Neuroanatomy of Cerebellar Mutism Syndrome: The Role of Lesion Location

Neuroanatomy of Cerebellar Mutism Syndrome: The Role of Lesion Location | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Neuroanatomy of Cerebellar Mutism Syndrome: The Role of Lesion Location Jax Skye, Joel Bruss, Sebastian Toescu, Kristian Aquilina, Amanda Grafft, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-2972206/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 05 Jun, 2024 Read the published version in Brain Communications → Version 1 posted You are reading this latest preprint version Abstract Approximately 25% of pediatric patients who undergo cerebellar tumor resection develop cerebellar mutism syndrome (CMS). Our group recently showed that damage to the cerebellar deep nuclei and superior cerebellar peduncles, which we refer to as the cerebellar outflow pathway, is associated with increased risk of CMS. Here, we tested whether these findings replicate in an independent cohort. We evaluated the relationship between lesion location and the development of CMS in an observational study of 56 pediatric patients who underwent cerebellar tumor resection. We hypothesized that individuals that developed CMS after surgery (CMS+), relative to those that did not (CMS-) would have lesions that preferentially intersected with: 1) the cerebellar outflow pathway, and 2) a previously generated ‘lesion-symptom map’ of CMS. Analyses were conducted in accordance with pre-registered hypotheses and analytic methods ( https://osf.io/r8yjv/ ). We found supporting evidence for both hypotheses. Compared with CMS- patients, CMS + patients (n = 10) had lesions with greater overlap with the cerebellar outflow pathway (Cohen’s d = .73, p = .05), and the CMS lesion-symptom map (Cohen’s d = 1.1, p = .004). These results strengthen the association of lesion location with risk of developing CMS and demonstrate generalizability across cohorts. These findings may help to inform the optimal surgical approach to pediatric cerebellar tumors. posterior fossa tumor mutism brainstem tumor cerebellum disease Figures Figure 1 Figure 2 Figure 3 Introduction The odds of survival from pediatric brain tumors have steadily improved in recent decades [ 1 ], escalating the importance of understanding and preventing long-term treatment-related adverse effects. Approximately 25% of children undergoing cerebellar tumor resection will experience a postoperative syndrome characterized by emotional lability, executive dysfunction, and language deficits [ 2 – 8 ]. This constellation of symptoms is commonly referred to as cerebellar mutism syndrome (CMS) [ 9 ], posterior fossa syndrome [ 6 ], or cerebellar cognitive affective syndrome +/- cerebellar mutism [ 6 ]; we will use the term CMS for this paper. The duration and severity of this syndrome is variable, but importantly, patients who develop CMS typically have worse long-term cognitive outcomes [ 4 , 6 , 10 – 12 ], highlighting the importance of this syndrome as a potential harbinger of long-term impairment. The pathophysiology of CMS is not fully understood. Recent work by our group has demonstrated the importance of lesion location. We hypothesized that damage to the cerebellar outflow pathway, an efferent pathway passing from the deep cerebellar nuclei through the superior cerebellar peduncles to the thalamus, is associated with the development of CMS in pediatric patients [ 7 ]. This hypothesis was based on the anatomical organization of cerebro-cerebellar communication, which has an anatomically constrained bottleneck whereby even relatively small lesions involving the cerebellar outflow pathway can disrupt communication of the cerebellum with a wide array of brainstem and forebrain regions. We found support for this hypothesis from both theory-driven and data-driven analyses [ 7 ]. Identifying lesion sites associated with a higher risk of CMS has the potential to inform clinical practice. It is possible that more personalized prognostic information could be provided to patients and their families about their risk for CMS based on the tumor location relative to the cerebellar outflow pathway. It is also possible that once critical anatomical regions associated with CMS are well established, they could be identified in advance of the tumor resection and used to inform image guided surgery to avoid those regions when possible. However, an important prerequisite to the development of any clinical application is demonstrating that lesion location is a reliable marker of risk for CMS that generalizes to other independent cohorts. This was the primary objective of the current study. Specifically, we aimed to evaluate whether the same anatomical regions associated with higher risk of CMS in our previous study would replicate in an independent cohort. Our anatomical hypotheses and the analytic strategy were pre-registered with the Open Science Framework ( https://osf.io/r8yjv/ ). In a cohort of 56 patients who underwent cerebellar tumor resection, we hypothesized that patients who developed CMS (CMS+) would have damage to the cerebellar outflow pathway to a greater extent than individuals who did not develop CMS (CMS-). Similarly, we hypothesized that CMS + individuals would have lesions that overlapped with a lesion-symptom ‘map’ of CMS previously derived from a sample of 195 patients [ 7 ]. Methods We analyzed clinical outcome and imaging data in patients with cerebellar tumor resection surgery (n = 56) from two sites: the University of Iowa (n = 9) and Great Ormond Street Children’s Hospital in London (n = 47). This study was approved by the Institutional Review Board and ethical standards committee prior to conducting this retrospective study. We included patients under the age of 21 with a diagnosis of a cerebellar tumor that had a surgical resection and follow-up imaging to show the tumor resection cavity. This study focused on a pediatric population since CMS is rare in adult patients [ 11 ]. Each patient also had clinical assessments by their treatment teams to determine whether