Altered Iron and Microstructure in Huntington's Disease Subcortical Nuclei: Insight From 7T MRI.

BACKGROUND: Pathophysiological changes of Huntington's disease (HD) can precede symptom onset by decades. Robust imaging biomarkers are needed to monitor HD progression, especially before the clinical onset. PURPOSE: To investigate iron dysregulation and microstructure alterations in subcortical regions as HD imaging biomarkers, and to associate such alterations with motor and cognitive impairments. STUDY TYPE: Prospective. POPULATION: Fourteen individuals with premanifest HD (38.0 ± 11.0 years, 9 females; far-from-onset N = 6, near-onset N = 8), 21 manifest HD patients (49.1 ± 12.1 years, 11 females), and 33 age-matched healthy controls (43.9 ± 12.2 years, 17 females). FIELD STRENGTH/SEQUENCE: 7 T, T1 -weighted imaging, quantitative susceptibility mapping, and diffusion tensor imaging. ASSESSMENT: Volume, susceptibility, fractional anisotropy (FA), and mean diffusivity (MD) within subcortical brain structures were compared across groups, used to establish HD classification models, and correlated to clinical measures and cognitive assessments. STATISTICAL TESTS: Generalized linear model, multivariate logistic regression, receiver operating characteristics with the area under the curve (AUC), and likelihood ratio test comparing a volumetric model to one that also includes susceptibility and diffusion metrics, Wilcoxon paired signed-rank test, and Pearson's correlation. A P-value <0.05 after Benjamini-Hochberg correction was considered statistically significant. RESULTS: Significantly higher striatal susceptibility and FA were found in premanifest and manifest HD preceding atrophy, even in far-from-onset premanifest HD compared to controls (putamen susceptibility: 0.027 ± 0.022 vs. 0.018 ± 0.013 ppm; FA: 0.358 ± 0.048 vs. 0.313 ± 0.039). The model with additional susceptibility, FA, and MD features showed higher AUC compared to volume features alone when differentiating premanifest HD from HC (0.83 vs. 0.66), and manifest from premanifest HD (0.94 vs. 0.83). Higher striatal susceptibility significantly correlated with cognitive deterioration in HD (executive function: r = -0.600; socioemotional function: r = -0.486). DATA CONCLUSION: 7 T MRI revealed iron dysregulation and microstructure alterations with HD progression, which could precede volume loss, provide added value to HD differentiation, and might be associated with cognitive changes. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 2.

Advances in Deep Brain Stimulation: From Mechanisms to Applications.

Deep brain stimulation (DBS) is an effective therapy for various neurologic and neuropsychiatric disorders, involving chronic implantation of electrodes into target brain regions for electrical stimulation delivery. Despite its safety and efficacy, DBS remains an underutilized therapy. Advances in the field of DBS, including in technology, mechanistic understanding, and applications have the potential to expand access and use of DBS, while also improving clinical outcomes. Developments in DBS technology, such as MRI compatibility and bidirectional DBS systems capable of sensing neural activity while providing therapeutic stimulation, have enabled advances in our understanding of DBS mechanisms and its application. In this review, we summarize recent work exploring DBS modulation of target networks. We also cover current work focusing on improved programming and the development of novel stimulation paradigms that go beyond current standards of DBS, many of which are enabled by sensing-enabled DBS systems and have the potential to expand access to DBS.

Human upper extremity motor cortex activity shows distinct oscillatory signatures for stereotyped arm and leg movements.

Introduction: Stepping and arm swing are stereotyped movements that require coordination across multiple muscle groups. It is not known whether the encoding of these stereotyped movements in the human primary motor cortex is confined to the limbs' respective somatotopy. Methods: We recorded subdural electrocorticography activities from the hand/arm area in the primary motor cortex of 6 subjects undergoing deep brain stimulation surgery for essential tremor and Parkinson's disease who performed stepping (all patients) and arm swing (n = 3 patients) tasks. Results: We show stepping-related low frequency oscillations over the arm area. Furthermore, we show that this oscillatory activity is separable, both in frequency and spatial domains, from gamma band activity changes that occur during arm swing. Discussion: Our study contributes to the growing body of evidence that lower extremity movement may be more broadly represented in the motor cortex, and suggest that it may represent a way to coordinate stereotyped movements across the upper and lower extremities.

