Sleep deprivation changes frequency-specific functional organization of the resting human brain.

Previous resting-state functional magnetic resonance imaging (rs-fMRI) studies have widely explored the temporal connection changes in the human brain following long-term sleep deprivation (SD). However, the frequency-specific topological properties of sleep-deprived functional networks remain virtually unclear. In this study, thirty-seven healthy male subjects underwent resting-state fMRI during rested wakefulness (RW) and after 36 hours of SD, and we examined frequency-specific spectral connection changes (0.01-0.08 Hz, interval = 0.01 Hz) caused by SD. First, we conducted a multivariate pattern analysis combining linear SVM classifiers with a robust feature selection algorithm, and the results revealed that accuracies of 74.29%-84.29% could be achieved in the classification between RW and SD states in leave-one-out cross-validation at different frequency bands, moreover, the spectral connection at the lowest and highest frequency bands exhibited higher discriminative power. Connection involving the cingulo-opercular network increased most, while connection involving the default-mode network decreased most following SD. Then we performed a graph-theoretic analysis and observed reduced low-frequency modularity and high-frequency global efficiency in the SD state. Moreover, hub regions, which were primarily situated in the cerebellum and the cingulo-opercular network after SD, exhibited high discriminative power in the aforementioned classification consistently. The findings may indicate the frequency-dependent effects of SD on the functional network topology and its efficiency of information exchange, providing new insights into the impact of SD on the human brain.

Cortical mapping of callosal connections in healthy young adults.

The corpus callosum (CC) is the principal white matter bundle supporting communication between the two brain hemispheres. Despite its importance, a comprehensive mapping of callosal connections is still lacking. Here, we constructed the first bidirectional population-based callosal connectional atlas between the midsagittal section of the CC and the cerebral cortex of the human brain by means of diffusion-weighted imaging tractography. The estimated connectional topographic maps within this atlas have the most fine-grained spatial resolution, demonstrate histological validity, and were reproducible in two independent samples. This new resource, a complete and comprehensive atlas, will facilitate the investigation of interhemispheric communication and come with a user-friendly companion online tool (CCmapping) for easy access and visualization of the atlas.

Cognitive deficits and altered functional brain network organization in pediatric brain tumor patients.

Survivors of pediatric brain tumors experience significant cognitive deficits from their diagnosis and treatment. The exact mechanisms of cognitive injury are poorly understood, and validated predictors of long-term cognitive outcome are lacking. Resting state functional magnetic resonance imaging allows for the study of the spontaneous fluctuations in bulk neural activity, providing insight into brain organization and function. Here, we evaluated cognitive performance and functional network architecture in pediatric brain tumor patients. Forty-nine patients (7-18 years old) with a primary brain tumor diagnosis underwent resting state imaging during regularly scheduled clinical visits. All patients were tested with a battery of cognitive assessments. Extant data from 139 typically developing children were used as controls. We found that obtaining high-quality imaging data during routine clinical scanning was feasible. Functional network organization was significantly altered in patients, with the largest disruptions observed in patients who received propofol sedation. Awake patients demonstrated significant decreases in association network segregation compared to controls. Interestingly, there was no difference in the segregation of sensorimotor networks. With a median follow-up of 3.1 years, patients demonstrated cognitive deficits in multiple domains of executive function. Finally, there was a weak correlation between decreased default mode network segregation and poor picture vocabulary score. Future work with longer follow-up, longitudinal analyses, and a larger cohort will provide further insight into this potential predictor.

Altered resting-state functional connectivity of the brain in children with autism spectrum disorder.

Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders. Brain mapping has shown that functional brain connections are altered in autism. This study investigated the pattern of brain connection changes in autistic people compared to healthy people. This study aimed to analyze functional abnormalities within the brain due to ASD, using resting-state functional magnetic resonance imaging (fMRI). Resting-state functional magnetic resonance images of 26 individuals with ASD and 26 healthy controls were obtained from the Autism Brain Imaging Data Exchange (ABIDE) database. The DPARSF (data processing assistant for resting-state fMRI) toolbox was used for resting-state functional image processing, and features related to functional connections were extracted from these images. Then, the extracted features from both groups were compared using an Independent Two-Sample T Test, and the features with significant differences between the two groups were identified. Compared with healthy controls, individuals with ASD showed hyper-connectivity in the frontal lobe, anterior cingulum, parahippocampal, left precuneus, angular, caudate, superior temporal, and left pallidum, as well as hypo-connectivity in the precentral, left superior frontal, left middle orbitofrontal, right amygdala, and left posterior cingulum. Our findings show that abnormal functional connectivity exists in patients with ASD. This study makes an important advancement in our understanding of the abnormal neurocircuits causing autism.

Convergence of the arcuate fasciculus and third branch of the superior longitudinal fasciculus with direct cortical stimulation-induced speech arrest area in the anterior ventral precentral gyrus.

OBJECTIVE: The objective was to identify the correspondence between the anterior terminations of the arcuate fasciculus (AF) and third branch of the superior longitudinal fasciculus (SLF-III) and the intraoperative direct cortical electrical stimulation (DCS)-induced speech arrest area. METHODS: The authors retrospectively screened 75 glioma patients (group 1) who received intraoperative DCS mapping in the left dominant frontal cortex. To minimize the influence of tumors or edema, we subsequently selected 26 patients (group 2) with glioma or edema not affecting Broca's area, the ventral precentral gyrus (vPCG), and the subcortical pathways to generate DCS functional maps and to construct the anterior terminations of AF and SLF-III with tractography. Next, a grid-by-grid pairwise comparison was performed between the fiber terminations and the DCS-induced speech arrest sites to calculate Cohen's kappa coefficient (κ) in both groups 1 and 2. Finally, the authors also demonstrated the distribution of the AF/SLF-III anterior projection maps obtained in 192 healthy participants (group 3) and subsequently correlated these with the speech arrest sites in group 2 to examine their validity in predicting speech output area. RESULTS: The authors found that speech arrest sites were substantially consistent with SLF-III anterior terminations (group 1, κ = 0.64 ± 0.03; group 2, κ = 0.73 ± 0.05) and moderately consistent with AF (group 1, κ = 0.51 ± 0.03; group 2, κ = 0.49 ± 0.05) and AF/SLF-III complex (group 1, κ = 0.54 ± 0.03; group 2, κ = 0.56 ± 0.05) terminations (all p < 0.0001). The DCS speech arrest sites of the group 2 patients mainly (85.1%) emerged at the anterior bank of the vPCG (vPCGa). In group 3, both terminations of AF and SLF-III converged onto the vPCGa, and their terminations well predicted the DCS speech output area of group 2 (AF, area under the curve [AUC] 86.5%; SLF-III, AUC 79.0%; AF/SLF-III complex, AUC 86.7%). CONCLUSIONS: This study supports the key role of the left vPCGa as the speech output node by showing convergence between speech output mapping and anterior AF/SLF-III connectivity in the vPCGa. These findings may contribute to the understanding of speech networks and could have clinical implications in preoperative surgical planning.

White matter alterations in MR-negative temporal and frontal lobe epilepsy using fixel-based analysis.

This study focuses on white matter alterations in pharmacoresistant epilepsy patients with no visible lesions in the temporal and frontal lobes on clinical MRI (i.e. MR-negative) with lesions confirmed by resective surgery. The aim of the study was to extend the knowledge about group-specific neuropathology in MR-negative epilepsy. We used the fixel-based analysis (FBA) that overcomes the limitations of traditional diffusion tensor image analysis, mainly within-voxel averaging of multiple crossing fibres. Group-wise comparisons of fixel parameters between healthy controls (N = 100) and: (1) frontal lobe epilepsy (FLE) patients (N = 9); (2) temporal lobe epilepsy (TLE) patients (N = 13) were performed. A significant decrease of the cross-section area of the fixels in the superior longitudinal fasciculus was observed in the FLE. Results in TLE reflected widespread atrophy of limbic, thalamic, and cortico-striatal connections and tracts directly connected to the temporal lobe (such as the anterior commissure, inferior fronto-occipital fasciculus, uncinate fasciculus, splenium of corpus callosum, and cingulum bundle). Alterations were also observed in extratemporal connections (brainstem connection, commissural fibres, and parts of the superior longitudinal fasciculus). To our knowledge, this is the first study to use an advanced FBA method not only on the datasets of MR-negative TLE patients, but also MR-negative FLE patients, uncovering new common tract-specific alterations on the group level.