they met criteria for CMS. CMS was defined by criteria outlined previously: post-surgical onset of reduced speech/mutism and emotional lability [ 7 ]. Additional common features included motor dysfunction or hypotonia. Post-surgical structural neuroimaging scans performed one month or more after the surgery were selected whenever available (see Supplementary Table 1 for exact timing per participant). All scans were reviewed in advance of the analysis and only included if they were of sufficient quality to clearly observe the borders of the post-surgical resection cavity. Scans were performed for clinical indications, so scanners and MRI sequence varied between patients, but all were reviewed and determined to be of sufficient quality for study inclusion. The pons, medulla, brainstem, and cerebellum were isolated from the rest of the brain using the “isolate” function in the SUIT toolbox ( https://www.diedrichsenlab.org/imaging/suit_function.htm ). The same was done for the MNI152 atlas. The lesion mask was transformed to the MNI152 1mm brain atlas using nonlinear transformation with cost-function masking [ 13 ]. The anatomical accuracy of the lesion tracing and the transformation to MNI space was confirmed by a neurologist (A.D.B.) blinded to CMS status. Our first hypothesis was that CMS + patients would have greater disruption to the cerebellar outflow pathway. The region of interest (ROI) that defines the cerebellar outflow pathway was the same as previously described [ 7 ] and is displayed in Fig. 1 a. Briefly, it was produced by combining the cerebellar deep nuclei atlas (Spatially Unbiased Infra-Tentorial Template, diedrichsenlab.org/imaging/propatlas.htm) with a mask of the superior cerebellar peduncles defined from a probabilistic atlas of these tracts [ 7 ]. The extent to which each individual patient’s lesion location, or lesion ‘mask’, intersected with the binary cerebellar outflow pathway ROI was quantified and referred to as cerebellar outflow pathway ‘lesion load’. The percentage of voxels in each slice of the cerebellar outflow pathway that intersected with the lesion mask was calculated. This required first separating the cerebellar outflow pathway ROI by 1mm oblique (17°) coronal slices perpendicular to the superior cerebellar peduncles. The slice of the cerebellar outflow pathway with the highest percentage of overlap between the lesion mask and ROI was used as the value of cerebellar outflow pathway ‘lesion load’ for that patient. A lesion intersecting all cerebellar outflow voxels, in a given slice, would have a value of 100% and a lesion that entirely spares this outflow pathway would have a value of 0%. The lesion load values of the CMS + and CMS- groups were compared using an independent samples t -test to evaluate the one-tailed hypothesis that higher cerebellar outflow pathway lesion load will be seen in the CMS + group compared with CMS- group. This study’s second main hypothesis was similar in design to the first but used a data-driven a priori ROI in place of the cerebellar outflow pathway ROI. We used the lesion-symptom map that was generated by Albazron and colleagues [ 7 ] using lesion and outcome data from 195 pediatric patients, displayed in Fig. 1 b. The multivariate lesion-symptom mapping was performed using the R package LESYMAP [ 14 ]. LESYMAP uses sparse canonical correlation analysis for neuroimaging (SCCAN) to associate loci of brain damage with CMS status as a binary outcome. A within-sample cross-validation is performed with mapping in 75% of the patients to predict the CMS status of the remaining 25%. This determines the optimal sparseness value with the highest cross-validation correlation between the measured and predicted score [ 7 , 14 ]. The resulting lesion-symptom map identified cerebellar regions statistically associated with severe post-operative cognitive and affective symptoms, which were referred to as cerebellar cognitive affective syndrome in that study, but also met the criteria for CMS as used in the current analysis. This statistical map showed localization to the cerebellar outflow pathway, specifically the fastigial nuclei, interposed and medial dentate nuclei, superior cerebellar peduncles and also regions outside of the cerebellar outflow pathway, including lobules IX and X of the vermis [ 7 ]. Using this lesion-symptom map as an a priori ROI we tested our second hypothesis that CMS + patients will have a higher lesion-symptom map lesion load than patients without CMS. The product of the weighted matrix of voxel values representing the lesion-symptom map, eigenvalue, and binary lesion mask of each patient in this study’s cohort are standardized to calculate the lesion-symptom map lesion load. We compared the lesion-symptom map lesion load between the CMS + and CMS- groups, again using a one-tailed independent samples t -test. A lesion-symptom mapping analysis was also performed in this cohort using the same approach as Albazron and colleagues [ 7 , 14 ]. Results A total of 56 pediatric patients who underwent posterior fossa tumor resections met inclusion criteria for the study. Ten patients had CMS (17.9%). The average age of the sample is 6.2 ± 3.7 years, median 6.0 years, range 5 months – 14 years with various types of tumors (24 pilocytic astrocytomas, 24 medulloblastomas, 3 atypical teratoid rhabdoid tumors, 2 gangliomas, 1 ependymoma ,1 hemangioblastoma, and 1 high-grade glioma; Supplementary Table 1). Children with CMS were younger (4.4 years old ± 2.4 years, compared to CMS- 6.9 years old ± 4.2 years; t(21)=-2.59, p = .016) and had similar lesion volume (6076 mm 3 ± 4891 mm 3 vs. 9831 mm 3 ± 10742 mm 3 ; t(30)=-1.7, p = .10). Medulloblastoma was the tumor type in 70% of CMS + patients and 32.6% of the CMS- cohort. The lesions of all CMS + patients crossed the midline, while 65% of CMS- lesions crossed the midline. The lesion masks from each patient were overlapped to show the spatial distribution of the lesions in the entire sample (Fig. 2 a) and split by CMS status. CMS + individuals (n = 10) are shown in