Anatomical MRI Research Articles

Does Diglossia Impact Brain Structure? Data from Swiss German Early Diglossic Speakers.

(1) Background: Bilingualism has been reported to shape the brain by inducing cortical changes in cortical and subcortical language and executive networks. Similar yet different to bilingualism, diglossia is common in Switzerland, where the German-speaking population switches between an everyday spoken Swiss German (CH-GER) dialect and the standard German (stGER) used for reading and writing. However, no data are available for diglossia, defined as the use of different varieties or dialects of the same language, regarding brain structure. The aim of our study is to investigate if the presence of this type of diglossia has an impact on the brain structure, similar to the effects seen in bilingualism. (2) Methods: T1-weighted anatomical MRI scans of participants were used to compare the grey matter density and grey matter volume of 22 early diglossic CH-GER-speaking and 20 non-diglossic French-speaking right-handed university students, matched for age, linguistics and academic background. The images were processed with Statistical Parametric Mapping SPM12 and analyzed via voxel- and surface-based morphometry. (3) Results: A Bayesian ANCOVA on the whole brain revealed no differences between the groups. Also, for the five regions of interest (i.e., planum temporale, caudate nucleus, ACC, DLPFC and left interior parietal lobule), no differences in the cortical volume or thickness were found using the same statistical approach. (4) Conclusion: The results of this study may suggest that early diglossia does not shape the brain structure in the same manner as bilingualism.

Beneficial effects of mindfulness-based intervention on hippocampal volumes and episodic memory for childhood adversity survivors

BackgroundAdverse Childhood Experience (ACE) has detrimental impacts on neural development, especially hippocampal morphometry. Mindfulness-Based Interventions (MBI) has been shown to induce adaptive hippocampal changes especially at the subiculum. The present study aims to investigate the effects of MBI on subiculum volumes among ACE survivors, as well as the effects on episodic memory as a probe into hippocampal functionality. MethodsWe analyzed anatomical MRI data and performance indices from an episodic memory task called the Mnemonic Similarity Task (MST) collected from a randomized controlled longitudinal study that compared an 8-week MBI (N = 20) to an active control condition of Stress Management Education (SME) (N = 19). FreeSurfer 6.0 was used for automated hippocampal subfield segmentation and volumetric estimation. ResultsSignificant group differences were observed with the volumetric changes of the right whole hippocampus and right subiculum. Only the MBI group showed improved pattern separation capability from MST, which was associated with stress reduction and right subiculum volumetric changes. LimitationsModest sample size. MST task was performed outside of MRI. ConclusionsThese findings suggest beneficial effects of MBI for hippocampal volumes and episodic memory, while highlighting the importance of the subiculum for MBI-induced neural and cognitive changes. The subiculum's known role in inhibitory control was interpreted as a potential mechanism for it to exhibit MBI-induced volumetric changes, which sheds light on the potential neural underpinnings of mindfulness meditation for reducing stress reactivity among ACE survivors.

Abstract 4157: Combining hyperpolarized magnetic resonance and positron emission tomography to interrogate prostate cancer metabolism

