Brain Morphology Normative modelling platform for abnormality and Centile estimation: Brain MoNoCle.

Normative models of brain structure estimate the effects of covariates such as age and sex using large samples of healthy controls. These models can then be applied to smaller clinical cohorts to distinguish disease effects from other covariates. However, these advanced statistical modelling approaches can be difficult to access, and processing large healthy cohorts is computationally demanding. Thus, accessible platforms with pre-trained normative models are needed. We present such a platform for brain morphology analysis as an open-source web application https://cnnplab.shinyapps.io/normativemodelshiny/, with six key features: (i) user-friendly web interface, (ii) individual and group outputs, (iii) multi-site analysis, (iv) regional and whole-brain analysis, (v) integration with existing tools, and (vi) featuring multiple morphology metrics. Using a diverse sample of 3,276 healthy controls across 21 sites, we pre-trained normative models on various metrics. We validated the models with a small clinical sample of individuals with bipolar disorder, showing outputs that aligned closely with existing literature only after applying our normative modelling. Further validation with a cohort of temporal lobe epilepsy showed agreement with previous group-level findings and individual-level seizure lateralisation. Finally, with the ability to investigate multiple morphology measures in the same framework, we found that biological covariates are better explained in specific morphology measures, and for clinical applications, only some measures are sensitive to the disease process. Our platform offers a comprehensive framework to analyse brain morphology in clinical and research settings. Validations confirm the superiority of normative models and the advantage of investigating a range of brain morphology metrics together.

Deliberately introduced dung beetles in Australia: 12 years of occurrence and abundance records from 2001 to 2022.

Since 1968, the Australian Dung Beetle Project has carried out field releases of 43 deliberately introduced dung beetle species for the biological control of livestock dung and dung-breeding pests. Of these, 23 species are known to have become established. For most of these species, sufficient time has elapsed for population expansion to fill the extent of their potential geographic range through both natural and human-assisted dispersal. Consequently, over the last 20 years, extensive efforts have been made to quantify the current distribution of these introduced dung beetles, as well as the seasonal and spatial variation in their activity levels. Much of these data and their associated metadata have remained unpublished, and they have not previously been synthesized into a cohesive dataset. Here, we collate and report data from the three largest dung beetle monitoring projects from 2001 to 2022. Together, these projects encompass data collected from across Australia, and include records for all 23 species of established dung beetles introduced for biocontrol purposes. In total, these data include 22,718 presence records and 213,538 absence records collected during 10,272 sampling events at 546 locations. Most presence records (97%) include abundance data. In total, 1,752,807 dung beetles were identified as part of these data. The distributional occurrence and abundance data can be used to explore questions such as factors influencing dung beetle species distributions, dung beetle biocontrol, and insect-mediated ecosystem services. These data are provided under a CC-BY-NC 4.0 license and users are encouraged to cite this data paper when using the data.

Human brain 7Li-MRI following low-dose lithium dietary supplementation in healthy participants.

BACKGROUND: Lithium is an effective mood stabiliser, but its mechanism of action is incompletely defined. Even at very low doses, lithium may have neuroprotective effects, but it is not clear if these relate to brain lithium concentration in vivo. We have developed magnetic resonance imaging (7Li-MRI) methods to detect lithium in the brain following supplementation at a very low dose. METHODS: Lithium orotate supplements were taken by nine healthy adult male subjects (5 mg daily) for up to 28 days, providing 2-7 % of the lithium content of a typical therapeutic lithium carbonate dose. One-dimensional 7Li-images were acquired on a 3.0 T MRI scanner. All subjects were scanned on day 14 or 28; seven were scanned on both, one at baseline and one after 7-days washout. RESULTS: 7Li-MR signal amplitude was broadly stable between days 14 and 28. Two subjects had notably higher 7Li-signal intensities (approximately 2-4×) compared to other study participants. LIMITATIONS: Lithium adherence was self-reported by all participants without formal validation. The coarse spatial resolution necessary for detection of low concentrations of 7Li exhibits imperfect spatial separation of signal from adjacent pixels. CONCLUSIONS: 7Li-MRI performed using a clinical 3T scanner demonstrated detection of lithium in the brain at very low concentration, in the range of approximately 10-60 mM. The methods are suited to studies assessing low dose lithium administration in psychiatric and neurodegenerative disorders, and permit the comparison of different lithium salt preparations at a time of emerging interest in the field.

