Improving treatments for psychotic disorders: beyond cognitive behaviour therapy for psychosis.

More effective treatments for people with psychotic disorders are urgently required. Here, we make three suggestions for progress: 1. Targeting the disorders' core phenomenological features ('phenomenological phenotype'), 2. Addressing social disconnection, isolation and loneliness, and 3. Leveraging 'hot' cognitions and using symptom capture approaches that combine psychotherapy with advances in technology and neuroscience.

The neurophenomenology of early psychosis: An integrative empirical study.

BACKGROUND: The integration of various domains or levels of analysis (clinical, neurobiological, genetic, etc.) has been a challenge in schizophrenia research. A promising approach is to use the core phenomenological features of the disorder as an organising principle for other levels of analysis. Minimal self-disturbance (fragility in implicit first-person perspective, presence and agency) is emerging as a strong candidate to play this role. This approach was adopted in a previously described theoretical neurophenomenological model that proposed that source monitoring deficits and aberrant salience may be neurocognitive/neurobiological processes that correlate with minimal self-disturbance on the phenomenological level, together playing an aetiological role in the onset of schizophrenia spectrum disorders. The current paper presents full cross-sectional data from the first empirical test of this model. METHODS: Fifty ultra-high risk for psychosis patients, 39 first episode psychosis patients and 34 healthy controls were assessed with a variety of clinical measures, including the Examination of Anomalous Self-Experience (EASE), and neurocognitive and neurophysiological (EEG) measures of source monitoring deficits and aberrant salience. RESULTS: Linear regression indicated that source monitoring (composite score across neurocognitive and neurophysiological measures), with study group as an interaction term, explained 39.8% of the variance in EASE scores (R2 = 0.41, F(3,85) = 14.78, p < 0.001), whereas aberrant salience (composite score) explained only 6% of the variance in EASE scores (R2 = 0.06, F(3,85) = 1.44, p = 0.93). Aberrant salience measures were more strongly related to general psychopathology measures, particularly to positive psychotic symptoms, than to EASE scores. DISCUSSION: A neurophenomenological model of minimal self-disturbance in schizophrenia spectrum disorders may need to be expanded from source monitoring deficits to encompass other relevant constructs such as temporal processing, intermodal/multisensory integration, and hierarchical predictive processing. The cross-sectional data reported here will be expanded with longitudinal analysis in subsequent reports. These data and other related recent research show an emerging picture of neuro-features of core phenomenological aspects of schizophrenia spectrum disorders beyond surface-level psychotic symptoms.

Catchment properties and the photosynthetic trait composition of freshwater plant communities.

Unlike in land plants, photosynthesis in many aquatic plants relies on bicarbonate in addition to carbon dioxide (CO2) to compensate for the low diffusivity and potential depletion of CO2 in water. Concentrations of bicarbonate and CO2 vary greatly with catchment geology. In this study, we investigate whether there is a link between these concentrations and the frequency of freshwater plants possessing the bicarbonate use trait. We show, globally, that the frequency of plant species with this trait increases with bicarbonate concentration. Regionally, however, the frequency of bicarbonate use is reduced at sites where the CO2 concentration is substantially above the air equilibrium, consistent with this trait being an adaptation to carbon limitation. Future anthropogenic changes of bicarbonate and CO2 concentrations may alter the species compositions of freshwater plant communities.

Fever in pregnancy and the risk of congenital malformations: a cohort study.