Abstract Background: There is an unmet clinical need for imaging biomarkers to distinguish indolent from aggressive prostate cancer (PCa). Many advanced and aggressive PCa patients receiving anti-androgens (enzalutamide) develop resistance. It is hypothesized that dysregulated cell metabolism is a key driver for PCa progression and therapy resistance. Two pathways commonly involved in PCa are glycolysis and fatty acid metabolism. Therefore, metabolic imaging and metabolomics were performed on enzalutamide sensitive/resistant, Androgen Receptor dependent (AR+) and AR independent (AR-) patient derived xenograft (PDX) tumors. To interrogate both pathways, [1-13C]-pyruvate hyperpolarized magnetic resonance spectroscopy (HP-MRS) and [18F]-fluorodeoxyglucose positron emission tomography (18F-FDG) for glycolysis, and [18F]-fluoro-pivalic acid positron emission tomography (18F-FPIA) for fatty acid metabolism were employed. 1H Nuclear Magnetic Resonance (NMR) spectroscopy and liquid chromatography with tandem mass spectrometry (LC-MS-MS) were employed for validation purposes. Methods: [1-13C]-labeled pyruvic acid was hyperpolarized using a DNP HyperSense polarizer following standard protocol. Anatomical MRI and 13C-MRS were obtained on different PCa PDX mouse models at two different time points using a Bruker 7T scanner. The PDX models included AR+ enzalutamide sensitive (183-A, 180-30), AR+ enzalutamide resistant (274-4), and AR- (144-4, 114-B). The time points imaged were before and after 7 days of treatment with enzalutamide. 1H-NMR spectroscopy was performed on extracted tissue. Simultaneously, 18F-FPIA-PET imaging were acquired on the same models on an Albira trimodal PET station. Results: The dynamic metabolic flux ratio, lactate-to-pyruvate (Lac/Pyr) was determined in vivo and used as a treatment response marker. The Lac/Pyr ratios were significantly higher in resistant tumors compared to sensitive tumors (p<0.01). The enzalutamide sensitive group had a lower Lac/Pyr ratio after treatment, while the enzalutamide resistant group had a higher Lac/Pyr ratio. After treatment, there was also a decrease in [18F]-FDG uptake, corresponding to the HP-MRS data. This was expected as both Pyruvate and [18F]-FDG interrogate the glycolytic pathway. As for the fatty acid metabolic imaging, PET imaging also revealed that [18F]-FPIA is transported into the tumors, and we are currently exploring how its uptake varies between AR (+/-) PCa-PDX tumors and enzalutamide resistant/sensitive models. Ex vivo NMR and mass spectrometry-based metabolomics validated the in vivo HP-MRS data with higher lactate levels in drug resistant tumors. Conclusion: Combining HP-MRS and PET presents an exciting opportunity to realize imaging-based personalized medicine in different AR (+/-) PCa-PDX preclinical models by interrogating glycolysis and fatty acid oxidation pathways. Citation Format: Muxin Wang, José S. Enriquez, Prasanta Dutta, Jenny Han, Peter Shepherd, Daniel Frigo, Federica Pisaneschi, Pratip K. Bhattacharya. Combining hyperpolarized magnetic resonance and positron emission tomography to interrogate prostate cancer metabolism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4157.

DDParcel: Deep Learning Anatomical Brain Parcellation From Diffusion MRI.

Parcellation of anatomically segregated cortical and subcortical brain regions is required in diffusion MRI (dMRI) analysis for region-specific quantification and better anatomical specificity of tractography. Most current dMRI parcellation approaches compute the parcellation from anatomical MRI (T1- or T2-weighted) data, using tools such as FreeSurfer or CAT12, and then register it to the diffusion space. However, the registration is challenging due to image distortions and low resolution of dMRI data, often resulting in mislabeling in the derived brain parcellation. Furthermore, these approaches are not applicable when anatomical MRI data is unavailable. As an alternative we developed the Deep Diffusion Parcellation (DDParcel), a deep learning method for fast and accurate parcellation of brain anatomical regions directly from dMRI data. The input to DDParcel are dMRI parameter maps and the output are labels for 101 anatomical regions corresponding to the FreeSurfer Desikan-Killiany (DK) parcellation. A multi-level fusion network leverages complementary information in the different input maps, at three network levels: input, intermediate layer, and output. DDParcel learns the registration of diffusion features to anatomical MRI from the high-quality Human Connectome Project data. Then, to predict brain parcellation for a new subject, the DDParcel network no longer requires anatomical MRI data but only the dMRI data. Comparing DDParcel's parcellation with T1w-based parcellation shows higher test-retest reproducibility and a higher regional homogeneity, while requiring much less computational time. Generalizability is demonstrated on a range of populations and dMRI acquisition protocols. Utility of DDParcel's parcellation is demonstrated on tractography analysis for fiber tract identification.

Connectome architecture shapes large-scale cortical alterations in schizophrenia: a worldwide ENIGMA study

