Contra-lesional hippocampus in low grade glioma patients with no hippocampal infiltration - a study of structural remodelling

Contra-lesional hippocampus in low grade glioma patients with no hippocampal infiltration - a study of structural remodelling | 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 Contra-lesional hippocampus in low grade glioma patients with no hippocampal infiltration - a study of structural remodelling Marcin Stański, Mikołaj Goralewski, Jacek Wątorek, Sylwia Antczak, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7780354/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 16 Mar, 2026 Read the published version in Neuroradiology → Version 1 posted You are reading this latest preprint version Abstract Background Low grade gliomas (LGG) are slowly growing tumours which induce neuroplasticity. It was previously shown that the invasion of hippocampus by LGG may induce enlargement of contra-lesional hippocampus, including its grey matter volume (GMV) and volumes of its subfields. Our goal was to assess if similar changes may occur also in patients with LGG which do not invade hippocampus. Objective To assess grey matter volume (GMV) and hippocampal subfields of the contra-lesional hippocampus in LGG patients with no hippocampal involvement. Methods This was a retrospective study of 3D T1 MRI scans of 30 LGG patients (17 left-, 13 right-sided) without hippocampal invasion and 26 healthy controls. GMV was analysed with voxel-based morphometry (VBM) and volume of hippocampal subfields with FreeSurfer 6.0. In analysis we focused on regions previously reported in the literature to be enlarged in LGG with hippocampal infiltration. Results Contra-lesional hippocampal GMV was significantly larger in left- (T = 7.78, p < 0.05) and right-sided LGG (T = 6.39, p < 0.05). A trend towards larger hippocampal-amygdala transitional area (HATA) was seen in both groups, reaching significance in right-sided LGG (Bonferroni corrected p = 0.04). In right-sided LGGs, trends for enlargement were also observed in GC-ML-DG head (the granule cell molecular layer of the dentate gyrus head), CA1 head, and CA3 head. Conclusions The hippocampus contralateral to LGG may undergo structural remodelling even when the ipsilateral one is not affected by tumour infiltration. glioma neuroplasticity brain morphometry brain volumetry magnetic resonance imaging hippocampus Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 1. Introduction Low grade gliomas (LGGs) are slowly growing tumours which induce neuroplasticity in both ipsilateral and contralateral brain hemispheres [1]. Although functional neuroplasticity in patients with LGG has been widely studied, in recent years a lot of interest is put in structural changes. These are expected to be found across whole brain, as it was shown that the presence of glioma can induce alterations also in distant regions. One of the most intriguing regions is hippocampus, which has an immense potential of remodelling due to the neural stem cells presence [2] . Recent advancements enabled researchers to perform automated analysis of hippocampal subfields volume using magnetic resonance imaging (MRI) scans [3]. This is of great importance, as they might have various biological properties. In the animal studies it was found that subfields are heterogenous regarding stress sensitivity and exhibit different potential of plasticity. Moreover, they can have various function in the memory association [2] . Lately, Liu et al.[4] analysed grey matter volume (GMV) of hippocampus contralateral to LGG in patients with hippocampal involvement, with subfields volume calculated. In their study, not only was GMV of this whole structure increased, but also volumes of five subfields - CA1-head, CA3-head, hippocampus amygdala transitional area (HATA), granule cell molecular layer of the dentate gyrus (GC-ML-DG) head and fimbria. Two other studies[5, 6] analysed groups of glioma patients without hippocampal involvement. One of them included heterogenous group of LGG and high-grade glioma (HGG) patients, and the other patients with HGG. They found increased overall volumes in both contra- and ipsi-lesional hippocampus. Only one of these studies analysed GMV, and found an increase only in the ipsilateral structure. Given current ongoing status of this research, and in reference to the aforementioned studies, we aimed to perform morphometric analysis of GMV and subfields of contra-lesional hippocampus of patients with only LGGs but with no hippocampal involvement. We hypothesized that in these patients, signs of plasticity in the contralateral structure may occur, even though there is no direct hippocampal infiltration. 2. Material and methods This was a retrospective study carried out at the tertiary, university hospital. We retrospectively collected MRI scans of patients with LGGs who underwent brain surgery at the Department of Neurosurgery in years 2021–2024. Then we enrolled patients to the analysis according to inclusion and exclusion criteria. The inclusion criteria were as follows: over 18 years of age, pathologically proven WHO 1 or 2 glioma, according to WHO 2016 classification, MRI scan obtained before the surgery, with T1 MPRAGE sequence available, only one side of the brain affected with no midline shift. The exclusion criteria were: hippocampal involvement, inadequate quality of examinations. Moreover, MRI scans of 26 matched healthy controls (HCs) were also retrospectively collected. All of HCs had no history of brain disorders or disease. Their scans were carefully evaluated by a radiologist with 7 years of experience, and consulted with a radiologist with 20 years of experience, to ensure that no intracranial lesions were present. 2.1 MRI acquistion The scans acquisition was done using MRI Skyra 3T (Siemens Healhineers, Germany). T1-weighted MR images were obtained using a 3D MPRAGE (Magnetization Prepared Rapid Acquisition Gradient Echo) sequence with following parameters: repetition time (TR) = 2200 ms; echo time (TE) = 3.03 ms; time of inversion (TI) = 938 ms; thickness = 1 mm; gap = 0.0 mm; flip angle = 8°; acquisition matrix = 256 x 256; slices = 192. Axial T2-weighted sequence was acquired with following parameters: TR = 6000 ms; TE = 99 ms; thickness = 4 mm; gap = 1,2 mm; flip angle = 150°; acquisition matrix = 640 x 640; percent phase view = 100%. Axial T2 fluid-attenuated inversion recovery (FLAIR) sequence was obtained with following parameters: TR = 8500 ms; TE = 81 ms; inversion time = 2440 ms; thickness = 4,0 mm; gap = 1,2 mm; flip angle = 150°; acquisition matrix = 217 x 320. 