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Functional segregation requires convergence and divergence of neuroanatomical connections. Furthermore, the nature of functional segregation suggests that (1) signals in convergent afferents are correlated and (2) signals in divergent efferents are uncorrelated. The aim of this article is to show that this arrangement can be predicted mathematically, using information theory and an idealized model of cortical processing. In theory, the existence of bifurcating axons limits the number of independent output channels from any small cortical region, relative to the number of inputs. An information theoretic analysis of this special (high input:output ratio) constraint indicates that the maximal transfer of information between inputs, to a cortical region, and its outputs will occur when (1) extrinsic connectivity to the area is organized such that the entropy of neural activity in afferents is optimally low and (2) connectivity intrinsic to the region is arranged to maximize the entropy measured at the initial segments of projection neurons. Under the constraints of the model, a low entropy is synonymous with high correlations between axonal firing rates (and vice versa). Consequently this antisymmetric arrangement of functional activity in convergent and divergent connections underlying functional segregation is exactly that predicted by the principle of maximum preservation of information, considered in the context of axonal bifurcation. The hypothesis that firing in convergent afferents is correlated (has low entropy) and spatially coherent was tested using positron emission tomographic measurements of cortical synaptic function in man. This hypothesis was confirmed.

We examined whether the known noradrenergic attenuation of the alerting effect (the beneficial effect of a warning cue) results from an underlying effect of noradrenaline on temporal orienting (orienting toward a particular moment in time). Following a within-subjects, counterbalanced design, 10 healthy human volunteers received placebo, 200 microg clonidine or 1 mg guanfacine (alpha2 agonists) in three separate testing sessions. Subjects were scanned by fMRI while performing attentional orienting tasks containing spatially informative, temporally informative, non-informative or no cues. The alerting effect primarily activated left-lateralized prefrontal, premotor and parietal regions. Clonidine, but not guanfacine, impaired behavioural measures of the alerting effect while attenuating activity in the left temporo-parietal junction. Replicating previous results, the temporal orienting task activated left parietal and frontal cortex, while parietal cortex was activated bilaterally during spatial orienting. Of these networks, clonidine, but not guanfacine, attenuated left prefrontal cortex and insula activity during temporal orienting and attenuated right superior parietal cortex activity during spatial orienting,. To complement these neuroanatomical changes, clonidine produced selective behavioural effects on both temporal and spatial orienting. The anatomical dissociation between the effects of clonidine during temporal orienting versus alerting suggests that noradrenergic modulation of the alerting effect does not result only from an underlying effect on temporal orienting. Furthermore, we have demonstrated lateralized neuroanatomical substrates for the noradrenergic modulation of human attentional orienting in the spatial and temporal domains.

Extensive clinical and imaging research has characterized the neural networks mediating the adaptive distribution of spatial attention. In everyday behavior, the distribution of attention is guided not only by extrapersonal targets but also by mental representations of their spatial layout. We used eventrelated functional magnetic resonance imaging to identify the neural system involved in directing attention to locations in arrays held as mental representations, and to compare it with the system for directing spatial attention to locations in the external world. We found that these two crucial aspects of spatial cognition are subserved by extensively overlapping networks. However, we also found that a region of right parietal cortex selectively participated in orienting attention to the extrapersonal space, whereas several frontal lobe regions selectively participated in orienting attention within on-line mental representations.

Under certain circumstances, implicit, automatic learning may be attenuated by explicit memory processes. We explored the brain basis of this phenomenon in a functional magnetic resonance imaging (fMRI) study of motor sequence learning. Using a factorial design that crossed subjective intention to learn (explicit versus implicit) with sequence difficulty (a standard versus a more complex alternating sequence), we show that explicit attempts to learn the difficult sequence produce a failure of implicit learning and, in a follow-up behavioural experiment, that this failure represents a suppression of learning itself rather than of the expression of learning. This suppression is associated with sustained right frontal activation and attenuation of learning-related changes in the medial temporal lobe and the thalamus. Furthermore, this condition is characterized by a reversal of the fronto-thalamic connectivity observed with unimpaired implicit learning. The findings demonstrate a neural basis for a well-known behavioural effect: the deleterious impact of an explicit search upon implicit learning.

We used event-related functional magnetic resonance imaging to study the neural correlates of endogenous spatial attention for vision and touch. We examined activity associated with attention-directing cues (central auditory pure tones), symbolically instructing subjects to attend to one hemifield or the other prior to upcoming stimuli, for a visual or tactile task. In different sessions, subjects discriminated either visual or tactile stimuli at the covertly attended side, during bilateral visuotactile stimulation. To distinguish cue-related preparatory activity from any modulation of stimulus processing, unpredictably on some trials only the auditory cue was presented. The use of attend-vision and attend-touch blocks revealed whether preparatory attentional effects were modality-specific or multimodal. Unimodal effects of spatial attention were found in somatosensory cortex for attention to touch, and in occipital areas for attention to vision, both contralateral to the attended side. Multimodal spatial effects (i.e. effects of attended side irrespective of task-relevant modality) were detected in contralateral intraparietal sulcus, traditionally considered a multimodal brain region; and also in the middle occipital gyrus, an area traditionally considered purely visual. Critically, all these activations were observed even on cue-only trials, when no visual or tactile stimuli were subsequently presented. Endogenous shifts of spatial attention result in changes of brain activity prior to the presentation of target stimulation (baseline shifts). Here, we show for the first time the separable multimodal and unimodal components of such preparatory activations. Additionally, irrespective of the attended side and modality, attention-directing auditory cues activated a network of superior frontal and parietal association areas that may play a role in voluntary control of spatial attention for both vision and touch.

