Publications by authors named "Jochen Kindler"

36 Publications

Excessive and pathological Internet use - Risk-behavior or psychopathology?

Addict Behav 2021 12 9;123:107045. Epub 2021 Jul 9.

National Centre for Suicide Research and Prevention of Mental Ill-Health (NASP), Karolinska Institutet, Stockholm, Sweden.

Pathological Internet use (but only with respect to gaming) is classified as mental disorder in the ICD-11. However, there is a large group of adolescents showing excessive Internet use, which may rather be considered adolescent risk-behavior. The aim was to test whether pathological and excessive Internet use should be considered as "psychopathology" or "risk-behavior". A representative, cross-sectional sample of 11.110 students from 10 European Union countries was analyzed. Structural equation models, including the factors "risk-behavior" and "psychopathology" and the variables excessive and pathological Internet use, were tested against each other. "Risk-behavior" was operationalized by several risk-behaviors (e.g. drug abuse, truancy, etc). "Psychopathology" included measures of several mental disorders (e.g. depression, hyperactivity, etc). Excessive Internet use was assessed as the duration and frequency of Internet use. Pathological Internet use was assessed with the Young Diagnostic Questionnaire (i.e., presence of addiction criteria). Excessive Internet use loaded on "risk-behavior" (λ = 0.484, p < .001) and on "psychopathology" (λ = 0.071, p < .007). Pathological Internet use loaded on "risk-behavior" (λ = 0.333, p < .001) and on "psychopathology" (λ = 0.852, p < .001). Chi-square tests determined that the loadings of excessive Internet use (χ (1) = 81.98, p < .001) were significantly stronger on "risk-behavior" than "psychopathology". Vice versa, pathological Internet use loaded significantly stronger on "psychopathology" (χ (1) = 107.10, p < .001). The results indicate that pathological Internet use should rather be considered as psychopathology. Excessive Internet use on the other hand, should be classified as adolescent risk-behavior.
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http://dx.doi.org/10.1016/j.addbeh.2021.107045DOI Listing
December 2021

The Bern Early Recognition and Intervention Centre for mental crisis (FETZ Bern)-An 8-year evaluation.

Early Interv Psychiatry 2021 May 6. Epub 2021 May 6.

University Hospital of Child and Adolescent Psychiatry and Psychotherapy, University of Bern, Bern, Switzerland.

Aim: Early detection of, and intervention for, psychosis during its prodromal phase has the potential to alter the course of the disease and has therefore become a major objective of modern clinical psychiatry. An increasing number of early detection and intervention services have been established in Europe and worldwide. This study aims to describe and evaluate an early detection and intervention service for children, adolescents and adults (FETZ Bern) aged from eight to 40 years with a population catchment area of 1.035 million in Bern, Switzerland.

Methods: Routine demographic, diagnostic and service usage data were collected upon admission to the service. Using a retrospective, descriptive and naturalistic study design, data was analysed for different age groups (children, adolescents and adults) and where available, outcome data after 12 and 24 months was evaluated.

Results: The FETZ Bern has received 827 referrals with full diagnostic data available for 353 patients. The majority of the assessed patients were young males. While 40% met criteria for a clinical high-risk state of psychosis, 20% were diagnosed with fully manifest psychosis at time of admission, and another 40% had one or more non-psychotic axis-I diagnoses.

Conclusions: The FETZ Bern is the first early detection centre worldwide assessing children aged younger than 12 years, as well as adolescents and young adults in one service. Given that developmental peculiarities are important in understanding and ultimately treating psychosis, the FETZ Bern, with its emphasis on developmental peculiarities, should be considered as a model for other similar services.
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http://dx.doi.org/10.1111/eip.13160DOI Listing
May 2021

Association of Structural Magnetic Resonance Imaging Measures With Psychosis Onset in Individuals at Clinical High Risk for Developing Psychosis: An ENIGMA Working Group Mega-analysis.

JAMA Psychiatry 2021 Jul;78(7):753-766

Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York.

Importance: The ENIGMA clinical high risk (CHR) for psychosis initiative, the largest pooled neuroimaging sample of individuals at CHR to date, aims to discover robust neurobiological markers of psychosis risk.

Objective: To investigate baseline structural neuroimaging differences between individuals at CHR and healthy controls as well as between participants at CHR who later developed a psychotic disorder (CHR-PS+) and those who did not (CHR-PS-).

Design, Setting, And Participants: In this case-control study, baseline T1-weighted magnetic resonance imaging (MRI) data were pooled from 31 international sites participating in the ENIGMA Clinical High Risk for Psychosis Working Group. CHR status was assessed using the Comprehensive Assessment of At-Risk Mental States or Structured Interview for Prodromal Syndromes. MRI scans were processed using harmonized protocols and analyzed within a mega-analysis and meta-analysis framework from January to October 2020.

Main Outcomes And Measures: Measures of regional cortical thickness (CT), surface area, and subcortical volumes were extracted from T1-weighted MRI scans. Independent variables were group (CHR group vs control group) and conversion status (CHR-PS+ group vs CHR-PS- group vs control group).

Results: Of the 3169 included participants, 1428 (45.1%) were female, and the mean (SD; range) age was 21.1 (4.9; 9.5-39.9) years. This study included 1792 individuals at CHR and 1377 healthy controls. Using longitudinal clinical information, 253 in the CHR-PS+ group, 1234 in the CHR-PS- group, and 305 at CHR without follow-up data were identified. Compared with healthy controls, individuals at CHR exhibited widespread lower CT measures (mean [range] Cohen d = -0.13 [-0.17 to -0.09]), but not surface area or subcortical volume. Lower CT measures in the fusiform, superior temporal, and paracentral regions were associated with psychosis conversion (mean Cohen d = -0.22; 95% CI, -0.35 to 0.10). Among healthy controls, compared with those in the CHR-PS+ group, age showed a stronger negative association with left fusiform CT measures (F = 9.8; P < .001; q < .001) and left paracentral CT measures (F = 5.9; P = .005; q = .02). Effect sizes representing lower CT associated with psychosis conversion resembled patterns of CT differences observed in ENIGMA studies of schizophrenia (ρ = 0.35; 95% CI, 0.12 to 0.55; P = .004) and individuals with 22q11.2 microdeletion syndrome and a psychotic disorder diagnosis (ρ = 0.43; 95% CI, 0.20 to 0.61; P = .001).

