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Tanja Veselinović,1,2 Ingo Vernaleken,1,2 Paul Cumming,3,4 Uwe Henning,5 Lina Winkler,1,2 Peter Kaleta,1,2 Michael Paulzen,1,2 Christian Luckhaus,6 Gerhard Gründer1,2,7 1Department of Psychiatry, Psychotherapy, and Psychosomatics, Faculty of Medicine, RWTH Aachen University, Aachen, 2Translational Brain Medicine, Jülich Aachen Research Alliance (JARA), Jülich, Germany; 3IHBI, School of Psychology and Counselling, Queensland University of Technology, 4QIMR Berghofer Institute, Brisbane, Australia; 5Neurobiochemical Research Unit, Department of Psychiatry, Heinrich Heine University, Düsseldorf, 6LWL University Hospital Bochum, Department of Psychiatry, Division of Cognitive Neuropsychiatry and Psychiatric Preventive Medicine, Ruhr University Bochum, Bochum, 7Department of Molecular Neuroimaging, Central Institute of Mental Health, Mannheim, Germany Objectives: Off-label prescription of antipsychotics to patients without psychotic symptoms has become a routine matter for many psychiatrists and also some general practitioners. Nonetheless, little is known about the possibly detrimental effects of antidopaminergic medications on general psychopathology, subjective mental state, or a possible association with physiological parameters in nonpsychotic individuals.Methods: In this randomized, single-blinded study, groups of healthy volunteers (n=18) received low doses of reserpine, aripiprazole, haloperidol, or placebo on 7 successive days. Relevant physiological parameters (plasma prolactin, concentrations of catecholamine metabolites in plasma, and 24-hour urine) and each subject’s mental state (Positive and Negative Syndrome Scale, Hamilton Rating Scale for Depression, visual analogue scale, Beck Depression Inventory II) were assessed at the start and end of the trial.Results: Of the three active treatments, only reserpine caused a significant increase in some plasma- and urine-catecholamine metabolites, but all three medications evoked objective and subjective changes in general psychopathology scores, which correlated with individual increases in plasma homovanillic acid concentrations. Both objective and subjective impairments were significantly more pronounced in the subgroup with greatest increase of plasma prolactin. Subjects experiencing the most pronounced side effects under haloperidol, which compelled them to drop out, showed significantly higher prolactin concentration increases than those who tolerated haloperidol well.Conclusion: We found consistent associations between altered markers of dopamine transmission and several objective and subjective mental impairments in healthy volunteers after 1 week’s treatment with antidopaminergic medications. These findings should draw attention to a more intensive risk–benefit evaluation in cases of off-label prescription of antipsychotic medications. Keywords: catecholamine metabolites, HVA, prolactin, dopamine, reserpine, aripiprazole, haloperidol, off-label prescription

Competing Interests: Declaration of competing interest We confirm that there are no declarations of interest in our currently submitted manuscript.

Objective: Describe the ear and hearing outcomes in Aboriginal infants in an Australian urban area., Design: Aboriginal infants enrolled in the Djaalinj Waakinj prospective cohort study had ear health screenings at ages 2-4, 6-8 and 12-18 months and audiological assessment at ∼12 months of age. Sociodemographic, environmental characteristics, otoscopy, otoacoustic emissions, tympanometry and visual reinforcement audiometry data were collected., Study Sample: 125 infants were enrolled in the study; 67 completed audiological assessment, 62, 54, and 58 of whom attended ear screenings at 2-4, 6-8 and 12-18 months., Results: Of the children that attended the audiological assessment, 36.5%, 50% and 64.3% of infants had otitis media (OM) at 2-4, 6-8 and 12-18 months. Using a 10 dB correction factor, 44.8% of infants had hearing loss (HL) (≥ 25 dB HL) at ∼ 12 months of age. More males (X 2 =5.4 (1df, p = 0.02)) and infants with OM at audiological assessment (X 2 =5.8 (1df, p = 0.02)) had HL. More infants that used a pacifier at 12-18 months of age had HL (X 2 =4.7 (1df, p = 0.03))., Conclusion: Aboriginal infants in an urban area have high rates of HL and OM, which requires early surveillance and timely treatment to reduce the medical and developmental impacts of OM and HL.

