Functional Connectivity Patterns In Patients Research Articles

Alterations in degree centrality and functional connectivity in tension-type headache: a resting-state fMRI study.

Previous studies have provided evidence of structural and functional changes in the brains of patients with tension-type headache (TTH). However, investigations of functional connectivity alterations in TTH have been inconclusive. The present study aimed to investigate abnormal intrinsic functional connectivity patterns in patients with TTH through the voxel-wise degree centrality (DC) method as well as functional connectivity (FC) analysis. A total of 33 patients with TTH and 30 healthy controls (HCs) underwent resting-state functional magnetic resonance imaging (rs-fMRI) scanning and were enrolled in the final study. The voxel-wise DC method was performed to quantify abnormalities in the local functional connectivity hubs. Nodes with abnormal DC were used as seeds for further FC analysis to evaluate alterations in functional connectivity patterns. In addition, correlational analyses were performed between abnormal DC and FC values and clinical features. Compared with HCs, patients with TTH had higher DC values in the left middle temporal gyrus (MTG.L) and lower DC values in the left anterior cingulate and paracingulate gyri (ACG.L) (GRF, voxel-wise p < 0.05, cluster-wise p < 0.05, two-tailed). Seed-based FC analyses revealed that patients with TTH showed greater connections between ACG.L and the right cerebellum lobule IX (CR-IX.R), and smaller connections between ACG.L and ACG.L. The MTG.L showed increased FC with the ACG.L, and decreased FC with the right caudate nucleus (CAU.R) and left precuneus (PCUN.L) (GRF, voxel-wise p < 0.05, cluster-wise p < 0.05, two-tailed). Additionally, the DC value of the MTG.L was negatively correlated with the DASS-depression score (p = 0.046, r=-0.350). This preliminary study provides important insights into the pathophysiological mechanisms of TTH.

Whole-brain functional gradients reveal cortical and subcortical alterations in patients with episodic migraine.

Migraine is a type of headache with multiple neurological symptoms. Prior neuroimaging studies in patients with migraine based on functional magnetic resonance imaging have found regional as well as network-level alterations in brain function. Here, we expand on prior studies by establishing whole-brain functional connectivity patterns in patients with migraine using dimensionality reduction techniques. We studied functional brain connectivity in 50 patients with episodic migraine and sex- and age-matched healthy controls. Using dimensionality reduction techniques that project high-dimensional functional connectivity onto low-dimensional representations (i.e., eigenvectors), we found significant between-group differences in the eigenvectors between patients with migraine and healthy controls, particularly in the sensory/motor and limbic cortices. Furthermore, we assessed between-group differences in subcortical connectivity with subcortical weighted manifolds defined by subcortico-cortical connectivity multiplied by cortical eigenvectors and revealed significant alterations in the amygdala. Finally, leveraging supervised machine learning, we moderately predicted headache frequency using cortical and subcortical functional connectivity features, again indicating that sensory and limbic regions play a particularly important role in predicting migraine frequency. Our study confirmed that migraine is a hierarchical disease of the brain that shows alterations along the sensory-limbic axis, and therefore, the functional connectivity in these areas could be a useful marker to investigate migraine symptomatology.

More Than Just Statics: Temporal Dynamic Changes in Inter- and Intrahemispheric Functional Connectivity in First-Episode, Drug-Naive Patients With Major Depressive Disorder.

Several functional magnetic resonance imaging (fMRI) studies have demonstrated abnormalities in static intra- and interhemispheric functional connectivity among diverse brain regions in patients with major depressive disorder (MDD). However, the dynamic changes in intra- and interhemispheric functional connectivity patterns in patients with MDD remain unclear. Fifty-eight first-episode, drug-naive patients with MDD and 48 age-, sex-, and education level-matched healthy controls (HCs) underwent resting-state fMRI. Whole-brain functional connectivity, analyzed using the functional connectivity density (FCD) approach, was decomposed into ipsilateral and contralateral functional connectivity. We computed the intra- and interhemispheric dynamic FCD (dFCD) using a sliding window analysis to capture the dynamic patterns of functional connectivity. The temporal variability in functional connectivity was quantified as the variance of the dFCD over time. In addition, intra- and interhemispheric static FCD (sFCD) patterns were calculated. Associations between the dFCD variance and sFCD in abnormal brain regions and the severity of depressive symptoms were analyzed. Compared to HCs, patients with MDD showed lower interhemispheric dFCD variability in the inferior/middle frontal gyrus and decreased sFCD in the medial prefrontal cortex/anterior cingulate cortex and posterior cingulate cortex/precuneus in both intra- and interhemispheric comparisons. No significant correlations were found between any abnormal dFCD variance or sFCD at the intra- and interhemispheric levels and the severity of depressive symptoms. Our results suggest intra- and interhemispheric functional connectivity alterations in the dorsolateral prefrontal cortex (DLPFC) and default mode network regions involved in cognition, execution and emotion. Furthermore, our study emphasizes the essential role of altered interhemispheric communication dynamics in the DLPFC in patients with MDD. These findings contribute to our understanding of the pathophysiology of MDD.