Lithium response in bipolar disorder is associated with focal adhesion and PI3K-Akt networks: a multi-omics replication study.

Lithium is the gold standard treatment for bipolar disorder (BD). However, its mechanism of action is incompletely understood, and prediction of treatment outcomes is limited. In our previous multi-omics study of the Pharmacogenomics of Bipolar Disorder (PGBD) sample combining transcriptomic and genomic data, we found that focal adhesion, the extracellular matrix (ECM), and PI3K-Akt signaling networks were associated with response to lithium. In this study, we replicated the results of our previous study using network propagation methods in a genome-wide association study of an independent sample of 2039 patients from the International Consortium on Lithium Genetics (ConLiGen) study. We identified functional enrichment in focal adhesion and PI3K-Akt pathways, but we did not find an association with the ECM pathway. Our results suggest that deficits in the neuronal growth cone and PI3K-Akt signaling, but not in ECM proteins, may influence response to lithium in BD.

Plus ça change? Switching lithium preparations.

AIMS AND METHOD: A supply disruption alert in 2020, now rescinded, notified UK prescribers of the planned discontinuation of Priadel® (lithium carbonate) tablets. This service evaluation explored lithium dose and plasma levels before and after the switching of lithium brands, in order to determine the interchangeability of different brands of lithium from a pharmacokinetic perspective. RESULTS: Data on the treatment of 37 patients switched from Priadel® tablets were analysed. Switching to Camcolit® controlled-release tablets at the same dose did not result in meaningful differences in plasma lithium levels. Dose adjustment and known or suspected poor medication adherence were associated with greater variability in plasma lithium levels on switching brands. CLINICAL IMPLICATIONS: For comparable pre- and post-switch doses in adherent patients, the most common brands of lithium carbonate appear to produce similar plasma lithium levels. British National Formulary guidance relating to switching lithium brands may be unnecessarily complex.

Identifying the neuropsychiatric health effects of low-dose lithium interventions: A systematic review.

BACKGROUND: Lithium is widely evidenced for its neuropsychiatric benefits. Advantages of 'sub-therapeutic' doses are increasingly being reported, which is apposite given enduring concerns around adverse effects of 'therapeutic' doses. We aimed to synthesise all available evidence from interventional studies investigating low-dose lithium (LDL) across neuropsychiatric outcomes. METHODS: Electronic databases were systematically searched to include studies where a group of adult humans were treated with LDL (∼serum level ≤0.6 mmol/L), where data describing a neuropsychiatric outcome were reported either before and after treatment, and/or between lithium and a comparator. RESULTS: 18 articles were examined and grouped according to outcome domain (cognition, depression, mania, and related constructs e.g., suicidality). Significant benefits (versus placebo) were identified for attenuating cognitive decline, and potentially as an adjunctive therapy for people with depression/mania. Across studies, LDL was reported to be safe. CONCLUSIONS: Despite the paucity and heterogeneity of studies, LDL's apparent pro-cognitive effects and positive safety profile open promising avenues in the fields of neurodegeneration, and augmentation in affective disorders. We urge future examinations of LDL's potential to prevent cognitive/affective syndromes.

Assessment for vagus nerve stimulation in patients with difficult-to-treat depression: a model from the Newcastle Regional Affective Disorders Service (RADS).

