Structural Connectivity Measures Research Articles

Brainwide Anatomical Connectivity and Prediction of Longitudinal Outcomes in Antipsychotic-Naïve First-Episode Psychosis

BackgroundDisruptions of axonal connectivity are thought to be a core pathophysiological feature of psychotic illness, but whether they are present early in the illness, prior to antipsychotic exposure, and whether they can predict clinical outcome remain unknown. MethodsWe acquired diffusion-weighted magnetic resonance images to map structural connectivity between each pair of 319 parcellated brain regions in 61 antipsychotic-naïve individuals with first-episode psychosis (15–25 years, 46% female) and a demographically matched sample of 27 control participants. Clinical follow-up data were also acquired in patients 3 and 12 months after the scan. We used connectome-wide analyses to map disruptions of inter-regional pairwise connectivity and connectome-based predictive modeling to predict longitudinal change in symptoms and functioning. ResultsIndividuals with first-episode psychosis showed disrupted connectivity in a brainwide network linking all brain regions compared with controls (familywise error–corrected p = .03). Baseline structural connectivity significantly predicted change in functioning over 12 months (r = 0.44, familywise error–corrected p = .041), such that lower connectivity within fronto-striato-thalamic systems predicted worse functional outcomes. ConclusionsBrainwide reductions of structural connectivity exist during the early stages of psychotic illness and cannot be attributed to antipsychotic medication. Moreover, baseline measures of structural connectivity can predict change in patient functional outcomes up to 1 year after engagement with treatment services.

Longitudinal Analysis of Brain Function-Structure Dependencies in 22q11.2 Deletion Syndrome and Psychotic Symptoms

BackgroundCompared with conventional unimodal analysis, understanding how brain function and structure relate to one another opens a new biologically relevant assessment of neural mechanisms. However, how function-structure dependencies (FSDs) evolve throughout typical and abnormal neurodevelopment remains elusive. The 22q11.2 deletion syndrome (22q11.2DS) offers an important opportunity to study the development of FSDs and their specific association with the pathophysiology of psychosis. MethodsPreviously, we used graph signal processing to combine brain activity and structural connectivity measures in adults, quantifying FSD. Here, we combined FSD with longitudinal multivariate partial least squares correlation to evaluate FSD alterations across groups and among patients with and without mild to moderate positive psychotic symptoms. We assessed 391 longitudinally repeated resting-state functional and diffusion-weighted magnetic resonance images from 194 healthy control participants and 197 deletion carriers (ages 7–34 years, data collected over a span of 12 years). ResultsCompared with control participants, patients with 22q11.2DS showed a persistent developmental offset from childhood, with regions of hyper- and hypocoupling across the brain. Additionally, a second deviating developmental pattern showed an exacerbation during adolescence, presenting hypocoupling in the frontal and cingulate cortices and hypercoupling in temporal regions for patients with 22q11.2DS. Interestingly, the observed aggravation during adolescence was strongly driven by the group with positive psychotic symptoms. ConclusionsThese results confirm a central role of altered FSD maturation in the emergence of psychotic symptoms in 22q11.2DS during adolescence. The FSD deviations precede the onset of psychotic episodes and thus offer a potential early indication for behavioral interventions in individuals at risk.

Structural connectivity as a predictive factor for perampanel response in patients with epilepsy

ObjectivesThis study aimed to identify clinical characteristics that could predict the response to perampanel (PER) and determine whether structural connectivity is a predictive factor. MethodsWe enrolled patients with epilepsy who received PER and were followed-up for a minimum of 12 months. Good PER responders, who were seizure-free or presented with more than 50 % seizure reduction, were classified separately from poor PER responders who had seizure reduction of less than 50 % or non-responders. A graph theoretical analysis was conducted based on diffusion tensor imaging to calculate network measures of structural connectivity among patients with epilepsy. Results106 patients with epilepsy were enrolled, including 26 good PER responders and 80 poor PER responders. Good PER responders used fewer anti-seizure medications before PER administration compared to those by poor PER responders (3 vs. 4; p = 0.042). Early PER treatment was more common in good PER responders than poor PER responders (46.2 vs. 21.3 %, p = 0.014). Regarding cortical structural connectivity, the global efficiency was higher and characteristic path length was lower in good PER responders than in poor PER responders (0.647 vs. 0.635, p = 0.006; 1.726 vs. 1,759, p = 0.008, respectively). For subcortical structural connectivity, the mean clustering coefficient and small-worldness index were higher in good PER responders than in poor PER responders (0.821 vs. 0.791, p = 0.009; 0.597 vs. 0.560, p = 0.009, respectively). ConclusionThis study demonstrated that early PER administration can predict a good PER response in patients with epilepsy, and structural connectivity could potentially offer clinical utility in predicting PER response.

