High-throughput sequencing of insect specimens with sub-optimal DNA preservation using a practical, plate-based Illumina-compatible Tn5 transposase library preparation method.

Entomological sampling and storage conditions often prioritise efficiency, practicality and conservation of morphological characteristics, and may therefore be suboptimal for DNA preservation. This practice can impact downstream molecular applications, such as the generation of high-throughput genomic libraries, which often requires substantial DNA input amounts. Here, we use a practical Tn5 transposase tagmentation-based library preparation method optimised for 96-well plates and low yield DNA extracts from insect legs that were stored under sub-optimal conditions for DNA preservation. The samples were kept in field vehicles for extended periods of time, before long-term storage in ethanol in the freezer, or dry at room temperature. By reducing DNA input to 6ng, more samples with sub-optimal DNA yields could be processed. We matched this low DNA input with a 6-fold dilution of a commercially available tagmentation enzyme, significantly reducing library preparation costs. Costs and workload were further suppressed by direct post-amplification pooling of individual libraries. We generated medium coverage (>3-fold) genomes for 88 out of 90 specimens, with an average of approximately 10-fold coverage. While samples stored in ethanol yielded significantly less DNA compared to those which were stored dry, these samples had superior sequencing statistics, with longer sequencing reads and higher rates of endogenous DNA. Furthermore, we find that the efficiency of tagmentation-based library preparation can be improved by a thorough post-amplification bead clean-up which selects against both short and large DNA fragments. By opening opportunities for the use of sub-optimally preserved, low yield DNA extracts, we broaden the scope of whole genome studies of insect specimens. We therefore expect these results and this protocol to be valuable for a range of applications in the field of entomology.

Disrupted longitudinal restoration of brain connectivity during weight normalization in severe anorexia nervosa.

Altered intrinsic brain connectivity of patients with anorexia nervosa has been observed in the acute phase of the disorder, but it remains unclear to what extent these alterations recover during weight normalization. In this study, we used functional imaging data from three time points to probe longitudinal changes in intrinsic connectivity patterns in patients with severe anorexia nervosa (BMI ≤ 15.5 kg/m2) over the course of weight normalization. At three distinct stages of inpatient treatment, we examined resting-state functional connectivity in 27 women with severe anorexia nervosa and 40 closely matched healthy controls. Using network-based statistics and graph-theoretic measures, we examined differences in global network strength, subnetworks with altered intrinsic connectivity, and global network topology. Patients with severe anorexia nervosa showed weakened intrinsic connectivity and altered network topology which did not recover during treatment. The persistent disruption of brain networks suggests sustained alterations of information processing in weight-recovered severe anorexia nervosa.

Performance of three freely available methods for extracting white matter hyperintensities: FreeSurfer, UBO Detector, and BIANCA.

White matter hyperintensities (WMH) of presumed vascular origin are frequently found in MRIs of healthy older adults. WMH are also associated with aging and cognitive decline. Here, we compared and validated three algorithms for WMH extraction: FreeSurfer (T1w), UBO Detector (T1w + FLAIR), and FSL's Brain Intensity AbNormality Classification Algorithm (BIANCA; T1w + FLAIR) using a longitudinal dataset comprising MRI data of cognitively healthy older adults (baseline N = 231, age range 64-87 years). As reference we manually segmented WMH in T1w, three-dimensional (3D) FLAIR, and two-dimensional (2D) FLAIR images which were used to assess the segmentation accuracy of the different automated algorithms. Further, we assessed the relationships of WMH volumes provided by the algorithms with Fazekas scores and age. FreeSurfer underestimated the WMH volumes and scored worst in Dice Similarity Coefficient (DSC = 0.434) but its WMH volumes strongly correlated with the Fazekas scores (rs  = 0.73). BIANCA accomplished the highest DSC (0.602) in 3D FLAIR images. However, the relations with the Fazekas scores were only moderate, especially in the 2D FLAIR images (rs  = 0.41), and many outlier WMH volumes were detected when exploring within-person trajectories (2D FLAIR: ~30%). UBO Detector performed similarly to BIANCA in DSC with both modalities and reached the best DSC in 2D FLAIR (0.531) without requiring a tailored training dataset. In addition, it achieved very high associations with the Fazekas scores (2D FLAIR: rs  = 0.80). In summary, our results emphasize the importance of carefully contemplating the choice of the WMH segmentation algorithm and MR-modality.