Cerebellar deep brain stimulation for the treatment of movement disorders in cerebral palsy.

OBJECTIVE: Cerebral palsy (CP) represents the most common childhood physical disability that encompasses disorders of movement and posture attributed to nonprogressive disturbances that occurred in the developmental fetal or infant brain. Dyskinetic CP (DCP), the second most common type of CP after spastic forms, refers to a subset of patients in whom dystonia and choreoathetosis are the predominant motor manifestations. Most children with CP have abnormal brain MRI studies indicative of cortical and deep gray matter damage consistent with hypoxic ischemic encephalopathy, which may preclude or suggest decreased efficacy of standard deep brain stimulation (DBS) targets. The cerebellum has been posited as an attractive target for treatment of DCP because it is frequently spared from hypoxic ischemic damage and has shown promise in alleviating patient symptoms both in early work in the 1970s and in more recent case series with DBS. METHODS: The authors performed bilateral cerebellar DBS implantation, targeting the dentate nucleus (DN) and cerebellar outflow pathway, in 3 patients with DCP. Leads were connected to a pulse generator that senses local field potentials during chronic continuous DBS. The authors report their surgical methods, examples of chronic cerebellar local field potential recordings, and preliminary clinical outcomes. Motor outcomes were assessed using the Burke-Fahn-Marsden Dystonia Rating Scale. RESULTS: Three patients 14-22 years old with DCP and MRI evidence of structural damage to the basal ganglia were offered cerebellar stimulation targeting the DN. All patients tolerated the procedure well and demonstrated improvement in subjective motor function as well as objective improvement in the Burke-Fahn-Marsden Dystonia Rating Scale movement subscale, although the range of responses was variable (19%-40%). Patients experienced subjective improvement in motor function including ease of hand movements and coordination, gait, head control, speech, decreased overflow, and diminished muscle tightness. CONCLUSIONS: DBS of the dentate nuclei in patients with DCP appears to be safe and shows preliminary evidence of clinical benefit. New chronic sensing technology may allow for determination of in vivo mechanisms of network disruption in DCP and allow for further understanding of the effects of neuromodulation on brain physiology. Larger studies with long-term follow up will be required to further elucidate the clinical benefits of this therapy. This report addresses a gap in the literature regarding the technical approach to image-based stereotactic targeting and chronic neural recording in the DN.

DeepSWI: Using Deep Learning to Enhance Susceptibility Contrast on T2*-Weighted MRI.

