Neural anomalies during sustained attention in first-degree biological relatives of schizophrenia patients.

BACKGROUND: A deficit in sustained attention might serve as an endophenotype for schizophrenia and therefore be a useful tool in understanding the genetic underpinnings of the disorder. We sought to detail functional brain abnormalities associated with sustained attention (i.e., vigilance) in individuals with genetic liability for schizophrenia. METHODS: We gathered electrophysiological data from 23 schizophrenia patients, 28 first-degree biological relatives of schizophrenia patients, and 23 nonpsychiatric control subjects while they performed a degraded-stimulus continuous performance task. Inclusion of sensory control trials allowed separation of target detection and vigilance effects on brain potentials. RESULTS: Schizophrenia patients, but not relatives, showed a behavioral deficit in sustained attention. During target detection, relatives exhibited diminished late positive amplitudes (P3b, i.e., P300) over parietal brain regions and augmented early posterior (P1) and right frontal (anterior N1) potentials. Electrophysiological anomalies were still evident after the exclusion of three relatives with histories of psychosis. CONCLUSIONS: Genetic liability for schizophrenia is associated with augmented early and diminished late brain potentials during sustained attention. Electrophysiological anomalies suggestive of right frontal-posterior parietal dysfunction might represent neural expression of genetic liability for schizophrenia. Electrophysiological indices also seem to be more sensitive than behavioral measures in assessing genetic liability for schizophrenia.     

Brain activation during executive processes in schizophrenia

Schizophrenia patients show some deficits in executive processes (impaired behavioural performance and abnormal brain functioning). The aim of this study is to explore the brain activity of schizophrenia patients during different inhibitory tasks. We used functional magnetic resonance imaging to investigate to investigate the restraint and deletion aspects of inhibition in 19 patients with schizophrenia and 12 normal subjects during the performance of the Hayling and the N-back tasks. The patients demonstrated impaired performance (more errors and longer reaction times) in the Hayling task. Schizophrenia subjects activated the same fronto-parietal network as the control subjects but demonstrated stronger parietal activations. For the N-back task, the deficit shown by the patients was limited to the number of target omissions. The reaction times and the number of false alarms did not differ in the two groups. We interpret this pattern of deficit as an alteration of working memory processes (and unaltered inhibition). Schizophrenia subjects showed higher activations in a fronto-parietal network. Since schizophrenia patients reached normal inhibitory performances in the N-back task and not in the Hayling task, the frontal hyperactivation may reflect an increased effort or a compensatory mechanism that facilitates the performance of executive tasks. During the Hayling task, this frontal hyperactivation was not achieved, and its absence was associated with a performance deficit relative to the performance of normal subjects.     

Neuropsychological deficit in siblings discordant for schizophrenia

This study was aimed, first, at detecting neuropsychological markers that assess vulnerability to schizophrenia in siblings of patients with schizophrenia, and second, at exploring possible relationships between markers. For these purposes, performances were assessed in 18 clinically stabilized patients with schizophrenia, 18 of their unaffected full siblings, and 15 controls on attentional abilities (the Degraded Stimuli-Continuous Performance Task [DS-CPT] and the Span of Apprehension [SOA] task) and on executive functions (the Wisconsin Card Sorting Test [WCST]). Both patients and siblings were impaired on the three tasks, leading to the conclusion that these poor performances may represent markers of genetic vulnerability to schizophrenia. Furthermore, significant relationships were found between DS-CPT and WCST performance in patients only, suggesting a possible implication of prefrontal brain areas for the two tasks. In spite of the lack of similar relationships between DS-CPT and WCST in siblings, this raises the question of a putative role of prefrontal areas in vulnerability to schizophrenia.     

Inefficient neural activity in patients with schizophrenia and nonpsychotic relatives of schizophrenic patients: Evidence from a working memory task

