Arabidopsis phosphoglycerate dehydrogenase1 of the phosphoserine pathway is essential for development and required for ammonium assimilation and tryptophan biosynthesis.

In plants, two independent serine biosynthetic pathways, the photorespiratory and glycolytic phosphoserine (PS) pathways, have been postulated. Although the photorespiratory pathway is well characterized, little information is available on the function of the PS pathway in plants. Here, we present a detailed characterization of phosphoglycerate dehydrogenases (PGDHs) as components of the PS pathway in Arabidopsis thaliana. All PGDHs localize to plastids and possess similar kinetic properties, but they differ with respect to their sensitivity to serine feedback inhibition. Furthermore, analysis of pgdh1 and phosphoserine phosphatase mutants revealed an embryo-lethal phenotype and PGDH1-silenced lines were inhibited in growth. Metabolic analyses of PGDH1-silenced lines grown under ambient and high CO2 conditions indicate a direct link between PS biosynthesis and ammonium assimilation. In addition, we obtained several lines of evidence for an interconnection between PS and tryptophan biosynthesis, because the expression of PGDH1 and phosphoserine aminotransferase1 is regulated by MYB51 and MYB34, two activators of tryptophan biosynthesis. Moreover, the concentration of tryptophan-derived glucosinolates and auxin were reduced in PGDH1-silenced plants. In essence, our results provide evidence for a vital function of PS biosynthesis for plant development and metabolism.

Loss of cytosolic phosphoglucose isomerase affects carbohydrate metabolism in leaves and is essential for fertility of Arabidopsis.

Carbohydrate metabolism in plants is tightly linked to photosynthesis and is essential for energy and carbon skeleton supply of the entire organism. Thus, the hexose phosphate pools of the cytosol and the chloroplast represent important metabolic resources that are maintained through action of phosphoglucose isomerase (PGI) and phosphoglucose mutase interconverting glucose 6-phosphate, fructose 6-phosphate, and glucose 1-phosphate. Here, we investigated the impact of disrupted cytosolic PGI (cPGI) function on plant viability and metabolism. Overexpressing an artificial microRNA targeted against cPGI (amiR-cpgi) resulted in adult plants with vegetative tissue essentially free of cPGI activity. These plants displayed diminished growth compared with the wild type and accumulated excess starch in chloroplasts but maintained low sucrose content in leaves at the end of the night. Moreover, amiR-cpgi plants exhibited increased nonphotochemical chlorophyll a quenching during photosynthesis. In contrast to amiR-cpgi plants, viable transfer DNA insertion mutants disrupted in cPGI function could only be identified as heterozygous individuals. However, homozygous transfer DNA insertion mutants could be isolated among plants ectopically expressing cPGI. Intriguingly, these plants were only fertile when expression was driven by the ubiquitin10 promoter but sterile when the seed-specific unknown seed protein promoter or the Cauliflower mosaic virus 35S promoter were employed. These data show that metabolism is apparently able to compensate for missing cPGI activity in adult amiR-cpgi plants and indicate an essential function for cPGI in plant reproduction. Moreover, our data suggest a feedback regulation in amiR-cpgi plants that fine-tunes cytosolic sucrose metabolism with plastidic starch turnover.

Jazz drummers recruit language-specific areas for the processing of rhythmic structure.

Rhythm is a central characteristic of music and speech, the most important domains of human communication using acoustic signals. Here, we investigated how rhythmical patterns in music are processed in the human brain, and, in addition, evaluated the impact of musical training on rhythm processing. Using fMRI, we found that deviations from a rule-based regular rhythmic structure activated the left planum temporale together with Broca's area and its right-hemispheric homolog across subjects, that is, a network also crucially involved in the processing of harmonic structure in music and the syntactic analysis of language. Comparing the BOLD responses to rhythmic variations between professional jazz drummers and musical laypersons, we found that only highly trained rhythmic experts show additional activity in left-hemispheric supramarginal gyrus, a higher-order region involved in processing of linguistic syntax. This suggests an additional functional recruitment of brain areas usually dedicated to complex linguistic syntax processing for the analysis of rhythmical patterns only in professional jazz drummers, who are especially trained to use rhythmical cues for communication.