Descending pain modulatory efficiency in healthy subjects is related to structure and resting connectivity of brain regions.

The descending pain modulatory system in humans is commonly investigated using conditioned pain modulation (CPM). Whilst variability in CPM efficiency, i.e., inhibition and facilitation, is normal in healthy subjects, exploring the inter-relationship between brain structure, resting-state functional connectivity (rsFC) and CPM readouts will provide greater insight into the underlying CPM efficiency seen in healthy individuals. Thus, this study combined CPM testing, voxel-based morphometry (VBM) and rsFC to identify the neural correlates of CPM in a cohort of healthy subjects (n =40), displaying pain inhibition (n = 29), facilitation (n = 10) and no CPM effect (n = 1). Clusters identified in the VBM analysis were implemented in the rsFC analysis alongside key constituents of the endogenous pain modulatory system. Greater pain inhibition was related to higher volume of left frontal cortices and stronger rsFC between the motor cortex and periaqueductal grey. Conversely, weaker pain inhibition was related to higher volume of the right frontal cortex - coupled with stronger rsFC to the primary somatosensory cortex, and rsFC between the amygdala and posterior insula. Overall, healthy subjects showed higher volume and stronger rsFC of brain regions involved with descending modulation, while the lateral and medial pain systems were related to greater pain inhibition and facilitation during CPM, respectively. These findings reveal structural alignments and functional interactions between supraspinal areas involved in CPM efficiency. Ultimately understanding these underlying variations and how they may become affected in chronic pain conditions, will advance a more targeted subgrouping in pain patients for future cross-sectional studies investigating endogenous pain modulation.

Widespread White Matter Alterations in Patients With Visual Snow Syndrome.

Background: Visual snow is considered a disorder of central visual processing resulting in a perturbed perception of constant binocular flickering or pixilation of the whole visual field. The underlying neurophysiological and structural alterations remain elusive. Methods: In this study, we included patients (final n = 14, five dropouts; five females, mean age: 32 years) with visual snow syndrome (VSS) and age- and sex-matched controls (final n = 20, 6 dropouts, 13 females, mean age: 28.2 years). We applied diffusion tensor imaging to examine possible white matter (WM) alterations in patients with VSS. Results: The patient group demonstrated higher (p-corrected < 0.05, adjusted for age and sex) fractional anisotropy (FA) and lower mean diffusivity (MD) and radial diffusivity (RD) compared to controls. These changes were seen in the prefrontal WM (including the inferior fronto-occipital fascicle), temporal and occipital WM, superior and middle longitudinal fascicle, and sagittal stratum. When additionally corrected for migraine or tinnitus-dominant comorbidities in VSS-similar group differences were seen for FA and RD, but less pronounced. Conclusions: Our results indicate that patients with VSS present WM alterations in parts of the visual cortex and outside the visual cortex. As parts of the inferior fronto-occipital fascicle and sagittal stratum are associated with visual processing and visual conceptualisation, our results suggest that the WM alterations in these regions may indicate atypical visual processing in patients with VSS. Yet, the frequent presence of migraine and other comorbidities such as tinnitus in VSS makes it difficult to attribute WM disruptions solely to VSS.

Automated volumetry of hippocampal subfields in temporal lobe epilepsy.

INTRODUCTION: Hippocampal sclerosis is the most frequent pathological substrate in drug resistant temporal lobe epilepsy (TLE). Recently 4 types of hippocampal sclerosis (HS) have been defined in a task force by the International League Against Epilepsy (ILAE), based on patterns of cell loss in specific hippocampal subfields. Type 1 HS is most frequent and has the most favorable outcome after epilepsy surgery. We hypothesized that volume loss in specific hippocampal subfields determined by automated volumetry of high resolution MRI would correspond to cell loss in histological reports. MATERIAL AND METHODS: In a group of well characterized patients with drug resistant TLE (N = 26 patients, 14 with right-sided focus, 12 with left-sided focus) volumes of the right and left hippocampus and the hippocampal subfields CA1, CA2 + 3, CA4 and dentate gyrus (DG) were estimated automatically using FreeSurfer version 6.0 from high-resolution cerebral MRI and compared to a large group of healthy controls (N = 121). HS subtype classification was attempted based on histological reports. RESULTS: Volumes of the whole hippocampus and all investigated hippocampal subfields (CA1, CA2 + 3, CA4 and DG) were significantly lower on the ipsilateral compared the contralateral side (p < 0.001) and compared to the healthy controls (p < 0.001). Conversely, whole hippocampal and hippocampal subfield volumes were not significantly different from healthy control values on the contralateral side. In 12 of 20 patients the pattern of hippocampal volume loss in specific subfields was in accordance with HS types from histology. The highest overlap between automated MRI and histology was achieved for type 1 HS (in 10 of 12 cases). CONCLUSION: The automated volumetry of hippocampal subfields, based on high resolution MRI, may have the potential to predict the pattern of cell loss in hippocampal sclerosis before operation.