Schizophrenia is a prototypical network disorder with widespread brain-morphological alterations, yet it remains unclear whether these distributed alterations robustly reflect the underlying network layout. We tested whether large-scale structural alterations in schizophrenia relate to normative structural and functional connectome architecture, and systematically evaluated robustness and generalizability of these network-level alterations. Leveraging anatomical MRI scans from 2439 adults with schizophrenia and 2867 healthy controls from 26 ENIGMA sites and normative data from the Human Connectome Project (n = 207), we evaluated structural alterations of schizophrenia against two network susceptibility models: (i) hub vulnerability, which examines associations between regional network centrality and magnitude of disease-related alterations; (ii) epicenter mapping, which identifies regions whose typical connectivity profile most closely resembles the disease-related morphological alterations. To assess generalizability and specificity, we contextualized the influence of site, disease stages, and individual clinical factors and compared network associations of schizophrenia with that found in affective disorders. Our findings show schizophrenia-related cortical thinning is spatially associated with functional and structural hubs, suggesting that highly interconnected regions are more vulnerable to morphological alterations. Predominantly temporo-paralimbic and frontal regions emerged as epicenters with connectivity profiles linked to schizophrenia’s alteration patterns. Findings were robust across sites, disease stages, and related to individual symptoms. Moreover, transdiagnostic comparisons revealed overlapping epicenters in schizophrenia and bipolar, but not major depressive disorder, suggestive of a pathophysiological continuity within the schizophrenia-bipolar-spectrum. In sum, cortical alterations over the course of schizophrenia robustly follow brain network architecture, emphasizing marked hub susceptibility and temporo-frontal epicenters at both the level of the group and the individual. Subtle variations of epicenters across disease stages suggest interacting pathological processes, while associations with patient-specific symptoms support additional inter-individual variability of hub vulnerability and epicenters in schizophrenia. Our work outlines potential pathways to better understand macroscale structural alterations, and inter- individual variability in schizophrenia.

Brain gray matter morphometry relates to onset age of bilingualism and theory of mind in young and older adults

Lifelong bilingualism may result in neural reserve against decline not only in the general cognitive domain, but also in social cognitive functioning. In this study, we show the brain structural correlates that are associated with second language age of acquisition (L2AoA) and theory of mind (the ability to reason about mental states) in normal aging. Participants were bilingual adults (46 young, 50 older) who completed a theory-of-mind task battery, a language background questionnaire, and an anatomical MRI scan to obtain cortical morphometric features (i.e., gray matter volume, thickness, and surface area). Findings indicated a theory-of-mind decline in older adults compared to young adults, controlling for education and general cognition. Importantly, earlier L2AoA and better theory-of-mind performance were associated with larger volume, higher thickness, and larger surface area in the bilateral temporal, medial temporal, superior parietal, and prefrontal brain regions. These regions are likely to be involved in mental representations, language, and cognitive control. The morphometric association with L2AoA in young and older adults were comparable, but its association with theory of mind was stronger in older adults than young adults. The results demonstrate that early bilingual acquisition may provide protective benefits to intact theory-of-mind abilities against normal age-related declines.

Abstract 115: Presenting Symptoms and Neuroimaging Correlates in North American Moyamoya Vasculopathy

Introduction: Moyamoya disease (MMD) is a steno-occlusion of the supraclinoid internal carotid arteries and proximal branches with the development of collateral vessels 1 . Once thought to affect primarily females of East Asian descent, more than 11,000 hospitalizations in patients with MMD of non-Asian ancestry are reported annually in the USA, with the majority presenting with ischemic stroke. Here, we present frequent non-stroke symptomatology in North American MMD along with hemodynamic imaging profiles at presentation. Methods: Participants provided informed consent and underwent anatomical MRI with hypercapnic blood oxygenation level-dependent 2 ; time regression was applied to quantify cerebrovascular reactivity (CVR) and reactivity delay time (CVR DELAY ) 3 in right and left MCA territories. A logistic regression analysis based on the Huber-White sandwich estimator compared the CVR metrics between cohorts. Significance criterion: Bonferroni corrected two-sided p<0.05. Results: 74 patients (age=11-77 years; Asian=6%, White=65%, Black=29%) diagnosed with MMD with symptom durations spanning hours to years prior to presentation were enrolled. Non-stroke symptoms and frequency prior to stroke are listed in Table 1. In more than 1/3 rd of patients, unprovoked headaches preceded stroke-like symptoms. In patients exhibiting ischemic symptoms within six months of neuroimaging, cerebrovascular reserve capacity was reduced (p=0.007), and cerebrovascular reactivity delay time increased (p<0.001), in the flow territory from which symptoms were derived compared to the contralateral flow territory. Discussion: North American MMD is being observed with increasing frequency and increasing the awareness of non-stroke MMD presentations may lead to early diagnosis that can lead to proactive revascularization to minimize the risk of first stroke in these patients.

Quantitative MRI reveals heterogeneous impacts of treatment on diseased bone marrow in a mouse model of myelofibrosis.

