Differential reward processing in subtypes of adult attention deficit hyperactivity disorder.

OBJECTIVES: Abnormalities in reward processing have been found in adolescents and adults with ADHD using the 'Monetary Incentive Delay' (MID) task. However, ADHD groups in previous studies were heterogeneous regarding ADHD subtype, gender and, in part, drug treatment status. This study sought to compare neural activations in the ventral striatum (VS) and prefrontal regions during reward processing in homogenous ADHD subtype groups and healthy adults, using the MID task. METHODS: In total, 24 drug-naïve, right-handed male adults with ADHD (12 subjects with combined type (ADHD-ct) and 12 subjects with predominantly inattentive (ADHD-it) type ADHD), and twelve healthy right-handed male control subjects were included. RESULTS: Compared to ADHD-ct and healthy subjects, ADHD-it subjects showed a bilateral ventral striatal deficit during reward anticipation. In contrast, ADHD-ct subjects showed orbitofrontal hyporesponsiveness to reward feedback when compared with ADHD-it and healthy subjects. CONCLUSIONS: This is the first fMRI study that delineates dysfunctional and subtype-divergent neural and behavioural reward processing in adults with ADHD.

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

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

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

BACKGROUND: Neuroimaging studies have suggested gray (GM) and white matter (WM) abnormalities in early stages of schizophrenia. We aimed at evaluating subtle parenchymal alterations in individuals at ultra-high risk (UHR) for transition into psychosis and first-episode schizophrenic (FES) patients by measuring the magnetization transfer ratio (MTR). METHODS AND MATERIAL: In a cross-sectional study magnetization transfer images and high-resolution volumetric T1-weighted images were acquired in 70 age- and gender-matched subjects (25 UHR subjects, 16 FES patients and 29 controls) in a 1.5Tesla scanner. Following normalization of MTR-maps the intensity histograms were analyzed by performing a Kruskal-Wallis-test. RESULTS: Gray matter MTR decreases were depicted in UHR subjects solely, involving the cingulate gyrus and precentral cortex. WM MTR alterations were more pronounced in FES than in UHR patients and exclusively affected the frontal lobe bilaterally. In addition, UHR subjects showed bilateral MTR decreases at the stria terminalis though statistically significant only on the left side (p=0.018.) CONCLUSION: Our results indicate GM affection earlier on during disease progression as well as cumulative WM affection within frontal lobes during transition from UHR to FES. MTR reductions at the stria terminalis of UHR patients points to the involvement of the extended amygdala in the prodromal disease stage.

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

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

"Theory of mind" is impaired in Huntington's disease.

BACKGROUND: Huntington's disease (HD) is an autosomal dominant degenerative brain disorder that is characterized by motor, cognitive, and affective symptoms. There is, to some, degree, phenomenological overlap with schizophrenia. Schizophrenia patients are frequently impaired in "theory of mind" (ToM), that is, the ability to reflect on the mental states of self and others, with mixed evidence for a ToM deficit in HD. METHODS: We examined ToM and neurocognitive functioning in 25 patients diagnosed with HD. For comparison, 25 patients with schizophrenia and 25 healthy controls, matched for age and gender, were included. RESULTS: Patients with HD were impaired in ToM relative to controls. The pattern of neurocognitive deficits including ToM strikingly resembled the one found in schizophrenia, suggesting a selectively impaired ToM. In contrast to previous schizophrenia research, ToM was not associated with functional measures on the Unified Huntington's Disease Rating Scale (UHDRS). CONCLUSIONS: The present study shows that patients with HD have deficits in ToM similar to schizophrenia. The association of impaired ToM with function needs to be established in future studies using rating scales that more specifically address interpersonal problems.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Validation of the Personal and Social Performance (PSP) Scale in a German sample of acutely ill patients with schizophrenia.