Fig. 2 b and CMS- individuals (n = 46) are shown in Fig. 2 c. A proportional subtraction map of CMS + minus CMS- lesion masks is displayed in Fig. 2 d [ 15 ]. The lesion-symptom map in Fig. 2 e shows that damage at MNI coordinate 1–47 -25 in the cerebellar vermis is most associated with developing CMS after tumor resection (r = .481, p < .001). To test our a priori hypothesis that damage to the cerebellar outflow pathway increases the risk of developing CMS, cerebellar outflow pathway lesion load values were calculated for patients with and without CMS. The cerebellar outflow pathway lesion load was higher in the CMS + group relative to the CMS- group (37 ± 30% vs. 19 ± 24%, respectively; t(11) = 1.8, p = .050; Cohen’s d = 0.73). Notably, the CMS rate was observed to increase in accordance with greater lesion involvement of the cerebellar outflow pathway (Fig. 3 ). We evaluated our second hypothesis that CMS + patients would have a greater lesion-symptom map lesion load when compared to CMS- patients. As hypothesized, CMS + patients had a greater lesion-symptom map lesion load than CMS- patients (.018 ± .010 vs. .009 ± .011, respectively; t(13) = 3.1, p = .004; Cohen’s d = 1.11). Discussion This study evaluates lesion location in relation to developing cerebellar mutism syndrome after cerebellar tumor resection in pediatric patients. Our results support prior work in showing that lesion location is associated with risk of CMS. We [ 5 – 7 , 16 – 22 ] tested two pre-registered hypotheses and found supporting evidence for both. Individuals that developed CMS had lesions with greater overlap with the cerebellar outflow pathway than those that did not develop CMS. In addition, patients with CMS had lesions that overlapped to a greater extent with a lesion-symptom map of CMS derived from an independent sample [ 7 ]. Surgical resection cavities in the cerebellar vermis were most associated with CMS in the lesion-symptom mapping analysis, which is consistent with prior work. Taken together, these findings emphasize that lesion location is useful in predicting the development of CMS in a way that generalizes across cohorts. This information may help to inform ongoing efforts to reduce the likelihood that a patient will develop CMS post-surgery, and to provide more accurate education to patients and families about the risks for developing CMS based on the precise location of the tumor There are limitations of this study. First, CMS was diagnosed by the treating clinicians without standardized assessments of behavioral deficits. It is possible that symptom-specific quantitative assessments may further clarify unique anatomical associations with specific symptoms. Other factors that likely influence the development of CMS, like post-surgical treatment plan, surgical approach, edema, hydrocephalus, and premorbid cognitive abilities were not evaluated here. The observation that lesion location significantly relates to CMS outcome without accounting for these other variables supports the robust effect of lesion location, but more sophisticated models that take these additional factors into account are likely to explain additional variance regarding CMS risk. Conclusion In closing, this study provides additional evidence that damage to critical regions of the cerebellum and its outflow pathway is associated with increased risk of a child developing CMS after cerebellar tumor resection. Further work in this line of research could be used to inform the surgical approach to pediatric cerebellar tumor resection. For instance, critical anatomical regions that, when resected, are associated with increased CMS risk could be displayed as an overlay onto a patient’s pre-operative MRI scan so that surgeons could design a minimally invasive MRI-guided approach that minimizes damage to these regions. Abbreviations CMS = cerebellar mutism syndrome; CMS+ = individuals with cerebellar mutism syndrome; CMS- = individuals without cerebellar mutism syndrome. Declarations Funding This study was supported by the National Institute of Neurological Disease and Stroke (R01 NS114405-03 & R01 NS114405-01S2) and the Roy J. Carver Trust. Author Contributions All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by J.S., J.B., S.T., K.A., A.G., G.B.L., and A.D.B. The first draft of the manuscript was written by J.S. and all authors commented on earlier drafts of the manuscript. All authors read and approved the final manuscript. Data Availability The cerebellar outflow pathway ROI and cerebellar outflow pathway and lesion-symptom map lesion load values are available on Open Science Forum (https://osf.io/9gqbu/?view_only=e6a83d1168754dd3927d75fea28db71b). Additional data are available upon request. Ethics Approval Statement All patients in this study provided informed consent. This study was approved by the ethics review boards of the University of Iowa and Great Ormond Street Children’s Hospital. Disclosures All authors declare no conflicts of interest. References Smith MA, Altekruse SF, Adamson PC, Reaman GH, Seibel NL. Declining childhood and adolescent cancer mortality. Cancer. 2014;120:2497–506. Wisoff JH, Epstein FJ. Pseudobulbar Palsy after Posterior Fossa Operation in Children. Neurosurgery. 1984;15:707–9. 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Transient cerebellar mutism caused by bilateral damage to the dentate nuclei after the second posterior fossa surgery. J Neurosurg. 2006;104:329–31. Morris EB, Phillips NS, Laningham FH, Patay Z, Gajjar A, Wallace D, et al. Proximal dentatothalamocortical tract involvement in posterior fossa syndrome. Brain. 2009;132:3087–95. Soelva V, Hernáiz Driever P, Abbushi A, Rueckriegel S, Bruhn H, Eisner W, et al. Fronto-cerebellar fiber tractography in pediatric patients following posterior fossa tumor surgery. Child’s Nervous System. 2013;29:597–607. Avula S, Kumar R, Pizer B, Pettorini B, Abernethy L, Garlick D, et al. Diffusion abnormalities on intraoperative magnetic resonance imaging as an early predictor for the risk of posterior fossa syndrome. Neuro Oncol. 