BACKGROUND: Vagus nerve stimulation (VNS) has been shown to improve long-term outcomes for some patients with difficult-to-treat depression (DTD). OBJECTIVES: Set out criteria to support the identification of patients for whom VNS is a suitable treatment option. METHODS: Published clinical evidence, coupled with clinical experience garnered at the Regional Affective Disorders Service (RADS; Newcastle, UK) to inform VNS criteria. RESULTS: Patients with major depressive disorder or bipolar disorder (predominantly depressive) and a history of failed trials of multiple treatment modalities including pharmacotherapy, psychotherapy and/or electroconvulsive therapy (ECT) may be suitable candidates for VNS, if no contraindications are present. In the RADS such patients are offered VNS if they are able to provide informed consent and two specialists agree it is appropriate. CONCLUSIONS: VNS provides a valuable treatment option for DTD when used under appropriate circumstances; these assessment criteria facilitate the identification of patients with greatest potential to benefit.

Prospective cohort study of early biosignatures of response to lithium in bipolar-I-disorders: overview of the H2020-funded R-LiNK initiative.

BACKGROUND: Lithium is recommended as a first line treatment for bipolar disorders. However, only 30% of patients show an optimal outcome and variability in lithium response and tolerability is poorly understood. It remains difficult for clinicians to reliably predict which patients will benefit without recourse to a lengthy treatment trial. Greater precision in the early identification of individuals who are likely to respond to lithium is a significant unmet clinical need. STRUCTURE: The H2020-funded Response to Lithium Network (R-LiNK; http://www.r-link.eu.com/ ) will undertake a prospective cohort study of over 300 individuals with bipolar-I-disorder who have agreed to commence a trial of lithium treatment following a recommendation by their treating clinician. The study aims to examine the early prediction of lithium response, non-response and tolerability by combining systematic clinical syndrome subtyping with examination of multi-modal biomarkers (or biosignatures), including omics, neuroimaging, and actigraphy, etc. Individuals will be followed up for 24 months and an independent panel will assess and classify each participants' response to lithium according to predefined criteria that consider evidence of relapse, recurrence, remission, changes in illness activity or treatment failure (e.g. stopping lithium; new prescriptions of other mood stabilizers) and exposure to lithium. Novel elements of this study include the recruitment of a large, multinational, clinically representative sample specifically for the purpose of studying candidate biomarkers and biosignatures; the application of lithium-7 magnetic resonance imaging to explore the distribution of lithium in the brain; development of a digital phenotype (using actigraphy and ecological momentary assessment) to monitor daily variability in symptoms; and economic modelling of the cost-effectiveness of introducing biomarker tests for the customisation of lithium treatment into clinical practice. Also, study participants with sub-optimal medication adherence will be offered brief interventions (which can be delivered via a clinician or smartphone app) to enhance treatment engagement and to minimize confounding of lithium non-response with non-adherence. CONCLUSIONS: The paper outlines the rationale, design and methodology of the first study being undertaken by the newly established R-LiNK collaboration and describes how the project may help to refine the clinical response phenotype and could translate into the personalization of lithium treatment.

Analysis of the Influence of microRNAs in Lithium Response in Bipolar Disorder.

Bipolar disorder (BD) is a common, highly heritable neuropsychiatric disease characterized by recurrent episodes of mania and depression. Lithium is the best-established long-term treatment for BD, even though individual response is highly variable. Evidence suggests that some of this variability has a genetic basis. This is supported by the largest genome-wide association study (GWAS) of lithium response to date conducted by the International Consortium on Lithium Genetics (ConLiGen). Recently, we performed the first genome-wide analysis of the involvement of miRNAs in BD and identified nine BD-associated miRNAs. However, it is unknown whether these miRNAs are also associated with lithium response in BD. In the present study, we therefore tested whether common variants at these nine candidate miRNAs contribute to the variance in lithium response in BD. Furthermore, we systematically analyzed whether any other miRNA in the genome is implicated in the response to lithium. For this purpose, we performed gene-based tests for all known miRNA coding genes in the ConLiGen GWAS dataset (n = 2,563 patients) using a set-based testing approach adapted from the versatile gene-based test for GWAS (VEGAS2). In the candidate approach, miR-499a showed a nominally significant association with lithium response, providing some evidence for involvement in both development and treatment of BD. In the genome-wide miRNA analysis, 71 miRNAs showed nominally significant associations with the dichotomous phenotype and 106 with the continuous trait for treatment response. A total of 15 miRNAs revealed nominal significance in both phenotypes with miR-633 showing the strongest association with the continuous trait (p = 9.80E-04) and miR-607 with the dichotomous phenotype (p = 5.79E-04). No association between miRNAs and treatment response to lithium in BD in either of the tested conditions withstood multiple testing correction. Given the limited power of our study, the investigation of miRNAs in larger GWAS samples of BD and lithium response is warranted.