Conclusions And Relevance: This study provides evidence for widespread subtle, lower CT measures in individuals at CHR. The pattern of CT measure differences in those in the CHR-PS+ group was similar to those reported in other large-scale investigations of psychosis. Additionally, a subset of these regions displayed abnormal age associations. Widespread disruptions in CT coupled with abnormal age associations in those at CHR may point to disruptions in postnatal brain developmental processes.
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http://dx.doi.org/10.1001/jamapsychiatry.2021.0638DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100913PMC
July 2021

Trapped in a Glass Bell Jar: Neural Correlates of Depersonalization and Derealization in Subjects at Clinical High-Risk of Psychosis and Depersonalization-Derealization Disorder.

Front Psychiatry 2020 11;11:535652. Epub 2020 Sep 11.

University Hospital of Child and Adolescent Psychiatry and Psychotherapy, University of Bern, Bern, Switzerland.

Background: Depersonalization (DP) and derealization (DR) are symptoms of a disruption of perceptual integration leading to an altered quality of subjective experiences such as feelings of unreality and detachment from the self (DP) or the surroundings (DR). Both DP and DR often occur in concert with other symptoms, for example in subjects at clinical high-risk (CHR) for psychosis, but also appear isolated in the form of DP/DR disorder. Despite evidence that DP/DR causes immense distress, little is known about their neurobiological underpinnings. Therefore, we investigated the neural correlates of DP/DR using pseudo-continuous arterial spin labeling MRI.

Methods: We evaluated the frequency of DP/DR symptoms in a clinical sample (N = 217) of help-seeking individuals from the Early Detection and Intervention Centre for Mental Crisis (CHR, n = 97; clinical controls (CC), n = 91; and first-episode psychosis (FEP), n = 29). Further, in a subsample of those CHR subjects who underwent MRI, we investigated the resting-state regional cerebral blood flow (rCBF). Here, individuals with (n = 21) and without (n = 23) DP/DR were contrasted. Finally, rCBF was measured in a small independent second sample of patients with DP/DR disorder (n = 6) and healthy controls (HC, n = 6).

Results: In the complete clinical sample, significantly higher frequency of DP/DR was found in CHR compared to CC (50.5 16.5%; χ = 24.218, p ≤ 0.001, Cramer's V = 0.359) as well as in FEP compared to CC (37.9 16.5%; χ = 5.960, = 0.015, Cramer's V = 0.223). In MRI, significantly lower rCBF was detected in the left orbitofrontal cortex in CHR with without DP/DR (x/y/z = -16/42/-22, p < 0.05, FWE corrected). In patients with DP/DR disorder, significantly higher rCBF was detected in the left caudate nucleus (x/y/z = -18/-32/18, p < 0.05) compared to HC.

Conclusions: This study shows that DP/DR symptoms are frequently found in CHR subjects. Investigating two separate DP/DR populations with an identical neuroimaging technique, our study also indicates that there may be divergent pathophysiological mechanisms-decreased neuronal activity in the orbitofrontal cortex, but increased activity within the caudate nucleus-leading to a final common pathway with similar psychopathological symptoms. This suggests that both top-down (orbitofrontal cortex) and bottom-up (caudate nucleus) mechanisms could contribute to the emergence of DP/DR.
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http://dx.doi.org/10.3389/fpsyt.2020.535652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7516266PMC
September 2020

Basic symptoms and gray matter volumes of patients at clinical high risk for psychosis.

Psychol Med 2020 May 14:1-9. Epub 2020 May 14.

University Hospital of Child and Adolescent Psychiatry and Psychotherapy, University of Bern, Switzerland.

Background: Clinical high-risk (CHR) for psychosis is indicated by ultra-high risk (UHR) and basic symptom (BS) criteria; however, conversion rates are highest when both UHR and BS criteria are fulfilled (UHR&BS). While BSs are considered the most immediate expression of neurobiological aberrations underlying the development of psychosis, research on neurobiological correlates of BS is scarce.

Methods: We investigated gray matter volumes (GMV) of 20 regions of interest (ROI) previously associated with UHR criteria in 90 patients from the Bern early detection service: clinical controls (CC), first-episode psychosis (FEP), UHR, BS and UHR&BS. We expected lowest GMV in FEP and UHR&BS, and highest volume in CC with UHR and BS in-between.

Results: Significantly, lower GMV was detected in FEP and UHR&BS patients relative to CC with no other significant between-group differences. When ROIs were analyzed separately, seven showed a significant group effect (FDR corrected), with five (inferior parietal, medial orbitofrontal, lateral occipital, middle temporal, precuneus) showing significantly lower GM volume in the FEP and/or UHR&BS groups than in the CC group (Bonferroni corrected). In the CHR group, only COGDIS scores correlated negatively with cortical volumes.

Conclusions: This is the first study to demonstrate that patients who fulfill both UHR and BS criteria - a population that has been associated with higher conversion rates - exhibit more severe GMV reductions relative to those who satisfy BS or UHR criteria alone. This result was mediated by the BS in the UHR&BS group, as only the severity of BS was linked to GMV reductions.
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http://dx.doi.org/10.1017/S0033291720001282DOI Listing
May 2020

Functional and structural correlates of abnormal involuntary movements in psychosis risk and first episode psychosis.

Schizophr Res 2019 10 9;212:196-203. Epub 2019 Aug 9.

Translational Research Center, University Hospital of Psychiatry, University of Bern, Bern, Switzerland.

Background: Abnormal involuntary movements (AIM) may occur throughout the course of psychosis. While AIM are thought to indicate striatal abnormalities, the functional and structural correlates of increased AIM remain elusive. Here, we examined the prevalence of AIM in patients with clinical high risk for psychosis (CHR), first episode psychosis (FEP) and clinical controls (CC). Furthermore, we tested the association of AIM with regional cerebral blood flow (rCBF), grey matter volume (GMV), and premorbid IQ.

Methods: We conducted a video-based analysis of AIM in patients with CHR (n = 45), FEP (n = 10) and CC (n = 39), recruited in the Early Detection and Intervention Center, Bern. Premorbid intelligence was evaluated using the Peabody Picture Vocabulary test. Additionally, arterial spin labeling MRIs and structural MRIs were acquired in a subgroup of the sample to investigate the association of AIM with rCBF and GMV.