2015;17:614–22. Ojemann JG, Partridge SC, Poliakov A V., Niazi TN, Shaw DW, Ishak GE, et al. Diffusion tensor imaging of the superior cerebellar peduncle identifies patients with posterior fossa syndrome. Child’s Nervous System. 2013;29:2071–7. Additional Declarations No competing interests reported. Supplementary Files SupplementaryTable1.docx Cite Share Download PDF Status: Published Journal Publication published 05 Jun, 2024 Read the published version in Brain Communications → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-2972206","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":203272500,"identity":"42424dc8-5104-4659-a8a3-8498e3f72563","order_by":0,"name":"Jax Skye","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA1klEQVRIiWNgGAWjYBACxgYQeYCBgR/KBHOI0yLZQKwWuCqDA0gcvIC5/YwB448zh+WMbyQ3PuapYZDju5FAwGE9aQnMPDcOG5vdSGw25jnGYCxJUEtD8vHfDB8OJ267kdgmncPGkLiBoJb+hw2MPz4crt88A6TlH0M9YS0zkg8wAB2WYCAB1JLbxpBgQFjLM6BfzqQbzjjzsNn4b5+E4cwzD/BrMezPAYbYMWt5/vb0hw9nfLOR5ztOwBbDBjDVDONL4FcOAvIQqo6wylEwCkbBKBi5AAB/AktaYhl2gAAAAABJRU5ErkJggg==","orcid":"","institution":"University of Iowa Carver College of Medicine, University of Iowa","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Jax","middleName":"","lastName":"Skye","suffix":""},{"id":203272503,"identity":"e42a19bf-978b-429b-b4ea-70949929cc4f","order_by":1,"name":"Joel Bruss","email":"","orcid":"","institution":"University of Iowa Carver College of Medicine, University of Iowa","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Joel","middleName":"","lastName":"Bruss","suffix":""},{"id":203272505,"identity":"9099b6af-b2de-4fea-bc95-d3558fed2597","order_by":2,"name":"Sebastian Toescu","email":"","orcid":"","institution":"Great Ormond Street Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Sebastian","middleName":"","lastName":"Toescu","suffix":""},{"id":203272506,"identity":"f1b0a624-dfc3-4dca-b074-577005b7dcb5","order_by":3,"name":"Kristian Aquilina","email":"","orcid":"","institution":"Great Ormond Street Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Kristian","middleName":"","lastName":"Aquilina","suffix":""},{"id":203272508,"identity":"f8effc2e-daf1-4bfa-828f-cd3a0fac63bf","order_by":4,"name":"Amanda Grafft","email":"","orcid":"","institution":"University of Iowa Carver College of Medicine, University of Iowa","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Amanda","middleName":"","lastName":"Grafft","suffix":""},{"id":203272510,"identity":"dcc95cde-fb49-4934-b864-068176e524a4","order_by":5,"name":"Gino Bardi Lola","email":"","orcid":"","institution":"University of Iowa Carver College of Medicine, University of Iowa","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Gino","middleName":"Bardi","lastName":"Lola","suffix":""},{"id":203272511,"identity":"a8c9a2cb-82ea-487d-b636-8e0f9994925b","order_by":6,"name":"Aaron D. Boes","email":"","orcid":"","institution":"University of Iowa Carver College of Medicine, University of Iowa","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Aaron","middleName":"D.","lastName":"Boes","suffix":""}],"badges":[],"createdAt":"2023-05-23 14:59:26","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-2972206/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-2972206/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1093/braincomms/fcae197","type":"published","date":"2024-06-05T10:48:53+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":37539296,"identity":"cac9e068-faa1-497e-b407-9c10526960f2","added_by":"auto","created_at":"2023-05-26 14:17:49","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":478286,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ea\u0026amp;b\u003c/strong\u003e 1a shows the cerebellar outflow pathway in red. 1b shows the lesion-symptom map from Albazron and colleague’s 2019 study used to generate lesion-symptom map lesion load\u003c/p\u003e","description":"","filename":"figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-2972206/v1/253a62f52afe9fec8430b538.png"},{"id":37539298,"identity":"7ccc81aa-2033-40fd-867e-7c91c8941225","added_by":"auto","created_at":"2023-05-26 14:17:49","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1514880,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ea – e \u003c/strong\u003e\u0026nbsp;2a shows the lesion overlap of all patients included in this study (n=56). The region of maximum lesion overlap (n=29 of 56) was the right vermian lobule IX (MNI coordinates 4 -53 -34). 2b shows the CMS+ lesion overlap (n=10) with the maximum overlap at the right vermian lobule IX (9 of 10 lesions, MNI 3 -54 -34). 2c displays the CMS- lesion overlap with peak overlap of 21 of 46 lesions in the right vermian lobule VIII at MNI coordinate 2 -61 -36. 2d shows the proportional subtraction map with a regional peak in the anterior vermis at MNI coordinate 3 -47 -26. The lesion-symptom map in 2e also supports that lesions to the anterior vermis are associated with CMS (r=.481, p\u0026lt;.001, peak MNI coordinate 1 -47 -25)\u003c/p\u003e","description":"","filename":"figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-2972206/v1/db11f219c65b66abe7bef4f9.png"},{"id":37539295,"identity":"91cfeca0-bd4e-40ec-94a5-01effe5fb7e4","added_by":"auto","created_at":"2023-05-26 14:17:48","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":60412,"visible":true,"origin":"","legend":"\u003cp\u003eThe rate of CMS development is progressively higher as cerebellar outflow pathway lesion overlap increases. This is shown in the current study in dark blue (N=56) and in the Albazron study (N=195), shown for reference in light blue\u003c/p\u003e","description":"","filename":"figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-2972206/v1/7b75a467740f31b4c27702b4.png"},{"id":60400173,"identity":"fde51437-c8ca-45b4-ab2a-724397cbef69","added_by":"auto","created_at":"2024-07-16 10:48:59","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3427244,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2972206/v1/60cddade-8605-4542-a608-ac4d9a24031f.pdf"},{"id":37539297,"identity":"6b48524c-b151-40a5-927f-1ebf6a8833b7","added_by":"auto","created_at":"2023-05-26 14:17:49","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":75247,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTable1.docx","url":"https://assets-eu.researchsquare.com/files/rs-2972206/v1/63dc1190e5549aa9021acccb.