Evidence for a critical role of the left inferior parietal lobule and underlying white matter connectivity in proficient text reading.

OBJECTIVE: Reading proficiency is an important skill for personal and socio-professional daily life. Neurocognitive models underlie a dual-route organization for word reading, in which information is processed by both a dorsal phonological "assembled phonology route" and a ventral lexical-semantic "addressed phonology route." Because proficient reading should not be reduced to the ability to read words one after another, the current study was designed to shed light on the neural bases specifically underpinning text reading and the relative contributions of each route to this skill. METHODS: Twenty-two patients with left-sided, diffuse, low-grade glioma who underwent operations while awake were included. They were divided into 3 groups on the basis of tumor location: the inferior parietal lobule (IPL) group (n = 6), inferior temporal gyrus (Tinf) group (n = 6), and fronto-insular (control) group (n = 10). Spoken language and reading abilities were tested in all patients the day before surgery, during surgery, and 3 months after surgery, and cognitive functioning was evaluated before and 3 months after surgery. Text-reading scores obtained before and 3 months after surgery were compared within each group and between groups, correlations between reading scores and both spoken language and cognitive scores were calculated, postoperative cortical-subcortical resection location was estimated, and multiple regression analysis was conducted to examine the relationship between reading proficiency and lesion location. RESULTS: The results indicated that only the patients in the IPL group showed a significant decrease in text-reading scores between periods, which was not associated with lower scores in naming or verbal fluency; patients in the Tinf group showed a slight nonsignificant decrease in text reading between periods, which was associated with a clear decrease in naming and semantic verbal fluency; and patients in the control group showed no differences between preoperative and postoperative reading and spoken language scores. The results of the analysis of these behavioral results and anatomical data (resection cavities and white matter damage) suggest critical roles for the left inferior parietal lobule and underlying white matter connectivity, especially the posterior segment of the arcuate fasciculus, in proficient text reading. CONCLUSIONS: Text-reading proficiency may depend on not only the integrity of both processing routes but also their capacity for interaction, with critical roles for the left inferior parietal lobule and posterior arcuate fasciculus. These findings have fundamental as well as clinical implications.

Alterations in resting-state functional connectivity associated to the age-related decline in time-based prospective memory.

Time-based prospective memory (TBPM) is defined as the ability to remember to perform intended actions at a specific time in the future. TBPM is impaired in aging, and this decline has been associated with white-matter alterations within the superior fronto-occipital fasciculus. In the present study, we used resting-state functional magnetic resonance imaging from 22 healthy young (26 ± 5.2 years) and 23 older (63 ± 6.1 years) participants to investigate how age-related alterations in resting-state functional connectivity are related to TBPM performance, and whether these alterations are associated with the white-matter disruptions we have previously observed with diffusion tensor imaging. Whole-brain analyses revealed lower resting-state functional connectivity in older participants compared with younger ones, which in turn correlated with TBPM performance. These correlations were mainly located in the salience network and the parietal part of the frontoparietal network. Our findings suggest that resting-state functional connectivity alterations contribute to the age-related decline in TBPM.

Preoperative language tract integrity is a limiting factor in recovery from aphasia after glioma surgery.

