Functional connectivity-hemodynamic (un)coupling changes in chronic mild brain injury are associated with mental health and neurocognitive indices: a resting state fMRI study.

PURPOSE: To examine hemodynamic and functional connectivity alterations and their association with neurocognitive and mental health indices in patients with chronic mild traumatic brain injury (mTBI). METHODS: Resting-state functional MRI (rs-fMRI) and neuropsychological assessment of 37 patients with chronic mTBI were performed. Intrinsic connectivity contrast (ICC) and time-shift analysis (TSA) of the rs-fMRI data allowed the assessment of regional hemodynamic and functional connectivity disturbances and their coupling (or uncoupling). Thirty-nine healthy age- and gender-matched participants were also examined. RESULTS: Patients with chronic mTBI displayed hypoconnectivity in bilateral hippocampi and parahippocampal gyri and increased connectivity in parietal areas (right angular gyrus and left superior parietal lobule (SPL)). Slower perfusion (hemodynamic lag) in the left anterior hippocampus was associated with higher self-reported symptoms of depression (r = - 0.53, p = .0006) and anxiety (r = - 0.484, p = .002), while faster perfusion (hemodynamic lead) in the left SPL was associated with lower semantic fluency (r = - 0.474, p = .002). Finally, functional coupling (high connectivity and hemodynamic lead) in the right anterior cingulate cortex (ACC)) was associated with lower performance on attention and visuomotor coordination (r = - 0.50, p = .001), while dysfunctional coupling (low connectivity and hemodynamic lag) in the left ventral posterior cingulate cortex (PCC) and right SPL was associated with lower scores on immediate passage memory (r = - 0.52, p = .001; r = - 0.53, p = .0006, respectively). Uncoupling in the right extrastriate visual cortex and posterior middle temporal gyrus was negatively associated with cognitive flexibility (r = - 0.50, p = .001). CONCLUSION: Hemodynamic and functional connectivity differences, indicating neurovascular (un)coupling, may be linked to mental health and neurocognitive indices in patients with chronic mTBI.

Distinct hemodynamic and functional connectivity features of fatigue in clinically isolated syndrome and multiple sclerosis: accounting for the confounding effect of concurrent depression symptoms.

PURPOSE: This study aims to identify common and distinct hemodynamic and functional connectivity (FC) features for self-rated fatigue and depression symptoms in patients with clinically isolated syndrome (CIS) and relapsing-remitting multiple sclerosis (RR-MS). METHODS: Twenty-four CIS, 29 RR-MS patients, and 39 healthy volunteers were examined using resting-state fMRI (rs-fMRI) to obtain whole-brain maps of (i) hemodynamic response patterns (through time shift analysis), (ii) FC (via intrinsic connectivity contrast maps), and (iii) coupling between hemodynamic response patterns and FC. Each regional map was correlated with fatigue scores, controlling for depression, and with depression scores, controlling for fatigue. RESULTS: In CIS patients, the severity of fatigue was associated with accelerated hemodynamic response in the insula, hyperconnectivity of the superior frontal gyrus, and evidence of reduced hemodynamics-FC coupling in the left amygdala. In contrast, depression severity was associated with accelerated hemodynamic response in the right limbic temporal pole, hypoconnectivity of the anterior cingulate gyrus, and increased hemodynamics-FC coupling in the left amygdala. In RR-MS patients, fatigue was associated with accelerated hemodynamic response in the insula and medial superior frontal cortex, increased functional role of the left amygdala, and hypoconnectivity of the dorsal orbitofrontal cortex, while depression symptom severity was linked to delayed hemodynamic response in the medial superior frontal gyrus; hypoconnectivity of the insula, ventromedial thalamus, dorsolateral prefrontal cortex, and posterior cingulate; and decreased hemodynamics-FC coupling of the medial orbitofrontal cortex. CONCLUSION: There are distinct FC and hemodynamic responses, as well as different magnitude and topography of hemodynamic connectivity coupling, associated with fatigue and depression in early and later stages of MS.