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Neuroanatomy of Cerebellar Mutism Syndrome: The Role of Lesion Location","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe odds of survival from pediatric brain tumors have steadily improved in recent decades [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e], escalating the importance of understanding and preventing long-term treatment-related adverse effects. Approximately 25% of children undergoing cerebellar tumor resection will experience a postoperative syndrome characterized by emotional lability, executive dysfunction, and language deficits [\u003cspan additionalcitationids=\"CR3 CR4 CR5 CR6 CR7\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. This constellation of symptoms is commonly referred to as cerebellar mutism syndrome (CMS) [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], posterior fossa syndrome [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e], or cerebellar cognitive affective syndrome +/- cerebellar mutism [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]; we will use the term CMS for this paper. The duration and severity of this syndrome is variable, but importantly, patients who develop CMS typically have worse long-term cognitive outcomes [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan additionalcitationids=\"CR11\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], highlighting the importance of this syndrome as a potential harbinger of long-term impairment.\u003c/p\u003e \u003cp\u003eThe pathophysiology of CMS is not fully understood. Recent work by our group has demonstrated the importance of lesion location. We hypothesized that damage to the cerebellar outflow pathway, an efferent pathway passing from the deep cerebellar nuclei through the superior cerebellar peduncles to the thalamus, is associated with the development of CMS in pediatric patients [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. This hypothesis was based on the anatomical organization of cerebro-cerebellar communication, which has an anatomically constrained bottleneck whereby even relatively small lesions involving the cerebellar outflow pathway can disrupt communication of the cerebellum with a wide array of brainstem and forebrain regions. We found support for this hypothesis from both theory-driven and data-driven analyses [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIdentifying lesion sites associated with a higher risk of CMS has the potential to inform clinical practice. It is possible that more personalized prognostic information could be provided to patients and their families about their risk for CMS based on the tumor location relative to the cerebellar outflow pathway. It is also possible that once critical anatomical regions associated with CMS are well established, they could be identified in advance of the tumor resection and used to inform image guided surgery to avoid those regions when possible. However, an important prerequisite to the development of any clinical application is demonstrating that lesion location is a reliable marker of risk for CMS that generalizes to other independent cohorts. This was the primary objective of the current study. Specifically, we aimed to evaluate whether the same anatomical regions associated with higher risk of CMS in our previous study would replicate in an independent cohort. Our anatomical hypotheses and the analytic strategy were pre-registered with the Open Science Framework (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://osf.io/r8yjv/\u003c/span\u003e\u003cspan address=\"https://osf.io/r8yjv/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn a cohort of 56 patients who underwent cerebellar tumor resection, we hypothesized that patients who developed CMS (CMS+) would have damage to the cerebellar outflow pathway to a greater extent than individuals who did not develop CMS (CMS-). Similarly, we hypothesized that CMS\u0026thinsp;+\u0026thinsp;individuals would have lesions that overlapped with a lesion-symptom \u0026lsquo;map\u0026rsquo; of CMS previously derived from a sample of 195 patients [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eWe analyzed clinical outcome and imaging data in patients with cerebellar tumor resection surgery (n\u0026thinsp;=\u0026thinsp;56) from two sites: the University of Iowa (n\u0026thinsp;=\u0026thinsp;9) and Great Ormond Street Children\u0026rsquo;s Hospital in London (n\u0026thinsp;=\u0026thinsp;47). This study was approved by the Institutional Review Board and ethical standards committee prior to conducting this retrospective study. We included patients under the age of 21 with a diagnosis of a cerebellar tumor that had a surgical resection and follow-up imaging to show the tumor resection cavity. This study focused on a pediatric population since CMS is rare in adult patients [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Each patient also had clinical assessments by their treatment teams to determine whether they met criteria for CMS. CMS was defined by criteria outlined previously: post-surgical onset of reduced speech/mutism and emotional lability [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Additional common features included motor dysfunction or hypotonia. Post-surgical structural neuroimaging scans performed one month or more after the surgery were selected whenever available (see Supplementary Table\u0026nbsp;1 for exact timing per participant). All scans were reviewed in advance of the analysis and only included if they were of sufficient quality to clearly observe the borders of the post-surgical resection cavity. Scans were performed for clinical indications, so scanners and MRI sequence varied between patients, but all were reviewed and determined to be of sufficient quality for study inclusion. The pons, medulla, brainstem, and cerebellum were isolated from the rest of the brain using the \u0026ldquo;isolate\u0026rdquo; function in the SUIT toolbox (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.diedrichsenlab.org/imaging/suit_function.htm\u003c/span\u003e\u003cspan address=\"https://www.diedrichsenlab.org/imaging/suit_function.htm\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e). The same was done for the MNI152 atlas. The lesion mask was transformed to the MNI152 1mm brain atlas using nonlinear transformation with cost-function masking [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. The anatomical accuracy of the lesion tracing and the transformation to MNI space was confirmed by a neurologist (A.D.B.) blinded to CMS status.