Evidence for a cognitive control network for goal-directed attention in simple sustained attention.

The deterioration of performance over time is characteristic for sustained attention tasks. This so-called "performance decrement" is measured by the increase of reaction time (RT) over time. Some behavioural and neurobiological mechanisms of this phenomenon are not yet fully understood. Behaviourally, we examined the increase of RT over time and the inter-individual differences of this performance decrement. On the neurophysiological level, we investigated the task-relevant brain areas where neural activity was modulated by RT and searched for brain areas involved in good performance (i.e. participants with no or moderate performance decrement) as compared to poor performance (i.e. participants with a steep performance decrement). For this purpose, 20 healthy, young subjects performed a carefully designed task for simple sustained attention, namely a low-demanding version of the Rapid Visual Information Processing task. We employed a rapid event-related functional magnetic resonance imaging (fMRI) design. The behavioural results showed a significant increase of RT over time in the whole group, and also revealed that some participants were not as prone to the performance decrement as others. The latter was statistically significant comparing good versus poor performers. Moreover, high BOLD-responses were linked to longer RTs in a task-relevant bilateral fronto-cingulate-insular-parietal network. Among these regions, good performance was associated with significantly higher RT-BOLD correlations in the pre-supplementary motor area (pre-SMA). We concluded that the task-relevant bilateral fronto-cingulate-insular-parietal network was a cognitive control network responsible for goal-directed attention. The pre-SMA in particular might be associated with the performance decrement insofar that good performers could sustain activity in this brain region in order to monitor performance declines and adjust behavioural output.

Musical training induces functional plasticity in human hippocampus.

Training can change the functional and structural organization of the brain, and animal models demonstrate that the hippocampus formation is particularly susceptible to training-related neuroplasticity. In humans, however, direct evidence for functional plasticity of the adult hippocampus induced by training is still missing. Here, we used musicians' brains as a model to test for plastic capabilities of the adult human hippocampus. By using functional magnetic resonance imaging optimized for the investigation of auditory processing, we examined brain responses induced by temporal novelty in otherwise isochronous sound patterns in musicians and musical laypersons, since the hippocampus has been suggested previously to be crucially involved in various forms of novelty detection. In the first cross-sectional experiment, we identified enhanced neural responses to temporal novelty in the anterior left hippocampus of professional musicians, pointing to expertise-related differences in hippocampal processing. In the second experiment, we evaluated neural responses to acoustic temporal novelty in a longitudinal approach to disentangle training-related changes from predispositional factors. For this purpose, we examined an independent sample of music academy students before and after two semesters of intensive aural skills training. After this training period, hippocampal responses to temporal novelty in sounds were enhanced in musical students, and statistical interaction analysis of brain activity changes over time suggests training rather than predisposition effects. Thus, our results provide direct evidence for functional changes of the adult hippocampus in humans related to musical training.

Sustained attention and planning deficits but intact attentional set-shifting in neuroleptic-naïve first-episode schizophrenia patients.

INTRODUCTION: The nature of deficits in tests of sustained attention, planning and attentional set-shifting has not been investigated in neuroleptic-naïve first-episode (FE) schizophrenia patients. Based on previous literature of chronic and medicated FE schizophrenia patients, we predicted that the neuroleptic-naïve patients would show deficits in these cognitive processes. METHODS: Twenty-nine neuroleptic-naïve FE schizophrenia patients and 33 healthy controls - matched by age, gender, and nicotine consumption - performed 3 tests from the Cambridge Automated Neuropsychological Test Battery (CANTAB) thought to measure these cognitive processes: the Rapid Visual Information Processing task (RVIP, sustained attention), the Stockings of Cambridge task (SOC, planning), and the Intradimensional/Extradimensional set-shifting task (IDED, attention shifting). RESULTS: The patients were significantly impaired in the sensitivity index (A') of the RVIP, and in the number of problems solved with minimum moves on the SOC. Nevertheless, the groups did not differ regarding the number of participants who failed at the crucial extradimensional shift stage of the IDED. CONCLUSION: Sustained attention and planning abilities are already impaired in neuroleptic-naïve FE schizophrenia patients, whereas set-shifting abilities as measured with the IDED task seem to be intact at illness onset. Since chronic schizophrenia patients have been shown to have impaired IDED performance, we tentatively propose that IDED performance deteriorates over time with illness chronicity and/or medication.

