–259 h Buchsbaum, M.S. et al. (1984) Anteroposterior gradients in cerebral glucose use in schizophrenics and affective disorders. Arch. Gen. Psychiatry 41, 1159–1166 i Farkas, T. et al. (1984) Regional brain glucose metabolism in chronic schizophrenia. Arch. Gen. Psychiatry 41, 293–300 j Sheppard, G. et al. (1983) 15O-positron emission tomographic scanning in predominantly never-treated acute schizophrenic patients. Lancet 8365, 1448–1452 k Widen, L. et al. (1983) Positron emission tomography studies of glucose metabolism in patients with schizophrenia. Am. J. Neuroradiol. 4, 550–552

regimes on symptoms. Mellers et al. studied whether performance of schizophrenic patients on the two-back task can be improved with cognitive rehabilitation, and what the concomitant neural changes might be51. fMRI studies have provided comparative evidence on the neural effects of atypical and typical antipsychotic drug treatment which is consistent with their differential effects on cognition. Schizophrenics under stable typical drug treatment exhibited significantly reduced activation of the PFC relative to patients receiving atypical medication52. Honey et al. showed that, compared with continued typical antipsychotic treatment, substitution of the atypical drug, risperidone, enhanced neural response levels in the DLPFC of http://tics.trends.com

schizophrenic subjects during working memory performance53. Yurgelun-Todd et al. used fMRI to assess the effects of medication regimes on verbal fluency54. They found that atypical antipsychotics had detectable neural effects (increased temporal activation) through modulation of the fronto–temporal network, though without normalising activity of these regions to patterns of activation demonstrated by control subjects. These studies demonstrate a direct practical application of fMRI in determining how different treatments impact upon cognitive processes. The technique could potentially provide an important way of assessing the efficacy of new drugs and other treatments as they are developed.

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Box 5. Abnormal laterality for language in schizophrenia Laterality refers to the dominance of one side of the brain for a particular function. Non-affective components of language have long been known to be left-lateralized in the majority of right-handed peoplea. Evidence for abnormal laterality for language in schizophrenia comes from two main sources. Structural evidence has included postmortem, MRI and lesion studies, whilst functional evidence has included neuropsychological (e.g. dichotic listening), electrophysiological and neuroimaging studies. We highlight here two lines of evidence: dichotic listening studies and studies of asymmetry of the planum temporale (PT), a critical region in the processing of language. In most healthy people, the PT is larger in the left hemisphere than in the righta. Abnormal patterns of PT asymmetry may include a smaller left PT than normal, a larger right PT than normal, or a combination of both. One of the first MRI studies to suggest reduced asymmetry of the PT in schizophrenia, was that Rossi et al. in 1992 (Ref. b). Since then there has been marked inconsistency in findings. Rossi et al. confirmed their original finding in 1994 (Ref. c), and further showed that the degree of thought disorder was related to the reduction of PT asymmetry. This relationship was confirmed by Petty et al.d, who found not only reduced asymmetry of the PT in patients with schizophrenia, but a ‘striking reversal’ of normal asymmetry, the right PT being larger than the left. This striking reversal has been elaborated upon by Barta et al.e, who showed that although the right PT was larger than in normal subjects, the underlying grey matter volume was actually less, suggesting that the greater right PT area (and consequent reversal of asymmetry) is the result of greater than normal surface folding of the right PT. MRI studies reporting abnormal asymmetry of the PT have also received support from a post-mortem studyf, which revealed a 20% volume reduction of the left PT in schizophrenic subjects. Studies which have not supported abnormal PT asymmetry in schizophreniag–i have included a study of first episode patients and one of adolescents with childhood onset schizophrenia. Reasons for discrepancies between these study findings might include: variability in anatomic definitions and in procedures used to estimate PT surface area, choice of image acquisition plane, and the whether surface area or cortical volume is measured.