BACKGROUND: Although susceptibility-weighted imaging (SWI) is the gold standard for visualizing cerebral microbleeds (CMBs) in the brain, the required phase data are not always available clinically. Having a postprocessing tool for generating SWI contrast from T2*-weighted magnitude images is therefore advantageous. PURPOSE: To create synthetic SWI images from clinical T2*-weighted magnitude images using deep learning and evaluate the resulting images in terms of similarity to conventional SWI images and ability to detect radiation-associated CMBs. STUDY TYPE: Retrospective. POPULATION: A total of 145 adults (87 males/58 females; 43.9 years old) with radiation-associated CMBs were used to train (16,093 patches/121 patients), validate (484 patches/4 patients), and test (2420 patches/20 patients) our networks. FIELD STRENGTH/SEQUENCE: 3D T2*-weighted, gradient-echo acquired at 3 T. ASSESSMENT: Structural similarity index (SSIM), peak signal-to-noise-ratio (PSNR), normalized mean-squared-error (nMSE), CMB counts, and line profiles were compared among magnitude, original SWI, and synthetic SWI images. Three blinded raters (J.E.V.M., M.A.M., B.B. with 8-, 6-, and 4-years of experience, respectively) independently rated and classified test-set images. STATISTICAL TESTS: Kruskall-Wallis and Wilcoxon signed-rank tests were used to compare SSIM, PSNR, nMSE, and CMB counts among magnitude, original SWI, and predicted synthetic SWI images. Intraclass correlation assessed interrater variability. P values <0.005 were considered statistically significant. RESULTS: SSIM values of the predicted vs. original SWI (0.972, 0.995, 0.9864) were statistically significantly higher than that of the magnitude vs. original SWI (0.970, 0.994, 0.9861) for whole brain, vascular structures, and brain tissue regions, respectively; 67% (19/28) CMBs detected on original SWI images were also detected on the predicted SWI, whereas only 10 (36%) were detected on magnitude images. Overall image quality was similar between the synthetic and original SWI images, with less artifacts on the former. CONCLUSIONS: This study demonstrated that deep learning can increase the susceptibility contrast present in neurovasculature and CMBs on T2*-weighted magnitude images, without residual susceptibility-induced artifacts. This may be useful for more accurately estimating CMB burden from magnitude images alone. EVIDENCE LEVEL: 3. TECHNICAL EFFICACY: Stage 2.

Comparison of quantitative susceptibility mapping methods for iron-sensitive susceptibility imaging at 7T: An evaluation in healthy subjects and patients with Huntington's disease.

Quantitative susceptibility mapping (QSM) is a promising tool for investigating iron dysregulation in neurodegenerative diseases, including Huntington's disease (HD). Many diverse methods have been proposed to generate accurate and robust QSM images. In this study, we evaluated the performance of different dipole inversion algorithms for iron-sensitive susceptibility imaging at 7T on healthy subjects of a large age range and patients with HD. We compared an iterative least-squares-based method (iLSQR), iterative methods that use regularization, single-step approaches, and deep learning-based techniques. Their performance was evaluated by comparing: (1) deviations from a multiple-orientation QSM reference; (2) visual appearance of QSM maps and the presence of artifacts; (3) susceptibility in subcortical brain regions with age; (4) regional brain susceptibility with published postmortem brain iron quantification; and (5) susceptibility in HD-affected basal ganglia regions between HD subjects and healthy controls. We found that single-step QSM methods with either total variation or total generalized variation constraints (SSTV/SSTGV) and the single-step deep learning method iQSM generally provided the best performance in terms of correlation with iron deposition and were better at differentiating between healthy controls and premanifest HD individuals, while deep learning QSM methods trained with multiple-orientation susceptibility data created QSM maps that were most similar to the multiple orientation reference and with the best visual scores.

Tractography-based DBS lead repositioning improves outcome in refractory OCD and depression.

Deep brain stimulation (DBS) of the anterior limb of the internal capsule (ALIC) has been used to treat refractory obsessive-compulsive disorder (OCD) and depression, but outcomes are variable, with some patients not responding to this form of invasive neuromodulation. A lack of benefit in some patients may be due to suboptimal positioning of DBS leads. Recently, studies have suggested that specific white matter tracts within the ALIC are associated with improved outcomes. Here, we present the case of a patient who initially had a modest improvement in OCD and depressive symptoms after receiving DBS within the ALIC. Subsequently, he underwent unilateral DBS lead repositioning informed by tractography targeting the ventrolateral and medial prefrontal cortex's connection with the mediodorsal thalamus. In this patient, we also conducted post-implant and post-repositioning diffusion imaging and found that we could successfully perform tractography even with DBS leads in place. Following lead repositioning into tracts predictive of benefit, the patient reached responder criteria for his OCD, and his depression was remitted. This case illustrates that tractography can potentially be used in the evaluation and planning of lead repositioning to achieve therapeutic outcomes.

