The neurobiological characterization of distinct cognitive subtypes in early-phase schizophrenia-spectrum disorders.

INTRODUCTION: Cognitive deficits are present in some, but not all patients with schizophrenia-spectrum disorders (SSD). We and others have demonstrated three cognitive clusters: cognitively intact patients, patients with deficits in a few domains and those with global cognitive deficits. This study aimed to identify cognitive subtypes of early-phase SSD with matched controls as a reference group, and evaluated cognitive subgroups regarding clinical and brain volumetric measures. METHODS: Eighty-six early-phase SSD patients were included. Hierarchical cluster analysis was conducted using global performance on the Brief Assessment of Cognition in Schizophrenia (BACS). Cognitive subgroups were subsequently related to clinical and brain volumetric measures (cortical, subcortical and cortical thickness) using ANCOVA. RESULTS: Three distinct cognitive clusters emerged: relative to controls we found one cluster of patients with preserved cognition (n = 25), one moderately impaired cluster (n = 38) and one severely impaired cluster (n = 23). Cognitive subgroups were characterized by differences in volume of the left postcentral gyrus, left middle caudal frontal gyrus and left insula, while differences in cortical thickness were predominantly found in fronto-parietal regions. No differences were demonstrated in subcortical brain volume. DISCUSSION: Current results replicate the existence of three distinct cognitive subgroups including one relatively large group with preserved cognitive function. Cognitive subgroups were characterized by differences in cortical regional brain volume and cortical thickness, suggesting associations with cortical, but not subcortical development and cognitive functioning such as attention, executive functions and speed of processing.

Auditory verbal hallucinations and childhood trauma subtypes across the psychosis continuum: a cluster analysis.

Introduction: A strong link between voice-hearing experience and childhood trauma has been established. The aim of this study was to identify whether there were unique clusters of childhood trauma subtypes in a sample across the clinical spectrum of auditory verbal hallucinations (AVH) and to examine clinical and phenomenological features across these clusters.Methods: Combining two independent international datasets (the Netherlands and Australia), childhood trauma subtypes were examined using hierarchical cluster analysis. Clinical and phenomenological characteristics were compared across emerging clusters using MANOVA and chi-squared analyses.Results: The total sample (n = 413) included 166 clinical individuals with a psychotic disorder and AVH, 122 non-clinical individuals with AVH and 125 non-clinical individuals without AVH. Three clusters emerged: (1) low trauma (n = 299); (2) emotion-focused trauma (n = 71); (3) multi-trauma (n = 43). The three clusters differed significantly on their AVH ratings of amount of negative content, with trend-level effects for loudness, degree of negative content and degree of experienced distress. Furthermore, perceptions of voices being malevolent, benevolent and resistance towards voices differed significantly.Conclusion: The data revealed different types of childhood trauma had different relationships between clinical and phenomenological features of voice-hearing experiences. Thus, implicating different mechanistic pathways and a need for tailored treatment approaches.

Language in schizophrenia: relation with diagnosis, symptomatology and white matter tracts.

Language deviations are a core symptom of schizophrenia. With the advances in computational linguistics, language can be easily assessed in exact and reproducible measures. This study investigated how language characteristics relate to schizophrenia diagnosis, symptom, severity and integrity of the white matter language tracts in patients with schizophrenia and healthy controls. Spontaneous speech was recorded and diffusion tensor imaging was performed in 26 schizophrenia patients and 22 controls. We were able to classify both groups with a sensitivity of 89% and a specificity of 82%, based on mean length of utterance and clauses per utterance. Language disturbances were associated with negative symptom severity. Computational language measures predicted language tract integrity in patients (adjusted R2 = 0.467) and controls (adjusted R2 = 0.483). Quantitative language analyses have both clinical and biological validity, offer a simple, helpful marker of both severity and underlying pathology, and provide a promising tool for schizophrenia research and clinical practice.

No association between anti-thyroidperoxidase antibodies and bipolar disorder: a study in the Dutch Bipolar Cohort and a meta-analysis.

BACKGROUND: Thyroid autoimmunity has been associated with bipolar disorder (BD). However, results from previous studies on the seroprevalence of anti-thyroid peroxidase antibodies (TPO-abs) in BD are inconsistent. OBJECTIVES: The aim of the present study is to investigate whether the seroprevalence and titer levels of TPO-abs are related to BD. METHOD: TPO-abs were measured in plasma samples of 760 patients with bipolar disorder, 261 first-degree relatives and 363 controls by enzyme-linked immunosorbent assay (ELISA). To address methodological limitations of previous studies, we assessed clinical characteristics with several (self-reported) questionnaires to investigate whether TPO-abs positivity is related to particular clinical subgroups of BD patients. We performed an additional meta-analysis of seroprevalences of TPO-abs in BD patients including data from present and previous studies. RESULTS: Seroprevalence or titer levels of TPO-abs did not significantly differ between patients with BD, their first-degree relatives, and controls. In BD patients, the prevalence of TPO-abs was unrelated to specific clinical factors, including lithium use. Our meta-analysis of twelve studies showed an overall odds ratio of 1.3 (CI 95 %: 0.7-2.3; p = 0.30), reaffirming the absence of an association of BD with TPO-abs. CONCLUSIONS: In the largest study of TPO-abs in BD to date, our findings indicate that TPO-abs are not associated with (the risk for) bipolar disorder.