Action Observation Responses Are Influenced by Movement Kinematics and Target Identity.

In order to inform the debate whether cortical areas related to action observation provide a pragmatic or a semantic representation of goal-directed actions, we performed 2 functional magnetic resonance imaging (fMRI) experiments in humans. The first experiment, involving observation of aimless arm movements, resulted in activation of most of the components known to support action execution and action observation. Given the absence of a target/goal in this experiment and the activation of parieto-premotor cortical areas, which were associated in the past with direction, amplitude, and velocity of movement of biological effectors, our findings suggest that during action observation we could be monitoring movement kinematics. With the second, double dissociation fMRI experiment, we revealed the components of the observation-related cortical network affected by 1) actions that have the same target/goal but different reaching and grasping kinematics and 2) actions that have very similar kinematics but different targets/goals. We found that certain areas related to action observation, including the mirror neuron ones, are informed about movement kinematics and/or target identity, hence providing a pragmatic rather than a semantic representation of goal-directed actions. Overall, our findings support a process-driven simulation-like mechanism of action understanding, in agreement with the theory of motor cognition, and question motor theories of action concept processing.

Converging evidence of impaired brain function in systemic lupus erythematosus: changes in perfusion dynamics and intrinsic functional connectivity.

PURPOSE: Τhe study examined changes in hemodynamics and functional connectivity in patients with systemic lupus erythematosus (SLE) with or without neuropsychiatric manifestations. METHODS: Participants were 44 patients with neuropsychiatric SLE (NPSLE), 20 SLE patients without such manifestations (non-NPSLE), and 35 healthy controls. Resting-state functional MRI (rs-fMRI) was used to obtain whole-brain maps of (a) perfusion dynamics derived through time shift analysis (TSA), (b) regional functional connectivity (intrinsic connectivity contrast (ICC) coefficients), and (c) hemodynamic-connectivity coupling. Group differences were assessed through independent samples t-tests, and correlations of rs-fMRI indices with clinical variables and neuropsychological test scores were, also, computed. RESULTS: Compared to HC, NPSLE patients demonstrated intrinsic hypoconnectivity of anterior Default Mode Network (DMN) and hyperconnectivity of posterior DMN components. These changes were paralleled by elevated hemodynamic lag. In NPSLE, cognitive performance was positively related to higher intrinsic connectivity in these regions, and to higher connectivity-hemodynamic coupling in posterior DMN components. Uncoupling between hemodynamics and connectivity in the posterior DMN was associated with worse task performance. Non-NPSLE patients displayed hyperconnectivity in posterior DMN and sensorimotor regions paralleled by relatively increased hemodynamic lag. CONCLUSION: Adaptation of regional brain function to hemodynamic changes in NPSLE may involve locally decreased or locally increased intrinsic connectivity (which can be beneficial for cognitive function). This process may also involve elevated coupling of hemodynamics with functional connectivity (beneficial for cognitive performance) or uncoupling, which may be detrimental for the cognitive skills of NPSLE patients.

Introduction of a new simple dynamic phantom for physical BOLD effect simulation.

OBJECTIVE: To propose a new method of simulating the BOLD contrast using a dynamic, easy to construct and operate, low-cost physical phantom. MATERIALS AND METHODS: A structure of thin pipelines passing through a gel volume was used to simulate blood vessels in human tissue. Quantitative T2*, R2* measurements were used to study the signal change of the phantom. BOLD fMRI experiments and analysis were performed to evaluate its potential use as an fMRI simulator. RESULTS: Experimental T2*, R2* measurements showed similar behavior with published references. BOLD contrast was successfully achieved with the proposed method. In addition, there were several proposed parameters, like the angle of the phantom relative to B0, which can easily adjust the signal change and the activation area. Coefficients of variation showed good reproducibility within a month period. Statistical t maps were produced with in-house software for the BOLD measurements. DISCUSSION: T2*maps and BOLD images confirm the potential use of this phantom as an fMRI simulator and also as a tool for studying sensitivity and specificity of BOLD sequences/algorithms.