2.2 Delineation of lesions All MRI scans were reviewed by a radiologist to identify artifacts or lesions which could be problematic in further workflow. Then the same researcher carefully drew the three-dimensional volume of interests (VOIs) in areas of tumours. For this purpose, MRIcroGL [7] was used. The VOIs were drawn on T1 MPRAGE non-contrast enhanced scans, with respect to T2 and FLAIR images. Eventually, the VOIs were used to create binary masks, which would be an input to VBG. 2.3 Morphometry workflow Similarly to previous studies[4, 8] we used virtual brain grafting (VBG)[9] to preprocess images with brain tumours. This approach enables using tools for morphometry in brains with large lesions, what otherwise would be impossible. VBG uses an array of neuroimaging tools to replace abnormal tissue with a clipping of healthy brain template. Such a synthetic image can be then included in regular workflow. All pre-processed images underwent FreeSurfer (documented and freely available online on http://surfer.nmr.mgh.harvard.edu/ ) recon-all analysis. We drew estimated total intracranial volume (eTIV) from the results. In addition, we performed FreeSurfer hippocampal subfields analysis (a method introduced and described in detail by Iglesias et al. [3] ). Finally, we used pre-processed images in CAT12 workflow. CAT12[10] is a computational anatomy toolbox which enables voxel-based morphometry (VBM) of MRI scans. All images were segmented into grey matter (GM), white matter (WM), and cerebrospinal fluid (CSF). Then, they were normalised using Diffeomorphic Anatomical Registration Through Exponentiated Lie Algebra (DARTEL) algorithm[11] to Montreal National Institute (MNI) space. After that, images were smoothed with 8 mm FWHM (Full Width at Half Maximum) Gaussian smoothing. 2.4 Statistical analysis We used IBM SPSS Statistics (version 27.0) for regular analyses. All tests were two-sided and p values < 0.05 were considered significant. As the study was designed to compare each group of glioma patients (left-sided and right-sided) with HCs separately, we performed two-sided t Student’s tests, Mann-Whitney U tests, and exact Fisher tests, as appropriate, to find differences in age, distribution of sexes, eTIV, and tumour volume. In ROI analysis, we used Neuromorphometrics atlas included in CAT12. For ROI-based morphometry, we used CAT12, with total intracranial volume (TIV) and age as covariates and Holmes-Bonferroni correction for multiple comparisons with corrected p < 0.05. We selected superior occipital gyrus (SOG) and external cerebellar cortex as control ROIs. Then we performed voxel-wise analysis to find significant clusters. This was restricted to the masks of the hippocampus contralateral to tumour in the examined group. The cluster level FWE correction was used, with cluster size k set to 50 voxels. Adjusted p values < 0.005 were considered statistically significant. The differences were reported at voxel levels. To analyse differences in volumes of hippocampal subfields, we used MANCOVA. We included age and eTIV, obtained with FreeSurfer, as covariates. The previous study of Liu et al. [4] found five hippocampal subfields (CA1-head, CA3-head, HATA, GC-ML-DG head and fimbria) to be significantly larger in patients with hippocampus invaded by glioma than in HCs. To limit the severity of multiple comparison correction, we restricted our analysis to these five subfields. For the correction for multiple comparisons, we used Bonferroni method. 3. Results The enrolling process was presented in Fig. 1 . After selection, MRI scans of 30 glioma patients (17 left-sided and 13 right-sided) were included in the analysis. We also enrolled 26 MRI scans of HCs. There were no significant differences in age, TIV and sex distribution between patients and HCs. There was no significant difference in tumour volumes between groups. The descriptive statistics was presented in Table 1 . Among right-sided gliomas, 9 frontal gliomas and 4 temporal gliomas were included. Among left-sided gliomas, we gathered 12 frontal gliomas, 3 parietal gliomas and 1 temporal glioma. All tumours were of WHO stage II according to the WHO 2016 classification. Table 1 Descriptive statistics of analysed groups. N – number of patients, SD – standard deviation, eTIV – estimated total intracranial volume obtained with Freesurfer, HCs – healthy controls, NA – not applicable Patients HCs Right-sided glioma Left-sided glioma N 13 17 26 Age [mean (SD)] 47.65 (16.32) 40.88 (10.20) 43.15 (12.44) eTIV [mean (SD)] 1544.198 (185.10) 1550.499 (177.84) 1428.67 (213.08) Sex (Females/Males) 7 vs 5 8 vs 9 20 vs 6 Tumour volume [median (IQR)) 32.75 (69.10) 38.63 (256.68) NA 3.1 Morphometry analysis We performed a region of interest (ROI) -based analysis to find if GMV was significantly larger in contra-lesional hippocampi in glioma patients compared with HCs. In right-sided glioma patients, left hippocampus had significantly larger GMV ( T = 6.39, p < 0.05, Holmes-Bonferroni corrected); mean GMV in patients was 4.49 (SD = 0.33) versus 3.03 (SD = 0.28) in HCs. After normalization for TIV (using a formula GMV / TIV * 1000 ) it was 2.45 (SD = 0.20) and 2.13 (SD = 0.14), respectively. In left-sided glioma patients we also found larger GMV in right hippocampus ( T = 7.78, p < 0.05, Holmes-Bonferroni corrected); mean GMV in glioma patients was 4.73 ml (SD = 0.35), whereas in HCs it was 3.20 (SD = 0.31). After normalization for TIV it was 2.55 (SD = 0.16) and 2.23 (SD = 0.17), respectively. There were no differences with HCs in control ROIs in both comparisons. We presented box plots with GMV values normalized to TIV in Figs. 1 and 2 . In voxel-based analysis, we found significant clusters in both comparisons. In right hippocampus, there was a significant cluster of 295 voxels ( p = 0.002, family wise error (FEW) correction, the highest peak at x = 24, y = -22, z = -12). In left hippocampus, there was a significant cluster of 845 voxels ( p = 0.002, FWE correction, the highest peak at x = -32, y = -38, z = -8). The T-maps were provided in Figs. 4 and 5 . 