Altered brain network functional connectivity patterns in patients with vestibular migraine diagnosed according to the diagnostic criteria of the Bárány Society and the International Headache Society

BackgroundVestibular migraine (VM) is considered one of the most common causes of episodic central vestibular disorders, the mechanism of VM is currently still unclear. The development of functional nuclear magnetic resonance (fMRI) in recent years offers the possibility to explore the altered functional connectivity patterns in patients with VM in depth. The study aimed to investigate altered patterns of brain network functional connectivity in patients with VM diagnosed based on the diagnostic criteria of the Bárány Society and the International Headache Society, and hope to provide a scientific theoretical basis for understanding whether VM is a no-structural central vestibular disease, i.e., functional central vestibular disease with altered brain function.MethodsSeventeen patients with VM who received treatment in our hospital from December 2018 to December 2020 were enrolled. Eight patients with migraine and 17 health controls (HCs) were also included. Clinical data of all patients were collected. Blood pressure, blood routine tests and electrocardiography were conducted to exclude other diseases associated with chronic dizziness. Videonystagmography, the vestibular caloric test, the video head impulse test and vestibular-evoked myogenic potentials were measured to exclude peripheral vestibular lesions. MRI was utilized to exclude focal lesions and other neurological diseases. All subjects underwent fMRI. The independent component analysis was performed to explore changes in intra- and inter-network functional connectivity in patients with VM.ResultsAmong 17 patients with VM, there were 7 males and 10 females with an average age of 39.47 ± 9.78 years old. All patients had a history of migraine. Twelve (70.6%) patients had recurrent spontaneous vertigo, 2 (11.7%) patients had visually induced vertigo, and 3 (17.6%) patients had head motion-induced vertigo. All 17 patients with VM reported worsening of dizziness vertigo during visual stimulation. The migraine-like symptoms were photophobia or phonophobia (n = 15, 88.2%), migraine-like headache (n = 8, 47.1%), visual aura during VM onset (n = 7, 41.2%). 5 (29.4%) patients with VM had hyperactive response during the caloric test, and 12 (70.6%) patients had caloric test intolerance. Eleven (64.7%) patients had a history of motion sickness. Totally 13 independent components were identified. Patients with VM showed decreased functional connectivity in the bilateral medial cingulate gyrus and paracingulate gyrus within sensorimotor network (SMN) compared with HCs. They also showed weakened functional connectivity between auditory network (AN) and anterior default mode network (aDMN) compared with HCs, and enhanced functional connectivity between AN and the salience network (SN) compared with patients with migraine.ConclusionPatients with vestibular migraine showed obvious altered functional connectivity in the bilateral medial cingulate gyrus and paracingulate gyrus within the SMN. The median cingulate and paracingulate gyri may be impaired, the disinhibition of sensorimotor network and vestibular cortical network may result in a hypersensitivity state (photophobia/phonophobia). Altered functional connectivity between AN and DMN, SN may lead to increased sensitivity to vestibular sensory processing.

Acupuncture Modulation Effect on Pain Processing Patterns in Patients With Migraine Without Aura.