Background. Contemporary cognitive models of auditory verbal hallucinations propose that they arise through defective self-monitoring. We used a paradigm that engages verbal self-monitoring to investigate this theory in patients with schizophrenia.Methods. Ten patients with auditory verbal hallucinations and delusions (hallucinators), eight patients with delusions but no hallucinations (non-hallucinators), and 20 non-psychiatric control subjects were tested. Participants read single adjectives aloud, under the following randomized conditions: reading aloud; reading aloud with acoustic distortion of their own voice; reading aloud with alien feedback (someone else's voice); and reading aloud with distorted alien feedback. Immediately after articulating each word, participants identified the source of the speech they heard (‘self’/‘other’/‘unsure’), via a button press. Response choice and reaction time were recorded.Results. When reading aloud with distorted feedback of their own voice, patients in both groups made more errors than controls; they either misidentified its source or were unsure. Hallucinators were particularly prone to misattributing their distorted voice to someone else, and were more likely to make errors when the words presented were derogatory. Both patient groups made faster decisions than controls about the source of distorted or alien speech, but faster responses were only associated with errors in the former condition.Conclusions. Impaired verbal self-monitoring was evident in both hallucinators and non-hallucinators. As both groups had delusions, the results suggest an association between delusions and impaired judgements about ambiguous sensory stimuli. The specific tendency of hallucinators to misattribute their distorted voice to someone else may reflect impaired awareness of internally generated verbal material.

Perception involves the processing of sensory stimuli and their translation into conscious experience. A novel percept can, once synthesized, be maintained or discarded from awareness. We used event-related functional magnetic resonance imaging to separate the neural responses associated with the maintenance of a percept, produced by single-image, random-dot stereograms, from the response evoked at the onset of the percept. The latter was associated with distributed bilateral activation in the posterior thalamus and regions in the occipito-temporal, parietal and frontal cortices. In contrast, sustained perception was associated with activation of the pre-frontal cortex and hippocampus. This observation suggests that sustaining a visual percept involves neuroanatomical systems which are implicated in memory function and which are distinct from those engaged during perceptual synthesis.

Attentional modulation of normal sensory processing has a two-fold impact on human brain activity: activation of a network of localized brain regions is associated with paying attention, and activation of specific sensory regions is enhanced relative to passive stimulation. The mechanisms underlying attentional modulation of perception in patients with lesions of sensory cortices are less well understood. Here we report a unique patient suffering from extensive bilateral destruction of the auditory cortices (including the primary auditory fields) who demonstrated conscious perception of the onset and offset of sounds only when selectively attending to the auditory modality. This is the first description of such an attentively modulated 'deaf-hearing' phenomenon and its neural correlates, using H(2)(15)O-PET. Increases in cerebral blood flow associated with conscious awareness of sound that was achieved by listening attentively (compared with identical auditory stimulation presented when the patient was inattentive) were found bilaterally in the lateral (pre)frontal cortices, the spared middle temporal cortices and the cerebellar hemispheres. We conclude that conscious awareness of sounds may be achieved in the absence of the primary auditory cortex, and that selective, 'top-down' attention, associated with prefrontal systems, exerts a crucial modulatory effect on auditory perception within the remaining auditory system.

Two groups of male university students who had been diagnosed as dyslexic when younger, and two groups of control subjects of similar age and IQ to the dyslexics, were scanned whilst reading aloud and during a task where reading was implicit. The dyslexics performed less well than their peers on a range of literacy tasks and were strikingly impaired on phonological tasks. In the reading aloud experiment, simple words and pseudowords were presented at a slow pace so that reading accuracy was equal for dyslexics and controls. Relative to rest, both normal and dyslexic groups activated the same peri- and extra-sylvian regions of the left hemisphere that are known to be involved in reading. However, the dyslexic readers showed less activation than controls in the left posterior inferior temporal cortex [Brodmann area (BA) 37, or Wernicke's Wortschatz], left cerebellum, left thalamus and medial extrastriate cortex. In the implicit reading experiment, word and pseudoword processing was contrasted to visually matched false fonts while subjects performed a feature detection paradigm. The dyslexic readers showed reduced activation in BA 37 relative to normals suggesting that this group difference, seen in both experiments, resides in highly automated aspects of the reading process. Since BA 37 has been implicated previously in modality-independent naming, the reduced activation may indicate a specific impairment in lexical retrieval. Interestingly, during the reading aloud experiment only, there was increased activation for the dyslexics relative to the controls in a pre-motor region of Broca's area (BA 6/44). We attribute this result to the enforced use of an effortful compensatory strategy involving sublexical assembly of articulatory routines. The results confirm previous findings that dyslexic readers process written stimuli atypically, based on abnormal functioning of the left hemisphere reading system. More specifically, we localize this deficit to the neural system underlying lexical retrieval.

