Ventral striatal activation during reward processing in subjects with ultra-high risk for schizophrenia.

BACKGROUND: Early dysfunction of the brain reward system in schizophrenia might be already recognized in the prodromal phase of this illness. We used functional magnetic resonance imaging to assess the blood oxygen level-dependent response in the ventral striatum (VS) of subjects with ultra-high risk for psychosis during the presentation of reward-indicating and loss-indicating stimuli. METHODS: Thirteen prodromal patients (mean age: 25.5 ± 4.6 years) and 13 age-matched healthy volunteers participated in an incentive monetary delay task, in which visual cues predicted that a rapid response to a subsequent target stimulus will gain money, avoid losing money or have no consequence. RESULTS: Compared with the neutral condition, anticipation of reward loss-avoidance elicited significant activation of the VS in both healthy subjects and subjects with ultra-high risk for psychosis, but there was only a statistical tendency for less activation during loss-avoidance anticipation in prodromal compared to healthy subjects. DISCUSSION: This study provides a first weak hint, as revealed by functional magnetic resonance imaging, for impaired activation of a central area of the mesolimbic dopaminergic brain reward system, the VS, already in subjects with ultra-high risk for psychosis, which is in line with results of patients with full-blown schizophrenic psychosis. This pilot study has, however, strong limitations, and its results need to be replicated first before they can be used e.g. for early recognition of patients in the schizophrenic prodrome.

1 H-MR spectroscopy in ultra-high risk and first episode stages of schizophrenia.

Using proton magnetic resonance spectroscopy biochemical characteristics in early stages of schizophrenia were examined. N-acetylaspartate, choline and creatine were measured in hippocampus, anterior cingulate gyrus (ACC) and medial prefrontal cortex (mPFC) of 24 first episode and 30 ultra-high risk patients. Careful LCModel analyses revealed no differences between the patient groups and 31 healthy controls, casting doubt upon the idea of metabolic changes in early stages of psychosis.

COMT Val108/158Met genotype modulates human sensory gating.

BACKGROUND: The catechol-O-methyltransferase (COMT) Val(108/158)Met polymorphism of the dopamine system is essential for prefrontal cortex processing capacity and efficiency. In addition, dopaminergic neurotransmission is also associated with the sensory gating phenomenon protecting the cerebral cortex from information overload. It is however unclear if COMT genotype as a predictor of prefrontal efficiency modulates sensory gating on the level of the auditory cortex, i.e. the gating of the auditory evoked P50 and N100 components. METHODS: P50 and N100 gating and COMT Val(108/158)Met genotype were determined in 282 healthy subjects of German descent carefully screened for psychiatric or neurological disorders. RESULTS: A significant effect of the COMT genotype was observed for N100 gating (F=4.510, df=2, p=0.012) but not for P50 gating (F=0.376, df=2, p=0.687). Contrast analysis showed that Met/Met individuals had poorer N100 gating compared to Val/Met (F=-12.931, p=0.003) and the Val/Val individuals (F=-11.056, p=0.057). CONCLUSION: The results indicate that a high prefrontal efficiency as suggested by the COMT Met/Met genotype is associated with to a poor sensory gating of the N100 component. This would fit in a model where a high prefrontal processing capacity allows a pronounced afferent input of sensory information from the auditory cortex as reflected by a poor sensory gating. The more pronounced prefrontal contribution to the N100 compared to the P50 component may explain the exclusive genotype association with the N100 sensory gating. This preliminary model should be replicated and validated in future investigations.

Test-performance after cognitive training in persons at risk mental state of schizophrenia and patients with schizophrenia.

