Decreased homotopic functional connectivity in traumatic brain injury.

INTRODUCTION: Homotopic functional connectivity (HoFC), the synchrony in activity patterns between homologous brain regions, is a fundamental characteristic of resting-state functional connectivity (RsFC). METHODS: We examined the difference in HoFC, computed as the correlation between atlas-based regions and their counterpart on the opposite hemisphere, in 16 moderate-severe traumatic brain injury patients (msTBI) and 36 healthy controls. Regions of decreased HoFC in msTBI patients were further used as seeds for examining differences between groups in correlations with other brain regions. Finally, we computed logistic regression models of regional HoFC and fractional anisotropy (FA) of the corpus callosum (CC). RESULTS: TBI patients exhibited decreased HoFC in the middle and posterior cingulate cortex, thalamus, superior temporal pole, and cerebellum III. Furthermore, decreased RsFC was found between left cerebellum III and right parahippocampal cortex and vermis, between superior temporal pole and left caudate and medial left and right frontal orbital gyri. Thalamic HoFC and FA of the CC discriminate patients as msTBI with a high accuracy of 96%. CONCLUSION: TBI is associated with regionally decreased HoFC. Moreover, a multimodality model of interhemispheric connectivity allowed for a high degree of accuracy in disease discrimination and enabled a deeper understanding of TBI effects on brain interhemispheric reorganization post-TBI.

In vivo measurements of lamination patterns in the human cortex.

The laminar composition of the cerebral cortex is tightly connected to the development and connectivity of the brain, as well as to function and pathology. Although most of the research on the cortical layers is done with the aid of ex vivo histology, there have been recent attempts to use magnetic resonance imaging (MRI) with potential in vivo applications. However, the high-resolution MRI technology and protocols required for such studies are neither common nor practical. In this article, we present a clinically feasible method for assessing the laminar properties of the human cortex using standard pulse sequence available on any common MRI scanner. Using a series of low-resolution inversion recovery (IR) MRI scans allows us to calculate multiple T1 relaxation time constants for each voxel. Based on the whole-brain T1 -distribution, we identify six different gray matter T1 populations and their variation across the cortex. Based on this, we show age-related differences in these population and demonstrate that this method is able to capture the difference in laminar composition across varying brain areas. We also provide comparison to ex vivo high-resolution MRI scans. We show that this method is feasible for the estimation of layer variability across large population cohorts, which can lead to research into the links between the cortical layers and function, behavior and pathologies that was heretofore unexplorable.

Predicting individual variability in task-evoked brain activity in schizophrenia.

What goes wrong in a schizophrenia patient's brain that makes it so different from a healthy brain? In this study, we tested the hypothesis that the abnormal brain activity in schizophrenia is tightly related to alterations in brain connectivity. Using functional magnetic resonance imaging (fMRI), we demonstrated that both resting-state functional connectivity and brain activity during the well-validated N-back task differed significantly between schizophrenia patients and healthy controls. Nevertheless, using a machine-learning approach we were able to use resting-state functional connectivity measures extracted from healthy controls to accurately predict individual variability in the task-evoked brain activation in the schizophrenia patients. The predictions were highly accurate, sensitive, and specific, offering novel insights regarding the strong coupling between brain connectivity and activity in schizophrenia. On a practical perspective, these findings may allow to generate task activity maps for clinical populations without the need to actually perform any tasks, thereby reducing patients inconvenience while saving time and money.

Quantitative platform for accurate and reproducible assessment of transverse (T2 ) relaxation time.

MRI's transverse relaxation time (T2 ) is sensitive to tissues' composition and pathological state. While variations in T2 values can be used as clinical biomarkers, it is challenging to quantify this parameter in vivo due to the complexity of the MRI signal model, differences in protocol implementations, and hardware imperfections. Herein, we provide a detailed analysis of the echo modulation curve (EMC) platform, offering accurate and reproducible mapping of T2 values, from 2D multi-slice multi-echo spin-echo (MESE) protocols. Computer simulations of the full Bloch equations are used to generate an advanced signal model, which accounts for stimulated echoes and transmit field (B1+ ) inhomogeneities. In addition to quantifying T2 values, the EMC platform also provides proton density (PD) maps, and fat-water fraction maps. The algorithm's accuracy, reproducibility, and insensitivity to T1 values are validated on a phantom constructed by the National Institute of Standards and Technology and on in vivo human brains. EMC-derived T2 maps show excellent agreement with ground truth values for both in vitro and in vivo models. Quantitative values are accurate and stable across scan settings and for the physiological range of T2 values, while showing robustness to main field (B0 ) inhomogeneities, to variations in T1 relaxation time, and to magnetization transfer. Extension of the algorithm to two-component fitting yields accurate fat and water T2 maps along with their relative fractions, similar to a reference three-point Dixon technique. Overall, the EMC platform allows to generate accurate and stable T2 maps, with a full brain coverage using a standard MESE protocol and at feasible scan times. The utility of EMC-based T2 maps was demonstrated on several clinical applications, showing robustness to variations in other magnetic properties. The algorithm is available online as a full stand-alone package, including an intuitive graphical user interface.

