How brain networks tic: Predicting tic severity through rs-fMRI dynamics in Tourette syndrome.

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.

Test-retest stability of spontaneous brain activity and functional connectivity in the core resting-state networks assessed with ultrahigh field 7-Tesla resting-state functional magnetic resonance imaging.

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.

mGluR5 and GABAA receptor-specific parametric PET atlas construction-PET/MR data processing pipeline, validation, and application.

The glutamate and γ-aminobutyric acid neuroreceptor subtypes mGluR5 and GABAA 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 (BPND ), and total distribution volume (VT ) 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 VT and BPND atlases of mGluR5 and GABAA , 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 δABP  = 3.0 ± 1.0% and δFMZ  = 3.8 ± 1.4% were lower than the expected variabilities σ of the tracers (σABP  = 4.0%-16.0%, σFMZ  = 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]H2 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.

A meta-analysis on shared and distinct neural correlates of the decision-making underlying altruistic and retaliatory punishment.

Individuals who violate social norms will most likely face social punishment sanctions. Those sanctions are based on different motivation aspects, depending on the context. Altruistic punishment occurs if punishment aims to re-establish the social norms even at cost for the punisher. Retaliatory punishment is driven by anger or spite and aims to harm the other. While neuroimaging research highlighted the neural networks supporting decision-making in both types of punishment in isolation, it remains unclear whether they rely on the same or distinct neural systems. We ran an activation likelihood estimation meta-analysis on functional magnetic resonance imaging data on 24 altruistic and 19 retaliatory punishment studies to investigate the neural correlates of decision-making underlying social punishment and whether altruistic and retaliatory punishments share similar brain networks. Social punishment reliably activated the bilateral insula, inferior frontal gyrus, midcingulate cortex (MCC), and superior and medial frontal gyri. This network largely overlapped with activation clusters found for altruistic punishment. However, retaliatory punishment revealed only one cluster in a posterior part of the MCC, which was not recruited in altruistic punishment. Our results support previous models on social punishment and highlight differential involvement of the MCC in altruistic and retaliatory punishments, reflecting the underlying different motivations.

mGluR5 receptor availability is associated with lower levels of negative symptoms and better cognition in male patients with chronic schizophrenia.

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 (BPND ) 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 BPND 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.

Dopamine D2 Receptor Occupancy Estimated From Plasma Concentrations of Four Different Antipsychotics and the Subjective Experience of Physical and Mental Well-Being in Schizophrenia: Results From the Randomized NeSSy Trial.

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.

Pharmacokinetic correlates of venlafaxine: associated adverse reactions.

To address the potential correlation between plasma concentrations of venlafaxine (VEN), its active metabolite O-desmethylvenlafaxine (ODVEN) and the active moiety, AM, (ODVEN + VEN) and adverse drug reactions (ADR) in a large naturalistic sample of in- and outpatients. We compared plasma concentrations of VEN, ODVEN and AM and dose-adjusted (C/D) levels as well the ODVEN/VEN ratios between patients complaining ADRs, following the Udvalg for Kliniske Undersogelser side effect rating scales (UKU) (n = 114) and patients without ADRs (control group, n = 688) out of a naturalistic database. We also investigated potential pharmacokinetic correlates of the four UKU categories by comparing patients complaining ADRs with those who did not. Based on previous literature we applied different ODVEN/VEN ratio values as cut-offs to split our sample into two groups at a time and compare frequencies of ADRs between the groups. No differences for demographic and pharmacokinetic variables including plasma and C/D concentrations as well as ODVEN/VEN ratios were observed between study groups. Neither the comparisons between females and males nor between elderly and non-elderly patients revealed significant differences (p > 0.05 in all cases). No differences were also reported exploring the patients complaining ADRs from the 4 UKU categories separately. After applying various ODVEN/VEN cut-offs, groups did not display differences in frequencies of ADRs (p > 0.05 in all cases). Our findings do not demonstrate a direct link between venlafaxine metabolism measures and ADRs. Therefore, additional dimensions are needed to be considered in future trials aiming to disentangle the involved aspects of ADRs in patients receiving venlafaxine.

The interaction effect of high social support and resilience on functional connectivity using seed-based resting-state assessed by 7-Tesla ultra-high field MRI.

Recent resilience research has increasingly emphasized the importance of focusing on investigating the protective factors in mentally healthy populations, complementing the traditional focus on psychopathology. Social support has emerged as a crucial element within the complex interplay of individual and socio-environmental factors that shape resilience. However, the neural underpinnings of the relationship between social support and resilience, particularly in healthy subjects, remain largely unexplored. With advances in neuroimaging techniques, such as ultra-high field MRI at 7T and beyond, researchers can more effectively investigate the neural mechanisms underlying these factors. Thus, our study employed ultra-high field rs-fMRI to explore how social support moderates the relationship between psychological resilience and functional connectivity in a healthy cohort. We hypothesized that enhanced social support would amplify resilience-associated connectivity within neural circuits essential for emotional regulation, cognitive processing, and adaptive problem-solving, signifying a synergistic interaction where strong social networks bolster the neural underpinnings of resilience. (n = 30). Through seed-based functional connectivity analyses and interaction analysis, we aimed to uncover the neural correlates at the interplay of social support and resilience. Our findings indicate that perceived social support significantly (p<0.001) alters functional connectivity in the right and left FP, PCC, and left hippocampus, affirming the pivotal roles of these regions in the brain's resilience network. Moreover, we identified significant moderation effects of social support across various brain regions, each showing unique connectivity patterns. Specifically, the right FP demonstrated a significant interaction effect where high social support levels were linked to increased connectivity with regions involved in socio-cognitive processing, while low social support showed opposite effects. Similar patterns by social support levels were observed in the left FP, with connectivity changes in clusters associated with emotional regulation and cognitive functions. The PCC's connectivity was distinctly influenced by support levels, elucidating its role in emotional and social cognition. Interestingly, the connectivity of the left hippocampus was not significantly impacted by social support levels, indicating a unique pattern within this region. These insights highlight the importance of high social support levels in enhancing the neural foundations of resilience and fostering adaptive neurological responses to environmental challenges.