Extraocular Muscle Volumetry for Assessment of Thyroid Eye Disease.

BACKGROUND: In this study we evaluate the diagnostic accuracy of extraocular muscle volumetry in detecting thyroid eye disease and to compare the results with simple measurements of maximal medial rectus (MR) diameter. METHODS: Cross-sectional study that included 47 eyes of 47 patients with thyroid eye disease and 47 healthy controls. Patients underwent slitlamp examination and imaging consisting of computed tomography scans. Image segmentation and volume measurements were performed by 2 independent researchers. Intraobserver and interobserver reliability testing was also conducted. RESULTS: Total extraocular muscle volume was 7.31 ± 1.88 cm3 and medial volume was 2.38 ± 0.73 cm3 in the study group. In this group, the maximum measured diameter of the MR was 6.67 ± 0.35 mm. MR volume was statistically associated with maximum MR diameter (r = 9.78; P < 0.001). Both MR volume and maximum MR diameter measurements showed good predictive efficacy as shown using receiver operator characteristic curve analysis. CONCLUSIONS: Complications of thyroid eye disease are often sight threatening, and timely diagnosis is crucial for the management of the entity and its sequelae. The results of this study imply that simple measurements of maximum MR diameter are sensitive enough to establish diagnosis.

T2 Relaxometry Evidence of Microstructural Changes in Diffusely Abnormal White Matter in Relapsing-Remitting Multiple Sclerosis and Clinically Isolated Syndrome: Impact on Visuomotor Performance.

BACKGROUND: Although diffusely abnormal white matter (DAWM) is commonly seen in multiple sclerosis (MS), it is rarely considered in clinical/imaging studies. PURPOSE: To evaluate quantitative markers of microstructural changes in DAWM of patients with clinically isolated syndrome (CIS) and relapsing-remitting MS (RR-MS) in relation to MS lesions and degree of neurocognitive impairment, by using a multi-echo spin echo (MESE) Proton Density PD-to-T2 sequence. STUDY TYPE: Prospective, cross-sectional. POPULATION: Thirty-seven RR-MS patients, 33 CIS patients, and 52 healthy controls. FIELD STRENGTH/SEQUENCE: 1.5 T/T1-, T2-weighted, fluid-attenuated inversion recovery, and MESE sequences. ASSESSMENT: Long T2, short T2, and myelin water fraction (MWF) values were estimated as indices of intra/extracellular water content and myelin content, respectively, in DAWM, posterior periventricular normal appearing white matter (NAWM), and focal MS lesions, classified according to their signal intensity on T1 sequences. Patients were, also, administered a battery of neuropsychological tests. STATISTICAL TESTS: Comparisons of T2 and MWF values in DAWM, NAWM, and MS lesions were examined, using two-way mixed analyses of variance. Associations of Grooved Pegboard performance with T2 and MWF values in DAWM and NAWM were assessed using Pearson correlation coefficients. RESULTS: T2 and MWF values of DAWM were intermediate between the respective values of NAWM and T1 hypointense focal lesions, while there was no difference between the respective values of DAWM and T1-isointense lesions. T2 values in DAWM were strongly associated with visuomotor performance in CIS patients. DATA CONCLUSION: Intra/extracellular water and myelin water content of DAWM are similar to those of T1-isointense lesions and predict visuomotor performance in CIS patients. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 2.

Age-related deep white matter changes in myelin and water content: A T2 relaxometry study.