This exploratory study aims to examine the differential effects of a computer-based cognitive training in 'prodromal' patients (mean age 27.20 years, S.D. 5.31 years) compared with patients with full-blown schizophrenia (mean age 30.13 years, S.D. 7.77 years). Ten patients at risk for schizophrenia and 16 patients suffering from schizophrenia underwent a computerized cognitive training program (Cogpack). Cognitive functioning before and after a total of 10 training sessions was assessed by different tests controlling for memory, attention, and logical thinking. Prodromal patients turned out to be able to significantly improve their long-term memory functions and their attention after cognitive training with the Cogpack software package whereas in the group of patients with schizophrenia no improvement occurred (e.g. continuous performance test, identical pairs-subtest 'shapes': improvement from 0.73 to 0.88 in persons at risk of schizophrenia vs. no improvement in patients with schizophrenia (0.55 to 0.53). Cognitive training using Cogpack is helpful for the improvement of cognitive functioning in persons at risk of schizophrenia. Thus, the application of cognitive training should be provided as early as possible in the prodromal phases of schizophrenia in order to use the full rehabilitative potential of the patients. These results should be confirmed by further investigations including larger sample sizes.

Low effective organizational strategies in visual memory performance of unmedicated alcoholics during early abstinence.

OBJECTIVE: Alcohol-dependent patients in early abstinence show an impairment of cognitive functions which can be seen in poor implementation of newly learned skills for avoiding relapse. Executive dysfunction may persist during abstinence in alcohol-dependent persons, thus mitigating long-term abstinence. This study assessed visual memory function and choice of organizational strategies in alcoholics, as these are major factors necessary to implement ongoing behavior changes which are required for maintaining abstinence. METHODS: We investigated 25 severely alcohol-dependent male patients between days 7 to 10 of abstinence, immediately after clinical withdrawal symptoms have ceased, compared to 15 healthy age, sex, and education matched controls. Pharmacological therapy had been terminated at least four half-lifes before inclusion into the study. Visual perceptual learning and organizational strategies were assessed with the Rey-Osterrieth Complex Figure Test (R-OCF). RESULTS: There were no group differences in copying or recalling the figure, but time differences occurred. Alcoholics and healthy controls performed worse in recalling than in copying. But, alcoholics used less effective organizational strategies. CONCLUSIONS: There was a deficit in choice of organizational strategy in newly abstinent and unmedicated alcohol-dependent patients. Due to the imperfect organizational strategies, alcoholics might need auxiliary therapeutic care to strengthen their cognitive ability.

Do locked doors in psychiatric hospitals preventpatients from absconding?

Background and Objectives: In the acute treatment of acute psychiatric patients coercive measures are often required and therapeutic relationships can be affected by such measures. In this study we assessed whether opening the entrance door of an acutepsychiatric ward influences absconding behaviour. Methods: An acute psychiatric ward was primarily closed (91.4%) for six months andprimarily open (75.6%) for six months over the time period of one year. In this one year period, 337 patients were treated (206 male, age: 40 ± 16 years): 60.2% of the patients hadschizophrenia, 13.6% had affective disorders, 11.6% suffered from addiction and 14.5%displayed other diagnoses. Results: In terms of age (t = 0.026, df = 335, p = 0.979), gender (chi2 = 1.6, df = 1, p = 0.13), diagnoses(chi2 = 7.337, df = 1, p = 0.062) and duration of stay (t = -0.90, df = 335, p = 0.928),we found no significant differences between the patients admitted in the closed and those admittedin the open ward period. Absconding (df = 1, chi2 = 5.107, p = 0.029), aggressive incidents(chi2 = 4.46, df = 1, p = 0.050) and coercive medications (chi2 = 4.646, df = 1, p =0.037) were observed significantly more often in the closed door period. Moreover, the duration up to readmission was reduced in the closed time period (t = 2.314, df = 54, p = 0.025).Conclusions: We hypothesize that open doors reduce patient´s discomfort, improveward atmosphere and aggressive acts and do not appear to increase the risk of absconding (AU)

[Operationalized psychodynamic diagnostics (OPD) in patients in a prodromal state of schizophrenia--an explorative study]. / Operationalisierte Psychodynamische Diagnostik (OPD) bei Patienten im schizophrenen Prodromalstadium--Eine explorative Studie.