Genetic variants associated with response to lithium treatment in bipolar disorder: a genome-wide association study.

BACKGROUND: Lithium is a first-line treatment in bipolar disorder, but individual response is variable. Previous studies have suggested that lithium response is a heritable trait. However, no genetic markers of treatment response have been reproducibly identified. METHODS: Here, we report the results of a genome-wide association study of lithium response in 2563 patients collected by 22 participating sites from the International Consortium on Lithium Genetics (ConLiGen). Data from common single nucleotide polymorphisms (SNPs) were tested for association with categorical and continuous ratings of lithium response. Lithium response was measured using a well established scale (Alda scale). Genotyped SNPs were used to generate data at more than 6 million sites, using standard genomic imputation methods. Traits were regressed against genotype dosage. Results were combined across two batches by meta-analysis. FINDINGS: A single locus of four linked SNPs on chromosome 21 met genome-wide significance criteria for association with lithium response (rs79663003, p=1·37 × 10(-8); rs78015114, p=1·31 × 10(-8); rs74795342, p=3·31 × 10(-9); and rs75222709, p=3·50 × 10(-9)). In an independent, prospective study of 73 patients treated with lithium monotherapy for a period of up to 2 years, carriers of the response-associated alleles had a significantly lower rate of relapse than carriers of the alternate alleles (p=0·03268, hazard ratio 3·8, 95% CI 1·1-13·0). INTERPRETATION: The response-associated region contains two genes for long, non-coding RNAs (lncRNAs), AL157359.3 and AL157359.4. LncRNAs are increasingly appreciated as important regulators of gene expression, particularly in the CNS. Confirmed biomarkers of lithium response would constitute an important step forward in the clinical management of bipolar disorder. Further studies are needed to establish the biological context and potential clinical utility of these findings. FUNDING: Deutsche Forschungsgemeinschaft, National Institute of Mental Health Intramural Research Program.

Lithium, gray matter, and magnetic resonance imaging signal.

BACKGROUND: Magnetic resonance imaging studies have reported that lithium can increase the volume of gray matter in the human brain, a finding that has been ascribed to the established neurotrophic or neuroprotective effects of the drug. Lithium, however, might directly influence the intensity of the magnetic resonance signal so it is possible that the volumetric findings are artifactual, essentially a consequence of altered image contrast. METHODS: Anatomical and quantitative magnetic resonance scans were acquired on 31 healthy young men before and after taking either lithium or placebo for 11 days. Brain volume change was derived with two established techniques: voxel-based morphometry (a statistical approach using signal intensity to segment images into tissue types), and Structural Image Evaluation, using Normalization, of Atrophy (a technique that operates by detecting changes in the position of the boundaries of the brain). In a subgroup (n = 12), tissue-specific magnetic resonance relaxation times were compared before and after lithium with quantitative T1-mapping techniques. RESULTS: Voxel-based morphometry revealed that gray matter volume was increased by lithium but not placebo (p = .001), whereas Structural Image Evaluation, using Normalization, of Atrophy showed no difference between lithium and placebo (p = .23). Taking lithium reduced the T1 relaxation of the gray matter only (p = .008). CONCLUSION: Magnetic resonance images of the brain differ before and after lithium, but this difference might derive from a change in the characteristics of the signal rather than a tangible increase in volume.

Interpreting magnetic resonance imaging findings in bipolar disorder.

