Parietal lobe and disorganisation syndrome in schizophrenia and psychotic bipolar disorder: A bimodal connectivity study.

Given the emerging evidence in support of parietal brain stimulation to treat speech disorder in psychosis, we investigated structural and functional parietal dysconnectivity in schizophrenia (n = 34) and bipolar disorder with psychotic symptoms (n = 16). We found that both patient groups demonstrated reduced left parietal structural connectivity compared to healthy controls (n = 32). The three groups also differed significantly on the variability of left and right parietal dynamic functional connectivity. In patients with schizophrenia, parietal dysconnectivity predicted the severity of disorganisation symptoms. These findings suggest that dysconnectivity between the parietal lobe and the rest of the brain plays a key role in disorganisation symptoms of schizophrenia.

The development of Kraepelin's mature diagnostic concept of hebephrenia: a close reading of relevant texts of Hecker, Daraszkiewicz, and Kraepelin.

In developing his mature concept of hebephrenic dementia praecox (DP) in his 4th (1893) through 6th textbook editions (1899), Kraepelin worked from the hebephrenic syndrome first described by Hecker (1871) and then carefully studied by his student Daraszkiewicz (1892). Working under Kraepelin's supervision, Daraszkiewicz followed Hecker in emphasizing several key features of hebephrenia (distinctive deteriorative course, importance of silliness and minimal positive psychotic symptoms) but expanded the syndrome to include cases developing severe dementia, rejected the link to prodromal depressive and manic phases, and reduced the emphasis on thought disorder. Daraszkiewicz proposed a soft subtyping of hebephrenia based on level of deterioration, which Kraepelin adopted in his 4th edition with an additional emphasis on severe positive psychotic symptoms. In his 5th edition, Kraepelin created a third subform with even more pronounced and bizarre delusions and hallucinations. In his 6th edition, which contained his first articulation of DP, Kraepelin eliminated his hebephrenia subforms presenting a single syndrome, which, compared to Hecker, included more emphasis on positive psychotic and catatonic symptoms and severe dementia. Kraepelin's paths to hebephrenic and paranoid DP differed in important ways. Paranoid DP was a de novo syndrome created by differentiation from paranoia. Hebephrenia, by contrast, evolved from a disorder created in the Kahlbaum/Hecker paradigm of the iterative study of clinical features, course and outcome. Kraepelin further implemented this approach in substantially reworking, over several drafts, the hebephrenic syndrome to fit into his emerging construct of dementia praecox.

Correlation between neuropsychological and social cognition measures and symptom dimensions in schizophrenic patients.

Neurocognitive and social cognition deficits have been largely reported in Schizophrenia (SKZ) but their association with psychopathology remains uncertain. Our purpose was to explore the relationship between symptom dimensions and neuropsychological performances. We enrolled 35 stabilized schizophrenic outpatients of the Department of Psychiatry of Policlinico Hospital, University of Milan, who completed psychiatric Rating Scales, the Brief Assessment of Cognition in Schizophrenia (BACS) and the Executive and Social Cognition Battery (ESCB). Disorganized dimension seems to have the most significant impact on cognition, being associated with performance in several BACS subtests (verbal memory, working memory, motor speed, symbol coding, Tower of London) and ESCB tasks (MET and Hotel task number of tasks attempted, number of broken MET rules, sum of deviations in Hotel Task). Positive dimension correlated with performance in verbal fluency, negative dimension with IOWA Test results, cognitive dimension with MET number of inefficiencies and Eyes test score. Impulsive-aggressive and depressive dimensions weakly correlated only with Faux Pas test. Our study supports the existence of a specific disorganized dimension in SKZ, separated from cognitive dimension evaluated through clinical instruments (e.g. PANSS), but capable of influencing cognitive abilities. Furthermore, it strengthens the validity of ecological tasks in evaluating cognition in SKZ.

Interaction of St John's wort (Hypericum perforatum) with clozapine.