OBJECTIVES: To obtain data and hypotheses regarding the amelioration of risk estimation and preventive psychotherapy in patients in a prodromal state of schizophrenia by using OPD. METHODS: 20 participants with a prodromal condition--6 subjects far from psychosis and 14 close to psychosis--along with 10 patients with paranoid schizophrenia as reference group were examined using the first four OPD axes. RESULTS: Both groups differed considerably in all four axes. Compared to the schizophrenic participants, prodromal probands appear to have more favourable preconditions for therapy. Moreover, they experienced the interaction partners, including the investigator, as less aversive and induced less distanced behaviour in the investigator. Conflicts of self-esteem were prominent in both prodromal subgroups. However, patients farther from psychosis showed less conflicts of autonomy versus dependence and displayed a higher integration in structures such as "defence" and "attachment" when compared to participants closer to psychosis. CONCLUSIONS: Particularly the differences between the prodromal subgroups suggest that application of the OPD may positively complement previous approaches of early detection, prevention,and psychotherapy for prodromal conditions. The hypotheses obtained should be tested in longitudinal studies with larger sample sizes.

Hippocampal subdivision and amygdalar volumes in patients in an at-risk mental state for schizophrenia.

BACKGROUND: Accumulating evidence from postmortem and magnetic resonance imaging (MRI) studies suggests that abnormalities of medial temporal lobe structures are critically involved in the pathogenesis of schizophrenia. It is still unclear, however, whether certain abnormalities are already present in individuals at ultra high-risk (UHR) for transition into psychosis. Recent studies involving patients at UHR showed contradictory results for hippocampal volume, and only 1 study reported that amygdalar volume was unchanged between healthy patients and those at UHR. Furthermore, no subregions of the hippocampus have been investigated in people at UHR. METHODS: We recruited 29 UHR patients, 23 first-episode patients and 29 age- and sex-matched healthy controls. We measured hippocampal and amygdalar volumes from MRI scans by use of BRAINS2 to manually trace the regions of interest. The hippocampi were divided in 2 regions: head and corpus/tail. RESULTS: Patients at UHR had significantly smaller volumes of the hippocampus corpus and tail bilaterally, but not of the head, compared with healthy controls. Group differences for the right hippocampus corpus and tail volume remained significant after we controlled for whole brain volume and other covariates. We found that UHR patients who later developed psychosis had smaller right hippocampus corpus and tail volumes than did those who did not develop psychosis. First-episode patients had significantly smaller left amygdalar volumes than did healthy individuals or those at UHR. LIMITATIONS: Our study had a small sample size, and we were unable to control for the effects of medication. CONCLUSION: Our findings suggest that parts of the hippocampal-amygdalar complex are involved in the pathogenesis of schizophrenia. Reduction of hippocampus corpus and tail volumes may be indicative of the prodromal phase of schizophrenia and represent risk factors for transition into psychosis. Further investigations are needed to determine whether structural changes of the left amygdala play a role during transition from the prodromal phase to the first manifest episode of schizophrenia.

Gray matter abnormalities in subjects at ultra-high risk for schizophrenia and first-episode schizophrenic patients compared to healthy controls.

Neuroimaging studies have revealed gray matter abnormalities in schizophrenia in various regions of the brain. It is, however, still unclear whether such abnormalities are already present in individuals at ultra-high risk (UHR) for transition into psychosis. We investigated this issue using voxel-based morphometry of structural magnetic resonance images (MRI) and compared UHR patients with first-episode patients with schizophrenia and healthy controls. Gray matter volume maps from high-resolution MR T1-weighted whole brain images were analyzed in a cross-sectional study in 30 UHR patients, 23 first-episode schizophrenic patients and 29 controls. UHR patients showed significantly lower gray matter volume in the cingulate gyrus bilaterally, in the right inferior frontal and right superior temporal gyrus, as well as in the left and right hippocampus in comparison to healthy subjects. First-episode patients with schizophrenia showed smaller gray matter volume in the cingulate cortex bilaterally, in the left orbitofrontal gyrus, in the right inferior frontal and superior temporal gyrus, in the right temporal pole, in the left and right hippocampus, in the left parahippocampus, left amygdala, and in the left fusiform gyrus compared to the UHR patients. This study provides further evidence that gray matter brain volume, especially in the anterior cingulate cortex, is already reduced in the prodromal state of schizophrenia.