Rationale: Diazepam and other benzodiazepines impair episodic memory encoding. Deficits in tests of executive function are also reported. In this study, we ask whether the latter effects are secondary to mnemonic impairment, or reflect specific and distinct effects of benzodiazepines on executive function. Objectives: Using positron emission tomography in healthy human volunteers, we examined similarities in the neuroanatomical correlates of the effect of diazepam on performance of executive compared to episodic memory tasks. Close similarities are proposed to reflect commonalities in the functional effects of the drug. Conversely, any evidence of task-specific regional changes in activity is proposed to reflect distinct functional effects of DZP on the two tasks. Methods: Twelve volunteers received placebo or 10 mg diazepam in a between-subjects design. During scanning, subjects performed one of four experimental conditions, corresponding to a 2×2 factorial design, with memory encoding and executive function (on-line ordering of stimuli) as the two factors. Drug- or task-induced changes in brain activation indexed the neuroanatomical correlates of each condition. Results: Averaged across all conditions, and compared to placebo, diazepam decreased activity bilaterally in prefrontal and temporal cortices. Within this network of deactivation, left dorsal prefrontal cortex activity was attenuated by diazepam during memory encoding, while left frontal opercular activity was attenuated during ordering. Conclusion: This neuroanatomical dissociation reflects distinct functional effects of diazepam on encoding versus ordering tasks. Therefore, the effects of diazepam on ordering tasks are not simply secondary to diazepam effects on episodic memory, but reflect real and distinct effects of the drug on executive function.

The right prefrontal and parietal cortices have been implicated in attentional processing in both neuropsychological and functional neuroimaging literature. However, attention is a heterogeneous collection of processes, each of which may be underpinned by different neural networks. These attentional networks may interact, such that engaging one type of attentional process could influence the efficiency of another via overlapping neural substrates. We investigated the hypothesis that right frontal and parietal cortices provide the neuroanatomical location of the functional interaction between sustained attention and the process of selectively monitoring for target objects. Six healthy volunteers performed one of two tasks which required either selective or non-selective responding. The task lasted continuously for 18 min, during which time 3 Positron Emission Tomography (PET) scans were acquired for each task. This was repeated to obtain 12 PET measurements of regional cerebral blood flow (rCBF) for each subject. The right inferior frontal and parietal cortices were differentially activated by increasing time on task during the selective (S) vs non-selective (NS) task. Specifically, rCBF decreased with increasing time spent performing the NS task but not the S task. This result suggests that the normal deactivation in these areas as time on task increases is counteracted by the extra cognitive demands of selectively responding to target objects. Therefore, we have confirmed our hypothesis that right frontal and parietal cortices provide the neuroanatomical location for the modulation of object selection by sustained attention. We also identified the neuroanatomical correlates of each process separately, and confirmed earlier reports of prefrontal cortex and anterior cingulate activation associated with selective responding, and a fronto-parietal-thalamic network associated with sustained attention.

INTRODUCTION: Patients with unipolar depression show impaired performance on the Tower of London planning task. Positron emission tomography, which has previously identified resting state blood flow abnormalities in depression, was used to investigate neural activity associated with performance of this task in depressed patients and normal controls. METHODS: Six patients with unipolar depression and six matched controls were scanned while performing easy and hard Tower of London problems in a one-touch computerized paradigm and while performing a perceptuomotor control task. RESULTS: The patients in this study showed an expected task-related performance deficit compared with normal subjects. In normal subjects, the task engaged a network of prefrontal cortex, anterior cingulate, posterior cortical areas and subcortical structures including the striatum, thalamus and cerebellum. Depressed patients failed to show significant activation in the cingulate and striatum; activation in the other prefrontal and posterior cortical regions was significantly attenuated relative to controls. Crucially, patients also failed to show the normal augmentation of activation in the caudate nucleus, anterior cingulate and right prefrontal cortex associated with increasing task difficulty. CONCLUSIONS: These findings provide evidence for cingulate, prefrontal and striatal dysfunction associated with impaired task performance in depression. The present results are consistent with a central role of cingulate dysfunction in depression as well as suggesting impaired frontostriatal function.

The prefrontal cortex has been suggested as a site of action for the noradrenergic modulation of cognition. In healthy volunteers attentional deficits can be induced by the alpha 2 adrenoceptor agonist clonidine, without impairment of more explicit tests of frontal lobe function. It is therefore possible that the effects of noradrenaline cannot be localized to a specific brain area such as the prefrontal cortex, but instead involve structures in a more widespread attentional network. A 1.5 micrograms/kg dose of clonidine or placebo was administered to 13 healthy male volunteers performing the rapid visual information processing task, which places demands on both sustained attention and working memory. Twelve positron emission tomography measurements of regional cerebral blood flow (rCBF) were collected during performance of this task and also during a rest state. A second experiment in 12 healthy volunteers examined the effects of a 1.3 micrograms/kg dose of clonidine on the rCBF changes associated with performance of a paired associates learning task compared with passive listening to word pairs. Comparison of each of the experimental tasks with its respective control replicated previous findings. A significant drug x task interaction, common to the two studies, was found in the right thalamus. Inspection of the adjusted rCBF values showed that the effect was due to attenuation of thalamic rCBF during the control states rather than to any effects of clonidine during performance of the cognitive tasks, although the effect was stronger in the rapid visual information processing study than in the paired associates learning study. The significant effect of clonidine during the control as opposed to the "cognitive' activation state is consistent with previous findings in animals and humans demonstrating greater effects of clonidine during states of relatively low arousal. The results suggest neuroanatomical dissociation of the noradrenergic modulation of arousal (via the thalamus) and attention.