Progress and Pitfalls in Developing Agents to Treat Neurocognitive Deficits Associated with Schizophrenia.

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 D2/D3 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.

Connectivity Patterns in the Core Resting-State Networks and Their Influence on Cognition.

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.

7T ultra-high-field neuroimaging for mental health: an emerging tool for precision psychiatry?

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.

Structural alterations of the insula in depression patients - A 7-Tesla-MRI study.

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.

mGluR5 binding changes during a mismatch negativity task in a multimodal protocol with [11C]ABP688 PET/MR-EEG.

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 [11C]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 (BPND) 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 BPND 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 BPND changes. There was a significant ΔBPND 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 ΔBPND 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.

Enhancing neuroimaging genetics through meta-analysis for Tourette syndrome (ENIGMA-TS): A worldwide platform for collaboration.

Tourette syndrome (TS) is characterized by multiple motor and vocal tics, and high-comorbidity rates with other neuropsychiatric disorders. Obsessive compulsive disorder (OCD), attention deficit hyperactivity disorder (ADHD), autism spectrum disorders (ASDs), major depressive disorder (MDD), and anxiety disorders (AXDs) are among the most prevalent TS comorbidities. To date, studies on TS brain structure and function have been limited in size with efforts mostly fragmented. This leads to low-statistical power, discordant results due to differences in approaches, and hinders the ability to stratify patients according to clinical parameters and investigate comorbidity patterns. Here, we present the scientific premise, perspectives, and key goals that have motivated the establishment of the Enhancing Neuroimaging Genetics through Meta-Analysis for TS (ENIGMA-TS) working group. The ENIGMA-TS working group is an international collaborative effort bringing together a large network of investigators who aim to understand brain structure and function in TS and dissect the underlying neurobiology that leads to observed comorbidity patterns and clinical heterogeneity. Previously collected TS neuroimaging data will be analyzed jointly and integrated with TS genomic data, as well as equivalently large and already existing studies of highly comorbid OCD, ADHD, ASD, MDD, and AXD. Our work highlights the power of collaborative efforts and transdiagnostic approaches, and points to the existence of different TS subtypes. ENIGMA-TS will offer large-scale, high-powered studies that will lead to important insights toward understanding brain structure and function and genetic effects in TS and related disorders, and the identification of biomarkers that could help inform improved clinical practice.

Impact of different antidopaminergic mechanisms on the dopaminergic control of prolactin secretion.

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.

Dynamics of task-induced modulation of spontaneous brain activity and functional connectivity in the triple resting-state networks assessed using the visual oddball paradigm.

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.

Common neurobiological correlates of resilience and personality traits within the triple resting-state brain networks assessed by 7-Tesla ultra-high field MRI.

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.

Excitatory-inhibitory balance within EEG microstates and resting-state fMRI networks: assessed via simultaneous trimodal PET-MR-EEG imaging.

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 GABAA 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, [11C]ABP688 (ABP) (N = 9), [11C]Flumazenil (FMZ) (N = 10) and 2-[18F]fluoro-2-deoxy-D-glucose (FDG) (N = 10) targeted to study the mGluR5, GABAA receptors and glucose metabolism respectively. Glucose metabolism and neuroreceptor binding availability (non-displaceable binding potential (BPND)) of GABAA 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 BPND of GABAA relative to mGluR5 BPND 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.

Dopamine D2/3 receptor occupancy by quetiapine in striatal and extrastriatal areas.

Quetiapine is next to clozapine an antipsychotic agent that exerts hardly any extrapyramidal side-effects at clinical efficacious doses. Some previous receptor occupancy studies reported preferential extrastriatal D2/3 receptor (D2/3R)-binding properties of second-generation antipsychotics and suggested this as possible reason for improved tolerability. This positron emission tomography (PET) investigation was designed to compare the occupancy of dopamine D2/3Rs by quetiapine in striatal and extrastriatal brain regions. Therefore, a cohort of 16 quetiapine-treated psychotic patients underwent an [18F]fallypride (FP) PET scan. Due to the high affinity of FP and its comparatively long half-life, striatal and extrastriatal binding potentials could be determined in one single scan. Receptor occupancy was calculated as percent reduction in binding potential relative to age-matched medication-free patients suffering from schizophrenia. Quetiapine occupied 44+/-18% in the temporal cortex and 26+/-17% in the putamen, a difference significant at the level of p=0.005 (Student's t test). Quetiapine showed a mean occupancy of 36+/-16% and in the thalamus. In the caudate nucleus there was an occupancy of 29+/-16% (p=0.0072). Individual occupancy levels did not exceed 59% in any of the striatal volumes of interest. The time-interval between scan and last drug ingestion did not influence the relationship between plasma concentration and central D2/3R occupancy. Taken together, quetiapine shows preferential extrastriatal binding at D2/3Rs; the extent of this difference is comparable to that previously described for clozapine. Both antipsychotics show very low affinity for D2/3Rs.