BACKGROUND: In a variety of animal species, hyperthermia in pregnancy has been recognized as teratogenic. Hyperthermia interferes with protein synthesis via heat-shock proteins, which can entail membrane disruption, cell death, vascular disruption, and placental infarction. This can induce severe fetal malformations or death. Fever during pregnancy, especially during embryogenesis, has also been associated with congenital malformations in human offspring. The purpose of this large cohort study of clinically recognized pregnancies was to investigate whether fever during first trimester was associated with an increased risk of congenital malformations in the offspring. METHODS: The Danish National Birth Cohort is a population-based cohort of 100,418 pregnant women and their offspring recruited in 1996 to 2002. Information on fever during pregnancy was collected prospectively by means of two telephone interviews. The study population comprised the 77,344 pregnancies enrolled in the Danish National Birth Cohort where self-reported information on fever during first trimester of pregnancy was available. Pregnancy outcomes were identified through linkage with the National Patient Registry. Congenital malformations within the first three and a half years of life were categorized according to EUROCAT's classification criteria. Logistic regression models were used to estimate the associations between fever in first trimester and overall congenital malformations and congenital malformations by subgroups. RESULTS: Eight thousand three hundred twenty-one women reported fever during first trimester (10.8%) and 2876 infants were diagnosed with a congenital malformation (3.7%). Fever during first trimester did not affect the risk of overall fetal congenital malformation (OR 0.99, 95% CI 0.88-1.12). The subgroup analyses indicated slightly higher risk of congenital anomalies in the eye, ear, face and neck (OR 1.29, 95% CI 0.78-2.12) and in the genitals (OR 1.17, 95% CI 0.79-1.12), whereas lower risk of malformations in the nervous system (OR 0.47, 95% CI 0.21-1.08), the respiratory system (OR 0.56, 95% CI 0.23-1.29) and in the urinary subgroup (OR 0.58, 95% CI 0.35-0.99) was suggested, the latter constituting the only statistically significant finding. CONCLUSIONS: Overall, this study did not show any association between maternal fever in pregnancy and risk of congenital anomalies.

What are the neurocognitive correlates of basic self-disturbance in schizophrenia?: Integrating phenomenology and neurocognition. Part 1 (Source monitoring deficits).

Phenomenological research indicates that disturbance of the basic sense of self may be a core phenotypic marker of schizophrenia spectrum disorders. Basic self-disturbance refers to disruption of the sense of ownership of experience and agency of action and is associated with a variety of anomalous subjective experiences. Little is known about the neurocognitive underpinnings of basic self-disturbance. In these two theoretical papers (of which this is Part 1), we review some recent phenomenological and neurocognitive research and point to a convergence of these approaches around the concept of self-disturbance. Specifically, we propose that subjective anomalies associated with basic self-disturbance may be associated with: 1. source monitoring deficits, which may contribute particularly to disturbances of "ownership" and "mineness" (the phenomenological notion of presence or self-affection) and 2. aberrant salience, and associated disturbances of memory, prediction and attention processes, which may contribute to hyper-reflexivity, disturbed "grip" or "hold" on the perceptual and conceptual field, and disturbances of intuitive social understanding ("common sense"). In this paper (Part 1) we focus on source monitoring deficits. Part 2 (this issue) addresses aberrant salience. Empirical studies are required in a variety of populations in order to test these proposed associations between phenomenological and neurocognitive aspects of self-disturbance in schizophrenia. An integration of findings across the phenomenological and neurocognitive "levels" would represent a significant advance in the understanding of schizophrenia and possibly enhance early identification and intervention strategies.

What are the neurocognitive correlates of basic self-disturbance in schizophrenia? Integrating phenomenology and neurocognition: Part 2 (aberrant salience).

Phenomenological research indicates that disturbance of the basic sense of self may be a core phenotypic marker of schizophrenia spectrum disorders. Basic self-disturbance refers to disruption of the sense of ownership of experience and agency of action and is associated with a variety of anomalous subjective experiences. Little is known about the neurocognitive underpinnings of basic self-disturbance. In these two theoretical papers (of which this is Part 2), we review some recent phenomenological and neurocognitive research and point to a convergence of these approaches around the concept of self-disturbance. Specifically, we propose that subjective anomalies associated with basic self-disturbance may be associated with: 1. source monitoring deficits, which may contribute particularly to disturbances of "ownership" and "mineness" (the phenomenological notion of presence or self-affection) and 2. aberrant salience, and associated disturbances of memory, prediction and attention processes, which may contribute to hyper-reflexivity, disturbed "grip" or "hold" on perceptual and conceptual fields, and disturbances of intuitive social understanding ("common sense"). In this paper (Part 2) we focus on aberrant salience. Part 1 (this issue) addressed source monitoring deficits. Empirical studies are required in a variety of populations in order to test these proposed associations between phenomenological and neurocognitive aspects of self-disturbance in schizophrenia. An integration of findings across the phenomenological and neurocognitive "levels" would represent a significant advance in the understanding of schizophrenia and possibly enhance early identification and intervention strategies.