Background: Otitis media (OM) has a high prevalence in childhood, and grommet insertion is the most common surgical treatment for OM. The public health system in Australia faces considerable strains, including high demand for Ear, Nose and Throat (ENT) specialists. Extending the scope of practice for audiologists to manage post-operative care for children receiving grommets has the potential to alleviate this burden., Methods: This non-randomised, cross-sectional study investigated the efficacy and feasibility of an audiology-led clinic for managing paediatric patients after grommet insertion at a tertiary teaching hospital in Western Australia. Senior audiologists reviewed children at 6 weeks and 10 months post-operatively, escalating care to an ENT specialist if abnormalities were observed. Children with normal hearing and patent grommets were reviewed and discharged by the audiologist., Results: A total of 93 children were included (mean age 5.18 ± 2.25 years, range 1.59-11.46 years). At the 6-week review, 72/93 (77 %) presented with in-situ grommets and normal hearing, while 21/93 (22 %) were escalated for immediate ENT care. At the 10-month review, 54/72 (75 %) were discharged without further ENT intervention, and 18/72 (25 %) required additional ENT investigation., Conclusion: This study demonstrated that an audiology-led follow-up clinic for post-grommet insertion is a viable option, providing efficient, high-quality care. Two-thirds of paediatric patients did not require ENT input or review post-operatively. The results support interdisciplinary models of care, which could help address challenges faced by overburdened ENT services., Competing Interests: Declaration of competing interest The authors of this paper declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Introduction: Shortage of ear, nose, and throat specialists in public hospitals can result in delays in the detection and management of otitis media. This study introduced a new hospital-based telehealth service, named the Ear Portal, and investigated its role in improving access to specialist care., Methods: The study included 87 children (aged 6 months to 6 years) referred to a tertiary children's hospital due to otitis media-related concerns. A specialist multidisciplinary team met fortnightly to review pre-recorded data and provide care plans., Results: The service resulted in a median waiting time of 28 days to receive a diagnosis and care plan by the multidisciplinary team, compared to a mean waiting time of 450 days for a reference group receiving standard healthcare services. Most children (90.3%) received bilateral ear diagnosis. Normal findings were found in 43.9%. However, the majority required further ear, nose, and throat with or without audiology face-to-face follow-up due to a diagnosis of middle-ear disease, unknown hearing status, or concerns not related to ears. The mean time required for clinical assessments completion by research assistants and multidisciplinary team review was 37.6 and 5.1 min per participant, respectively., Discussion: Children in the Ear Portal service received a diagnosis and care plan in a median of 28 days, which is within the clinically recommended timeframes. With sufficient clinical information, this service can provide faster access to specialist care than the standard healthcare pathway. The service can reduce the time required by the specialist to provide a diagnosis and care plan which may help increase the specialists' capacity., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Major depressive disorder (MDD) typically manifests itself in depressed affect, anhedonia, low energy, and additional symptoms. Despite its high global prevalence, its pathophysiology still gives rise to questions. Current research places alterations in functional connectivity among MDD's most promising biomarkers. However, given the heterogeneity of previous findings, the use of higher-resolution imaging techniques, like ultra-high field (UHF) fMRI (≥7 Tesla, 7T), may offer greater specificity in delineating fundamental impairments. In this study, 7T UHF fMRI scans were conducted on 31 MDD patients and 27 age-gender matched healthy controls to exploratorily contrast cerebral resting-state functional connectivity patterns between both groups. The CONN toolbox was used to generate functional network connectivity (FNC) analysis based on the region of interest (ROI)-to-ROI correlations in order to enable the identification of clusters of significantly different connections. Correction for multiple comparisons was implemented at the cluster level using a false discovery rate (FDR). The analysis revealed three significant clusters differentiating MDD patients and healthy controls. In Clusters 1 and 2, MDD patients exhibited between-network hypoconnectivity in basal ganglia-cortical pathways as well as hyperconnectivity in thalamo-cortical pathways, including several individual ROI-to-ROI connections. In Cluster 3, they showed increased occipital interhemispheric within-network connectivity. These findings suggest that alterations in basal ganglia-thalamo-cortical circuits play a substantial role in the pathophysiology of MDD. Furthermore, they indicate potential MDD-related deficits relating to a combination of perception (vision, audition, and somatosensation) as well as more complex functions, especially social-emotional processing, modulation, and regulation. It is anticipated that these findings might further inform more accurate clinical procedures for addressing MDD., (© 2024. The Author(s).)

Objective: Investigating the impact of early childhood ventilation tube insertion (VTI) on long-term language outcomes., Design: Longitudinal cohort study., Setting: A total of 2900 pregnant women participated in the Raine Study between 1989 and 1991 in Western Australia, and 2868 children have been followed up., Participants: Based on parental reports, 314 children had a history of recurrent otitis media but did not undergo VTI (rOM group); another 94 received VTI (VTI group); while 1735 had no history of rOM (reference group) in the first 3 years of childhood. Children with data on outcomes and confounders were included in analyses of PPVT-R at ages 6 (n = 1567) and 10 years (n = 1313) and CELF-III at 10 years (n = 1410) (approximately 5% in the VTI group and 15% in the rOM group)., Main Outcome Measures: Peabody Picture Vocabulary Test-Revised edition and Clinical Evaluation of Language Fundamentals® Preschool-3., Results: At 6 years, mean PPVT-R scores were significantly lower in the VTI group than the reference group (β = -3.3; 95% CI [-6.5 to -0.04], p = .047). At 10 years, while the difference between the VTI and reference groups was less pronounced for PPVT-R scores, there was a small but consistent trend of lower measures, on average, across CELF-III scores (expressive: β = -3.4 [-7.1 to 0.27], p = .069; receptive: β = -4.1 [-7.9 to -0.34], p = .033; total: β = -3.9 [-7.5 to -0.21], p = .038). There was no evidence to suggest that language outcomes in the rOM group differed from the reference group., Conclusion: Lower scores of language outcomes in school-aged children who received VTI in early childhood may suggest a long-term risk which should be considered alongside the potential benefits of VTI., (© 2023 The Authors. Clinical Otolaryngology published by John Wiley & Sons Ltd.)

Aim: The purpose of this study is to explore the effectiveness of a hospital-based asynchronous ear, nose, and throat (ENT) telehealth service (the Ear Portal) in reducing cost and improving access for children with otitis media., Methods: Participants were recruited to the Ear Portal from a tertiary hospital ENT waiting list. Ear and hearing assessments were conducted during appointments by the Ear Portal research assistant, and data was stored for an asynchronous review by the Ear Portal multidisciplinary team. A cost-minimisation analysis was conducted for the Ear Portal and the standard care pathways. Waiting times to provide care for both pathways were calculated for children with semi-urgent (i.e. Category 2) and non-urgent (i.e. Category 3) referrals., Results: The running cost for the Ear Portal was $67.70 for initial appointments and $37.34 for follow-up appointments. Conversely, the running cost for the standard care pathway was $154.65 for initial appointments and $86.10 for follow-up appointments. A total of 223 appointments were required to offset the initial Ear Portal investment of $19,384.00. The median waiting time for the Ear Portal from initial contact to care plan delivery was <30 days, whereas the median waiting times for children in the standard care pathway were 291 days (interquartile range (IQR) = 117) for Category 2 and 371 days (IQR = 311) for Category 3 referrals., Conclusion: Under the current circumstances, the Ear Portal service can reduce costs for the health care system by reducing marginal costs per patient in addition to providing ENT specialist care within the clinically recommended timeframes., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.

