The negative impact of vitamin D on antipsychotic drug exposure may counteract its potential benefits in schizophrenia.

AIMS: Patients with schizophrenia frequently show insufficient vitamin D levels, which are associated with somatic comorbidity and may contribute to psychopathology. For many reasons, vitamin D supplementation may be indicated for this patient cohort. However, there is growing evidence for a vitamin D-mediated increase of drug metabolism by induction of cytochrome P450 (CYP) 3A4. Hence, this study aimed to assess vitamin D's impact on both antipsychotic drug concentrations and psychopathology in a non-interventional manner. METHODS: Totals of 107 serum concentrations of different antipsychotic drugs (amisulpride, aripiprazole, clozapine, olanzapine, quetiapine and risperidone), 80 serum concentrations of vitamin D and psychopathological assessments were obtained from 80 patients with schizophrenia. The impact of Vitamin D on antipsychotic drug concentrations and symptomatology was assessed using a generalized linear model, path and correlation analyses. RESULTS: We observed a negative relationship between vitamin D and dose-adjusted antipsychotic drug concentrations, which was particularly pronounced for drugs which are predominantly metabolized via CYP3A4 (i.e., aripiprazole and quetiapine). A path analysis suggested a relieving effect of vitamin D on symptomatology which was, however, counteracted by its negative impact on antipsychotic drug levels. Finally, patients with vitamin D levels above the median exhibited a significantly higher proportion of therapeutically insufficient dose-normalized drug concentrations of aripiprazole and quetiapine. CONCLUSION: Despite vitamin D's potential benefits on physical and mental health, clinicians should be aware of its negative impact on blood concentrations of antipsychotics metabolized by CYP3A4 in patients with schizophrenia. Therefore, when considering its supplementation, therapeutic drug monitoring should be applied to guide dose adjustment.

Feasibility of interstitial stepping-source electronic brachytherapy to locally inoperable tumors.

PURPOSE: Radiotherapy is the mainstay in the treatment of locally inoperable tumors. Interstitial electronic needle-based kilovoltage brachytherapy (EBT) could be an economic alternative to high-dose-rate (HDR) brachytherapy or permanent seed implantation (PSI). In this work, we evaluated if locally inoperable tumors treated with PSI at our institution may be suitable for EBT. MATERIAL AND METHODS: A total of 10 post-interventional computed tomography (CT) scans of patients, who received PSI and simulated stepping-source EBT applied with Intrabeam system and needle applicator were used. EBT treatment planning software with 3-dimensional image and projection of applicator were applied for designing trajectories and establishing dwell positions. Dwell position doses were summarized, and doses covering 90% of the target volume (D90) achieved with stepping-source EBT were compared to those of PSI. Additionally, conformality of dose distributions and total irradiation time were assessed using conformation number (CN) or conformal index (COIN). RESULTS: In all patients, D90 of EBT exceeded the prescribed dose or D90 of PSI on average by 4.7% or 21.3% relative to the prescribed dose, respectively. Mean number of trajectories was 5.0 for EBT and 6.9 for PSI. Average CN/COIN for EBT was 0.69, with a mean irradiation time of 27.8 minutes for standardized dose of 13 Gy. CONCLUSIONS: Stepping-source EBT allowed for a conformal treatment of inoperable interstitial tumors with similar D90. Fewer trajectories were required for EBT in majority of cases.

Neurofeedback of core language network nodes modulates connectivity with the default-mode network: A double-blind fMRI neurofeedback study on auditory verbal hallucinations.