Cortico-Subthalamic Field Potentials Support Classification of the Natural Gait Cycle in Parkinson's Disease and Reveal Individualized Spectral Signatures.

The ability of humans to coordinate stereotyped, alternating movements between the two legs during bipedal walking is a complex motor behavior that requires precisely timed activities across multiple nodes of the supraspinal network. Understanding of the neural network dynamics that underlie natural walking in humans is limited. We investigated cortical and subthalamic neural activities during overground walking and evaluated spectral biomarkers to decode the gait cycle in three patients with Parkinson's disease without gait disturbances. Patients were implanted with chronic bilateral deep brain stimulation (DBS) leads in the subthalamic nucleus (STN) and electrocorticography paddles overlaying the primary motor and somatosensory cortices. Local field potentials were recorded from these areas while the participants performed overground walking and synchronized to external gait kinematic sensors. We found that the STN displays increased low-frequency (4-12 Hz) spectral power during the period before contralateral leg swing. Furthermore, STN shows increased theta frequency (4-8 Hz) coherence with the primary motor through the initiation and early phase of contralateral leg swing. Additional analysis revealed that each patient had specific frequency bands that could detect a significant difference between left and right initial leg swing. Our findings indicate that there are alternating spectral changes between the two hemispheres in accordance with the gait cycle. In addition, we identified patient-specific, gait-related biomarkers in both the STN and cortical areas at discrete frequency bands that may be used to drive adaptive DBS to improve gait dysfunction in patients with Parkinson's disease.

Functional network alterations in young brain tumor patients with radiotherapy-induced memory impairments and vascular injury.

Background: Cognitive impairment and cerebral microbleeds (CMBs) are long-term side-effects of cranial radiation therapy (RT). Previously we showed that memory function is disrupted in young patients and that the rate of cognitive decline correlates with CMB development. However, vascular injury alone cannot explain RT-induced cognitive decline. Here we use resting-state functional MRI (rsfMRI) to further investigate the complex mechanisms underlying memory impairment after RT. Methods: Nineteen young patients previously treated with or without focal or whole-brain RT for a brain tumor underwent cognitive testing followed by 7T rsfMRI and susceptibility-weighted imaging for CMB detection. Global brain modularity and efficiency, and rsfMRI signal variability within the dorsal attention, salience, and frontoparietal networks were computed. We evaluated whether MR metrics could distinguish age- and sex-matched controls (N = 19) from patients and differentiate patients based on RT exposure and aggressiveness. We also related MR metrics with memory performance, CMB burden, and risk factors for cognitive decline after RT. Results: Compared to controls, patients exhibited widespread hyperconnectivity, similar modularity, and significantly increased efficiency (p < 0.001) and network variability (p < 0.001). The most abnormal values were detected in patients treated with high dose whole-brain RT, having supratentorial tumors, and who did not undergo RT but had hydrocephalus. MR metrics and memory performance were correlated (R = 0.34-0.53), though MR metrics were more strongly related to risk factors for cognitive worsening and CMB burden with evidence of functional recovery. Conclusions: MR metrics describing brain connectivity and variability represent promising candidate imaging biomarkers for monitoring of long-term cognitive side-effects after RT.

An Integrated Analysis of Clinical, Genomic, and Imaging Features Reveals Predictors of Neurocognitive Outcomes in a Longitudinal Cohort of Pediatric Cancer Survivors, Enriched with CNS Tumors (Rad ART Pro).

