Glutamate levels across deep brain structures in patients with a psychotic disorder and its relation to cognitive functioning.

BACKGROUND: Patients with psychotic disorders often show prominent cognitive impairment. Glutamate seems to play a prominent role, but its role in deep gray matter (DGM) regions is unclear. AIMS: To evaluate glutamate levels within deep gray matter structures in patients with a psychotic disorder in relation to cognitive functioning, using advanced spectroscopic acquisition, reconstruction, and post-processing techniques. METHODS: A 7-Tesla magnetic resonance imaging scanner combined with a lipid suppression coil and subject-specific water suppression pulses was used to acquire high-resolution magnetic resonance spectroscopic imaging data. Tissue fraction correction and registration to a standard brain were performed for group comparison in specifically delineated DGM regions. The brief assessment of cognition in schizophrenia was used to evaluate cognitive status. RESULTS: Average glutamate levels across DGM structures (i.e. caudate, pallidum, putamen, and thalamus) in mostly medicated patients with a psychotic disorder (n = 16, age = 33, 4 females) were lower compared to healthy controls (n = 23, age = 24, 7 females; p = 0.005, d = 1.06). Stratified analyses showed lower glutamate levels in the caudate (p = 0.046, d = 0.76) and putamen p = 0.013, d = 0.94). These findings were largely explained by age differences between groups. DGM glutamate levels were positively correlated with psychomotor speed (r(30) = 0.49, p = 0.028), but not with other cognitive domains. CONCLUSIONS: We find reduced glutamate levels across DGM structures including the caudate and putamen in patients with a psychotic disorder that are linked to psychomotor speed. Despite limitations concerning age differences, these results underscore the potential role of detailed in vivo glutamate assessments to understand cognitive deficits in psychotic disorders.

Impairment of gaze-directed spatial coding in recent-onset schizophrenia.

Patients with schizophrenia show deficits in core cognitive functions as well as in social cognition. The aim of the present study was to test whether deficits in social cognition influence nonsocial, "cold", cognition. Thirty-five patients with recent-onset schizophrenia (SC) and 30 healthy controls (HC) performed a Simon task with social and simple geometric stimuli. We investigated whether the Simon effect, the slowing of reaction times produced by stimulus incongruities in the task-irrelevant spatial domain, differs between patients and healthy participants as a function of the social nature of the cues. The Simon effect was generated by a schematic drawing of human eyes (social cues) or rectangles (nonsocial cues). Overall, patients had longer reaction times than HC. In the eye-like condition, the Simon effect was significantly stronger for HC than for SC. In HC the Simon effect was significantly stronger in the eye-like than in the rectangle condition. In patients, the Simon effect did not differ significantly between both conditions. Thus, the influence of social cues was greatly reduced in the patient group. Current psychopathology or antipsychotic treatment did not influence results. The present study supports earlier findings of altered processing of schematic social cues in patients with schizophrenia, especially when gaze is task-irrelevant.

Cerebellar motor learning deficits in medicated and medication-free men with recent-onset schizophrenia.

BACKGROUND: The notion that cerebellar deficits may underlie clinical symptoms in people with schizophrenia is tested by evaluating 2 forms of cerebellar learning in patients with recent-onset schizophrenia. A potential medication effect is evaluated by including patients with or without antipsychotics. METHODS: We assessed saccadic eye movement adaptation and eyeblink conditioning in men with recent-onset schizophrenia who were taking antipsychotic medication or who were antipsychotic-free and in age-matched controls. RESULTS: We included 39 men with schizophrenia (10 who were taking clozapine, 16 who were taking haloperidol and 13 who were antipsychotic-free) and 29 controls in our study. All participants showed significant saccadic adaptation. Adaptation strength did not differ between healthy controls and men with schizophrenia. The speed of saccade adaptation, however, was significantly lower in men with schizophrenia. They showed a significantly lower increase in the number of conditioned eyeblink responses. Over all experiments, no consistent effects of medication were observed. These outcomes did not correlate with age, years of education, psychopathology or dose of antipsychotics. LIMITATIONS: As patients were not randomized for treatment, an influence of confounding variables associated with medication status cannot be excluded. Individual patients also varied along the schizophrenia spectrum despite the relative homogeneity with respect to onset of illness and short usage of medication. Finally, the relatively small number of participants may have concealed effects as a result of insufficient statistical power. CONCLUSION: We found several cerebellar learning deficits in men with schizophrenia that we cannot attribute to the use of antipsychotics. Although this finding, combined with the fact that deficits are already present in patients with recent-onset schizophrenia, could suggest that cerebellar impairments are a trait deficit in people with schizophrenia. This should be confirmed in longitudinal studies.