BACKGROUND: The experience of auditory verbal hallucinations in schizophrenia is associated with changes in brain network function. In particular, studies indicate altered functional coupling between nodes of the language and default mode networks. Neurofeedback based on real-time functional magnetic resonance imaging (rtfMRI) can be used to modulate such aberrant network connectivity. METHODS: We investigated resting-state connectivity changes after neurofeedback (NF) in 21 patients with schizophrenia and 35 healthy individuals. All participants underwent two days of neurofeedback training of important nodes of the left-hemispheric language network including the inferior frontal gyrus (IFG) and posterior superior temporal gyrus (pSTG). In a double-blind randomized cross-over design, participants learned to down- and up-regulate their brain activation in the designated target regions based on NF. Prior to and after each training day, a resting state measurement took place. RESULTS: Coupling between nodes of the language and the default mode network (DMN) selectively increased after down-as compared to up-regulation NF. Network analyses revealed more pronounced increases in functional connectivity between nodes of the language network and the DMN in patients compared to healthy individuals. In particular, down-regulation NF led to increased coupling between nodes of the language network and bilateral inferior parietal lobe (IPL) as well as posterior cingulate cortex (PCC)/precuneus in patients. Up-regulation strengthened connectivity with the medial prefrontal cortex (mPFC). Improved well-being four weeks after the training predicted increased functional coupling between the left IFG and left IPL. CONCLUSION: Modulatory effects emerged as increased internetwork communication, indicating that down-regulation NF selectively enhances coupling between language and DM network nodes in patients with AVH. RtfMRI NF may thus be used to modulate brain network function that is relevant to the phenomenology of AVH. Specific effects of self-regulation on symptom improvement have to be explored in therapeutic interventions.

Don't worry, be happy - Neural correlates of the influence of musically induced mood on self-evaluation.

Self-evaluation affects one's own mental state, social interactions and everyday life. Mood, in turn, has an impact on self-evaluation. However, the influence of mood on self-evaluation at the neural level has barely been examined. In this fMRI study, the interaction of mood and self-perception was investigated in 20 healthy participants. Happy, sad and neutral music was presented while participants were instructed to immerse themselves in the mood of the music and to rate how well presented traits characterized themselves. In a lexical control condition, subjects had to count a specific letter in the word. Behavioral data reflected successful mood induction. While self-ascription of positive traits was unaffected by mood, self-ascription of negative characteristics was decreased by negative affect. A positive correlation was found between self-worth scores and the difference in the amount of self-ascribed positive versus negative traits during negative mood induction. At the neural level, amygdalo-hippocampal, superior and middle temporal structures were differently involved in self-evaluation (vs. lexical processing) depending on the mood. While activation of the amygdalo-hippocampal complex was found during sad in comparison to both happy and neutral mood, superior/middle temporal gyrus (STG/MTG) activation was only found when contrasting sad vs. neutral mood. Further, a correlation analysis with self-worth ratings revealed a positive relation to STG activation during self-ascription of trait adjectives in sad compared to neutral mood. Our results underscore the importance of the current emotional state for self-evaluation and identify some neural correlates of this effect. Our findings in healthy research participants suggest a compensatory mechanism during sad mood induction to maintain a positive self-image, which is supported by activation of limbic and fronto-temporal cortex. Studies in clinically depressed populations could reveal whether this compensatory mechanism is aberrant.

Neural responses to dynamic multimodal stimuli and pathology-specific impairments of social cognition in schizophrenia and depression.

BACKGROUND: Individuals with schizophrenia and people with depression both show abnormal behavioural and neural responses when perceiving and responding to emotional stimuli, but pathology-specific differences and commonalities remain mostly unclear. AIMS: To directly compare empathic responses to dynamic multimodal emotional stimuli in a group with schizophrenia and a group with depression, and to investigate their neural correlates using functional magnetic resonance imaging (fMRI). METHOD: The schizophrenia group (n = 20), the depression group (n = 24) and a control group (n = 24) were presented with portrait-shot video clips expressing emotion through three possible communication channels: facial expression, prosody and content. Participants rated their own and the actor's emotional state as an index of empathy. RESULTS: Although no group differences were found in empathy ratings, characteristic differences emerged in the fMRI activation patterns. The schizophrenia group demonstrated aberrant activation patterns during the neutral speech content condition in regions implicated in multimodal integration and formation of semantic constructs. Those in the depression group were most affected during conditions with trimodal emotional and trimodal neutral stimuli, in key regions of the mentalising network. CONCLUSIONS: Our findings reveal characteristic differences in patients with schizophrenia compared with those with depression in their cortical responses to dynamic affective stimuli. These differences indicate that impairments in responding to emotional stimuli may be caused by pathology-specific problems in social cognition.