Results: Higher total AIM scores were detected in CHR (p = 0.02) and FEP (p = 0.04) as compared to CC. When separated for different muscle groups, lips and perioral movements were significantly increased in CHR patients as compared to CC (p = 0.009). AIM scores correlated positively with rCBF in the premotor cortex, Brodmann area 6 (p < 0.05, FWE corrected). Negative correlations were found between AIM and GMV of the corresponding caudal middle frontal gyrus (p = 0.04, FWE corrected) and premorbid intelligence (p = 0.02).

Conclusions: AIM were more frequent in the psychosis spectrum than in clinical controls. Neuroimaging findings indicate an involvement of cortical motor areas in abnormal motor behavior, instead of pure basal ganglia pathology.
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http://dx.doi.org/10.1016/j.schres.2019.07.032DOI Listing
October 2019

Dysregulation of kynurenine metabolism is related to proinflammatory cytokines, attention, and prefrontal cortex volume in schizophrenia.

Mol Psychiatry 2020 11 3;25(11):2860-2872. Epub 2019 Apr 3.

School of Psychiatry, University of New South Wales, Randwick, NSW, 2031, Australia.

The kynurenine pathway (KP) of tryptophan (TRP) catabolism links immune system activation with neurotransmitter signaling. The KP metabolite kynurenic acid (KYNA) is increased in the brains of people with schizophrenia. We tested the extent to which: (1) brain KP enzyme mRNAs, (2) brain KP metabolites, and (3) plasma KP metabolites differed on the basis of elevated cytokines in schizophrenia vs. control groups and the extent to which plasma KP metabolites were associated with cognition and brain volume in patients displaying elevated peripheral cytokines. KP enzyme mRNAs and metabolites were assayed in two independent postmortem brain samples from a total of 71 patients with schizophrenia and 72 controls. Plasma KP metabolites, cognition, and brain volumes were measured in an independent cohort of 96 patients with schizophrenia and 81 healthy controls. Groups were stratified based on elevated vs. normal proinflammatory cytokine mRNA levels. In the prefrontal cortex (PFC), kynurenine (KYN)/TRP ratio, KYNA levels, and mRNA for enzymes, tryptophan dioxygenase (TDO) and kynurenine aminotransferases (KATI/II), were significantly increased in the high cytokine schizophrenia subgroup. KAT mRNAs significantly correlated with mRNA for glial fibrillary acidic protein in patients. In plasma, the high cytokine schizophrenia subgroup displayed an elevated KYN/TRP ratio, which correlated inversely with attention and dorsolateral prefrontal cortex (DLPFC) volume. This study provides further evidence for the role of inflammation in a subgroup of patients with schizophrenia and suggests a molecular mechanism through which inflammation could lead to schizophrenia. Proinflammatory cytokines may elicit conversion of TRP to KYN in the periphery and increase the N-methyl-D-aspartate receptor antagonist KYNA via increased KAT mRNA and possibly more enzyme synthesis activity in brain astrocytes,  leading to DLPFC volume loss, and attention impairment in schizophrenia.
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http://dx.doi.org/10.1038/s41380-019-0401-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577855PMC
November 2020

The trait-state distinction between schizotypy and clinical high risk: results from a one-year follow-up.

World Psychiatry 2019 Feb;18(1):108-109

University Hospital of Child and Adolescent Psychiatry and Psychotherapy, University of Bern, Bern, Switzerland.

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http://dx.doi.org/10.1002/wps.20595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6313228PMC
February 2019

Age effects on basic symptoms in the community: A route to gain new insight into the neurodevelopment of psychosis?

Eur Arch Psychiatry Clin Neurosci 2020 Apr 25;270(3):311-324. Epub 2018 Oct 25.

University Hospital of Child and Adolescent Psychiatry and Psychotherapy, University of Bern, Bern, Switzerland.

Reports of limited clinical significance of attenuated psychotic symptoms before age 15/16 indicate an important role of neurodevelopment in the early detection of psychoses. Therefore, we examined if age also exerts an influence on the prevalence and clinical significance of the 14 cognitive and perceptive basic symptoms (BS) used in psychosis-risk criteria and conceptualized as the most direct self-experienced expression of neurobiological aberrations. A random representative general population sample of the Swiss canton Bern (N = 689, age 8-40 years, 06/2011-05/2014) was interviewed for BS, psychosocial functioning, and current mental disorder. BS were reported by 18% of participants, mainly cognitive BS (15%). In regression analyses, age affected perceptive and cognitive BS differently, indicating an age threshold for perceptive BS in late adolescence (around age 18) and for cognitive BS in young adulthood (early twenties)-with higher prevalence, but a lesser association with functional deficits and the presence of mental disorder in the below-threshold groups. Thereby, interaction effects between age and BS on functioning and mental disorder were commonly stronger than individual effects of age and BS. Indicating support of the proposed "substrate-closeness" of BS, differential age effects of perceptual and cognitive BS seem to follow normal brain maturation processes, in which they might occur as infrequent and temporary non-pathological disturbances. Their persistence or occurrence after conclusion of main brain maturation processes, however, might signify aberrant maturation or neurodegenerative processes. Thus, BS might provide important insight into the pathogenesis of psychosis and into differential neuroprotective or anti-inflammatory targets.
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http://dx.doi.org/10.1007/s00406-018-0949-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7069926PMC
April 2020

Striatal cerebral blood flow, executive functioning, and fronto-striatal functional connectivity in clinical high risk for psychosis.

Schizophr Res 2018 11 6;201:231-236. Epub 2018 Jul 6.

University Hospital of Child and Adolescent Psychiatry and Psychotherapy, University of Bern, Bern, Switzerland. Electronic address:

Background: Patients at clinical high risk (CHR) for psychosis exhibit increased striatal cerebral blood flow (CBF) during the resting state and impaired cognitive function. However, the relation between CBF and cognitive impairment is unknown. We therefore studied the association between striatal CBF and executive functioning and evaluated the functional connectivity (FC) between dorsal striatum and the frontal cortex in CHR.

Methods: In total, 47 participants [29 with CHR, 18 matched clinical controls (CC)] were assessed for ultra-high-risk criteria and basic symptoms and were tested for executive functioning using the trail making test-B (TMT-B). Resting state mean CBF and FC were calculated from arterial spin labeling 3T MRI data.