Serotonergic dysfunction in the prodromal, first-episode and chronic course of schizophrenia as assessed by the loudness dependence of auditory evoked activity.

Recent studies revealing evidence of increased serotonergic neurotransmission in schizophrenia has generated substantial interest in the role of serotonin in its pathophysiology. None of these studies, however, have queried whether dysfunctional serotonergic activity might already have been present in subjects of at-risk mental state for schizophrenia before the onset of psychotic symptoms, and whether serotonergic activity further increases during the development of schizophrenia and the chronic course. Although no valid indicator for measuring the activity level of serotonergic neurotransmission has yet been found, a series of evidence from human and animal studies suggests that a weak loudness dependence of auditory evoked potentials (LDAEP) indicates high serotonergic activity and vice versa. We examined the LDAEP (N1/P2 component) in 60 patients with at-risk mental state for schizophrenia who showed characteristic prodromal symptoms, 34 first-episode patients, 28 patients with a chronic course of schizophrenia and 57 healthy controls. Prodromal patients showed significantly weaker LDAEP in comparison to healthy volunteers, but similarly to that in first-episode and chronic patients. None of the covariates such as age, gender, medication, age of onset, or psychopathology had an influence on this finding. In a subsample of prodromal patients, LDAEP values remain the same after retesting 10 months later. These results indicate that serotonergic neurotransmission had already increased before the onset of the full-blown psychosis of schizophrenia and remains enhanced in the further course of the disease. A weak LDAEP may therefore represent a vulnerability marker rather than an expression of illness progression.

Psychoeducation with patients at-risk for schizophrenia--an exploratory pilot study.

OBJECTIVE: To introduce a psychoeducational program for patients of at-risk mental state and its preliminary evaluation. METHODS: The psychoeducational program was designed as a purely informative intervention and consisted of seven 1-h sessions. Sixteen at-risk mental state patients (mean age 26+/-4.9 years, 12 males/4 females, mean score on prodromal psychopathology (Bonn Scale for Assessment of predictive Basis Symptoms [BSABS-P] 18.6+/-13.3) were investigated. RESULTS: Comparisons of means before and after psychoeducation showed a significant reduction in psychopathology and fatalistic LoC as well as an improvement in knowledge, global functioning and various areas of QoL. A qualitative evaluation of the psychoeducational program also showed advantages from patients' perspectives. CONCLUSIONS: This study provides empirical evidence for benefits of psychoeducation with patients of at-risk mental state for schizophrenia but is exploratory and has some limitations, e.g. the small sample size. Therefore the results have to be replicated in a randomized controlled trial in order to be able to demonstrate conclusively the effectiveness of psychoeducation in the pre-psychotic phase. PRACTICE IMPLICATIONS: Results from this preliminary study suggest that psychoeducation is a promising intervention for patients of at-risk mental state for schizophrenia, and therefore worthy of more investigations.

Neurocognitive performances in participants of at-risk mental state for schizophrenia and in first-episode patients.