IntroductionIn this retrospective study, resting-state functional connectivity (FC) in patients with migraine was analyzed to identify potential pathological pain processing patterns and compared them to those in healthy controls (HCs). The FC patterns in patients between pre- and post-acupuncture sessions were also analyzed to determine how acupuncture affects neurological activity and pain perception during the migraine interictal period.MethodsIn total, 52 patients with migraine without aura (MwoA) and 60 HCs were recruited. Patients with migraine were given acupuncture treatment sessions for 4 weeks. As a primary observation, functional magnetic resonance images were obtained at the beginning and end of the sessions. HCs received no treatment and underwent one functional magnetic resonance imaging (fMRI) scan after enrollment. After the fMRI data were preprocessed, a region of interest (ROI)-to-ROI analysis was performed with predefined ROIs related to pain processing regions.ResultsThe first analysis showed significantly different FCs between patients with MwoA and HCs [false discovery rate corrected p-value (p-FDR) < 0.05]. The FCs were found to be mainly between the cingulate gyrus (CG) and the insular gyrus, the CG and the inferior parietal lobule (IPL), the CG and the superior frontal gyrus, and the middle frontal gyrus and the IPL. The second analysis indicated that acupuncture treatment partly restored the different FCs found in the first analysis (p-FDR < 0.05). Furthermore, subgroup analysis found different brain activity patterns in headache-intensity restored condition and headache-frequency restored condition. Lastly, the correlation analysis suggested a potential correlation between FCs and clinical symptoms (p < 0.05).ConclusionThis study suggests that pain processing is abnormal in migraine, with significantly abnormal FCs in the frontal, parietal, and limbic regions. This finding could be a typical pathological feature of migraine. Acupuncture has been identified to relieve headache symptoms in two ways: it restores the pain processing function and regulates pain perception.

Altered hippocampal functional connectivity patterns in patients with cognitive impairments following ischaemic stroke: A resting-state fMRI study

BackgroundIschemic stroke with cognitive impairment is a considerable risk factor for developing dementia. Identifying imaging markers of cognitive impairment following ischemic stroke will help to develop prevention strategies against post-stroke dementia. MethodsWe investigated the hippocampal functional connectivity (FC) pattern following ischemic stroke, using resting-state fMRI (rs-fMRI). Thirty-three cognitively impaired patients after ischemic stroke and sixteen age-matched controls with no known history of neurological disorder were recruited for the study. No patient had a direct ischaemic insult to hippocampus on the examination of brain imaging. Seven subfields of hippocampus were used as seeds region for FC analyses. ResultsAcross all hippocampal subfields, FC with the inferior parietal lobule was reduced in stroke patients as compared with healthy controls. This decreased FC included both supramarginal gyrus and angular gyrus. The FC of hippocampal subfields with cerebellum was increased. Importantly, the degree of the altered FC between hippocampal subfields and inferior parietal lobule was associated with their impaired memory function. ConclusionOur results demonstrated that decreased hippocampal-inferior parietal lobule connectivity was associated with cognitive impairment in patients with ischemic stroke. These findings provide novel insights into the role of hippocampus in cognitive impairment following ischemic stroke.

The brain as a complex network: assessment of EEG-based functional connectivity patterns in patients with childhood absence epilepsy.

The human brain is increasingly seen as a dynamic neural system, the function of which relies on a diverse set of connections between brain regions. To assess these complex dynamical interactions, formalism of complex networks was suggested as one of the most promising tools to offer new insight into the brain's structural and functional organization, with a potential also for clinical implications. Irrespective of the brain mapping technique, modern network approaches have revealed fundamental aspects of normal brain-network organization, such as small-world and scale-free patterns, hierarchical modularity, and the presence of hubs. Moreover, the utility of these approaches, to gain a better understanding of neurological diseases, is of great interest. In the present contribution, we first describe the basic network measures and how the brain networks are constructed on the basis of brain activity data in order to introduce clinical neurologists to this new theoretical paradigm. We then demonstrate how network formalism can be used to detect changes in EEG-based functional connectivity patterns in six paediatric patients with childhood absence epilepsy. Notably, our results do not only indicate enhanced synchronicity during epileptic episodes but also reveal specific spatial changes in the electrical activity of the brain. We argue that the network-based evaluation of functional brain networks can provide clinicians with more detailed insight into the activity of a pathological brain and can also be regarded as a support for objective diagnosis and treatment for various neurological diseases.

Proactive Motor Functional Recovery Following Immersive Virtual Reality-Based Limb Mirroring Therapy in Patients with Subacute Stroke.