\u003c/p\u003e \u003cp\u003eOur first hypothesis was that CMS\u0026thinsp;+\u0026thinsp;patients would have greater disruption to the cerebellar outflow pathway. The region of interest (ROI) that defines the cerebellar outflow pathway was the same as previously described [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] and is displayed in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ea. Briefly, it was produced by combining the cerebellar deep nuclei atlas (Spatially Unbiased Infra-Tentorial Template, diedrichsenlab.org/imaging/propatlas.htm) with a mask of the superior cerebellar peduncles defined from a probabilistic atlas of these tracts [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. The extent to which each individual patient\u0026rsquo;s lesion location, or lesion \u0026lsquo;mask\u0026rsquo;, intersected with the binary cerebellar outflow pathway ROI was quantified and referred to as cerebellar outflow pathway \u0026lsquo;lesion load\u0026rsquo;. The percentage of voxels in each slice of the cerebellar outflow pathway that intersected with the lesion mask was calculated. This required first separating the cerebellar outflow pathway ROI by 1mm oblique (17\u0026deg;) coronal slices perpendicular to the superior cerebellar peduncles. The slice of the cerebellar outflow pathway with the highest percentage of overlap between the lesion mask and ROI was used as the value of cerebellar outflow pathway \u0026lsquo;lesion load\u0026rsquo; for that patient. A lesion intersecting all cerebellar outflow voxels, in a given slice, would have a value of 100% and a lesion that entirely spares this outflow pathway would have a value of 0%. The lesion load values of the CMS\u0026thinsp;+\u0026thinsp;and CMS- groups were compared using an independent samples \u003cem\u003et\u003c/em\u003e-test to evaluate the one-tailed hypothesis that higher cerebellar outflow pathway lesion load will be seen in the CMS\u0026thinsp;+\u0026thinsp;group compared with CMS- group.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThis study\u0026rsquo;s second main hypothesis was similar in design to the first but used a data-driven \u003cem\u003ea priori\u003c/em\u003e ROI in place of the cerebellar outflow pathway ROI. We used the lesion-symptom map that was generated by Albazron and colleagues [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] using lesion and outcome data from 195 pediatric patients, displayed in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eb. The multivariate lesion-symptom mapping was performed using the R package LESYMAP [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. LESYMAP uses sparse canonical correlation analysis for neuroimaging (SCCAN) to associate loci of brain damage with CMS status as a binary outcome. A within-sample cross-validation is performed with mapping in 75% of the patients to predict the CMS status of the remaining 25%. This determines the optimal sparseness value with the highest cross-validation correlation between the measured and predicted score [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. The resulting lesion-symptom map identified cerebellar regions statistically associated with severe post-operative cognitive and affective symptoms, which were referred to as cerebellar cognitive affective syndrome in that study, but also met the criteria for CMS as used in the current analysis. This statistical map showed localization to the cerebellar outflow pathway, specifically the fastigial nuclei, interposed and medial dentate nuclei, superior cerebellar peduncles and also regions outside of the cerebellar outflow pathway, including lobules IX and X of the vermis [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Using this lesion-symptom map as an \u003cem\u003ea priori\u003c/em\u003e ROI we tested our second hypothesis that CMS\u0026thinsp;+\u0026thinsp;patients will have a higher lesion-symptom map lesion load than patients without CMS. The product of the weighted matrix of voxel values representing the lesion-symptom map, eigenvalue, and binary lesion mask of each patient in this study\u0026rsquo;s cohort are standardized to calculate the lesion-symptom map lesion load. We compared the lesion-symptom map lesion load between the CMS\u0026thinsp;+\u0026thinsp;and CMS- groups, again using a one-tailed independent samples \u003cem\u003et\u003c/em\u003e-test. A lesion-symptom mapping analysis was also performed in this cohort using the same approach as Albazron and colleagues [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eA total of 56 pediatric patients who underwent posterior fossa tumor resections met inclusion criteria for the study. Ten patients had CMS (17.9%). The average age of the sample is 6.2\u0026thinsp;\u0026plusmn;\u0026thinsp;3.7 years, median 6.0 years, range 5 months \u0026ndash; 14 years with various types of tumors (24 pilocytic astrocytomas, 24 medulloblastomas, 3 atypical teratoid rhabdoid tumors, 2 gangliomas, 1 ependymoma ,1 hemangioblastoma, and 1 high-grade glioma; Supplementary Table\u0026nbsp;1). Children with CMS were younger (4.4 years old\u0026thinsp;\u0026plusmn;\u0026thinsp;2.4 years, compared to CMS- 6.9 years old\u0026thinsp;\u0026plusmn;\u0026thinsp;4.2 