Studies of schizophrenia with functional MRI have shown hyper- and hypoactivations in various brain regions including the prefrontal cortex. Functional anomalies have also been reported in first-degree relatives of schizophrenic patients. The aim of this study was to examine working memory related brain functions in healthy subjects, schizophrenic patients and unaffected relatives and to determine the influence of psychopathology on these processes. A parametric n-back working memory task and functional MRI were used to examine 61 patients with schizophrenia, 11 nonpsychotic relatives of schizophrenic patients and a comparison group of 61 healthy subjects. The results indicated increased as well as decreased brain functions in schizophrenic patients compared to the control group depending on the task difficulty and the performance: during the attention task (0-back), which served as control condition, behavioral responses of patients and healthy subjects hardly differed but BOLD responses were considerably enhanced in schizophrenic patients. With increasing task difficulty differences between groups in BOLD responses diminished whereas behavioral deficits of patients increased. The examination of attention-independent working memory-functions (2- vs. 0-back) produced hypoactivations in patients, especially in frontal, temporal and subcortical brain regions. Furthermore, positive symptoms were associated with parietal dysfunctions. Behavioral performance and neural responses of unaffected relatives of schizophrenic patients were intermediate between schizophrenic patients and controls indicating slight brain dysfunctions. In addition, compensatory strategies were demonstrated. These findings suggest that the genetic risk for schizophrenia is accompanied by neural inefficiency which is associated with cognitive deficits, especially in difficult tasks.     

Verbal working memory impairment in schizophrenia patients and their first-degree relatives: evidence from the digit span task

OBJECTIVE: The evidence for verbal working memory deficits in schizophrenia has been inconsistent. Few studies have evaluated verbal working memory in the first-degree relatives of schizophrenia patients, who likely share the genetic diathesis for schizophrenia but not the potential confounds associated with chronic mental illness. METHOD: The Wechsler Digit Span Task was used to investigate verbal working memory in 52 schizophrenia patients, 56 of their first-degree relatives, and 73 nonpsychiatric comparison subjects. RESULTS: The nonpsychotic relatives showed no impairment on the forward digit span task, a measure of general attention, but did show impairment on the backward digit span task, a measure of verbal working memory. Schizophrenia patients showed impairment on both the forward and backward digit span tasks. CONCLUSIONS: These results indicate that the forward and backward digit span tasks tap different cognitive abilities that are differentially associated with the diathesis for schizophrenia. Working memory deficits associated with schizophrenia appear to be generalized and not limited to the spatial modality.     

Verbal memory processes in schizophrenia patients and biological relatives of schizophrenia patients: intact implicit memory, impaired explicit recollection

Verbal memory deficits are arguably the most common cognitive abnormalities in biological relatives of schizophrenia patients. Because verbal memory is a complex cognitive function, it is necessary to differentiate its intact and compromised aspects in order to reveal aberrant neural systems that reflect genetic risk in relatives of schizophrenia patients. Using an experimental verbal memory task, we examined encoding, free-recall, repetition priming, and recognition of verbal material in 22 schizophrenia patients, 22 first-degree biological relatives of schizophrenia patients, and 23 nonpsychiatric control participants. Schizophrenia patients exhibited intact repetition priming, but worse size judgment task performance (encoding), recall, and recognition than the control participants. Biological relatives of schizophrenia patients exhibited intact size judgment task performance, repetition priming, and recognition, but a free-recall deficit. Although size judgment task performance at encoding was associated with recall of verbal material in schizophrenia and control groups, in the relative group encoding performance was associated with the degree of repetition priming. Findings are consistent with impaired explicit recollection of verbal material, but intact implicit verbal memory in schizophrenia patients and biological relatives of schizophrenia patients.     

Abnormal functional motor lateralization in healthy siblings of patients with schizophrenia

Earlier neuroimaging studies of motor function in schizophrenia have demonstrated reduced functional lateralization in the motor network during motor tasks. Here, we used event-related functional magnetic resonance imaging during a visually guided motor task in 18 clinically unaffected siblings of patients with schizophrenia and 24 matched controls to investigate if abnormal functional lateralization is related to genetic risk for this brain disorder. Whereas activity associated with motor task performance was mainly contralateral with only a marginal ipsilateral component in healthy participants, unaffected siblings had strong bilateral activity with significantly greater response in ipsilateral and contralateral premotor areas as well as in contralateral subcortical motor regions relative to controls. Reduced lateralization in siblings was also identified with a measure of laterality quotient. These findings suggest that abnormal functional lateralization of motor circuitry is related to genetic risk of schizophrenia.     