Aim: To investigate the long-term effects of early-life recurrent otitis media (OM) and subsequent behavioural problems in children at the age of 10 years., Methods: Data from the Raine Study, a longitudinal pregnancy cohort, were used to categorise children into those with three or more episodes of OM (rOM group) and those without a history of recurrent OM in the first 3 years of life (reference group). The parent report Strengths and Difficulties Questionnaire was used to assess child behaviour at the age of 10 years. Parental questionnaires were used to report past and present diagnoses of various mental health and developmental conditions, including attention, anxiety, depression, learning, and speech-language problems. Multiple linear and logistic models were used to analyse the data and were adjusted for a fixed set of key confounding variables., Results: The linear regression analysis revealed significant, independent associations between a history of recurrent OM and higher Strengths and Difficulties Questionnaire scores, including total, internalising, externalising, emotional, attention/hyperactivity and peer problems subscales. Logistic regression analyses revealed an independent increased likelihood for children in the rOM group to have a diagnosis of attention, anxiety, learning and speech-language problems., Conclusion: Children at 10 years of age with an early history of recurrent OM are more likely to exhibit attentional and behavioural problems when compared to children without a history of recurrent OM. These findings highlight the association between early-life recurrent OM and later behavioural problems that may require professional allied health-care interventions., (© 2023 The Authors. Journal of Paediatrics and Child Health published by John Wiley & Sons Australia, Ltd on behalf of Paediatrics and Child Health Division (The Royal Australasian College of Physicians).)

Aim: Children with otitis media (OM) experience long waiting times to access Australia's public hospitals due to limited capacity. The aim of this article is to utilize an Ear, Nose, and Throat (ENT) telehealth service (the Ear Portal) to examine whether delayed access to specialist care is associated with poorer behavioral outcomes for children with OM., Methods: Participants in the study included 45 children who were referred to ENT specialists due to recurrent and persistent OM. Children were triaged as semiurgent with a target time-to-assessment of 90 days or nonurgent with a target time-to-assessment of 365 days. The behavioral outcomes of children were assessed using the parent report Strengths and Difficulties Questionnaire (SDQ). Descriptive statistics and adjusted multiple linear regression models were used to compare children who received access to the service within the time-to-assessment target of their triage category ("on-boundary"; n  = 17) and outside the time-to-assessment target ("off-boundary"; n  = 28). Spearman correlation analysis was used to explore the relationship between the internalizing, externalizing, and total SDQ scores as a function of waiting times in days., Results: Borderline or abnormal SDQ scores ranged from 24.4% to 42.2% across the study participants. The regression analysis showed a statistically significant association between the off-boundary group and higher scores (i.e., poorer) on the peer, emotional, conduct, internalizing, and total problems subscales. Further, lengthy waiting times were significantly correlated with higher internalizing problems. These findings indicate that longer waiting times may lead to poorer behavioral outcomes for children with OM., Clinical Trial Registration: (ACTRN1269000039189p)., Conclusion: Children with recurrent and persistent OM referred to ENT outpatient care were found to have significantly more behavioral difficulties if their waiting times exceeded the recommended timeframes for their triaged referrals. Additionally, they experienced more internalizing problems that correlated with longer waiting times. This highlights the calls for alterations in current clinical practice given the lengthy waiting times in Australia's public hospitals., Competing Interests: No competing financial interests exist., (© Ali A.H. Altamimi et al., 2023; Published by Mary Ann Liebert, Inc.)

Tourette syndrome (TS) is a neuropsychiatric disorder characterized by motor and phonic tics, which several different theories, such as basal ganglia-thalamo-cortical loop dysfunction and amygdala hypersensitivity, have sought to explain. Previous research has shown dynamic changes in the brain prior to tic onset leading to tics, and this study aims to investigate the contribution of network dynamics to them. For this, we have employed three methods of functional connectivity to resting-state fMRI data - namely the static, the sliding window dynamic and the ICA based estimated dynamic; followed by an examination of the static and dynamic network topological properties. A leave-one-out (LOO-) validated regression model with LASSO regularization was used to identify the key predictors. The relevant predictors pointed to dysfunction of the primary motor cortex, the prefrontal-basal ganglia loop and amygdala-mediated visual social processing network. This is in line with a recently proposed social decision-making dysfunction hypothesis, opening new horizons in understanding tic pathophysiology., (© 2023 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Objectives: The present study aims to investigate the association between an early history of recurrent otitis media (OM) with or without ventilation tube insertion (VTI) and later behavioural problems in childhood and adolescence., Methods: Parental reports in a longitudinal pregnancy cohort were used to classify children into three groups; recurrent OM without VTI (rOM group; n = 276), recurrent OM with VTI (VTI group; n = 62), and no history of early-life recurrent OM as a reference group (n = 1485). The Child Behaviour Checklist (CBCL) was administered at ages 5, 8, 10, and 13 years and data were analysed for psychological wellbeing. Mixed-effects regression modelling was used to investigate the associations between a history of rOM and CBCL T-scores across all ages for rOM and VTI groups compared to the reference group. All analyses were controlled for a wide range of confounding variables., Results: The analyses revealed a significant association between recurrent OM and behavioural problems. While there was a general decline in scores (i.e. improvement) observed over the duration of the follow-up period, children in the rOM group displayed significantly higher scores for internalising and externalising behaviours at ages five, eight and 10 years. Attention scores were significantly higher across all ages in the rOM group. A transient increase in internalising behaviour was observed in the VTI group at ages eight and 10 years. Logistic regression models showed an increased overall likelihood for the rOM group only to fall within the abnormal clinical range for internalising and externalising behaviours., Conclusion: Early-life recurrent OM with and without VTI was associated with increased behavioural and attention problems in early and late childhood. This suggests that recurrent OM can have a significant impact on children's behaviour and attention that can persist into early adolescence., Competing Interests: Declaration of interest statement The authors have no competing interests to declare., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Aim: Australian Aboriginal and/or Torres Strait Islander children in rural/remote areas suffer high rates of persistent otitis media (OM) from early infancy. We aimed to determine the proportion of Aboriginal infants living in an urban area who have OM and investigate associated risk factors., Methods: Between 2017 and 2020, the Djaalinj Waakinj cohort study enrolled 125 Aboriginal infants at 0-12 weeks of age in the Perth South Metropolitan region, Western Australia. Proportion of children with OM based on tympanometry at ages 2, 6 and 12 months was evaluated, type B tympanogram indicating middle ear effusion. Potential risk factors were investigated by logistic regression with generalised estimating equations., Results: The proportion of children with OM was 35% (29/83) at 2 months, 49% (34/70) at 6 months and 49% (33/68) at 12 months of age. About 70% (16/23) of those with OM at ages 2 and/or 6 months had OM at 12 months compared with 20% (3/15) if no prior OM (relative risk = 3.48, 95% confidence interval (CI): 1.22-40.1). On multivariate analysis, infants living in houses with ≥1 person/room were at increased risk of OM (odds ratio = 1.78, 95% CI: 0.96-3.32)., Conclusion: Approximately half of Aboriginal infants enrolled into the South Metropolitan Perth project have OM by the age of 6 months and early onset of disease strongly predicts subsequent OM. Early surveillance for OM in urban areas is needed for early detection and management to reduce the risk of long-term hearing loss which can have serious developmental, social, behavioural, educational and economic consequences., (© 2023 The Authors. Journal of Paediatrics and Child Health published by John Wiley & Sons Australia, Ltd on behalf of Paediatrics and Child Health Division (The Royal Australasian College of Physicians).)