Effects of overnight fasting on working memory-related brain network: an fMRI study.

Glucose metabolism serves as the central source of energy for the human brain. Little is known about the effects of blood glucose level (BGL) on higher-order cognitive functions within a physiological range (e.g., after overnight fasting). In this randomized, placebo-controlled, double blind study, we assessed the impact of overnight fasting (14 h) on brain activation during a working memory task. We sought to mimic BGLs that occur naturally in healthy humans after overnight fasting. After standardized periods of food restriction, 40 (20 male) healthy participants were randomly assigned to receive either glucagon to balance the BGL or placebo (NaCl). A parametric fMRI paradigm, including 2-back and 0-back tasks, was used. Subclinically low BGL following overnight fasting was found to be linked to reduced involvement of the bilateral dorsal midline thalamus and the bilateral basal ganglia, suggesting high sensitivity of those regions to minimal changes in BGLs. Our results indicate that overnight fasting leads to physiologically low levels of glucose, impacting brain activation during working memory tasks even when there are no differences in cognitive performance.

fMRI feedback enhances emotion regulation as evidenced by a reduced amygdala response.

Deficits in emotion regulation are a prominent feature of psychiatric conditions and a promising target for treatment. For instance, cognitive reappraisal is regarded as an effective strategy for emotion regulation. Neurophysiological models have established the lateral prefrontal cortex (LPFC) as a key structure in the regulation of emotion processing through modulations of emotion-eliciting structures such as the amygdala. Feedback of the LPFC activity by real-time functional magnetic resonance (fMRI) may thus enhance the efficacy of cognitive reappraisal. During cognitive reappraisal of aversive visual stimuli, LPFC activity was fed back to the experimental group, whereas control participants received no such information. As a result, during reappraisal, amygdala activity was lower in the experimental group than in the controls. Furthermore, an increase of inter-hemispheric functional connectivity emerged in the feedback group. The current study extends the neurofeedback literature by suggesting that fMRI feedback can modify brain activity during a given task.

Manual khalifa therapy improves functional and morphological outcome of patients with anterior cruciate ligament rupture in the knee: a randomized controlled trial.

Rupture of the anterior cruciate ligament (ACL) is a high incidence injury usually treated surgically. According to common knowledge, it does not heal spontaneously, although some claim the opposite. Regeneration therapy by Khalifa was developed for injuries of the musculoskeletal system by using specific pressure to the skin. This randomized, controlled, observer-blinded, multicentre study was performed to validate this assumption. Thirty patients with complete ACL rupture, magnetic resonance imaging (MRI) verified, were included. Study examinations (e.g., international knee documentation committee (IKDC) score) were performed at inclusion (t 0). Patients were randomized to receive either standardised physiotherapy (ST) or additionally 1 hour of Khalifa therapy at the first session (STK). Twenty-four hours later, study examinations were performed again (t 1). Three months later control MRI and follow-up examinations were performed (t 2). Initial status was comparable between both groups. There was a highly significant difference of mean IKDC score results at t 1 and t 2. After 3 months, 47% of the STK patients, but no ST patient, demonstrated an end-to-end homogeneous ACL in MRI. Clinical and physical examinations were significantly different in t 1 and t 2. ACL healing can be improved with manual therapy. Physical activity can be performed without pain and nearly normal range of motion after one treatment of specific pressure.

Hyperactivation balances sensory processing deficits during mood induction in schizophrenia.

While impairments in emotion recognition are consistently reported in schizophrenia, there is some debate on the experience of emotion. Only few studies investigated neural correlates of emotional experience in schizophrenia. The present functional magnetic resonance imaging study compared a standard visual mood induction paradigm with an audiovisual method aimed at eliciting emotions more automatically. To investigate the interplay of sensory, cognitive and emotional mechanisms during emotion experience, we examined connectivity patterns between brain areas. Sixteen schizophrenia patients and sixteen healthy subjects participated in two different mood inductions (visual and audiovisual) that were administered for different emotions (happiness, sadness and neutral). Confirming the dissociation of behavioral and neural correlates of emotion experience, patients rated their mood similarly to healthy subjects but showed differences in neural activations. Sensory brain areas were activated less, increased activity emerged in higher cortical areas, particularly during audiovisual stimulation. Connectivity was increased between primary and secondary sensory processing areas in schizophrenia. These findings support the hypothesis of a deficit in filtering and processing sensory information alongside increased higher-order cognitive effort compensating for perception deficits in the affective domain. This may suffice to recover emotion experience in ratings of clinically stable patients but may fail during acute psychosis.