EEG-fMRI Signal Coupling Is Modulated in Subjects With Mild Cognitive Impairment and Amyloid Deposition.

Cognitive impairment indicates disturbed brain physiology which can be due to various mechanisms including Alzheimer's pathology. Combined functional magnetic resonance imaging (fMRI) and electroencephalography (EEG) recordings (EEG-fMRI) can assess the interplay between complementary measures of brain activity and EEG changes to be localized to specific brain regions. We used a two-step approach, where we first examined changes related to a syndrome of mild cognitive impairment irrespective of pathology and then studied the specific impact of amyloid pathology. After detailed clinical and neuropsychological characterization as well as a positron emission tomography (PET) scans with the tracer 11-[C]-Pittsburgh Compound B to estimate cerebral amyloid deposition, 14 subjects with mild cognitive impairment (MCI) (mean age 75.6 SD: 8.9) according to standard criteria and 21 cognitively healthy controls (HCS) (mean age 71.8 SD: 4.2) were assessed with EEG-fMRI. Thalamo-cortical alpha-fMRI signal coupling was only observed in HCS. Additional EEG-fMRI signal coupling differences between HCS and MCI were observed in parts of the default mode network, salience network, fronto-parietal network, and thalamus. Individuals with significant cerebral amyloid deposition (amyloid-positive MCI and HCS combined compared to amyloid-negative HCS) displayed abnormal EEG-fMRI signal coupling in visual, fronto-parietal regions but also in the parahippocampus, brain stem, and cerebellum. This finding was paralleled by stronger absolute fMRI signal in the parahippocampus and weaker absolute fMRI signal in the inferior frontal gyrus in amyloid-positive subjects. We conclude that the thalamocortical coupling in the alpha band in HCS more closely reflects previous findings observed in younger adults, while in MCI there is a clearly aberrant coupling in several networks dominated by an anticorrelation in the posterior cingulate cortex. While these findings may broadly indicate physiological changes in MCI, amyloid pathology was specifically associated with abnormal fMRI signal responses and disrupted coupling between brain oscillations and fMRI signal responses, which especially involve core regions of memory: the hippocampus, para-hippocampus, and lateral prefrontal cortex.

Investigation of Cerebral White Matter Changes After Spinal Cord Injury With a Measure of Fiber Density.

Remote neurodegenerative changes in supraspinal white matter (WM) can manifest after central lesions such as spinal cord injury (SCI). The majority of diffusion tensor imaging (DTI) studies use traditional metrics such as fractional anisotropy (FA) and mean diffusivity (MD) to investigate microstructural changes in cerebral WM after SCI. However, interpretation of FA readouts is often challenged by inherent limitations of the tensor model. Recent developments in novel diffusion markers, such as fiber density (FD), allows more accurate depictions of WM pathways and has shown more reliable quantification of WM alterations compared to FA in recent studies of neurological diseases. This study investigated if FD provides useful characterization of supraspinal WM integrity after SCI in addition to the traditional DTI readouts. FA, MD, and FD maps were derived from diffusion datasets of 20 patients with chronic SCI and compared with 19 healthy controls (HC). Group differences were investigated across whole brain WM using tract-based spatial statistics and averaged diffusion values of the corticospinal tract (CST) and thalamic radiation (TR) were extracted for comparisons between HC and SCI subgroups. We also related diffusion readouts of the CST and TR with clinical scores of sensorimotor function. To investigate which diffusion markers of the CST and TR delineate HC and patients with SCI a receiver operating characteristic (ROC) analysis was performed. Overall, patients with an SCI showed decreased FA of the TR and CST. ROC analysis differentiated HC and SCI based on diffusion markers of large WM tracts including FD of the TR. Furthermore, patients' motor function was positively correlated with greater microstructural integrity of the CST. While FD showed the strongest correlation, motor function was also associated with FA and MD of the CST. In summary, microstructural changes of supraspinal WM in patients with SCI can be detected using FD as a complementary marker to traditional DTI readouts and correlates with their clinical characteristics. Future DTI studies may benefit from utilizing this novel marker to investigate complex large WM tracts in patient cohorts with varying presentations of SCI or neurodegenerative diseases.