3.2 Hippocampal subfields analysis All patients correctly underwent the Freesurfer pipeline. For right-sided glioma patients, we found a tendency towards larger volumes in left HATA (L-HATA), L-GC-ML-DG-head, L-CA1-head, and L-CA3-head. After Bonferroni correction, only L-HATA was held with corrected p = 0.04. For left-sided glioma patients, we found a trend towards larger volume only in right HATA (R-HATA), which however disappeared after correction (Bonferroni p = 0.2, η2 = 0.104). The results were presented in Table 2 . Table 2. Results of multivariate analysis (MANCOVA) of hippocampal subfields. For the subfields, mean volume in ml, with standard deviation in brackets, is given. HCs – healthy controls, p – uncorrected p , Bonf. p – Bonferroni-corrected p , η2 – partial eta-squared. 4. Discussion In this study, we gathered a group of LGGs patients with no hippocampal involvement and aimed to find structural changes in the hippocampus contralateral to tumour. First, we found a larger GMV in this structure. Then we considered hippocampal subfields, and found trends towards volume enlargement in both right-sided and left-sided glioma groups. To increase sensitivity in relatively small groups, we restricted our analysis solely to subfields which exhibited such trend in the recent work of Liu et al. [4], where they considered LGGs with involved hippocampus. Many previous studies demonstrated contralateral plasticity in LGG patients. This included both homotopic and non-homotopic regions in the opposite hemisphere [12]. We focused on the hippocampus, as it is particularly well known for its plasticity potential due to the population of neural stem cells which persists throughout the lifetime [6]. It has been shown that this structure is sensitive for both environmental and endogenous factors, such as environmental complexity, physical activity, social isolation, drugs, levels of neurotrophic factors, steroids, and many others [2] . So far, studies on hippocampi contralateral to gliomas without hippocampal involvement included either only HGGs or mixed groups of HGG and LGG patients. They also gave different results. Karunamuni et al. [13] found decreased hippocampal volume in patients prior to radiotherapy in such a heterogenous group. Ziliolli et al. [6] reported increased volumes of this structure in brains with small glioblastomas. Yuan et al. [5] analysed patients in heterogenous group and found that overall volume of hippocampus in contra-tumoral hemisphere increased. However, they found no significant GMV increase. Those groups were heterogenous or consisted only HGG patients. However, LGGs are typically slowly growing tumours, as such being a model for chronic brain injury. HGGs, on the other hand, have more aggressive nature and induce acute stress on surrounding tissue. It was previously shown that hippocampus presents different response for acute and chronic stress. Acute stress can induce loss of neurons and inhibit neurogenesis, whether chronic and restraint stress can promote neurogenesis [2]. Therefore, we restricted our research to solely LGG patients. Hippocampus is a heterogenous structure and it has been shown that its subfields present different response to stress and have various plasticity potentials [2, 14]. Liu et al. [4] found enlarged volumes of specific subfields in hippocampus contralateral to LGG involving hippocampus. Our study supports the hypothesis that even in the absence of direct hippocampal infiltration, the contralateral hippocampus may undergo structural remodelling in specific pattern. In our study, similarly to the findings of Liu et al [4], the trend towards enlargement was particularly well exhibited in contra-lesional HATA. HATA lies in the medial region of the hippocampus and is superior to the other subfields[15]. It plays an important role in hippocampus-amygdala network, which is involved in information processing[16]. Moreover, amygdala modulates through it the function and synaptic plasticity of hippocampus[4]. Importantly, HATA plays a crucial role in cognition[16] and the association between its volume and cognitive abilities of LGG patients may be an interesting subject for further research. Moreover, the comparison with HGG patients could be intriguing, to inquire if hippocampal subfield analysis could serve as a biomarker of brain adaptive capacity, distinguishing between chronic and acute pathological stressors. Importantly, the increase in GMV and subfields volume should be interpreted with caution. Enlargement of GMV does not necessarily indicate neurogenesis alone; it may also reflect changes in dendritic arborization, synaptic density, glial reactivity, or even subtle alterations in vascular and interstitial fluid compartments [17]. Future studies incorporating multimodal imaging, such as diffusion weighted imaging, arterial spin labelling (ASL) or vascular architecture mapping (VAM), could provide more granular insight into the biological mechanisms underlying volumetric changes. There are several limitations of our study. Our cohort size was small due to epidemiology of LGGs and inclusion criteria. Groups were heterogenous regarding tumour volumes due to difficulty in adjusting it with small samples. As the study was retrospective and no such data were available, we did not include level of education. In multivariate analysis, we restricted statistics only to 5 subfields to increase sensitivity with small sample sizes. Our results underscore the need for larger, multicenter studies with standardized imaging pipelines and integration of clinical, cognitive, and molecular data. Such studies would allow validation of hippocampal subfield hypertrophy as a reproducible biomarker of adaptive neuroplasticity in LGG. Importantly, given the growing interest in hippocampal sparing strategies during radiotherapy, further research may help refine treatment planning by identifying regions most sensitive to structural remodelling and most critical for functional resilience. Declarations Ethics approval: Ethical approval was waived by the Bioethics Committee of Poznan University of Medical Sciences due to the retrospective nature of the study. All performer procedures were part of routine care. The study was conducted in accordance with the 1964 Declaration of Helsinki and its subsequent amendments. Consent to publish : Not applicable. Consent to participate: Due to the retrospective nature of the study informed consent was not required. References Duffau H (2005) Lessons from brain mapping in surgery for low-grade glioma: insights into associations between tumour and brain plasticity. 