Neural correlates of semantic associations in patients with schizophrenia.

Patients with schizophrenia have semantic processing disturbances leading to expressive language deficits (formal thought disorder). The underlying pathology has been related to alterations in the semantic network and its neural correlates. Moreover, crossmodal processing, an important aspect of communication, is impaired in schizophrenia. Here we investigated specific processing abnormalities in patients with schizophrenia with regard to modality and semantic distance in a semantic priming paradigm. Fourteen patients with schizophrenia and fourteen demographically matched controls made visual lexical decisions on successively presented word-pairs (SOA = 350 ms) with direct or indirect relations, unrelated word-pairs, and pseudoword-target stimuli during fMRI measurement. Stimuli were presented in a unimodal (visual) or crossmodal (auditory-visual) fashion. On the neural level, the effect of semantic relation indicated differences (patients > controls) within the right angular gyrus and precuneus. The effect of modality revealed differences (controls > patients) within the left superior frontal, middle temporal, inferior occipital, right angular gyri, and anterior cingulate cortex. Semantic distance (direct vs. indirect) induced distinct activations within the left middle temporal, fusiform gyrus, right precuneus, and thalamus with patients showing fewer differences between direct and indirect word-pairs. The results highlight aberrant priming-related brain responses in patients with schizophrenia. Enhanced activation for patients possibly reflects deficits in semantic processes that might be caused by a delayed and enhanced spread of activation within the semantic network. Modality-specific decreases of activation in patients might be related to impaired perceptual integration. Those deficits could induce and increase the prominent symptoms of schizophrenia like impaired speech processing.

The electrophysiological signature of motivational salience in mice and implications for schizophrenia.

According to the aberrant-salience hypothesis, attribution of motivational salience is severely disrupted in patients with schizophrenia. To provide a translational approach for investigating underlying mechanisms, neural correlates of salience attribution were examined in normal mice and in a MK-801 model of schizophrenia. Electrophysiological responses to standard and deviant tones were assessed in the medial prefrontal cortex (mPFC) using an auditory oddball paradigm. Motivational salience was induced by aversive conditioning to the deviant tone. Analysis of the auditory evoked potential (AEP) showed selective modulation of the late frontal negativity (LFN) by motivational salience, which persisted throughout a 4-week delay. MK-801, an N-methyl-D-aspartic acid receptor antagonist, abolished this differential response to motivational salience in conditioned mice. In contrast, a pronounced LFN response was observed towards the deviant, ie, perceptually salient tone, in nonconditioned mice. The finding of a selective modulation of a late frontal slow wave suggests increased top-down processing and emotional evaluation of motivationally salient stimuli. In particular, the LFN is discussed as the mouse analog to the human stimulus preceding negativity, which reflects preparatory processes in anticipation of reward or punishment. MK-801 led to a disruption of the normal response in conditioned and nonconditioned mice, including an aberrantly increased LFN in nonconditioned mice. This pattern of 'false-negative' and 'false-positive' responses suggests a degradation of salience attribution, which points to mPFC responses to be relevant for translational research on cognitive alterations in schizophrenia.

Cardiovascular effects, pharmacokinetics and cross-reactivity in digitalis glycoside immunoassays of an antidiarrheal uzara root extract.