Structural brain network characteristics in patients with episodic and chronic migraine.

BACKGROUND: Migraine is a primary headache disorder that can be classified into an episodic (EM) and a chronic form (CM). Network analysis within the graph-theoretical framework based on connectivity patterns provides an approach to observe large-scale structural integrity. We test the hypothesis that migraineurs are characterized by a segregated network. METHODS: 19 healthy controls (HC), 17 EM patients and 12 CM patients were included. Cortical thickness and subcortical volumes were computed, and topology was analyzed using a graph theory analytical framework and network-based statistics. We further used support vector machines regression (SVR) to identify whether these network measures were able to predict clinical parameters. RESULTS: Network based statistics revealed significantly lower interregional connectivity strength between anatomical compartments including the fronto-temporal, parietal and visual areas in EM and CM when compared to HC. Higher assortativity was seen in both patients' group, with higher modularity for CM and higher transitivity for EM compared to HC. For subcortical networks, higher assortativity and transitivity were observed for both patients' group with higher modularity for CM. SVR revealed that network measures could robustly predict clinical parameters for migraineurs. CONCLUSION: We found global network disruption for EM and CM indicated by highly segregated network in migraine patients compared to HC. Higher modularity but lower clustering coefficient in CM is suggestive of more segregation in this group compared to EM. The presence of a segregated network could be a sign of maladaptive reorganization of headache related brain circuits, leading to migraine attacks or secondary alterations to pain.

Considering non-bladder aetiologies of overactive bladder: a functional neuroimaging study.

OBJECTIVES: To better understand the neuropathophysiology of overactive bladder (OAB) in women by characterising supraspinal activity in response to bladder distention and cold stimulation. SUBJECTS/PATIENTS AND METHODS: We recruited 24 female participants, 12 with OAB (median [interquartile range, IQR] age 40 [32-42] years) and 12 healthy controls (HCs) without lower urinary tract (LUT) symptoms (median [IQR] age 34 [28-44] years), and assessed LUT and cognitive function through neuro-urological examination, 3-day bladder diary, urodynamic investigation, and questionnaires. Functional magnetic resonance (MR) imaging using a 3-T scanner was performed in all participants during automated, repetitive bladder filling and draining (block design) with 100 mL body temperature (37 °C) saline using a MR-compatible and MR-synchronised infusion-drainage device until strong desire to void (HIGH-FILLING/DRAINING) and bladder filling with cold saline (4 °C, i.e. COLD). Whole-brain and region-of-interest analyses were conducted using Statistical Parametric Mapping, version 12. RESULTS: Significant between-group differences were found for 3-day bladder diary variables (i.e. voiding frequency/24 h, P < 0.001; voided volume/void, P = 0.04; and urinary incontinence [UI] episodes/24 h, P = 0.007), questionnaire scores (International Consultation on Incontinence Questionnaire-Female LUT symptoms [overall, filling, and UI scores, all P < 0.001]; the Overactive Bladder Questionnaire short form [symptoms and quality-of-life scores, both P < 0.001]; the Hospital Anxiety and Depression Scale [anxiety P = 0.004 and depression P = 0.003 scores]), as well as urodynamic variables (strong desire to void, P = 0.02; maximum cystometric capacity, P = 0.007; and presence of detrusor overactivity, P = 0.002). Age, weight and cognitive function (i.e. Mini-Mental State Examination, P = 1.0) were similar between groups (P > 0.05). In patients with OAB, the HIGH task elicited activity in the superior temporal gyrus, ventrolateral prefrontal cortex (VLPFC), and mid-cingulate cortex; and the COLD task elicited activity in the VLPFC, cerebellum, and basal ganglia. Compared to HCs, patients with OAB showed significantly stronger cerebellar activity during HIGH-FILLING and significantly less activity in the insula and VLPFC during HIGH-DRAINING. CONCLUSIONS: The present findings suggest a sensory processing and modulation deficiency in our OAB group, probably as part of their underlying pathophysiology, as they lacked activity in essential sensory processing areas, such as the insula. Instead, accessory areas, such as the cerebellum, showed significantly stronger activation compared to HCs, presumably supporting pelvic-floor motor activity to prevent UI. The novel findings of the present study provide physiological evidence of the necessity to consider non-bladder aetiologies of bladder symptoms.