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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-7780354","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":530912783,"identity":"cc44aabb-be3a-49b1-a6f9-3b0cf31b6e9f","order_by":0,"name":"Marcin Stański","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA00lEQVRIiWNgGAWjYPCCBB5+CIMZhBsIqGaGaJFsgPMYidPCYHCAWC26/ecPfi74kyZjfCM77QFDhXVig3Qjfi1mN5KZpWe25fCY3cjdbsBwJj2xQeYgIS3MDNK8DRUgLdskGNsOJzZIJBLQcv4w82+ePxU8xjNAWv4Ro+VAMps0D1sOj4EESEsDMVpuJJtZ87al8UicebvdIOFYunEbQb+cP/j4Ns+fZHv+9txtDz7UWMv2SzcfwKsFGbABowdIShCtAaQFDEjRMgpGwSgYBSMCAACjXkWWpfsqmwAAAABJRU5ErkJggg==","orcid":"","institution":"Poznan University of Medical Sciences","correspondingAuthor":true,"prefix":"","firstName":"Marcin","middleName":"","lastName":"Stański","suffix":""},{"id":530912784,"identity":"4096781a-ee9c-4df7-bae7-e85e798e171f","order_by":1,"name":"Mikołaj Goralewski","email":"","orcid":"","institution":"Poznan University of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Mikołaj","middleName":"","lastName":"Goralewski","suffix":""},{"id":530912785,"identity":"702c9518-fc48-4d51-b795-3c37cbe31064","order_by":2,"name":"Jacek Wątorek","email":"","orcid":"","institution":"Poznan University of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Jacek","middleName":"","lastName":"Wątorek","suffix":""},{"id":530912786,"identity":"1d310a4f-bdc7-4c03-8a1f-cd9647e2bc2a","order_by":3,"name":"Sylwia Antczak","email":"","orcid":"","institution":"Poznan University of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Sylwia","middleName":"","lastName":"Antczak","suffix":""},{"id":530912787,"identity":"9454646a-4605-4ed4-8b08-4989610bf31c","order_by":4,"name":"Alicja Stańska","email":"","orcid":"","institution":"Poznan University of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Alicja","middleName":"","lastName":"Stańska","suffix":""},{"id":530912788,"identity":"691ca049-2868-4594-851e-afc60c52d8a3","order_by":5,"name":"Antoni Tundak","email":"","orcid":"","institution":"Poznan University of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Antoni","middleName":"","lastName":"Tundak","suffix":""},{"id":530912789,"identity":"e8bcc8d2-1103-4d31-87f9-bcd683fdcc43","order_by":6,"name":"Jakub Moskal","email":"","orcid":"","institution":"Poznan University of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Jakub","middleName":"","lastName":"Moskal","suffix":""},{"id":530912790,"identity":"e5a4c70b-6a05-4fca-ad76-1f792a00695d","order_by":7,"name":"Katarzyna Katulska","email":"","orcid":"","institution":"Poznan University of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Katarzyna","middleName":"","lastName":"Katulska","suffix":""}],"badges":[],"createdAt":"2025-10-04 14:08:22","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7780354/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7780354/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00234-026-03958-1","type":"published","date":"2026-03-16T15:58:39+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":95005852,"identity":"8ae143a5-3c57-4e99-9d98-c5efcaa84fa8","added_by":"auto","created_at":"2025-11-03 09:36:34","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":41014,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFlow chart of study identification, inclusion and exclusion criteria\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7780354/v1/e9bd2f762111d360a6e2cb42.png"},{"id":95221335,"identity":"2319e121-d3f0-402c-9d05-6f34195fd42e","added_by":"auto","created_at":"2025-11-05 16:18:50","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":13003,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eNormalised GMV in HCs and right-sided glioma patients. \u003c/strong\u003eThe normalized GMV was obtained as \u003cem\u003eGMV / TIV x 1000\u003c/em\u003e.\u003cstrong\u003e \u003c/strong\u003eLower and upper box boundaries standard deviation, line inside box mean, lower and upper error lines minimum and maximum, respectively. GMV – gray matter volume, TIV – total intracranial HCs – healthy controls.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7780354/v1/0571160e2c6acee4123bc1d9.png"},{"id":95005850,"identity":"537e8bcf-942a-4f8c-9ef2-1d13d26aa412","added_by":"auto","created_at":"2025-11-03 09:36:34","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":12943,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eNormalised GMV in HCs and left-sided glioma patients. \u003c/strong\u003eThe normalized GMV was obtained as \u003cem\u003eGMV / TIV x 1000\u003c/em\u003e.\u003cstrong\u003e \u003c/strong\u003eLower and upper box boundaries standard deviation, line inside box mean, lower and upper error lines minimum and maximum, respectively. GMV – gray matter volume, TIV – total intracranial volume, HCs – healthy controls.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-7780354/v1/235e17e85b1456b222d8a8bd.png"},{"id":95005854,"identity":"66c988f3-b847-43da-a3b2-789da0fbe10e","added_by":"auto","created_at":"2025-11-03 09:36:34","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":285789,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSignificantly larger GMV in left hippocampus in right-sided glioma patients.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSignificant peaks: x = -32, y = -38 z = -8 (T = 7.63, p\u0026lt;0.005), x = - 33, y = -27, z =-14 (T = 6.60, p\u0026lt;0.005), x = - 24, y = -15, z = - 14 (T=6.58, p\u0026lt;0.005).\u003c/p\u003e\n\u003cp\u003eThe image was prepared using MRIcroGL [7] \u0026nbsp;.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-7780354/v1/e0b15674359919627bb2eef4.png"},{"id":95005853,"identity":"43d9b3b0-a635-475f-b181-08c6d9867955","added_by":"auto","created_at":"2025-11-03 09:36:34","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":289071,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSignificantly larger GMV in right hippocampus in left-sided glioma patients.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSignificant peaks: x = 22, y = -24, z = -12 (T = 7.78, p\u0026lt;0.005), x = 21, y = -14, z =-14 (T = 7.32, \u003cem\u003ep\u003c/em\u003e\u0026lt;0.005), x = 36, y = -28, z = - 14 (T= 5.81, p\u0026lt;0.005).\u003c/p\u003e\n\u003cp\u003eThe image was prepared using MRIcroGL [7] .\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-7780354/v1/cabf1f7742e31fd6b6dd7bc9.png"},{"id":105223522,"identity":"b9fffbb8-a711-4c97-9c80-f0d5542d3e6a","added_by":"auto","created_at":"2026-03-23 16:08:04","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1534960,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7780354/v1/73d45030-e777-455b-8a16-dd975ad3e39b.