Aphasia can occur in a broad range of pathological conditions that affect cortical or subcortical structures. Here we test the hypothesis that white matter integrity of language pathways assessed by preoperative diffusion tensor imaging (DTI) is associated with language performance and its recovery after glioma resection. 27 patients with preoperative DTI were included. Segmentation of the arcuate fascicle (AF), the inferior fronto-occipital fascicle (IFOF), the inferior longitudinal fascicle (ILF), the superior longitudinal fascicle (SLF), and the uncinate fascicle (UF) was performed with a fully-connected neural network (FCNN, TractSeg). Median fractional anisotropy (FA) was extracted from the resulting volumes as surrogate marker for white matter integrity and tested for correlation with clinical parameters. After correction for demographic data and multiple testing, preoperative white matter integrity of the IFOF, the ILF, and the UF in the left hemisphere were independently and significantly associated with aphasia three months after surgery. Comparison between patients with and without aphasia three months after surgery revealed significant differences in preoperative white matter integrity of the left AF (p = 0.021), left IFOF (p = 0.015), left ILF (p = 0.003), left SLF (p = 0.001, p = 0.021, p = 0.043 for respective sub-bundles 1-3), left UF (p = 0.041) and the right AF (p = 0.027). Preoperative assessment of white matter integrity of the language network by time-efficient MRI protocols and FCNN-driven segmentation may assist in the evaluation of postoperative rehabilitation potential in glioma patients.

Cytology, architecture, development, and connections of the primate striatum: Hints for human pathology.

Degeneration of neurons and circuits across the striatum shows stereotyped time-course and spatial topography patterns that are distinct for Huntington's disease, Parkinson's disease, or the Tauopathies. These patterns of neurodegeneration in humans have not yet been systematically related to developmental, connectional, cellular, and chemical factors studied in human and non-human primates, that may underlie potential differences in selective vulnerability across striatal sectors. Relating primate anatomy to human pathology could provide new venues for identifying molecular, cellular, and connectional factors linked to the degeneration of striatal neurons and circuits. This review describes and summarizes several developmental, cellular, structural, and connectional features of the primate striatum in relation to patterns of neurodegeneration in the striatum of humans and of non-human primate models. We review (1) the types of neurons in the primate striatum, (2) the cyto-, myelo-, and chemoarchitecture of the primate striatum, (3) the developmental origin of the striatum in light of modern patterning studies, (4) the organization of corticostriatal projections in relation to cortical types, and (5) the topography and time-course of neuron loss, glial reaction, and protein aggregation induced by neurodegenerative diseases in humans and in non-human primate models across striatal sectors and their corresponding cortical areas. We summarize current knowledge about key aspects of primate striatal anatomy and human pathology and indicate knowledge gaps that should be addressed in future studies. We aim to identify factors for selective vulnerability to neurodegeneration of striatal neurons and circuits and obtain hints that could help elucidate striatal pathology in humans.

Early white matter connectivity and plasticity in post stroke aphasia recovery.

A disruption of white matter connectivity is negatively associated with language (recovery) in patients with aphasia after stroke, and behavioral gains have been shown to coincide with white matter neuroplasticity. However, most brain-behavior studies have been carried out in the chronic phase after stroke, with limited generalizability to earlier phases. Furthermore, few studies have investigated neuroplasticity patterns during spontaneous recovery (i.e., not related to a specific treatment) in the first months after stroke, hindering the investigation of potential early compensatory mechanisms. Finally, the majority of previous research has focused on damaged left hemisphere pathways, while neglecting the potential protective value of their right hemisphere counterparts for language recovery. To address these outstanding issues, we present a longitudinal study of thirty-two patients with aphasia (21 males and 11 females, M = 69.47 years, SD = 10.60 years) who were followed up for a period of 1 year with test moments in the acute (1-2 weeks), subacute (3-6 months) and chronic phase (9-12 months) after stroke. Constrained Spherical Deconvolution-based tractography was performed in the acute and subacute phase to measure Fiber Bundle Capacity (FBC), a quantitative connectivity measure that is valid in crossing fiber regions, in the bilateral dorsal arcuate fasciculus (AF) and the bilateral ventral inferior fronto-occipital fasciculus (IFOF). First, concurrent analyses revealed positive associations between the left AF and phonology, and between the bilateral IFOF and semantics in the acute - but not subacute - phase, supporting the dual-stream language model. Second, neuroplasticity analyses revealed a decrease in connection density of the bilateral AF - but not the IFOF - from the acute to the subacute phase, possibly reflecting post stroke white matter degeneration in areas adjacent to the lesion. Third, predictive analyses revealed no contribution of acute FBC measures to the prediction of later language outcomes over and above the initial language scores, suggesting no added value ofthe diffusion measures for languageprediction. Our study provides new insights on (changes in) connectivity of damaged and undamaged language pathways in patients with aphasia in the first months after stroke, as well as if/how such measures are related to language outcomes at different stages of recovery. Individual results are discussed in the light of current frameworks of language processing and aphasia recovery.