Brain connectivity in status epilepticus as a predictor of outcome: A diffusion tensor imaging study.

We aimed to explore structural connectivity in status epilepticus. We enrolled participants who underwent diffusion tensor imaging. We applied graph theory to investigate structural connectivity. We compared the structural connectivity measures between patients and healthy controls and between patients with poor (modified Rankin Scale [mRS] >3) and good (mRS ≤3) admissionoutcomes. We enrolled 28 patients and 31 healthy controls (age 65.5 vs.62.0 years, p=.438). Of these patients, 16 and 12 showed poor and good admissionoutcome (age 65.5vs.62.0 years, p=.438). The assortative coefficient (-0.113vs. -0.121, p=.021), mean clustering coefficient (0.007vs.0.006, p=.009), global efficiency (0.023vs.0.020, p=.009), transitivity (0.007vs.0.006, p=.009), and small-worldness index (0.006vs.0.005, p=.021) were higher in patients with status epilepticus than in healthy controls. The assortative coefficient (-0.108vs. -0.119, p=.042), mean clustering coefficient (0.007vs.0.006, p=.042), and transitivity (0.008vs.0.007, p=.042) were higher in patients with poor admissionoutcome than in those with good admissionoutcome. MRS score was positively correlated with structural connectivity measures, including the assortative coefficient (r=0.615, p=.003), mean clustering coefficient (r=0.544, p=.005), global efficiency (r=0.515, p=.007), transitivity (r=0.547, p=.007), and small-worldness index (r=0.435, p=.024). We revealed alterations in structural connectivity, showing increased integration and segregation in status epilepticus, which might be related with neuronal synchronization. This effect was more pronounced in patients with a poor admissionoutcome, potentially reshaping our understanding for comprehension of status epilepticus mechanisms and the development of more targeted treatments.

Genetic architecture of the structural connectome

Myelinated axons form long-range connections that enable rapid communication between distant brain regions, but how genetics governs the strength and organization of these connections remains unclear. We perform genome-wide association studies of 206 structural connectivity measures derived from diffusion magnetic resonance imaging tractography of 26,333 UK Biobank participants, each representing the density of myelinated connections within or between a pair of cortical networks, subcortical structures or cortical hemispheres. We identify 30 independent genome-wide significant variants after Bonferroni correction for the number of measures studied (126 variants at nominal genome-wide significance) implicating genes involved in myelination (SEMA3A), neurite elongation and guidance (NUAK1, STRN, DPYSL2, EPHA3, SEMA3A, HGF, SHTN1), neural cell proliferation and differentiation (GMNC, CELF4, HGF), neuronal migration (CCDC88C), cytoskeletal organization (CTTNBP2, MAPT, DAAM1, MYO16, PLEC), and brain metal transport (SLC39A8). These variants have four broad patterns of spatial association with structural connectivity: some have disproportionately strong associations with corticothalamic connectivity, interhemispheric connectivity, or both, while others are more spatially diffuse. Structural connectivity measures are highly polygenic, with a median of 9.1 percent of common variants estimated to have non-zero effects on each measure, and exhibited signatures of negative selection. Structural connectivity measures have significant genetic correlations with a variety of neuropsychiatric and cognitive traits, indicating that connectivity-altering variants tend to influence brain health and cognitive function. Heritability is enriched in regions with increased chromatin accessibility in adult oligodendrocytes (as well as microglia, inhibitory neurons and astrocytes) and multiple fetal cell types, suggesting that genetic control of structural connectivity is partially mediated by effects on myelination and early brain development. Our results indicate pervasive, pleiotropic, and spatially structured genetic control of white-matter structural connectivity via diverse neurodevelopmental pathways, and support the relevance of this genetic control to healthy brain function.

