Fabry's disease and psychosis: causality or coincidence?

A 21-year-old female with Fabry's disease (FD) presented acute psychotic symptoms such as delusions, auditory hallucinations and formal thought disorders. Since the age of 14, she had suffered from various psychiatric symptoms increasing in frequency and intensity. We considered the differential diagnoses of prodromal symptoms of schizophrenia and organic schizophrenia-like disorder. Routine examinations including cognitive testing, electroencephalography and structural magnetic resonance imaging revealed no pathological findings. Additional structural and functional imaging demonstrated a minor CNS involvement of FD, yet without functional limitations. In summary our examination results support the thesis that in the case of our patient a mere coincidence of FD and psychotic symptoms is more likely than a causal connection.

Perception of causality in schizophrenia spectrum disorder

Patients with schizophrenia spectrum disorders often maintain deviating views on cause-effect relationships, especially when positive and disorganization symptoms are manifest. Altered perceived causality is prominent in delusional ideation, in ideas of reference, and in the mentalizing ability (theory of mind [ToM]) of patients. Perceiving causal relationships may be understood either as higher order cognitive reasoning or as low-level information processing. In the present study, perception of causality was investigated as a low-level, preattentional capability similar to gestalt-like perceptual organization. Thirty-one patients (24 men and 7 women with mean age 27.7 years) and the same number of healthy control subjects matched to patients with respect to age and sex were tested. A visual paradigm was used in which 2 identical discs move, from opposite sides of a monitor, steadily toward and then past one another. Their coincidence generates an ambiguous, bistable percept (discs either "stream through" or "bounce off" one another). The bouncing perception, ie, perceived causality, is enhanced when auditory stimuli are presented at the time of coincidence. Psychopathology was measured using the Positive and Negative Syndrome Scale. It was found that positive symptoms were strongly associated with increased perceived causality and disorganization with attenuated perceived causality. Patients in general were not significantly different from controls, but symptom subgroups showed specifically altered perceived causality. Perceived causality as a basic preattentional process may contribute to higher order cognitive alterations and ToM deficiencies. It is suggested that cognitive remediation therapy should address both increased and reduced perception of causality.

In vitro drug causality assessment in Stevens-Johnson syndrome - alternatives for lymphocyte transformation test

BACKGROUND Patients with Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) are often exposed simultaneously to a few potentially culprit drugs. However, both the standard lymphocyte transformation tests (LTT) with proliferation as the assay end-point as well as skin tests, if done, are often negative. OBJECTIVE As provocation tests are considered too dangerous, there is an urgent need to identify the relevant drug in SJS/TEN and to improve sensitivity of tests able to identify the causative drug. METHODS Fifteen patients with SJS/TEN with the ALDEN score ≥ 6 and 18 drug-exposed controls were included. Peripheral blood mononuclear cells (PBMC) were isolated and cultured under defined conditions with drugs. LTT was compared to the following end-points: cytokine levels in cell culture supernatant, number of granzyme B secreting cells by ELISpot and intracellular staining for granulysin and IFNγ in CD3(+) CD4(+), CD3(+) CD8(+) and NKp46(+) cells. To further enhance sensitivity, the effect of IL-7/IL-15 pre-incubation of PBMC was evaluated. RESULTS Lymphocyte transformation tests was positive in only 4/15 patients (sensitivity 27%, CI: 8-55%). Similarly, with granzyme B-ELISpot culprit drugs were positive in 5/15 patients (sensitivity 33%, CI: 12-62%). The expression of granulysin was significantly induced in NKp46(+) and CD3(+) CD4(+) cells (sensitivity 40%, CI: 16-68% and 53%, CI: 27-79% respectively). Cytokine production could be demonstrated in 38%, CI: 14-68% and 43%, CI: 18-71% of patients for IL-2 and IL-5, respectively, and in 55%, CI: 23-83% for IFNγ. Pre-incubation with IL-7/IL-15 enhanced drug-specific response only in a few patients. Specificities of tested assays were in the range of 95 (CI: 80-99%)-100% (CI: 90-100%). CONCLUSIONS AND CLINICAL RELEVANCE Granulysin expression in CD3(+) CD4(+) , Granzyme B-ELISpot and IFNγ production considered together provided a sensitivity of 80% (CI: 52-96%) and specificity of 95% (80-99%). Thus, this study demonstrated that combining different assays may be a feasible approach to identify the causative drug of SJS/TEN reactions; however, confirmation on another group of patients is necessary.

What do brain network interactions tell about cognitive processes? How to seek causality?

Optimal adjustment of brain networks allows the biased processing of information in response to the demand of environments and is therefore prerequisite for adaptive behaviour. It is widely shown that a biased state of networks is associated with a particular cognitive process. However, those associations were identified by backward categorization of trials and cannot provide a causal association with cognitive processes. This problem still remains a big obstacle to advance the state of our field in particular human cognitive neuroscience. In my talk, I will present two approaches to address the causal relationships between brain network interactions and behaviour. Firstly, we combined connectivity analysis of fMRI data and a machine leaning method to predict inter-individual differences of behaviour and responsiveness to environmental demands. The connectivity-based classification approach outperforms local activation-based classification analysis, suggesting that interactions in brain networks carry information of instantaneous cognitive processes. Secondly, we have recently established a brand new method combining transcranial alternating current stimulation (tACS), transcranial magnetic stimulation (TMS), and EEG. We use the method to measure signal transmission between brain areas while introducing extrinsic oscillatory brain activity and to study causal association between oscillatory activity and behaviour. We show that phase-matched oscillatory activity creates the phase-dependent modulation of signal transmission between brain areas, while phase-shifted oscillatory activity blunts the phase-dependent modulation. The results suggest that phase coherence between brain areas plays a cardinal role in signal transmission in the brain networks. In sum, I argue that causal approaches will provide more concreate backbones to cognitive neuroscience.