Widespread cortical dyslamination in epilepsy patients with malformations of cortical development.

PURPOSE: Recent research in epilepsy patients confirms our understanding of epilepsy as a network disorder with widespread cortical compromise. Here, we aimed to investigate the neocortical laminar architecture in patients with focal cortical dysplasia (FCD) and periventricular nodular heterotopia (PNH) using clinically feasible 3 T MRI. METHODS: Eighteen epilepsy patients (FCD and PNH groups; n = 9 each) and age-matched healthy controls (n = 9) underwent T1 relaxation 3 T MRI, from which component probability T1 maps were utilized to extract sub-voxel composition of 6 T1 cortical layers. Seventy-eight cortical areas of the automated anatomical labeling atlas were divided into 1000 equal-volume sub-areas for better detection of cortical abnormalities, and logistic regressions were performed to compare FCD/PNH patients with healthy controls with the T1 layers composing each sub-area as regressors. Statistical significance (p < 0.05) was determined by a likelihood-ratio test with correction for false discovery rate using Benjamini-Hochberg method. RESULTS: Widespread cortical abnormalities were observed in the patient groups. Out of 1000 sub-areas, 291 and 256 bilateral hemispheric cortical sub-areas were found to predict FCD and PNH, respectively. For each of these sub-areas, we were able to identify the T1 layer, which contributed the most to the prediction. CONCLUSION: Our results reveal widespread cortical abnormalities in epilepsy patients with FCD and PNH, which may have a role in epileptogenesis, and likely related to recent studies showing widespread structural (e.g., cortical thinning) and diffusion abnormalities in various human epilepsy populations. Our study provides quantitative information of cortical laminar architecture in epilepsy patients that can be further targeted for study in functional and neuropathological studies.

Short-term plasticity following motor sequence learning revealed by diffusion magnetic resonance imaging.

Current noninvasive methods to detect structural plasticity in humans are mainly used to study long-term changes. Diffusion magnetic resonance imaging (MRI) was recently proposed as a novel approach to reveal gray matter changes following spatial navigation learning and object-location memory tasks. In the present work, we used diffusion MRI to investigate the short-term neuroplasticity that accompanies motor sequence learning. Following a 45-min training session in which participants learned to accurately play a short sequence on a piano keyboard, changes in diffusion properties were revealed mainly in motor system regions such as the premotor cortex and cerebellum. In a second learning session taking place immediately afterward, feedback was given on the timing of key pressing instead of accuracy, while participants continued to learn. This second session induced a different plasticity pattern, demonstrating the dynamic nature of learning-induced plasticity, formerly thought to require months of training in order to be detectable. These results provide us with an important reminder that the brain is an extremely dynamic structure. Furthermore, diffusion MRI offers a novel measure to follow tissue plasticity particularly over short timescales, allowing new insights into the dynamics of structural brain plasticity.

Effects of aquatic physical intervention on fall risk, working memory and hazard-perception as pedestrians in older people: a pilot trial.