Objectives: To investigate the long-term impact of recurrent otitis media (rOM) and ventilation tube insertion (VTI) in early childhood on hearing outcomes and middle-ear health three to five years later, in a prospective pregnancy cohort study., Methods: Children were classified into rOM (n = 314), VTI (n = 94), and reference (n = 1735) groups, according to their otitis media (OM) history in their first three years of life. Audiometry at frequencies 500 Hz, 1000 Hz, 2000 Hz, and 4000 Hz, and tympanometry were performed when children were approximately six years of age., Results: A binary logistic regression incorporating a range of potential confounding variables showed that hearing outcomes and middle-ear health status in children who had early childhood rOM with or without undergoing VTI were not significantly different to those in the reference group. The only significant difference was found in the VTI group for both tympanometry (OR = 2.190; 95% CI = 1.123, 4.270) and audiometry outcomes at 4000 Hz (OR = 3.202; 95% CI 1.341, 6.717), in the left ear only. The median score of the better ear 4FA was 20 dB in children in all groups., Conclusion: Children with rOM with or without undergoing VTI in the first three years of childhood had comparable hearing outcomes and middle-ear health status to those with no history of the disease, at around the age of six years. Although children who underwent VTI had an increased risk of abnormal middle-ear status and some elevation in hearing levels in their left ear only, their audiometry results were still within normal limits, indicating that the impact of VTI in early childhood is unlikely to have clinically significant adverse impact on later hearing outcomes., Competing Interests: Declaration of competing interest None., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Cognitive impairments associated with schizophrenia (CIAS) represent a central element of the symptomatology of this severe mental disorder. CIAS substantially determine the disease prognosis and hardly, if at all, respond to treatment with currently available antipsychotics. Remarkably, all drugs presently approved for the treatment of schizophrenia are, to varying degrees, dopamine D 2 /D 3 receptor blockers. In turn, rapidly growing evidence suggests the immense significance of systems other than the dopaminergic system in the genesis of CIAS. Accordingly, current efforts addressing the unmet needs of patients with schizophrenia are primarily based on interventions in other non-dopaminergic systems. In this review article, we provide a brief overview of the available evidence on the importance of specific systems in the development of CIAS. In addition, we describe the promising targets for the development of new drugs that have been used so far. In doing so, we present the most important candidates that have been investigated in the field of the specific systems in recent years and present a summary of the results available at the time of drafting this review (May 2022), as well as the currently ongoing studies., (© 2022. The Author(s).)

Introduction: Three prominent resting-state networks (rsNW) (default mode network [DMN], salience network [SN], and central executive network [CEN]) are recognized for their important role in several neuropsychiatric conditions. However, our understanding of their relevance in terms of cognition remains insufficient. Materials and Methods: In response, this study aims at investigating the patterns of different network properties (resting-state activity [RSA] and short- and long-range functional connectivity [FC]) in these three core rsNWs, as well as the dynamics of age-associated changes and their relation to cognitive performance in a sample of healthy controls ( N  = 74) covering a large age span (20-79 years). Using a whole-network based approach, three measures were calculated from the functional magnetic resonance imaging (fMRI) data: amplitude of low-frequency fluctuations (ALFF), regional homogeneity (ReHo), and degree of network centrality (DC). The cognitive test battery covered the following domains: memory, executive functioning, processing speed, attention, and visual perception. Results: For all three fMRI measures (ALFF, ReHo, and DC), the highest values of spontaneous brain activity (ALFF), short- and long-range connectivity (ReHo, DC) were observed in the DMN and the lowest in the SN. Significant age-associated decrease was observed in the DMN for ALFF and DC, and in the SN for ALFF and ReHo. Significant negative partial correlations were observed for working memory and ALFF in all three networks, as well as for additional cognitive parameters and ALFF in CEN. Discussion: Our results show that higher RSA in the three core rsNWs may have an unfavorable effect on cognition. Conversely, the pattern of network properties in healthy subjects included low RSA and FC in the SN. This complements previous research related to the three core rsNW and shows that the chosen approach can provide additional insight into their function. Impact statement Using a whole network-based approach, our study characterizes the normal patterns (including resting-state activity [RSA], short- and long-range functional connectivity [FC]) of three prominent resting-state networks (rsNW) within the context of age-dependent changes and explores their relevance for different cognitive domains. Our results revealed a pattern with low RSA and FC in the salience network in healthy volunteers, whereas higher RSA, particularly in the central executive network, seemed to have a negative effect on cognition. These results increase the knowledge about the three core rsNWs and the understanding about their relevance for cognition.