An fMRI investigation of procedural learning in unaffected siblings of individuals with schizophrenia

Vulnerability for schizophrenia is related, in part, to genetic predisposition. The identification of pathophysiological abnormalities associated with the disorder that are also present in unaffected family members of individuals with schizophrenia may assist in delineating the genetic contributions to vulnerability for schizophrenia. Previous functional Magnetic Resonance Imaging (fMRI) investigations of procedural learning in patients with schizophrenia identified reduced activity in the frontal cortex, basal ganglia, and parietal cortex during performance of the serial reaction time (SRT) task suggesting that abnormal function of these regions may relate to genetic vulnerability for schizophrenia. In order to examine this hypothesis, 12 unaffected siblings of patients and 15 controls underwent fMRI during performance of the SRT task. Unaffected siblings demonstrated normal performance on the SRT task. However, compared to controls unaffected siblings demonstrated less activity in regions of the frontal and parietal lobes and, to a lesser extent, basal ganglia, during procedural learning. Interestingly, unaffected siblings demonstrated greater activity in regions of the frontal cortex during the control condition compared to the procedural learning condition of the SRT task, an idiosyncratic pattern that was also observed in patient groups but not control subjects of two prior imaging studies. The findings support previous investigations suggesting that altered cerebral neurophysiology during performance of cognitive tasks may be related to genetic vulnerability for schizophrenia. Identification of genes related to the function of cerebral regions such as the prefrontal cortex, parietal lobe, and basal ganglia may assist in delineating the genetic contributions to schizophrenia.     

Striatal dysfunction in schizophrenia and unaffected relatives.

BACKGROUND: Schizophrenia has been frequently associated with impaired inhibitory control. Such control is known to involve the striatum. Here, we investigate whether impaired inhibitory control is associated with abnormal striatal activation in schizophrenia. First-degree relatives of patients were also tested to examine whether striatal abnormality is associated with schizophrenia, or with the risk for the illness. METHODS: Both functional MRI and behavioral data were acquired during a task designed to invoke inhibitory control in 21 patients, 15 unaffected siblings, and 36 matched controls. Subjects must refrain from responding to designated stop cues occurring within a series of motor cues. Subjects could anticipate the occurrence of stop cues as the likelihood of these cues increased in a linear fashion throughout the task. RESULTS: Control subjects showed striatal activation while responding to motor cues. This activation increased in a linear fashion when the likelihood of having to inhibit the response was increased. Both patients siblings did not show anticipation-related increase in either striatal activation. However, only patients showed behavioral impairments. CONCLUSIONS: Striatal abnormalities occur in schizophrenia patients and unaffected siblings. Thus striatal abnormalities may be related to an increased (genetic) risk to develop schizophrenia.     

Event-related gamma activity in schizophrenia patients during a visual backward-masking task

OBJECTIVE: Schizophrenia patients experience deficits in many aspects of cognition and perception. Abnormalities in gamma activity may underlie some of these deficits, including rapid processing of visual stimuli. This study examined event-related gamma range activity during a visual backward-masking task in schizophrenia patients and normal comparison subjects. METHOD: Event-related gamma activity was recorded in 15 normal comparison subjects and 32 schizophrenia patients. Participants had event-related gamma activity recorded while viewing 60 unmasked visual targets and 240 trials of visual backward masking. Effects of group, accuracy (correct versus incorrect), stimulus-onset asynchrony, and regional activity (left versus right hemisphere, anterior versus posterior regions) were assessed. RESULTS: Schizophrenia patients had significantly reduced gamma activity in relation to comparison subjects during the backward-masking task. Normal comparison subjects showed significantly greater gamma activity in the right hemisphere, whereas schizophrenia patients did not show this pattern of lateralization. For the unmasked target, there was no group effect and no significant interactions in gamma-band responses. CONCLUSIONS: These results extend previous findings of abnormal gamma range activity in schizophrenia patients. Patients showed overall less gamma activity and failed to show lateralization of activity to the right hemisphere during masking, but they showed comparable levels of gamma activity to unmasked stimuli. Schizophrenia patients' poorer performance during a masking task may be partly influenced by this abnormal level and the distribution of gamma activity.     

