Fronto-thalamic structural and effective connectivity and delusions in schizophrenia: a combined DTI/DCM study.

BACKGROUND: Schizophrenia (SZ) is a complex disorder characterized by a range of behavioral and cognitive symptoms as well as structural and functional alterations in multiple cortical and subcortical structures. SZ is associated with reduced functional network connectivity involving core regions such as the anterior cingulate cortex (ACC) and the thalamus. However, little is known whether effective coupling, the directed influence of one structure over the other, is altered during rest in the ACC-thalamus network. METHODS: We collected resting-state fMRI and diffusion-weighted MRI data from 18 patients and 20 healthy controls. We analyzed fronto-thalamic effective connectivity using dynamic causal modeling for cross-spectral densities in a network consisting of the ACC and the left and right medio-dorsal thalamic regions. We studied structural connectivity using fractional anisotropy (FA). RESULTS: We found decreased coupling strength from the right thalamus to the ACC and from the right thalamus to the left thalamus, as well as increased inhibitory intrinsic connectivity in the right thalamus in patients relative to controls. ACC-to-left thalamus coupling strength correlated with the Positive and Negative Syndrome Scale (PANSS) total positive syndrome score and with delusion score. Whole-brain structural analysis revealed several tracts with reduced FA in patients, with a maximum decrease in white matter tracts containing fronto-thalamic and cingulo-thalamic fibers. CONCLUSIONS: We found altered effective and structural connectivity within the ACC-thalamus network in SZ. Our results indicate that ACC-thalamus network activity at rest is characterized by reduced thalamus-to-ACC coupling. We suggest that positive symptoms may arise as a consequence of compensatory measures to imbalanced fronto-thalamic coupling.

Altered social decision making in borderline personality disorder: an Ultimatum Game study.

The authors examined social decision-making strategies in borderline personality disorder (BPD) using the Ultimatum Game (UG). They sought to extend previous findings by investigating altruistic punishment, a behavior that increases group cooperation in the long term. They tested the effect of the proposer's facial expression on responses. BPD patients (n = 47) and healthy controls (n = 43) played the responder's role in a series of computerized UG interactions, with proposers expressing positive or negative emotions. BPD patients accepted unfair offers at a higher rate compared to controls. The effect of facial expression differed in the two groups, as positive expressions increased the acceptance likelihood in the control group at stakes from 20:80 to 50:50. In the BPD group, this effect was observed only at higher stakes (40:60 and 50:50). These results suggest that BPD patients exhibit altruistic punishment to a lesser extent and are less influenced by their partners' emotional expression in the UG.

Theory of mind impairments in patients with deficit schizophrenia.

The deficit syndrome, a subgroup within schizophrenia, is characterized by enduring, idiopathic negative symptoms. Theory of mind (ToM), a domain of social cognition, is the ability of attributing mental states to ourselves and other people. ToM impairments have not been investigated earlier in deficit schizophrenia. The aim of the present study was to examine ToM differences between patients with deficit (SZ-D) and non-deficit schizophrenia (SZ-ND). Gender differences were also investigated, and based on the literature a better ToM performance was expected in female patients. The participants were 28 patients with SZ-ND, 30 patients with SZ-D, and 29 healthy control volunteers. The "Reading the Mind in the Eyes Test" was used to asses ToM deficits. Control subjects outperformed both patient groups, while there were no significant differences between the two schizophrenia subgroups. In female subjects, both controls and patients with SZ-ND performed significantly better than the SZ-D subgroup. In male subjects, controls performed significantly better than both patient groups. The "diminished emotional range" and the "curbing of interest" items of the Schedule for the Deficit Syndrome showed significant negative relationship with the ToM score. Our main finding is that female subjects with SZ-ND performed significantly better than female subjects with SZ-D.

General and domain-specific neurocognitive impairments in deficit and non-deficit schizophrenia.