The glutamate and γ-aminobutyric acid neuroreceptor subtypes mGluR 5 and GABA A are hypothesized to be involved in the development of a variety of psychiatric diseases. However, detailed information relating to their in vivo distribution is generally unavailable. Maps of such distributions could potentially aid clinical studies by providing a reference for the normal distribution of neuroreceptors and may also be useful as covariates in advanced functional magnetic resonance imaging (MR) studies. In this study, we propose a comprehensive processing pipeline for the construction of standard space, in vivo distributions of non-displaceable binding potential (BP ND ), and total distribution volume (V T ) based on simultaneously acquired bolus-infusion positron emission tomography (PET) and MR data. The pipeline was applied to [ 11 C]ABP688-PET/MR (13 healthy male non-smokers, 26.6 ± 7.0 years) and [ 11 C]Flumazenil-PET/MR (10 healthy males, 25.8 ± 3.0 years) data. Activity concentration templates, as well as V T and BP ND atlases of mGluR 5 and GABA A , were generated from these data. The maps were validated by assessing the percent error δ from warped space to native space in a selection of brain regions. We verified that the average δ ABP  = 3.0 ± 1.0% and δ FMZ  = 3.8 ± 1.4% were lower than the expected variabilities σ of the tracers (σ ABP  = 4.0%-16.0%, σ FMZ  = 3.9%-9.5%). An evaluation of PET-to-PET registrations based on the new maps showed higher registration accuracy compared to registrations based on the commonly used [ 15 O]H 2 O-template distributed with SPM12. Thus, we conclude that the resulting maps can be used for further research and the proposed pipeline is a viable tool for the construction of standardized PET data distributions., (© 2022 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

The growing demand for precise and reliable biomarkers in psychiatry is fueling research interest in the hope that identifying quantifiable indicators will improve diagnoses and treatment planning across a range of mental health conditions. The individual properties of brain networks at rest have been highlighted as a possible source for such biomarkers, with the added advantage that they are relatively straightforward to obtain. However, an important prerequisite for their consideration is their reproducibility. While the reliability of resting-state (RS) measurements has often been studied at standard field strengths, they have rarely been investigated using ultrahigh-field (UHF) magnetic resonance imaging (MRI) systems. We investigated the intersession stability of four functional MRI RS parameters-amplitude of low-frequency fluctuations (ALFF) and fractional ALFF (fALFF; representing the spontaneous brain activity), regional homogeneity (ReHo; measure of local connectivity), and degree centrality (DC; measure of long-range connectivity)-in three RS networks, previously shown to play an important role in several psychiatric diseases-the default mode network (DMN), the central executive network (CEN), and the salience network (SN). Our investigation at individual subject space revealed a strong stability for ALFF, ReHo, and DC in all three networks, and a moderate level of stability in fALFF. Furthermore, the internetwork connectivity between each network pair was strongly stable between CEN/SN and moderately stable between DMN/SN and DMN/SN. The high degree of reliability and reproducibility in capturing the properties of the three major RS networks by means of UHF-MRI points to its applicability as a potentially useful tool in the search for disease-relevant biomarkers., (© 2022 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Given the huge symptom diversity and complexity of mental disorders, an individual approach is the most promising avenue for clinical transfer and the establishment of personalized psychiatry. However, due to technical limitations, knowledge about the neurobiological basis of mental illnesses has, to date, mainly been based on findings resulting from evaluations of average data from certain diagnostic groups. We postulate that this could change substantially through the use of the emerging ultra-high-field MRI (UHF-MRI) technology. The main advantages of UHF-MRI include high signal-to-noise ratio, resulting in higher spatial resolution and contrast and enabling individual examinations of single subjects. Thus, we used this technology to assess changes in the properties of resting-state networks over the course of therapy in a naturalistic study of two depressed patients. Significant changes in several network property measures were found in regions corresponding to prior knowledge from group-level studies. Moreover, relevant parameters were already significantly divergent in both patients at baseline. In summary, we demonstrate the feasibility of UHF-MRI for capturing individual neurobiological correlates of mental diseases. These could serve as a tool for therapy monitoring and pave the way for a truly individualized and predictive clinical approach in psychiatric care., (© 2022. The Author(s).)

Currently, the metabotropic glutamate receptor 5 (mGluR5) is the subject of several lines of research in the context of neurology and is of high interest as a target for positron-emission tomography (PET). Here, we assessed the feasibility of using [ 11 C]ABP688, a specific antagonist radiotracer for an allosteric site on the mGluR5, to evaluate changes in glutamatergic neurotransmission through a mismatch-negativity (MMN) task as a part of a simultaneous and synchronized multimodal PET/MR-EEG study. We analyzed the effect of MMN by comparing the changes in nondisplaceable binding potential (BP ND ) prior to (baseline) and during the task in 17 healthy subjects by applying a bolus/infusion protocol. Anatomical and functional regions were analyzed. A small change in BP ND was observed in anatomical regions (posterior cingulate cortex and thalamus) and in a functional network (precuneus) after the start of the task. The effect size was quantified using Kendall's W value and was 0.3. The motor cortex was used as a control region for the task and did not show any significant BP ND changes. There was a significant ΔBP ND between acquisition conditions. On average, the reductions in binding across the regions were - 8.6 ± 3.2% in anatomical and - 6.4 ± 0.5% in the functional network (p ≤ 0.001). Correlations between ΔBP ND and EEG latency for both anatomical (p = 0.008) and functional (p = 0.022) regions were found. Exploratory analyses suggest that the MMN task played a role in the glutamatergic neurotransmission, and mGluR5 may be indirectly modulated by these changes., (© 2021. The Author(s).)