Abnormal Connectivity and Brain Structure in Patients With Visual Snow.

OBJECTIVE: Visual snow (VS) is a distressing, life-impacting condition with persistent visual phenomena. VS patients show cerebral hypermetabolism within the visual cortex, resulting in altered neuronal excitability. We hypothesized to see disease-dependent alterations in functional connectivity and gray matter volume (GMV) in regions associated with visual perception. METHODS: Nineteen patients with VS and 16 sex- and age-matched controls were recruited. Functional magnetic resonance imaging (fMRI) was applied to examine resting-state functional connectivity (rsFC). Volume changes were assessed by means of voxel-based morphometry (VBM). Finally, we assessed associations between MRI indices and clinical parameters. RESULTS: Patients with VS showed hyperconnectivity between extrastriate visual and inferior temporal brain regions and also between prefrontal and parietal (angular cortex) brain regions (p < 0.05, corrected for age and migraine occurrence). In addition, patients showed increased GMV in the right lingual gyrus (p < 0.05 corrected). Symptom duration positively correlated with GMV in both lingual gyri (p < 0.01 corrected). CONCLUSION: This study found VS to be associated with both functional and structural changes in the early and higher visual cortex, as well as the temporal cortex. These brain regions are involved in visual processing, memory, spatial attention, and cognitive control. We conclude that VS is not just confined to the visual system and that both functional and structural changes arise in VS patients, be it as an epiphenomenon or a direct contributor to the pathomechanism of VS. These in vivo neuroimaging biomarkers may hold potential as objective outcome measures of this so far purely subjective condition.

Effects of Visceral Interoception on Topological Properties of the Brain - A Graph Theory Analysis of Resting state fMRI.

Recent neuroimaging studies have employed graph theory as a data-driven approach to describe topological organization of the brain under different neurological disorders or task conditions and across life span. In this exploratory study, we tested whether subtle differences in interoception related to intravesical fullness can alter brain topological architecture in healthy participants. 17 right-handed women underwent a series of resting state fMRI scans that included catheterization and partial bladder filling. Using a whole brain regions of interest (ROIs), we computed several graph theory metrics to assess the efficiency of brain-wide information exchange. Results showed that brain network's topological properties significantly changed in many brain regions when we binary compared different interoceptive resting state conditions. Notably, we observed changes in global efficiency in the salience network, the central executive network, anterior dorsal attention network and the posterior default-mode network (DMN) as bladder became full and interoceptive signals intensified. Moreover, degree (the number of connections for each node), and betweenness centrality (how connected a particular region is to other regions) differed between the empty bladder, the catheterized empty bladder, and the catheterized and partially filled bladder. Comparing resting state data before and after an interoceptive task (repeated intravesical infusion and drainage) further showed increased average path length for the salience networks and decreased clustering coefficient of the DMN. These results suggest visceral interoception influences brain topological properties of resting state networks.

Impact of Intravesical Cold Sensation on Functional Network Connectivity Estimated Using ICA at Rest & During Interoceptive Task.

Afferent nerves that carry interoceptive signals from the viscera to the brain include Aδ and C-fibers. Previously, we examined the effects of detrusor distention (conveyed mainly by Aδ fibers) on the static functional network connectivity (FNC) of the brain using independent component analysis (ICA) of fMRI time series. In the present study, we investigate the impact of intravesical cold sensation (thought to be conveyed by C-fibers) on brain FNC using similar ICA approach. Thirteen healthy women were scanned on a 3.0T MRI scanner during a resting state scan and an intravesical cold sensation task fMRI. High dimensional ICA (n = 75) were used to decompose the fMRI data into several intrinsic connectivity networks (ICNs) including the default-mode (DMN), subcortical (SCN; amygdala, thalamus), salience (SN), central executive (CEN), sensorimotor (SMN), and cerebellar/brainstem (CBN) networks. Results demonstrate significant FNC differences in several ICN pairs primarily between the SCN and cognitive networks such as CEN, as well as between SN and CBN and DMN when intravesical cold water condition was compared to rest (FDR-corrected p-value of 0.05). Significant increases in FNC between CBN and between SMN were also observed during interoceptive condition. The results indicate significant impact of Aδ and C-fiber-originated interoceptive signals on the brain connectivity when compared to the baseline rest.