Earlier studies suggested more severe overall cognitive impairments in deficit versus non-deficit schizophrenia; however, the specific contribution of different cognitive domains to this overall cognitive impairment remains unclear. The purpose of this study was to compare the two subtypes in general cognitive functioning as well as in individual cognitive domains using the composite score approach. One hundred and forty-three patients fulfilling the criteria for the deficit syndrome were compared with 123 patients diagnosed with non-deficit schizophrenia. Neurocognitive functioning was assessed by a neuropsychological test battery measuring the domains of sustained vigilance/attention, working memory, short-term memory, verbal memory, cognitive flexibility, and ideation fluency. Using the raw neuropsychological measures, we calculated a global index of cognitive impairment and domain-specific composite z-scores. Association between these composite scores and the deficit syndrome was examined by logistic regression analysis. After adjusting for relevant covariates including sex, age, education, smoking, and antipsychotic dose, results indicated a significant increase in the likelihood of deficit syndrome as a function of global (OR = 5.40; 95% CI 3.02-9.65) as well as domain-specific impairments (OR > 2 for all individual domains except for short-term memory). Cognitive flexibility was an independent predictor (OR = 2.92; 95% CI 1.47-5.80), whereas other cognitive domains demonstrated no unique contribution to the general cognitive impairment. Patients with deficit schizophrenia suffer from a more severe degree of neurocognitive impairment, which is qualitatively similar to the dysfunction seen in non-deficit schizophrenia. However, our results indicate that cognitive flexibility is specifically impaired in deficit versus non-deficit patients and may therefore represent a core feature of this subtype.

[Differentiation of deficit and non-deficit schizophrenia based on cognitive functions]. / Deficit és nem deficit szkizofrénia elkülönítése a kognitív funkciók mentén.

Cognitive dysfunction is a core feature in schizophrenia and has a great impact on psychosocial functioning. Still it remains unclear, whether the different diagnostic subgroups have a specific cognitive profile. The topic of this research was to investigate the neurocognitive characteristics of deficit and non-deficit schizophrenia, and to examine if the two diagnostic subgroups have a qualitative difference in cognitive functioning. In Study 1., 275 patient and 130 healthy controls completed the WCST (Wisconsin Card Sorting Test). We performed an exploratory factor analytic study on the variables for the total group and each subgroups, then we assessed the ability of the factors to distinguish between the deficit, non deficit and control groups. In Study 2., I used the Kilroy-test to investigate procedural and context-dependent learning. 78 patients and 30 healthy controls completed the test, which has two phases: while the training phase is dominantly related to basal ganglia circuits, the context-dependent probe phase requires intact medial-temporal lobe functioning. Thus the two interactive memory systems can be examined separately within one test. Study 1.: Results of the exploratory factor analysis of the whole sample yielded two factors which together explained approximately 95% of the total variance. Comparison of the diagnostic groups on each of the factors revealed that both schizophrenia groups showed executive function impairment in comparison to controls. Deficit patients suffer from a more severe degree of impairment on the "General executive function" factor (conceptualization, flexibility, set shifting) than non-deficit patients. On the other hand, non-perseverative error type (factor 2.) seems to be less typical to deficit than to the non-deficit patients. Study 2.: Results revealed that deficit and non-deficit patients were similarly impaired on the probe phase compared with controls. However, the training phase was not compromised in non-deficit patients, but deficit patients showed a significant impairment. While context-dependent learning is uniformly impaired in schizophrenia, procedural learning remains relatively intact in non-deficit patients. In conclusion, the two diagnostic subgroups seem to differ not only in the degree of cognitive impairment, but in the characteristics as well. The deficit-syndrome can be characterized by a specific profile regarding executive function, and shows greater impairment in procedural learning.

Are patients with schizophrenia rational maximizers? Evidence from an ultimatum game study.