Analyzing bone marrow in the hematologic cancer myelofibrosis requires endpoint histology in mouse models and bone marrow biopsies in patients. These methods hinder the ability to monitor therapy over time. Preclinical studies typically begin treatment before mice develop myelofibrosis, unlike patients who begin therapy only after onset of disease. Using clinically relevant, quantitative MRI metrics allowed us to evaluate treatment in mice with established myelofibrosis. We used chemical shift-encoded fat imaging, DWI, and magnetization transfer sequences to quantify bone marrow fat, cellularity, and macromolecular components in a mouse model of myelofibrosis. We monitored spleen volume, the established imaging marker for treatment, with anatomic MRI. After confirming bone marrow disease by MRI, we randomized mice to treatment with an approved drug (ruxolitinib or fedratinib) or an investigational agent, navitoclax, for 33 days. We measured the effects of therapy over time with bone marrow and spleen MRI. All treatments produced heterogeneous responses with improvements in bone marrow evident in subsets of individual mice in all treatment groups. Reductions in spleen volume commonly occurred without corresponding improvement in bone marrow. MRI revealed patterns associated with effective and ineffective responses to treatment in bone marrow and identified regional variations in efficacy within a bone. Quantitative MRI revealed modest, heterogeneous improvements in bone marrow disease when treating mice with established myelofibrosis. These results emphasize the value of bone marrow MRI to assess treatment in preclinical models and the potential to advance clinical trials for patients.

The effect of estradiol add-back: a longitudinal MRI study in prostate cancer patients.

We investigated the effect of estradiol add-back therapy (EAT) on brain activation related to cognitive function and affect in addition to putative changes in gray and white matter volume in testosterone depleted participants with prostate cancer. We conducted a randomized controlled, double-blinded trial in which 40 patients received 0.9 mg of transdermal estradiol per day for 6 months or matched placebo. Anatomical MRI and three functional MRI (fMRI) scans were obtained for the emotion recognition task, verbal memory task, and visuospatial memory task. Activation in corresponding cognitive and affective brain networks was demonstrated for all tasks. Longitudinally, there was no difference in brain activation, reaction time, or accuracy in response to the fMRI tasks between the EAT group and placebo group at 6 months. In addition, there was no detectable change in whole-brain gray or white matter volume or in hippocampal volume between the two groups after 6 months. This study supports earlier findings that EAT does not improve verbal memory or affect and has no immediate effect on hippocampal volume in testosterone depleted patients with prostate cancer.

End-to-end volumetric segmentation of white matter hyperintensities using deep learning

Background and objectivesReliable detection of white matter hyperintensities (WMH) is crucial for studying the impact of diffuse white-matter pathology on brain health and monitoring changes in WMH load over time. However, manual annotation of 3D high-dimensional neuroimages is laborious and can be prone to biases and errors in the annotation procedure. In this study, we evaluate the performance of deep learning (DL) segmentation tools and propose a novel volumetric segmentation model incorporating self-attention via a transformer-based architecture. Ultimately, we aim to evaluate diverse factors that influence WMH segmentation, aiming for a comprehensive analysis of the state-of-the-art algorithms in a broader context. MethodsWe trained state-of-the-art DL algorithms, and incorporated advanced attention mechanisms, using structural fluid-attenuated inversion recovery (FLAIR) image acquisitions. The anatomical MRI data utilized for model training was obtained from healthy individuals aged 62–70 years in the Live active Successful Aging (LISA) project. Given the potential sparsity of lesion volume among healthy aging individuals, we explored the impact of incorporating a weighted loss function and ensemble models. To assess the generalizability of the studied DL models, we applied the trained algorithm to an independent subset of data sourced from the MICCAI WMH challenge (MWSC). Notably, this subset had vastly different acquisition parameters compared to the LISA dataset used for training. ResultsConsistently, DL approaches exhibited commendable segmentation performance, achieving the level of inter-rater agreement comparable to expert performance, ensuring superior quality segmentation outcomes. On the out of sample dataset, the ensemble models exhibited the most outstanding performance. ConclusionsDL methods generally surpassed conventional approaches in our study. While all DL methods performed comparably, incorporating attention mechanisms could prove advantageous in future applications with a wider availability of training data. As expected, our experiments indicate that the use of ensemble-based models enables the superior generalization in out-of-distribution settings. We believe that introducing DL methods in the WHM annotation workflow in heathy aging cohorts is promising, not only for reducing the annotation time required, but also for eventually improving accuracy and robustness via incorporating the automatic segmentations in the evaluation procedure.