Cognitive-behavioral therapy for schizophrenia: a critical evaluation of its theoretical framework from a clinical-phenomenological perspective.

BACKGROUND: Cognitive-behavioral therapy (CBT) has played an increasingly important role in psychotherapy for schizophrenia since the 1990s, but it has also encountered many theoretical and practical limitations. For example, methodologically rigorous meta-analyses have recently found only modest overall effect sizes of CBT treatment, and therefore questions have emerged about forwhat and for whom it actually works. METHOD: The focus of the present paper is to elucidate the theoretical assumptions underlying CBT for schizophrenia and to examine their consistency with abnormalities of experience and self-awareness frequently reported by schizophrenia patients and systematically studied in phenomenological psychopathology from the beginning of the 20th century. RESULTS: We argue that a strong theoretical emphasis on cognitive appraisals with only subsidiary attention devoted to affective and behavioral processes - as is characteristic of many forms of CBT - cannot satisfactorily account for the complex subjective experiences of schizophrenia patients. We further argue that certain theoretical strategies widely employed in CBT to explore and explain mental disorders, which involve atomization and, at times, a reification of mental phenomena, can be problematic and may result in a loss of explanatory potential. Finally, we provide a detailed account of how negative symptoms and delusions are conceptualized in CBT and consider the question of how these concepts fit the actual phenomenology of schizophrenia. CONCLUSION: We suggest that further advancement of CBT theory and practice can benefit from a dialogue with phenomenological psychiatry in the search for effective psychotherapeutic strategies for schizophrenia patients.

What is bizarre in bizarre delusions? A critical review.

Diagnostic and Statistical Manual of Mental Disorder, Fourth Edition (DSM-IV) treats the presence of bizarre delusions (BD) as the heaviest-weighted clinical criterion of schizophrenia. Although BD play a major role in contemporary diagnostic systems, only a few empirical studies explore this issue. These studies provide highly heterogenous results because they are based on different experimental paradigms, in terms of definition, clinical sample, and number of raters. Here, we first discuss the psychopathological sources of the concept of BD, which were initially described as either nonsensical or incomprehensible. Then, we provide a critical review of contemporary studies on the reliability of BD and their methodological and conceptual limitations. Current approaches have focused intensely on BD's reliability and have defined BD strictly in terms of delusional content--mainly in terms of the physical impossibility or the cultural or historical incomprehensibility of the delusional claims. These approaches have neglected formal features of experience that underlie BD and the crucial issue of the nature and validity of BD. In the discussion, we argue that clinical diagnosis of BD cannot be limited to delusional contents alone and requires taking into account the subjective side of BD (how altered experience manifests itself) as well as the conditions of intersubjective encounter (how BD are expressed to and experienced by the clinician). The notion of "bizarreness" in schizophrenia is not purely theoretical; it has practical relevance for the therapeutic encounter and implications on further empirical research and on diagnostic approaches.

A disturbed sense of self in the psychosis prodrome: linking phenomenology and neurobiology.

Interest in the early phase of psychotic disorders has risen dramatically in recent years. Neurobiological investigations have focused specifically on identifying brain changes associated with the onset of psychosis. The link between these neurobiological findings and the complex phenomenology of the early psychosis period is not well understood. In this article, we re-cast some of these observations, primarily from neuroimaging studies, in the context of phenomenological models of "the self" and disturbance thereof in psychotic illness. Specifically, we argue that disturbance of the basic or minimal self ("ipseity"), as articulated in phenomenological literature, may be associated with abnormalities in midline cortical structures as observed in neuroimaging studies of pre-onset and early psychotic patients. These findings are discussed with regards to current ideas on the neural basis of self-referential mental activity, including the notion of a putative "default-mode" of brain function, and its relation to distinguishing between self- and other-generated stimuli. Further empirical work examining the relationship between neurobiological and phenomenological variables may be of value in identifying risk markers for psychosis onset.

Anhedonia, self-experience in schizophrenia, and implications for treatment.