As suggested by the neurodevelopmental model, neurocognitive disturbances are core features of schizophrenia spectrum disorders. The aim of the present study was to explore the neurocognitive performance of symptomatically defined high-risk participants as well as first-episode patients on tests of verbal memory, executive functioning, working memory, and attention. The sample consisted of 54 participants at risk for schizophrenia and 37 patients with a first episode of psychosis. The high-risk group exhibited a similar cognitive performance profile to that of the first-episode participants when compared with normative data. The neurocognitive functioning of both patient groups were within standard average range at most of the cognitive domains. Moreover the intellectual functioning of both groups was within higher average level, while decreased "hit rates" could be observed within both subtests "Figures" and "Symbols" of the Continuous Performance Test-Identical Pairs Version (CPT-IP) in the group of first-episode patients. Direct comparison between the clinical groups did show increasing impairments of these parameters in first-episode patients compared to high-risk participants. Results suggest that high-risk participants do perform at average neurocognitive performance levels at all tested domains compared with normative data. Compared to norm values first-episode patients showed decreased attention abilities.

Reduction of auditory event-related P300 amplitude in subjects with at-risk mental state for schizophrenia.

Neurophysiological methods allow the examination of cognitive-cortical functioning in patients with schizophrenia in its prodromal states. As revealed by previous studies, event-related potential components such as auditory evoked P300 associated with cognitive processes, such as attention and orientation, are known to be reduced in amplitude in acute and chronic as well as in medicated and unmedicated patients. It is, however, unclear whether a P300 amplitude reduction occurs before the schizophrenic psychosis is fully manifested. We studied patients in the prodromal phase of the schizophrenic disorder (i.e. subjects with an at-risk mental state showing attenuated psychotic symptoms or brief limited intermittent symptoms) as well as first-episode patients and chronic patients with schizophrenia and compared these groups to healthy subjects. The event-related P300 was recorded during an auditory oddball paradigm. Groups differed significantly from each other in the P300 amplitude at Pz (F(3/149)=2.532, p=0.02). Post-hoc tests revealed significantly lower P300 amplitudes of non-medicated prodromal (p=.03), first-episode (p=.01) and chronic patients (p=.001) compared to the healthy controls. The study revealed that there are neurophysiological changes as the reduction in P300 amplitudes begins early in schizophrenia at the prodromal phase, i.e. before a manifestation of full-blown psychosis, and that these changes seem to have a progressive course from prodromal to chronic state of schizophrenia as assumed in this cross-sectional study.

White matter abnormalities in subjects at ultra high-risk for schizophrenia and first-episode schizophrenic patients.

Schizophrenia is associated with neuroanatomical abnormalities. Gray matter decrease seems to predate first schizophrenic episode. Whether white matter abnormalities predate the onset of psychotic symptoms is unclear. We investigated this issue using voxel-based morphometry (VBM) of structural magnetic resonance images to examine individuals with prodromal symptoms who were at ultra high-risk (UHR) of developing schizophrenia and compared them to first-episode schizophrenic patients and healthy controls. White matter volume maps from high-resolution magnetic resonance T1 weighted whole brain images were analyzed in a cross-sectional study using SPM2 in 30 UHR patients, 23 first-episode schizophrenic patients and 29 healthy controls. UHR patients showed significant lower white matter volume in the right superior temporal lobe compared to healthy controls. First-episode patients with schizophrenia showed widespread smaller white matter volume bilaterally compared to UHR patients. This study provides first evidence for smaller white matter volume in the right temporal lobe of UHR patients, one of the key structures in the pathophysiology of schizophrenia. Furthermore, white matter abnormalities seem to progress after transition into schizophrenia.

Loudness dependence of the auditory evoked N1/P2 component as an indicator of serotonergic dysfunction in patients with schizophrenia--a replication study.

Serotonergic dysfunction appears to be involved in the pathogenesis of schizophrenia. The loudness dependence of auditory evoked potentials (LDAEP) has been suggested to be a valid indicator of the brain serotonin system's activity in humans. Patients with schizophrenia showed weaker LDAEP, indicating high serotonergic activity, in comparison to healthy controls. Thus, we were able again to demonstrate electrophysiological evidence for an upregulated serotonergic system in schizophrenia.