BACKGROUND: Normal aging is associated with balance, mobility and working memory decline that increase fall risk and influence activity of daily living functions. Mounting evidence suggests that physical activity is beneficial for decreasing aging effects. Previous studies have focused on land-based physical activity. Research concerning the aquatic environment is scarce. The primary objectives of this three arm intervention pilot study were to examine the effects of an aquatic physical intervention program on balance, gait, fall risk and working memory among community-dwelling older individuals. The secondary objective was to examine the effects of an aquatic physical intervention program on safety of street-crossing among community-dwelling older individuals. METHODS: Forty-two healthy participants aged 65 or older were enrolled into one of three intervention groups: aquatic physical intervention (API) (N = 13), on-land physical intervention (OLPI) (N = 14) or non-physical intervention (NPI) (N = 15). The intervention took place from 2018 until 2019 at Tel-Aviv University, Sheba medical center and Reich Center. The protocol included 30-min sessions twice a week for 12 weeks. Balance, gait and fall risk were assessed by the Tinneti test, working memory abilities were assessed by digit span and Corsi blocks tests and simulated safe streets-crossing was assessed by the hazard perception test for pedestrians. Testing and data collection was conducted at baseline, after six weeks and 12 weeks of intervention. All members of the professional team involved in evaluating participants were blind to the intervention group to which participants were allocated. RESULTS: The differences in Tinetti balance (F (2, 39)=10.03, p < 0.01), fall risk (F (2, 39)=5.62, p0 > .05), digit span forward (F (2, 39)=8.85, p < 0.01) and Corsi blocks forward (F (2, 39)=3.54, p < 0.05) and backward (F (2, 39)=6.50, p < 0.05) scores after 12 weeks between the groups were significant. The API group showed improved scores. The differences in hazard perception test for pedestrians scores after 12 weeks of intervention between the groups were marginally significant (F (2, 39)=3.13, p = 0.055). The API group showed improved scores. CONCLUSIONS: These findings may affect experts working with the elderly population when making decisions concerning therapeutic prevention interventions for the deficiencies of elderly patients. Older adults practicing aquatic physical activity could contribute to their increased safety. TRIAL REGISTRATION: Trial registration number: ClinicalTrials.gov Registry NCT03510377. Date of registration: 10/31/2017.

Analysis of magnetization transfer (MT) influence on quantitative mapping of T2 relaxation time.

PURPOSE: Multi-echo spin-echo (MESE) protocol is the most effective tool for mapping T2 relaxation in vivo. Still, MESE extensive use of radiofrequency pulses causes magnetization transfer (MT)-related bias of the water signal, instigated by the presence of macromolecules (MMP). Here, we analyze the effects of MT on MESE signal, alongside their impact on quantitative T2 measurements. METHODS: Study used 3 models: in vitro urea phantom, ex vivo horse brain, and in vivo human brain. MT ratio (MTR) was measured between single-SE and MESE protocols under different scan settings including varying echo train lengths, number of slices, and inter-slice gap. MTR and T2 values were extracted for each model and protocol. RESULTS: MT interactions biased MESE signals, and in certain settings, the corresponding T2 values. T2 underestimation of up to 4.3% was found versus single-SE values in vitro and up to 13.8% ex vivo, correlating with the MMP content. T2 bias originated from intra-slice saturation of the MMP, rather than from indirect saturation in multi-slice acquisitions. MT-related signal attenuation was caused by slice crosstalk and/or partial T1 recovery, whereas smaller contribution was caused by MMP interactions. Inter-slice gap had a similar effect on in vivo MTR (21.2%), in comparison to increasing the number of slices (18.9%). CONCLUSIONS: MT influences MESE protocols either by uniformly attenuating the entire echo train or by cumulatively attenuating the signal along the train. Although both processes depend on scan settings and MMP content, only the latter will cause underestimation of T2 .

Growing up with Bilateral parieto-occipital injury: over ten years of clinical observation and neuropsychological follow-up.

This paper presents a follow-up of a child with Balint's syndrome over more than a decade. The patient experienced traumatic brain injury before age 12, resulting in bilateral occipito-parietal infarctions and a clinical presentation of Balint's syndrome. Neuropsychological assessments at three time points showed average verbal abilities alongside persistent difficulties in visual orientation, mirrored in the patient's daily life. Her outstanding compensatory abilities in the face of these impairments are discussed with respect to the recruitment of the ventral visual stream and the role of top-down processing. This profile may help to determine interventions for younger patients with similar lesions.

Despite dystonia: natural history of delayed-onset pediatric secondary dystonia.

Background: Dystonia is a movement disorder involving involuntary movements and/or postures of the limbs, trunk, neck or face. Secondary dystonia following brain injury is uncommon, with unfavorable long-term consequences. Given the limited evidence regarding pediatric secondary dystonia, this study's aim was to document the natural history of the condition and the effect of interventions on its symptomatology. Methods: We describe three cases of girls (age 8 to 11 y) who developed dystonia secondary to an acquired brain injury, received intensive rehabilitation treatments and were followed for 8-33 months post-injury. In all three cases, secondary dystonia appeared 1-3 months post-insult. Results: In none of the cases was there alleviation of dystonic symptoms over time despite physical and pharmacological interventions; in two cases the dystonic hand is now used as an assisting hand only, whereas in the third it is completely non-functional. However, despite their impairment, two girls achieved basic functional independence and one is partly independent in activities of daily living. Conclusions: Rehabilitation professionals who work with pediatric patients susceptible to developing secondary dystonia should be aware of its possible consequences and inform families and staff. Intensive task-specific training during rehabilitation may be key to regaining overall functional capabilities despite residual impairment.

