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Given psychotic illnesses' high heritability and associations with brain structure, numerous neuroimaging-genetics findings have been reported in the last two decades. However, few findings have been replicated. In the present independent sample we aimed to replicate any psychosis-implicated SNPs (single nucleotide polymorphisms), which had previously shown at least two main effects on brain volume.
A systematic review for SNPs showing a replicated effect on brain volume yielded 25 studies implicating seven SNPs in five genes. Their effect was then tested in 113 subjects with either schizophrenia, bipolar disorder, ‘at risk mental state’ or healthy state, for whole-brain and region-of-interest (ROI) associations with grey and white matter volume changes, using voxel-based morphometry.
We found FWER-corrected (Family-wise error rate) (i.e. statistically significant) associations of: (1) CACNA1C-rs769087-A with larger bilateral hippocampus and thalamus white matter, across the whole brain; and (2) CACNA1C-rs769087-A with larger superior frontal gyrus, as ROI. Higher replication concordance with existing literature was found, in decreasing order, for: (1) CACNA1C-rs769087-A, with larger dorsolateral-prefrontal/superior frontal gyrus and hippocampi (both with anatomical and directional concordance); (2) ZNF804A-rs11681373-A, with smaller angular gyrus grey matter and rectus gyri white matter (both with anatomical and directional concordance); and (3) BDNF-rs6265-T with superior frontal and middle cingulate gyri volume change (with anatomical and allelic concordance).
Most literature findings were not herein replicated. Nevertheless, high degree/likelihood of replication was found for two genome-wide association studies- and one candidate-implicated SNPs, supporting their involvement in psychosis and brain structure.
Schizophrenia is associated with disturbances in neurophysiological processes. However, the relation of EEG and ERP parameters to structural supragranular cortical abnormalities, observed in schizophrenia, remains unclear.
The purpose was to characterize EEG and ERP disturbances and their relationship to changes occurring in supragranular cortical layers in subjects with schizophrenia.
43 first-episode schizophrenia (FES) male patients and 43 matched healthy controls (HC) underwent background EEG and standard two-tones oddball ERP recording and structural MRI at 3T Philips scanner. MRI images were processed via FreeSurfer and MATLAB to derive two markers specific to supragranular thickness change: gyral-sulcal thickness differences (GSTD) and gyral-sulcal intrinsic curvature differences on pial surface (GSCD) (github.com/kwagstyl/schizophrenia_gyral_sulcal).
Theta rhythm spectral power was increased in FES while P300 amplitudes and latencies, N100 (to non-targets) amplitudes, alpha rhythm spectral power were not altered compared to HC. GSCD measures were increased in temporal, parietal and occipital cortices, whereas both GSTD and GSCD were increased in the right frontal cortex in FES. No correlations between altered EEG and supragranular thickness markers survived correction for multiple comparisons.
Presumably, theta rhythm has a widespread circuit of generators, including the cortical ones. However, we have not found correlations between EEG and supragranular markers in FES. Considering an absence of correlations between theta and hippocampal volumes (Lebedeva et al., 2020), a speculative interpretation is that the neurophysiological disturbances may be associated with a more complex patterns of more localized structural and functional impairments.
The work was supported by RFBR grant 20-013-00748.
Bipolar disorder has been repeatedly associated with abnormalities of white matter. However, DTI is intrinsically limited and the precise cellular mechanisms that underlie these alterations remains unknown.
Our aim was to investigate microscopical characteristics of white matter using MRI in patients with bipolar and healthy controls.
77 patients and 71 controls from 3 sites had a T1 structural MRI, a multi-shell HARDI MRI and at one site with a T1-weighted VFA-SPGR acquisition, and a T2 MSME acquisition. The volume fraction and the orientation dispersion was extracted using NODDI from DW images in each site. Myelin Water Fraction was extracted in 33 patients and 36 controls to probe myelin characteristics. White matter bundles were reconstructed using deterministic tractography. Statistical analyses were performed after harmonization by the ComBat algorithm and controlled for age, gender and handedness.