Toward Printing the Brain: A Microstructural Ground Truth Phantom for MRI

AbstractMagnetic resonance imaging (MRI) has become the prime imaging technique for in vivo examination of the brain. In addition to anatomical and functional MRI, diffusion MRI (dMRI) is widely used in both clinics and research to assess tissue structure and fiber directions, particularly in the nervous system. While diffusion tensor imaging is the most widespread approach for assessing orientation measures, other, more sophisticated models have also been proposed. Validation of dMRI is, however, a challenging endeavor that requires specialized test samples. Here it is shown that two‐photon polymerization (2PP) 3D printing allows for manufacturing such test objects, a.k.a. phantoms. After upscaling the 2PP fabrication process, 3D structures at high spatial resolution and sufficient size to image in a human 7T MRI scanner are created. These phantoms reliably mimic human white matter and thus enable the systematic validation and verification of dMRI data and their analyses. The 3D‐printed structures include up to 51 000 microchannels that mimic the diffusion behavior of larger axons, with a cross‐section of 12 × 12 µm2 each, in parallel and crossing arrangements. The acquired dMRI data demonstrates and verifies the utility of these novel brain phantoms.

Combined free-running four-dimensional anatomical and flow magnetic resonance imaging with native contrast using Synchronization of Neighboring Acquisitions by Physiological Signals

Four-dimensional (4D) flow magnetic resonance imaging (MRI) often relies on the injection of gadolinium- or iron-oxide-based contrast agents to improve vessel delineation. In this work, a novel technique is developed to acquire and reconstruct 4D flow data with excellent dynamic visualization of blood vessels but without the need for contrast injection. Synchronization of Neighboring Acquisitions by Physiological Signals (SyNAPS) uses pilot tone (PT) navigation to retrospectively synchronize the reconstruction of two free-running three-dimensional radial acquisitions, to create co-registered anatomy and flow images. Thirteen volunteers and two Marfan syndrome patients were scanned without contrast agent using one free-running fast interrupted steady-state (FISS) sequence and one free-running phase-contrast MRI (PC-MRI) sequence. PT signals spanning the two sequences were recorded for retrospective respiratory motion correction and cardiac binning. The magnitude and phase images reconstructed, respectively, from FISS and PC-MRI, were synchronized to create SyNAPS 4D flow datasets. Conventional two-dimensional (2D) flow data were acquired for reference in ascending (AAo) and descending aorta (DAo). The blood-to-myocardium contrast ratio, dynamic vessel area, net volume, and peak flow were used to compare SyNAPS 4D flow with Native 4D flow (without FISS information) and 2D flow. A score of 0-4 was given to each dataset by two blinded experts regarding the feasibility of performing vessel delineation. Blood-to-myocardium contrast ratio for SyNAPS 4D flow magnitude images (1.5±0.3) was significantly higher than for Native 4D flow (0.7±0.1, p<0.01) and was comparable to 2D flow (2.3±0.9, p=0.02). Image quality scores of SyNAPS 4D flow from the experts (M.P.: 1.9±0.3, E.T.: 2.5±0.5) were overall significantly higher than the scores from Native 4D flow (M.P.: 1.6±0.6, p=0.03, E.T.: 0.8±0.4, p<0.01) but still significantly lower than the scores from the reference 2D flow datasets (M.P.: 2.8±0.4, p<0.01, E.T.: 3.5±0.7, p<0.01). The Pearson correlation coefficient between the dynamic vessel area measured on SyNAPS 4D flow and that from 2D flow was 0.69±0.24 for the AAo and 0.83±0.10 for the DAo, whereas the Pearson correlation between Native 4D flow and 2D flow measurements was 0.12±0.48 for the AAo and 0.08±0.39 for the DAo. Linear correlations between SyNAPS 4D flow and 2D flow measurements of net volume (r2 =0.83) and peak flow (r2 =0.87) were larger than the correlations between Native 4D flow and 2D flow measurements of net volume (r2 =0.79) and peak flow (r2 =0.76). The feasibility and utility of SyNAPS were demonstrated for joint whole-heart anatomical and flow MRI without requiring electrocardiography gating, respiratory navigators, or contrast agents. Using SyNAPS, a high-contrast anatomical imaging sequence can be used to improve 4D flow measurements that often suffer from poor delineation of vessel boundaries in the absence of contrast agents.

Neuroanatomical correlates of distracted straight driving performance: a driving simulator MRI study across the lifespan.