Resolution considerations in imaging of the cortical layers.

The cortical layers are a finger print of brain development, function, connectivity and pathology. Obviously, the formation of the layers and their composition is essential to cognition and behavior. The layers were traditionally measured by histological means but recent studies utilizing MRI suggested that T1 relaxation imaging consist of enough contrast to separate the layers. Indeed extreme resolution, post mortem, studies demonstrated this phenomenon. Yet, one of the limiting factors of using T1 MRI to visualize the layers in neuroimaging research is partial volume effect. This happen when the image resolution is not high enough and two or more layers resides within the same voxel. In this paper we demonstrate that due to the physical small thickness of the layers it is highly unlikely that high resolution imaging could resolve the layers. By contrast, we suggest that low resolution multi T1 mapping conjugate with composition analysis could provide practical means for measuring the T1 layers. We suggest an acquisition platform that is clinically feasible and could quantify measures of the layers. The key feature of the suggested platform is that separation of the layers is better achieved in the T1 relaxation domain rather than in the spatial image domain.

Detection of cavernous malformations after whole-brain radiotherapy in primitive neuroectodermal tumor patients-comparing susceptibility-weighted imaging and T2 gradient-echo sequences.

PURPOSE: The aim of this retrospective study is to investigate the value of the susceptibility-weighted imaging (SWI) sequence compared to gradient echo (GRE) in the detection and follow-up of cavernous malformations in patients who underwent whole-brain irradiation as part of their medulloblastoma treatment. METHODS: We retrospectively examined MRI studies of 28 subjects (16 males, 12 females) who received whole-brain irradiation as part of their treatment. Ages at irradiation ranged from 2 to 38 years. All patients were periodically followed up with MR imaging (ranging from 9 to 336 months). Two neuroradiologists reviewed studies of the same patients, comparing the number of suspected cavernomas detected on GRE and SWI sequences performed at different times (median time between studies, 10 months). RESULTS: Hypointense lesions were detected in 24 subjects on SWI sequences and in 19 subjects on GRE sequences. More lesions were seen on SWI than on GRE (p = 0.006). Four patients had no detectable lesions. The minimal period from irradiation to first lesion detection was 14 months. Cavernomas larger than 3 mm were detected in 14 subjects by both GRE and SWI. None of the subjects had symptoms related to cavernomas. CONCLUSIONS: The sensitivity of SWI in the detection of hypointense lesions in patients after whole-brain irradiation is significantly higher than that of the GRE sequence. It appears that almost all subjects eventually develop small hypointense lesions after radiotherapy, and some of them progress to cavernous malformations. The clinical significance of the increased sensitivity of SWI in this group of patients is not entirely certain.

Quantitative functional MRI biomarkers improved early detection of colorectal liver metastases.

PURPOSE: To implement and evaluate the performance of a computerized statistical tool designed for robust and quantitative analysis of hemodynamic response imaging (HRI) -derived maps for the early identification of colorectal liver metastases (CRLM). MATERIALS AND METHODS: CRLM-bearing mice were scanned during the early stage of tumor growth and subsequently during the advanced-stage. Three experienced radiologists marked various suspected-foci on the early stage anatomical images and classified each as either highly certain or as suspected tumors. The statistical model construction was based on HRI maps (functional-MRI combined with hypercapnia and hyperoxia) using a supervised learning paradigm which was further trained either with the advanced-stage sets (late training; LT) or with the early stage sets (early training; ET). For each group of foci, the classifier results were compared with the ground-truth. RESULTS: The ET-based classification significantly improved the manual classification of the highly certain foci (P < 0.05) and was superior compared with the LT-based classification (P < 0.05). Additionally, the ET-based classification, offered high sensitivity (57-63%), accompanied with high positive predictive value (>94%) and high specificity (>98%) for suspected-foci. CONCLUSION: The ET-based classifier can strengthen the radiologist's classification of highly certain foci. Additionally, it can aid in classifying suspected-foci, thus enabling earlier intervention which can often be lifesaving.

Higher Regional Gray Matter Volume and White Matter Integrity in Individuals With Central Neuropathic Pain After Spinal Cord Injury.