Attention modulates the dorsal striatum response to love stimuli.

In previous functional magnetic resonance imaging (fMRI) studies concerning romantic love, several brain regions including the caudate and putamen have consistently been found to be more responsive to beloved-related than control stimuli. In those studies, infatuated individuals were typically instructed to passively view the stimuli or to think of the viewed person. In the current study, we examined how the instruction to attend to, or ignore the beloved modulates the response of these brain areas. Infatuated individuals performed an oddball task in which pictures of their beloved and friend served as targets and distractors. The dorsal striatum showed greater activation for the beloved than friend, but only when they were targets. The dorsal striatum actually tended to show less activation for the beloved than the friend when they were distractors. The longer the love and relationship duration, the smaller the response of the dorsal striatum to beloved-distractor stimuli was. We interpret our findings in terms of reinforcement learning. By virtue of using a cognitive task with a full factorial design, we show that the dorsal striatum is not activated by beloved-related information per se, but only by beloved-related information that is attended.

Feedback processing in schizophrenia: effects of affective value and remedial action.

Error-monitoring deficits in schizophrenia have been found, but results with respect to feedback processing and remedial action were unclear. The present study examined the role of emotion in feedback processing in medication-free patients with recent-onset schizophrenia. Patients and controls performed a time-estimation task, and brain activation was measured with functional magnetic resonance imaging (fMRI). Participants had to estimate a 1-s interval and received feedback about their performance in the form of words or facial expressions. Patients performed the task at the same level as the controls and used the feedback to improve performance. Brain activation following the feedback stimuli in the rostral cingulate zone differed between groups, but this effect depended on the modality of the feedback stimulus. Patients showed a differential response to verbal and facial feedback in the rostral cingulate zone, whereas healthy controls did not differ between modalities. Furthermore, activation in the rostral cingulate zone following facial feedback was negatively related to severity of the disease as expressed by the scores on positive symptom subscale of the Positive and Negative Syndrome Scale. Both findings point in the direction of a specific deficit in patients which is related to the emotional impact of external feedback.

Cardiac Responses during Picture Viewing in Young Male Patients with Schizophrenia.

Previous research investigating the emotion recognition ability in patients with schizophrenia has mainly focused on the recognition of facial expressions. To broaden our understanding of emotional processes in patients with schizophrenia, this study aimed to investigate whether these patients experience and process other emotionally evocative stimuli differently from healthy participants. To investigate this, we measured the cardiac and subjective responses of 33 male patients (9 with and 24 without antipsychotic medication) and 40 male control subjects to emotion-eliciting pictures. Cardiac responses were chosen as an outcome measure because previous research has indicated that these are linked with attentional and emotional processes and provide a more objective measure than self-report measures alone. The differences in cardiac responses between patients and controls were limited to medicated patients: only the medicated patients showed significantly decreased cardiac orienting responses compared with control subjects, regardless of picture contents. These results indicate that medicated patients directed less attention towards emotion-eliciting pictures than controls. Decreased attentional resources while processing emotional evocative stimuli could lead to incorrect appraisals of the environment and may have detrimental emotional and social consequences, contributing to chronic stress levels and an increased risk for cardiovascular disease.

Remedial action and feedback processing in a time-estimation task: evidence for a role of the rostral cingulate zone in behavioral adjustments without learning.