Auditory hallucinations, top-down processing and language perception: a general population study.

BACKGROUND: Studies investigating the underlying mechanisms of hallucinations in patients with schizophrenia suggest that an imbalance in top-down expectations v. bottom-up processing underlies these errors in perception. This study evaluates this hypothesis by testing if individuals drawn from the general population who have had auditory hallucinations (AH) have more misperceptions in auditory language perception than those who have never hallucinated. METHODS: We used an online survey to determine the presence of hallucinations. Participants filled out the Questionnaire for Psychotic Experiences and participated in an auditory verbal recognition task to assess both correct perceptions (hits) and misperceptions (false alarms). A hearing test was performed to screen for hearing problems. RESULTS: A total of 5115 individuals from the general Dutch population participated in this study. Participants who reported AH in the week preceding the test had a higher false alarm rate in their auditory perception compared with those without such (recent) experiences. The more recent the AH were experienced, the more mistakes participants made. While the presence of verbal AH (AVH) was predictive for false alarm rate in auditory language perception, the presence of non-verbal or visual hallucinations were not. CONCLUSIONS: The presence of AVH predicted false alarm rate in auditory language perception, whereas the presence of non-verbal auditory or visual hallucinations was not, suggesting that enhanced top-down processing does not transfer across modalities. More false alarms were observed in participants who reported more recent AVHs. This is in line with models of enhanced influence of top-down expectations in persons who hallucinate.

Clinical use of semantic space models in psychiatry and neurology: A systematic review and meta-analysis.

Verbal communication disorders are a hallmark of many neurological and psychiatric illnesses. Recent developments in computational analysis provide objective characterizations of these language abnormalities. We conducted a meta-analysis assessing semantic space models as a diagnostic or prognostic tool in psychiatric or neurological disorders. Diagnostic test accuracy analyses revealed reasonable sensitivity and specificity and high overall efficacy in differentiating between patients and controls (n=1680: Hedges' g =.73, p=.001). Analyses of full sentences (Hedges' g =.95 p <.0001) revealed a higher efficacy than single words (Hedges' g = .51, p <.0001). Specifically, models examining psychotic patients (Hedges' g =.96, p=.003) and those with autism (Hedges' g = .84, p <.0001) were highly effective. Our results show semantic space models are effective as a diagnostic tool in a variety of psychiatric and neurological disorders. The field is still exploratory in nature; techniques differ and models are only used to distinguish patients from healthy controls so far. Future research should aim to distinguish between disorders and perhaps explore newer semantic space tools like word2vec.

Auditory hallucinations across the lifespan: a systematic review and meta-analysis.

BACKGROUND: Auditory Hallucinations (AH) are nowadays regarded as symptoms following a continuum; from a (transient) phenomenon in healthy individuals on one end to a symptom of (psychiatric) illnesses at the other. An accumulating number of epidemiological studies focused on the prevalence of AH in the general population, but results vary widely. The current meta-analysis aims to synthesize existing evidence on lifetime prevalence of AH across the lifespan. METHODS: We conducted a quantitative review and meta-analysis according to PRISMA guidelines. Studies were combined to calculate a mean lifetime general population AH prevalence rate. Moreover, prevalences were calculated for four age groups: children (5-12 years), adolescents (13-17 years), adults (18-60 years) and elderly (⩾60 years). RESULTS: We retrieved 25 study samples including 84 711 participants. Mean lifetime prevalence rate of AH was 9.6% (95% CI 6.7-13.6%). The mean lifetime prevalence was similar in children (12.7%) and adolescents (12.4%), but these two groups differed significantly from the adults (5.8%) and the elderly (4.5%). Significant heterogeneity indicated that there is still dispersion in true prevalence rates between studies, even within the different age categories. CONCLUSIONS: Current meta-analysis shows that AH are quite common (up to one in ten individuals) in the general population during lifetime, with children and adolescents reporting these experiences significantly more often compared with adults and elderly. Large follow-up studies on the longitudinal course of AH are needed to reveal associated risk and resilience factors.