We found significant lower axonal density in patients along the short fibers of the left cingulum, the left anterior arcuate and the left inferior fronto-occipital fasciculus. We found lower mean MWF in patients along the short fibers of the right cingulum, the left inferior fronto-occipital fasciculus, the left anterior arcuate and the splenium of the corpus callosum. We found higher mean orientation dispersion in patients only along the left uncinate fasciculus.
We report alterations of limbic and inter-hemispheric white matter tracts in patients with bipolar disorder reflecting axonal loss, demyelination and architecture alterations. These results contribute to better capture the plurality of the mechanisms involved in bipolar disorder that cannot be deciphered with classical diffusion MRI.
The hippocampus is a complex brain structure with key roles in cognitive and emotional processing and with subregion abnormalities associated with a range of disorders and psychopathologies. Here we combine data from two large independent young adult twin/sibling cohorts to obtain the most accurate estimates to date of genetic covariation between hippocampal subfield volumes and the hippocampus as a single volume. The combined sample included 2148 individuals, comprising 1073 individuals from 627 families (mean age = 22.3 years) from the Queensland Twin IMaging (QTIM) Study, and 1075 individuals from 454 families (mean age = 28.8 years) from the Human Connectome Project (HCP). Hippocampal subfields were segmented using FreeSurfer version 6.0 (CA4 and dentate gyrus were phenotypically and genetically indistinguishable and were summed to a single volume). Multivariate twin modeling was conducted in OpenMx to decompose variance into genetic and environmental sources. Bivariate analyses of hippocampal formation and each subfield volume showed that 10%–72% of subfield genetic variance was independent of the hippocampal formation, with greatest specificity found for the smaller volumes; for example, CA2/3 with 42% of genetic variance being independent of the hippocampus; fissure (63%); fimbria (72%); hippocampus-amygdala transition area (41%); parasubiculum (62%). In terms of genetic influence, whole hippocampal volume is a good proxy for the largest hippocampal subfields, but a poor substitute for the smaller subfields. Additive genetic sources accounted for 49%–77% of total variance for each of the subfields in the combined sample multivariate analysis. In addition, the multivariate analyses were sufficiently powered to identify common environmental influences (replicated in QTIM and HCP for the molecular layer and CA4/dentate gyrus, and accounting for 7%–16% of total variance for 8 of 10 subfields in the combined sample). This provides the clearest indication yet from a twin study that factors such as home environment may influence hippocampal volumes (albeit, with caveats).
Nearly one in five children with CHD is born with white matter injury that can be recognised on postnatal MRI by the presence of T1 hyperintense lesions. This pattern of white matter injury is known to portend poor neurodevelopmental outcomes, but the exact aetiology and histologic characterisation of these lesions have never been described. A fetal sheep was cannulated at gestational age 110 days onto a pumpless extracorporeal oxygenator via the umbilical vessels and supported in a fluid environment for 14.5 days. The fetus was supported under hypoxic conditions (mean oxygen delivery 16 ml/kg/day) to simulate the in utero conditions of CHD. At necropsy, the brain was fixed, imaged with MRI, and then stained to histologically identify areas of injury. Under hypoxemic in utero conditions, the fetus developed a T1 hyperintense lesion in its right frontal lobe. Histologically, this lesion was characterised by microvascular proliferation and astrocytosis without gliosis. These findings may provide valuable insight into the aetiology of white matter injury in neonates with CHD.