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eContra-lesional hippocampus in low grade glioma patients with no hippocampal infiltration - a study of structural remodelling\u003c/p\u003e","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eLow grade gliomas (LGGs) are slowly growing tumours which induce neuroplasticity in both ipsilateral and contralateral brain hemispheres [1]. Although functional neuroplasticity in patients with LGG has been widely studied, in recent years a lot of interest is put in structural changes. These are expected to be found across whole brain, as it was shown that the presence of glioma can induce alterations also in distant regions. One of the most intriguing regions is hippocampus, which has an immense potential of remodelling due to the neural stem cells presence [2] .\u003c/p\u003e\u003cp\u003eRecent advancements enabled researchers to perform automated analysis of hippocampal subfields volume using magnetic resonance imaging (MRI) scans [3]. This is of great importance, as they might have various biological properties. In the animal studies it was found that subfields are heterogenous regarding stress sensitivity and exhibit different potential of plasticity. Moreover, they can have various function in the memory association [2] .\u003c/p\u003e\u003cp\u003eLately, Liu et al.[4] analysed grey matter volume (GMV) of hippocampus contralateral to LGG in patients with hippocampal involvement, with subfields volume calculated. In their study, not only was GMV of this whole structure increased, but also volumes of five subfields - CA1-head, CA3-head, hippocampus amygdala transitional area (HATA), granule cell molecular layer of the dentate gyrus (GC-ML-DG) head and fimbria.\u003c/p\u003e\u003cp\u003eTwo other studies[5, 6] analysed groups of glioma patients without hippocampal involvement. One of them included heterogenous group of LGG and high-grade glioma (HGG) patients, and the other patients with HGG. They found increased overall volumes in both contra- and ipsi-lesional hippocampus. Only one of these studies analysed GMV, and found an increase only in the ipsilateral structure.\u003c/p\u003e\u003cp\u003eGiven current ongoing status of this research, and in reference to the aforementioned studies, we aimed to perform morphometric analysis of GMV and subfields of contra-lesional hippocampus of patients with only LGGs but with no hippocampal involvement. We hypothesized that in these patients, signs of plasticity in the contralateral structure may occur, even though there is no direct hippocampal infiltration.\u003c/p\u003e"},{"header":"2. Material and methods","content":"\u003cp\u003eThis was a retrospective study carried out at the tertiary, university hospital. We retrospectively collected MRI scans of patients with LGGs who underwent brain surgery at the Department of Neurosurgery in years 2021\u0026ndash;2024. Then we enrolled patients to the analysis according to inclusion and exclusion criteria.\u003c/p\u003e\u003cp\u003eThe inclusion criteria were as follows: over 18 years of age, pathologically proven WHO 1 or 2 glioma, according to WHO 2016 classification, MRI scan obtained before the surgery, with T1 MPRAGE sequence available, only one side of the brain affected with no midline shift. The exclusion criteria were: hippocampal involvement, inadequate quality of examinations.\u003c/p\u003e\u003cp\u003eMoreover, MRI scans of 26 matched healthy controls (HCs) were also retrospectively collected. All of HCs had no history of brain disorders or disease. Their scans were carefully evaluated by a radiologist with 7 years of experience, and consulted with a radiologist with 20 years of experience, to ensure that no intracranial lesions were present.\u003c/p\u003e\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003e2.1 MRI acquistion\u003c/h2\u003e\u003cp\u003eThe scans acquisition was done using MRI Skyra 3T (Siemens Healhineers, Germany).\u003c/p\u003e\u003cp\u003eT1-weighted MR images were obtained using a 3D MPRAGE (Magnetization Prepared Rapid Acquisition Gradient Echo) sequence with following parameters: repetition time (TR)\u0026thinsp;=\u0026thinsp;2200 ms; echo time (TE)\u0026thinsp;=\u0026thinsp;3.03 ms; time of inversion (TI)\u0026thinsp;=\u0026thinsp;938 ms; thickness\u0026thinsp;=\u0026thinsp;1 mm; gap\u0026thinsp;=\u0026thinsp;0.0 mm; flip angle\u0026thinsp;=\u0026thinsp;8\u0026deg;; acquisition matrix\u0026thinsp;=\u0026thinsp;256 x 256; slices\u0026thinsp;=\u0026thinsp;192.\u003c/p\u003e\u003cp\u003eAxial T2-weighted sequence was acquired with following parameters: TR\u0026thinsp;=\u0026thinsp;6000 ms; TE\u0026thinsp;=\u0026thinsp;99 ms; thickness\u0026thinsp;=\u0026thinsp;4 mm; gap\u0026thinsp;=\u0026thinsp;1,2 mm; flip angle\u0026thinsp;=\u0026thinsp;150\u0026deg;; acquisition matrix\u0026thinsp;=\u0026thinsp;640 x 640; percent phase view\u0026thinsp;=\u0026thinsp;100%.\u003c/p\u003e\u003cp\u003e Axial T2 fluid-attenuated inversion recovery (FLAIR) sequence was obtained with following parameters: TR\u0026thinsp;=\u0026thinsp;8500 ms; TE\u0026thinsp;=\u0026thinsp;81 ms; inversion time\u0026thinsp;=\u0026thinsp;2440 ms; thickness\u0026thinsp;=\u0026thinsp;4,0 mm; gap\u0026thinsp;=\u0026thinsp;1,2 mm; flip angle\u0026thinsp;=\u0026thinsp;150\u0026deg;; acquisition matrix\u0026thinsp;=\u0026thinsp;217 x 320.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\u003ch2\u003e2.2 Delineation of lesions\u003c/h2\u003e\u003cp\u003eAll MRI scans were reviewed by a radiologist to identify artifacts or lesions which could be problematic in further workflow. Then the same researcher carefully drew the three-dimensional volume of interests (VOIs) in areas of tumours. For this purpose, MRIcroGL [7] was used. The VOIs were drawn on T1 MPRAGE non-contrast enhanced scans, with respect to T2 and FLAIR images. Eventually, the VOIs were used to create binary masks, which would be an input to VBG.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\u003ch2\u003e2.3 Morphometry workflow\u003c/h2\u003e\u003cp\u003eSimilarly to previous studies[4, 8] we used virtual brain grafting (VBG)[9] to preprocess images with brain tumours. This approach enables using tools for morphometry in brains with large lesions, what otherwise would be impossible. VBG uses an array of neuroimaging tools to replace abnormal tissue with a clipping of healthy brain template. Such a synthetic image can be then included in regular workflow.