Schizophrenia is associated with impaired social cognition and community functioning. Social decision-making strategies of healthy controls and patients with schizophrenia were compared by using the ultimatum game (UG). In this game two players have to split a sum of money. The proposer offers a portion to the responder, who decides to either accept or reject the offer. Rejection results in no income to either of the parties. Unfair proposals are frequently rejected by nonclinical individuals, a phenomenon described as altruistic punishment. Patients and controls participated in a series of UG interactions as responders in a computerized test setting. We also tested the effect of the proposer's facial expression on decision-making. Our results indicate that patients with schizophrenia accepted unfair offers at a significantly higher rate than did healthy controls. In contrast, at fair proposals, the acceptance rate was lower in patients compared with controls. At higher offers, the proposer's facial expression (positive/negative) significantly influenced the acceptance rate (positive facial expression increased the likelihood of acceptance) in the control group. This effect was not observed in the patient group. These results suggest that schizophrenia patients are impaired in socioeconomic interactions requiring emotion recognition and decision-making, which may result in unstable behavioral strategies.

Association study of NRG1, DTNBP1, RGS4, G72/G30, and PIP5K2A with schizophrenia and symptom severity in a Hungarian sample.

Genetic association studies have yielded extensive but frequently inconclusive data about genetic risk factors for schizophrenia. Clinical and genetic heterogeneity are possible factors explaining the inconsistent findings. The objective of this study was to test the association of commonly incriminated candidate genes with two clinically divergent subgroups, non-deficit (SZ-ND) and deficit-schizophrenia (SZ-D), and symptom severity, in order to test for replication of previously reported results. A homogeneous sample of 280 schizophrenia patients and 230 healthy controls of Hungarian, Caucasian descent were genotyped for polymorphisms in schizophrenia candidate genes NRG1, DTNBP1, RGS4, G72/G30, and PIP5K2A. Patients were divided into the diagnostic subgroups of SZ-ND and SZ-D using the Schedule for Deficit Syndrome (SDS), and assessed clinically by the Positive and Negative Symptom Scale (PANSS). SNP8NRG241930 in NRG1 and rs1011313 in DTNBP1 were associated with SZ-ND (P = 0.04 and 0.03, respectively). Polymorphisms in RGS4, G72/G30, and PIP5K2A were neither associated with SZ-ND nor with SZ-D. SNP8NRG241930 showed association with the PANSS cognitive and hostility/excitability factors, rs1011313 with the negative factor and SDS total score, and rs10917670 in RGS4 was associated with the depression factor. Although these results replicate earlier findings about the genetic background of SZ-ND and SZ-D only partially, our data seem to confirm previously reported association of NRG1 with schizophrenia without prominent negative symptoms. It was possible to detect associations of small-to-medium effect size between the investigated candidate genes and symptom severity. Such studies have the potential to unravel the possible connection between genetic and clinical heterogeneity in schizophrenia.

[Recent advances in the genetics of schizophrenia and the practical implications of the results]. / A szkizofrénia genetikai hátterére irányuló kutatások ujabb eredményei es ezek alkalmazási lehetoségei. Irodalmi osszefoglalás.

Research targeting the genetic background of schizophrenia has expanded our knowledge substantially about genes and possible pathophysiological processes playing a role in the disorder. In addition to earlier approaches, new genetic methods have been developed which offer new insight. In this review we make an attempt to summarize the findings of earlier genetic research, as well as to interpret newly emerging results that help the development of pathophysiologically oriented models of schizophrenia. We argue that besides genetic research, findings on cognitive function and of imaging studies, as well as gene-expression analyses and pharmacogenetic studies must be interpreted to reach a better understanding of the complex phenomena in schizophrenia. Synthesis of data from the different areas allows speculation about future research and practical implications.

Associative learning in deficit and nondeficit schizophrenia.

When two stimuli are associated and treated as equivalent, generalization occurs between them (acquired equivalence). The feedback-guided learning of associations is related to the basal ganglia, whereas the medial temporal lobe participates in acquired equivalence learning. In this study, we investigated feedback-guided associative learning and acquired equivalence in deficit and nondeficit schizophrenia. Results revealed that acquired equivalence learning was similarly impaired in deficit and nondeficit patients, whereas feedback-guided associative learning was impaired only in deficit patients. Associative learning and acquired equivalence were not related to frontal lobe tests. These results suggest that the enduring negative symptoms of deficit patients may be related to decreased response to cognitive feedback and deficient basal ganglia functioning.

How to find the way out from four rooms? The learning of "chaining" associations may shed light on the neuropsychology of the deficit syndrome of schizophrenia.