Spinal cord injury (SCI) is a debilitating neurological condition that often leads to central neuropathic pain (CNP). As the fundamental mechanism of CNP is not fully established, its management is one of the most challenging problems among people with SCI. To shed more light on CNP mechanisms, the aim of this cross-sectional study was to compare the brain structure between individuals with SCI and CNP and those without CNP by examining the gray matter (GM) volume and the white matter (WM) integrity. Fifty-two individuals with SCI-28 with CNP and 24 without CNP-underwent a magnetic resonance imaging (MRI) session, including a T1-weighted scan for voxel-based morphometry, and a diffusion-weighted imaging (DWI) scan for WM integrity analysis, as measured by fractional anisotropy (FA) and mean diffusivity (MD). We found significantly higher GM volume in individuals with CNP compared with pain-free individuals in the right superior (p < 0.0014) and middle temporal gyri (p < 0.0001). Moreover, individuals with CNP exhibited higher WM integrity in the splenium of the corpus callosum (p < 0.0001) and in the posterior cingulum (p < 0.0001), compared with pain-free individuals. The results suggest that the existence of CNP following SCI is associated with GM and WM structural abnormalities in regions involved in pain intensification and spread, and which may reflect maladaptive neural plasticity in CNP.

Neural correlates of subjective cognitive decline in adults at high risk for Alzheimer's disease.

Introduction: Recently, interest has emerged in subjective cognitive decline (SCD) as a potential precursor to Alzheimer's disease (AD) dementia. Whether individuals with SCD harbor brain alterations in midlife, when AD-related pathology begins, is yet to be elucidated. Furthermore, the role of apolipoprotein ε4 (APOE ε4) allele, a robust AD risk factor, in the relationship between SCD and brain alterations is unknown. We examined whether APOE genotype modulates the association of SCD with brain measures in individuals at high AD risk. Methods: Middle-aged adults with parental history of AD dementia underwent magnetic resonance imaging (MRI) and the Memory Functioning Questionnaire. Regression analysis tested the extent to which SCD was associated with activation during an functional MRI (fMRI) working-memory task, and white-matter microstructure. APOE ε4 genotype was tested as a moderator. Results: Among APOE ε4 carriers, but not among non-carriers, SCD was associated with higher activation in the anterior cingulate (p = 0.003), inferior, middle, and superior frontal cortices (p = 0.041, p = 0.048, p = 0.037, respectively); and with lower fractional anisotropy in the uncinate fasciculus (p = 0.002), adjusting for age, sex, and education. Conclusion: In middle aged, cognitively normal individuals at high AD risk, higher SCD was associated with greater brain alterations possibly reflecting incipient AD pathology. When accompanied by a family history of AD and an APOE ε4 allele, SCD may have important clinical value, allowing a window for early intervention and for participants' stratification in AD prevention clinical trials.

The metastatic microenvironment: brain-residing melanoma metastasis and dormant micrometastasis.

Brain metastasis occurs frequently in melanoma patients with advanced disease whereby the prognosis is dismal. The underlying mechanisms of melanoma brain metastasis development are not well understood. We generated a reproducible melanoma brain metastasis model, consisting of brain-metastasizing variants and local, subdermal variants that originate from the same melanomas thus sharing a common genetic background. The brain-metastasizing variants were obtained by intracardiac inoculation. Brain metastasis variants when inoculated subdermally yielded spontaneous brain dormant micrometastasis. Cultured cells from the spontaneous brain micrometastasis grew very well in vitro and generated subdermal tumors after an orthotopic inoculation. Expression analysis assays indicated that the brain metastasis and micrometastasis cells expressed higher levels of angiopoietin-like 4, prostaglandin-synthesizing enzyme cyclooxygenase-2, matrix metalloproteinase-1 and preferentially expressed antigen in melanoma and lower levels of claudin-1 and cysteine-rich protein 61 than the corresponding cutaneous variants. The reproducible models of human melanoma metastasizing experimentally and spontaneously to the brain will facilitate the identification of novel biomarkers and targets for therapy and contribute to the deciphering of mechanisms underlying melanoma metastasis.

Linking L2 proficiency and patterns of functional connectivity during L1 word retrieval.