Results: Striatal CBF was highest in CHR patients with TMT-B deficits and was significantly higher than that in CC with and without TMT-B impairment. Further, a significantly lower CBF FC between the dorsal striatum and the anterior cingulate cortex was revealed in CHR.

Conclusions: Our study suggests that higher striatal CBF might represent focal pathology in CHR and is associated with disrupted cingulo-striatal FC and executive dysfunctions.
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http://dx.doi.org/10.1016/j.schres.2018.06.018DOI Listing
November 2018

Increased Striatal and Reduced Prefrontal Cerebral Blood Flow in Clinical High Risk for Psychosis.

Schizophr Bull 2018 01;44(1):182-192

Translational Research Center, University Hospital of Psychiatry, University of Bern, Bern, Switzerland.

Increased striatal dopaminergic activity and decreased prefrontal functioning have been reported in individuals at clinical high risk (CHR) for psychosis. Abnormal metabolic rate might affect resting-state cerebral blood flow (rCBF) in the respective regions. Here, we examined if striatal and prefrontal rCBF differ between patients with CHR, first-episode psychosis (FEP), chronic schizophrenia-spectrum disorder (SZ) and controls. Two cohorts with a total of 122 participants were included and analyzed separately: 32 patients with SZ and 31 healthy controls (HC) from the University Hospital of Psychiatry, and 59 patients from the Bern Early Recognition and Intervention Center (29 with CHR, 12 with FEP, and 18 clinical controls [CC]). Ultra-high risk criteria were assessed with the Structured Interview for Psychosis-Risk Syndromes, basic symptom criteria with the Schizophrenia Proneness Instrument. rCBF was measured with pseudo-continuous arterial spin labeling 3T-Magnetic Resonance Imaging. Striatal rCBF was significantly increased and prefrontal rCBF significantly decreased in the SZ group compared to HC group and in the CHR and FEP groups compared to CC group. Striatal rCBF correlated significantly with positive symptom scores in SZ and CHR. An inverse correlation between striatal and frontal rCBF was found in controls (HC, CC), but not in patient groups (SZ, FEP, CHR). This is the first study to demonstrate increased neuronal activity within the striatum, but reduced prefrontal activity in patients with CHR, FEP, and SZ compared to the respective controls. Our results indicate that alterations in striatal and prefrontal rCBF are reflecting metabolic abnormalities preceding the onset of frank psychosis.
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http://dx.doi.org/10.1093/schbul/sbx070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5768043PMC
January 2018

Raloxifene increases prefrontal activity during emotional inhibition in schizophrenia based on estrogen receptor genotype.

Eur Neuropsychopharmacol 2016 12 12;26(12):1930-1940. Epub 2016 Nov 12.

School of Psychiatry, University of New South Wales, Randwick, NSW 2031 Australia; Neuroscience Research Australia, Randwick, NSW 2031, Australia; Schizophrenia Research Institute, Randwick, NSW 2031 Australia. Electronic address:

People with schizophrenia show decreased prefrontal cortex (PFC) activity during emotional response inhibition, a cognitive process sensitive to hormonal influences. Raloxifene, a selective estrogen receptor modulator, binds estrogen receptor alpha (ESR-α), improves memory, attention and normalizes cortical and hippocampal activity during learning and emotional face recognition in schizophrenia. Here, we tested the extent to which raloxifene restores neuronal activity during emotional response inhibition in schizophrenia. Since genetic variation in estrogen receptor alpha (ESR-1) determines cortical ESR-α production and correlates with cognition, we also predicted that genetic ESR-1 variation would differentially relate to increased cortical activity by raloxifene administration. Thirty people with schizophrenia participated in a thirteen-week randomized, double-blind, placebo-controlled, cross-over adjunctive treatment trial of raloxifene administered at 120mg/day. Effects of raloxifene on brain activation were assessed based on ESR-1 genotype using functional magnetic resonance imaging during emotional word inhibition. Raloxifene increased PFC activity during inhibition of response to negative words and the raloxifene related increased PFC activity was greater in patients homozygous for ESR-1 rs9340799 AA relative to G carriers. Comparison to 23 healthy controls demonstrated that PFC activity of people with schizophrenia receiving raloxifene was more similar to controls than to their own brain activity during placebo. Estrogen receptor modulation by raloxifene restores PFC activity during emotional response inhibition in schizophrenia and ESR-1 genotype predicts degree of increased neural activity in response to raloxifene. While these preliminary results require replication, they suggest the potential for personalized pharmacotherapy using ESR-1 and estrogen receptor targeting compounds in schizophrenia.
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http://dx.doi.org/10.1016/j.euroneuro.2016.10.009DOI Listing
December 2016

Disturbances of Agency and Ownership in Schizophrenia: An Auditory Verbal Event Related Potentials Study.

Brain Topogr 2016 09 21;29(5):716-27. Epub 2016 May 21.

Translational Research Center, University Hospital of Psychiatry, University of Bern, 3000, Bern 60, Switzerland.

A 'sense of self' is essentially the ability to distinguish between self-generated and external stimuli. It consists of at least two very basic senses: a sense of agency and a sense of ownership. Disturbances seem to provide a basic deficit in many psychiatric diseases. The aim of our study was to manipulate those qualities separately in 28 patients with schizophrenia (14 auditory hallucinators and 14 non-hallucinators) and 28 healthy controls (HC) and to investigate the effects on the topographies and the power of the event-related potential (ERP). We performed a 76-channel EEG while the participants performed the task as in our previous paper. We computed ERPs and difference maps for the conditions and compared the amount of agency and ownership between the HC and the patients. Furthermore, we compared the global field power and the topographies of these effects. Our data showed effects of agency and ownership in the healthy controls and the hallucinator group and to a lesser degree in the non-hallucinator group. We found a reduction of the N100 during the presence of agency, and a bilateral temporal negativity related to the presence of ownership. For the agency effects, we found significant differences between HC and the patients. Contrary to the expectations, our findings were more pronounced in non-hallucinators, suggesting a more profoundly disturbed sense of agency compared to hallucinators. A contemporary increase of global field power in both patient groups indicates a compensatory recruitment of other mechanisms not normally associated with the processing of agency and ownership.
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http://dx.doi.org/10.1007/s10548-016-0495-1DOI Listing
September 2016

Abnormal involuntary movements are linked to psychosis-risk in children and adolescents: Results of a population-based study.