Recent meta-analytic evidence suggests that clinical neuropsychological methods are not likely to uncover circumscribed cognitive impairments in the deficit syndrome of schizophrenia. To overcome this issue, we adapted a cognitive neuroscience perspective and used a new "chaining" habit learning task. Participants were requested to navigate a cartoon character through a sequence of 4 rooms by learning to choose the open door from 3 colored doors in each room. The aim of the game was to learn the full sequence of rooms until the character reached the outside. In the training phase, each stimulus leading to reward (open door in each room) was trained via feedback until the complete sequence was learned. In the probe phase, the context of rewarded stimuli was manipulated: in a given room, in addition to the correct door of that room, there also appeared a door which was open in another room. Whereas the training phase is dominantly related to basal ganglia circuits, the context-dependent probe phase requires intact medial-temporal lobe functioning. Results revealed that deficit and non-deficit patients were similarly impaired on the probe phase compared with controls. However, the training phase was only compromised in deficit patients. More severe negative symptoms were associated with more errors on the training phase. Executive functions were unrelated to performance on the "chaining" task. These results indicate that the deficit syndrome is associated with prominently impaired stimulus-response reinforcement learning, which may indicate abnormal functioning of basal ganglia circuits.

[Learning cognitive skills in depression: the effect of context-change]. / Kognitív készségek tanulása depresszióban: a kontextus-váltas hatása.

AIMS: Patients with depression show cognitive impairment, including executive function deficit, impairments in attention, declarative memory and psychomotor performance. In addition to classic, widely studied cognitive functions, in depression implicit learning and the interpretation of feedback and its impact on performance can also be impaired compared to healthy individuals. While cognitive functions have been widely studied, much less is known about implicit learning in depression. METHODS: The two-phased Kilroy sequence association test examines the basal ganglia-mediated and the temporal lobe and hippocampus-mediated learning processes within one test. We compared the performance of 22 depressed patients (according to DSM-IV) and 20 healthy control subjects using the Kilroy test. In the depressed group, we also compared the performance on each step of the test with the symptom severity measured by the Hamilton D symptom scale. RESULTS: Depressed patients showed impaired performance compared to healthy subjects on the first, learning phase of the test. The degree of deficit on the learning phase correlated with symptom severity. We found no difference between the two groups on the second, context-dependent phase of the test. CONCLUSION: Our results confirm the presence of a striatal deficit in depressed patients. Results indicate that parallel memory systems are not equally affected in depression, and the character of deficit in depression may be specific to the illness.

Innovations: Alcohol & drug abuse: Methadone maintenance in Europe and Hungary: degrees of sociocultural resistance.

Opiate substitution treatment, commonly referred to as maintenance treatment, was introduced in the United States and Europe in the 1960s. This column discusses approaches to opioid maintenance treatment in Europe and focuses on the introduction of methadone maintenance treatment in Hungary. Although persons have received methadone maintenance in Hungary since 1987, consensus guidelines were not adopted until 1998 and were not confirmed by the Hungarian parliament until 2000. Hungary encountered initial difficulties in introducing methadone maintenance, and it is hoped that Hungary's joining the European Union in 2004 will help to make opiate substitution treatment more widely available.

[Methadone maintenance: adoption of a new harm reduction approach in Hungary]. / Metadonkezelés: egy ártalomcsökkento módszer meghonosodása Magyarországon.

Methadone with its favourable physiological effects in comparison to heroin has been the most well-known and widely used tool of substitution treatment in heroinism. Research on efficiency has produced evidence of the fact that methadone maintenance as a model method of harm reduction is an efficient treatment of heroin dependent patients if used in the appropriate dose and indication. Due to its addictive effects, there has been some resistance against its worldwide spreading, especially in Central Eastern Europe. Methadone maintenance became a legal medical method in Hungary during the last ten years with approved classified protocol and manual owing to the consistent efforts of addiction-professionals, who were convinced of the treatment's efficacy. The process involved numerous conflicts, police provisions and media scandals. Professional legitimacy of methadone maintenance may hopefully be proved by research on efficiency in the near future.