Imagery of a moving object: the role of occipital cortex and human MT/V5+

Visual imagery – similar to visual perception – activates feature-specific and category-specific visual areas. This is frequently observed in experiments where the instruction is to imagine stimuli that have been shown immediately before the imagery task. Hence, feature-specific activation could be related to the short-term memory retrieval of previously presented sensory information. Here, we investigated mental imagery of stimuli that subjects had not seen before, eliminating the effects of short-term memory. We recorded brain activation using fMRI while subjects performed a behaviourally controlled guided imagery task in predefined retinotopic coordinates to optimize sensitivity in early visual areas. Whole brain analyses revealed activation in a parieto-frontal network and lateral–occipital cortex. Region of interest (ROI) based analyses showed activation in left hMT/V5+. Granger causality mapping taking left hMT/V5+ as source revealed an imagery-specific directed influence from the left inferior parietal lobule (IPL). Interestingly, we observed a negative BOLD response in V1–3 during imagery, modulated by the retinotopic location of the imagined motion trace. Our results indicate that rule-based motion imagery can activate higher-order visual areas involved in motion perception, with a role for top-down directed influences originating in IPL. Lower-order visual areas (V1, V2 and V3) were down-regulated during this type of imagery, possibly reflecting inhibition to avoid visual input from interfering with the imagery construction. This suggests that the activation in early visual areas observed in previous studies might be related to short- or long-term memory retrieval of specific sensory experiences.

Cognitive binding in schizophrenia: weakened integration of temporal intersensory information

Cognitive functioning is based on binding processes, by which different features and elements of neurocognition are integrated and coordinated. Binding is an essential ingredient of, for instance, Gestalt perception. We have implemented a paradigm of causality perception based on the work of Albert Michotte, in which 2 identical discs move from opposite sides of a monitor, steadily toward, and then past one another. Their coincidence generates an ambiguous percept of either "streaming" or "bouncing," which the subjects (34 schizophrenia spectrum patients and 34 controls with mean age 27.9 y) were instructed to report. The latter perception is a marker of the binding processes underlying perceived causality (type I binding). In addition to this visual task, acoustic stimuli were presented at different times during the task (150 ms before and after visual coincidence), which can modulate perceived causality. This modulation by intersensory and temporally delayed stimuli is viewed as a different type of binding (type II). We show here, using a mixed-effects hierarchical analysis, that type II binding distinguishes schizophrenia spectrum patients from healthy controls, whereas type I binding does not. Type I binding may even be excessive in some patients, especially those with positive symptoms; Type II binding, however, was generally attenuated in patients. The present findings point to ways in which the disconnection (or Gestalt) hypothesis of schizophrenia can be refined, suggesting more specific markers of neurocognitive functioning and potential targets of treatment.

Estimating the net contribution of interleukin-28B variation to spontaneous hepatitis C virus clearance

The identification of associations between interleukin-28B (IL-28B) variants and the spontaneous clearance of hepatitis C virus (HCV) raises the issues of causality and the net contribution of host genetics to the trait. To estimate more precisely the net effect of IL-28B genetic variation on HCV clearance, we optimized genotyping and compared the host contributions in multiple- and single-source cohorts to control for viral and demographic effects. The analysis included individuals with chronic or spontaneously cleared HCV infections from a multiple-source cohort (n = 389) and a single-source cohort (n = 71). We performed detailed genotyping in the coding region of IL-28B and searched for copy number variations to identify the genetic variant or haplotype carrying the strongest association with viral clearance. This analysis was used to compare the effects of IL-28B variation in the two cohorts. Haplotypes characterized by carriage of the major alleles at IL-28B single-nucleotide polymorphisms (SNPs) were highly overrepresented in individuals with spontaneous clearance versus those with chronic HCV infections (66.1% versus 38.6%, P = 6 × 10(-9) ). The odds ratios for clearance were 2.1 [95% confidence interval (CI) = 1.6-3.0] and 3.9 (95% CI = 1.5-10.2) in the multiple- and single-source cohorts, respectively. Protective haplotypes were in perfect linkage (r(2) = 1.0) with a nonsynonymous coding variant (rs8103142). Copy number variants were not detected. CONCLUSION: We identified IL-28B haplotypes highly predictive of spontaneous HCV clearance. The high linkage disequilibrium between IL-28B SNPs indicates that association studies need to be complemented by functional experiments to identify single causal variants. The point estimate for the genetic effect was higher in the single-source cohort, which was used to effectively control for viral diversity, sex, and coinfections and, therefore, offered a precise estimate of the net host genetic contribution.