In trying to more broadly define outcome in the efficient long-term treatment of patients with schizophrenia it is necessary to consider not only a reduction in psychopathological symptoms but also a successful psychosocial reintegration. Thus, a more exact assessment of psychosocial functioning is needed. Since the GAF (Global Assessment of Functioning) scale and the SOFAS (Social and Occupational Functioning Assessment Scale) are less operationalized and confuse psychosocial facts with psychopathological symptoms, the Personal and Social Performance (PSP) scale was developed [Morosini, P.L., Magliano, L., Brambilla, L., Ugolini, S., Pioli, R. (2000). Development, reliability and acceptability of a new version of the DSM-IV Social and Occupational Functioning Assessment Scale (SOFAS) to assess routine social functioning. Acta Psychiatrica Scandinavica, 1001, 323-329.] containing the four main areas "socially useful activities, personal and social relationships, self-care, as well as disturbing and aggressive behaviour". Validation of the PSP scale was conducted in a sample of 62 patients with acute schizophrenia. Rating instruments were PSP, GAF, SOFAS, PANSS, CGI, and Mini-ICF-P (Mini-ICF-Rating for Mental Disorders). The results showed good reliability with alpha=.64-.84, high test-retest reliability as well as good inter-rater reliability for the PSP scale. Furthermore, PSP proved good validity with high correlations to GAF (r=.91), SOFAS (r=.91), and Mini-ICF-P (r=-.69). The hypothesis that more critically ill patients would show lower scores on PSP than lesser ill patients was only confirmed for PANSS negative symptoms. Thus, the findings prove the PSP scale to be a reliable and valid instrument for assessing social functioning of patients with schizophrenia during the course of treatment as well as in the acute state.

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

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

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

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

Cooperation and deception recruit different subsets of the theory-of-mind network.

The term "theory of mind" (ToM) describes an evolved psychological mechanism that is necessary to represent intentions and expectations in social interaction. It is thus involved in determining the proclivity of others to cooperate or defect. While in cooperative settings between two parties the intentions and expectations of the protagonists match, they diverge in deceptive scenarios, in which one protagonist is intentionally manipulated to hold a false belief about the intention of the other. In a functional magnetic resonance imaging paradigm using cartoons showing social interactions (including the outcome of the interaction) between two or three story characters, respectively, we sought to determine those brain areas of the ToM network involved in reasoning about cooperative versus deceptive interactions. Healthy volunteers were asked to reflect upon the protagonists' intentions and expectations in cartoons depicting cooperation, deception or a combination of both, where two characters cooperated to deceive a third. Reasoning about the mental states of the story characters yielded substantial differences in activation patterns: both deception and cooperation activated bilateral temporoparietal junction, parietal and cingulate regions, while deception alone additionally recruited orbitofrontal and medial prefrontal regions. These results indicate an important role for prefrontal cortex in processing a mismatch between a character's intention and another's expectations as required in complex social interactions.

An fMRI study of theory of mind in schizophrenic patients with "passivity" symptoms.

Several studies have shown that patients with schizophrenia underactivate brain regions involved in theory of mind relative to controls during functional brain imaging. However, in most studies the samples were fairly heterogeneous in terms of clinical symptomatology. We examined a group of nine patients with first episode or recurrent episodes, who clinically presented with predominant "passivity" symptoms such as third-person auditory hallucinations or delusion of control, using a cartoon-based theory of mind task and compared activation patterns with a group of 13 healthy controls. All patients responded well to antipsychotic treatment and were only mildly symptomatic at the time of testing. The patient group showed significantly less activation of the right anterior cingulate cortex (ACC) and right insula compared with controls, but greater activation in dorsal areas of the medial prefrontal cortex, right temporal areas and left temporo-parietal junction. Patients with schizophrenia with predominant "passivity" symptoms and good response to antipsychotic treatment show a markedly diverging pattern of brain activation during theory of mind task performance compared with healthy controls. These findings suggest abnormal activation of those brain areas involved in the evaluation of self-reference during mental state attribution.

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

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

Smoking and structural brain deficits: a volumetric MR investigation.

Growing evidence from animal studies indicates brain-damaging properties of nicotine exposure. Investigations in humans found a wide range of functional cerebral effects of nicotine and cigarette smoking, but studies focusing on brain damage are sparse. In 22 smokers and 23 never-smokers possible differences of the cerebral structures were investigated using magnetic resonance imaging and voxel-based morphometry. Significantly smaller grey matter volume and lower grey matter density (P = 0.05, corrected) were observed in the frontal regions (anterior cingulate, prefrontal and orbitofrontal cortex), the occipital lobe and the temporal lobe including parahippocampal gyrus, in smokers than in never-smokers. Group differences of either grey matter volume or grey matter density were also found in the thalamus, cerebellum and substantia nigra, among other regions. Smokers did not show greater volumes than never-smokers in any cerebral region. Magnitude of lifetime exposure to tobacco smoke (pack-years) was inversely correlated with volume of frontal and temporal lobes and cerebellum (P = 0.001, uncorrected). The data indicate structural deficits of several cortical and subcortical regions in smokers relative to never-smokers. The topographic profile of the group differences show some similarities to brain networks known to mediate drug reinforcement, attention and working memory processing. The present findings may explain in part the frequently reported cognitive dysfunctions in chronic cigarette consumers.