Schizophr Res 2016 07 7;174(1-3):58-64. Epub 2016 May 7.

University Hospital of Psychiatry and Psychotherapy, University of Bern, Bolligenstrasse 111, 3000 Bern 60, Switzerland.

Background: Altered motor behavior has consistently been reported in medication-naive adult patients with schizophrenia and first episode psychosis and adults at clinical high risk for psychosis (CHR). This study is the first to evaluate the prevalence of abnormal involuntary movements in a community sample of children and adolescents with and without CHR.

Methods: We examined CHR in 102 children and adolescents aged 8-17years from the general population of the Canton Bern. Attenuated and brief intermittent psychotic symptoms, as well as basic symptoms, were assessed using the Structured Interview for Psychosis Risk Syndromes and the Schizophrenia Proneness Instrument, Child & Youth Version. Motor symptoms were assessed using the Abnormal Involuntary Movement Scale (AIMS). Additionally, psychosocial functioning, a neurocognitive test battery, and DSM-IV Axis I disorders were examined.

Results: Eleven (10.8%) participants met CHR criteria, 13 (12.7%, 5 with and 8 without CHR) met criteria for increased abnormal involuntary movements (AIMS≥2). Both AIMS total scores and the percentage of children with AIMS≥2 were significantly higher in the CHR group. Psychosocial functioning was reduced in subjects with abnormal involuntary movements, and movement abnormalities were linked to deficits in attention and perception but not to the presence of non-psychotic mental disorders.

Conclusions: Our findings suggest that abnormal involuntary movements are linked to psychosis risk in children and adolescents from the general population. Thus, abnormal involuntary movements might represent an additional useful and easily accessible predictor of psychosis.
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http://dx.doi.org/10.1016/j.schres.2016.04.032DOI Listing
July 2016

Revisiting the Basic Symptom Concept: Toward Translating Risk Symptoms for Psychosis into Neurobiological Targets.

Front Psychiatry 2016 28;7. Epub 2016 Jan 28.

Institute of Neuroscience and Psychology, University of Glasgow , Glasgow , UK.

In its initial formulation, the concept of basic symptoms (BSs) integrated findings on the early symptomatic course of schizophrenia and first in vivo evidence of accompanying brain aberrations. It argued that the subtle subclinical disturbances in mental processes described as BSs were the most direct self-experienced expression of the underlying neurobiological aberrations of the disease. Other characteristic symptoms of psychosis (e.g., delusions and hallucinations) were conceptualized as secondary phenomena, resulting from dysfunctional beliefs and suboptimal coping styles with emerging BSs and/or concomitant stressors. While BSs can occur in many mental disorders, in particular affective disorders, a subset of perceptive and cognitive BSs appear to be specific to psychosis and are currently employed in two alternative risk criteria. However, despite their clinical recognition in the early detection of psychosis, neurobiological research on the aetiopathology of psychosis with neuroimaging methods has only just begun to consider the neural correlate of BSs. This perspective paper reviews the emerging evidence of an association between BSs and aberrant brain activation, connectivity patterns, and metabolism, and outlines promising routes for the use of BSs in aetiopathological research on psychosis.
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http://dx.doi.org/10.3389/fpsyt.2016.00009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4729935PMC
February 2016

Selective Estrogen Receptor Modulation Increases Hippocampal Activity during Probabilistic Association Learning in Schizophrenia.

Neuropsychopharmacology 2015 Sep 1;40(10):2388-97. Epub 2015 Apr 1.

1] School of Psychiatry, University of New South Wales, Randwick, NSW, Australia [2] Neuroscience Research Australia, Randwick, NSW, Australia [3] Schizophrenia Research Institute, Darlinghurst, NSW, Australia.

People with schizophrenia show probabilistic association learning impairment in conjunction with abnormal neural activity. The selective estrogen receptor modulator (SERM) raloxifene preserves neural activity during memory in healthy older men and improves memory in schizophrenia. Here, we tested the extent to which raloxifene modifies neural activity during learning in schizophrenia. Nineteen people with schizophrenia participated in a twelve-week randomized, double-blind, placebo-controlled, cross-over adjunctive treatment trial of the SERM raloxifene administered orally at 120 mg daily to assess brain activity during probabilistic association learning using functional magnetic resonance imaging (fMRI). Raloxifene improved probabilistic association learning and significantly increased fMRI BOLD activity in the hippocampus and parahippocampal gyrus relative to placebo. A separate region of interest confirmatory analysis in 21 patients vs 36 healthy controls showed a positive association between parahippocampal neural activity and learning in patients, but no such relationship in the parahippocampal gyrus of healthy controls. Thus, selective estrogen receptor modulation by raloxifene concurrently increases activity in the parahippocampal gyrus and improves probabilistic association learning in schizophrenia. These results support a role for estrogen receptor modulation of mesial temporal lobe neural activity in the remediation of learning disabilities in both men and women with schizophrenia.
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http://dx.doi.org/10.1038/npp.2015.88DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4538353PMC
September 2015

Symptom dimensions of the psychotic symptom rating scales in psychosis: a multisite study.

Schizophr Bull 2014 Jul;40 Suppl 4:S265-74

Fraser North Early Psychosis Program, Royal Columbian Hospital, New Westminster, British Columbia, Canada.

The Psychotic Symptom Rating Scales (PSYRATS) is an instrument designed to quantify the severity of delusions and hallucinations and is typically used in research studies and clinical settings focusing on people with psychosis and schizophrenia. It is comprised of the auditory hallucinations (AHS) and delusions subscales (DS), but these subscales do not necessarily reflect the psychological constructs causing intercorrelation between clusters of scale items. Identification of these constructs is important in some clinical and research contexts because item clustering may be caused by underlying etiological processes of interest. Previous attempts to identify these constructs have produced conflicting results. In this study, we compiled PSYRATS data from 12 sites in 7 countries, comprising 711 participants for AHS and 520 for DS. We compared previously proposed and novel models of underlying constructs using structural equation modeling. For the AHS, a novel 4-dimensional model provided the best fit, with latent variables labeled Distress (negative content, distress, and control), Frequency (frequency, duration, and disruption), Attribution (location and origin of voices), and Loudness (loudness item only). For the DS, a 2-dimensional solution was confirmed, with latent variables labeled Distress (amount/intensity) and Frequency (preoccupation, conviction, and disruption). The within-AHS and within-DS dimension intercorrelations were higher than those between subscales, with the exception of the AHS and DS Distress dimensions, which produced a correlation that approached the range of the within-scale correlations. Recommendations are provided for integrating these underlying constructs into research and clinical applications of the PSYRATS.
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http://dx.doi.org/10.1093/schbul/sbu014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4141314PMC
July 2014

Agency and ownership are independent components of 'sensing the self' in the auditory-verbal domain.