Driving is the preferred mode of transportation for adults across the healthy age span. However, motor vehicle crashes are among the leading causes of injury and death, especially for older adults, and under distracted driving conditions. Understanding the neuroanatomical basis of driving may inform interventions that minimize crashes. This exploratory study examined the neuroanatomical correlates of undistracted and distracted simulated straight driving. One-hundred-and-thirty-eight participants (40.6% female) aged 17-85 years old (mean and SD = 58.1 ± 19.9 years) performed a simulated driving task involving straight driving and turns at intersections in a city environment using a steering wheel and foot pedals. During some straight driving segments, participants responded to auditory questions to simulate distracted driving. Anatomical T1-weighted MRI was used to quantify grey matter volume and cortical thickness for five brain regions: the middle frontal gyrus (MFG), precentral gyrus (PG), superior temporal cortex (STC), posterior parietal cortex (PPC), and cerebellum. Partial correlations controlling for age and sex were used to explore relationships between neuroanatomical measures and straight driving behavior, including speed, acceleration, lane position, heading angle, and time speeding or off-center. Effects of interest were noted at an unadjusted p-value threshold of 0.05. Distracted driving was associated with changes in most measures of straight driving performance. Greater volume and cortical thickness in the PPC and cerebellum were associated with reduced variability in lane position and heading angle during distracted straight driving. Cortical thickness of the MFG, PG, PPC, and STC were associated with speed and acceleration, often in an age-dependent manner. Posterior regions were correlated with lane maintenance whereas anterior and posterior regions were correlated with speed and acceleration, especially during distracted driving. The regions involved and their role in straight driving may change with age, particularly during distracted driving as observed in older adults. Further studies should investigate the relationship between distracted driving and the aging brain to inform driving interventions.

Childhood adversity severity modulates the associations between adaptive psychological changes and amygdala volumetric changes in response to behavioral interventions

BackgroundAdverse Childhood Experience (ACE) has been shown to have detrimental impact on amygdala structure. Prior research found that adaptive psychological changes after Mindfulness-Based Interventions (MBI) were associated with amygdala volumetric changes. The present study aims to further investigate whether such effects also occur among ACE survivors and whether the effects are unique to MBI. MethodsA total of 64 young adult childhood adversity survivors were randomized to an eight-week MBI or Stress Management Education (SME) as an active control condition. Anatomical MRI and questionnaires on mindfulness, stress and psychological health were collected at baseline and post-intervention. Due to subject dropout, the final sample included 39 subjects (MBI:20, SME:19). ResultsBoth groups showed increased mindfulness levels, reduced stress, and improved psychological symptoms (depression, anxiety, and somatization), with no significant group by time interaction effect. There was no significant group difference on amygdala volumetric changes. Within the MBI group, childhood maltreatment severity was a significant mediator between changes of mindfulness levels and right amygdala volumetric changes. Across pooled sample of both groups, childhood maltreatment was a significant moderator for the effect of trait anxiety level changes on left amygdala volumetric changes. LimitationsModest sample size, relatively low retention rates, suboptimal monitoring of home practice. ConclusionsMBI did not demonstrate overall better clinical effects than SME. Psychological-change-dependent amygdala volumetric change was not specific to MBI. Childhood maltreatment severity modulated the relationships between adaptive psychological changes and amygdala volumetric changes.

Cortical Structure in Pre-Readers at Cognitive Risk for Dyslexia: Baseline Differences and Response to Intervention.

Early childhood is a critical period for structural brain development as well as an important window for the identification and remediation of reading difficulties. Recent research supports the implementation of interventions in at-risk populations as early as kindergarten or first grade, yet the neurocognitive mechanisms following such interventions remain understudied. To address this, we investigated cortical structure by means of anatomical MRI before and after a 12-week tablet-based intervention in: (1) at-risk children receiving phonics-based training (n = 29; n = 16 complete pre-post datasets), (2) at-risk children engaging with AC training (n = 24; n = 15 complete pre-post datasets) and (3) typically developing children (n = 25; n = 14 complete pre-post datasets) receiving no intervention. At baseline, we found higher surface area of the right supramarginal gyrus in at-risk children compared to typically developing peers, extending previous evidence that early anatomical differences exist in children who may later develop dyslexia. Our longitudinal analysis revealed significant post-intervention thickening of the left supramarginal gyrus, present exclusively in the intervention group but not the active control or typical control groups. Altogether, this study contributes new knowledge to our understanding of the brain morphology associated with cognitive risk for dyslexia and response to early intervention, which in turn raises new questions on how early anatomy and plasticity may shape the trajectories of long-term literacy development.