Background: Neurocognitive deficits in pediatric cancer survivors occur frequently; however, individual outcomes are unpredictable. We investigate clinical, genetic, and imaging predictors of neurocognition in pediatric cancer survivors, with a focus on survivors of central nervous system (CNS) tumors exposed to radiation. Methods: One hundred eighteen patients with benign or malignant cancers (median diagnosis age: 7; 32% embryonal CNS tumors) were selected from an existing multi-institutional cohort (RadART Pro) if they had: 1) neurocognitive evaluation; 2) available DNA; 3) standard imaging. Utilizing RadART Pro, we collected clinical history, genomic sequencing, CNS imaging, and neurocognitive outcomes. We performed single nucleotide polymorphism (SNP) genotyping for candidate genes associated with neurocognition: COMT, BDNF, KIBRA, APOE, KLOTHO. Longitudinal neurocognitive testing were performed using validated computer-based CogState batteries. The imaging cohort was made of patients with available iron-sensitive (n = 28) and/or T2 FLAIR (n = 41) sequences. Cerebral microbleeds (CMB) were identified using a semi-automated algorithm. Volume of T2 FLAIR white matter lesions (WML) was measured using an automated method based on a convolutional neural network. Summary statistics were performed for patient characteristics, neurocognitive assessments, and imaging. Linear mixed effects and hierarchical models assessed patient characteristics and SNP relationship with neurocognition over time. Nested case-control analysis was performed to compare candidate gene carriers to non-carriers. Results: CMB presence at baseline correlated with worse performance in 3 of 7 domains, including executive function. Higher baseline WML volumes correlated with worse performance in executive function and verbal learning. No candidate gene reliably predicted neurocognitive outcomes; however, APOE ϵ4 carriers trended toward worse neurocognitive function over time compared to other candidate genes and carried the highest odds of low neurocognitive performance across all domains (odds ratio 2.85, P=0.002). Hydrocephalus and seizures at diagnosis were the clinical characteristics most frequently associated with worse performance in neurocognitive domains (5 of 7 domains). Overall, executive function and verbal learning were the most frequently negatively impacted neurocognitive domains. Conclusion: Presence of CMB, APOE ϵ4 carrier status, hydrocephalus, and seizures correlate with worse neurocognitive outcomes in pediatric cancer survivors, enriched with CNS tumors exposed to radiation. Ongoing research is underway to verify trends in larger cohorts.

Relationship between 7T MR-angiography features of vascular injury and cognitive decline in young brain tumor patients treated with radiation therapy.

PURPOSE: Although radiation therapy (RT) is a common treatment for pediatric brain tumors, it is associated with detrimental long-term effects such as impaired cognition, vascular injury, and increased stroke risk. This study aimed to develop metrics that describe vascular injury and relate them to the presence of cerebral microbleeds (CMBs) and cognitive performance scores. METHODS: Twenty-five young adult survivors of pediatric brain tumors treated with either whole-brain (n = 12), whole-ventricular (n = 7), or no RT (n = 6) underwent 7T MRI and neurocognitive testing. Simultaneously acquired MR angiography and susceptibility-weighted images were used to segment CMBs and vessels and quantify their radii and volume. RESULTS: Patients treated with whole-brain RT had significantly lower arterial volumes (p = 0.003) and a higher proportion of smaller vessels (p = 0.003) compared to the whole-ventricular RT and non-irradiated control patients. Normalized arterial volume decreased with increasing CMB count (R = - 0.66, p = 0.003), and decreasing trends were observed with time since RT and at longitudinal follow-up. Global cognition and verbal memory significantly decreased with smaller normalized arterial volume (p ≤ 0.05). CONCLUSIONS: Arterial volume is reduced with increasing CMB presence and is influenced by the total brain volume exposed to radiation. This work highlights the potential use of vascular-derived metrics as non-invasive markers of treatment-induced injury and cognitive impairment in pediatric brain tumor patients.

DBS targeting for essential tremor using intersectional dentato-rubro-thalamic tractography and direct proton density visualization of the VIM: technical note on 2 cases.