The episodic nature of bipolar disorder together with the ostensibly polar extremes of mania and depression have favored the acceptance of a functional model postulating regionally disturbed brain activity returning to normal with time or treatment. Seemingly contrary to that view, anatomical imaging studies have demonstrated abnormalities in brain structure which could reflect neurodegeneration or represent disturbed neuronal development. Resolution may come from an appreciation of adult neurogenesis, especially given the neuroprotective properties of drugs, such as lithium and their effects on brain volume. The brain regions vulnerable to structural changes also show evidence of dysfunction, giving rise to corticolimbic dysregulation interpretations of bipolar disorder. This article reviews the structural and functional magnetic resonance imaging data in bipolar disorder. Its focus is on the interpretation of findings in light of recent developments in the fields of neurobiology and image analysis, with particular attention paid to both the confounding effects of medication and the baseline energy state of the brain.

Quantitative lithium magnetic resonance spectroscopy in the normal human brain on a 3 T clinical scanner.

Lithium (Li) is a core for many neuropsychiatric conditions. The safe serum range of Li treatment is narrow, and regular monitoring by blood test is required, although serum levels are thought to be a poor indicator of Li concentration in the brain itself. Brain Li concentration can be measured by magnetic resonance spectroscopy. However, little data exist in the healthy human brain, and there are no studies of the relaxation properties of brain (7)Li at 3 T. Here, 11 healthy male subjects were prescribed Li over a period of 11 days. In seven subjects, the in vivo T(1) of (7)Li was measured to be 2.1 ± 0.7 s. In the remaining subjects, spectroscopic imaging (1D) yielded a mean brain (7)Li concentration of 0.71 ± 0.1 mM, with no significant difference between gray and white matter. Mean serum concentration was 0.9 ± 0.16 mM, giving a mean brain/serum ratio of 0.78 ± 0.26.

Functional connectivity in late-life depression using resting-state functional magnetic resonance imaging.

OBJECTIVE: To investigate whether there are differences in brain connectivity in late-life depression (LLD) and nondepressed subjects using the left and right heads of caudate nuclei (hCN) as the seed regions. DESIGN: Resting-state functional magnetic resonance imaging (fMRI) data were collected using a 3-Tesla MRI System. SETTING: Subjects were recruited from primary or secondary care services in the Newcastle area. PARTICIPANTS: Thirty-three subjects aged 65 years and older; 16 who had a recent episode of LLD and 17 nondepressed subjects. MEASUREMENTS: Functional connectivity was analyzed by extracting the temporal signal variation from the left and right hCN and cross correlating with the rest of the brain. RESULTS: Significant connectivity between the hCN and frontal areas was observed in the nondepressed group, whereas in LLD, connectivity was seen over a much wider area. Regions showing significantly greater connectivity (p < or =0.05) in LLD compared with the nondepressed group were frontal (precentral, subgyral, middle frontal, and paracentral lobule), sublobar (thalamus and insula), limbic (cingulate), parietal (postcentral gyrus, precuneus, inferior parietal lobule, and supramarginal gyrus), and temporal (superior temporal gyrus). Conversely, no brain regions showed greater connectivity in the nondepressed group than LLD. In both groups, the right hCN showed significantly greater connectivity than the left in numerous brain regions, but connectivity for the left hCN did not exceed the right in any brain regions. CONCLUSIONS: This resting-state study showed increased connectivity in specific brain regions in LLD compared with the nondepressed group, which supports the view that functional connectivity is altered in depression.

Pituitary volume and third ventricle width in euthymic patients with bipolar disorder.