Imaging biomarkers are important in the diagnosis and evaluation of treatment effect in AD. The “A/T/N” (amyloid/tau/neurodegeneration) classification notably focused on disease characteristics measurable using imaging or CSF biomarkers. Information obtained with imaging biomarkers can address several challenges in AD trials, by confirming pathology for patient inclusion and target engagement, enabling stratification for analysis based on likely rate of clinical decline, and detecting treatment effect with fewer subjects; it also help to characterize treatment responders and to better understand the neurological basis for clinical response. This chapter discusses how imaging data are generated, the applicability of various imaging endpoints within the overall AD progression pathway, technical issues influencing the reliability and interpretability of the data, and practical steps to incorporate imaging into clinical trials. Applications of volumetric MRI, MRI used in safety assessment, amyloid PET, tau PET, and FDG PET measurement of glucose metabolism are described. Relevant regulatory guidance and the fit of imaging data with blood based or other biomarkers are discussed.
The incorporation of target engagement, efficacy, and imaging abnormalities biomarkers on preclinical (animal) drug development brings the promise of accelerating drug development. In this chapter, we will highlight innovative methodological considerations that will bring greater predictive power relative to the traditional approaches in the preclinical stage of drug discovery. First, we discuss various animal models used in Alzheimer’s disease research and important aspects to consider when choosing the appropriate model to test a novel therapeutic intervention. Second, compared to the traditional histological methods, utilizing in vivo biomarkers in preclinical assessment allows quantifying disease pathophysiology with complex longitudinal designs. We discuss the feasibility and implications of longitudinal study designs and how the same in vivo biomarkers used in human clinical trials can be implemented to evaluate the preclinical development stages. Lastly, we discuss why the incorporation of methods from human clinical trials can advance the preclinical phases of drug discovery.
Gray matter morphometry studies have lent seminal insights into the etiology of mental illness. Existing research has primarily focused on adults and then, typically on a single disorder. Examining brain characteristics in late childhood, when the brain is preparing to undergo significant adolescent reorganization and various forms of serious psychopathology are just first emerging, may allow for a unique and highly important perspective of overlapping and unique pathogenesis.
A total of 8645 youth were recruited as part of the Adolescent Brain and Cognitive Development study. Magnetic resonance imaging scans were collected, and psychotic-like experiences (PLEs), depressive, and anxiety symptoms were assessed three times over a 2-year period. Cortical thickness, surface area, and subcortical volume were used to predict baseline symptomatology and symptom progression over time.
Some features could possibly signal common vulnerability, predicting progression across forms of psychopathology (e.g. superior frontal and middle temporal regions). However, there was a specific predictive value for emerging PLEs (lateral occipital and precentral thickness), anxiety (parietal thickness/area and cingulate), and depression (e.g. parahippocampal and inferior temporal).
Findings indicate common and distinct patterns of vulnerability for varying forms of psychopathology are present during late childhood, before the adolescent reorganization, and have direct relevance for informing novel conceptual models along with early prevention and intervention efforts.
Quantum sensing is the most exciting quantum technology and it has the most potential to change our lives in the next decade and beyond. Quantum sensors will offer new capabilities with benefits for medicine, defense, intelligence, extractive industries and many others. Quantum sensing is a precursor technology to quantum computing and communications. Quantum sensors use quantum properties and effects to measure or sense physical things. This chapter explores quantum sensing as a topic in its own right, because the capabilities of quantum sensing are surprising and offer new forms of knowledge discovery and at new levels of analysis. Furthermore quantum sensors are here today---indeed, they have been in use for more than fifty years.
Brain magnetic resonance imaging (MRI) studies of clinical populations often require comparison to a normative ‘control’ cohort, usually of similar age/sex, scanned with the same protocol. The goal here was to create a normative brain MRI database of common quantitative methods to be used in comparisons with a variety of neurological disorders across the lifespan. 378 neurotypical controls (aged 5–90 years; median 31 years; 216 females, 162 males) completed brain MRI, cognitive testing, clinical assessment, and a demographics questionnaire. In addition, this large normative sample will yield novel insight into healthy brain development and aging.