The present study examined the role of the rostral cingulate zone (RCZ) in feedback processing, and especially focused on effects of modality of the feedback stimulus and remedial action. Participants performed a time-estimation task in which they had to estimate a 1-second interval. After the estimation participants received verbal (correct/false) or facial (fearful face/happy face) feedback. Percentage of positive and negative feedback was kept at 50% by dynamically adjusting the interval in which estimations were labeled correct. Contrary to predictions of the reinforcement learning theory, which predicts more RCZ activation when the outcome of behavior is worse than expected, we found that the RCZ was more active after positive feedback than after negative feedback, independent of the modality of the feedback stimulus. More in line with the suggested role of the RCZ in reinforcement learning was the finding that the RCZ was more active after negative feedback that was followed by a correct adjustment as compared to negative feedback followed by an incorrect adjustment. Both findings can be explained in terms of the RCZ being involved in facilitating remedial action as opposed to the suggested signaling function (outcome is worse than expected) proposed by the reinforcement learning theory.

Retention of identity versus expression of emotional faces differs in the recruitment of limbic areas.

Faces are multidimensional stimuli that convey information for complex social and emotional functions. Separate neural systems have been implicated in the recognition of facial identity (mainly extrastriate visual cortex) and emotional expression (limbic areas and the superior temporal sulcus). Working-memory (WM) studies with faces have shown different but partly overlapping activation patterns in comparison to spatial WM in parietal and prefrontal areas. However, little is known about the neural representations of the different facial dimensions during WM. In the present study 22 subjects performed a face-identity or face-emotion WM task at different load levels during functional magnetic resonance imaging. We found a fronto-parietal-visual WM-network for both tasks during maintenance, including fusiform gyrus. Limbic areas in the amygdala and parahippocampal gyrus demonstrated a stronger activation for the identity than the emotion condition. One explanation for this finding is that the repetitive presentation of faces with different identities but the same emotional expression during the identity-task is responsible for the stronger increase in BOLD signal in the amygdala. These results raise the question how different emotional expressions are coded in WM. Our findings suggest that emotional expressions are re-coded in an abstract representation that is supported at the neural level by the canonical fronto-parietal WM network.

Diurnal cortisol patterns of young male patients with schizophrenia.

AIMS: It has been suggested that schizophrenic patients are more vulnerable to stress than healthy persons, and that stressors can trigger a psychotic episode or worsen symptoms. The biological system often studied in relation to stress is the hypothalamic-pituitary-adrenal (HPA) axis, which controls the release of cortisol. We investigated whether the diurnal basal activity of the HPA axis differed between young male patients with schizophrenia and healthy controls. METHODS: Twenty-seven male patients (mean age 22 ± 5 years) and 38 healthy male control subjects (mean age 22 ± 3 years) were included in the present study. Saliva was sampled at five time points during the day: directly after awakening, 30 min thereafter, and at 12.00 hours, 16.00 hours and 22.00 hours. RESULTS: The cortisol concentration decreased significantly more during the day in the patient group thanin the control group. Patients also showed a significantly decreased area under the curve with respect to the increase, again indicating that the cortisol concentrations decreased more during the day in patients than in controls. Both the morning increase and the area under the curve with respect to the increase were significantly negatively correlated with negative symptom severity. CONCLUSIONS: Patients with schizophrenia showed a different daytime sensitivity of the HPA axis. Our findings further suggest that an increase in negative symptom severity is related to a decreased HPA axis sensitivity.

FMRI, antipsychotics and schizophrenia. Influence of different antipsychotics on BOLD-signal.

In the last decade, functional Magnetic Resonance Imaging (FMRI) has been increasingly used to investigate the neurobiology of schizophrenia. This technique relies on changes in the blood-oxygen-level-dependent (BOLD) - signal, which changes in response to neural activity. Many FMRI studies on schizophrenia have examined medicated patients, but little is known about the effects of antipsychotic medication on the BOLD-signal. In this review we investigated to what extent studies in patients with schizophrenia (SC), who were treated with different antipsychotics, could give insight in the effects of antipsychotics on the BOLD-signal. A PubMed search was performed using the search items "schizophrenia", "FMRI", "antipsychotics" and "schizophrenia", "BOLD", "antipsychotics". Only articles in which there were at least two groups of patients with different treatments or in which patients were scanned twice with different treatments were selected. 18 articles, published between 1999 and 2009, fulfilled these criteria. Paradigms and results of these studies were compared regarding differences induced by the administered antipsychotics. This analysis showed no general effect of antipsychotics on the BOLD-signal. However, there is some evidence that the extent of blockade of the dopamine (DA) D(2) receptor does influence the BOLD-signal. Higher affinity to the dopamine D2 receptor, as expressed by a higher/lower inhibition constant (Ki) seems to cause a decrease in BOLD-signal.