Impaired performance on the Rapid Visual Information Processing task (RVIP) could be an endophenotype of schizophrenia.

The aim of the present study was to investigate whether healthy first-degree relatives of schizophrenia patients show reduced sensitivity performance, higher intra-individual variability (IIV) in reaction time (RT), and a steeper decline in sensitivity over time in a sustained attention task. Healthy first-degree relatives of schizophrenia patients (n=23) and healthy control subjects (n=46) without a family history of schizophrenia performed a demanding version of the Rapid Visual Information Processing task (RVIP). RTs, hits, false alarms, and the sensitivity index A' were assessed. The relatives were significantly less sensitive, tended to have higher IIV in RT, but sustained the impaired level of sensitivity over time. Impaired performance on the RVIP is a possible endophenotype for schizophrenia. Higher IIV in RT, apparently caused by impaired context representations, might result in fluctuations in control and lead to more frequent attentional lapses.

[Aetiology of depressive disorders--the biopsychosocial model]. / Ätiologie von depressiven Störungen - das "biopsychosoziale Modell"

The biopsychosocial model has been developed from general system theory and describes the interaction of body and mind. Unipolar depression has a complex pathogenesis which on an individual level presents in very diverse ways. The article focuses on biological factors such as heritability, changes in neurotransmitters, endocrinological factors and chronobiological patterns. The psychosocial factors include critical life events, social pressure, cognitive and learning theory-based factors as well as personality factors.It was found that the biological, psychological and (eco-) social factors that contribute to etiopathogenesis frequently interact. The biopsychosocial model lends itself to collecting all the factors that are linked to a depression etiopathogenetically and to using them for the purpose of diagnostics.It thus provides a suitable basis for individually tailored therapy and also has valuable applications in the field of psychoeducation.

Multi-parametric classification of Alzheimer's disease and mild cognitive impairment: the impact of quantitative magnetization transfer MR imaging.

Multi-parametric and quantitative magnetic resonance imaging (MRI) techniques have come into the focus of interest, both as a research and diagnostic modality for the evaluation of patients suffering from mild cognitive decline and overt dementia. In this study we address the question, if disease related quantitative magnetization transfer effects (qMT) within the intra- and extracellular matrices of the hippocampus may aid in the differentiation between clinically diagnosed patients with Alzheimer disease (AD), patients with mild cognitive impairment (MCI) and healthy controls. We evaluated 22 patients with AD (n=12) and MCI (n=10) and 22 healthy elderly (n=12) and younger (n=10) controls with multi-parametric MRI. Neuropsychological testing was performed in patients and elderly controls (n=34). In order to quantify the qMT effects, the absorption spectrum was sampled at relevant off-resonance frequencies. The qMT-parameters were calculated according to a two-pool spin-bath model including the T1- and T2 relaxation parameters of the free pool, determined in separate experiments. Histograms (fixed bin-size) of the normalized qMT-parameter values (z-scores) within the anterior and posterior hippocampus (hippocampal head and body) were subjected to a fuzzy-c-means classification algorithm with downstreamed PCA projection. The within-cluster sums of point-to-centroid distances were used to examine the effects of qMT- and diffusion anisotropy parameters on the discrimination of healthy volunteers, patients with Alzheimer and MCIs. The qMT-parameters T2(r) (T2 of the restricted pool) and F (fractional pool size) differentiated between the three groups (control, MCI and AD) in the anterior hippocampus. In our cohort, the MT ratio, as proposed in previous reports, did not differentiate between MCI and AD or healthy controls and MCI, but between healthy controls and AD.

Neural correlates of pre-attentive processing of pattern deviance in professional musicians.