A total of 80% of fibromyalgia (FM) population have reported poor sleep. In this regard, the pineal gland, involved in circadian rhythm processes as a key neuroendocrine organ which mainly synthesises and secretes melatonin, has never been studied before in this population. Therefore, this study aimed to evaluate the parenchyma pineal volume and its relation to sleep hours, sleep quality index and melatonin level at night. A total of 50 participants, 30 women with FM and 20 healthy control women underwent cranial magnetic resonance imaging. The total pineal volume, cyst pineal volume and parenchyma pineal volume were manually calculated in cubic millimetres. Also, the total pineal volume was estimated using Hasehawa method. Parenchyma pineal volume was significantly correlated with sleep hours (p-value = 0.041) and nocturnal melatonin level (p-value = 0.027). Moreover, there was also a non-significant correlation between parenchyma pineal volume and sleep quality index (p-value = 0.055). Furthermore, a mean parenchyma pineal volume of 102.00 (41.46) mm³ was observed, with a prevalence of 29.60% cyst in FM group. This is the first study that has reported pineal gland volumes, cyst prevalence and correlative relationships between parenchyma pineal volume and sleep hours and melatonin levels in women with FM.
With a lifetime prevalence of up to 75%, uterine fibroids are the most common benign tumour of the female reproductive system. Fibroids present the most common indication for hysterectomy and are associated with high health-related costs. They can severely affect the quality of life of these women and may diminish fertility. This chapter provides an overview of the aetiology, prevalence, diagnosis and treatment options for uterine fibroids. As the reproductive phase is shifting ever further back into the life of a woman, conservative therapy options are becoming increasingly important.
In this chapter, we provide a historical and a contemporary overview of the hearing brain. We will review how various brain-imaging methods are employed to study how sounds and meanings are represented in the brain. These studies have provided the foundation from which network models of the brain are built. We will conclude with a discussion of the practical aspects of the neuroscience of language, such as how it will further our understanding of the brain and lead to clinical applications.
The focus of this chapter is to discuss a multidisciplinary approach to maternal-fetal patients undergoing minimally invasive (shunt or fetoscopic) procedures, open fetal surgery, or the ex-utero intrapartum therapy (EXIT) procedure. The team requires a diverse group of personnel. We will discuss the nature of this team and the pertinent aspects of the preoperative, intraoperative, and postoperative phase of care for the maternal-fetal patient. The preparation required for the team members providing care for these patients as well as the long-term follow-up and research aspects are outlined. Comprehensive expert care for these interventions requires administrative, institutional, research, and philanthropic support.
We compared entorhinal cortex atrophy (ERICA) score vs. medial temporal atrophy (MTA) score’s ability to predict conversion from amnestic mild cognitive impairment (aMCI) to Alzheimer’s disease (AD) using magnetic resonance imaging (MRI). We hypothesized that ERICA would show higher specificity. Data from 61 aMCI patients were analyzed. Positive ERICA was associated with AD conversion with a sensitivity of 56% (95% CI: 30–80%) and a specificity of 78% (63–89%) vs. 69% (41–89%) SE and 60% (44–74%) SP for the MTA. Results suggest that ERICA is superior to MTA in predicting conversion from aMCI to AD in a small sample of participants.
Progressive brain structural MRI changes are described in schizophrenia and have been ascribed to both illness progression and antipsychotic treatment. We investigated treatment effects, in terms of total cumulative antipsychotic dose, efficacy and tolerability, on brain structural changes over the first 24 months of treatment in schizophrenia.
A prospective, 24-month, single-site cohort study in 99 minimally treated patients with first-episode schizophrenia, schizophreniform and schizoaffective disorder, and 98 matched healthy controls. We treated the patients according to a fixed protocol with flupenthixol decanoate, a long-acting injectable antipsychotic. We assessed psychopathology, cognition, extrapyramidal symptoms and BMI, and acquired MRI scans at months 0, 12 and 24. We selected global cortical thickness, white matter volume and basal ganglia volume as the regions of interest.