BACKGROUND: According to the retrogenesis hypothesis, the rate of age-related changes in white matter (WM) myelin content varies between early myelinating (parietal, occipital) and late myelinating (prefrontal, lateral-posterior temporal) areas. The multiecho spin echo (MESE), PD-to-T2 -weighted sequence provides an index of myelin content (myelin water fraction [MWF]) derived from measurements of myelin water (via the short T2 component [10-50 msec]) and intra- and extracellular water (via the long T2 component [>50-200 msec]). PURPOSE: To assess the shape and regional variations in the rate of age-related myelin and water content changes in deep WM regions using the MESE sequence. STUDY TYPE: Prospective, cross-sectional. POPULATION: In all, 90 healthy adults aged 22-81 years. FIELD STRENGTH/SEQUENCE: 1.5T/ T1 w, T2 w, fluid attenuated inversion recovery (FLAIR), MESE sequences. ASSESSMENT: Short T2 , long T2 , and MWF values were measured in prefrontal, parietal, lateral-posterior temporal, and occipital normal-appearing WM (NAWM) areas. STATISTICAL TESTS: Linear and quadratic effects of age on long T2 and MWF were assessed through regression analyses. Regional variations in the effect of age on long T2 and MWF values at both the individual and group level were examined, using regression and analysis of covariance (ANCOVA) analyses, respectively, controlling for total WM volume. RESULTS: The rate of age-related changes in long T2 and MWF was higher for older persons and a significant increase or decline, respectively, was first noted at 60-69 years (P < 0.0033). MWF values peaked earlier (at 30 years of age) and displayed a steeper age-related reduction in prefrontal and lateral-posterior temporal NAWM as compared with the occipital lobes (P < 0.05). The opposite pattern of age-related effect was found for long T2 values. DATA CONCLUSION: Significant age-related reductions in myelin content were closely followed by corresponding increases in intra- and extracellular water content. These changes were more pronounced among elderly people and followed an anterior-posterior pattern. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;50:1393-1404.

Ex vivo orbital volumetry using stereology and CT imaging: A comparison with manual planimetry.

OBJECTIVES: To evaluate the applicability of stereology and planimetry in orbital volume measurements using computed tomography (CT) and to compare the results between the two measurements. METHODS: Experimental study using sheep craniums for CT imaging. Water filling measurements were performed, as the validation technique. Quantification techniques were also evaluated in five human subjects. To examine the proportion of agreement among measurements, we tested intra- and inter-observer agreement. RESULTS: For stereology customization, a 1/8 systematic sampling scheme was considered as optimal; this resulted in a low coefficient of error (2.59 %) and low measurement time (1.9 mins). In sheep craniums, mean volume measured by water displacement, planimetry and stereology was 17.81 ± 0.59 cm3, 17.87 ± 0.68 cm3 and 17.54 ± 0.49 cm3, respectively. Total volumes, obtained by stereology, were highly correlated with the water-filling method (r=0.893; p = 0.001) and a paired t-test showed significant difference between methods (t=3.047; p = 0.014). Planimetry results displayed a high correlation with the water-filling method (r=0.957; p ≈ 0.001) but no statistically significant difference was found (p = 0.154). Mean difference using planimetry and stereology was 0.332 ± 0.322 cm3. In human subjects, using stereology, the estimated volume ranged between 18.57 cm3 and 19.27 cm3, and the mean orbital volume was 19.05 ± 0.50 cm3 with CE=3.75 ± 0.16 %. Mean measure time was 2.1 ± 0.1 mins. CONCLUSIONS: Stereological measurements were superior to manual planimetry in terms of user effort and time spent. Stereology sampling of 1/8 was successfully applied in human subjects and yielded a strong correlation with manual planimetry. KEY POINTS: • Stereology can be applied to measure the orbital volume using computed tomography. • Stereological measurements display high correlation with gold standard planimetry and combine low coefficient of error (2.59%) with low measurement time (1.9 min). • Stereology is superior in terms of user effort and time spent.

Neuropsychiatric lupus or not? Cerebral hypoperfusion by perfusion-weighted MRI in normal-appearing white matter in primary neuropsychiatric lupus erythematosus.