St John's wort (Hypericum perforatum) is notorious for its ability to induce the enzymes of the P450 system. Especially, it induces CYP1A2 and CYP3A4, enzymes that are closely involved in the metabolism of clozapine. We present a patient with schizophrenia, who was stable on a fixed dose with stable plasma level of clozapine, and who deteriorated after she started self-medicating with St John's wort. The reduced plasma clozapine level and the psychiatric condition normalized after the withdrawal of St John's wort. It is possible that, beside the induction of P450-enzymes, the induction of P-glycoprotein by St John's wort aggravated psychiatric deterioration of the patient. Physicians should be alert to patients self-medicating with over-the-counter medicines, especially when these medicines can lower clozapine concentrations below the therapeutic range.

An abnormal relation between basal prolactin levels and prolactin response to 12.5 microg TRH i.v. in drug-naïve patients with first-episode schizophrenia.

At doses lower than those needed to stimulate prolactin release directly, TRH almost completely antagonizes the inhibitory effect of dopamine on prolactin release. We have previously reported that prolactin response to administration of 12.5 microg TRH i.v. correlates with prolactin response to 0.5 mg i.m. haloperidol and negatively with 24-h urinary excretion of HVA in normal subjects, suggesting that the response reflects dopamine activity. An association between central dopamine hyperactivity and SANS scores relating to poverty of content of speech and inattention has been suggested by studies utilizing methylphenidate administration in patients with first-episode schizophrenia. The hypothesis that small plasma prolactin responses to administration of 12.5 microg TRH i.v. (Delta prolactin) correlate with SANS scores for these symptoms was tested in 19 drug-naïve patients with first-episode schizophrenia. Significant negative correlations were found between the response and scores relating to poverty of content of speech (r = - 0.55, p = 0.014) and inattention (r = - 0.52, p = 0.022), supporting the hypothesis of increased dopamine activity in association with disorganization symptoms. A significant positive correlation between basal prolactin levels and prolactin response to stimulation by 12.5 microg TRH was also found (r = + 0.61, p = 0.0058). Our previous study in normal subjects found a similar positive correlation between basal prolactin levels and prolactin response to stimulation by 200 microg TRH i.v., but not by 12.5 microg TRH i.v. As far as we know, this is the first study to report an abnormality in TRH-induced prolactin release in acute schizophrenia.

Organization of cognitive control within the lateral prefrontal cortex in schizophrenia.

CONTEXT: Cognitive control is highly affected in schizophrenia, but its overall functional architecture remains poorly understood. A recent study demonstrated that, in healthy subjects, cognitive control is functionally organized within the lateral prefrontal cortex (LPFC) as a cascade of representations ranging from premotor to anterior LPFC regions according to stimuli, the present perceptual context, and the temporal episode in which stimuli occur. OBJECTIVE: To determine the functional hierarchical organization of cognitive control within the LPFC in patients with schizophrenia. DESIGN: Case-control study. SETTING: Hospital-based research units. PARTICIPANTS: Fifteen schizophrenic patients and 14 controls. MAIN OUTCOME MEASURES: Behavioral performance and regional brain activity as measured by functional magnetic resonance imaging during a task, varying the amount of information conveyed by episodic and contextual signals. RESULTS: In patients and healthy controls, activity in caudal LPFC regions varied as episodic and contextual signals, whereas rostral LPFC regions only exhibited an episodic effect. However, patients made more errors than controls when information conveyed by contextual and episodic signals increased. These impairments were related to hypoactivation in caudal LPFC regions and hyperactivation in rostral LPFC regions, respectively. Activation in caudal LPFC regions negatively correlated with the disorganization syndrome score of patients. CONCLUSIONS: In schizophrenic patients, the architecture of cognitive control follows the cascading organization from rostral LPFC regions to caudal LPFC and premotor regions depending on the temporal framing of action and events. We found, however, that immediate contextual signals insufficiently bias the caudal LPFC activity required to select the appropriate behavioral representation. This specific deficit could thus alter the internal consistency of schizophrenic patients' behavior. To compensate for this weakening of contextual influence, schizophrenic patients may inefficiently use temporal episodic information through higher activation in rostral LPFC regions.