Graph Theory Analysis of Structural Connectivity in Limbic‐predominant Age‐related TDP‐43 Encephalopathy Neuropathological Change (LATE‐NC)

AbstractBackgroundThe anatomical distribution of limbic‐predominant age‐related TDP‐43 encephalopathy neuropathological change (LATE‐NC) typically involves the amygdala, hippocampus, and other subcortical, temporal and frontal lobe regions. But its impact on the structural integrity of this network of regions remains unknown. In this study, we tested the hypothesis that LATE‐NC is associated with abnormalities in graph theoretic measures of structural connectivity in the network of regions known to be involved in LATE‐NC.MethodThis study included 148 deceased older adults participating in Rush Memory and Aging Project and Religious Orders Study (Fig.1A). Ex‐vivo diffusion tensor imaging (DTI) scans were acquired on 3T scanners, followed by detailed neuropathologic examination by a board‐certified neuropathologist (Fig.1B). Fractional anisotropy (FA) maps derived from DTI scans were used to define region‐to‐region structural connectivity in a network of 19 regions known to be involved in LATE‐NC using graph theory‐based network measures (Fig.2). General linear models were used to investigate the association of global and local graph measures with LATE‐NC stages, controlling for other neuropathologies (Alzheimer’s disease, Lewy bodies, arteriolosclerosis, atherosclerosis, cerebral amyloid angiopathy, gross and microscopic infarcts), demographics (age at death, sex, education), total white matter hyperintensity volume, postmortem intervals and scanner variables. Statistical significance was set at p<0.05.ResultLinear regression revealed that greater LATE‐NC stage was associated with increased characteristic path length and with lower values of the remaining global network measures (p<0.05) (Fig.3A). LATE‐NC was also associated with lower local efficiency, increased path length, lower nodal strength, and lower clustering coefficient in 74%, 79%, 32%, and 63% of the nodes, respectively (p<0.05) (Fig.3B). Finally, LATE‐NC was associated with both greater (in 21% of nodes) and lower (in 16% of nodes) eigenvector centrality, and with both greater and lower betweenness centrality in 21% of nodes, respectively (p<0.05) (Fig.3B).ConclusionUsing graph theory and a hypothesis‐driven approach, we found significant degradation of structural integrity in white matter of the network of regions affected by LATE‐NC. These findings may shed light on the effects of LATE‐NC on brain connectivity, and in combination with other imaging and clinical information, may aid towards the development of tools for in‐vivo detection of this devastating neuropathology.

Graph Theory Analysis of Structural Connectivity in Limbic‐predominant Age‐related TDP‐43 Encephalopathy Neuropathological Change (LATE‐NC)

AbstractBackgroundThe anatomical distribution of limbic‐predominant age‐related TDP‐43 encephalopathy neuropathological change (LATE‐NC) typically involves the amygdala, hippocampus, and other subcortical, temporal and frontal lobe regions. But its impact on the structural integrity of this network of regions remains unknown. In this study, we tested the hypothesis that LATE‐NC is associated with abnormalities in graph theoretic measures of structural connectivity in the network of regions known to be involved in LATE‐NC.MethodThis study included 148 deceased older adults participating in Rush Memory and Aging Project and Religious Orders Study (Fig.1A). Ex‐vivo diffusion tensor imaging (DTI) scans were acquired on 3T scanners, followed by detailed neuropathologic examination by a board‐certified neuropathologist (Fig.1B). Fractional anisotropy (FA) maps derived from DTI scans were used to define region‐to‐region structural connectivity in a network of 19 regions known to be involved in LATE‐NC using graph theory‐based network measures (Fig.2).General linear models were used to investigate the association of global and local graph measures with LATE‐NC stages, controlling for other neuropathologies (Alzheimer’s disease, Lewy bodies, arteriolosclerosis, atherosclerosis, cerebral amyloid angiopathy, gross and microscopic infarcts), demographics (age at death, sex, education), total white matter hyperintensity volume, postmortem intervals and scanner variables. Statistical significance was set at p<0.05.ResultLinear regression revealed that greater LATE‐NC stage was associated with increased characteristic path length and with lower values of the remaining global network measures (p<0.05) (Fig.3A). LATE‐NC was also associated with lower local efficiency, increased path length, lower nodal strength, and lower clustering coefficient in 74%, 79%, 32%, and 63% of the nodes, respectively (p<0.05) (Fig.3B). Finally, LATE‐NC was associated with both greater (in 21% of nodes) and lower (in 16% of nodes) eigenvector centrality, and with both greater and lower betweenness centrality in 21% of nodes, respectively (p<0.05) (Fig.3B).ConclusionUsing graph theory and a hypothesis‐driven approach, we found significant degradation of structural integrity in white matter of the network of regions affected by LATE‐NC. These findings may shed light on the effects of LATE‐NC on brain connectivity, and in combination with other imaging and clinical information, may aid towards the development of tools for in‐vivo detection of this devastating neuropathology.