Conclusions

The use of fMRI in the study of schizophrenia is a rapidly expanding field, and although still early in its development compared with some neuroimaging techniques, fMRI has already made a significant contribution. To date, fMRI findings have supported three main observations of the neuroanatomical basis of schizophrenia: that sufferers exhibit hypofrontality http://tics.trends.com

In one of the earliest dichotic listening studiesj group differences in cerebral laterality were not reported, but large interindividual differences in the schizophrenic patients were noted, the authors suggesting this to be consistent with a hypothesis of a breakdown in acute psychotic illness, of the interhemispheric inhibition that normally mediates cerebral laterality. Subsequent to this early study smaller right ear (left hemisphere) advantages have been noted in schizophrenic patients in a number of studiesk–m, independent of gender or medicationl. It has been suggested that the reduced right-ear advantage in patients with schizophrenia on dichotic listening tests may be due to attentional abnormalities present in these patientsm,n. References a Geschwind, N. and Levitsky, W. (1968) Human brain left–right asymmetries in temporal speech region. Science 16, 186–187 b Rossi, A. et al. (1992) Planum temporale in schizophrenia: a magnetic resonance study. Schizophr. Res. 7, 19–22 c Rossi, A. et al. (1994) Planum temporale asymmetry and thought disorder in schizophrenia. Schizophr. Res. 12, 1–7 d Petty, R.G. et al. (1995) Reversal of asymmetry of the planum temporale in schizophrenia. Am. J. Psychiatry 152, 715–721 e Barta, P.E. et al. (1997) Planum temporale asymmetry reversal in schizophrenia: replication and relationship to gray matter abnormalities. Am. J. Psychiatry 154, 661–667 f Falkai, P. et al. (1995) Disturbed planum temporale asymmetry in schizophrenia: a quantitative post-mortem study. Schizophr. Res. 14, 161–176 g Jacobsen, L.K. et al. (1997) Three-dimensional cortical morphometry of the planum temporale in childhood-onset schizophrenia. Am. J. Psychiatry 154, 685–687 h Kleinschmidt, A. et al. (1994) In vivo morphometry of planum temporale asymmetry in first-episode schizophrenia. Schizophr. Res. 12, 9–18 i Kulynych, J.J. et al. (1995) Normal asymmetry of the planum temporale in patients with schizophrenia: three-dimensional cortical morphometry with MRI. Br. J. Psychiatry 166, 742–749 j Wexler, B.E. and Heninger, G.R. (1979) Alterations in cerebral laterality during acute psychotic illness. Arch. Gen. Psychiatry 36, 278–284 k Wexler, B.E. et al. (1991) Cerebral laterality, symptoms, and diagnosis in psychotic patients. Biol. Psychiatry 29, 103–116 l Bruder, G. et al. (1995) Smaller right ear (left hemisphere) advantage for dichotic fused words in patients with schizophrenia. Am. J. Psychiatry 152, 932–935 m Ragland, J.D. et al. (1992) Dichotic listening in monozygotic twins discordant and concordant for schizophrenia. Schizophr. Res. 7, 177–183 n Wale, J. and Carr, V. (1988) Dichotic listening asymmetries and psychotic symptoms in schizophrenia: a preliminary report. Psychiatry Res. 25, 31–39

(see Box 4), that a high proportion of schizophrenic symptoms may result from disrupted fronto–temporal connectivity (see Box 3) (something which can be assessed with methods such as fMRI), and that schizophrenic patients display a reversal of the normal left-sided laterality for language (see Box 5). It is hoped that future fMRI research will move beyond confirmation of pre-existing findings and

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Acknowledgement Rachel Mitchell gratefully acknowledges a PhD studentship from Neuraxis.

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towards developing a broader and deeper understanding of unresolved aspects of schizophrenia. Important directions might include greater use of multiple imaging and event-related fMRI. Multiple imaging studies use more than one functional imaging technique. For instance, fMRI (good spatial resolution) could be combined with electrophysiological imaging (good temporal resolution) to show neural events as they occur in real time, at a high level of spatial resolution. Eventrelated fMRI, meanwhile, can pinpoint the haemodynamic response to single stimuli55. This new class of imaging experimental designs exploits the temporal resolution of fMRI by modelling signal changes associated with single behavioural trials as opposed to blocks of trials. Its use in the study of schizophrenia is already emerging37,40, and when event-related fMRI is fully exploited, fMRI could supersede PET in the advances made to our knowledge of schizophrenia. Advantages of this method include the ability to (1) randomize trial presentations, (2) test for functional correlates of behavioural measures with greater power, (3) directly examine the neural correlates of behavioural trials, and (4) test for differences in the onset time of neural activity evoked by different trial types. Consequently, event-related fMRI has the potential to address a number of cognitive psychology questions with a degree of statistical power not previously available56 in more traditional blocked designs. Another approach suited to further advancing the study of schizophrenia with fMRI, is the application of direct measures of connectivity such as EFFECTIVE CONNECTIVITY (the influence one neural system exerts over another) and STRUCTURAL EQUATION MODELLING (models data according to the variance-covariance structure rather than considering variables individually). These measures are ideally suited to investigating the strength of functional connections between regions of the brain. In particular, they could be applied to test directly the hypothesis that fronto–temporal connectivity is disrupted in patients with schizophrenia. A role for fMRI in assessing the impact of treatment regimes is also emerging. These studies will be able to elucidate whether individual