Pre-attentive registration of aberrations in predictable sound patterns is attributed to the temporal cortex. However, electrophysiology suggests that frontal areas become more important when deviance complexity increases. To play an instrument in an ensemble, professional musicians have to rely on the ability to detect even slight deviances from expected musical patterns and therefore have highly trained aural skills. Here, we aimed to identify the neural correlates of experience-driven plasticity related to the processing of complex sound features. We used functional magnetic resonance imaging in combination with an event-related oddball paradigm and compared brain activity in professional musicians and non-musicians during pre-attentive processing of melodic contour variations. The melodic pattern consisted of a sequence of five tones each lasting 50 ms interrupted by silent interstimulus intervals of 50 ms. Compared to non-musicians, the professional musicians showed enhanced activity in the left middle and superior temporal gyri, the left inferior frontal gyrus and in the right ventromedial prefrontal cortex in response to pattern deviation. This differential brain activity pattern was correlated with behaviorally tested musical aptitude. Our results thus support an experience-related role of the left temporal cortex in fast melodic contour processing and suggest involvement of the prefrontal cortex.

Subclinical hallucinations in adolescent outpatients: an outcome study.

OBJECTIVE: We assessed the continued prevalence at one year and association with clinical variables of subclinical hallucinations ascertained at baseline in a cohort of adolescent outpatients referred to a specialized early psychosis service. We further assessed the prevalence of psychiatric disorders in adolescents presenting subclinical hallucinations. METHOD: 84 adolescent patients were sampled from a longitudinal, prospective study that assesses the course of clinical and neuropsychological measures in patients identified as at high clinical risk for psychosis. Subclinical hallucinations were measured using the Scale of Prodromal Symptoms (SOPS) with its companion interview manual (Structured Interview for Prodromal Symptoms, SIPS) [Miller, T.J., McGlashan, T.H., Woods, S.W., Stein, K., Driesen, N., Corcoran, C.M., Hoffman, R., Davidson, L., 1999. Symptom assessment in schizophrenic prodromal states. Psychiatr. Q. 70, 273-287; McGlashan, T.H., Miller, T.J., Woods, S.W., Rosen, J.L., Hoffman, R.E., Davidson, L., 2001. Structured Interview for Prodromal Syndromes (Version 3.0, unpublished manuscript). PRIME Research Clinic, Yale School of Medicine New Haven, Connecticut. ], and the Schizophrenia Proneness Instrument -Adult Version (SPI-A) [Schultze-Lutter, F., Addington, J., Ruhrmann, S., Klosterkötter, J., 2007. Schizophrenia Proneness Instrument (SPI-A). Giovanni Fioriti, Rome, Italy]. At one-year follow-up, only patients reporting subclinical hallucinations at initial assessment were studied. RESULTS: Full remission of subclinical hallucinations occurred in over half and at least partial remission in two thirds of these patients at one-year follow-up. Mood disorders were present in 62.5% of adolescents with subclinical hallucinations at initial assessment. SOPS measures for depression, deficient attention and for unusual/delusional thought were significantly associated with subclinical hallucinations at baseline. However, sustained experience of subclinical hallucinations at one-year follow-up was only predicted by the global level of functioning at baseline, while cannabis abuse, psychiatric and psychopharmacological treatment were not predictors. CONCLUSIONS: Subclinical hallucinations occur across a wide range of mental states in adolescents and show high rates of remission. Our results warrant that the clinical meaning of such phenomena needs to be carefully weighed against the specific developmental phenomena in this particular age range.

Interference during the implicit learning of two different motor sequences.

It has been demonstrated that learning a second motor task after having learned a first task may interfere with the long-term consolidation of the first task. However, little is known about immediate changes in the representation of the motor memory in the early acquisition phase within the first minutes of the learning process. Therefore, we investigated such early interference effects with an implicit serial reaction time task in 55 healthy subjects. Each subject performed either a sequence learning task involving two different sequences, or a random control task. The results showed that learning the first sequence led to only a slight, short-lived interference effect in the early acquisition phase of the second sequence. Overall, learning of neither sequence was impaired. Furthermore, the two processes, sequence-unrelated task learning (i.e. general motor training) and the sequence learning itself did not appear to interfere with each other. In conclusion, although the long-term consolidation of a motor memory has been shown to be sensitive to other interfering memories, the present study suggests that the brain is initially able to acquire more than one new motor sequence within a short space of time without significant interference.

[Antipsychotics]. / Antipsychotika.