OBJECTIVES: Cerebral perfusion abnormalities have been reported in systemic lupus erythematosus (SLE) but their value in distinguishing lupus from non-lupus-related neuropsychiatric events remains elusive. We examined whether dynamic susceptibility contrast-enhanced perfusion MRI (DSC-MRI), a minimally invasive and widely available method of cerebral perfusion assessment, may assist neuropsychiatric SLE (NPSLE) diagnosis. METHODS: In total, 76patients with SLE (37 primary NPSLE, 16 secondary NPSLE, 23 non-NPSLE) and 31 healthy controls underwent conventional MRI (cMRI) and DSC-MRI. Attribution of NPSLE to lupus or not was based on multidisciplinary assessment including cMRI results and response to treatment. Cerebral blood volume and flow were estimated in 18 normal-appearing white and deep grey matter areas. RESULTS: The most common manifestations were mood disorder, cognitive disorder and headache. Patients with primary NPSLE had lower cerebral blood flow and volume in several normal-appearing white matter areas compared with controls (P<0.0001) and lower cerebral blood flow in the semioval centre bilaterally, compared with non-NPSLE and patients with secondary NPSLE (P<0.001). A cut-off for cerebral blood flow of 0.77 in the left semioval centre discriminated primary NPSLE from non-NPSLE/secondary NPSLE with 80% sensitivity and 67%-69% specificity. Blood flow values in the left semioval centre showed substantially higher sensitivity than cMRI (81% vs 19%-24%) for diagnosing primary NPSLE with the combination of the two modalities yielding 94%-100% specificity in discriminating primary from secondary NPSLE. CONCLUSION: Primary NPSLE is characterised by significant hypoperfusion in cerebral white matter that appears normal on cMRI. The combination of DSC-MRI-measured blood flow in the brain semioval centre with conventional MRI may improve NPSLE diagnosis.

Myelin content changes in probable Alzheimer's disease and mild cognitive impairment: Associations with age and severity of neuropsychiatric impairment.

BACKGROUND: Existing indices of white matter integrity such as fractional anisotropy and magnetization transfer ratio may not provide optimal specificity to myelin content. In contrast, myelin water fraction (MWF) derived from the multiecho T2 relaxation time technique may serve as a more direct measure of myelin content. PURPOSE/HYPOTHESIS: The goal of the present study was to identify markers of regional demyelination in patients with probable Alzheimer's disease (AD) and mild cognitive impairment (MCI) in relation to age and severity of neuropsychiatric impairment. POPULATION: The sample included patients diagnosed with probable AD (n = 25) or MCI (n = 43), and cognitively intact elderly controls (n = 33). FIELD STRENGTH/SEQUENCE ASSESSMENT: Long T2 , short T2 , and MWF values were measured with a 1.5T scanner in periventricular and deep normal-appearing white matter (NAWM), serving as indices of intra/extracellular water content and myelin content. A comprehensive neuropsychological and neuropsychiatric assessment was administered to all participants. STATISTICAL TESTS, RESULTS: AD patients displayed higher age-adjusted long and short T2 values and reduced MWF values in left temporal/parietal and bilateral periventricular NAWM than controls and MCI patients (P < 0.004; one-way analysis of covariance [ANCOVA] tests). Short T2 /MWF values in temporal, frontal, and periventricular NAWM of controls and/or MCI patients were significantly associated with episodic and semantic memory performance and depressive symptomatology (P < 0.004; partial correlation indices). The impact of age on memory performance was significantly (P < 0.01; mediated linear regression analyses) mediated by age-related changes in short T2 and MWF values in these regions. DATA CONCLUSION: Age-related demyelination is associated with memory impairment (especially in prodromal dementia states) and symptoms of depression in an anatomically specific manner. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2018;47:1359-1372.

Neural foundations of overt and covert actions.