Uzara glycosides (UG) extracted from Xysmalobium undulatum are used for treating non-specific diarrhea.Cross-reactivity has been described for UG in digitalis glycoside assays but digitalis-like cardiac effects are controversially discussed. Therefore, we performed a randomized, singleblind cross-over study in 18 healthy volunteers receiving a commercially available Uzara product (Uzara® Lösung N, Stada AG, Bad Vilbel, Germany (ULN)), digoxin (1 mg, i.v., positive control) and placebo in double-dummy technique. Pharmacodynamic effects were quantified by means of ECG and impedance cardiography (ICG). After oral administration of ULN, main metabolites were determined using HPLC-MS/MS and digitalis-like serum levels (DLSL) were measured in two digitoxin and digoxin assays, respectively. In comparison to placebo, ULN did not change significantly any PD parameters whereas digoxin altered significantly area under the effect curve of several ECG and ICG parameters, respectively. Since some serum levels of three ULN ingredients (uzarin, uzarigenin and xysmalorin) were below LLQ, PK analyses could only be performed for allouzarigenin and revealed a marked inter-individual variability. Therefore, median values (min; max) were calculated as follows: Cmax = 0.39 (0.15; 1.81) ng/ml, tmax = 7.0 (3.0; 36.0) h, T1/2 = 5.2 (0.8; 23.6) h, AUC0-36h = 4.2 (0.8; 11.1) ng/ml×h, AUC0-∞ = 5.8 (1.8; 13.1) ng/ml×h. DLSL reached Cmax of 28 ng/ml and 1,980 ng/ml for digoxin and digitoxin, respectively. We could not observe significant cardiovascular pharmacodynamic effects after oral administration of the recommended single dose of Uzara extract to healthy volunteers. However, considerable DLSL could be detected, proving cross-reactivity of uzara components with the conventional digitalis assays used. However, none of the metabolites we had suspected to be the cause for the crossreactivity could be identified in reasonable quantities.

The differential contribution of facial expressions, prosody, and speech content to empathy.

BACKGROUND: Facial expressions, prosody, and speech content constitute channels by which information is exchanged. Little is known about the simultaneous and differential contribution of these channels to empathy when they provide emotionality or neutrality. Especially neutralised speech content has gained little attention with regards to influencing the perception of other emotional cues. METHODS: Participants were presented with video clips of actors telling short-stories. One condition conveyed emotionality in all channels while the other conditions either provided neutral speech content, facial expression, or prosody, respectively. Participants judged the emotion and intensity presented, as well as their own emotional state and intensity. Skin conductance served as a physiological measure of emotional reactivity. RESULTS: Neutralising channels significantly reduced empathic responses. Electrodermal recordings confirmed these findings. The differential effect of the communication channels on empathy prerequisites was that target emotion recognition of the other decreased mostly when the face was neutral, whereas decreased emotional responses attributed to the target emotion were especially present in neutral speech. CONCLUSION: Multichannel integration supports conscious and autonomous measures of empathy and emotional reactivity. Emotional facial expressions influence emotion recognition, whereas speech content is important for responding with an adequate own emotional state, possibly reflecting contextual emotion-appraisal.

Incongruence effects in crossmodal emotional integration.

Emotions are often encountered in a multimodal fashion. Consequently, contextual framing by other modalities can alter the way that an emotional facial expression is perceived and lead to emotional conflict. Whole brain fMRI data was collected when 35 healthy subjects judged emotional expressions in faces while concurrently being exposed to emotional (scream, laughter) or neutral (yawning) sounds. The behavioral results showed that subjects rated fearful and neutral faces as being more fearful when accompanied by screams than compared to yawns (and laughs for fearful faces). Moreover, the imaging data revealed that incongruence of emotional valence between faces and sounds led to increased activation in the middle cingulate cortex, right superior frontal cortex, right supplementary motor area as well as the right temporoparietal junction. Against expectations no incongruence effects could be found in the amygdala. Further analyses revealed that, independent of emotional valence congruency, the left amygdala was consistently activated when the information from both modalities was emotional. If a neutral stimulus was present in one modality and emotional in the other, activation in the left amygdala was significantly attenuated. These results indicate that incongruence of emotional valence in audiovisual integration activates a cingulate-fronto-parietal network involved in conflict monitoring and resolution. Furthermore in audiovisual pairing amygdala responses seem to signal also the absence of any neutral feature rather than only the presence of an emotionally charged one.