Prognostic value of O-(2-[18F]-fluoroethyl)-L-tyrosine PET in relapsing oligodendroglioma.

PURPOSE: To assess the relationship between F-18-fluoro-ethyl-tyrosine positron emission tomography (FET-PET) parameters of relapsing oligodendroglioma and progression-free survival. MATERIAL AND METHODS: The relationship of clinical parameters, FET-PET parameters (SUVmax, TBRmax, BTV, time-activity curves) and progression-free survival was analyzed using univariate and multivariate analysis in 42 adult patients with relapsing oligodendroglioma. Kaplan-Meier analysis was used to assess survival. RESULTS: Patients who did not undergo surgical resection of their relapsing tumor had significantly lower PFS if the tumor exhibited an SUVmax above 3.40 than those with an SUVmax below 3.40 (13.1 ± 2.3 months vs. 47.3 ± 6.0 months, respectively, p < .001). Patients who underwent surgery had similar PFS as the aforementioned non-operated patients with low SUVmax (53.6 ± 6.7 months, p = .948). The same was true for TBRmax using a threshold of 3.03 (PFS 12.5 ± 2.4 months vs. 44.0 ± 6.3 months / 53.6 ± 6.7 months, respectively; p < .001 / p = .825). Also, subjects with BTV below 10 cm3 that did not undergo surgery had a similar PFS as subjects who underwent surgery (40.2 ± 6.0 months vs. 52.4 ± 8.9 months, respectively, p = .587). Subjects with BTV above 10 cm3 and without surgery had a significantly worse PFS (13.8 ± 3.3 months, p < .001). Multivariate analysis showed that the prognostication by clinical parameters is improved by adding TBRmax to the model (AUC 0.945 (95% CI: 0.881-1.000), true classification rate 88.1%). CONCLUSION: FET-PET may provide added value for the prognostication of relapsing oligodendroglioma in addition to clinical parameters.

Age influences structural brain restoration during weight gain therapy in anorexia nervosa.

Neuroimaging studies on anorexia nervosa (AN) have consistently reported globally reduced gray matter in patients with acute AN. While first studies on adolescent AN patients provide evidence for the reversibility of these impairments after weight gain, longitudinal studies with detailed regional analysis for adult AN patients are lacking and factors associated with brain restitution are poorly understood. We investigated structural changes in anorexia nervosa using T1-weighted magnetic resonance images with surface-based morphometry. The sample consisted of 26 adult women with severe AN and 30 healthy controls. The longitudinal design comprised three time points, capturing the course of weight-restoration therapy in AN patients at distinct stages of weight gain (BMI ≤ 15.5 kg/m2; 15.5 < BMI < 17.5 kg/m2; BMI ≥ 17.5 kg/m2). Compared to controls, AN patients showed globally decreased cortical thickness and subcortical volumes at baseline. Linear mixed effect models revealed the reversibility of these alterations, with brain restoration being most pronounced during the first half of treatment. The restoration of cortical thickness of AN patients negatively correlated with age, but not duration of illness. After weight restoration, residual group differences of cortical thickness remained in the superior frontal cortex. These findings indicate that structural brain alterations of adult patients with severe AN recuperate independently of the duration of illness during weight-restoration therapy. The temporal pattern of brain restoration suggests a decrease in restoration rate over the course of treatment, with patients' age as a strong predictor of brain restitution, possibly reflecting decreases of brain plasticity as patients grow older.

Cortical Volume Differences in Subjects at Risk for Psychosis Are Driven by Surface Area.

In subjects at risk for psychosis, the studies on gray matter volume (GMV) predominantly reported volume loss compared with healthy controls (CON). However, other important morphological measurements such as cortical surface area (CSA) and cortical thickness (CT) were not systematically compared. So far, samples mostly comprised subjects at genetic risk or at clinical risk fulfilling an ultra-high risk (UHR) criterion. No studies comparing UHR subjects with at-risk subjects showing only basic symptoms (BS) investigated the differences in CSA or CT. Therefore, we aimed to unravel the contribution of the 2 morphometrical measures constituting the cortical volume (CV) and to test whether these groups inhere different morphometric features. We conducted a surface-based morphometric analysis in 34 CON, 46 BS, and 39 UHR to examine between-group differences in CV, CSA, and CT vertex-wise across the whole cortex. Compared with BS and CON, UHR individuals presented increased CV in frontal and parietal regions, which was driven by larger CSA. These groups did not differ in CT. Yet, at-risk subjects who later developed schizophrenia showed thinning in the occipital cortex. Furthermore, BS presented increased CSA compared with CON. Our results suggest that volumetric differences in UHR subjects are driven by CSA while CV loss in converters seems to be based on cortical thinning. We attribute the larger CSA in UHR to aberrant pruning representing a vulnerability to develop psychotic symptoms reflected in different levels of vulnerability for BS and UHR, and cortical thinning to a presumably stress-related cortical decomposition.