We used fMRI to assess the human brain areas activated for execution, observation and 1st person motor imagery of a visually guided tracing task with the index finger. Voxel-level conjunction analysis revealed several cortical areas activated in common across all three motor conditions, namely, the upper limb representation of the primary motor and somatosensory cortices, the dorsal and ventral premotor, the superior and inferior parietal cortices as well as the posterior part of the superior and middle temporal gyrus including the temporo-parietal junction (TPj) and the extrastriate body area (EBA). Functional connectivity analyses corroborated the notion that a common sensory-motor fronto-parieto-temporal cortical network is engaged for execution, observation, and imagination of the very same action. Taken together these findings are consistent with the more parsimonious account of motor cognition provided by the mental simulation theory rather than the recently revised mirror neuron view Action imagination and observation were each associated with several additional functional connections, which may serve the distinction between overt action and its covert counterparts, and the attribution of action to the correct agent. For example, the central position of the right middle and inferior frontal gyrus in functional connectivity during motor imagery may reflect the suppression of movements during mere imagination of action, and may contribute to the distinction between 'imagined' and 'real' action. Also, the central role of the right EBA in observation, assessed by functional connectivity analysis, may be related to the attribution of action to the 'external agent' as opposed to the 'self'.

The current status of noninvasive intracranial pressure monitoring: A literature review.

Elevated intracranial pressure (ICP) is a life-threatening condition that must be promptly diagnosed. However, the gold standard methods for ICP monitoring are invasive, time-consuming, and they involve certain risks. To address these risks, many noninvasive approaches have been proposed. This study undertakes a literature review of the existing noninvasive methods, which have reported promising results. The experimental base on which they are established, however, prevents their application in emergency conditions and thus none of them are capable of replacing the traditional invasive methods to date. On the other hand, contemporary methods leverage Machine Learning (ML) which has already shown unprecedented results in several medical research areas. That said, only a few publications exist on ML-based approaches for ICP estimation, which are not appropriate for emergency conditions due to their restricted capability of employing the medical imaging data available in intensive care units. The lack of such image-based ML models to estimate ICP is attributed to the scarcity of annotated datasets requiring directly measured ICP data. This ascertainment highlights an active and unexplored scientific frontier, calling for further research and development in the field of ICP estimation, particularly leveraging the untapped potential of ML techniques.

Altered hippocampal connectivity dynamics predicts memory performance in neuropsychiatric lupus: a resting-state fMRI study using cross-recurrence quantification analysis.

OBJECTIVE: Τo determine whole-brain and regional functional connectivity (FC) characteristics of patients with neuropsychiatric SLE (NPSLE) or without neuropsychiatric manifestations (non-NPSLE) and examine their association with cognitive performance. METHODS: Cross-recurrence quantification analysis (CRQA) of resting-state functional MRI (rs-fMRI) data was performed in 44 patients with NPSLE, 20 patients without NPSLE and 35 healthy controls (HCs). Volumetric analysis of total brain and specific cortical and subcortical regions, where significant connectivity changes were identified, was performed. Cognitive status of patients with NPSLE was assessed by neuropsychological tests. Group comparisons on nodal FC, global network metrics and regional volumetrics were conducted, and associations with cognitive performance were estimated (at p<0.05 false discovery rate corrected). RESULTS: FC in patients with NPSLE was characterised by increased modularity (mean (SD)=0.31 (0.06)) as compared with HCs (mean (SD)=0.27 (0.06); p=0.05), hypoconnectivity of the left (mean (SD)=0.06 (0.018)) and right hippocampi (mean (SD)=0.051 (0.0.16)), and of the right amygdala (mean (SD)=0.091 (0.039)), as compared with HCs (mean (SD)=0.075 (0.022), p=0.02; 0.065 (0.019), p=0.01; 0.14 (0.096), p=0.05, respectively). Hyperconnectivity of the left angular gyrus (NPSLE/HCs: mean (SD)=0.29 (0.26) and 0.10 (0.09); p=0.01), left (NPSLE/HCs: mean (SD)=0.16 (0.09) and 0.09 (0.05); p=0.01) and right superior parietal lobule (SPL) (NPSLE/HCs: mean (SD)=0.25 (0.19) and 0.13 (0.13), p=0.01) was noted in NPSLE versus HC groups. Among patients with NPSLE, verbal episodic memory scores were positively associated with connectivity (local efficiency) of the left hippocampus (r2=0.22, p=0.005) and negatively with local efficiency of the left angular gyrus (r2=0.24, p=0.003). Patients without NPSLE displayed hypoconnectivity of the right hippocampus (mean (SD)=0.056 (0.014)) and hyperconnectivity of the left angular gyrus (mean (SD)=0.25 (0.13)) and SPL (mean (SD)=0.17 (0.12)). CONCLUSION: By using dynamic CRQA of the rs-fMRI data, distorted FC was found globally, as well as in medial temporal and parietal brain regions in patients with SLE, that correlated significantly and adversely with memory capacity in NPSLE. These results highlight the value of dynamic approaches to assessing impaired brain network function in patients with lupus with and without neuropsychiatric symptoms.