This study utilised positron emission tomography (PET) to identify the cortical areas involved in verbal initiation and suppression in normal subjects whilst performing a sentence completion test (the Hayling Test). In the first condition (response initiation) subjects were required to complete a sentence from which the last word was omitted, whereas in the second condition (response suppression) subjects were asked to complete a sentence with a word which made no sense in the context of the sentence. Subjects were also required to perform a control task in which they had to read out the last word of given sentences. Compared to the control task, response initiation was associated with left-sided activation of the frontal operculum, inferior frontal gyrus, middle temporal gyrus and the right anterior cingulate gyrus, whereas response suppression was associated with left frontal operculum, inferior frontal gyrus and right anterior cingulate gyrus activation. The difference in activation between the two conditions of the Hayling Test lay in the increased activation of the left middle temporal gyrus and the left inferior frontal gyrus during response initiation. ©1997 Elsevier Science Ltd. All rights reserved.

Lesion studies indicate distinct neural systems for recognition of facial identity and emotion. Split-brain experiments also suggest that emotional evaluation of a stimulus can occur without conscious identification. The present study tested a hypothesis of a differential neural response, independent of explicit conscious mediation, to emotional compared to nonemotional faces. The experimental paradigm involved holding in mind an image of a face across a 45-s delay while regional cerebral blood flow was measured using positron emission tomography. Prior to the delay, a single face was presented with an explicit instruction to match it to one of two faces, photographed at different angles from the target face, presented at the end of the delay. Repeated blood flow measures were obtained while subjects held happy or neutral faces in mind or during a neutral control fixation condition without initial face presentation. The representation of emotional faces over a delay period, compared to either the nonemotional or the fixation condition, was associated with significant activation in the left ventral prefrontal cortex, the left anterior cingulate cortex, and the right fusiform gyrus. The findings support our hypothesis of a differential neural response to facial emotion, independent of conscious mediation, in regions implicated in the processing of faces and of emotions.

Psychological Medicine / Volume 26 / Issue 04 / July 1996, pp 663 667 DOI: 10.1017/S0033291700037673, Published online: 09 July 2009 Link to this article: http://journals.cambridge.org/abstract_S0033291700037673 How to cite this article: P. K. McGuire and C. D. Frith (1996). Disordered functional connectivity in schizophrenia. Psychological Medicine, 26, pp 663-667 doi:10.1017/S0033291700037673 Request Permissions : Click here

SynopsisFacial behaviour may be an important determinant in clinical ratings of psychopathology. A standardized objective technique was used to quantify measures of facial behaviour in 21 chronic schizophrenic subjects, in comparison with control groups of depressed, demented and Parkinsonian subjects. Facial behaviours were counted and timed from video-recordings of each subjects' face during a clinical interview. Separate measurement of behaviours were obtained while subjects were speaking and silent. For most variables, the amount of facial behaviour was significantly less in schizophrenic subjects than in control groups. The groups differed significantly on a number of measures, but schizophrenics could not be reliably identified by a single facial behaviour variable. However, using a discriminant function analysis with measures for eye contact while speaking and silent, broad smiles and small smiles, discrimination between groups was good, with over 80% correctly classified as either schizophrenic, or not schizophrenic. These techniques may increase our understanding of psychopathological signs and the mechanisms that underly them.

SynopsisThree hundred and twenty-six consecutively admitted patients with definite or possible functional psychotic illnesses to which no diagnostic classification had been applied were followed up after 2·5 years. In 86 cases symptomatology had been inadequate for the patients to enter the functional psychosis study, and in 75 cases this was because the symptoms were partial or transient. These patients were compared at follow-up with those who fulfilled operational criteria for schizophrenic, affective or schizoaffective psychoses. Differences between the ‘partial’ cases and those fulfilling specific diagnostic criteria were few, but the transient cases fared significantly better. Although the transient illnesses were recurrent, at follow-up at 2·5 years they appeared to have a good outcome in terms of social variables and symptomatology.

In neuroimaging, functional mapping usually implies mapping function into an anatomical space, for example, using statistical parametric mapping to identify activation foci, or the characterization of distributed changes with spatial modes (eigenimages or principal components) (Friston et al., 1993a). This article is about a complementary approach, namely, mapping anatomy into a functional space. We describe a simple variant of multidimensional scaling (principal coordinates analysis; Gower, 1966) that uses functional connectivity as its metric. The scaling transformation maps anatomy into a functional space. The topography, or proximity relationships, in this space embody the functional connectivity among brain regions. The higher the functional connectivity, the closer the regions. Functional connectivity is defined here as the correlation between remote neurophysiological events. The technique represents a descriptive characterization of anatomically distributed changes in the brain that reveals the structure of corticocortical interactions in terms of functional correlations. To illustrate the approach we have analyzed data from normal subjects and schizophrenic patients obtained with PET during the performance of word generation tasks. In particular, we focus on prefrontotemporal integration in normal subjects and show that, in schizophrenia, the left temporal regions and prefrontal cortex evidence abnormal functional connectivity.

BackgroundAlthough poor prognosis has been considered a defining characteristic of schizophrenia, long-term studies show marked heterogeneity of outcome.MethodAssessments of positive and negative symptoms, premorbid and current IQ, and months of in-patient care made in an outcome study of 342 schizophrenic patients were categorised by severity. Determinants of these categorisations were sought from the historical variables available, using analysis of variance. Vignettes of patients with the best and worst symptomatic outcomes were then compared.ResultsNegative symptoms were associated with early onset, male sex and poor academic record. Positive symptoms were associated with occupational decline. Cognitive decline was associated with occupational variables, and in-patient care with academic and occupational variables. The vignettes showed that good outcome was associated with family psychiatric history and poor outcome with unavailability of family history.ConclusionsThe findings support the view that the most malignant form of schizophrenia is neurodevelopmental, but poor outcome was clearly associated with family fragmentation.