years; t(21)=-2.59, p\u0026thinsp;=\u0026thinsp;.016) and had similar lesion volume (6076 mm\u003csup\u003e3\u003c/sup\u003e\u0026thinsp;\u0026plusmn;\u0026thinsp;4891 mm\u003csup\u003e3\u003c/sup\u003e vs. 9831 mm\u003csup\u003e3\u003c/sup\u003e\u0026thinsp;\u0026plusmn;\u0026thinsp;10742 mm\u003csup\u003e3\u003c/sup\u003e; t(30)=-1.7, p\u0026thinsp;=\u0026thinsp;.10). Medulloblastoma was the tumor type in 70% of CMS\u0026thinsp;+\u0026thinsp;patients and 32.6% of the CMS- cohort. The lesions of all CMS\u0026thinsp;+\u0026thinsp;patients crossed the midline, while 65% of CMS- lesions crossed the midline. The lesion masks from each patient were overlapped to show the spatial distribution of the lesions in the entire sample (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ea) and split by CMS status. CMS\u0026thinsp;+\u0026thinsp;individuals (n\u0026thinsp;=\u0026thinsp;10) are shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eb and CMS- individuals (n\u0026thinsp;=\u0026thinsp;46) are shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ec. A proportional subtraction map of CMS\u0026thinsp;+\u0026thinsp;minus CMS- lesion masks is displayed in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ed [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. The lesion-symptom map in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ee shows that damage at MNI coordinate 1\u0026ndash;47 -25 in the cerebellar vermis is most associated with developing CMS after tumor resection (r\u0026thinsp;=\u0026thinsp;.481, p\u0026thinsp;\u0026lt;\u0026thinsp;.001).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eTo test our \u003cem\u003ea priori\u003c/em\u003e hypothesis that damage to the cerebellar outflow pathway increases the risk of developing CMS, cerebellar outflow pathway lesion load values were calculated for patients with and without CMS. The cerebellar outflow pathway lesion load was higher in the CMS\u0026thinsp;+\u0026thinsp;group relative to the CMS- group (37\u0026thinsp;\u0026plusmn;\u0026thinsp;30% vs. 19\u0026thinsp;\u0026plusmn;\u0026thinsp;24%, respectively; t(11)\u0026thinsp;=\u0026thinsp;1.8, p\u0026thinsp;=\u0026thinsp;.050; Cohen\u0026rsquo;s d\u0026thinsp;=\u0026thinsp;0.73). Notably, the CMS rate was observed to increase in accordance with greater lesion involvement of the cerebellar outflow pathway (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). We evaluated our second hypothesis that CMS\u0026thinsp;+\u0026thinsp;patients would have a greater lesion-symptom map lesion load when compared to CMS- patients. As hypothesized, CMS\u0026thinsp;+\u0026thinsp;patients had a greater lesion-symptom map lesion load than CMS- patients (.018\u0026thinsp;\u0026plusmn;\u0026thinsp;.010 vs. .009\u0026thinsp;\u0026plusmn;\u0026thinsp;.011, respectively; t(13)\u0026thinsp;=\u0026thinsp;3.1, p\u0026thinsp;=\u0026thinsp;.004; Cohen\u0026rsquo;s d\u0026thinsp;=\u0026thinsp;1.11).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study evaluates lesion location in relation to developing cerebellar mutism syndrome after cerebellar tumor resection in pediatric patients. Our results support prior work in showing that lesion location is associated with risk of CMS. We [\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan additionalcitationids=\"CR17 CR18 CR19 CR20 CR21\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e] tested two pre-registered hypotheses and found supporting evidence for both. Individuals that developed CMS had lesions with greater overlap with the cerebellar outflow pathway than those that did not develop CMS. In addition, patients with CMS had lesions that overlapped to a greater extent with a lesion-symptom map of CMS derived from an independent sample [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Surgical resection cavities in the cerebellar vermis were most associated with CMS in the lesion-symptom mapping analysis, which is consistent with prior work. Taken together, these findings emphasize that lesion location is useful in predicting the development of CMS in a way that generalizes across cohorts. This information may help to inform ongoing efforts to reduce the likelihood that a patient will develop CMS post-surgery, and to provide more accurate education to patients and families about the risks for developing CMS based on the precise location of the tumor\u003c/p\u003e \u003cp\u003eThere are limitations of this study. First, CMS was diagnosed by the treating clinicians without standardized assessments of behavioral deficits. It is possible that symptom-specific quantitative assessments may further clarify unique anatomical associations with specific symptoms. Other factors that likely influence the development of CMS, like post-surgical treatment plan, surgical approach, edema, hydrocephalus, and premorbid cognitive abilities were not evaluated here. The observation that lesion location significantly relates to CMS outcome without accounting for these other variables supports the robust effect of lesion location, but more sophisticated models that take these additional factors into account are likely to explain additional variance regarding CMS risk.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn closing, this study provides additional evidence that damage to critical regions of the cerebellum and its outflow pathway is associated with increased risk of a child developing CMS after cerebellar tumor resection. Further work in this line of research could be used to inform the surgical approach to pediatric cerebellar tumor resection. For instance, critical anatomical regions that, when resected, are associated with increased CMS risk could be displayed as an overlay onto a patient\u0026rsquo;s pre-operative MRI scan so that surgeons could design a minimally invasive MRI-guided approach that minimizes damage to these regions.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eCMS = cerebellar mutism syndrome; CMS+ = individuals with cerebellar mutism syndrome; CMS- = individuals without cerebellar mutism syndrome.