Virtual reality (VR) is considered to be a promising therapeutic technology for the rehabilitation of upper extremities (UEs) post-stroke. Recently, we designed and then implemented a neuroscientifically grounded VR protocol for the rehabilitation of patients with stroke. The system provides unilateral and bilateral limb mirroring exercises in a fully immersive virtual environment that may stimulate and activate the mirror neuron system in the brain to help patients for their rehabilitation. Twelve patients with subacute stroke underwent the newly implemented VR treatment in addition to conventional rehabilitation for 8 consecutive weekdays. The treatment effect on brain reorganization and motor function was investigated using resting-state fMRI (rs-fMRI) and the Fugl-Meyer assessment for Upper Extremity (FM-UE), respectively. Fifteen healthy controls (HCs) also underwent rs-fMRI scanning one time. The study finally obtained usable data from 8 patients and 13 HCs. After the intervention, patients demonstrated significant improvement in their FM-UE scores (p values < 0.042). Voxel-wise functional connectivity (FC) analysis based on the rs-fMRI data found that HCs showed widespread bilateral FC patterns associated with the dominant hemispheric primary motor cortex (M1). However, the FC patterns in patients revealed intra-hemispheric association with the ipsilesional M1 seed and this association became visible in the contra-hemisphere after the intervention. Moreover, the change of FC values between the bilateral M1 was significantly correlated with the changes in FM-UE scores (p values < 0.037). We conclude that unilateral and bilateral limb mirroring exercise in an immersive virtual environment may enhance cortical reorganization and lead to improved motor function.

Magnetoencephalography resting state connectivity patterns as indicatives of surgical outcome in epilepsy patients

Objective. Focal epilepsy is a disorder affecting several brain networks; however, epilepsy surgery usually targets a restricted region, the so-called epileptic focus. There is a growing interest in embedding resting state (RS) connectivity analysis into pre-surgical workup. Approach. In this retrospective study, we analyzed Magnetoencephalography (MEG) long-range RS functional connectivity patterns in patients with drug-resistant focal epilepsy. MEG recorded prior to surgery from seven seizure-free (Engel Ia) and five non seizure-free (Engel III or IV) patients were analyzed (minimum 2-years post-surgical follow-up). MEG segments without any detectable epileptic activity were source localized using wavelet-based Maximum Entropy on the Mean method. Amplitude envelope correlation in the theta (4–8 Hz), alpha (8–13 Hz), and beta (13–26 Hz) bands were used for assessing connectivity. Main results. For seizure-free patients, we found an isolated epileptic network characterized by weaker connections between the brain region where interictal epileptic discharges (IED) are generated and the rest of the cortex, when compared to connectivity between the corresponding contralateral homologous region and the rest of the cortex. Contrarily, non seizure-free patients exhibited a widespread RS epileptic network characterized by stronger connectivity between the IED generator and the rest of the cortex, in comparison to the contralateral region and the cortex. Differences between the two seizure outcome groups concerned mainly distant long-range connections and were found in the alpha-band. Significance. Importantly, these connectivity patterns suggest specific mechanisms describing the underlying organization of the epileptic network and were detectable at the individual patient level, supporting the prospect use of MEG connectivity patterns in epilepsy to predict post-surgical seizure outcome.

Dysregulation of resting-state functional connectivity in patients with Cushing's disease.

To explore the anatomical distance-dependent functional connectivity patterns in patients with active phase of Cushing's disease (CD) and to evaluate the associations between hypercortisol exposure and regional normalized functional connectivity strengths (nFCSs). Based on the fMRI data in 32 CD patients and 32 healthy controls (HCs), we computed the nFCSs for each voxel in the brain and further divided them into long-range and short-range nFCSs. General linear models was used to investigate between-group differences in these nFCS metrics and the correlations between the nFCSs and clinical variables. Compared with HC, CD patients showed dysregulation of the nFCSs mainly in the default mode network. They showed an overall higher nFCS in bilateral parahippocampal cortex mainly owing to the disruption of long-range nFCS and a relatively lower nFCS in bilateral posterior cingulate cortex (PCC), bilateral lateral parietal cortex (LP), and right prefrontal cortex (PFC). In addition, their long-range nFCS was lower in the bilateral anterior cingulate cortex, PCC, and LP; short-range nFCS was lower in the bilateral PFC. Notably, the positive correlation between the nFCSs in their right parahippocampal cortex and serum cortisol levels at 08:00 remained significant after taking the anatomical distance into consideration. The discrepant functional connectivity patterns found in our study indicated a hypercortisol-associated, distance-dependent disruption of resting-state functional connectivity in patients with active CD. We provide novel insights into the impacts of hypercortisol exposure and the pathophysiologic mechanisms of CD, which may facilitate advances in CD intervention ultimately.