A variety of cognitive impairments can be observed in patients with schizophrenia, including substantial reductions in the intelligence quotient (IQ). I propose that these impairments can be best understood in terms of the abnormal processes underlying the signs and symptoms manifested by the patient at the time of the cognitive assessment. Negative signs such as poverty of speech are associated with defects of willed action, while positive symptoms such as hallucinations are associated with defects of self-monitoring. Hypotheses about the brain systems underlying these processes can be examined using functional brain imaging.

In order to study brain activity associated with “incidental” cognitive processing, regional cerebral blood flow (rCBF) was measured in six volunteers while they monitored a sequence of pseudo-words (e.g., FLOPE) for the rare occasions when the letters were displayed in blue rather than white. In the control condition, the same pseudo-word was presented repeatedly. In one experimental condition all 60 pseudo-words were different, while in the other there were 18 repetitions. Although it was not necessary to “read” the pseudo-words to perform the monitoring task, subsequent forced choice recognition memory for these stimuli was significantly greater than chance. Furthermore, there were significant differences in blood flow between the three conditions. When different pseudo-words were presented there was significantly greater activity in brain areas concerned with shape and object identity (extrastriate cortex bilaterally), with visual word form (left inferior temporal gyrus), and with articulatory word form (Broca's area) even though none of this information about the pseudo-words was needed for performance of the monitoring task. In the condition in which some of the words were repeated, there was significantly reduced activity in the right lingual gyrus. This area may therefore be a possible anatomical locus for repetition priming with verbal stimuli. These results indicate the importance of taking into account incidental processing when designing tasks for functional imaging experiments. © 1995 Wiley-Liss, Inc.

H2(15)O-PET was used to investigate the functional anatomy of recovery in a patient (J.B.) with bilateral perisylvian strokes and auditory agnosia, who partially regained the ability to recognize environmental sounds, but remained clinically word-deaf. The patient and a group of six normal volunteers were scanned in the following three conditions: (i) passive listening to environmental sounds; (ii) categorization of environmental sounds; (iii) at rest. In normal subjects, passive listening as compared with rest was associated with significant activations in the auditory cortices and posterior thalami, and in the inferior parietal lobe and anterior insula/frontal opercular region on the right. In J.B., activations were observed in the spared auditory cortex and inferior parietal lobe of the right hemisphere and in regions adjacent to the perisylvian lesion in the left hemisphere (anterior insula/frontal opercular region, middle temporal gyrus and inferior parietal lobe). The recovered function, as measured by categorization of sounds compared with passive listening, in J.B. was associated with bilateral activation of a distributed network comprising (pre)frontal, middle temporal and inferior parietal cortices, as well as the right cerebellum and the right caudate nucleus. In addition, there was a left-sided activation of the anterior cingulate gyrus. In normal subjects, the same categorization task led to activation of a network comprising (pre)frontal, middle temporal and inferior parietal cortices in the left hemisphere only. These results suggest that bilateral activation (with recruitment of areas homologous to those known to be responsible for normal function), the engagement of peri-infarct regions, and the involvement of a more widespread neocortical network, are mechanisms of functional reorganization after injury that may enable recovery from, or compensation for, cognitive deficits.

BackgroundAlthough previous studies have attempted to identify predictors of outcome in schizophrenia, few have prospectively studied first episode patients for an adequate follow-up period.MethodThe psychopathological predictors of outcome were investigated in a subgroup of 51 subjects, originally included in the Northwick Park study of first episode schizophrenia who were followed up 7.3 years (s.d. 1.1, range 5.3– 10.3) after first admission in the Harrow study. Forty-four subjects (24 men, 20 women) were traced. Outcome measures were time to first readmission, occupational level and total duration of hospital admission at five years after first admission.ResultsA survival analysis of time to first relapse revealed that the presence of subjective feelings of depression (CATEGO syndrome SD) during the first admission was associated with early relapse while the presence of depressive delusions (CATEGO syndrome DD) and higher educational attainment protected against early relapse. Total duration of hospitalisation at five years after first onset was positively associated with the presence of CATEGO syndromes SD and OD (biological features of depression) and negatively associated with female sex. Poor occupational outcome was not significantly associated with any psychopathological predictors.ConclusionsOur findings challenge the conventional view that symptoms of depression are associated with better outcome in schizophrenia.

From a postmortem study of the brains of 56 patients with schizophrenia and 56 controls, 38 cases whose clinical state had been objectively documented in life were examined to determine whether relations existed between features of the illness and postmortem findings. Decreased brain weight was significantly related (p < 0.05) to poor premorbid global function and to poor academic record, and decreased brain length was related to poorer premorbid global function (p < 0.05) and more severe negative symptoms. These relations are consistent with the view that morphological changes in the brain occur early in the course of the disease--that is, they are in some sense "developmental." An excess of "focal damage" in the patient group relative to controls was unrelated to the presence of morphological change or to features of illness, but was more common in female schizophrenic patients and was also correlated with evidence of cerebrovascular disease. This may possibly be due to a discrepancy between the groups in mode and cause of death.