Introduction: The insular cortex is part of a network of highly connected cerebral "rich club" - regions and has been implicated in the pathophysiology of various psychiatric and neurological disorders, of which major depressive disease is one of the most prevalent. "Rich club" vulnerability can be a contributing factor in disease development. High-resolution structural subfield analysis of insular volume in combination with cortical thickness measurements and psychological testing might elucidate the way in which the insula is changed in depression., Material and Methods: High-resolution structural images of the brain were acquired using a 7T-MRI scanner. The mean grey matter volume and cortical thickness within the insular subfields were analysed using voxel-based morphometry (VBM) and surface analysis techniques respectively. Insular subfields were defined according to the Brainnetome Atlas for VBM - and the Destrieux-Atlas for cortical thickness - analysis. Thirty-three patients with confirmed major depressive disease, as well as thirty-one healthy controls matched for age and gender, were measured. The severity of depression in MDD patients was measured via a BDI-II score and objective clinical assessment (AMDP). Intergroup statistical analysis was performed using ANCOVA. An intragroup multivariate regression analysis of patient psychological test results was calculated. Corrections for multiple comparisons was performed using FDR., Results: Significant differences between groups were observed in the left granular dorsal insula according to VBM-analysis. AMDP-scores positively correlated with cortical thickness in the right superior segment of the circular insular sulcus., Conclusions: The combination of differences in grey matter volume between healthy controls and patients with a positive correlation of cortical thickness with disease severity underscores the insula's role in the pathogeneses of MDD. The connectivity hub insular cortex seems vulnerable to disruption in context of affective disease., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

The default mode network (DMN), the salience network (SN), and the central executive network (CEN) are considered as the core resting-state brain networks (RSN) due to their involvement in a wide range of cognitive tasks. Despite the large body of knowledge related to their regional spontaneous activity (RSA) and functional connectivity (FC) of these networks, less is known about the dynamics of the task-associated modulation on these parameters and the task-induced interaction between these three networks. We have investigated the effects of the visual-oddball paradigm on three fMRI measures (amplitude of low-frequency fluctuations for RSA, regional homogeneity for local FC, and degree centrality for global FC) in these three core RSN. A rest-task-rest paradigm was used and the RSNs were identified using independent component analysis (ICA) on the resting-state data. The observed patterns of change differed noticeably between the networks and were tightly associated with the task-related brain activity and the distinct involvement of the networks in the performance of the single subtasks. Furthermore, the inter-network analysis showed an increased synchronization of CEN with the DMN and the SN immediately after the task, but not between the DMN and SN. Higher pre-task inter-network synchronization between the DMN and the CEN was associated with shorter reaction times and thus better performance. Our results provide some additional insights into the dynamics within and between the triple RSN. Further investigations are required in order to understand better their functional importance and interplay., Competing Interests: The authors have declared that no competing interests exist.

Despite numerous studies investigating resilience and personality trials, a paucity of information regarding their neurobiological commonalities at the level of the large resting-state networks (rsNWs) remains. Here we address this topic using the advantages of ultra-high-field (UHF) 7T-MRI, characterized by higher signal-to-noise ratio and increased sensitivity. The association between resilience, personality traits and three fMRI measures (fractional amplitude of low-frequency fluctuations (fALFF), degree centrality (DC) and regional homogeneity (ReHo)) determined for three core rsNWs (default mode (DMN), salience (SN), and central executive network (CEN)) were examined in 32 healthy volunteers. The investigation revealed a significant role of SN in both resilience and personality traits and a tight association of the DMN with resilience. DC in CEN emerged as a significant moderator for the correlations of resilience with the personality traits of neuroticism and extraversion. Our results indicate that the common neurobiological basis of resilience and the Big Five personality traits may be reflected at the level of the core rsNWs.

The symbiosis of neuronal activities and glucose energy metabolism is reflected in the generation of functional magnetic resonance imaging (fMRI) and electroencephalography (EEG) signals. However, their association with the balance between neuronal excitation and inhibition (E/I-B), which is closely related to the activities of glutamate and γ-aminobutyric acid (GABA) and the receptor availability (RA) of GABA A and mGluR5, remains unexplored. This research investigates these associations during the resting state (RS) condition using simultaneously recorded PET/MR/EEG (trimodal) data. The trimodal data were acquired from three studies using different radio-tracers such as, [ 11 C]ABP688 (ABP) (N = 9), [ 11 C]Flumazenil (FMZ) (N = 10) and 2-[ 18 F]fluoro-2-deoxy-D-glucose (FDG) (N = 10) targeted to study the mGluR5, GABA A receptors and glucose metabolism respectively. Glucose metabolism and neuroreceptor binding availability (non-displaceable binding potential (BP ND )) of GABA A and mGluR5 were found to be significantly higher and closely linked within core resting-state networks (RSNs). The neuronal generators of EEG microstates and the fMRI measures were most tightly associated with the BP ND of GABA A relative to mGluR5 BP ND and the glucose metabolism, emphasising a predominance of inhibitory processes within in the core RSNs at rest. Changes in the neuroreceptors leading to an altered coupling with glucose metabolism may render the RSNs vulnerable to psychiatric conditions. The paradigm employed here will likely help identify the precise neurobiological mechanisms behind these alterations in fMRI functional connectivity and EEG oscillations, potentially benefitting individualised healthcare treatment measures.