White matter connectivity in brain networks supporting social and affective processing predicts real-world social network characteristics.

Human behavior is embedded in social networks. Certain characteristics of the positions that people occupy within these networks appear to be stable within individuals. Such traits likely stem in part from individual differences in how people tend to think and behave, which may be driven by individual differences in the neuroanatomy supporting socio-affective processing. To investigate this possibility, we reconstructed the full social networks of three graduate student cohorts (N = 275; N = 279; N = 285), a subset of whom (N = 112) underwent diffusion magnetic resonance imaging. Although no single tract in isolation appears to be necessary or sufficient to predict social network characteristics, distributed patterns of white matter microstructural integrity in brain networks supporting social and affective processing predict eigenvector centrality (how well-connected someone is to well-connected others) and brokerage (how much one connects otherwise unconnected others). Thus, where individuals sit in their real-world social networks is reflected in their structural brain networks. More broadly, these results suggest that the application of data-driven methods to neuroimaging data can be a promising approach to investigate how brains shape and are shaped by individuals' positions in their real-world social networks.

Connectivity of the corticostriatal and thalamostriatal systems in normal and parkinsonian states: An update.

The striatum receives abundant glutamatergic afferents from the cortex and thalamus. These inputs play a major role in the functions of the striatal neurons in normal conditions, and are significantly altered in pathological states, such as Parkinson's disease. This review summarizes the current knowledge of the connectivity of the corticostriatal and thalamostriatal pathways, with emphasis on the most recent advances in the field. We also discuss novel findings regarding structural changes in cortico- and thalamostriatal connections that occur in these connections as a consequence of striatal loss of dopamine in parkinsonism.

Prenatal immune stress blunts microglia reactivity, impairing neurocircuitry.

Recent studies suggested that microglia, the primary brain immune cells, can affect circuit connectivity and neuronal function1,2. Microglia infiltrate the neuroepithelium early in embryonic development and are maintained in the brain throughout adulthood3,4. Several maternal environmental factors-such as an aberrant microbiome, immune activation and poor nutrition-can influence prenatal brain development5,6. Nevertheless, it is unknown how changes in the prenatal environment instruct the developmental trajectory of infiltrating microglia, which in turn affect brain development and function. Here we show that, after maternal immune activation (MIA) in mice, microglia from the offspring have a long-lived decrease in immune reactivity (blunting) across the developmental trajectory. The blunted immune response was accompanied by changes in chromatin accessibility and reduced transcription factor occupancy of the open chromatin. Single-cell RNA-sequencing analysis revealed that MIA does not induce a distinct subpopulation but, rather, decreases the contribution to inflammatory microglia states. Prenatal replacement of microglia from MIA offspring with physiological infiltration of naive microglia ameliorated the immune blunting and restored a decrease in presynaptic vesicle release probability onto dopamine receptor type-two medium spiny neurons, indicating that aberrantly formed microglia due to an adverse prenatal environment affect the long-term microglia reactivity and proper striatal circuit development.