Abnormal vascular structure and function within brain metastases is linked to pembrolizumab resistance.

We recently conducted a phase 2 trial (NCT028865685) evaluating intracranial efficacy of pembrolizumab for brain metastases (BM) of diverse histologies. Our study met its primary efficacy endpoint and illustrates that pembrolizumab exerts promising activity in a select group of patients with BM. Given the importance of aberrant vasculature in mediating immunosuppression, we explored the relationship between immune checkpoint inhibitor (ICI) efficacy and vascular architecture in the hopes of identifying potential mechanisms of intracranial ICI response or resistance for BM. Using Vessel Architectural Imaging, a histologically validated quantitative metric for in vivo tumor vascular physiology, we analyzed dual-echo DSC/DCE MRI for 44 patients on trial. Tumor and peri-tumor cerebral blood volume/flow, vessel size, arterial and venous dominance, and vascular permeability were measured before and after treatment with pembrolizumab. BM that progressed on ICI were characterized by a highly aberrant vasculature dominated by large-caliber vessels. In contrast, ICI-responsive BM possessed a more structurally balanced vasculature consisting of both small and large vessels, and there was a trend toward a decrease in under-perfused tissue, suggesting a reversal of the negative effects of hypoxia. In the peri-tumor region, the development of smaller blood vessels, consistent with neo-angiogenesis, was associated with tumor growth before radiographic evidence of contrast enhancement on anatomical MRI. This study, one of the largest functional imaging studies for BM, suggests that vascular architecture is linked with ICI efficacy. Studies identifying modulators of vascular architecture, and effects on immune activity, are warranted and may inform future combination treatments.

CSF Fraction Mapping Derived from Multi‐echo MR FAST‐T2 Sequence Could be an Alternative Measure of Total Perivascular Space in the Brain Parenchyma

AbstractBackgroundPerivascular space (PVS), as the key pathway of the glymphatic clearance, has been studied from various aspects. The volume of PVS is considered a biomarker of the enlargement of PVS, which may reflect the deficits of the clearance function. However, most of the methods for the estimation of PVS depends on the segmentation of visible PVS on anatomical MRI, which inherently ignored the invisible PVS that are of sub‐voxel size and dominant of the total PVS. We proposed a muti‐echo T2 relaxometry based CSF water fraction (CSFF) mapping method using 3‐water compartment model. The CSFF mapping corresponding to the long T2 (&gt;200 ms) compartment in the total signal fitted using a 6 echo FAST‐T2 data.MethodForty‐one subjects were recruited (Age: 58.5±17.0, 25 normal (NL), 16 Aβ+ MCI/AD) including 26 females and 15 males. CSFF was reconstructed from the 6 echo FASTT2 data by fitting a three‐water compartment model. PVS in cerebral white matter was segmented using the Frangi filter on the enhanced PVS image. Intracranial volume was segmented using SPM12 for the PVS load normalization.ResultFigure 1 shows the distribution of CSFF and PVS by groups. There is significant difference of CSFF between NL and MCI/AD groups, and no difference of PVS between groups. Figure 2 shows the linear relationship between GM CSFF and normalized PVS load. We see CSFF is about 10 times larger than PVS load. We know the CBV is about 3∼5% of the whole brain. CSFF value is about the same level of CBF, which is very reasonable. It also shows that CSFF has better ability to distinguish NL and MCI/AD than PVS load. Figure 3 shows the high consistency between the CSFF from both high and low resolution FASTT2 data. High resolution CSFF has less partial volume effect, that’s why it has about 0.5% higher value than the low resolution CSFF.ConclusionThe CSF fraction (CSFF) mapping is useful to detect early changes in AD, which may reflect the subtle changes of total PVS space in the brain. Acknowledgement: This study is supported by NIA grant AG057848

Vascular synthesis based on hemodynamic efficiency principle recapitulates measured cerebral circulation properties in the human brain

Quantifying anatomical and hemodynamical properties of the brain vasculature in vivo is difficult due to limited spatiotemporal resolution neuroimaging, variability between subjects, and bias between acquisition techniques. This work introduces a metabolically inspired vascular synthesis algorithm for creating a digital representation of the cortical blood supply in humans. Spatial organization and segment resistances of a cortical vascular network were generated. Cortical folding and macroscale arterial and venous vessels were reconstructed from anatomical MRI and MR angiography. The remaining network, including ensembles representing the parenchymal capillary bed, were synthesized following a mechanistic principle based on hydrodynamic efficiency of the cortical blood supply. We evaluated the digital model by comparing its simulated values with in vivo healthy human brain measurements of macrovessel blood velocity from phase contrast MRI and capillary bed transit times and bolus arrival times from dynamic susceptibility contrast. We find that measured and simulated values reasonably agree and that relevant neuroimaging observables can be recapitulated in silico. This work provides a basis for describing and testing quantitative aspects of the cerebrovascular circulation that are not directly observable. Future applications of such digital brains include the investigation of the organ-wide effects of simulated vascular and metabolic pathologies.