Structural connectivity as a predictive factor for responsiveness to levetiracetam treatment in epilepsy.

To investigate whether structural connectivity or glymphatic system function is a potential predictive factor for levetiracetam (LEV) response in patients with newly diagnosed epilepsy. We enrolled patients with newly diagnosed epilepsy who were administered LEV as initial monotherapy and underwent diffusion tensor imaging (DTI) at diagnosis. We categorized the patients into drug response. We used graph theory to calculate the network measures for structural connectivity based on the DTI scans in patients with epilepsy. Additionally, we evaluated glymphatic system function by calculating the DTI analysis along the perivascular space (DTI-ALPS) index based on DTI scans. We enrolled 84 patients with epilepsy. The clinical factors and DTI-ALPS index did not differ between the groups. However, some of the structural connectivity measures significantly differ between the groups. The poor responders exhibited a higher mean clustering coefficient, global efficiency, and small-worldness index than the good responders (p = 0.003, p = 0.048, and p = 0.038, respectively). In the receiver operating characteristic curve analysis, the mean clustering coefficient exhibited the highest performance in predicting the responsiveness to LEV (area under the curve of 0.677). In the multiple logistic regression analysis, the mean clustering coefficient of the structural connectivity measures was the only significant predictor of LEV response (p = 0.014). Furthermore, in the survival analysis, the mean clustering coefficient was the only significant predictor of LEV response (p = 0.026). We demonstrated that structural connectivity is a potential predictive factor for responsiveness to LEV treatment in patients with newly diagnosed epilepsy.

In humans, striato-pallido-thalamic projections are largely segregated by their origin in either the striosome-like or matrix-like compartments

Cortico-striato-thalamo-cortical (CSTC) loops are fundamental organizing units in mammalian brains. CSTCs process limbic, associative, and sensorimotor information in largely separated but interacting networks. CTSC loops pass through paired striatal compartments, striosome (aka patch) and matrix, segregated pools of medium spiny projection neurons with distinct embryologic origins, cortical/subcortical structural connectivity, susceptibility to injury, and roles in behaviors and diseases. Similarly, striatal dopamine modulates activity in striosome and matrix in opposite directions. Routing CSTCs through one compartment may be an anatomical basis for regulating discrete functions. We used differential structural connectivity, identified through probabilistic diffusion tractography, to distinguish the striatal compartments (striosome-like and matrix-like voxels) in living humans. We then mapped compartment-specific projections and quantified structural connectivity between each striatal compartment, the globus pallidus interna (GPi), and 20 thalamic nuclei in 221 healthy adults. We found that striosome-originating and matrix-originating streamlines were segregated within the GPi: striosome-like connectivity was significantly more rostral, ventral, and medial. Striato-pallido-thalamic streamline bundles that were seeded from striosome-like and matrix-like voxels transited spatially distinct portions of the white matter. Matrix-like streamlines were 5.7-fold more likely to reach the GPi, replicating animal tract-tracing studies. Striosome-like connectivity dominated in six thalamic nuclei (anteroventral, central lateral, laterodorsal, lateral posterior, mediodorsal-medial, and medial geniculate). Matrix-like connectivity dominated in seven thalamic nuclei (centromedian, parafascicular, pulvinar-anterior, pulvinar-lateral, ventral lateral-anterior, ventral lateral-posterior, ventral posterolateral). Though we mapped all thalamic nuclei independently, functionally-related nuclei were matched for compartment-level bias. We validated these results with prior thalamostriate tract tracing studies in non-human primates and other species; where reliable data was available, all agreed with our measures of structural connectivity. Matrix-like connectivity was lateralized (left > right hemisphere) in 18 thalamic nuclei, independent of handedness, diffusion protocol, sex, or whether the nucleus was striosome-dominated or matrix-dominated. Compartment-specific biases in striato-pallido-thalamic structural connectivity suggest that routing CSTC loops through striosome-like or matrix-like voxels is a fundamental mechanism for organizing and regulating brain networks. Our MRI-based assessments of striato-thalamic connectivity in humans match and extend the results of prior tract tracing studies in animals. Compartment-level characterization may improve localization of human neuropathologies and improve neurosurgical targeting in the GPi and thalamus.