Segregated circuits for phonemic and semantic fluency: A novel patient-tailored disconnection study.

Phonemic and semantic fluency are neuropsychological tests widely used to assess patients' language and executive abilities and are highly sensitive tests in detecting language deficits in glioma patients. However, the networks that are involved in these tasks could be distinct and suggesting either a frontal (phonemic) or temporal (semantic) involvement. 42 right-handed patients (26 male, mean age = 52.5 years, SD=±13.3) were included in this retrospective study. Patients underwent awake (54.8%) or asleep (45.2%) surgery for low-grade (16.7%) or high-grade-glioma (83.3%) in the frontal (64.3%) or temporal lobe (35.7%) of the left (50%) or right (50%) hemisphere. Pre-operative tractography was reconstructed for each patient, with segmentation of the inferior fronto-occipital fasciculus (IFOF), arcuate fasciculus (AF), uncinate fasciculus (UF), inferior longitudinal fasciculus (ILF), third branch of the superior longitudinal fasciculus (SLF-III), frontal aslant tract (FAT), and cortico-spinal tract (CST). Post-operative percentage of damage and disconnection of each tract, based on the patients' surgical cavities, were correlated with verbal fluencies scores at one week and one month after surgery. Analyses of differences between fluency scores at these timepoints (before surgery, one week and one month after surgery) were performed; lesion-symptom mapping was used to identify the correlation between cortical areas and post-operative scores. Immediately after surgery, a transient impairment of verbal fluency was observed, that improved within a month. Left hemisphere lesions were related to a worse verbal fluency performance, being a damage to the left superior frontal or temporal gyri associated with phonemic or semantic fluency deficit, respectively. At a subcortical level, disconnection analyses revealed that fluency scores were associated to the involvement of the left FAT and the left frontal part of the IFOF for phonemic fluency, and the association was still present one month after surgery. For semantic fluency, the correlation between post-surgery performance emerged for the left AF, UF, ILF and the temporal part of the IFOF, but disappeared at the follow-up. This approach based on the patients' pre-operative tractography, allowed to trace for the first time a dissociation between white matter pathways integrity and verbal fluency after surgery for glioma resection. Our results confirm the involvement of a frontal anterior pathway for phonemic fluency and a ventral temporal pathway for semantic fluency. Finally, our longitudinal results suggest that the frontal executive pathway requires a longer interval to recover compared to the semantic one.

[A case of bilingual aphasia with language mixing between Japanese and English caused by superior longitudinal fasciculus lesion-a study using functional MRI and diffusion tensor imaging].

We report a case of left-handed bilingual aphasia with phonemic paraphasia and language mixing from Japanese as a first language to English as a second language. The lesion caused by cerebral infarction was mainly localized in the left parietal lobe white matter. The patient was a 46-year-old, left-handed woman who was bilingual in Japanese and English. Both auditory and visual comprehensions were well maintained after the acute phase of the disease; however, language mixing between Japanese and English was observed during Japanese speech. A pathophysiological interpretation of this case required a focus on the brain network. Our findings suggest that lesions of the superior longitudinal fasciculus and arcuate fasciculus of the white matter fibers just below the left inferior parietal lobule are associated with bilingual aphasia.

Resting-state functional nuclear magnetic resonance imaging in patients with bipolar disorder: Beyond euthymia.

INTRODUCTION: Functional nuclear magnetic resonance imaging in the resting state (R-fMRI) allows the identification of complete functional connectivity networks and the possible neuronal correlations of psychiatric disorders. The literature on R-fMRI and bipolar disorder (BD) will be reviewed, emphasising the findings in the phases of mania, hypomania and depression. METHODS: It is a narrative review of the literature in which articles were searched in PubMed and Embase, with the key words in English "bipolar disorder" AND "resting state", without limit on the date of publication. RESULTS: The studies of BD patients in the mania and hypomania phases who underwent R-fMRI show concordant results in terms of decreased functional cerebral connectivity between the amygdala and some cortical regions, which indicates that this functional connection would have some implication in the normal affect regulation. Patients in the depressive phase show a decrease in functional brain connectivity, but as there are several anatomical structures involved and neural networks reported in the studies, it is not possible to compare them. CONCLUSIONS: There is a decrease in functional connectivity in patients with BD, but current evidence does not allow establishing specific changes in specific functional brain connectivity networks. However, there are already some findings that show correlation with the patients' symptoms.