Antipsychotics are classified in two groups, the first generation (conventional, typical) and the second generation (modern, atypical). In the treatment of schizophrenia and psychoses antipsychotics of the second generation are the preferred choice due to their effectiveness and side effects profile. First and second generation antipsychotics are commonly used to treat acute mania. Moreover, second generation antipsychotics are used in the maintenance-treatment of bipolar disorder. Several second generation antipsychotics have been shown to be effective in the treatment of acute bipolar depression and as an augmentation-strategy in combination with an antidepressant in the treatment of unipolar depression. In clinical practice there is a big off-label use of antipsychotics, for example in the treatment of personality disorders. In addition to the oral dosage form, there exist two parenteral dosage forms of antipsychotics: quick-acting and long-acting injections. The side effects profile for first generation antipsychotics is characterized by extrapyramidal-motoric side effects. Second generation antipsychotics are, with respect to their effectiveness and side effects, very heterogeneous. Some substances present in the second generation grouping can lead to, in particular, an increased risk for weight gain and metabolic syndrome.

Deficient associative learning in drug-naive first-episode schizophrenia: results obtained using a new visual within-subjects learned irrelevance paradigm.

One of the key features of schizophrenia is the inability to filter out irrelevant stimuli which consequently leads to stimulus overload. There are different methods which aim at investigating these deficient filter mechanisms; one of these is the learned irrelevance (LIrr) paradigm. LIrr refers to the retardation of associative learning that occurs if the conditioned stimulus (CS) and the unconditioned stimulus (US) are preexposed in an explicitly unpaired manner prior to the establishment of the association between the stimuli. In the present study we used a recently developed computerized within-subject visual LIrr test. We measured 11 drug-naive first-episode schizophrenia patients and compared their performance to that of 17 healthy control subjects. LIrr was observed to be intact in normal individuals but disrupted in drug-naive first-episode schizophrenia patients. After one month elapsed, 5 of the 11 patients and 16 of the 17 control subjects were retested in a follow-up study. By this time, patients had been medicated with antipsychotic drugs for at least 3 weeks. While healthy controls exhibited a robust LIrr effect, patients still failed to show LIrr. Correlations were found between the performance of unmedicated patients and the depression component of the PANSS psychopathology scale.

Decision-making dysregulation in first-episode schizophrenia.

Studies with chronic schizophrenia patients have demonstrated that patients fluctuate between rigid and unpredictable responses in decision-making situations, a phenomenon which has been called dysregulation. The aim of this study was to investigate whether schizophrenia patients already display dysregulated behavior at the beginning of their illness. Thirty-two first-episode schizophrenia or schizophreniform patients and 30 healthy controls performed the two-choice prediction task. The decision-making behavior of first-episode patients was shown to be characterized by a high degree of dysregulation accompanied by low metric entropy and a tendency towards increased mutual information. These results indicate that behavioral abnormalities during the two-choice prediction task are already present during the early stages of the illness.

Beliefs about the mentally ill: a comparative study between healthcare professionals in Brazil and in Switzerland.

OBJECTIVE: Little is known in our own as well as in other cultures about the knowledge and prejudices mental health professionals have about mental illness and those affected. We therefore: 1) assessed mental health literacy and general attitudes towards people with mental illness in a sample of Brazilian mental health professionals; 2) compared the outcomes among the different professional groups; and 3) compared the data with a sample of Swiss mental health professionals. METHODS: A questionnaire used to assess knowledge and attitudes towards the mentally ill among mental health professionals in Switzerland was translated into Portuguese. Mental health professionals were presented a case vignette describing a person suffering from a major depression as well as related treatment proposals. Furthermore, general attitudes towards people with mental illness were assessed. RESULTS: Both samples had equal scores for social acceptance. Brazilian mental health professionals displayed a more positive attitude towards community psychiatry whereas the Swiss sample showed more stigmatization and social distance, and a more positive attitude towards psychopharmacology. Recognition of the case vignette was significantly better in Brazil than in Switzerland (94.7% versus 71%). Mental health professionals in Brazil were more conservative/medically orientated in their treatment propositions whereas professionals from Switzerland also proposed social interventions and alternative treatment strategies. CONCLUSIONS: There are some major differences in attitudes towards people with mental illness between mental health professionals in Switzerland and Brazil. With respect to therapeutic interventions, the different healthcare systems as well as the cultural differences seem to have an impact.