High-resolution multi-shot diffusion imaging of structural networks in healthy neurocognitive aging

Healthy neurocognitive aging has been associated with the microstructural degradation of white matter pathways that connect distributed gray matter regions, assessed by diffusion-weighted imaging (DWI). However, the relatively low spatial resolution of standard DWI has limited the examination of age-related differences in the properties of smaller, tightly curved white matter fibers, as well as the relatively more complex microstructure of gray matter. Here, we capitalize on high-resolution multi-shot DWI, which allows spatial resolutions < 1 mm3 to be achieved on clinical 3T MRI scanners. We assessed whether traditional diffusion tensor-based measures of gray matter microstructure and graph theoretical measures of white matter structural connectivity assessed by standard (1.5 mm3 voxels, 3.375 μl volume) and high-resolution (1 mm3 voxels, 1μl volume) DWI were differentially related to age and cognitive performance in 61 healthy adults 18–78 years of age. Cognitive performance was assessed using an extensive battery comprising 12 separate tests of fluid (speed-dependent) cognition. Results indicated that the high-resolution data had larger correlations between age and gray matter mean diffusivity, but smaller correlations between age and structural connectivity. Moreover, parallel mediation models including both standard and high-resolution measures revealed that only the high-resolution measures mediated age-related differences in fluid cognition. These results lay the groundwork for future studies planning to apply high-resolution DWI methodology to further assess the mechanisms of both healthy aging and cognitive impairment.

Young versus older subject diffusion magnetic resonance imaging data for virtual white matter lesion tractography.

White matter hyperintensity (WMH) lesions on T2 fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI) and changes in adjacent normal-appearing white matter can disrupt computerized tract reconstruction and result in inaccurate measures of structural brain connectivity. The virtual lesion approach provides an alternative strategy for estimating structural connectivity changes due to WMH. To assess the impact of using young versus older subject diffusion MRI data for virtual lesion tractography, we leveraged recently available diffusion MRI data from the Human Connectome Project (HCP) Lifespan database. Neuroimaging data from 50 healthy young (39.2 ± 1.6 years) and 46 healthy older (74.2 ± 2.5 years) subjects were obtained from the publicly available HCP-Aging database. Three WMH masks with low, moderate, and high lesion burdens were extracted from the WMH lesion frequency map of locally acquired FLAIR MRI data. Deterministic tractography was conducted to extract streamlines in 21 WM bundles with and without the WMH masks as regions of avoidance in both young and older cohorts. For intact tractography without virtual lesion masks, 7 out of 21 WM pathways showed a significantly lower number of streamlines in older subjects compared to young subjects. A decrease in streamline count with higher native lesion burden was found in corpus callosum, corticostriatal tract, and fornix pathways. Comparable percentages of affected streamlines were obtained in young and older groups with virtual lesion tractography using the three WMH lesion masks of increasing severity. We conclude that using normative diffusion MRI data from young subjects for virtual lesion tractography of WMH is, in most cases, preferable to using age-matched normative data.

Prediction of Post-stroke Motor Recovery Benefits from Measures of Sub-acute Widespread Network Damages (P12-8.002)

<h3>Objective:</h3> Developing a more accurate post-stroke motor recovery prediction model leveraging brain network connectivity measurements. <h3>Background:</h3> Following an acute ischemic stroke, some patients recover almost completely, while others barely recover. It is known that lesion volume, initial motor impairment, and cortico-spinal tract asymmetry (benchmark features) significantly impact motor changes over time. However, accurate prediction models of patients’ recovery are still missing. Recent work suggested that disabilities arise not only from focal structural changes but also from widespread alterations in inter-regional connectivity. Here, we built on this hypothesis to develop a more accurate post-stroke motor recovery prediction model. <h3>Design/Methods:</h3> We evaluated a dataset of 37 patients (17 women) with upper extremity motor strokes. Their impairment was assessed at 2 weeks (baseline) and 3 months after the stroke using the Fugl-Meyer-Assessment. 18 graph measures of global structural connectivity were obtained using the patients’ T2 lesion mask to virtually reproduce the lesions in 60 healthy streamline tractography connectomes. We added these indirect measures to the benchmark features, and we used a ridge regression regularization in a leave-one-out cross-validation framework to predict motor recovery at 3 months post-injury. <h3>Results:</h3> Prediction accuracy significantly increased when using brain connectivity measures (R²=0.68, 95% CI: 0.64–0.74) as compared to benchmark features alone (R²=0.38, 95% CI: 0.31–0.51). <h3>Conclusions:</h3> We report that global measures of brain connectivity estimated by introducing virtual lesions in healthy structural connectomes significantly increase the accuracy of motor recovery prediction in stroke patients compared to focal and clinical measures used until now. This indirect estimation of the stroke impact on the whole brain connectome is more readily available than direct measures of structural connectivity obtained with magnetic resonance imaging (MRI) and would, therefore, have a more substantial clinical impact. <b>Disclosure:</b> An immediate family member of Dr. Pirondini has stock in Reach Neuro. The institution of Dr. Pirondini has received research support from NIH. The institution of an immediate family member of Dr. Pirondini has received research support from NIH. Dr. Pirondini has received intellectual property interests from a discovery or technology relating to health care. An immediate family member of Dr. Pirondini has received intellectual property interests from a discovery or technology relating to health care. Maria Giulia Preti has nothing to disclose. Dimitri Van De Ville has nothing to disclose. Prof. Guggisberg has nothing to disclose. Dr. Rivier has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Pyxis Partners.