Association of dorsolateral prefrontal cortex dysfunction with disrupted coordinated brain activity in schizophrenia: relationship with impaired cognition, behavioral disorganization, and global function.

OBJECTIVE: Although deficits in cognitive control are thought to contribute to the diverse cognitive and behavioral abnormalities in individuals with schizophrenia, the neural mechanisms underlying these deficits remain unclear. In this event-related functional magnetic resonance imaging (fMRI) study, the authors tested the hypothesis that during cognitive control tasks, impaired activation of the dorsolateral prefrontal cortex in schizophrenia patients is associated with disrupted coordinated activity between this prefrontal region and a distributed brain network that supports cognitive control. METHOD: Through the use of an event-related design, 25 patients with first-episode schizophrenia and 24 healthy comparison subjects, matched on demographic characteristics, were assessed while performing a version of the AX continuous performance task. Functional neuroimaging data were analyzed using 1) univariate (region-of-interest blood-oxygen-level-dependent [BOLD] time series and whole brain voxel-wise regression) analysis to confirm the presence of dorsolateral prefrontal cortex dysfunction and 2) multivariate analysis to examine dorsolateral prefrontal cortex functional connectivity. In addition, correlations between dorsolateral prefrontal cortex functional connectivity and the following variables were investigated: clinical symptoms, task performance, and coordinated brain activity associated with cognitive control. RESULTS: Schizophrenia patients exhibited a specific deficit in cognitive control, with significantly reduced accuracy in the BX condition relative to any other condition. Univariate fMRI revealed dorsolateral prefrontal cortex dysfunction during the high cognitive control condition. Multivariate analysis revealed significant impairment in functional connectivity between the dorsolateral prefrontal cortex and task-relevant brain regions. Significant correlations were also found between dorsolateral prefrontal cortex functional connectivity and cognitive performance, behavioral disorganization, and global functioning. CONCLUSIONS: These findings suggest that there is an association between decreased dorsolateral prefrontal cortex activity and connectivity and a task-related neural network. This deficit in coordinated brain activity may result in the disabling disorganization symptoms related to impaired cognition in individuals with schizophrenia.

Amoxapine as an antipsychotic: comparative study versus haloperidol.

It has been proposed that the lack of extrapyramidal side effects of atypical antipsychotic drugs is caused by their fast dissociation or low affinity for the D2 receptor or their concomitant high affinity for other receptors, for example, 5HT2 and D4. We noted that amoxapine, an established antidepressant, has affinity for 5HT2 and D2 receptors, and its effects in preclinical model are very similar to atypical antipsychotics. The objective of this study was to examine the antipsychotic effect and side effect profile of amoxapine versus haloperidol in a double-blind study for 6 weeks in patients with schizophrenia. A total of 54 patients with schizophrenia were titrated to the starting dose of 150 mg/d of amoxapine or 5 mg/d of haloperidol within 3 days. Clinical efficacy and side effects were monitored at baseline, and Weeks 2, 4, and 6.Forty-one patients completed 5 weeks, and 36 patients completed the 6 weeks of follow-up. Both treatment groups showed significant improvement in Positive and Negative Syndrome Scale positive (30%) and total scores (20%), without significant differences between the groups. In addition, in the amoxapine group, significant improvement was seen in the negative symptoms and the Clinical Global Impression. No significant changes were seen on Calgary Depression Scale for Schizophrenia, side effect checklists, and prolactin levels in both groups. The results suggest that amoxapine may be as effective an antipsychotic as haloperidol as predicted by its affinity for D2 and 5HT2 receptors, supporting earlier studies. However, it did not prove to have fewer extrapyramidal side effects than haloperidol, possibly because the baseline scores were very low.

Mixed handedness is associated with the Disorganization dimension of schizotypy in a young male population.