Non-glutamatergic clozapine augmentation strategies: a review and meta-analysis.

Persistent negative symptoms and cognitive impairment are major clinical problems in the treatment of schizophrenia. There is no convincing evidence regarding the efficacy of augmentation of clozapine with a second antipsychotic, ethyl eicosapentaenoic acid (E-EPA), an antidepressant, a mood stabilizer or extract of Ginkgo biloba in clozapine-resistant schizophrenia. We present an overview of studies in which the potential clinical utility of the addition of non-glutamatergic agents to clozapine is assessed. We performed a meta-analysis on the efficacy of both risperidone and aripiprazole compared to placebo. We compared the effects of the addition of a second antipsychotic or an antidepressant to clozapine on positive, negative, overall and affective symptoms of schizophrenia in double-blind placebo-controlled trials.

Clozapine augmented with glutamate modulators in refractory schizophrenia: a review and metaanalysis.

Clozapine is an efficacious antipsychotic drug for patients with treatment-resistant schizophrenia, but does not sufficiently improve these symptoms in a substantial proportion of this population. There is no convincing evidence for the efficacy of any clozapine augmentation strategy. New evidence suggests that glutamate receptors are a candidate target for therapeutic effects in schizophrenia. We present an overview of studies assessing the potential clinical utility of adding glutamatergic agents to clozapine. We conducted 3 metaanalyses of data on positive, negative and overall symptoms of schizophrenia, analysing results from 3 studies on clozapine augmentation with glycine, 6 studies on lamotrigine add-on therapy to clozapine and 4 studies on topiramate addition to clozapine.

Steady-state and dynamic behavior of ventricular repolarization and refractoriness in the dog: the effect of multiple cycle length changes and d-sotalol administration.

In anesthetized dogs with chronic, complete AV block we studied the characteristics of ventricular repolarization and refractoriness. Therefore, we determined: (1) steady-state values of ventricular effective refractory period (VERP), action potential duration (APD), and stimulus T interval (STI) before and after d-sotalol treatment at various pacing cycle lengths (PCLs); and (2) the dynamics of VERP, APD, and STI before and after d-sotalol treatment after the abrupt PCL decreases. VERP, APD, and STI showed a normal frequency dependency. All three parameters increased significantly after d-sotalol administration. During steady-state and dynamic measurements, STI was always longer than APD and APD was always longer than VERP in an individual animal, irrespective of PCL and conditions. Standard deviations of steady-state and dynamic values indicated a considerable interindividual variation. However, the dynamics of VERP, APD, and STI after an abrupt decrease in PCL were highly correlated (linear regression analysis: r2 > or = 0.93). The best mathematical model to describe these dynamics was a bi-exponential model (r2 > or = 0.98) with a very short first and a much longer second time constant. We found that there was a very consistent relation between VERP, APD, and STI, not only during steady-state but also in the dynamic situation after various abrupt PCL decreases. This relation does not change after the administration of d-sotalol. Therefore, STI could be used to predict steady-state and dynamic values of VERP and APD. Since STI can be made available online in implantable pacing systems this could lead to the development of new features in these devices.

Analysis of atrial sensed far-field ventricular signals: a reassessment.

Accurate detection of the spontaneous far-field ventricular signal may be used to determine the ventricular activation, and hence, the interval from atrial stimulus to the ventricular R wave (AR interval) using a standard atrial pacing lead. This can be useful in developing a physiological atrial rate responsive (AAIR) pacemaker and in further improving DDD(R) pacing algorithms. In order to better characterize the atrial sensed far-field ventricular signal, 200 consecutive patients undergoing pacemaker implantation were studied. The amplitude of the far-field ventricular signal was significantly smaller than that of the atrial deflection. In all recordings, the slew rate of the atrial deflection was larger than that of the far-field ventricular signal. Subdivision of the recordings by electrode position, pocket location, or QRS duration on the surface ECG resulted in significantly different signal characteristics. The amplitude and slew rate of the far-field ventricular signal were significantly smaller in bipolar versus unipolar sensing. Atrial sensed far-field ventricular recordings could also be obtained in the case of ventricular pacing. Our results indicate that accurate sensing of the far-field ventricular signal from an atrial pacing lead is conceivable in most patients. The different signal characteristics in relation to parameters, such as electrode position, sensing mode, and pocket location, may be useful in determining the optimal conditions for signal sensing.

Inter- and intraindividual variations in shortening of ventricular effective refractory period after an abrupt decrease in pacing cycle length.