Anhedonia - the inability to experience pleasure - is a symptom of several psychiatric disorders such as depression, drug and alcohol dependence, but also schizophrenia. The concept of anhedonia played a major role in psychiatric and psychoanalytic explanations of psychotic behavior. The relationship between notions of anhedonia and of mental evolution and regression (in the work of Myerson and Bleuler) is discussed. The non-evolutionist views of Rado and Meehl are described. Then the concept of anhedonia is discussed in relationship to the phenomenological approach of Sass and Parnas, who view anhedonia as one manifestation of a self-disturbance or self-disorder that is fundamental in schizophrenia. Concerning treatment of anhedonia, it was often hypothesized that anhedonia is associated with a dysfunction of the mesolimbic dopaminergic reward system. However, studies in humans and non-human animal models indicate that dysfunction of central dopaminergic neurotransmission interferes with the process of motivation rather than with the ability to experience pleasure; the latter may be more mediated by the opioidergic and serotonergic neurotransmission. Understanding the neurobiological correlates of motivation and pleasure may provide new options to treat anhedonia in patients with schizophrenia.

A novel aldose/aldehyde reductase protects transgenic plants against lipid peroxidation under chemical and drought stresses.

Rapid accumulation of toxic products from reactions of reactive oxygen species (ROS) with lipids and proteins significantly contributes to the damage of crop plants under biotic and abiotic stresses. Here we have identified a stress-activated alfalfa gene encoding a novel plant NADPH-dependent aldose/aldehyde reductase that also exhibited characteristics of the homologous human enzyme. The recombinant alfalfa enzyme is active on 4-hydroxynon-2-enal, a known cytotoxic lipid peroxide degradation product. Ectopic synthesis of this enzyme in transgenic tobacco plants provided considerable tolerance against oxidative damage caused by paraquat and heavy metal treatment. These transformants could also resist a long period of water deficiency and exhibited improved recovery after rehydration. We found a reduced production of lipid peroxidation-derived reactive aldehydes in these transformed plants under different stresses. These studies reveal a new and efficient detoxification pathway in plants.

Nuclear localization of a hypoxia-inducible novel non-symbiotic hemoglobin in cultured alfalfa cells.

We have isolated a 483-bp-long full-length cDNA clone encoding a non-symbiotic hemoglobin called Mhb1, the first one found in alfalfa. This non-symbiotic hemoglobin is a single copy gene localized in linkage group 4 in diploid Medicago genome. The Mhb1 mRNA was found only in the roots of alfalfa plants. The Mhb1 gene was inducible by hypoxia and showed no induction by cold stress treatment. The Mhb1 transcript level increased at the G2/M boundary in a synchronized alfalfa cell suspension culture. The majority of Mhb1 protein was shown to be localized in the nucleus and smaller amounts were detected in the cytoplasm. A potential link to the nitric oxide signalling pathway is also discussed.

Plants ectopically expressing the iron-binding protein, ferritin, are tolerant to oxidative damage and pathogens.

Transgenic tobacco plants that synthesize alfalfa ferritin in vegetative tissues--either in its processed form in chloroplasts or in the cytoplasmic nonprocessed form--retained photosynthetic function upon free radical toxicity generated by iron excess or paraquat treatment. Progeny of transgenic plants accumulating ferritin in their leaves exhibited tolerance to necrotic damage caused by viral (tobacco necrosis virus) and fungal (Alternaria alternata, Botrytis cinerea) infections. These transformants exhibited normal photosynthetic function and chlorophyll content under greenhouse conditions. We propose that by sequestering intracellular iron involved in generation of the very reactive hydroxyl radicals through a Fenton reaction, ferritin protects plant cells from oxidative damage induced by a wide range of stresses.

UV-B-induced differential transcription of psbA genes encoding the D1 protein of photosystem II in the Cyanobacterium synechocystis 6803.