SynopsisApomorphine, a non-selective dopamine agonist, has been used as a pharmacological probe for investigating central dopaminergic neurotransmission in psychiatric illness. In this study repeated measurements of regional cerebral blood flow (rCBF) were made in normal volunteers before, and after, the administration of apomorphine (5 or 10 μg/kg), or placebo. The difference in rCBF, before and after drug (apomorphine versus placebo), was used to identify brain areas affected by apomorphine. Compared to placebo, both doses of apomorphine increased blood flow in the anterior cingulate cortex. Apomorphine 10 μg/kg also increased prefrontal rCBF (right > left). No decreases in rCBF were noted following either dose of apomorphine. Apomorphine-induced increases of anterior cingulate blood flow might serve as an in vivo index of central dopamine function. Such an approach would complement established neuroendocrine challenge paradigms for investigating central dopamine neurotransmission in psychiatric illness.

A voxel‐based method of measuring the effective connectivity between brain regions is presented. The approach is based on electrophysiological concepts and is applied to neurophysiological data obtained with [positron emission tomography (PET)] functional imaging. Time‐dependent changes in effective connectivity were assessed during a verbal fluency activation paradigm using 12 consecutive measurements of regional cerebral blood flow (rCBF). The changes observed were predicted by an associative (Hebbian) model of plasticity, applied to cortical activity, measured in terms of rCBF. The main finding was, in most regions, a selective enhancement of effective connections from the distributed brain regions exhibiting the dominant pattern of correlated activity. © 1993 Wiley‐Liss, Inc. Copyright © 1993 Wiley‐Liss, Inc.

SYNOPSISThree hundred and twenty-six consecutively admitted patients with functional psychotic illnesses to which no diagnostic classification had been applied were followed up after 2·5 years. They were examined in social, clinical and psychological terms and the CATEGO programme and DSM-III criteria were applied to data concerning the index episode to derive diagnostic classifications. The deterioration in occupational functioning and the hospital careers of patients with diagnostic classifications of schizophrenia were worse than those in the other groups and positive and negative features were also more severe in patients with a classification of schizophrenia. By contrast, no differences in psychological test performance were found between the groups based upon diagnostic classification. Impaired psychological test performance was found and it was strongly related to concurrent mental state abnormalities, particularly negative symptoms. It is concluded that the diagnostic classifications used were of limited value in predicting outcome in functional psychosis.

A single case of Korsakoff's syndrome, showing classic circumscribed amnesia on traditional neuropsychological tests, performed a number of learning tasks previously used in primates to demonstrate the different anatomical basis of memory systems used to learn about the properties of objects or to learn about rules of responding. The patient (CJ) performed in a manner very similar to lesioned monkeys in that he could learn evaluative tasks (e.g. a red object is nice), but not rule based tasks (e.g. a red object means go left). In consequence CJ learned an object discrimination task in a manner qualitatively different from a group of non-amnesic controls. Although he could not learn rule based tasks, CJ could perform them once he had been given the rule. Detailed analysis of learning showed that CJ could choose the object he had chosen previously, but could not say where it had been or whether he had been rewarded. Furthermore he could recognise a word as familiar, while not remembering its source. We propose that he has a specific impairment in a memory system concerned with the representation of the signification of objects in particular contexts, while representation of the properties of objects remains intact.

Genealogical and molecular studies were carried out in four families in which early onset dementia is inherited as an autosomal dominant. These studies indicated that the four families derive from four siblings whose parents were born in the late 18th century in South-East England. The disease was found to be closely linked to a 144 bp insertion within the open reading frame of the prion protein (PrP) gene with a maximum LOD score of 11.02 at zero recombination. Within the general population the PrP gene is polymorphic at codon 129 (allele frequency approximately 30% valine, 70% methionine). The insertion in this family is always within a methionine-129 allele. The age at death of affected individuals whose normal allele encoded methionine at codon 129 was significantly lower than those whose normal allele encoded valine. The clinical features which were very variable and the neuropathological findings, which sometimes included spongiform encephalopathy, but which often did not, are described fully in the accompanying article (Collinge et al., 1992).

It has become increasingly apparent that schizophrenic patients can suffer from many cognitive deficits (Hemsley, 1982). These include a decline in IQ (Nelson et al, 1990), loss of concentration (Garmezy, 1978), and various ‘executive’ difficulties similar to those observed in patients with frontal lobe lesions (Morice, 1990). The availability of a large, population-based sample of schizophrenic patients in the Harrow study provided the opportunity to examine the prevalence of these impairments and to relate them to the signs and symptoms of the disorder.

Persisting positive symptoms largely unresponsive to treatment (Tuma & May, 1979; Macmillan et al, 1986; May et al, 1989) occur in about 7% of patients with schizophrenia but lesser degrees of treatment resistance are common (Hogarty, 1988; Johnstone, 1990) and problems of recurrence of positive symptoms and deterioration of negative symptoms are well known (Johnstone, 1990). Schizophrenic patients have also been found to have persisting non-psychotic symptoms, particularly depression (Cheadle et al, 1978). Disorders of movement in relation to schizophrenia and their treatment have been found to be disabling in a few patients and to cause lesser problems for many (Kane et al, 1985). The assessment of the mental state and of clinical evidence of movement disorder in the patients who form the subjects of the Harrow study was therefore clearly of interest, as it is rarely possible to examine these issues in a large, unselected sample.