\u003c/p\u003e\n"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding \u0026nbsp;\u003c/strong\u003eThis study was supported by the National Institute of Neurological Disease and Stroke (R01 NS114405-03 \u0026amp; R01 NS114405-01S2) and the Roy J. Carver Trust.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eAuthor Contributions \u0026nbsp;\u003c/strong\u003eAll authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by J.S., J.B., S.T., K.A., A.G., G.B.L., and A.D.B. The first draft of the manuscript was written by J.S. and all authors commented on earlier drafts of the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eData Availability \u0026nbsp;\u003c/strong\u003eThe cerebellar outflow pathway ROI and cerebellar outflow pathway and lesion-symptom map lesion load values are available on Open Science Forum (https://osf.io/9gqbu/?view_only=e6a83d1168754dd3927d75fea28db71b). Additional data are available upon request.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eEthics Approval Statement \u0026nbsp;\u003c/strong\u003eAll patients in this study provided informed consent. This study was approved by the ethics review boards of the University of Iowa and Great Ormond Street Children\u0026rsquo;s Hospital.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eDisclosures \u0026nbsp;\u003c/strong\u003eAll authors declare no conflicts of interest.\u0026nbsp;\u003c/p\u003e\n"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSmith MA, Altekruse SF, Adamson PC, Reaman GH, Seibel NL. Declining childhood and adolescent cancer mortality. Cancer. 2014;120:2497\u0026ndash;506. \u003c/li\u003e\n\u003cli\u003eWisoff JH, Epstein FJ. Pseudobulbar Palsy after Posterior Fossa Operation in Children. Neurosurgery. 1984;15:707\u0026ndash;9. \u003c/li\u003e\n\u003cli\u003eRekate HL, Grubb RL, Aram DM, Hahn JF, Ratcheson RA. Muteness of Cerebellar Origin. Arch Neurol. 1985;42:697\u0026ndash;8. \u003c/li\u003e\n\u003cli\u003eSchmahmann J. The cerebellar cognitive affective syndrome. 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Brain. 2009;132:3087\u0026ndash;95. \u003c/li\u003e\n\u003cli\u003eSoelva V, Hern\u0026aacute;iz Driever P, Abbushi A, Rueckriegel S, Bruhn H, Eisner W, et al. Fronto-cerebellar fiber tractography in pediatric patients following posterior fossa tumor surgery. Child\u0026rsquo;s Nervous System. 2013;29:597\u0026ndash;607. \u003c/li\u003e\n\u003cli\u003eAvula S, Kumar R, Pizer B, Pettorini B, Abernethy L, Garlick D, et al. Diffusion abnormalities on intraoperative magnetic resonance imaging as an early predictor for the risk of posterior fossa syndrome. Neuro Oncol. 2015;17:614\u0026ndash;22. \u003c/li\u003e\n\u003cli\u003eOjemann JG, Partridge SC, Poliakov A V., Niazi TN, Shaw DW, Ishak GE, et al. Diffusion tensor imaging of the superior cerebellar peduncle identifies patients with posterior fossa syndrome. Child\u0026rsquo;s Nervous System. 2013;29:2071\u0026ndash;7. \u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"posterior fossa tumor, mutism, brainstem tumor, cerebellum disease","lastPublishedDoi":"10.21203/rs.3.rs-2972206/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-2972206/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eApproximately 25% of pediatric patients who undergo cerebellar tumor resection develop cerebellar mutism syndrome (CMS). Our group recently showed that damage to the cerebellar deep nuclei and superior cerebellar peduncles, which we refer to as the cerebellar outflow pathway, is associated with increased risk of CMS. Here, we tested whether these findings replicate in an independent cohort. We evaluated the relationship between lesion location and the development of CMS in an observational study of 56 pediatric patients who underwent cerebellar tumor resection. We hypothesized that individuals that developed CMS after surgery (CMS+), relative to those that did not (CMS-) would have lesions that preferentially intersected with: 1) the cerebellar outflow pathway, and 2) a previously generated \u0026lsquo;lesion-symptom map\u0026rsquo; of CMS. Analyses were conducted in accordance with pre-registered hypotheses and analytic methods (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://osf.io/r8yjv/\u003c/span\u003e\u003cspan address=\"https://osf.io/r8yjv/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e). We found supporting evidence for both hypotheses. Compared with CMS- patients, CMS\u0026thinsp;+\u0026thinsp;patients (n\u0026thinsp;=\u0026thinsp;10) had lesions with greater overlap with the cerebellar outflow pathway (Cohen\u0026rsquo;s d\u0026thinsp;=\u0026thinsp;.73, p\u0026thinsp;=\u0026thinsp;.05), and the CMS lesion-symptom map (Cohen\u0026rsquo;s d\u0026thinsp;=\u0026thinsp;1.1, p\u0026thinsp;=\u0026thinsp;.004). These results strengthen the association of lesion location with risk of developing CMS and demonstrate generalizability across cohorts. These findings may help to inform the optimal surgical approach to pediatric cerebellar tumors.\u003c/p\u003e","manuscriptTitle":"Neuroanatomy of Cerebellar Mutism Syndrome: The Role of Lesion Location","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-05-26 14:17:44","doi":"10.21203/rs.3.rs-2972206/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"22c4fd8c-52ca-486a-843d-e1caea320b82","owner":[],"postedDate":"May 26th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-07-16T10:48:53+00:00","versionOfRecord":{"articleIdentity":"rs-2972206","link":"https://doi.org/10.1093/braincomms/fcae197","journal":{"identity":"brain-communications","isVorOnly":true,"title":"Brain Communications"},"publishedOn":"2024-06-05 10:48:53","publishedOnDateReadable":"June 5th, 2024"},"versionCreatedAt":"2023-05-26 14:17:44","video":"","vorDoi":"10.1093/braincomms/fcae197","vorDoiUrl":"https://doi.org/10.1093/braincomms/fcae197","workflowStages":[]},"version":"v1","identity":"rs-2972206","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-2972206","identity":"rs-2972206","version":["v1"]},"buildId":"cBFmMYwuxLRRLfASyISRj","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}