After an abrupt decrease in pacing cycle length (PCL), the ventricular effective refractory period (VERP) shortens. The pacing protocol needed to determine accurate and reproducible values for the VERP during this process is elaborate and time consuming. In this study, steady-state values of VERP at 800 and 350 msec PCL and dynamic values of VERP due to an abrupt change in PCL from 800 to 350 msec were determined. This was done for 11 different dogs to test the interindividual variation and repetitively in the same dog to test the intraindividual variation. The results for steady-state and dynamic values of the VERP show a wide range for both groups. This means that accurate prediction of steady-state and dynamic values of VERP based on previous measurements is not possible.

The A-R interval as exercise indicator: a new option for rate adaptation in single and dual chamber pacing.

We investigated the possibility to use the interval from an atrial stimulus to the ventricular R wave (A-R interval) as an indicator of physical stress, in 16 patients with pacemakers implanted for severe atrial bradycardia but with intact AV conduction. The A-R interval was studied during incremental atrial pacing at rest and during exercise with a constant workload. In addition, the atrial pacing rate was kept constant just above spontaneous sinus rate and the dynamics of the A-R interval were studied during exercise with a low constant workload and during a maximal exercise test with increasing workload. Incremental atrial pacing prolonged the A-R interval and this response was blunted during exercise (P less than 0.003). Atrial pacing at a constant rate and during a constant workload resulted in an almost direct shortening of the A-R interval. When the workload was increased but the atrial rate kept constant, a pronounced shortening of the A-R interval was noted (P less than 0.0001). It is concluded that changes of the A-R interval during different kinds of exercise were prompt and predictable in patients with sinus node dysfunction but intact AV conduction. In these patients the shortening of the A-R interval during exercise may be a suitable indicator for rate adaptive atrial pacing.

Improved pattern of rate responsiveness with dynamic slope setting for the QT sensing pacemaker.

We have recently described the electrophysiological basis of a new algorithm for the QT (TX) sensing rate responsive pacemaker. By using the new software program running on the standard programmer it has been possible to simulate the new algorithm in ten patients with complete heart block (seven patients had implanted TX units and three were paced with an external TX pacemaker) during routine exercise testing. In this way a single-blind, intra-patient comparison of the pattern of pacing rate change using both the existing and new algorithms was possible. In nine out of the ten cases the time taken to increase the pacing rate from 70 to 80 bpm was reduced significantly when the new algorithm was used (P = 0.037). Additionally, the correlation between the atrial and ventricular rates in those patients with normal sinus node function (seven patients) was determined. In all cases we have observed a significantly improved correlation between the atrial and ventricular paced rates during exercise with the new algorithm (P less than 0.001).

Automatic refractory period.

Pacemakers have become more and more complex over the years, whereby technological advances were used to create more and new possibilities in existing pacemaker applications. As a result a demand has grown for more automatic functions to reduce the time to program the pacemakers and eleviate follow-up procedures. One of the parameters which can be adjusted automatically is the refractory period. We measured the pacing threshold as a function of coupling interval between the stimulus and the previous paced complex and related this to the morphology of the paced evoked T-wave. When the stimulus falls far away from the T-wave the pacing threshold is constant. When it approaches the T-wave the threshold reduces slightly (superconductivity) and at the peak of the T-wave there is a sharp increase of the pacing threshold. The refractory period coincides with the period from the stimulus until the top of the T-wave (stim-T interval). This result is used in the Rhythmyx pacemaker where the stim-T interval is used to automatically adjust the pace refractory period. Automatically adjusting the refractory period has the extra advantage of higher allowable pacing rates as the refractory period shortens with increasing heart rates. Future applications will include use antitachycardia pacing where the stim-T interval can be used to prevent pacing in the refractory period or in the vulnerable zone.

Heart rate monitoring in implanted pacemakers.

Increasing pacemaker memory allows integration of heart rate monitoring into the pacemaker. Two main methods can be distinguished. 1. Heart rate monitoring in histograms. 2. Heart rate monitoring in the time domain (heart rate holter). Method 1 is useful in antitachycardia and diagnostic pacemakers when short specific events must be detected (tachycadia, bradycardia). For the analysis of a rate adaptive pacemaker this method is less appropriate as it does not give any information about the dynamics of rate changes or its time relations. For this purpose Method 2 will give more information about the functioning of the pacemaker as it does not only store the heart rate but also the timing of the heart rate so that changes in heart rate can be correlated to the activity of the patient. An algorithm was developed to store the average heart rate over 7.8 minute periods in a pacemaker. On interrogation of the pacemaker the information will always reveal the heart rate over the 24 hours prior to interrogation. This monitor can also be temporarily programmed to store the average heart rate in 20 second intervals to monitor the response to an exercise test for a period of 1 hour. The time needed for a standard follow-up procedure of a rate adaptive pacemaker can be dramatically reduced to a value close to the follow-up time of a standard VVI pacemaker.