Regional brain morphometry in patients with schizophrenia or bipolar disorder and their unaffected relatives

OBJECTIVE: Schizophrenia and psychotic bipolar disorder have a number of overlapping symptoms and risk factors, but it is not yet clear if the disorders are characterized by similar deviations in brain morphometry or whether any such deviations reflect the impact of shared susceptibility genes on brain structure. The authors used region-of-interest morphometry to volumetrically assess brain structures frequently implicated in psychotic illness in families affected with schizophrenia or psychotic bipolar disorder. METHOD: Magnetic resonance imaging brain scans were obtained from 243 subjects, comprising 42 patients with schizophrenia or schizoaffective disorder, 57 of their unaffected first-degree relatives, 38 patients with psychotic bipolar disorder, 52 of their unaffected first-degree relatives, and 54 healthy comparison subjects. Most of the families affected with schizophrenia and all of the families affected with bipolar disorder were multiply affected with the illness. Volumetric measurements of the cerebrum, lateral ventricles, third ventricle, and hippocampus were completed with stereological methods. RESULTS: Patients with schizophrenia had increased volume of the lateral and third ventricles and reduced hippocampal volume. None of these volumetric abnormalities was present in psychotic bipolar disorder. Unaffected relatives of patients with schizophrenia from multiply affected families had enlarged lateral ventricles but no other volumetric deviations. Unaffected relatives of patients with bipolar disorder showed preservation of ventricular and hippocampal volume. CONCLUSIONS: Schizophrenia and psychotic bipolar disorder are characterized by morphometric distinctions in ventricular and hippocampal regions. Lateral ventricular enlargement represents a potential morphometric endophenotype for schizophrenia.     

Clear distinction between preattentive and attentive process in schizophrenia by visual search performance

Visual information-processing deficits were investigated in patients with schizophrenia using visual search tasks. Subjects comprised 20 patients with schizophrenia and 20 normal subjects. Visual search tasks were modified from those used previously to reveal more distinct differences between feature and conjunction search tasks. The presentation area of items in the present study was more than double the area used in our previous study [Mori, S., Tanaka, G., Ayaka, Y., Michitsuji, S., Niwa, H., Uemura, M., Ohta, Y., 1996. Preattentive and focal attentional processes in schizophrenia: a visual search study. Schizophrenia Research 22, 69-76], and items were distributed over the area randomly in each trial to produce a certain range of locational jitter for each item across trials that prevented a matrix-like presentation of items at fixed positions [Mori, S., Tanaka, G., Ayaka, Y., Michitsuji, S., Niwa, H., Uemura, M., Ohta, Y., 1996. Preattentive and focal attentional processes in schizophrenia: a visual search study. Schizophrenia Research 22, 69-76]. The target was a red square, and distractors were red circles in the feature search task and red circles and green squares in the conjunction search task. Slopes and intercepts of a linear function relating reaction times to set size were computed. In the feature search task, slopes for both groups were almost zero. In the conjunction search task, significant differences in slopes were seen between the two groups irrespective of target presence or absence. Moreover, the slopes were approximately twice as steep during target absence as during target presence. These results indicate more definitively than the results of our previous study [Mori, S., Tanaka, G., Ayaka, Y., Michitsuji, S., Niwa, H., Uemura, M., Ohta, Y., 1996. Preattentive and focal attentional processes in schizophrenia: a visual search study. Schizophrenia Research 22, 69-76] that patients with schizophrenia have deficits in focal attentional processing, although their preattentive processing functions at a normal level.     

Familial loading associates with impairment in visual span among healthy siblings of schizophrenia patients.

BACKGROUND: The effect of familial loading on neurocognitive deficits in relatives of schizophrenia patients has been detected in family and twin studies. The present study examined this effect among healthy siblings of schizophrenia patients in a Finnish isolate with high prevalence of schizophrenia. METHODS: We assessed performance in verbal and visual span tasks, in tests measuring intelligence, and in declarative verbal memory and learning tasks in 31 and 67 healthy siblings from families with one schizophrenia patient, or with two or more patients, respectively. The differences between the groups were tested using linear mixed effects models. RESULTS: An effect of familial loading was detected in the backward visual span task, measuring immediate visual memory with requirements from the visual domain of working memory. In this task, the healthy siblings from multiply affected families performed worse than those from the singleton families. CONCLUSIONS: The finding that the multiplex vs. singleton differences were selective to the backward visual span task, strengthens the view that the visual domain of working memory may provide a valuable endophenotypic marker for genetic schizophrenia studies.     