References 1 Kraepelin, E. (1919) Dementia Praecox and Paraphrenia, E. and S. Livingstone 2 Bleuler, E. (1966) Dementia Praecox or the Group of Schizophrenias, International Universities Press 3 Jablensky, A. et al. (1992) Schizophrenia: manifestations, incidence and course in different cultures. A World Health Organization tencountry study. Psychol. Med. Monogr. Suppl. 20, 1–97 4 Jones, P. et al. (1995) Child developmental risk factors for adult schizophrenia in the British 1946 birth cohort. Lancet 344, 1398–1402 5 Cannon, T. et al. (1994) Neuropsychological functioning in siblings discordant for schizophrenia and healthy volunteers. Arch. Gen. Psychiatry 51, 651–661 http://tics.trends.com

schizophrenic symptoms are ameliorated, or caused by medication. It is likely that fMRI will play an increasing role in developing drugs with less problematic side effects. Recent searches for other molecules with PARAMAGNETIC properties that will for example, bind to neuroreceptors may prove particularly relevant here. This would allow fMRI investigation of the functional effects of medication at the level of the neuroreceptor. Finally, the ability to perform fMRI repeatedly on the same subject, lends itself to longitudinal studies of schizophrenia. This would allow functional abnormalities to be related to clinical progression and assess Kraepelin’s original hypothesis that schizophrenia has a progressive course. Ultimately, such studies may enable us to gain an understanding of how this disorder develops and progresses at a neural level. Outstanding questions •

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Is the functionally abnormal response to speech in schizophrenia best explained by functional or structural theories? Why did the schizophrenic subjects show increased temporal lobe activation during performance of the WCST when this has not been seen before in studies using the WCST? Is this an example of impaired fronto–temporal connectivity? Could impaired fronto–temporal connectivity be the neuropathology that underlies specific subtypes of schizophrenia? Can fMRI be used as successfully to study negative symptoms as it has been used to look at positive symptoms? Can fMRI be developed to capture functional images at the level of the neuroreceptor, thus enabling assessment of the full impact of different drug treatments? Studies rarely differentiate between schizophrenic patients with different kinds of symptoms. Might the subtypes of schizophrenia display different activation patterns to different ‘activation paradigms’?

6 Wexler, B.E. et al. (1998) Word and tone working memory deficits in schizophrenia. Arch. Gen. Psychiatry 55, 1093–1096 7 Keefe, R.S. et al. (1997) Performance of patients with schizophrenia on a pen and paper visuospatial working memory task with short delay. Schizophr. Res. 26, 9–14 8 Levin, S. et al. (1989) Contributions of clinical neuropsychology to the study of schizophrenia. J. Abnorm. Psychol. 98, 341–356 9 Payne, R.W. et al. (1973) Cognitive abnormalities. In Handbook of Abnormal Psychology (Eysenck, H.J., ed.), pp. 420–483, Pitman Press 10 Frith, C.D. et al. (1991) Performance on psychological tasks: demographic and clinical correlates of the results of these tests. Br. J. Psychiatry 159 (Suppl. 13), 26–29

11 Goldberg, T.E. et al. (1990) Assessment of procedural learning and problem solving in schizophrenic patients by Tower of Hanoi type tasks. J. Neuropsychiatry Clin. Neurosci. 2, 165–173 12 Parellada, E. et al. (2000) Psychopathology and Wisconsin card sorting test performance in young unmedicated schizophrenic patients. Psychopathology 33, 14–18 13 Cutting, J. (1985) Language. In The Psychology of Schizophrenia, pp. 243–265, Churchill Livingstone 14 Benes, F.M. (2000) Emerging principles of altered neural circuitry in schizophrenia. Brain Res. Rev. 31, 251–269 15 Johnstone, E.C. et al. (1976) Cerebral ventricular size and cognitive impairment in schizophrenia. Lancet 7992, 924–926