\u003c/p\u003e\u003cp\u003eAll pre-processed images underwent FreeSurfer (documented and freely available online on \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://surfer.nmr.mgh.harvard.edu/\u003c/span\u003e\u003cspan address=\"http://surfer.nmr.mgh.harvard.edu/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) \u003cem\u003erecon-all\u003c/em\u003e analysis. We drew estimated total intracranial volume (eTIV) from the results. In addition, we performed FreeSurfer hippocampal subfields analysis (a method introduced and described in detail by Iglesias et al. [3] ).\u003c/p\u003e\u003cp\u003eFinally, we used pre-processed images in CAT12 workflow. CAT12[10] is a computational anatomy toolbox which enables voxel-based morphometry (VBM) of MRI scans. All images were segmented into grey matter (GM), white matter (WM), and cerebrospinal fluid (CSF). Then, they were normalised using Diffeomorphic Anatomical Registration Through Exponentiated Lie Algebra (DARTEL) algorithm[11] to Montreal National Institute (MNI) space. After that, images were smoothed with 8 mm FWHM (Full Width at Half Maximum) Gaussian smoothing.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\u003ch2\u003e2.4 Statistical analysis\u003c/h2\u003e\u003cp\u003eWe used IBM SPSS Statistics (version 27.0) for regular analyses. All tests were two-sided and \u003cem\u003ep\u003c/em\u003e values\u0026thinsp;\u0026lt;\u0026thinsp;0.05 were considered significant. As the study was designed to compare each group of glioma patients (left-sided and right-sided) with HCs separately, we performed two-sided t Student\u0026rsquo;s tests, Mann-Whitney U tests, and exact Fisher tests, as appropriate, to find differences in age, distribution of sexes, eTIV, and tumour volume.\u003c/p\u003e\u003cp\u003eIn ROI analysis, we used Neuromorphometrics atlas included in CAT12. For ROI-based morphometry, we used CAT12, with total intracranial volume (TIV) and age as covariates and Holmes-Bonferroni correction for multiple comparisons with corrected \u003cem\u003ep\u0026thinsp;\u0026lt;\u003c/em\u003e\u0026thinsp;0.05. We selected superior occipital gyrus (SOG) and external cerebellar cortex as control ROIs. Then we performed voxel-wise analysis to find significant clusters. This was restricted to the masks of the hippocampus contralateral to tumour in the examined group. The cluster level FWE correction was used, with cluster size \u003cem\u003ek\u003c/em\u003e set to 50 voxels. Adjusted \u003cem\u003ep\u003c/em\u003e values\u0026thinsp;\u0026lt;\u0026thinsp;0.005 were considered statistically significant. The differences were reported at voxel levels.\u003c/p\u003e\u003cp\u003eTo analyse differences in volumes of hippocampal subfields, we used MANCOVA. We included age and eTIV, obtained with FreeSurfer, as covariates. The previous study of Liu et al. [4] found five hippocampal subfields (CA1-head, CA3-head, HATA, GC-ML-DG head and fimbria) to be significantly larger in patients with hippocampus invaded by glioma than in HCs. To limit the severity of multiple comparison correction, we restricted our analysis to these five subfields. For the correction for multiple comparisons, we used Bonferroni method.\u003c/p\u003e\u003c/div\u003e"},{"header":"3. Results","content":"\u003cp\u003eThe enrolling process was presented in Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. After selection, MRI scans of 30 glioma patients (17 left-sided and 13 right-sided) were included in the analysis. We also enrolled 26 MRI scans of HCs. There were no significant differences in age, TIV and sex distribution between patients and HCs. There was no significant difference in tumour volumes between groups. The descriptive statistics was presented in Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\n\u003cp\u003eAmong right-sided gliomas, 9 frontal gliomas and 4 temporal gliomas were included. Among left-sided gliomas, we gathered 12 frontal gliomas, 3 parietal gliomas and 1 temporal glioma. All tumours were of WHO stage II according to the WHO 2016 classification.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n \u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eDescriptive statistics of analysed groups. \u003cem\u003eN \u0026ndash;\u003c/em\u003e number of patients, SD \u0026ndash; standard deviation, eTIV \u003cem\u003e\u0026ndash;\u003c/em\u003e estimated total intracranial volume obtained with Freesurfer, HCs \u003cem\u003e\u0026ndash;\u003c/em\u003e healthy controls, NA \u0026ndash; not applicable\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003ePatients\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eHCs\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eRight-sided glioma\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eLeft-sided glioma\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eN\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e26\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge [mean (SD)]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e47.65 (16.32)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e40.88 (10.20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e43.15 (12.44)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eeTIV [mean (SD)]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1544.198 (185.10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1550.499 (177.84)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1428.67 (213.08)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eSex (Females/Males)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7 vs 5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8 vs 9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e20 vs 6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eTumour volume [median (IQR))\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e32.75 (69.10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e38.63 (256.68)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n \u003ch2\u003e3.1 Morphometry analysis\u003c/h2\u003e\n \u003cp\u003eWe performed a region of interest (ROI) -based analysis to find if GMV was significantly larger in contra-lesional hippocampi in glioma patients compared with HCs. In right-sided glioma patients, left hippocampus had significantly larger GMV (\u003cem\u003eT\u0026thinsp;=\u003c/em\u003e\u0026thinsp;6.39, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05, Holmes-Bonferroni corrected); mean GMV in patients was 4.49 (SD\u0026thinsp;=\u0026thinsp;0.33) versus 3.03 (SD\u0026thinsp;=\u0026thinsp;0.28) in HCs. After normalization for TIV (using a formula \u003cem\u003eGMV / TIV * 1000\u003c/em\u003e) it was 2.45 (SD\u0026thinsp;=\u0026thinsp;0.20) and 2.13 (SD\u0026thinsp;=\u0026thinsp;0.14), respectively.