Postchemotherapy hippocampal functional connectivity patterns in patients with breast cancer: a longitudinal resting state functional MR imaging study

The hippocampus plays a key role in cognitive function and emotion regulation due to its wide connection with the whole brain. This study examined the acute effect of chemotherapy on hippocampal and subfield functional connectivity and neuropsychological status in breast cancer patients (BC). This IRB approved study included 29BC and 25 age matched healthy controls (HCs) who underwent resting state functional magnetic resonance imaging (Rs-fMRI), neuropsychological tests and blood examinations at baseline and one week after completing chemotherapy or in the same time interval. Within-group comparisons and group-by-time interactions analysis of hippocampus- and subregion- based functional connectivity were performed between the two groups. Functional connectivity changes were correlated with changes of blood examination and neuropsychological test scores in the BC group. The BC group had higher depression and anxiety scores, poorer performance on visual mobility, auditory memory and executive function than HCs (p < 0.05), and significantly abnormal estrodiol, total cholesterol and triglycerides (p < 0.05). BC survivors showed significant hippocampal functional connectivity changes mainly in the left insula, temporal lobe (Gaussian Random Field theory correction, P < 0.001) and the left inferior frontal gyrus (P < 0.01). The functional connections from the anterior hippocampus to the left temporal lobe were greater than the posterior hippocampus (P < 0.05). The hippocampus functional connectivity alterations were closely related to changes in depression scores, estrodiol and triglycerides (all p < 0.05). Chemotherapy induced especially anterior hippocampal functional connectivity abnormality, which is related to depression symptom, estrodiol and triglycerides disorders.

Cover Picture: Similarity of functional connectivity patterns in patients with multiple sclerosis who void spontaneously versus patients with voiding dysfunction (Neurourology and Urodynamics 38/2019)

Cover Picture: Similarity of functional connectivity patterns in patients with multiple sclerosis who void spontaneously versus patients with voiding dysfunction (Neurourology and Urodynamics 38/2019)

Similarity of functional connectivity patterns in patients with multiple sclerosis who void spontaneously versus patients with voiding dysfunction.

To investigate if Multiple Sclerosis (MS) lesion characteristics affect functional brain connectivity (FC) during bladder voiding. Twenty-seven ambulatory female patients with MS completed our functional magnetic resonance imaging (fMRI)/urodynamic testing (UDS) platform. Individual fMRI activation maps were generated at initiation of voiding. FC patterns of these regions were calculated and compared. Similarity of the FC pattern from one patient relative to all others was expressed by a parameter FC_sim. A statistical analysis was performed to reveal the relationship of the existence of an enhancing brain lesion, the size of the largest lesion and the ability to void spontaneously to this FC similarity measure. FC_sim values were significantly lower for patients with an enhancing MS lesion (11.7 ± 3.1 vs 5.3 ± 2.1 P < 0.001). Lesion size smaller than 20 mm inversely correlated significantly with FC_sim (R = -0.43, P = 0.05). Patients with the ability to void spontaneously had a higher FC_sim value (12.0 ± 2.8 vs 9.3 ± 4.4 s, P = 0.08). Patients that exhibited a decrease of compliance also showed a significantly lower FC_sim value (11.3 ± 3.5 vs 4.7 ± 0.7, P < 1e-5). FC connectivity analysis derived from an fMRI task-based study including repetitive voiding cycles is able to quantify the heterogeneity of connectivity patterns in the brain of MS patients. FC similarity decreased with maximum lesion size or the presence of enhancing lesions affecting the ability to void spontaneously.

Altered functional connectivity density in patients with herpes zoster and postherpetic neuralgia.

PurposeThe aim of this study was to explore intrinsic functional connectivity patterns in patients with herpes zoster (HZ) and postherpetic neuralgia (PHN).Patients and methodsThirty-three right-handed HZ patients (13 males; mean age 57.15±9.30 years), 22 right-handed PHN patients (9 males; mean age 66.13±6.77 years), and 28 well-matched healthy controls (HC) (9 males; mean age 54.21±7.72 years) underwent resting-state functional magnetic resonance imaging for intrinsic functional connectivity analyses. Functional connectivity density (FCD) was calculated and compared among the PHN, HZ, and HC groups. In addition, the Pearson correlation coefficient was calculated to compare various clinical indices in the regions with abnormal FCD values.ResultsCompared with the HC, both HZ and PHN patients showed significantly decreased FCD in the precuneus, and patients with HZ displayed significantly increased FCD in the brainstem/limbic lobe/parahippocampalgyrus, whereas patients with PHN displayed significantly increased FCD in the hippocampus (correlation thresholds r=0.25, voxel level of P<0.01 and Gaussian random field theory at a cluster level of P<0.05). However, the FCD was not significantly different between the PHN and HZ patients. Furthermore, the decreased FCD in the precuneus was positively correlated with the visual analog scale score in the PHN group (r=0.672; P=0.001).ConclusionDecreased connectivity of the precuneus occurred in both HZ and PHN patients, indicating a disrupted default-mode network. Furthermore, in the HZ group (initial stage of the virus infection), hyperconnectivity was observed in systems involved in pain transmission and interpretation, but hyperconnectivity only occurred in the hippocampus in the PHN group (neuropathic pain stage).