Pain response in depersonalization: a functional imaging study using hypnosis in healthy subjects.

BACKGROUND: Depersonalization (DP) is characterized by persistent or recurrent episodes of detachment from one's self with reduced pain perception being a common feature. Alterations in the body schema similar to the cortico-limbic disconnection syndrome of pain asymbolia are suggested to be responsible for DP. In this study we used hypnosis to induce DP in healthy subjects and to examine neural patterns of pain perception in the state of DP by means of functional magnetic resonance imaging (fMRI). METHODS: Pain perception was investigated in 7 healthy subjects with high susceptibility to hypnosis in three different mental states: waking state (N-W), hypnotic relaxation (H-R) and hypnotic DP (H-DP). Pain was induced with electrical stimulation to the median nerve at the right wrist. fMRI measurements were performed during all states. RESULTS: Nociceptive stimuli led to an activation of the well described pain network including somatosensory and insular regions and the cerebellum. Activation was markedly reduced in the contralateral somatosensory cortex, parietal cortex (Brodmann area 40, BA40), prefrontal cortex (BA9), putamen and the ipsilateral amygdala during H-DP. Subjects also reported a significant decrease in pain intensity from N-W to H-DP. CONCLUSION: Pain response during H-DP was reduced in sensory and affective pain-related areas, reflecting the diminished intensity of the perceived pain. Moreover, a network of cortical and subcortical areas that have been implicated in the perception of the own body was less responsive during DP, which might point to a specific neural mechanism underlying the 'out-of-body' experience. Although the small number of subjects does not allow a generalization of our findings, H-DP seems to be a promising tool for the investigation of psychological and biological mechanisms of self-inflicted injuries as well as the mind-body interplay within the realm of psychosomatic disorders.

The spatiotemporal pattern of auditory cortical responses during verbal hallucinations.

Functional magnetic resonance imaging (fMRI) studies can provide insight into the neural correlates of hallucinations. Commonly, such studies require self-reports about the timing of the hallucination events. While many studies have found activity in higher-order sensory cortical areas, only a few have demonstrated activity of the primary auditory cortex during auditory verbal hallucinations. In this case, using self-reports as a model of brain activity may not be sensitive enough to capture all neurophysiological signals related to hallucinations. We used spatial independent component analysis (sICA) to extract the activity patterns associated with auditory verbal hallucinations in six schizophrenia patients. SICA decomposes the functional data set into a set of spatial maps without the use of any input function. The resulting activity patterns from auditory and sensorimotor components were further analyzed in a single-subject fashion using a visualization tool that allows for easy inspection of the variability of regional brain responses. We found bilateral auditory cortex activity, including Heschl's gyrus, during hallucinations of one patient, and unilateral auditory cortex activity in two more patients. The associated time courses showed a large variability in the shape, amplitude, and time of onset relative to the self-reports. However, the average of the time courses during hallucinations showed a clear association with this clinical phenomenon. We suggest that detection of this activity may be facilitated by examining hallucination epochs of sufficient length, in combination with a data-driven approach.

[Convergence of psychotherapeutic and neurobiological outcome measure in a patient with OCD]. / Konvergenzen psychotherapeutischer und neurobiologischer Ergebniskontrolle bei einer schweren Zwangsstörung.