\u003c/p\u003e\n \u003cp\u003eIn left-sided glioma patients we also found larger GMV in right hippocampus (\u003cem\u003eT\u0026thinsp;=\u003c/em\u003e\u0026thinsp;7.78, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05, Holmes-Bonferroni corrected); mean GMV in glioma patients was 4.73 ml (SD\u0026thinsp;=\u0026thinsp;0.35), whereas in HCs it was 3.20 (SD\u0026thinsp;=\u0026thinsp;0.31). After normalization for TIV it was 2.55 (SD\u0026thinsp;=\u0026thinsp;0.16) and 2.23 (SD\u0026thinsp;=\u0026thinsp;0.17), respectively.\u003c/p\u003e\n \u003cp\u003eThere were no differences with HCs in control ROIs in both comparisons.\u003c/p\u003e\n \u003cp\u003eWe presented box plots with GMV values normalized to TIV in Figs. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e and \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e\n \u003cp\u003eIn voxel-based analysis, we found significant clusters in both comparisons. In right hippocampus, there was a significant cluster of 295 voxels (\u003cem\u003ep\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.002, family wise error (FEW) correction, the highest peak at x\u0026thinsp;=\u0026thinsp;24, y = -22, z = -12). In left hippocampus, there was a significant cluster of 845 voxels (\u003cem\u003ep\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.002, FWE correction, the highest peak at x = -32, y = -38, z = -8).\u003c/p\u003e\n \u003cp\u003eThe T-maps were provided in Figs. \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e and \u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003e.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\n \u003ch2\u003e3.2 Hippocampal subfields analysis\u003c/h2\u003e\n \u003cp\u003eAll patients correctly underwent the Freesurfer pipeline. For right-sided glioma patients, we found a tendency towards larger volumes in left HATA (L-HATA), L-GC-ML-DG-head, L-CA1-head, and L-CA3-head. After Bonferroni correction, only L-HATA was held with corrected \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.04. For left-sided glioma patients, we found a trend towards larger volume only in right HATA (R-HATA), which however disappeared after correction (Bonferroni \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.2, \u0026eta;2\u0026thinsp;=\u0026thinsp;0.104). The results were presented in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\u003cstrong\u003eTable 2. Results of multivariate analysis (MANCOVA) of hippocampal subfields.\u003c/strong\u003e\u003c/div\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cimg 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\"\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eFor the subfields, mean volume in ml, with standard deviation in brackets, is given.\u003c/p\u003e\n \u003cp\u003e\u003cem\u003eHCs \u0026ndash;\u003c/em\u003e healthy controls, \u003cem\u003ep \u0026ndash;\u003c/em\u003e uncorrected \u003cem\u003ep\u003c/em\u003e, Bonf. \u003cem\u003ep \u0026ndash;\u003c/em\u003e Bonferroni-corrected \u003cem\u003ep\u003c/em\u003e, \u003cstrong\u003e\u0026eta;2\u003c/strong\u003e \u0026ndash; partial eta-squared.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eIn this study, we gathered a group of LGGs patients with no hippocampal involvement and aimed to find structural changes in the hippocampus contralateral to tumour. First, we found a larger GMV in this structure. Then we considered hippocampal subfields, and found trends towards volume enlargement in both right-sided and left-sided glioma groups. To increase sensitivity in relatively small groups, we restricted our analysis solely to subfields which exhibited such trend in the recent work of Liu et al. [4], where they considered LGGs with involved hippocampus.\u003c/p\u003e\u003cp\u003eMany previous studies demonstrated contralateral plasticity in LGG patients. This included both homotopic and non-homotopic regions in the opposite hemisphere [12]. We focused on the hippocampus, as it is particularly well known for its plasticity potential due to the population of neural stem cells which persists throughout the lifetime [6]. It has been shown that this structure is sensitive for both environmental and endogenous factors, such as environmental complexity, physical activity, social isolation, drugs, levels of neurotrophic factors, steroids, and many others [2] .\u003c/p\u003e\u003cp\u003eSo far, studies on hippocampi contralateral to gliomas without hippocampal involvement included either only HGGs or mixed groups of HGG and LGG patients. They also gave different results. Karunamuni et al. [13] found decreased hippocampal volume in patients prior to radiotherapy in such a heterogenous group. Ziliolli et al. [6] reported increased volumes of this structure in brains with small glioblastomas. Yuan et al. [5] analysed patients in heterogenous group and found that overall volume of hippocampus in contra-tumoral hemisphere increased. However, they found no significant GMV increase.\u003c/p\u003e\u003cp\u003eThose groups were heterogenous or consisted only HGG patients. However, LGGs are typically slowly growing tumours, as such being a model for chronic brain injury. HGGs, on the other hand, have more aggressive nature and induce acute stress on surrounding tissue. It was previously shown that hippocampus presents different response for acute and chronic stress. Acute stress can induce loss of neurons and inhibit neurogenesis, whether chronic and restraint stress can promote neurogenesis [2]. Therefore, we restricted our research to solely LGG patients.\u003c/p\u003e\u003cp\u003eHippocampus is a heterogenous structure and it has been shown that its subfields present different response to stress and have various plasticity potentials [2, 14]. Liu et al. [4] found enlarged volumes of specific subfields in hippocampus contralateral to LGG involving hippocampus. Our study supports the hypothesis that even in the absence of direct hippocampal infiltration, the contralateral hippocampus may undergo structural remodelling in specific pattern.\u003c/p\u003e\u003cp\u003eIn our study, similarly to the findings of Liu et al [4], the trend towards enlargement was particularly well exhibited in contra-lesional HATA. HATA lies in the medial region of the hippocampus and is superior to the other subfields[15]. It plays an important role in hippocampus-amygdala network, which is involved in information processing[16]. Moreover, amygdala modulates through it the function and synaptic plasticity of hippocampus[4]. Importantly, HATA plays a crucial role in cognition[16] and the association between its volume and cognitive abilities of LGG patients may be an interesting subject for further research. Moreover, the comparison with HGG patients could be intriguing, to inquire if hippocampal subfield analysis could serve as a biomarker of brain adaptive capacity, distinguishing between chronic and acute pathological stressors.