OBJECTIVE: Direct visualization of the ventral intermediate nucleus (VIM) of the thalamus on standard MRI sequences remains elusive. Therefore, deep brain stimulation (DBS) surgery for essential tremor (ET) indirectly targets the VIM using atlas-derived consensus coordinates and requires awake intraoperative testing to confirm clinical benefits. The objective of this study was to evaluate the utility of proton density (PD)-weighted MRI and tractography of the intersecting dentato-rubro-thalamic tract (DRTT) for direct "intersectional" targeting of the VIM in ET. METHODS: DBS targets were selected by identifying the VIM on PD-weighted images relative to the DRTT in 2 patients with ET. Tremor reduction was confirmed with intraoperative clinical testing. Intended target coordinates based on the direct intersectional targeting technique were compared with consensus coordinates obtained with indirect targeting. Pre- and postoperative tremor scores were assessed using the Fahn-Tolosa-Marin tremor rating scale (TRS). RESULTS: Planned DBS coordinates based on direct versus indirect targeting of the VIM differed in both the anteroposterior (range 0 to 2.3) and lateral (range -0.7 to 1) directions. For 1 patient, indirect targeting-without PD-weighted visualization of the VIM and DRTT-would have likely resulted in suboptimal electrode placement within the VIM. At the 3-month follow-up, both patients demonstrated significant improvement in tremor symptoms subjectively and according to the TRS (case 1: 68%, case 2: 72%). CONCLUSIONS: Direct intersectional targeting of the VIM using PD-weighted imaging and DRTT tractography is a feasible method for DBS placement in patients with ET. These advanced targeting techniques can supplement awake intraoperative testing or be used independently in asleep cases to improve surgical efficiency and confidence.

Beyond the Superordinate Categories of "Gay Men" and "Lesbian Women": Identification of Gay and Lesbian Subgroups.

Nation-wide opinion polls and social scientific studies indicate that evaluations of gay men and lesbian women have become increasingly favourable. These positive trends do not explain the widespread discrimination experiences being reported. To assist researchers in investigating attitudes towards gay and lesbian persons, the current research examines whether there are multiple "types" that are identifiable and salient. Two Canadian studies (Ns = 67 and 206) were conducted to establish the presence of gay and lesbian subgroups. Using subgroups generated by Study 1 participants, community and student sub-samples selected those they perceive to exist. Results indicated that, for gay men, the subgroups Drag Queen and Flamboyant emerged, as did Butch for lesbian women. Amongst students, Closeted and Feminine also emerged for gay men, as well as Feminist and Tomboy for lesbian women. These findings have implications for contemporary research on gay- and lesbian-related attitudes and the methodology used to assess them.

Simultaneous multi-slice spin- and gradient-echo dynamic susceptibility-contrast perfusion-weighted MRI of gliomas.

Although combined spin- and gradient-echo (SAGE) dynamic susceptibility-contrast (DSC) MRI can provide perfusion quantification that is sensitive to both macrovessels and microvessels while correcting for T1 -shortening effects, spatial coverage is often limited in order to maintain a high temporal resolution for DSC quantification. In this work, we combined a SAGE echo-planar imaging (EPI) sequence with simultaneous multi-slice (SMS) excitation and blipped controlled aliasing in parallel imaging (blipped CAIPI) at 3 T to achieve both high temporal resolution and whole brain coverage. Two protocols using this sequence with multi-band (MB) acceleration factors of 2 and 3 were evaluated in 20 patients with treated gliomas to determine the optimal scan parameters for clinical use. ΔR2 *(t) and ΔR2 (t) curves were derived to calculate dynamic signal-to-noise ratio (dSNR), ΔR2 *- and ΔR2 -based relative cerebral blood volume (rCBV), and mean vessel diameter (mVD) for each voxel. The resulting SAGE DSC images acquired using MB acceleration of 3 versus 2 appeared visually similar in terms of image distortion and contrast. The difference in the mean dSNR from normal-appearing white matter (NAWM) and that in the mean dSNR between NAWM and normal-appearing gray matter were not statistically significant between the two protocols. ΔR2 *- and ΔR2 -rCBV maps and mVD maps provided unique contrast and spatial heterogeneity within tumors.