BACKGROUND: Many of the clinical and neuroendocrine features of bipolar disorder involve hypothalamic structures. Although current neuroimaging techniques inadequately resolve the structural components of the hypothalamus, evidence of derangement can be sought by examining the adjacent third ventricle and the functionally related pituitary. AIMS: To investigate the structure and function of the hypothalamic-pituitary-adrenal axis in euthymic patients with bipolar disorder. METHOD: Euthymic adult patients with bipolar disorder (n=49) were compared with matched normal control subjects (n=47). Pituitary volume and third ventricle width were assessed on MRI scans. Basal salivary cortisol levels were measured. RESULTS: The width of the third ventricle in patients with bipolar disorder exceeded that of controls (mean +/- SD (in mm): 3.87 +/- 1.96 versus 2.56 +/- 1.34; d=0.76, ANOVA F=12.7, p=0.001), with the greatest differences found in males. Third ventricle width increased with age across the groups (F=16.97, p<0.001). Pituitary volumes did not differ between patients and controls (mean +/- SD (in mm(3)): 632 +/- 176 versus 679 +/- 159). Overall, females had larger pituitaries than males (703 +/- 160 versus 595 +/- 161; d=0.67, F=9.65, p=0.003; all subjects), but female patients had smaller pituitaries compared to female controls (637 +/- 178 versus 756 +/- 126; d=0.65, F=5.04, p=0.03). No difference was found in a comparable analysis of males. Pituitary volume did not differ between patients prescribed and not prescribed antipsychotic drugs. Basal salivary cortisol levels did not differ between patients and controls. CONCLUSIONS: In euthymic patients with normal basal cortisol levels, pituitary volume and third ventricle width were found to differ from normal controls. These differences were related to gender, may be important in the pathogenesis of bipolar disorder and could link the vegetative and endocrine abnormalities seen in this condition. Such findings may reflect a trait abnormality or be a consequence of previous episodes.

The role of dopamine in bipolar disorder.

OBJECTIVE: Despite effective pharmacological treatments for bipolar disorder, we still lack a comprehensive pathophysiological model of the illness. Recent neurobiological research has implicated a number of key brain regions and neuronal components in the behavioural and cognitive manifestations of bipolar disorder. Dopamine has previously been investigated in some depth in bipolar disorder, but of late has not been a primary focus of attention. This article examines the role of dopamine in bipolar disorder, incorporating recent advances into established models where possible. METHODS: A critical evaluation of the literature was undertaken, including a review of behavioural, neurochemical, receptor, and imaging studies, as well as genetic studies focusing on dopamine receptors and related metabolic pathways. In addition, pharmacologic manipulation of the central dopaminergic pathways and comparisons with other disease states such as schizophrenia were considered, principally as a means of exploring the hypothesised models. RESULTS: Multiple lines of evidence, including data from pharmacological interventions and structural and functional magnetic resonance imaging studies, suggest that the dopaminergic system may play a central role in bipolar disorder. CONCLUSION: Future research into the pathophysiological mechanisms of bipolar disorder and the development of new treatments for bipolar disorder should focus on the dopaminergic system.

The armamentarium of treatments for bipolar disorder: a review of the literature.

To assess current pharmacotherapeutic options for bipolar disorder, with particular emphasis on the use of antipsychotic agents, Medline and EMBASE were searched between January 1980 and December 2005 using the keywords "schizoaffective disorder" and "bipolar disorder", combined with various antidepressants, antipsychotics, lithium or other mood stabilizers. English-language articles, review articles and original research articles were reviewed. Most data are available for the "mood stabilizers" lithium and valproate. However, these agents have important limitations regarding their tolerability and efficacy in certain groups. Newer anticonvulsants, especially lamotrigine, have demonstrated efficacy across mood-symptom domains. Antidepressants are not generally favoured as monotherapy in patients with bipolar depression or schizoaffective disorder, due to their potential to induce switching to manic states. However, data are emerging for the efficacy of selective serotonin reuptake inhibitors for bipolar depression in combination with atypical antipsychotics. Atypical antipsychotics may also be used as monotherapy or in conjunction with mood stabilizers for the treatment of acute mania and for continuing maintenance therapy. The choice of antipsychotic may be influenced by the therapeutic situation; formulations that facilitate administration in the acute scenario can provide rapid tranquillization, whereas those that enhance compliance may have a place in maintenance therapy. Our results suggest a growing role for atypical antipsychotics in the treatment of bipolar disorder and further data are anticipated.