Chronic Mild Traumatic Brain Injury: Aberrant Static and Dynamic Connectomic Features Identified Through Machine Learning Model Fusion.

Traumatic Brain Injury (TBI) is a frequently occurring condition and approximately 90% of TBI cases are classified as mild (mTBI). However, conventional MRI has limited diagnostic and prognostic value, thus warranting the utilization of additional imaging modalities and analysis procedures. The functional connectomic approach using resting-state functional MRI (rs-fMRI) has shown great potential and promising diagnostic capabilities across multiple clinical scenarios, including mTBI. Additionally, there is increasing recognition of a fundamental role of brain dynamics in healthy and pathological cognition. Here, we undertake an in-depth investigation of mTBI-related connectomic disturbances and their emotional and cognitive correlates. We leveraged machine learning and graph theory to combine static and dynamic functional connectivity (FC) with regional entropy values, achieving classification accuracy up to 75% (77, 74 and 76% precision, sensitivity and specificity, respectively). As compared to healthy controls, the mTBI group displayed hypoconnectivity in the temporal poles, which correlated positively with semantic (r = 0.43, p < 0.008) and phonemic verbal fluency (r = 0.46, p < 0.004), while hypoconnectivity in the right dorsal posterior cingulate correlated positively with depression symptom severity (r = 0.54, p < 0.0006). These results highlight the importance of residual FC in these regions for preserved cognitive and emotional function in mTBI. Conversely, hyperconnectivity was observed in the right precentral and supramarginal gyri, which correlated negatively with semantic verbal fluency (r=-0.47, p < 0.003), indicating a potential ineffective compensatory mechanism. These novel results are promising toward understanding the pathophysiology of mTBI and explaining some of its most lingering emotional and cognitive symptoms.

Progressive Multifocal Leukoencephalopathy in Systemic Lupus Erythematosus: A Consequence of Patient-Intrinsic or -Extrinsic Factors?

Progressive multifocal leukoencephalopathy (PML) is a severe demyelinating disease of the central nervous system (CNS) caused by reactivation of the polyomavirus JC (JCV) typically in immunocompromised individuals. The risk of PML among rheumatic diseases may be higher for systemic lupus erythematosus (SLE), without, however, a clear association with the type and intensity of background therapy. We present the development and outcome of PML in a 32-year-old female lupus patient under mild immunosuppressive treatment, yet with marked B-cell lymphopenia in the peripheral blood and bone marrow (<1% of total lymphocytes). Despite treatment with the immune checkpoint inhibitor pembrolizumab, the patient showed progressive neurological and brain imaging deterioration and eventually died 15 months after PML diagnosis. To unveil possible underlying genetic liabilities, whole exome sequencing was performed which identified deleterious variants in GATA2 and CDH7 genes, which both have been linked to defective T- and/or B-lymphocyte production. These findings reiterate the possible role of disease-/patient-intrinsic factors, rather than that of drug-induced immunosuppression, in driving immune dysregulation and susceptibility to PML in certain patients with SLE.

White matter and deep gray matter hemodynamic changes in multiple sclerosis patients with clinically isolated syndrome.