Within the ASPIS (Athens Study of Psychosis Proneness and Incidence of Schizophrenia) we sought out to examine in accordance with previous reports if a deviation from dextrality is associated with an augmented endorsement of self rated schizotypal personality traits in a large population of 1129 young male army recruits. Schizotypal traits were assessed using the Schizotypal Personality Questionnaire and hand preference membership was determined by applying stringent criteria derived from the Annett Handedness Questionnaire and the Porac-Coren questionnaire of lateral preferences. By adopting three different definitions of hand preference membership, we confirmed an association between mixed handedness and increased schizotypal personality traits, and in particular with Disorganization schizotypy that encompasses aspects of self perceived difficulties in verbal communication. Non-verbal cognitive ability, as indexed by measurement of non-verbal IQ, sustained attention and working memory was not associated with hand preference. We argue that a deviation from normal cerebral lateralization, as indexed by mixed handedness, is associated with mild sub clinical language dysfunction, rather than non-verbal cognitive ability, and this might be relevant to the expression of psychosis phenotype.

Cortical coordination dynamics and the disorganization syndrome in schizophrenia.

There has been a long history of investigation in the fields of neuropsychology and cognitive psychology into the question of functional integration in the brain. Each of the several dominant themes in that history can be interpreted as representing an important feature of a unitary general mechanism that integrates distributed processes in the cerebral cortex. This mechanism must allow local areas to function within the large-scale anatomical structure of the cortex so as to satisfy competing requirements for stability and flexibility. Each specialized cortical area must perform a unique role by expressing its own form of information, yet must have its performance constrained by interactions with other areas to which it is connected. In order to generate adaptive behavior within changing and not fully predictable environments, the cortex as a whole must be able to rapidly coordinate the activities of variable assemblages of areas that can collectively express consensual information that is appropriate for the functional requirements engendered by each successive stage of behavioral performance. This paper proposes that the phase synchronization of neuronal population activity from different cortical areas may serve a role in large-scale coordination. Theoretical studies suggest that the cortex normally operates in a metastable dynamic regime in which groups of areas are able to coordinate rapidly and reversibly their activities through changes in their degree of phase synchronization. A disruption of phase synchronization, leading to an excess of local information expression by cortical areas, is proposed as a contributing factor to the disorganization syndrome in schizophrenia.

N100 evoked potential latency variation and startle in schizophrenia.

The contribution of evoked potential (EP) latency jitter, a measure of CNS temporal variability, on startle and EP gating defects in schizophrenic subjects has not been characterized. The amplitude of the N100/P200 EP complex (peak to trough) derived using a time-locked averaging procedure, N100 EP latency jitter derived from single trial analysis, acoustic startle response and clinical symptoms were measured in 51 schizophrenic subjects. N100 latency jitter was inversely correlated with N100/P200 EP amplitude in both cross-sectional and longitudinal analysis. Subjects with elevated EP gating ratios (>0.5) had similar latency jitter values for initial (S1) and test (S2) stimuli, while subjects with a low gating ratio (0-0.5) had a lower level of S1 latency jitter. Temporal variability thus plays a significant and complex role in previously reported sensory gating deficits in schizophrenic subjects.

Hemispheric function in disorganized type schizophrenia: performance on the quality extinction test.

We assessed hemisphere function in right-handed male chronic, disorganized type schizophrenic patients (N = 60, age range 18-45 years) using the Quality Extinction Test (QET), in comparison to 20 right-handed male healthy controls in the same age range. The QET analysis discriminated between the disorganized schizophrenic patients and the controls. QET results indicated that chronic schizophrenic patients were less sensitive to tactile stimuli in both hands as compared to controls. Furthermore, the sensitivity to tactile stimuli of the left hand was less than that of the right hand in the schizophrenic patients. In contrast, in the normal controls the sensitivity was similar in both hands. These results indicate possible right hemisphere dysfunction together with disturbance in interhemispheric transmission through the corpus callosum in chronic, disorganized type schizophrenic patients.

Perceptual organization, the disorganization syndrome, and context processing in chronic schizophrenia.