Modulation of attention during visual masking in schizophrenia

OBJECTIVE: Schizophrenia patients consistently demonstrate performance deficits on visual masking procedures. The present study examined whether attentional manipulation would improve subjects' performance on visual masking. METHOD: A metacontrast task was administered to 105 schizophrenia patients and 52 healthy comparison subjects. Attention was manipulated by associating selected trials of the task with monetary reward. RESULTS: Schizophrenia patients exhibited poorer performance than the comparison subjects across conditions. Patients demonstrated modest, but statistically significant, improvement in performance with the attentional manipulation. This improvement was not significant for the comparison subjects. CONCLUSIONS: These findings suggest that early visual processes in schizophrenia are responsive to attentional manipulation but that the degree of improvement is relatively small, suggesting that these processes are not easily altered.     

Switch and maintenance of task set in schizophrenia

Task set maintenance and switching deficits are robust in schizophrenia. However, little is known about how these constructs are related to one another. The development of an improved understanding of set switching and maintenance deficits in schizophrenia requires that these constructs be explicated in terms of elementary cognitive processes rather than grouped into broad psychological concepts like executive functioning. A relevant dichotomy has been proposed in which sensory and perceptual ("attentional") processes are distinguished from decisional ("intentional") processes in task maintenance and switching; however, the contributions these processes make to performance deficits in schizophrenia is not known. In the present study, 30 participants with schizophrenia and 27 healthy comparisons completed a cued attentional set switching task. In addition to analyses of mean response times, the contributions of attentional and intentional processes to task performance were estimated using an ex-Gaussian distributional analysis. Schizophrenia was associated with a set maintenance deficit that was accounted for by an attentional, rather than intentional, dysfunction. Both groups showed significant switch costs that could be attributed to attentional processes, but there was no evidence for an attentional set switching deficit in schizophrenia. The findings suggest that set switching and set maintenance may reflect distinct cognitive deficits in schizophrenia and that they may be associated with unique information processing mechanisms.     

Cognitive deficits in unaffected first-degree relatives of schizophrenia patients: a meta-analytic review of putative endophenotypes

Cognitive deficits may index genetic liability for schizophrenia and are candidate endophenotypes for the illness. In order to compare the degree of sensitivity among cognitive tasks to group differences between healthy relatives and controls and the influence of moderator variables, this review reports mean effect sizes for 43 cognitive test scores from 58 studies of cognitive performance in the unaffected adult relatives of schizophrenia patients. Results indicate reliable relative-control differences, in the small to medium effect size range, over a diverse array of tasks, with the largest effect sizes seen in complex versions of continuous performance tasks, auditory verbal learning, design copy tests, and category fluency. Three study design features were found to have significant effects on overall effect size magnitude: groups unmatched on education, groups unmatched on age, and asymmetric psychiatric exclusion criteria. After excluding studies with the latter 2 design features, reliable performance differences were still observed over a smaller subset of cognitive test variables, with the largest effect sizes seen in Trails B (d = 0.50) and performance measures from both simple (d = 0.56) and complex (d = 0.60-0.66) versions of continuous performance tasks. Four of the 6 largest effect sizes reflect tasks with high executive control demands in common, such as working memory demands, set shifting, and inhibition of prepotent responses. Cognitive deficits, particularly those tapping such executive control functions, should continue to prove valuable as endophenotypes of interest in the search for specific genetic factors related to schizophrenia.     

Working memory in siblings of schizophrenia patients

Working memory (WM) has hardly been explored in non-psychotic relatives of schizophrenic patients despite its potential suitability as a neurocognitive endophenotype. Indeed, WM modalities, components and processes have rarely been compared in the same group of relatives. The present study examined neurocognitive performance in healthy siblings of schizophrenic patients, including both spatial and verbal WM modalities and tests tapping maintenance (Spatial Span Backwards and CPT-IP d') and manipulative (Letters and Numbers Sequencing) WM processes. METHODS: 68 schizophrenia patients, 38 healthy siblings and 63 controls were assessed on IQ, attention, memory, WM, and executive functions. Cluster A symptoms were screened out in siblings and controls. RESULTS: Siblings had an intermediate performance between that of schizophrenic patients and controls. They performed worse than controls on IQ, LNS, animal naming, backwards spatial span, phonemic fluency, numbers d', and forward spatial span. DISCUSSION: Consistent with the WM literature in schizophrenia, both verbal and spatial WM differed significantly between siblings and controls, suggesting that WM deficits are modality independent. Our results failed to support the hypothesis that tests tapping WM manipulative processes heavily loading on DLFPC are quantitatively more impaired in relatives and, therefore, more sensitive to liability for schizophrenia. However, firm conclusions cannot be drawn until more studies assessing both maintenance and manipulative WM processes in relatives are available.     