We used psychotherapeutic measures and functional magnetic resonance imaging (fMRI) to assess the effect of a combined psychodynamic and cognitive behavioral treatment of a patient suffering from a severe obsessive compulsive disorder (OCD). The clinical outcome was controlled by a detailed case description and psychometric test instruments. Intensive exploration of the patient made possible the creation of an idiosyncratic imagination paradigm suitable for fMRI. The patient shows at the end of treatment a decrease in symptoms as assessed by clinical as well as psychometric instruments. Especially recapitulation and cleaning obsessions decreased, but the cognitive avoidance strategies remained almost unchanged. fMRI showed no orbito-fronto-striatothalamic activation corresponding to obsessive compulsive symptoms, but an increased activation of the medial prefrontal (MFC) and anterior cingulate cortex (ACC). The lack of activation of the orbito-fronto-striatothalamic circuits and at the same time the occurrence of the increased activation of the MFC and ACC reflects the cognitive avoidance strategies still triggered by the symptom provoking stimulus.

Schizophrenia and Parkinson's disease lead to equal motor-related changes in cortical and subcortical brain activation: an fMRI fingertapping study.

In schizophrenia and Parkinson's disease, cortical and subcortical motor organization is influenced by primary disease conditions and neuroleptic treatment. Using functional magnetic resonance imaging patients with schizophrenia were compared, according to Diagnostic and Statistical Manual of Mental Disorders (4th edn), under stable treatment with olanzapine (n = 7; OL) or haloperidol (n = 7; HA) to healthy controls (n = 7; HC), patients with schizophrenia without any neuroleptic treatment (n = 7; UN) and to patients with left (n = 7; LHP)- and right (n = 7; RHP)-sided hemiparkinsonism. All subjects performed a unilateral left-handed fingertapping task. All groups had significant activation in the contralateral motor cortex and the putamen (P < 0.001). Different activation patterns between groups within cortical and subcortical regions of interest were revealed. In particular, different subcortical activation patterns were found between OL- and HA-treated patients with schizophrenia. Activation of the contralateral putamen was increased in right-sided hemiparkinsonism. Significant thalamus activation was found in patients under neuroleptic treatment as well as in hemiparkinsonism, whereas the thalamus was not activated in untreated patients with schizophrenia and in healthy controls. Comparing dopaminergic depletion in hemiparkinsonism and dopaminergic blockade in HA-treated patients, an increase in activation was found within the contralateral primary motorcortex, in the ipsilateral putamen and the contralateral thalamus in hemiparkinsonism. In contrast, activation of the contralateral putamen differed between OL and HA, LHP and RHP. These findings confirm that cortical and subcortical motor-related brain loop functions are influenced by both primary neuropsychiatric conditions as well as by treatment effects. It is hypothesized that dopaminergic depletion in hemiparkinsonism and dopaminergic blockade under neuroleptic agents influence basal ganglia activity in a different way; in particular regarding functional connectivity. Basal ganglia and thalamic interaction seems to have a key role in cortical-subcortical interaction.

Abnormalities in emotion processing within cortical and subcortical regions in criminal psychopaths: evidence from a functional magnetic resonance imaging study using pictures with emotional content.

BACKGROUND: Neurobiology of psychopathy is important for our understanding of current neuropsychiatric questions. Despite a growing interest in biological research in psychopathy, its neural underpinning remains obscure. METHODS: We used functional magnetic resonance imaging to study the influence of affective contents on brain activation in psychopaths. Series containing positive and negative pictures from the International Affective Picture System were shown to six male psychopaths and six male control subjects while 100 whole-brain echo-planar-imaging measurements were acquired. Differences in brain activation were evaluated using BrainVoyager software 4.6. RESULTS: In psychopaths, increased activation through negative contents was found right-sided in prefrontal regions and amygdala. Activation was reduced right-sided in the subgenual cingulate and the temporal gyrus, and left-sided in the dorsal cingulate and the parahippocampal gyrus. Increased activation through positive contents was found left-sided in the orbitofrontal regions. Activation was reduced in right medial frontal and medial temporal regions. CONCLUSIONS: These findings underline the hypotheses that psychopathy is neurobiologically reflected by dysregulation and disturbed functional connectivity of emotion-related brain regions. These findings may be interpreted within a framework including prefrontal regions that provide top-down control to and regulate bottom-up signals from limbic areas. Because of the small sample size, the results of this study have to be regarded as preliminary.