Prediction of post-stroke motor recovery benefits from measures of sub-acute widespread network damages.

Following a stroke in regions of the brain responsible for motor activity, patients can lose their ability to control parts of their body. Over time, some patients recover almost completely, while others barely recover at all. It is known that lesion volume, initial motor impairment and cortico-spinal tract asymmetry significantly impact motor changes over time. Recent work suggested that disabilities arise not only from focal structural changes but also from widespread alterations in inter-regional connectivity. Models that consider damage to the entire network instead of only local structural alterations lead to a more accurate prediction of patients' recovery. However, assessing white matter connections in stroke patients is challenging and time-consuming. Here, we evaluated in a data set of 37 patients whether we could predict upper extremity motor recovery from brain connectivity measures obtained by using the patient's lesion mask to introduce virtual lesions in 60 healthy streamline tractography connectomes. This indirect estimation of the stroke impact on the whole brain connectome is more readily available than direct measures of structural connectivity obtained with magnetic resonance imaging. We added these measures to benchmark structural features, and we used a ridge regression regularization to predict motor recovery at 3 months post-injury. As hypothesized, accuracy in prediction significantly increased (R 2 = 0.68) as compared to benchmark features (R 2 = 0.38). This improved prediction of recovery could be beneficial to clinical care and might allow for a better choice of intervention.

Abstract 7: Prediction Of Post-stroke Motor Recovery Benefits From Measures Of Sub-acute Widespread Network Damages

Background: Following an acute ischemic stroke, some patients recover almost completely, while others barely recover. It is known that lesion volume, initial motor impairment, and cortico-spinal tract asymmetry (benchmark features) significantly impact motor changes over time. However, accurate prediction models of patients’ recovery are still missing. Recent work suggested that disabilities arise not only from focal structural changes, but also from widespread alterations in inter-regional connectivity. Here, we built on this hypothesis to develop a more accurate post-stroke motor recovery prediction model. Methods: We evaluated a dataset of 37 patients (17 women) with upper extremity motor strokes. Their impairment was assessed at 2 weeks (baseline) and 3 months after the stroke using the Fugl-Meyer-Assessment. 18 graph measures of global structural connectivity were obtained using the patients’ T2 lesion mask to virtually reproduce the lesions in 60 healthy streamline tractography connectomes. We added these indirect measures to the benchmark features, and we used a ridge regression regularization in a leave-one-out cross-validation framework to predict motor recovery at 3 months post-injury. Results: Accuracy in prediction significantly increased when using brain connectivity measures (R 2 =0.68, 95% CI: 0.64-0.74) as compared to benchmark features alone (R 2 =0.38, 95% CI: 0.31-0.51). Conclusion: We reported that global measures of brain connectivity estimated by introducing virtual lesions in healthy structural connectomes significantly increase the accuracy of motor recovery prediction in stroke patients compared to focal and clinical measures used until now. This indirect estimation of the stroke impact on the whole brain connectome is more readily available than direct measures of structural connectivity obtained with magnetic resonance imaging (MRI) and would, therefore, have a more substantial clinical impact.