The aims of this study were to identify and trace all schizophrenic patients discharged from in-patient and day-patient psychiatric services in Harrow between 1 January 1975 and 1 January 1985, to examine the patients in terms of their mental state, cognitive functioning, extrapyramidal function and social disability, and to relate their current status in those terms to demographic, historical and treatment variables. The data collection was conducted between 1 February 1987 and 1 January 1990. The project was devised against the background of developing community care policies for psychiatric patients. In the UK, policies of closure of the mental hospitals have been advocated for a considerable time (Tooth & Brooke, 1961). In the US the plan of closing the mental hospitals and replacing in-patient care with care in the community was partially adopted (Scharfstein, 1978; Fink & Weinstein, 1979; Winslow, 1979). In Italy it was carried out in a much more complete way, at least in some areas (Jones & Poletti, 1985, 1986), but problems appear to have arisen in both of these countries (Donovan, 1982; Papeschi, 1985).

This report concerns 532 patients with schizophrenia. Many items of information have been recorded and the results have been quickly drawn together for publication. It is likely that more detailed analyses of the data will be conducted in time, but this publication reports the central facts derived from this extensive investigation. They can be simply stated. The disorder remains very common. Five hundred and thirty-two individuals with schizophrenia as defined by the Feighner criteria were discharged from Harrow services over 10 years. It was possible to trace the great majority of these patients. In many cases the illness was clearly associated with recurrent or persistent problems. The mean number of admissions required was 5.37 (Fig. 1) and on average patients spent 13.7 of the 120 months between 1975 and 1985 in hospital (Fig. 2).

Recent advances in Alzheimer's disease imply a need for adequate clinical trials of new treatments which require careful design. The disorder is progressive and shows clinical heterogeneity. While large-scale trials of elderly subjects are appropriate in relation to assessment of drugs or other treatments designed to prevent progression of the disorder, the outcome measurements in such biological treatment trials require careful planning. Studies of individual patients are relevant for answering certain specific questions. Relatively short cross-over trial designs may be appropriate to some pharmacological studies. The choice of neuropsychological instruments for measuring change is critically important, particularly in excluding test/retest artefact and in avoiding floor and ceiling effects. Test scales designed for assessment of specific neuropsychological deficits, or forming part of standard IQ assessments are unlikely to prove robust. Tests can be selected and developed for individual patients, but generalisation of the results of such experiments to the disease as a whole is not inevitable. There is a need to develop psychological instruments for measuring change that are robust and relevant to the clinical problem of progressive dementia.

The outcome at two years of patients who were eligible for a study of first schizophrenic episodes was assessed in terms of occupation (n = 237) and in terms of number of days spent as an in-patient from the time of first admission (n = 252), and was related to social, behavioural, mental state and neurological measures during the initial admission. Poor outcome was in general associated with more social withdrawal, inactivity and abnormal social presentation and with more ‘neurological soft signs'. Good occupational outcome in patients with a relatively short pre-treatment duration of illness was associated with the prescription of placebo medication during the follow-up period.

To perform eye or hand movements toward a relevant location, the brain must translate sensory input into motor output. Recent studies revealed segregation between circuits for translating visual information into saccadic or manual movements, but less is known about translation of tactile information into such movements. Using human functional magnetic resonance imaging (fMRI) in a delay paradigm, we factorially crossed sensory modality (vision or touch) and motor effector (eyes or hands) for lateralized movements (gaze shifts to left or right or pressing a left or right button with the corresponding left or right hand located there). We investigated activity in the delay-period between stimulation and response, asking whether the currently relevant side (left or right) during the delay was encoded according to sensory modality, upcoming motor response, or some interactive combination of these. Delay activity mainly reflected the motor response subsequently required. Irrespective of visual or tactile input, we found sustained activity in posterior partial cortex, frontal-eye field, and contralateral visual cortex when subjects would later make an eye movement. For delays prior to manual button-press response, activity increased in contralateral precentral regions, again regardless of stimulated modality. Posterior superior temporal sulcus showed sustained delay activity, irrespective of sensory modality, side, and response type. We conclude that the delay activations reflect translation of sensory signals into effector-specific motor circuits in parietal and frontal cortex (plus an impact on contralateral visual cortex for planned saccades), regardless of cue modality, whereas posterior STS provides a representation that generalizes across both sensory modality and motor effector.

Environmental sounds convey specific meanings and the neural circuitry for their recognition may have preceded language. To dissociate semantic mnemonic from sensory perceptual processing of non-verbal sound stimuli we systematically altered the inherent semantic properties of non-verbal sounds from natural and man-made sources while keeping their acoustic characteristics closely matched. We hypothesized that acoustic analysis of complex non-verbal sounds would be right lateralized in auditory cortex regardless of meaning content and that left hemisphere regions would be engaged when meaningful concept could be extracted. Using H(2) (15)O-PET imaging and SPM data analysis, we demonstrated that activation of the left superior temporal and left parahippocampal gyrus along with left inferior frontal regions was specifically associated with listening to meaningful sounds. In contrast, for both types of sounds, acoustic analysis was associated with activation of right auditory cortices. We conclude that left hemisphere brain regions are engaged when sounds are meaningful or intelligible.