The only significant group × time interaction was for basal ganglia volumes. However, patients, but not controls, displayed cortical thickness reductions and increases in white matter and basal ganglia volumes. Cortical thickness reductions were unrelated to treatment. White matter volume increases were associated with lower cumulative antipsychotic dose, greater improvements in psychopathology and cognition, and more extrapyramidal symptoms. Basal ganglia volume increases were associated with greater improvements in psychopathology, greater increases in BMI and more extrapyramidal symptoms.
We provide evidence for plasticity in white matter and basal ganglia associated with antipsychotic treatment in schizophrenia, most likely linked to the dopamine blocking actions of these agents. Cortical changes may be more closely related to the neurodevelopmental, non-dopaminergic aspects of the illness.
Exercise has been found to be important in maintaining neurocognitive health. However, the effect of exercise intensity level remains relatively underexplored. Thus, to test the hypothesis that self-paced high-intensity exercise and cardiorespiratory fitness (peak aerobic capacity; VO2peak) increase grey matter (GM) volume, we examined the effect of a 6-month exercise intervention on frontal lobe GM regions that support the executive functions in older adults.
Ninety-eight cognitively normal participants (age = 69.06 ± 5.2 years; n = 54 female) were randomised into either a self-paced high- or moderate-intensity cycle-based exercise intervention group, or a no-intervention control group. Participants underwent magnetic resonance imaging and fitness assessment pre-intervention, immediately post-intervention, and 12-months post-intervention.
The intervention was found to increase fitness in the exercise groups, as compared with the control group (F = 9.88, p = <0.001). Changes in pre-to-post-intervention fitness were associated with increased volume in the right frontal lobe (β = 0.29, p = 0.036, r = 0.27), right supplementary motor area (β = 0.30, p = 0.031, r = 0.29), and both right (β = 0.32, p = 0.034, r = 0.30) and left gyrus rectus (β = 0.30, p = 0.037, r = 0.29) for intervention, but not control participants. No differences in volume were observed across groups.
At an aggregate level, six months of self-paced high- or moderate-intensity exercise did not increase frontal GM volume. However, experimentally-induced changes in individual cardiorespiratory fitness was positively associated with frontal GM volume in our sample of older adults. These results provide evidence of individual variability in exercise-induced fitness on brain structure.
Survivors of patients with artery of Percheron infarction (API) often have a prolonged and disabling form of cognitive impairment that remains insufficiently characterized. We aimed to examine the clinical and cognitive features of API in the short and long term after stroke.
We reviewed 6400 patients with a first-ever stroke included in the Stroke Registry between 2011 and 2021. The diagnosis of API was based on clinical diagnosis and imaging confirmation. All patients underwent neuropsychological assessment at hospital stay and 1 year after stroke. A z-score of each patients’ cognitive test point was calculated, and a z-score inferior to 2 was considered as pathological.
Of the 10 patients enrolled, all had cognitive impairment, consciousness, and behavioral disorders at stroke onset. Six patients had pure bilateral thalamic involvement while four had bilateral thalamic and rostral midbrain involvement. At 12 months, 50% of patients had global mental state scores 2 SD below the population mean (z-score mean ± SD, −2.17 ± 0.4). Most of the prefrontal cortex cognitive processes including executive functions such as planning and cognitive control (z-score mean ± SD, −3.92 ± 0.3), processing speed (−4.42 ± 0.5), working memory (−3.97 ± 0.3) were severely impaired at stroke onset. Especially in patients with thalamic and rostral midbrain involvement, deficiencies in executive function (z-score mean ± SD, −2.60 ± 0.4), processing speed (−2.22 ± 0.5), working (−3.76 ± 0.4), and episodic memory (−2.23 ± 0.3) continued 12 months after stroke.
The occlusion of the artery of Percheron results in severe behavioral and cognitive disorders in the short and long term after stroke.