Alteration of the pro-oxidant xanthine oxidase (XO) in the thalamus and occipital cortex of patients with schizophrenia.

OBJECTIVES: Mounting evidence shows that oxidative stress (OS) and the purine/adenosine system play a key role in the pathophysiology of schizophrenia. Lately, our group pointed out that not only antioxidants, but also the prooxidant system plays an important role in neuro-psychiatric disorders. Xanthine oxidase (XO) is an enzyme of special interest in this context, since it acts as a prooxidant, but its main product is a vastly important antioxidant, uric acid (UA). Furthermore, XO plays major part in the purine/adenosine metabolism, which has been hypothesised to play a role in schizophrenia as well. METHODS: We examined the activity of XO in the striato-cortico-limbic system of schizophrenic patients (SP) and controls using a commercially available activity assay. RESULTS: We found decreased activity of XO in the occipital cortex and thalamus of patients with psychosis. Furthermore, XO shows a significant positive correlation with chlorpromazine equivalents in the putamen and the temporal cortex. CONCLUSIONS: Nevertheless, our results might suggest a downregulation of cellular defence mechanisms in schizophrenia in several brain regions, which could account for neuronal alterations which have been described before. This demonstrates that more research is needed to fully understand the role of the complex enzyme XO in the pathophysiology of schizophrenia.

Emotion-cognition interactions in schizophrenia.

OBJECTIVES: Negative emotion exerts a considerable influence on cognitive processes. This may have clinical implications in mental illnesses, such as schizophrenia, where negative emotions often prevail. Experimentally this influence can be studied by using olfactory emotion induction. METHODS: Fourteen schizophrenia patients and 14 healthy volunteers were investigated with functional magnetic resonance imaging with respect to the neural correlates of emotion-cognition interactions. Emotion was induced by odorants during an n-back working memory task. RESULTS: Similar detrimental effects of negative stimulation on working memory performance were observed in patients and control subjects. Among the neural correlates modulating this interaction a decreased activation emerged in patients in the anterior cingulate and the medial superior frontal cortex and increased activation in the medial orbitofrontal and middle frontal area. CONCLUSIONS: During emotion-cognition interaction hypoactivations were found in regions crucial for the monitoring/control of ongoing processes but also for emotion regulation. Decreased activations may reflect failure to adapt to higher task requirements. In contrast, increased activations could be indicative of a greater emotional response and irritation induced by the odour. These patterns may represent the neural correlates of an inefficient control of emotional influences on cognitive processes in patients with schizophrenia.

Brain imaging: on the way toward a therapeutic discipline.

Brain imaging has proven its importance as an essential tool of neuroscientific research, especially in psychiatry. Several of these methods at hand promise to enhance our understanding of function and dysfunction of neural processes and their disturbances in mental disorders in the near future. But the convincing success of imaging tools in research has not yet answered the demand to lead to new therapies or to new and useful tools in the diagnosis and treatment of single subjects. This article tries to point out how new methodological developments are promising to lead to a further step in this way. This therapeutic option is based on technical developments like high-field magnetic resonance imaging (MRI) or the further development of neurofeedback. This concept might make brain imaging such as realtime fMRI a therapeutic option at least in specialized institutions in the foreseeable future, especially since MR-scanners are already widely available nowadays.

Models of mental health care in psychiatry across sectoral borders.

Since 2004, article 140 of the fifth German Social Code Book (SGB V) provides the opportunity for developing and implementing models of Integrated Care (IC). The main aim of integrated care projects is to improve the quality and efficiency of health care in Germany by ameliorating the cooperation between the different sectors hospitals, ambulatory and rehabilitative care. As an example of implementing an integrated care network in the psychiatric sector, the first local network for integrated care in psychiatry in Aachen is described. It was founded in 2006 by the department of Psychiatry and Psychotherapy of the University Hospital Aachen, the DGPPN (German Association of Psychiatry and Psychotherapy) and the BVDN (Professional Association of German Neuropsychiatrists). The present interface problem between the separated sectors of medical care in Germany is being solved by evidence-based therapy, coordinated treatment between the different sectors, a standardised documentation and advanced training for all clinical participants. Early diagnosis and treatment of depression are improved by integrating clinical diagnostics, acute therapy, maintenance therapy, prophylaxis of relapse and after-care within one network. By the end of 2008, 1,081 patients have been treated within the integrated care network in Aachen by 56 ambulant general practitioners and psychiatrists and by 3 local psychiatric hospitals. Currently the network is going to be enlarged by integrating the diagnosis of schizophrenia. Following this, other mental illnesses should be integrated. The aim is to create a nationwide integrated care network across all diagnostic borders of mental illnesses.