Longitudinal changes in global structural brain connectivity and cognitive performance in former hospitalized COVID-19 survivors: an exploratory study

BackgroundLong-term sequelae of COVID-19 can result in reduced functionality of the central nervous system and substandard quality of life. Gaining insight into the recovery trajectory of admitted COVID-19 patients on their cognitive performance and global structural brain connectivity may allow a better understanding of the diseases' relevance.ObjectivesTo assess whole-brain structural connectivity in former non-intensive-care unit (ICU)- and ICU-admitted COVID-19 survivors over 2 months following hospital discharge and correlate structural connectivity measures to cognitive performance.MethodsParticipants underwent Magnetic Resonance Imaging brain scans and a cognitive test battery after hospital discharge to evaluate structural connectivity and cognitive performance. Multilevel models were constructed for each graph measure and cognitive test, assessing the groups' influence, time since discharge, and interactions. Linear regression models estimated whether the graph measurements affected cognitive measures and whether they differed between ICU and non-ICU patients.ResultsSix former ICU and six non-ICU patients completed the study. Across the various graph measures, the characteristic path length decreased over time (β = 0.97, p = 0.006). We detected no group-level effects (β = 1.07, p = 0.442) nor interaction effects (β = 1.02, p = 0.220). Cognitive performance improved for both non-ICU and ICU COVID-19 survivors on four out of seven cognitive tests 2 months later (p < 0.05).ConclusionAdverse effects of COVID-19 on brain functioning and structure abate over time. These results should be supported by future research including larger sample sizes, matched control groups of healthy non-infected individuals, and more extended follow-up periods.

Reproducibility of regional structural and functional MRI networks in cerebral small vessel disease compared to age matched and stroke-free controls.

Abnormalities in structural and functional MRI connectivity measures have been reported in cerebral small vessel disease (SVD). Previous research has shown that whole-brain structural connectivity was highly reproducible in SVD patients, while whole-brain functional connectivity showed low reproducibility. It remains unclear whether the lower reproducibility of functional networks reported in SVD is due to selective disruption of reproducibility in specific networks or is generalised in patients with SVD. In this case-control study 15 SVD and 10 age-matched control participants were imaged twice with diffusion tensor imaging and resting state fMRI. Structural and functional connectivity matrices were constructed from this data and the default mode, fronto-parietal, limbic, salience, somatomotor and visual networks were extracted and the average connectivity between connections calculated and used to determine their reproducibility. Regional structural networks were more reproducible than functional networks, all structural networks showed ICC values ≥0.64 (except the salience network in SVD). The functional networks showed greater reproducibility in the controls compared to SVD with ICC values >0.7 for control participants and <=0.5 for the SVD group. The default mode network showed the greatest reproducibility for both control and SVD groups. Reproducibility of functional networks was affected by disease status with lower reproducibility in SVD compared with controls.

Outcomes of Babies with Opioid Exposure (OBOE): protocol of a prospective longitudinal cohort study

BackgroundWhile the health, social, and economic impacts of opioid addiction on adults and their communities are well known, the impact of maternal opioid use on the fetus exposed in utero is less well understood.MethodsThis paper presents the protocol of the ACT NOW Outcomes of Babies with Opioid Exposure (OBOE) Study, a multi-site prospective longitudinal cohort study of infants with antenatal opioid exposure and unexposed controls. Study objectives are to determine the impact of antenatal opioid exposure on brain development and neurodevelopmental outcomes over the first 2 years of life and explore whether family, home, and community factors modify developmental trajectories during this critical time period.ResultsPrimary outcomes related to brain development include cortical volumes, deep cerebral gray matter volumes, resting-state functional connectivity measures, and structural connectivity measures using diffusion tensor imaging. Primary neurodevelopmental outcomes include visual abnormalities, cognitive, language, and motor skills measured using the Bayley Scales of Infant Development and social–emotional and behavioral problems and competence measured by the Brief Infant-Toddler Social and Emotional Assessment.ConclusionsThe OBOE study has been designed to overcome challenges of previous studies and will help further understanding of the effects of antenatal opioid exposure on early infant development.ImpactThis study will integrate MRI findings and comprehensive neurodevelopmental assessments to provide early insights into the functional topography of the brain in this high-risk population and assess MRI as a potential biomarker.Rather than conducting neuroimaging at a single time point, the study will include serial MRI assessments from birth to 2 years, allowing for the examination of trajectories throughout this period of rapid brain development.While previous studies often have had limited information on exposures, this study will use umbilical cord assays to accurately measure amounts of opioids and other substances from 20 weeks of gestation to birth.

Neurofilament light-associated connectivity in young-adult Huntington's disease is related to neuronal genes.