Second language (L2) learners differ greatly in language proficiency, which is partially explained by variability in native language (L1) skills. The present fMRI study explored the neural underpinnings of the L1-L2 link. Twenty L2 learners completed a tip-of-the-tongue (TOT) task that required retrieving words in L1. Low-proficiency L2 learners showed greater functional connectivity for correct and TOT responses between the left inferior frontal gyrus and right-sided homologues of the temporoparietal regions that support phonological processing (e.g., supramarginal gyrus), possibly reflecting difficulty with phonological retrieval. High-proficiency L2 learners showed greater connectivity for erroneous responses (TOT in particular) between the left inferior frontal gyrus and regions of left medial temporal lobe (e.g., hippocampus), associated with implicit learning processes. The difference between low- and high-proficiency L2 learners in functional connectivity, which is evident even during L1 processing, may affect L2 learning processes and outcomes.

Effects of Ai-Chi Practice on Balance and Left Cerebellar Activation during High Working Memory Load Task in Older People: A Controlled Pilot Trial.

BACKGROUND: Normal aging is associated with balance and working memory decline. From a neurobiological standpoint, changes in cerebellar functional plasticity may mediate the decline in balance and working memory for older adults. Mounting evidence suggests that physical activity is beneficial for decreasing aging effects. Previous studies have focused on land-based physical activity and research concerning the aquatic environment is scarce. This study investigated the effectiveness of Ai-Chi on balance abilities and cerebral activation during a high working memory load task among community-dwelling older people. METHODS: A total of 19 people aged 65-86 years were allocated to receive Ai-Chi practice (n = 6), structured on-land Ai-Chi practice (n = 7) or guided-imagery of Ai-Chi practice (n = 6) for a bi-weekly, 30-min exercise session for 12 weeks. Balance was measured by the Tinetti balance sub-test and working memory was measured by the N-back test during functional-MRI scan. RESULTS: The Ai-Chi practice group presented a significant change in balance between pre and post intervention (balance t = -4.8, p < 0.01). In the whole-brain analysis, during high working memory load task, the Ai-Chi practice group presented a decrease in left cerebellar activation. Region of interest analyses yielded similar results by which pre-cerebellar activation was higher than post-intervention (t = 2.77, p < 0.05). CONCLUSIONS: Ai-Chi is an available, non-invasive intervention method that may serve as a tool to improve cerebellar activation that in turn might improve balance. In addition, our findings may provide new insights into the neuronal mechanisms that underlie both motor and cognitive abilities.

Neural Segmentation of Seeding ROIs (sROIs) for Pre-Surgical Brain Tractography.

White matter tractography mapping is an important tool for neuro-surgical planning and navigation. It relies on the accurate manual delineation of anatomical seeding ROIs (sROIs) by neuroanatomy experts. Stringent pre-operative time-constraints and limited availability of experts suggest that automation tools are strongly needed for the task. In this article, we propose and compare several multi-modal fully convolutional network architectures for segmentation of sROIs. Inspired by their manual segmentation practice, anatomical information from T1w maps is fused by the network with directionally encoded color (DEC) maps to compute the segmentation. Qualitative and quantitative validation was performed on image data from 75 real tumor resection candidates for the sROIs of the motor tract, the arcuate fasciculus, and optic radiation. Favorable comparison was also obtained with state-of-the-art methods for the tumor dataset as well as the ISMRM 2017 traCED challenge dataset. The proposed networks showed promising results, indicating they may significantly improve the efficiency of pre-surgical tractography mapping, without compromising its quality.

Fibroblast-Derived IL33 Facilitates Breast Cancer Metastasis by Modifying the Immune Microenvironment and Driving Type 2 Immunity.

Lungs are one of the main sites of breast cancer metastasis. The metastatic microenvironment is essential to facilitate growth of disseminated tumor cells. Cancer-associated fibroblasts (CAF) are prominent players in the microenvironment of breast cancer. However, their role in the formation of a permissive metastatic niche is unresolved. Here we show that IL33 is upregulated in metastases-associated fibroblasts in mouse models of spontaneous breast cancer metastasis and in patients with breast cancer with lung metastasis. Upregulation of IL33 instigated type 2 inflammation in the metastatic microenvironment and mediated recruitment of eosinophils, neutrophils, and inflammatory monocytes to lung metastases. Importantly, targeting of IL33 in vivo resulted in inhibition of lung metastasis and significant attenuation of immune cell recruitment and type 2 immunity. These findings demonstrate a key function of IL33 in facilitating lung metastatic relapse by modulating the immune microenvironment. Our study shows a novel interaction axis between CAF and immune cells and reveals the central role of CAF in establishing a hospitable inflammatory niche in lung metastasis. SIGNIFICANCE: This study elucidates a novel role for fibroblast-derived IL33 in facilitating breast cancer lung metastasis by modifying the immune microenvironment at the metastatic niche toward type 2 inflammation.