The multi-level outcome study of psychoanalysis for chronically depressed patients with early trauma (MODE): rationale and design of an international multicenter randomized controlled trial

BackgroundWhether and how psychotherapies change brain structure and function is unknown. Its study is of great importance for contemporary psychotherapy, as it may lead to discovery of neurobiological mechanisms that predict and mediate lasting changes in psychotherapy, particularly in severely mentally ill patients, such as those with chronic depression. Previous studies have shown that psychoanalytic psychotherapies produce robust and enduring improvements in not only symptom severity but also personality organization in patients who have chronic depression and early life trauma, especially if therapy is delivered at a high weekly frequency.Methods/designPatients with chronic major depression and a history of early life trauma will be recruited, assessed, and treated across 3 international sites: Germany, Switzerland, and the United States. They will be randomized to one of two treatment arms: either (1) once weekly psychoanalytic psychotherapies, or (2) 3–4 times weekly psychoanalytic psychotherapies. They will have full clinical characterization as well as undergo MRI scanning at study baseline prior to randomization and again one year later. A group of matched healthy controls will undergo similar assessments and MRI scanning at the same time points to help discern whether study treatments induce brain changes toward or away from normal values. Primary study outcomes will include anatomical MRI, functional MRI, and Diffusion Tensor Imaging measures. Study hypotheses will be tested using the treatment-by-time interaction assessed in multiple general linear models with repeated measures analyses in an intent-to-treat analysis.DiscussionMODE may allow the identification of brain-based biomarkers that may be more sensitive than traditional behavioral and clinical measures in discriminating, predicting, and mediating treatment response. These findings could help to personalize care for patients who have chronic depression patients and early life trauma, and they will provide new therapeutic targets for both psychological and biological treatments for major depressive illness.

Impulsive-compulsive behaviour in early Parkinson’s disease is determined by apathy and dopamine receptor D3 polymorphism

Impulsive-compulsive behaviour (ICB) is a frequently observed non-motor symptom in early Parkinson’s disease after initiating dopamine replacement therapy. At the opposite end of the motivated behaviour spectrum, apathy occurs in early Parkinson’s disease even before dopamine replacement is started. The co-occurrence of these behavioural conditions in Parkinson’s disease raises questions about their relationship and underlying pathophysiological determinants. In previous imaging or genetic studies, both conditions have been associated with the limbic dopaminergic system. The risk variant of the Ser9Gly polymorphism of the dopamine receptor D3 (DRD3) is linked to increased dopamine affinity in the limbic striatum. With this in mind, we investigated how ICB expression is explained by apathy and DRD3 polymorphisms and their effects on grey matter volume and dopamine synthesis capacity. Fifty-four patients with early Parkinson’s disease took part in anatomical T1-weighted MRI. Forty of them also underwent dynamic PET imaging using [18F]DOPA to measure striatal dopamine synthesis capacity. Further, Ser9Gly (rs6280) gene polymorphism influencing the DRD3 dopamine-binding affinity was determined in all patients. The severity of impulsive-compulsive behaviour and apathy was assessed using the Questionnaire for Impulsive-Compulsive Disorders Rating Scale and the Apathy Evaluation Scale. ICB and the severity of apathy were indeed positively correlated. Apathy and the DRD3 polymorphism were interactive risk factors for ICB severity. Apathy was significantly linked to atrophy of the bilateral putamen. Patients with the DRD3 risk type had reduced dopamine synthesis capacity in the putamen and limbic striatum, apathy was associated with reduced dopamine synthesis capacity in the limbic striatum. The results of [18F]DOPA reached only trend significance. Apathy in drug-naïve PD patients might be a consequence of impaired striatal dopaminergic tone. This may represent a predisposing factor for the development of ICB after the initiation of dopamine replacement therapy. The risk type of DRD3 could further amplify this predisposition due to its higher affinity to dopamine.