Cerebral dysfunctions of emotion-cognition interactions in adolescent-onset schizophrenia.

OBJECTIVE: Schizophrenia is among the most severe of psychiatric disorders, leading to impairments of affective and cognitive abilities. These dysfunctions affect each other mutually. Adolescent-onset schizophrenia (AOS) constitutes a particularly severe form of the disorder. In this study, possible dysfunctions of the neural correlates underlying the interaction of negative emotion and working memory in AOS were investigated. METHOD: During functional magnetic resonance imaging, 12 patients with AOS and 12 non-AOS adolescents performed a verbal n-back task. Intermittently, negative and neutral emotions were induced by olfactory stimulation. Group differences in working memory, emotion, and their interaction were evaluated. RESULTS: In patients with AOS, lower performance sensitivity was observed, along with dorsolateral prefrontal, anterior cingulate, and inferior parietal hypoactivation during working memory demands. For negative versus neutral emotion induction, patients with AOS mainly showed increased brain activation compared with control subjects in widespread brain regions including the left orbitofrontal cortex and the medial frontal gyrus. Finally, during the interaction of emotion and cognition, altered patterns of activation in patients with AOS were found in the thalamocortical network, including the angular and the middle cingulate gyri extending to the precuneus. These activation differences were further decomposed by parameter estimates. CONCLUSIONS: Our results provide new insights into the neural correlates underlying the mutual influence of affective and cognitive symptoms in AOS. During the n-back task, areas typically associated with working memory performance were found hypoactivated in patients relative to the control subjects, including the dorsolateral prefrontal and parietal cortex and the anterior cingulate. However, patients with AOS mainly demonstrated increased activation in key areas of emotion processing, such as the left orbitofrontal cortex and medial frontal areas, during negative emotion induction. A dysfunctional thalamocortical network during the interaction mainly included regions involved in the integration of converging information--either on the subcortical (thalamus) or on a higher-order cortical level (comprising the angular gyrus). These findings point to dysfunctional emotion-cognition interactions in AOS, which may explain its poor prognosis.

Neural correlates of working memory dysfunction in first-episode schizophrenia patients: an fMRI multi-center study.

Working memory dysfunction is a prominent impairment in patients with schizophrenia. Our aim was to determine cerebral dysfunctions by means of functional magnetic resonance imaging (fMRI) in a large sample of first-episode schizophrenia patients during a working memory task. 75 first-episode schizophrenia patients and 81 control subjects, recruited within a multi-center study, performed 2- and 0-back tasks while brain activation was measured with fMRI. In order to guarantee comparability between data quality from different scanners, we developed and adopted a standardized, fully automated quality assurance of scanner hard- and software as well as a measure for in vivo data quality. After these quality-control measures had been implemented, 48 patients and 57 controls were included in the final analysis. During attention-related processes, even when the performance between patients and controls was comparable, there was a recognizable emergence of cerebral dysfunctions with hypoactivations in the ventrolateral prefrontal cortex (VLPFC), in the superior temporal cortex and in the thalamus. During working memory performance, parietal hypoactivations, especially in the precuneus, were prominent and were accompanied by poorer performance in patients. A hyperfrontality emerged in the ventrolateral prefrontal cortex. Hence, results point to a dysfunctional ventrolateral prefrontal-parietal network during working memory in patients, suggesting impairments in basic functions such as retrieval, storage and maintenance. The brain activation pattern of this large and significant sample of first-episode schizophrenia patients indicates an imbalanced system failing to adjust the amount of brain activity required in the cerebral network involved in attention and working memory.