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30 Fletcher, P.C. et al. (1996) Local and distributed effects of apomorphine on fronto–temporal function in acute unmedicated schizophrenics. J. Neurosci. 16, 7055–7062 31 Curtis, V.A. et al. (1999) Differential engagement of the prefrontal and fusiform cortex during language tasks in schizophrenia. Schizophr. Res. 36, 220 32 Kotrla, K.J. et al. (1994) Three-dimensional functional MRI in schizophrenics and normal volunteers performing the Wisconsin card sorting test. Biol. Psychiatry 35, 623 33 Volz, H.P. et al. (1997) Brain activation during cognitive stimulation with the Wisconsin cardsorting test: a functional MRI study on healthy volunteers and schizophrenics. Psychiatry Res. Neuroimaging 75, 145–157 34 Weinberger, D.R. et al. (1996) fMRI applications in schizophrenia research. NeuroImage 4, S118–S126 35 Callicott, J.H. et al. (1998) Functional magnetic resonance imaging brain mapping in psychiatry: methodological issues illustrated in a study of working memory in schizophrenia. Neuropsychopharmacology 18, 186–196 36 Liddle, P.F. et al. (1999) An fMRI study of fronto–temporal co-ordination during working memory in schizophrenia. Schizophr. Res. 36, 225 37 Belger, A. et al. (1999) Abnormal anterior cingulate and inferior frontal activation during cognitive inhibition in schizophrenia: an eventrelated fMRI study. Schizophr. Res. 36, 218 38 Benes, F.M. (1993) Neurobiological investigations in cingulate cortex of schizophrenic brain. Schizophr. Bull. 19, 537–549 39 Carter, C.S. et al. (1999) The contribution of the anterior cingulate cortex to executive processes in cognition. Rev. Neurosci. 10, 49–57 40 Carter, C.S. et al. (1999) Anterior cingulate cortex and cognitive disability in schizophrenia: an event-related fMRI study. Schizophr. Res. 36, 219–220 41 Barch, D.M. et al. (1999) Prefrontal cortex and context processing in medication-naïve firstepisode patients with schizophrenia. Schizophr. Res. 36, 217–218 42 Ramsey, N.F. et al. (1999) Left-hemisphere activation with a set-shifting task is reduced in medicated schizophrenic patients, but performance is not affected. Schizophr. Res. 36, 231

43 Goodman, J.M. et al. (1999) A functional MRI study of working memory in first-episode schizophrenic patients. Schizophr. Res. 36, 221–222 44 McGuire, P.K. et al. (1993) Increased blood flow in Broca’s area during auditory hallucinations in schizophrenia. Lancet 342, 702–706 45 Silbersweig, D.A. et al. (1995) A functional neuroanatomy of hallucinations in schizophrenia. Nature 378, 176–179 46 Woodruff, P. et al. (1995) Auditory hallucinations and perception of external speech. Lancet 346, 1035 47 Woodruff, P.W.R. et al. (1997) Auditory hallucinations and the temporal cortical response to speech in schizophrenia: a functional magnetic resonance imaging study. Am. J. Psychiatry 154, 1676–1682 48 Lennox, B.R. et al. (1999) Temporal lobe activation during auditory hallucinations: a functional MRI study. Schizophr. Res. 36, 225 49 Djerks, T. et al. (1999) Activation of Heschl’s gyrus during auditory hallucinations. Neuron 22, 615–621 50 David, A.S. et al. (1996) Auditory hallucinations inhibit exogenous activation of auditory association cortex. NeuroReport 7, 932–936 51 Mellers, J.D.C. et al. (1999) An fMRI study of patients with schizophrenia before and after cognitive rehabilitation. Schizophr. Res. 36, 227 52 Braus, D.F. et al. (1999) The influence of antipsychotics on the disturbed frontal network in schizophrenia: an fMRI study. Schizophr. Res. 36, 219 53 Honey, G.D. et al. (1999) Risperidone restores fronto–parietal activation by a working memory task in patients with schizophrenia. Schizophr. Res. 36, 223 54 Yurgelun-Todd, D.A. et al. (1999) Functional magnetic resonance imaging studies of cortical activation during word production: effects of pharmacologic intervention. Schizophr. Res. 36, 237 55 Buckner, R.L. (1998) Event-related fMRI and the haemodynamic response. Hum. Brain Mapp. 6, 373–377 56 D’Esposito, M. et al. (1999) Event-related functional MRI: implications for cognitive psychology. Psychol. Bull. 125, 155–164

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