Schizophrenia patients' perceptual organization abilities were assessed with a psychophysically well-controlled measure of contour integration. Compared with psychiatric and staff controls, schizophrenia patients were less able to detect contours comprising Gabor elements as the detection of these contours relied increasingly on long-range spatial interactions. Impaired task performance was also found to correlate significantly with higher levels of disorganized symptomatology. These data provide further evidence for impaired perceptual grouping in schizophrenia. In addition, the findings support the hypothesis that a common cortical processing algorithm involving contextual coordination is impaired in schizophrenia, leading to reduced binding of object features in vision, and reduced contextual disambiguation of linguistic information during thought and speech.

Cognitive correlates of the negative, disorganized, and psychotic symptom dimensions of schizophrenia.

Knowledge of the relationship between specific cognitive abnormalities and the clinical symptoms of schizophrenia could give insight into the nature of their underlying pathophysiology. Composite scores were generated for negative, disorganized, and psychotic symptom ratings in 134 patients with schizophrenia (DSM-IV criteria). Partial correlations (each composite corrected for the others) were computed with neuropsychological measures. Negative symptoms were related to poor performance on tests of verbal learning and memory, verbal fluency, visual memory, and visual-motor sequencing. Disorganized symptoms were correlated with lower verbal IQ and poor concept attainment. Psychotic symptoms had no significant relationship with cognitive deficit.

Subtype-associated metabolite differences in the temporal lobe in schizophrenia detected by proton magnetic resonance spectroscopy.

Brain imaging studies have indicated that the medial temporal lobe functions aberrantly in schizophrenic patients. Both diagnostic subtype and gender may affect functional and morphologic abnormalities in this region. We investigated subtype- and gender-associated differences in metabolites in the left medial temporal lobe in 40 medicated schizophrenic patients by proton magnetic resonance spectroscopy and compared findings with those in 40 healthy control subjects. Peaks corresponding to N-acetylaspartate (NAA), choline-containing compounds (Cho), creatine-phosphocreatine (Cr), and inositol were measured. Schizophrenic patients showed a decrease in the NAA/Cr ratio in the left medial temporal lobe, and patients with the disorganized subtype of illness showed significantly lower NAA/Cr and Cho/Cr ratios than those with paranoid schizophrenia. The NAA/Cr ratio in patients with the undifferentiated subtype also was significantly lower than in the paranoid subtype. No significant associations were observed between metabolite ratios and clinical symptom scores, age at onset of illness, or gender. These findings suggest that patients with the disorganized and undifferentiated subtypes have greater impairments in neuronal integrity or function in the left medial temporal lobe than patients with other subtypes of schizophrenia.

Dynamical aspects of the EEG in different psychopathological states in an interview situation: a pilot study.

Dynamical brain states can be characterized by non-linear measures of EEG. The present study shows that critical transitions, i.e., abrupt changes from one dynamic pattern of neural mass activity to another one, may be detected by abrupt variations in local chaoticity. Using an ambulatory device, EEG was recorded from 10 patients with a schizophrenic and two patients with an affective disorder during a series of 25-min interviews. Dynamical aspects, in particular, phase transitions in the EEG-dynamics of the EEG were characterized by means of a measure that continuously estimates the chaoticity of the EEG signal and is thus related to its predictability. Results indicate simpler dynamics of the EEG time series in paranoid-hallucinatory patients, while at the same time these patients tended to exhibit more abrupt transitions/unit of time between different dynamical EEG states. Such sudden phase transitions in brain activity were significantly enhanced prior to expressions of thought disorders that were detected by the interviewer and an observer in the conversation, compared with time periods during the interview without such symptoms.

The core symptoms of schizophrenia.

The diagnosis of schizophrenia is made on the basis of a diverse set of characteristic signs and symptoms. These include disturbances in perception and inference, abnormalities in communication, behaviour and motor activity, and deficits in emotional expressivity, hedonic capacity and drive. No single symptom or set of symptoms is pathognomonic, and the question of which symptoms are indeed at the 'core' of schizophrenia has been an issue of much debate, opinion and study since the disorder was first described a century ago. In this review, the symptoms emphasized in current diagnostic criteria for schizophrenia are described and the relative importance of these symptoms in the evolution of the schizophrenia construct is discussed.