UV-B irradiation of intact Synechocystis sp. PCC 6803 cells results in the loss of photosystem II activity, which can be repaired via de novo synthesis of the D1 (and D2) reaction center subunits. In this study, we investigated the effect of UV-B irradiation on the transcription of the psbA2 and psbA3 genes encoding identical D1 proteins. We show that UV-B irradiation increases the level of psbA2 mRNA 2-3-fold and, more dramatically, it induces a 20-30-fold increase in the accumulation of the psbA3 mRNA even at levels of irradiation too low to produce losses of either photosystem II activity or D1 protein. The induction of psbA3 transcript accumulation is specific for UV-B light (290-330 nm). Low intensity UV-A emission (330-390 nm) and white light induce only a small, at most, 2-3-fold enhancement, whereas no effect of blue light was observed. Expression patterns of chimeric genes containing the promoter regions of the psbA2, psbA3 genes fused to the firefly luciferase (luc) reporter gene indicate that (i) transcription of psbA2/luc and psbA3/luc transgenes was elevated, similarly to that of the endogenous psbA genes, by UV-B irradiation, and that (ii) a short, 80-base pair psbA3 promoter fragment is sufficient to maintain UV-B-induced transcription of the luc reporter gene. Furthermore, our findings indicate that UV-B-induced expression of the psbA2 and psbA3 genes is a defense response against UV-B stress, which is regulated, at least, partially at the level of transcription and does not require active electron transport.

UV-B-induced inhibition of photosystem II electron transport studied by EPR and chlorophyll fluorescence. Impairment of donor and acceptor side components.

Inhibition of photosystem II electron transport by UV-B radiation has been studied in isolated spinach photosystem II membrane particles using low-temperature EPR spectroscopy and chlorophyll fluorescence measurements. UV-B irradiation results in the rapid inhibition of oxygen evolution and the decline of variable chlorophyll fluorescence. These effects are accompanied by the loss of the multiline EPR signal arising from the S2 state of the water-oxidizing complex and the induction of Signal IIfast originating from stabilized Try-Z+. The EPR signals from the QA-Fe2+ acceptor complex, Tyr-D+, and the oxidized non-heme iron (Fe3+) are also decreased during the course of UV-B irradiation, but at a significantly slower rate than oxygen evolution and the multiline signal. The decrease of the Fe3+ signal at high g values (g = 8.06, g = 5.6) is accompanied by the induction of another EPR signal at g = 4.26 that arises most likely from the same Fe3+ ion in a modified ligand environment. UV-B irradiation also affects cytochrome b-559. The g = 2.94 EPR signal that arises from the dark- oxidized form is enhanced, whereas the light inducible g = 3.04 signal that arises from the photo-oxidizable population of cytochrome b-559 is diminished. UV-B irradiation also induces the degradation of the D1 reaction center protein. The rate of the D1 protein loss is slower than the inhibition of oxygen evolution and of the multiline signal but follows closely the loss of Signal IIslow, the QA-Fe2+ and the Fe3+ EPR signals, as well as the release of protein-bound manganese. It is concluded from the results that UV-B radiation affects photosystem II redox components at both the donor and acceptor side. The primary damage occurs at the water-oxidizing complex. Modification and/or inactivation of tyrosine-D, cytochrome b-559, and the QAFe2+ acceptor complex are subsequent events that coincide more closely with the UV-B-induced damage to the protein structure of the photosystem II reaction center.

Thermoluminescence studies on the function of Photosystem II in the desiccation tolerant lichen Cladonia convoluta.

The effect of desiccation and rehydration on the function of Photosystem II has been studied in the desiccation tolerant lichen Cladonia convoluta by thermoluminescence. We have shown that in functional fully hydrated thalli thermoluminescence signals can be observed from the recombination of the S2(3)QB (-) (B band), S2QA (-) (Q band), Tyr-D(+)QA (-) (C band) and Tyr-Z(+)(His(+))QA (-) (A band) charge stabilization states. These thermoluminescence signals are completely absent in desiccated thalli, but rapidly reappear on rehydration. Flash-induced oscillation in the amplitude of the thermoluminescence band from the S2(3)QB (-) recombination shows the usual pattern with maxima after 2 and 6 flashes when rehydration takes place in light. However, after rehydration in complete darkness, there is no thermoluminescence emission after the 1 st flash, and the maxima of the subsequent oscillation are shifted to the 3rd and 7th flashes. It is concluded that desiccation of Cladonia convoluta converts PS II into a nonfunctional state. This state is characterized by the lack of stable charge separation and recombination, as well as by a one-electron reduction of the water-oxidizing complex. Restoration of PS II function during rehydration can proceed both in the light and in darkness. After rehydration in the dark, the first charge separation act is utilized in restoring the usual oxidation state of the water-oxidizing comples.