Structural connectivity and intelligence in brain-injured children.

In children, higher general intelligence corresponds with better processing speed ability. However, the relationship between structural brain connectivity and processing speed in the context of intelligence is unclear. Furthermore, the impact of brain injury on this relationship is also unknown. Structural networks were constructed for 36 brain tumor patients (mean age: 13.45 ± 2.73, 58% males) and 35 typically developing children (13.30 ± 2.86, 51% males). Processing speed and general intelligence scores were acquired using standard batteries. The relationship between network properties, processing speed, and intelligence was assessed using a partial least squares analysis. Results indicated that structural networks in brain-injured children were less integrated (ß = -.38, p = 0.001) and more segregated (ß = 0.4, p = 0.0005) compared to typically developing children. There was an indirect effect of network segregation on general intelligence via processing speed, where greater network segregation predicted slower processing speed which in turn predicted worse general intelligence (GoF = 0.37). These findings provide the first evidence of relations between structural connectivity, processing speed, and intelligence in children. Injury-related disruption to the structural network may result in worse intelligence through impacts on information processing. Our findings are discussed in the context of a network approach to understanding brain-behavior relationships.

Magnetic Resonance Imaging in Diplopia: Neural Pathway, Imaging, and Clinical Correlation.

The role of magnetic resonance imaging (MRI) in diplopia is to diagnose various diseases that occur along the neural pathway governing eye movement. However, the lesions are frequently small and subtle and are therefore difficult to detect on MRI. This article presents representative cases of diseases that cause diplopia. The purpose of this article was to 1) describe the anatomy of the neural pathway governing eye movement, 2) recommend optimal MRI targets and protocols for the diagnosis of diseases causing diplopia, 3) correlate MRI findings with misalignment of the eyes (i.e., strabismus), and 4) help familiarize the reader with the imaging diagnosis of diplopia.

Network alterations underlying anxiety symptoms in early multiple sclerosis.

BACKGROUND: Anxiety, often seen as comorbidity in multiple sclerosis (MS), is a frequent neuropsychiatric symptom and essentially affects the overall disease burden. Here, we aimed to decipher anxiety-related networks functionally connected to atrophied areas in patients suffering from MS. METHODS: Using 3-T MRI, anxiety-related atrophy maps were generated by correlating longitudinal cortical thinning with the severity of anxiety symptoms in MS patients. To determine brain regions functionally connected to these maps, we applied a technique termed "atrophy network mapping". Thereby, the anxiety-related atrophy maps were projected onto a large normative connectome (n = 1000) performing seed-based functional connectivity. Finally, an instructed threat paradigm was conducted with regard to neural excitability and effective connectivity, using transcranial magnetic stimulation combined with high-density electroencephalography. RESULTS: Thinning of the left dorsal prefrontal cortex was the only region that was associated with higher anxiety levels. Atrophy network mapping identified functional involvement of bilateral prefrontal cortex as well as amygdala and hippocampus. Structural equation modeling confirmed that the volumes of these brain regions were significant determinants that influence anxiety symptoms in MS. We additionally identified reduced information flow between the prefrontal cortex and the amygdala at rest, and pathologically increased excitability in the prefrontal cortex in MS patients as compared to controls. CONCLUSION: Anxiety-related prefrontal cortical atrophy in MS leads to a specific network alteration involving structures that resemble known neurobiological anxiety circuits. These findings elucidate the emergence of anxiety as part of the disease pathology and might ultimately enable targeted treatment approaches modulating brain networks in MS.