Brain Topogr 2014 Sep 28;27(5):672-82. Epub 2014 Jan 28.

Department of Psychiatric Neurophysiology, University Hospital of Psychiatry, Bolligenstrasse 111, CH-3000, Bern 60, Switzerland,

'Sensing the self' relies on the ability to distinguish self-generated from external stimuli. It requires functioning mechanisms to establish feelings of agency and ownership. Agency is defined causally, where the subjects action is followed by an effect. Ownership is defined by the features of the effect, independent from the action. In our study, we manipulated these qualities separately. 13 right-handed healthy individuals performed the experiment while 76-channel EEG was recorded. Stimuli consisted of visually presented words, read aloud by the subject. The experiment consisted of six conditions: (a) subjects saw a word, read it aloud, heard it in their own voice; (b) like a, but the word was heard in an unfamiliar voice; (c) subject heard a word in his/her own voice without speaking; (d) like c, but the word was heard in an unfamiliar voice; (e) like a, but subjects heard the word with a delay; (f) subjects read without hearing. ERPs and difference maps were computed for all conditions. Effects were analysed topographically. The N100 (86-172 ms) displayed significant main effects of agency and ownership. The topographies of the two effects shared little common variance, suggesting independent effects. Later effects (174-400 ms) of agency and ownership were topographically similar, suggesting common mechanisms. Replicating earlier studies, significant N100 suppression was observed, with a topography resembling the agency effect. 'Sensing the self' appears to recruit from at least two very distinct processes: an agency assessment that represents causality and an ownership assessment that compares stimulus features with memory content.
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http://dx.doi.org/10.1007/s10548-014-0351-0DOI Listing
September 2014

Static and dynamic characteristics of cerebral blood flow during the resting state in schizophrenia.

Schizophr Bull 2015 Jan 10;41(1):163-70. Epub 2013 Dec 10.

Department of Psychiatric Neurophysiology, University Hospital of Psychiatry, University of Bern, Bern, Switzerland;

Background: The cerebral network that is active during rest and is deactivated during goal-oriented activity is called the default mode network (DMN). It appears to be involved in self-referential mental activity. Atypical functional connectivity in the DMN has been observed in schizophrenia. One hypothesis suggests that pathologically increased DMN connectivity in schizophrenia is linked with a main symptom of psychosis, namely, misattribution of thoughts.

Methods: A resting-state pseudocontinuous arterial spin labeling (ASL) study was conducted to measure absolute cerebral blood flow (CBF) in 34 schizophrenia patients and 27 healthy controls. Using independent component analysis (ICA), the DMN was extracted from ASL data. Mean CBF and DMN connectivity were compared between groups using a 2-sample t test.

Results: Schizophrenia patients showed decreased mean CBF in the frontal and temporal regions (P < .001). ICA demonstrated significantly increased DMN connectivity in the precuneus (x/y/z = -16/-64/38) in patients than in controls (P < .001). CBF was not elevated in the respective regions. DMN connectivity in the precuneus was significantly correlated with the Positive and Negative Syndrome Scale scores (P < .01).

Conclusions: In schizophrenia patients, the posterior hub--which is considered the strongest part of the DMN--showed increased DMN connectivity. We hypothesize that this increase hinders the deactivation of the DMN and, thus, the translation of cognitive processes from an internal to an external focus. This might explain symptoms related to defective self-monitoring, such as auditory verbal hallucinations or ego disturbances.
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http://dx.doi.org/10.1093/schbul/sbt180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4266282PMC
January 2015

Repeated measurements of cerebral blood flow in the left superior temporal gyrus reveal tonic hyperactivity in patients with auditory verbal hallucinations: a possible trait marker.

Front Hum Neurosci 2013 25;7:304. Epub 2013 Jun 25.

Department of Psychiatric Neurophysiology, University Hospital of Psychiatry, University of Bern Bern, Switzerland.

Background: The left superior temporal gyrus (STG) has been suggested to play a key role in auditory verbal hallucinations (AVH) in patients with schizophrenia.

Methods: Eleven medicated subjects with schizophrenia and medication-resistant AVH and 19 healthy controls underwent perfusion magnetic resonance (MR) imaging with arterial spin labeling (ASL). Three additional repeated measurements were conducted in the patients. Patients underwent a treatment with transcranial magnetic stimulation (TMS) between the first 2 measurements. The main outcome measure was the pooled cerebral blood flow (CBF), which consisted of the regional CBF measurement in the left STG and the global CBF measurement in the whole brain.

Results: Regional CBF in the left STG in patients was significantly higher compared to controls (p < 0.0001) and to the global CBF in patients (p < 0.004) at baseline. Regional CBF in the left STG remained significantly increased compared to the global CBF in patients across time (p < 0.0007), and it remained increased in patients after TMS compared to the baseline CBF in controls (p < 0.0001). After TMS, PANSS (p = 0.003) and PSYRATS (p = 0.01) scores decreased significantly in patients.

Conclusions: This study demonstrated tonically increased regional CBF in the left STG in patients with schizophrenia and auditory hallucinations despite a decrease in symptoms after TMS. These findings were consistent with what has previously been termed a trait marker of AVH in schizophrenia.
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http://dx.doi.org/10.3389/fnhum.2013.00304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3691504PMC
June 2013

Theta burst transcranial magnetic stimulation for the treatment of auditory verbal hallucinations: results of a randomized controlled study.

Psychiatry Res 2013 Aug 4;209(1):114-7. Epub 2013 May 4.