Voxel-based morphometry was used to assess the consistency among functional imaging and brain morphometry data in developmental dyslexia. Subjects, from three different cultural contexts (UK, France and Italy), were the same as those described in a previous PET activation paper, which revealed a common pattern of reduced activation during reading tasks in the left temporal and occipital lobes. We provide evidence that altered activation observed within the reading system is associated with altered density of grey and white matter of specific brain regions, such as the left middle and inferior temporal gyri and the left arcuate fasciculus. This supports the view that dyslexia is associated with both local grey matter dysfunction and with altered connectivity among phonological/reading areas. The differences were replicable across samples confirming that the neurological disorder underlying dyslexia is the same across the cultures investigated in the study.

Empathie wird sowohl als individuelle Charaktereigenschaft als auch als beeinflussbarer Zustand beschrieben. Preis und Kroner-Herwig untersuchten, inwieweit verschiedene kontrollierbare Faktoren die Empathie von Probanden beeinflussten, die das Schmerzerleben einer anderen Person beurteilen mussten.

Event-related functional magnetic resonance imaging was used to identify brain areas involved in spatial attention and determine whether these operate unimodally or supramodally for vision and touch. On a trial-by-trial basis, a symbolic auditory cue indicated the most likely side for the subsequent target, thus directing covert attention to one side. A subsequent target appeared in vision or touch on the cued or uncued side. Invalidly cued trials (as compared with valid trials) activated the temporo-parietal junction and regions of inferior frontal cortex, regardless of target modality. These brain areas have been associated with multimodal spatial coding in physiological studies of the monkey brain and were linked to a change in the location that must be attended to in the present study. The intraparietal sulcus and superior frontal cortex were also activated in our task, again, regardless of target modality, but did not show any specificity for invalidly cued trials. These results identify a supramodal network for spatial attention and reveal differential activity for inferior circuits involving the temporo-parietal junction and inferior frontal cortex (specific to invalid trials) versus more superior intraparietal-frontal circuits (common to valid and invalid trials).

Covert attention can be directed spatially in several different sensory modalities (e.g. vision and touch). Recent psychological experiments indicate the existence of crossmodal links in spatial attention, but their neural basis in humans remains underspecified. We used positron emission tomography (PET) to assess the role of stimulus modality in the activity of brain regions involved in different rates of spatial attention shifting. A 2× 2 factorial design manipulated the rate (high versus low) of spatial attention shifts between left and right hemifields, plus the sensory modality (vision versus touch) of stimulation. Two brain regions showed activa- tions related to attentional shift-rate, independent of the stimulated modality: these were the right frontopolar gy- rus, and the right posterior superior temporal sulcus (STS). The anterior area showed higher blood flow with the high rate of shifts in spatial attention, while the pos- terior area showed higher flow during the low rate condi- tions, where attention was sustained for longer on one side. No area showed a significant rate effect in one mo- dality without an effect in the second modality. These re- sults demonstrate multimodal roles for the activated brain regions in relation to the rate of spatial attention shifting, plus right-hemisphere dominance for this. They also suggest that anterior and posterior regions of the spatial-attention network play different roles in attention shifting.

The recognition of dyslexia as a neurodevelopmental disorder has been hampered by the belief that it is not a specific diagnostic entity because it has variable and culture-specific manifestations. In line with this belief, we found that Italian dyslexics, using a shallow orthography which facilitates reading, performed better on reading tasks than did English and French dyslexics. However, all dyslexics were equally impaired relative to their controls on reading and phonological tasks. Positron emission tomography scans during explicit and implicit reading showed the same reduced activity in a region of the left hemisphere in dyslexics from all three countries, with the maximum peak in the middle temporal gyrus and additional peaks in the inferior and superior temporal gyri and middle occipital gyrus. We conclude that there is a universal neurocognitive basis for dyslexia and that differences in reading performance among dyslexics of different countries are due to different orthographies.

We combined fMRI and EEG recording to study the neurophysiological responses associated with auditory stimulation across the sleep-wake cycle. We found that presentation of auditory stimuli produces bilateral activation in auditory cortex, thalamus, and caudate during both wakefulness and nonrapid eye movement (NREM) sleep. However, the left parietal and, bilaterally, the prefrontal and cingulate cortices and the thalamus were less activated during NREM sleep compared to wakefulness. These areas may play a role in the further processing of sensory information required to achieve conscious perception during wakefulness. Finally, during NREM sleep, the left amygdala and the left prefrontal cortex were more activated by stimuli having special affective significance than by neutral stimuli. These data suggests that the sleeping brain can process auditory stimuli and detect meaningful events.

BackgroundPET studies of verbal fluency in schizophrenia report a failure of ‘deactivation’ of left superior temporal gyrus (STG) in the presence of activation of left dorsolateral prefrontal cortex (DLPFC), which deficit has been attributed to underlying ‘functional disconnectivity’.AimTo test whether these findings provide trait-markers for schizophrenia.MethodWe used H215O PET to examine verbal fluency in 10 obligate carriers of the predisposition to schizophrenia, 10 stable patients and 10 normal controls.ResultsWe found no evidence of a failure of left STG deactivation in carriers or patients. Instead, patients failed to deactivate the precuneus relative to other groups. We found no differences in functional connectivity between left DLPFC and left STG but patients exhibited significant disconnectivity between left DLPFC and anterior cingulate cortex.ConclusionsFailure of left STG ‘deactivation’ and left fronto-temporal disconnectivity are not consistent findings in schizophrenia; neither are they trait-markers for genetic risk. Prefrontal functional disconnectivity here may characterise the schizophrenic phenotype.