The dynamic susceptibility contrast magnetic resonance imaging perfusion technique was used to investigate possible hemodynamic changes in normal appearing white matter and deep gray matter (DGM) of 30 patients with clinically isolated syndrome (CIS) and 30 patients with relapsing-remitting multiple sclerosis. Thirty normal volunteers were studied as controls. Cerebral blood volume, cerebral blood flow (CBF), and mean transit time values were estimated. Normalization was achieved for each subject with respect to average values of CBF and mean transit time of the hippocampi's dentate gyrus. Measurements concerned three regions of normal white matter of normal volunteers, normal appearing white matter of CIS and patients with relapsing-remitting multiple sclerosis, and DGM regions, bilaterally. All measured normal appearing white matter and DGM regions of the patients with CIS had significantly higher cerebral blood volume and mean transit time values, while averaged DGM regions had significantly lower CBF values, compared to those of normal volunteers (P < 0.001). Regarding patients with relapsing-remitting multiple sclerosis, all measured normal appearing white matter and DGM regions showed lower CBF values than those of normal volunteers and lower cerebral blood volume and CBF values compared to patients with CIS (P < 0.001). These data provide strong evidence that hemodynamic changes--affecting both white and DGM--may occur even at the earliest stage of multiple sclerosis, with CIS patients being significantly different than relapsing-remitting multiple sclerosis patients.

Multisubject Task-Related fMRI Data Processing via a Two-Stage Generalized Canonical Correlation Analysis.

Functional magnetic resonance imaging (fMRI) is one of the most popular methods for studying the human brain. Task-related fMRI data processing aims to determine which brain areas are activated when a specific task is performed and is usually based on the Blood Oxygen Level Dependent (BOLD) signal. The background BOLD signal also reflects systematic fluctuations in regional brain activity which are attributed to the existence of resting-state brain networks. We propose a new fMRI data generating model which takes into consideration the existence of common task-related and resting-state components. We first estimate the common task-related temporal component, via two successive stages of generalized canonical correlation analysis and, then, we estimate the common task-related spatial component, leading to a task-related activation map. The experimental tests of our method with synthetic data reveal that we are able to obtain very accurate temporal and spatial estimates even at very low Signal to Noise Ratio (SNR), which is usually the case in fMRI data processing. The tests with real-world fMRI data show significant advantages over standard procedures based on General Linear Models (GLMs).

Individualized dosimetry in Ru-106 ophthalmic brachytherapy based on MRI-derived ocular anatomical parameters.

PURPOSE: To estimate ocular geometry-related inaccuracies of the dosimetric plan in Ru-106 ophthalmic brachytherapy. METHODS AND MATERIALS: Thirty patients with intraocular lesions were treated with brachytherapy using a Ru-106 plaque-shell of inner radius of 12 mm. Magnetic resonance imaging was employed to determine the external scleral radius at tumor site and the tumor margins. A mathematical model was developed to determine the distance between the external sclera and the internal surface of the plaque associated with the tangential application of the plaque on the treated eye. Differences in delivered dose to the tumor apex, sclera and tumor margins as derived by considering the default eye-globe of standard size (external sclera radius = 12 mm) against the individual-specific eye globe were determined. RESULTS: The radius of external sclera at the tumor site was found to range between 10.90 and 13.05 mm for the patient cohort studied. When the patient specific eye-globe/tumor geometry is not taken into account, the delivered dose was found to be overestimated by 8.1% ± 4.1% (max = 15.3%) at tumor apex, by 1.5% ± 2.8% (max = 5.7%) at anterior tumor margin, by 16.6% ± 7.5% (max = 36.4%) at posterior tumor margin and 8.1% ± 3.8% (max = 13.2%) at central sclera of eyes with lower than the default radius. The corresponding dose overestimations for eyes with higher than the default radius was 13.5% ± 4.3% (max = 22.3%), 1.5% ± 2.8% (max = 5.7%), 12.6% ± 4.5% (max = 20.0%), and 15.1% ± 5.0% (max = 24.4%). CONCLUSIONS: The proposed patient-specific approach for Ru-106 brachytherapy treatment planning may improve dosimetric accuracy. Individualized treatment planning dosimetry may prevent undertreatment of intraocular tumors especially for highly myopic or hyperopic eyes.