Department of Psychiatric Neurophysiology, University Hospital of Psychiatry, University of Bern, Bolligenstrasse 111, CH-3000 Bern 60, Switzerland.

One Hertz (1 Hz) repetitive transcranial magnetic stimulation (rTMS) is an effective therapy for auditory verbal hallucinations (AVH). Theta burst protocols (TBS) show longer after-effects. This single-blind, randomized controlled study compared continuous TBS with 1Hz rTMS in a 10-day treatment. Patients were diagnosed with schizophrenia or schizoaffective disorder. TBS demonstrated equal clinical effects compared to 1Hz TMS.
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http://dx.doi.org/10.1016/j.psychres.2013.03.029DOI Listing
August 2013

Auditory verbal hallucinations: imaging, analysis, and intervention.

Eur Arch Psychiatry Clin Neurosci 2012 Nov 2;262 Suppl 2:S91-5. Epub 2012 Sep 2.

Department of Psychiatric Neurophysiology, University Hospital of Psychiatry, University of Bern, Bolligenstrasse 111, 3000 Bern 60, Switzerland.

In this article, we will link neuroimaging, data analysis, and intervention methods in an important psychiatric condition: auditory verbal hallucinations (AVH). The clinical and phenomenological background as well as neurophysiological findings will be covered and discussed with respect to noninvasive brain stimulation. Additionally, methods of noninvasive brain stimulation will be presented as ways to intervene with AVH. Finally, preliminary conclusions and possible future perspectives will be proposed.
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http://dx.doi.org/10.1007/s00406-012-0355-2DOI Listing
November 2012

Reduced neuronal activity in language-related regions after transcranial magnetic stimulation therapy for auditory verbal hallucinations.

Biol Psychiatry 2013 Mar 27;73(6):518-24. Epub 2012 Jul 27.

Department of Psychiatric Neurophysiology, University Hospital of Psychiatry, Bern, Switzerland.

Background: Transcranial magnetic stimulation (TMS) is a novel therapeutic approach, used in patients with pharmacoresistant auditory verbal hallucinations (AVH). To investigate the neurobiological effects of TMS on AVH, we measured cerebral blood flow with pseudo-continuous magnetic resonance-arterial spin labeling 20 ± 6 hours before and after TMS treatment.

Methods: Thirty patients with schizophrenia or schizoaffective disorder were investigated. Fifteen patients received a 10-day TMS treatment to the left temporoparietal cortex, and 15 received the standard treatment. The stimulation location was chosen according to an individually determined language region determined by a functional magnetic resonance imaging language paradigm, which identified the sensorimotor language area, area Spt (sylvian parietotemporal), as the target region.

Results: TMS-treated patients showed positive clinical effects, which were indicated by a reduction in AVH scores (p ≤ .001). Cerebral blood flow was significantly decreased in the primary auditory cortex (p ≤ .001), left Broca's area (p ≤ .001), and cingulate gyrus (p ≤ .001). In control subjects, neither positive clinical effects nor cerebral blood flow decreases were detected. The decrease in cerebral blood flow in the primary auditory cortex correlated with the decrease in AVH scores (p ≤ .001).

Conclusions: TMS reverses hyperactivity of language regions involved in the emergence of AVH. Area Spt acts as a gateway to the hallucination-generating cerebral network. Successful therapy corresponded to decreased cerebral blood flow in the primary auditory cortex, supporting its crucial role in triggering AVH and contributing to the physical quality of the false perceptions.
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http://dx.doi.org/10.1016/j.biopsych.2012.06.019DOI Listing
March 2013

Theta burst stimulation over the right Broca's homologue induces improvement of naming in aphasic patients.

Stroke 2012 Aug 10;43(8):2175-9. Epub 2012 May 10.

Department of Psychiatric Neurophysiology, University Hospital of Psychiatry, and University of Bern, Switzerland.

Background And Purpose: Improvements of language production in aphasic patients have been reported following repeated 1-Hz transcranial magnetic stimulation over the nondamaged right hemisphere. Most studies examined aphasic patients in the chronic phase. The effect of transcranial magnetic stimulation application in acute or subacute patients has not been systematically studied. We aimed to evaluate whether continuous theta burst stimulation, an inhibitory protocol with a shorter application time than the common 1-Hz protocol, is able to improve naming performance in aphasic patients in different poststroke phases.

Methods: Eighteen right-handed aphasic patients performed a picture naming task and a language independent alertness test before and after the application of theta burst stimulation over the intact right Broca's homologue localized by the 10-20 electroencephalogram system in a randomized, sham-controlled, crossover trial.

Results: We found that naming performance was significantly better, and naming latency was significantly shorter, after theta burst stimulation than after the sham intervention. Patients who responded best were in the subacute phase after stroke.

Conclusions: This setting with the short theta burst stimulation application time and the simple stimulation localization procedure is suitable for clinical purposes.
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http://dx.doi.org/10.1161/STROKEAHA.111.647503DOI Listing
August 2012

Neurophysiological studies of auditory verbal hallucinations.

Schizophr Bull 2012 Jun 23;38(4):715-23. Epub 2012 Feb 23.

Psychiatry Service, San Francisco Veterans Affairs Medical Center, Department of Psychiatry, University of California, San Francisco, CA, USA.

We discuss 3 neurophysiological approaches to study auditory verbal hallucinations (AVH). First, we describe "state" (or symptom capture) studies where periods with and without hallucinations are compared "within" a patient. These studies take 2 forms: passive studies, where brain activity during these states is compared, and probe studies, where brain responses to sounds during these states are compared. EEG (electroencephalography) and MEG (magnetoencephalography) data point to frontal and temporal lobe activity, the latter resulting in competition with external sounds for auditory resources. Second, we discuss "trait" studies where EEG and MEG responses to sounds are recorded from patients who hallucinate and those who do not. They suggest a tendency to hallucinate is associated with competition for auditory processing resources. Third, we discuss studies addressing possible mechanisms of AVH, including spontaneous neural activity, abnormal self-monitoring, and dysfunctional interregional communication. While most studies show differences in EEG and MEG responses between patients and controls, far fewer show symptom relationships. We conclude that efforts to understand the pathophysiology of AVH using EEG and MEG have been hindered by poor anatomical resolution of the EEG and MEG measures, poor assessment of symptoms, poor understanding of the phenomenon, poor models of the phenomenon, decoupling of the symptoms from the neurophysiology due to medications and comorbidites, and the possibility that the schizophrenia diagnosis breeds truer than the symptoms it comprises. These problems are common to studies of other psychiatric symptoms and should be considered when attempting to understand the basic neural mechanisms responsible for them.
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http://dx.doi.org/10.1093/schbul/sbs009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3406526PMC
June 2012

Bipolar disorder susceptibility region on chromosome 3q29 not confirmed in a case-control association study.