Disease and genetic contributions toward local tissue volume disturbances in schizophrenia: a tensor-based morphometry study

Structural brain deficits, especially frontotemporal volume reduction and ventricular enlargement, have been repeatedly reported in patients with schizophrenia. However, it remains unclear whether brain structural deformations may be attributable to disease-related or genetic factors. In this study, the structural magnetic resonance imaging data of 48 adult-onset schizophrenia patients, 65 first-degree nonpsychotic relatives of schizophrenia patients, 27 community comparison (CC) probands, and 73 CC relatives were examined using tensor-based morphometry (TBM) to isolate global and localized differences in tissue volume across the entire brain between groups. We found brain tissue contractions most prominently in frontal and temporal regions and expansions in the putamen/pallidum, and lateral and third ventricles in schizophrenia patients when compared with unrelated CC probands. Results were similar, though less prominent when patients were compared with their nonpsychotic relatives. Structural deformations observed in unaffected patient relatives compared to age-similar CC relatives were suggestive of schizophrenia-related genetic liability and were pronounced in the putamen/pallidum and medial temporal regions. Schizophrenia and genetic liability effects for the putamen/pallidum were confirmed by regions-of-interest analysis. In conclusion, TBM findings complement reports of frontal, temporal, and ventricular dysmorphology in schizophrenia and further indicate that putamen/pallidum enlargements, originally linked mainly with medication exposure in early studies, also reflect a genetic predisposition for schizophrenia. Thus, brain deformation profiles revealed in this study may help to clarify the role of specific genetic or environmental risk factors toward altered brain morphology in schizophrenia.     

Fronto-striatal Dysfunction During Reward Processing in Unaffected Siblings of Schizophrenia Patients

Schizophrenia is a psychiatric disorder that is associated with impaired functioning of the fronto-striatal network, in particular during reward processing. However, it is unclear whether this dysfunction is related to the illness itself or whether it reflects a genetic vulnerability to develop schizophrenia. Here, we examined reward processing in unaffected siblings of schizophrenia patients using functional magnetic resonance imaging. Brain activity was measured during reward anticipation and reward outcome in 27 unaffected siblings of schizophrenia patients and 29 healthy volunteers using a modified monetary incentive delay task. Task performance was manipulated online so that all subjects won the same amount of money. Despite equal performance, siblings showed reduced activation in the ventral striatum, insula, and supplementary motor area (SMA) during reward anticipation compared to controls. Decreased ventral striatal activation in siblings was correlated with sub-clinical negative symptoms. During the outcome of reward, siblings showed increased activation in the ventral striatum and orbitofrontal cortex compared to controls. Our finding of decreased activity in the ventral striatum during reward anticipation and increased activity in this region during receiving reward may indicate impaired cue processing in siblings. This is consistent with the notion of dopamine dysfunction typically associated with schizophrenia. Since unaffected siblings share on average 50% of their genes with their ill relatives, these deficits may be related to the genetic vulnerability for schizophrenia.Key words: ventral striatum, orbitofrontal cortex, ventromedial prefrontal cortex, monetary incentive delay task, genetic vulnerability, cue processing     

Information processing and attentional dysfunctions as vulnerability indicators in schizophrenia spectrum disorders.

The schizotypal personality disorder is believed to be part of the schizophrenic spectrum of disorders including schizophrenic patients as well as some of their seemingly unaffected relatives with discreet symptoms. Spectrum-individuals are characterised by a genetic vulnerability for schizophrenia. The vulnerability is connected with neurocognitive deficits independent of clinical state. Some cognitive dysfunctions are unspecific and probably related to non-genetic brain damage. A consistent finding has, however, been poor performance in tasks involving information processing and attention. The findings point to the existence of specific sensory-perceptual deficits or a general attentional dysfunction. Identification of cognitive disturbances characteristic not only of schizophrenics, but also of schizotypal disordered and their relatives in the boundaries of schizophrenia, is relevant in order better to understand the pathogenetic mechanisms and treatment of schizophrenia. In the present review clinical data are analysed based on models of vulnerability and information processing with reference to a characterisation of the neuro-integrative deficits that form the core abnormalities of the spectrum.