7-T Magnetic Resonance Imaging in the Management of Brain Tumors.

This article provides an overview of the current status of ultrahigh-field 7-T magnetic resonance (MR) imaging in neuro-oncology, specifically for the management of patients with brain tumors. It includes a discussion of areas across the pretherapeutic, peritherapeutic, and posttherapeutic stages of patient care where 7-T MR imaging is currently being exploited and holds promise. This discussion includes existing technical challenges, barriers to clinical integration, as well as our impression of the future role of 7-T MR imaging as a clinical tool in neuro-oncology.

Rate of radiation-induced microbleed formation on 7T MRI relates to cognitive impairment in young patients treated with radiation therapy for a brain tumor.

BACKGROUND: Radiation therapy (RT) is essential to the management of many brain tumors, but has been known to lead to cognitive decline and vascular injury in the form of cerebral microbleeds (CMBs). PURPOSE: In a subset of children, adolescents, and young adults recruited from a larger trial investigating arteriopathy and stroke risk after RT, we evaluated the prevalence of CMBs after RT, examined risk factors for CMBs and cognitive impairment, and related their longitudinal development to cognitive performance changes. METHODS: Twenty-five patients (mean 17 years, range: 10-25 years) underwent 7-Tesla MRI and cognitive assessment. Nineteen patients were treated with whole-brain or focal RT 1-month to 20-years prior, while 6 non-irradiated patients with posterior-fossa tumors served as controls. CMBs were detected on 7T susceptibility-weighted imaging (SWI) using semi-automated software, a first use in this population. RESULTS: CMB detection sensitivity with 7T SWI was higher than previously reported at lower field strengths, with one or more CMBs detected in 100% of patients treated with RT at least 1-year prior. CMBs were localized to dose-targeted brain volumes with risk factors including whole-brain RT (p = 0.05), a higher RT dose (p = 0.01), increasing time since RT (p = 0.03), and younger age during RT (p = 0.01). Apart from RT dose, these factors were associated with impaired memory performance. Follow-up data in a subset of patients revealed a proportional increase in CMB count with worsening verbal memory performance (r = -0.85, p = 0.03). CONCLUSIONS: Treatment with RT during youth is associated with the chronic development of CMBs that evolve with memory impairment over time.

Identification of occult cerebral microbleeds in adults with immune thrombocytopenia.

Management of symptoms and prevention of life-threatening hemorrhage in immune thrombocytopenia (ITP) must be balanced against adverse effects of therapies. Because current treatment guidelines based on platelet count are confounded by variable bleeding phenotypes, there is a need to identify new objective markers of disease severity for treatment stratification. In this cross-sectional prospective study of 49 patients with ITP and nadir platelet counts <30 × 109/L and 18 aged-matched healthy controls, we used susceptibility-weighted magnetic resonance imaging to detect cerebral microbleeds (CMBs) as a marker of occult hemorrhage. CMBs were detected using a semiautomated method and correlated with clinical metadata using multivariate regression analysis. No CMBs were detected in health controls. In contrast, lobar CMBs were identified in 43% (21 of 49) of patients with ITP; prevalence increased with decreasing nadir platelet count (0/4, ≥15 × 109/L; 2/9, 10-14 × 109/L; 4/11, 5-9 × 109/L; 15/25 <5 × 109/L) and was associated with longer disease duration (P = 7 × 10-6), lower nadir platelet count (P = .005), lower platelet count at time of neuroimaging (P = .029), and higher organ bleeding scores (P = .028). Mucosal and skin bleeding scores, number of previous treatments, age, and sex were not associated with CMBs. Occult cerebral microhemorrhage is common in patients with moderate to severe ITP. Strong associations with ITP duration may reflect CMB accrual over time or more refractory disease. Further longitudinal studies in children and adults will allow greater understanding of the natural history and clinical and prognostic significance of CMBs.