World J Biol Psychiatry 2011 Jun 17;12(4):309-15. Epub 2011 Feb 17.

Department of Psychiatry and Psychotherapy, Medical University Vienna, Austria.

Objectives: We identified a bipolar disorder (BPD) susceptibility region on chromosome 3q29 in a genome-wide linkage scan (Bailer et al. 2002 (Biol Psychiatry 52: 40), NPL-score 4.09) and follow-up linkage analysis (Schosser et al. 2004 (J Psychiatr Res 38(3): 357), NPL-scores >3 with five markers). These findings were supported by further fine-mapping of this region (Schosser et al. 2007 (Eur Neuropsychopharmacol 17(6-7): 501)), finding NPL-scores >3.9 with SNPs (single nucleotide polymorphisms) spanning a region of 3.46 Mbp in BPD families. Since genetic association studies are more powerful than linkage studies for detecting susceptibility genes of small effect size, we aimed to replicate these findings in an independent case-control sample collected in London (UK) and Vienna (Austria).

Methods: A total of 51 SNPs were genotyped using Sequenom MassARRAY(®) iPLEX Gold and tested for association in a sample of 526 cases suffering from DSM-IV and/or ICD-10 diagnosis of BPD and 691 controls.

Results: No genotypic and/or allelic association, as well as no haplotypic association, was found for any SNP after multiple testing correction.

Conclusions: However, we cannot exclude the possibility that our sample might not have the power to detect rare variants associated with susceptibility to BPD.
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http://dx.doi.org/10.3109/15622975.2010.551407DOI Listing
June 2011

No association of the neuropeptide Y (Leu7Pro) and ghrelin gene (Arg51Gln, Leu72Met, Gln90Leu) single nucleotide polymorphisms with eating disorders.

Nord J Psychiatry 2011 Jun 3;65(3):203-7. Epub 2010 Nov 3.

Department of Psychiatry and Psychotherapy, Division of Biological Psychiatry, Medical University Vienna, Vienna, Austria.

Background: Genetic factors likely contribute to the biological vulnerability of eating disorders.

Aims: Case-control association study on one neuropeptide Y gene (Leu7Pro) polymorphism and three ghrelin gene (Arg51Gln, Leu72Met and Gln90Leu) polymorphisms.

Methods: 114 eating disorder patients (46 with anorexia nervosa, 30 with bulimia nervosa, 38 with binge eating disorder) and 164 healthy controls were genotyped.

Results: No differences were detected between patients and controls for any of the four polymorphisms in allele frequency and genotype distribution (P > 0.05). Allele frequencies and genotypes had no significant influence on body mass index (P > 0.05) in eating disorder patients.

Conclusion: Positive findings of former case-control studies of associations between ghrelin gene polymorphisms and eating disorders could not be replicated. Neuropeptide Y gene polymorphisms have not been investigated in eating disorders before.
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http://dx.doi.org/10.3109/08039488.2010.525258DOI Listing
June 2011

Extraordinary transmission through a single coaxial aperture in a thin metal film.

Opt Express 2010 May;18(10):10896-904

Max Planck Institute for the Science of Light, Guenther-Scharowsky-Str. 1, D-91058 Erlangen, Germany.

We investigate experimentally the transmission properties of single sub-wavelength coaxial apertures in thin metal films (t = 110 nm). Enhanced transmission through a single sub-wavelength coaxial aperture illuminated with a strongly focused radially polarized light beam is reported. In our experiments we achieved up to four times enhanced transmission through a single coaxial aperture as compared to a (hollow) circular aperture with the same outer diameter.We attribute this enhancement of transmission to the excitation of a TEM-mode for illumination with radially polarized light inside the single coaxial aperture. A strong polarization contrast is observed between the transmission for radially and azimuthally polarized illumination. Furthermore, the observed transmission through a single coaxial aperture can be strongly reduced if surface plasmons are excited. The experimental results are in good agreement with finite difference time domain (FDTD) simulations.
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http://dx.doi.org/10.1364/OE.18.010896DOI Listing
May 2010

Interaction between serotonin 5-HT2A receptor gene and dopamine transporter (DAT1) gene polymorphisms influences personality trait of persistence in Austrian Caucasians.

World J Biol Psychiatry 2010 Mar;11(2 Pt 2):417-24

Division of Biological Psychiatry, Department of Psychiatry & Psychotherapy, Medical University Vienna, Vienna, Austria.

We examined 89 normal volunteers using Cloninger's Temperament and Character Inventory (TCI). Genotyping the 102T/C polymorphism of the serotonin 5HT2A receptor gene and the ser9gly polymorphism in exon 1 of the dopamine D3 receptor (DRD3) gene was performed using PCR-RFLP, whereas the dopamine transporter (DAT1) gene variable number of tandem repeats (VNTR) polymorphism was investigated using PCR amplification followed by electrophoresis in an 8% acrylamide gel with a set of size markers. We found a nominally significant association between gender and harm avoidance (P=0.017; women showing higher scores). There was no association of either DAT1, DRD3 or 5HT2A alleles or genotypes with any dimension of the TCI applying Kruskal-Wallis rank-sum tests. Comparing homozygote and heterozygote DAT1 genotypes, we found higher novelty seeking scores in homozygotes (P=0.054). We further found a nominally significant interaction between DAT1 and 5HT2A homo-/heterozygous gene variants (P=0.0071; DAT1 and 5HT2A genotypes P value of 0.05), performing multivariate analysis of variance (MANOVA). Examining the temperamental TCI subscales, this interaction was associated with persistence (genotypes: P=0.004; homo-/heterozygous gene variants: P=0.0004). We conclude that an interaction between DAT1 and 5HT2A genes might influence the temperamental personality trait persistence.
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http://dx.doi.org/10.3109/15622970801935586DOI Listing
March 2010
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