Repeated measurements of learned irrelevance by a novel within-subject paradigm in humans.

Learned irrelevance (LIrr) refers to the retardation of classical conditioning following preexposure of the to-be-associated stimuli. Healthy volunteers have been tested on three occasions with a new LIrr paradigm avoiding methodological problems which afflict traditional paradigms. A significant LIrr effect was demonstrated on each occasion. Thus, the new paradigm enables repeated measurements of LIrr and might be useful in evaluating long-term effects of medication in psychiatric disorders exhibiting aberrant LIrr.

Cognitive functioning in the schizophrenia prodrome.

In the last decade, there has been an increasing interest in cognitive alterations during the early course of schizophrenia. From a clinical perspective, a better understanding of cognitive functioning in putative at-risk states for schizophrenia is essential for developing optimal early intervention models. Two approaches have more recently been combined to assess the entire course of the initial schizophrenia prodrome: the predictive "basic symptom at-risk" (BS) and the ultra high-risk (UHR) criteria. Basic symptoms are considered to be present during the entire disease progression, including the initial prodrome, while the onset of symptoms captured by the UHR criteria expresses further disease progression toward frank psychosis. The present study investigated the cognitive functioning in 93 subjects who met either BS or UHR criteria and thus were assumed to be at different points on the putative trajectory to psychosis. We compared them with 43 patients with a first episode of psychosis and to 49 help-seeking patient controls. All groups performed significantly below normative values. Both at-risk groups performed at intermediate levels between the first-episode (FE) group and normative values. The UHR group demonstrated intermediate performance between the FE and BS groups. Overall, auditory working memory, verbal fluency/processing speed, and declarative verbal memory were impaired the most. Our results suggest that cognitive impairments may still be modest in the early stages of the initial schizophrenia prodrome and thus support current efforts to intervene in the early course of impending schizophrenia because early intervention may prevent or delay the onset of frank psychosis and thus prevent further cognitive damage.

Help-seeking pathways in early psychosis.

INTRODUCTION: Understanding the help-seeking pathways of patients with a putative risk of developing psychosis helps improving development of specialised care services. This study aimed at obtaining information about: type of health professionals contacted by patients at putative risk for psychosis on their help-seeking pathways; number of contacts; type of symptoms leading to contacts with health professionals; interval between initial contact and referral to a specialised outpatient service. METHOD: The help-seeking pathways were assessed as part of a prospective study in 104 patients with suspected at-risk states for psychosis. RESULTS: The mean number of contacts prior to referral was 2.38. Patients with psychotic symptoms more often contacted mental health professionals, whereas patients with insidious and more unspecific features more frequently contacted general practitioners (GPs). CONCLUSIONS: GPs have been found to under-identify the insidious features of emerging psychosis (Simon et al. (2005) Br J Psychiatry 187:274-281). The fact that they were most often contacted by patients with exactly these features calls for focussed and specialised help for primary care physicians. Thus, delays along the help-seeking pathways may be shortened. This may be of particular relevance for patients with the deficit syndrome of schizophrenia.

Effect of oral donepezil on intraocular pressure in normotensive Alzheimer patients.

Donepezil, a selective acetylcholinesterase (AChE) inhibitor, has been shown to reduce intraocular pressure (IOP) in ocular normotensive rabbit eyes. The aim of this investigation was to evaluate the effect of oral donepezil on IOP and pupil diameter after mid-term oral treatment in normotensive persons. Thirty-two newly diagnosed Alzheimer patients with normal IOP and no further antiglaucomatous treatment were included in the study. IOP and pupil diameter were evaluated before and 4 weeks after daily intake of 5 mg donepezil. IOP and pupil diameter were significantly lower/smaller after 4 weeks of treatment. The mean IOP of all 63 eyes was 14.1 mmHg before and 12.8 mmHg after treatment (8.8% reduction). Mean pupil diameter constricted from 3.9 to 3.6 mm (-7.4%). These findings show that donepezil, and, possibly, other selective AChE inhibitors, can potentially be used to treat glaucoma. They are also known to have neuroprotective effects in Alzheimer's, and, therefore, might have an additional therapeutic benefit.