\u003c/p\u003e\u003cp\u003eImportantly, the increase in GMV and subfields volume should be interpreted with caution. Enlargement of GMV does not necessarily indicate neurogenesis alone; it may also reflect changes in dendritic arborization, synaptic density, glial reactivity, or even subtle alterations in vascular and interstitial fluid compartments [17]. Future studies incorporating multimodal imaging, such as diffusion weighted imaging, arterial spin labelling (ASL) or vascular architecture mapping (VAM), could provide more granular insight into the biological mechanisms underlying volumetric changes.\u003c/p\u003e\u003cp\u003eThere are several limitations of our study. Our cohort size was small due to epidemiology of LGGs and inclusion criteria. Groups were heterogenous regarding tumour volumes due to difficulty in adjusting it with small samples. As the study was retrospective and no such data were available, we did not include level of education. In multivariate analysis, we restricted statistics only to 5 subfields to increase sensitivity with small sample sizes. Our results underscore the need for larger, multicenter studies with standardized imaging pipelines and integration of clinical, cognitive, and molecular data. Such studies would allow validation of hippocampal subfield hypertrophy as a reproducible biomarker of adaptive neuroplasticity in LGG. Importantly, given the growing interest in hippocampal sparing strategies during radiotherapy, further research may help refine treatment planning by identifying regions most sensitive to structural remodelling and most critical for functional resilience.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval:\u003c/strong\u003e Ethical approval was waived by the Bioethics Committee of Poznan University of Medical Sciences due to the retrospective nature of the study. All performer procedures were part of routine care. The study was conducted in accordance with the 1964 Declaration of Helsinki and its subsequent amendments.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to publish\u003c/strong\u003e: Not applicable.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate:\u0026nbsp;\u003c/strong\u003eDue to the retrospective nature of the study informed consent was not required.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eDuffau H (2005) Lessons from brain mapping in surgery for low-grade glioma: insights into associations between tumour and brain plasticity. Lancet Neurol 4:476\u0026ndash;486. https://doi.org/10.1016/s1474-4422(05)70140-x\u003c/li\u003e\n\u003cli\u003eLieberwirth C, Pan Y, Liu Y, et al (2016) Hippocampal adult neurogenesis: Its regulation and potential role in spatial learning and memory. 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Neurology 91:E1902\u0026ndash;E1908. https://doi.org/10.1212/wnl.0000000000006517\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"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":"glioma, neuroplasticity, brain morphometry, brain volumetry, magnetic resonance imaging, hippocampus","lastPublishedDoi":"10.21203/rs.3.rs-7780354/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7780354/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eLow grade gliomas (LGG) are slowly growing tumours which induce neuroplasticity. It was previously shown that the invasion of hippocampus by LGG may induce enlargement of contra-lesional hippocampus, including its grey matter volume (GMV) and volumes of its subfields. Our goal was to assess if similar changes may occur also in patients with LGG which do not invade hippocampus.\u003c/p\u003e\u003ch2\u003eObjective\u003c/h2\u003e\u003cp\u003eTo assess grey matter volume (GMV) and hippocampal subfields of the contra-lesional hippocampus in LGG patients with no hippocampal involvement.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eThis was a retrospective study of 3D T1 MRI scans of 30 LGG patients (17 left-, 13 right-sided) without hippocampal invasion and 26 healthy controls. GMV was analysed with voxel-based morphometry (VBM) and volume of hippocampal subfields with FreeSurfer 6.0. In analysis we focused on regions previously reported in the literature to be enlarged in LGG with hippocampal infiltration.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eContra-lesional hippocampal GMV was significantly larger in left- (T\u0026thinsp;=\u0026thinsp;7.78, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05) and right-sided LGG (T\u0026thinsp;=\u0026thinsp;6.39, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). A trend towards larger hippocampal-amygdala transitional area (HATA) was seen in both groups, reaching significance in right-sided LGG (Bonferroni corrected \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.04). In right-sided LGGs, trends for enlargement were also observed in GC-ML-DG head (the granule cell molecular layer of the dentate gyrus head), CA1 head, and CA3 head.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e\u003cp\u003eThe hippocampus contralateral to LGG may undergo structural remodelling even when the ipsilateral one is not affected by tumour infiltration.\u003c/p\u003e","manuscriptTitle":"Contra-lesional hippocampus in low grade glioma patients with no hippocampal infiltration - a study of structural remodelling","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-03 09:36:29","doi":"10.21203/rs.3.rs-7780354/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":"e9baaa1b-8ceb-4d4a-8d87-7dbc1b407f0e","owner":[],"postedDate":"November 3rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-03-23T16:04:34+00:00","versionOfRecord":{"articleIdentity":"rs-7780354","link":"https://doi.org/10.1007/s00234-026-03958-1","journal":{"identity":"neuroradiology","isVorOnly":false,"title":"Neuroradiology"},"publishedOn":"2026-03-16 15:58:39","publishedOnDateReadable":"March 16th, 2026"},"versionCreatedAt":"2025-11-03 09:36:29","video":"","vorDoi":"10.1007/s00234-026-03958-1","vorDoiUrl":"https://doi.org/10.1007/s00234-026-03958-1","workflowStages":[]},"version":"v1","identity":"rs-7780354","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7780354","identity":"rs-7780354","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}