Triple Network Model Dynamically Revisited: Lower Salience Network State Switching in Pre-psychosis.

Emerging evidence has attributed altered network coordination between the default mode, central executive, and salience networks (DMN/CEN/SAL) to disturbances seen in schizophrenia, but little is known for at-risk psychosis stages. Moreover, pinpointing impairments in specific network-to-network interactions, although essential to resolve possibly distinct harbingers of conversion to clinically diagnosed schizophrenia, remains particularly challenging. We addressed this by a dynamic approach to functional connectivity, where right anterior insula brain interactions were examined through co-activation pattern (CAP) analysis. We utilized resting-state fMRI in 19 subjects suffering from subthreshold delusions and hallucinations (UHR), 28 at-risk for psychosis with basic symptoms describing only self-experienced subclinical disturbances (BS), and 29 healthy controls (CTR) matched for age, gender, handedness, and intelligence. We extracted the most recurring CAPs, compared their relative occurrence and average dwell time to probe their temporal expression, and quantified occurrence balance to assess the putative loss of competing relationships. Our findings substantiate the pivotal role of the right anterior insula in governing CEN-to-DMN transitions, which appear dysfunctional prior to the onset of psychosis, especially when first attenuated psychotic symptoms occur. In UHR subjects, it is longer active in concert with the DMN and there is a loss of competition between a SAL/DMN state, and a state with insula/CEN activation paralleled by DMN deactivation. These features suggest that abnormal network switching disrupts one's capacity to distinguish between the internal world and external environment, which is accompanied by inflexibility and an excessive awareness to internal processes reflected by prolonged expression of the right anterior insula-default mode co-activation pattern.

18F-FET PET for Diagnosis of Pseudoprogression of Brain Metastases in Patients With Non-Small Cell Lung Cancer.

PURPOSE: To evaluate whether F-fluoroethyltyrosine (FET) PET can discriminate progression from pseudoprogression of brain metastases in patients with non-small cell lung cancer undergoing immunotherapy and radiotherapy to the brain. METHODS: Retrospective analysis of F-FET PET scans in cases with documented progression of brain metastases on MRI in a cohort of 53 patients with non-small cell lung cancer receiving immune-checkpoint inhibitors and radiotherapy of brain metastases at the University Hospital of Zürich from June 2015 until January 2019. Response to radiotherapy was assessed by MRI. In case of equivocal findings and/or radiological progression in clinically asymptomatic patients, further assessment with F-FET PET was performed. RESULTS: From the cohort of 53 patients, the restaging MRI showed in 30 patients (56.6%) progression of at least 1 treated metastasis. Thereof, F-FET PET was performed in 11 patients, based on the absence of neurological symptoms or presence of systemic response and physicians' decision. F-FET PET correctly identified pseudoprogression in 9 of 11 patients (81.8%). In patients who did not undergo F-FET PET, 5 of 19 (26.3%) were diagnosed with pseudoprogression. CONCLUSIONS: Pseudoprogression of brain metastases occurred in 50% of patients diagnosed with progression on MRI. F-FET PET may help differentiate pseudoprogression from real progression in order to avoid discontinuation of effective therapy or unneeded interventions.

Interictal Hyperperfusion in the Higher Visual Cortex in Patients With Episodic Migraine.