Consistent findings postulate disturbed glutamatergic function (more specifically a hypofunction of the ionotropic NMDA receptors) as an important pathophysiologic mechanism in schizophrenia. However, the role of the metabotropic glutamatergic receptors type 5 (mGluR5) in this disease remains unclear. In this study, we investigated their significance (using [ 11 C]ABP688) for psychopathology and cognition in male patients with chronic schizophrenia and healthy controls. In the patient group, lower mGluR5 binding potential (BP ND ) values in the left temporal cortex and caudate were associated with higher general symptom levels (negative and depressive symptoms), lower levels of global functioning and worse cognitive performance. At the same time, in both groups, mGluR5 BP ND were significantly lower in smokers (F [27,1] = 15.500; p = .001), but without significant differences between the groups. Our findings provide support for the concept that the impaired function of mGluR5 underlies the symptoms of schizophrenia. They further supply a new perspective on the complex relationship between tobacco addiction and schizophrenia by identifying glutamatergic neurotransmission-in particularly mGluR5-as a possible connection to a shared vulnerability., (© 2020 The Authors. Human Brain Mapping published by Wiley Periodicals, Inc.)

Background: Impaired subjective well-being in schizophrenia patients treated with antipsychotics has often been linked inter alia to the antidopaminergic effects of medication. Thus, it is important to capture the association between striatal dopamine D2 receptor occupancy (D2-RO) and global subjective well-being. We examined this association using data from our multicenter, randomized, double-blind Neuroleptic Strategy Study (NeSSy)., Methods: An innovative double randomization process was used for allocation of patients to the specific treatment groups. Plasma drug concentrations were measured after 6 and 24 weeks of treatment to obtain the estimated D2-RO (eD2-RO) relative to literature values. We made an exploratory analysis of associations between eD2-RO and subjective well-being scores. One hundred two blood samples from 69 patients were available for the analysis. Because of the lack of a satisfactory occupancy model for quetiapine, only haloperidol, flupentixol, and olanzapine treatment groups were pooled, whereas aripiprazole data were analyzed separately, because of its partial agonistic properties., Results: In the pooled antagonist group, eD2-RO correlated negatively with the summarized well-being score. In a more detailed analysis, this association could be confirmed for all first-generation antipsychotic-treated patients, but not for the separate second-generation antipsychotic groups. In the aripiprazole group, higher eD2-RO was associated with impaired physical well-being, but had no association with mental well-being., Conclusions: Our results suggest that high plasma levels and consequently high occupancy at D2 receptors are disadvantageous for subjective well-being, as distinct from the objective extrapyramidal side effects. To minimize patients' malaise, which disfavors adherence, implementation of therapeutic drug monitoring in the clinical routine may be useful.

Cognitive impairment represents a core feature of schizophrenia. Uncertainty about demonstrable benefits of available antipsychotics on cognition remains an important clinical question relevant to patients' quality of life. The aim of our multi-center, randomized, double-blind "Neuroleptic Strategy Study" (NeSSy) was to compare the effectiveness of selected antipsychotics, conventionally classified as second- (SGAs) (haloperidol, flupentixol) and first generation antipsychotics (FGAs) (aripiprazole, olanzapine, quetiapine), on quality of life in schizophrenia. The effects on cognitive deficits represented a secondary outcome. We used an innovative double randomization for assignment of treatment group, and followed the patients with a neurocognitive test-battery upon six and 24 weeks of treatment. Psychopathology and quality of life were assessed using CGI, PANSS and SF-36. Assessment of cognitive performance was conducted in 114 of the 136 randomized patients. The SGA group (N = 62) showed beneficial effects of small to moderate effect size on cognition during the initial six weeks of treatment (executive functions, verbal fluency) and at 24 weeks (executive functions, working memory). In contrast, the FGA group (N = 52) showed moderately improved executive function, but a decline in verbal fluency at six weeks, with significant declines of moderate to large effect size in executive function, verbal learning and memory, and verbal fluency at 24 weeks. Our study indicates that SGAs present an advantage over FGAs regarding cognitive function during a medium-term treatment for schizophrenia. The results further emphasize a distinction between progression to detrimental effects of FGAs with prolonged treatment in contrast to more persistent cognitive benefits with SGA treatment., (Copyright © 2019 Elsevier B.V. and ECNP. All rights reserved.)

Objective: A considerable body of research links cognitive function to dopaminergic transmission in the prefrontal cortex, but less is known about cognition in relation to striatal dopamine D 2/3 receptors in unmedicated patients with psychosis., Methods: We investigated this association by obtaining PET recordings with the high-affinity D 2/3 antagonist ligand [ 18 F] fallypride in 15 medication-free patients with schizophrenia and 11 healthy controls. On the day of PET scanning, we undertook comprehensive neuropsychological testing and assessment of psychopathology using the Positive and Negative Syndrome Scale (PANSS)., Results: The patients' performance in cognitive tests was significantly impaired in almost all domains. Irrespective of medication history, the mean [ 18 F] fallypride binding potential (BP ND ) in the patient group tended to be globally 5-10% higher than that of the control group, but without reaching significance in any brain region. There were significant positive correlations between individual patient performance in the Trail Making Test (TMT(A) and TMT(B)) and Digit-Symbol-Substitution-Test with regional [ 18 F] fallypride BP ND , which remained significant after Bonferroni correction for the TMT(A) in caudate nucleus (CN) and for the TMT(B) in CN and putamen. No such correlations were evident in the control group., Discussion: The association between better cognitive performance and greater BP ND in schizophrenia patients may imply that relatively lower receptor occupancy by endogenous dopamine favors better sparing of cognitive function. Absence of comparable correlations in healthy controls could indicate a greater involvement of signaling at dopamine D 2/3 receptors in certain cognitive functions in schizophrenia patients than in healthy controls.