Convergent and divergent functional connectivity patterns in patients with long-term left-sided and right-sided deafness.

Cortical reorganization may be induced in long-term single-sided deafness (SD); however, the influence of the deafness side on the functional changes remains poorly understood. Here, we investigated whole-brain functional connectivity patterns in long-term SD patients. The normalized voxel-based functional connectivity strength (FCS) was determined using resting-state fMRI (rs-fMRI) in 17 left-sided deafness (LD) patients, 21 right-sided deafness (RD) patients and 21 healthy controls (HCs). Relative to the HCs, both the LD and RD patients exhibited a reduction in the FCS in the ipsilateral visual cortex. However, compared to that in the HCs, a significantly higher FCS was observed in some regions in the salience and default-mode networks in the RD patients, but this FCS alternation pattern was not observed in the LD patients. A direct comparison of the two patient groups revealed a significantly increased FCS in the supplemental motor area in the LD group. Altogether, the long-term SD groups with LD and RD exhibited convergent and divergent functional connectivity patterns in whole-brain networks, providing promising evidence that the functional changes in long-term SD are highly deafness-side-dependent.

Negative mood influences default mode network functional connectivity in patients with chronic low back pain: implications for functional neuroimaging biomarkers.

The default mode network (DMN) has been proposed as a biomarker for several chronic pain conditions. Default mode network functional connectivity (FC) is typically examined during resting-state functional neuroimaging, in which participants are instructed to let thoughts wander. However, factors at the time of data collection (eg, negative mood) that might systematically impact pain perception and its brain activity, influencing the application of the DMN as a pain biomarker, are rarely reported. This study measured whether positive and negative moods altered DMN FC patterns in patients with chronic low back pain (CLBP), specifically focusing on negative mood because of its clinical relevance. Thirty-three participants (CLBP = 17) underwent resting-state functional magnetic resonance imaging scanning before and after sad and happy mood inductions, and rated levels of mood and pain intensity at the time of scanning. Two-way repeated-measures analysis of variances were conducted on resting-state functional connectivity data. Significant group (CLBP > healthy controls) × condition (sadness > baseline) interaction effects were identified in clusters spanning parietal operculum/postcentral gyrus, insular cortices, anterior cingulate cortex, frontal pole, and a portion of the cerebellum (PFDR < 0.05). However, only 1 significant cluster covering a portion of the cerebellum was identified examining a two-way repeated-measures analysis of variance for happiness > baseline (PFDR < 0.05). Overall, these findings suggest that DMN FC is affected by negative mood in individuals with and without CLBP. It is possible that DMN FC seen in patients with chronic pain is related to an affective dimension of pain, which is important to consider in future neuroimaging biomarker development and implementation.

MRI in the evaluation of pediatric multiple sclerosis.

MRI plays a pivotal role in the diagnosis of multiple sclerosis (MS) in children, as it does in adults. The presence of multiple lesions in CNS locations commonly affected by MS, along with the presence of both enhancing and nonenhancing lesions, can facilitate a diagnosis of MS at the time of a first attack, whereas the accrual of serial lesions or new clinical attacks over time confirms the diagnosis in patients not meeting such criteria at onset. T2 and enhancing lesion accrual could serve as a primary outcome metric for pediatric MS clinical trials of selected therapies with anti-inflammatory activity in order to facilitate feasible trial size numbers. More-advanced MRI techniques reveal the impact of MS on tissue integrity within both T2-bright and T1-hypointense lesions and regions of normal-appearing tissue. Volumetric MRI analyses quantify the impact of MS on age-expected brain growth, and fMRI reveals activation and resting-state functional connectivity patterns in patients with pediatric MS that differ from those seen in healthy age-matched youth. Such studies are of critical importance because MS onset during childhood may profoundly influence maturing and actively myelinating neural networks. High-field MRI visualizes MS pathology at a near-microscopic level and has the potential to more fully explain mechanisms for cognitive impairment, fatigue, and disability in patients with pediatric MS.