BACKGROUND: Migraine pathophysiology is complex and probably involves cortical and subcortical alterations. Structural and functional brain imaging studies indicate alterations in the higher order visual cortex in patients with migraine. Arterial spin labeling magnetic resonance imaging (ASL-MRI) is a non-invasive imaging method for assessing changes in cerebral blood flow (CBF) in vivo. OBJECTIVE: To examine if interictal CBF differs between patients with episodic migraine (EM) with or without aura and healthy controls (HC). METHODS: We assessed interictal CBF using 2D pseudo-continuous ASL-MRI on a 3 Tesla Philips scanner (University Hospital Zurich, Switzerland) in EM (N = 17, mean age 32.7 ± 9.9, 13 females) and HC (N = 19, mean age 31.0 ± 9.3, 11 females). RESULTS: Compared to HC, EM showed exclusively hyperperfusion in the right MT+ and Cohen's d effect size was 0.99 (HC mean CBF ± SD: 33.1 ± 5.9 mL/100 g/minutes; EM mean CBF: 40.9 ± 9.4 mL/100 g/minutes). EM with aura (N = 13, MwA) revealed hyperperfusion compared to HC in the right MT+ and superior temporal gyrus. For MT, Cohen's d effect size was 1.34 (HC mean CBF ± SD: 33.1 ± 5.9 mL/100 g/minutes; MwA mean CBF: 43.3 ± 8.6 mL/100 g/minutes). For the superior temporal gyrus, Cohen's d effect size was 1.28 (HC mean CBF ± SD: 40.1 ± 4.9 mL/100 g/minutes; MwA mean CBF: 47.4 ± 6.4 mL/100 g/minutes). In EM, anxiety was positively associated with CBF in the parietal operculum and angular gyrus. CONCLUSIONS: Our results suggest that extrastriate brain regions probably involved in cortical spreading depression are associated with CBF changes in the interictal state. We conclude that ASL-MRI is a sensitive method to identify local neuro-functional abnormalities in CBF in patients with EM in the interictal state.

Reliability of supraspinal correlates to lower urinary tract stimulation in healthy participants - A fMRI study.

Previous functional neuroimaging studies provided evidence for a specific supraspinal network involved in lower urinary tract (LUT) control. However, data on the reliability of blood oxygenation level-dependent (BOLD) signal changes during LUT task-related functional magnetic resonance imaging (fMRI) across separate measurements are lacking. Proof of the latter is crucial to evaluate whether fMRI can be used to assess supraspinal responses to LUT treatments. Therefore, we prospectively assessed task-specific supraspinal responses from 20 healthy participants undergoing two fMRI measurements (test-retest) within 5-8 weeks. The fMRI measurements, conducted in a 3T magnetic resonance (MR) scanner, comprised a block design of repetitive bladder filling and drainage using an automated MR-compatible and MR-synchronized infusion-drainage device. Following transurethral catheterization and bladder pre-filling with body warm saline until participants perceived a persistent desire to void (START condition), fMRI was recorded during repetitive blocks (each 15 s) of INFUSION and WITHDRAWAL of 100 mL body warm saline into respectively from the bladder. BOLD signal changes were calculated for INFUSION minus START. In addition to whole brain analysis, we assessed BOLD signal changes within multiple 'a priori' region of interest (ROI), i.e. brain areas known to be involved in the LUT control from previous literature. To evaluate reliability of the fMRI results between visits, we applied different types of analyses: coefficient of variation (CV), intraclass correlation coefficient (ICC), Sørensen-Dice index, Bland-Altman method, and block-wise BOLD signal comparison. All participants completed the study without adverse events. The desire to void was rated significantly higher for INFUSION compared to START or WITHDRAWAL at both measurements without any effect of visit. At whole brain level, significant (p < 0.05, cluster corrected, k ≥ 41 voxels) BOLD signal changes were found for the contrast INFUSION compared to START in several brain areas. Overlap of activation maps from both measurements were observed in the orbitofrontal cortex, insula, ventrolateral prefrontal cortex (VLPFC), and inferior parietal lobe. The two highest ICCs, based on a ROI's mean beta weight, were 0.55 (right insular cortex) and 0.47 (VLPFC). Spatial congruency (Sørensen-Dice index) of all voxels within each ROI between measurements was highest in the insular cortex (left 0.55, right 0.44). In addition, the mean beta weight of the right insula and right VLPFC demonstrated the lowest CV and narrowest Bland and Altman 95% limits of agreement. In conclusion, the right insula and right VLPFC were revealed as the two most reliable task-specific ROIs using our automated, MR-synchronized protocol. Achieving high reliability using a viscero-sensory/interoceptive task such as repetitive bladder filling remains challenging and further endeavour is highly warranted to better understand which factors influence fMRI outcomes and finally to assess LUT treatment effects on the supraspinal level.