Upregulation of functional network connectivity in the presence of structural degeneration is seen in the premanifest stages of Huntington's disease (preHD) 10-15 years from clinical diagnosis. However, whether widespread network connectivity changes are seen in gene carriers much further from onset has yet to be explored. We characterized functional network connectivity throughout the brain and related it to a measure of disease pathology burden (CSF neurofilament light, NfL) and measures of structural connectivity in asymptomatic gene carriers, on average 24 years from onset. We related these measurements to estimates of cortical and subcortical gene expression. We found no overall differences in functional (or structural) connectivity anywhere in the brain comparing control and preHD participants. However, increased functional connectivity, particularly between posterior cortical areas, correlated with increasing CSF NfL level in preHD participants. Using the Allen Human Brain Atlas and expression-weighted cell-type enrichment analysis, we demonstrated that this functional connectivity upregulation occurred in cortical regions associated with regional expression of genes specific to neuronal cells. This relationship was validated using single-nucleus RNAseq data from post-mortem Huntington's disease and control brains showing enrichment of neuronal-specific genes that are differentially expressed in Huntington's disease. Functional brain networks in asymptomatic preHD gene carriers very far from disease onset show evidence of upregulated connectivity correlating with increased disease burden. These changes occur among brain areas that show regional expression of genes specific to neuronal GABAergic and glutamatergic cells.

An integrated approach to support a river ecological network: A case study from the Mediterranean

Riverine ecosystems are among the most impacted ecosystems worldwide since they are exposed to multiple stressors. Land Use/Land Cover (LULC) changes is the main human imprint on those ecosystems whose spatiotemporal habitat destructions pose a threat to biodiversity, ecosystem integrity and ecological processes. The most important statutory instruments for riverine ecosystem protection, conservation and restoration in the European Union are the Water Framework Directive (WFD) and the Habitats and Birds Directive (HBDs). In this study, we develop a methodological framework to spatially link the ecological integrity of river sub-basins with the protected areas therein, taking into account the influence of land use as expressed in the WFD. We combined a multi-criteria evaluation approach using six of the most frequently applied criteria for conservation evaluation to assess river basin integrity (RBI) index at the sub-basin level, and used as a proxy for functional connectivity categories. In addition, we used the distance of every sub-basin from the surrounding Natura 2000 sites as a measure of structural connectivity. Using ecological network design principles (i.e. Core areas; Corridors; Stepping Stones; Buffer areas; and Restoration areas), we incorporated the two aspects of connectivity into a framework, which links river management at the basin level with the site level assessment as dictated by the HBDs. We implemented this framework in a Mediterranean river basin located in Southern Tuscany, which is part of the Natura 2000 network. Six of the sub-basins (20%) have high functional connectivity, 14 sub-basins (47%) medium and 10 sub-basins (33%) low functional connectivity. Structural connectivity of the study area followed the same tendency as that of functional connectivity, with the majority of the sub-basins having medium connectivity (57%; 17 sub-basins), and 23% (7 sub-basins) and 20% (6 sub-basins) high and low structural connectivity respectively. As a result, six of the sub-basins were characterised as corridor areas while the majority of the sub-basins were identified as buffer areas (57%). Two sub-basins were characterised restoration areas and one as stepping stone (SS). Our approach is one of many plausible ecological networks, which although analytically simple, can be enriched with data on species and stakeholders’ involvement.

Mapping of Structure-Function Age-Related Connectivity Changes on Cognition Using Multimodal MRI

The relationship between age-related changes in brain structural connectivity (SC) and functional connectivity (FC) with cognition is not well understood. Furthermore, it is not clear whether cognition is represented via a similar spatial pattern of FC and SC or instead is mapped by distinct sets of distributed connectivity patterns. To this end, we used a longitudinal, within-subject, multimodal approach aiming to combine brain data from diffusion-weighted MRI (DW-MRI), and functional MRI (fMRI) with behavioral evaluation, to better understand how changes in FC and SC correlate with changes in cognition in a sample of older adults. FC and SC measures were derived from the multimodal scans acquired at two time points. Change in FC and SC was correlated with 13 behavioral measures of cognitive function using Partial Least Squares Correlation (PLSC). Two of the measures indicate an age-related change in cognition and the rest indicate baseline cognitive performance. FC and SC—cognition correlations were expressed across several cognitive measures, and numerous structural and functional cortical connections, mainly cingulo-opercular, dorsolateral prefrontal, somatosensory and motor, and temporo-parieto-occipital, contributed both positively and negatively to the brain-behavior relationship. Whole-brain FC and SC captured distinct and independent connections related to the cognitive measures. Overall, we examined age-related function-structure associations of the brain in a comprehensive and integrated manner, using a multimodal approach. We pointed out the behavioral relevance of age-related changes in FC and SC. Taken together, our results highlight that the heterogeneity in distributed FC and SC connectivity patterns provide unique information about the variable nature of healthy cognitive aging.