Rationale: Many aspects of the neurobiology of schizophrenia, especially the physiological basis of the negative symptoms and associated cognitive deficits, remain inadequately understood. Tandon and Greden (1989) postulated a central role of dopaminergic/cholinergic imbalance in schizophrenia., Objective/methods: In light of this hypothesis, we elected to investigate the effects of anticholinergic challenge on psychopathology, cognition and attention in 12 unmedicated patients with schizophrenia and 12 healthy controls. The first examination occurred before any pharmacological intervention; the second examination was carried out immediately following an intravenous infusion of 5 mg biperiden, a centrally acting antimuscarinergic agent., Results: The biperiden challenge provoked a considerable increase in PANSS scores in both groups which was significantly more pronounced in patients (repeated measures analysis of variance (ANOVA) (rmANOVA): F(df) = 6.4(1,22); p = 0.019). The increase in the PANSS scores showed a significant negative correlation with age in patients. Biperiden caused considerable cognitive impairments in both groups. A significant group difference (rmANOVA) could be observed for TMT-B (F(df) = 11.29(1,22); p = 0.003)., Conclusions: The anticholinergic intervention caused more pronounced psychopathological and cognitive deteriorating effects in patients suffering from schizophrenia than in healthy volunteers. This could be related to the disrupted cholinergic transmission in schizophrenia. Our findings speak on behalf of the need of a more restrictive use of anticholinergics in psychiatric patients. The age-related attenuation of PANSS score increases in patients could be related to the age-dependent changes in dopamine dynamics and also to the age-associated decline of the availability of muscarinic receptors. Our results emphasise the need for further investigation of cholinergic disturbances in schizophrenia.

Cariprazine is a novel drug with partial agonist activity at dopamine D2/3 receptors and six- to eightfold higher affinity for human dopamine D3 over D2 receptors. Results from several placebo-controlled Phase II/III trials in patients with a The Diagnostic and Statistical Manual of Mental Disorders IV diagnosis of schizophrenia or bipolar I disorder suggest that cariprazine is superior to placebo with respect to antipsychotic and antimanic activity. Reports concerning safety and tolerability of cariprazine are mainly favorable, although the rates of treatment-associated adverse events, which most commonly included akathisia and extrapyramidal symptom, are rather high. However, only minor alterations of clinical laboratory values, prolactin concentrations and ECG parameters are reported in cariprazine-treated patients. A new drug application to the U.S. F DA for cariprazine for the treatment of both schizophrenia and manic or mixed episodes associated with bipolar I disorder was submitted in November 2012. A more precise assessment of the clinical properties of this new drug will require additional studies, aimed to compare and contrast cariprazine with other antipsychotic agents.

This review provides the general principles for a rational therapy with psychotropic drugs. It covers the discussion on the basics of the pharmacokinetics (with consideration of drug metabolism and the importance of genetic polymorphisms), pharmacodynamics (drug-receptor interaction, receptor pharmacology) and the effects of chronic administration of neuropsychotropic drugs on behavior. The reader will thus obtain the basis and stimulation for further study.

Rationale: There is increased interest in elucidating the range of symptoms of schizophrenia and their response to treatment with medications. Particularly negative and cognitive symptoms are often resistant to the therapy with currently available antipsychotics. There are even similarities between negative symptoms in psychosis and the side effects of antidopaminergic antipsychotic drugs., Objectives: The aim of this randomized, single-blinded, placebo-controlled study was to investigate the influence of a subchronic, prolonged neuroleptic-induced dopamine deficit on psychopathology and subjective well-being in healthy subjects., Methods: Seventy-two healthy volunteers without history of psychiatric diseases were included. A 7-day antidopaminergic intervention was provided with aripiprazole, haloperidol, and reserpine. For the clinical assessment, structured interviews and psychopathology and extrapyramidal symptom scales were used., Results: Seven out of 18 participants (38.9%) randomized to the haloperidol group terminated the study ahead of schedule. In the reserpine and the haloperidol group, significantly higher levels of negative and positive symptoms (PANSS scale) were documented. Depressive symptoms predominantly occurred in the reserpine group. Among all participants experiencing the antidopaminergic intervention, the subgroup with positive family history among first and second-generation relatives developed more pronounced depressive symptoms. Concerning extrapyramidal motor symptoms, the haloperidol group had significantly more severe manifestations than all three other groups., Conclusion: Antidopaminergic modulation in healthy subjects induced substantial impairments in several domains of subjective well-being. In particular an association between hypodopaminergic states and depressive symptoms was observed which may be amplified by a genetic predisposition.

Antipsychotics are the most common cause of pharmacologically induced hyperprolactinemia. Although this adverse effect was the subject of numerous observations, the mechanisms and promotive factors were not completely investigated yet. Increased awareness of clinical consequences of hyperprolactinemia implicates the necessity for further examinations. The aim of this randomized, single-blinded, placebo-controlled study was to do a systematic examination of the effects of different antidopaminergic mechanisms on prolactin secretion in healthy volunteers. A 7-day intervention was performed with aripiprazole, haloperidol, or reserpine. Prolactin levels changed significantly in the haloperidol (from 177.2 ± 74.6 to 350.7 ± 202.6 mU/L; P < 0.0001) and in the reserpine groups (from 149.6 ± 80.2 to 540.3 ± 280.8 mU/L; P < 0.0001) but not after aripiprazole (from 160.9 ± 65.0 to 189.6 ± 209.6 mU/L; P = 0.69) or placebo (from 211.6 ± 113.4 mU/L to 196.1 ± 85.6 mU/L; P = 0.8). After haloperidol and reserpine, increases in prolactin were significantly more pronounced in women than in men. Furthermore, in women using hormonal contraception, the increase in prolactin was significantly greater than in those without additional estrogen supply. These results demonstrate that the effect of antipsychotic drugs on prolactin levels strongly depends on their mechanism of action. Reserpine, a vesicular monoamine transporter type 2 blocker, causes the most distinct increase. This implies that D₂ receptor blockade on the lactotrophs is not the sole major cause leading to hyperprolactinemia. The partial agonistic effect of aripiprazole was sufficient to maintain prolactin on physiologic levels. The strong influences of sex and hormonal contraception underline the sensitizing effect of estrogens to the antipsychotic-induced prolactin increase.