Structural brain alterations in persistent developmental stuttering: a whole- brain voxel-based morphometry (VBM) analysis of grey and white matter

Structural brain alterations in persistent developmental stuttering: a whole- brain voxel-based morphometry (VBM) analysis of grey and white matter | 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 Structural brain alterations in persistent developmental stuttering: a whole- brain voxel-based morphometry (VBM) analysis of grey and white matter Seyedehsamaneh Shojaeilangari, Mohammad Ehsan Taghizadeh, Narges Radman This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4106515/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Persistent developmental stuttering (PDS), known as childhood-onset speech fluency disorder involves, significant involuntary problems in normal fluency such as repetition and prolongation of sounds, syllables, or words, as well as silence for certain syllables or words, or pauses within a word. Given the significance of brain morphological abnormalities in unraveling the origins of various neurological disorders, the scientific community has displayed a longstanding fascination with the advancement of structural neuroimaging methods like voxel-based morphometry (VBM). Despite numerous investigations using structural neuroimaging techniques to examine alterations in brain structure associated with stuttering, the precise brain regions predominantly affected by this speech disorder remain unclear. Here, adults with PDS (n = 15) and fluent speakers (n = 15) carefully matched based on age, sex, education, and hand preference were examined utilizing MRI scans to detect possible brain volumetric abnormalities in the stuttering group compared to the healthy control group. Using a whole-brain VBM technique, the brains of adults with PDS and normal subjects were compared concerning grey matter (GM) and white matter (WM) volume differences. Our investigation revealed a reduction in WM volume within the cerebellum. Moreover, we observed increased GM volumes in two specific regions: the right Superior Frontal Gyrus (SFG) and the left Middle Temporal Gyrus (MTG). Conversely, a decrease in GM volume was observed in the left SFG, bilateral paracentral lobule, the right cuneus and the right cerebellum. These findings strengthen the potential significance of brain structures in persistent stuttering. Persistent developmental stuttering voxel-based morphometry Structural brain alterations MRI speech fluency disorder Figures Figure 1 Figure 2 Figure 3 1 Introduction Persistent developmental stuttering (PDS), also referred to as developmental stuttering or childhood-onset fluency disorder, is a speech disorder that manifests as disruptions or interruptions in the typical rhythm and flow of speech. It typically begins in childhood and may persist into adulthood. People with persistent developmental stuttering often experience repetitions, prolongations, or blocks of sounds, syllables, or words [ 1 ]. While the precise cause of PDS is not completely understood, researchers posit that a multifactorial etiology involving genetic, neurological, and environmental factors may contribute to the development of this disorder. [ 2 ]. It is not caused by anxiety, stress, or emotional trauma, although these factors can exacerbate stuttering symptoms. Stuttering can vary in severity and can be influenced by factors such as fatigue, excitement, or speaking in certain situations. It can also affect the individual's social interactions, self-esteem, and overall well-being. MRI (Magnetic Resonance Imaging) studies have been conducted to investigate the structural differences in the brains of individuals with PDS compared to those without the disorder. These studies aim to understand the potential neural basis of stuttering and identify any structural abnormalities that may contribute to the condition. Several MRI studies have documented variations in brain structure and connectivity among individuals with PDS [ 3 ] [ 4 ] [ 5 ] [ 6 ]. For example, some studies have found differences in the size or activation of certain brain regions involved in speech production and motor control, such as the prefrontal cortex, premotor cortex, and basal ganglia [ 7 ]. Additionally, evidence suggests that the white matter (WM) tracts connecting different brain regions involved in speech production may be altered in individuals with PDS. Diffusion tensor imaging (DTI) has been used to examine the integrity and connectivity of WM tracts in the brains of people who stutter [ 8 ]. Within the WM pathway, the superior longitudinal fasciculus serves as a connection between brain regions associated with speech planning in the inferior frontal region and the auditory regions involved in processing speech sounds. This pathway also involves the motor cortex, which plays a role in executing speech movements. Research has indicated that individuals who stutter, both children and adults, exhibit subtle reductions in WM integrity, specifically within the left superior longitudinal fasciculus [ 9 ]. However, it is important to note that findings from MRI studies on PDS have been somewhat inconsistent, and further research is needed to better understand the structural differences associated with the disorder. The small sample sizes and methodological variations across studies make it challenging to draw definitive conclusions. In this study, a whole brain voxel-based morphometry technique was employed to compare the WM and grey matter (GM) differences between individuals who stutter and those who do not. 2 Method 2.1 Participants This study involved a total of thirty participants, consisting of 15 adults with persistent developmental stuttering (PDS) (12 males and 3 females) and a control group of 15 fluent speakers who were matched in terms of age, sex, and education (12 males and 3 females). The mean age of the PDS group was 27.8, ranging from 21 to 41, while the mean age of the control group was 25.66, ranging from 20 to 36. Table 1 provides detailed demographic information about the participants in both groups. All individuals with PDS experienced the onset of stuttering during preadolescence and had not received any treatment for their condition in the year leading up to the study. They were in good physical health and did not have a history of neurological disorders or psychiatric conditions based on their self-report. All participants were native Persian speakers and were right-handed, as confirmed by the Edinburgh-handedness inventory [ 10 ]. A safety questionnaire was administered prior to the fMRI data acquisition to verify the absence of any contraindications for MRI recording. Informed consent was obtained from each participant prior to the experiment, and the study protocol was approved by the local ethical committees at the Institute for Research in Fundamental Sciences (IPM) (Ref. No. SCS. REC: 98/60.1/3440) . The PDS group exhibited a range of stuttering severity, spanning from mild to severe, as evaluated by the Stuttering Severity Instrument-3 (SSI3) [ 11 ] [ 12 ] and the criteria outlined in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) [ 13 ]. Table 1 Participant demographic information. An independent-sample t-test was used: TIV = total intracranial volume; STD = standard deviation; NA = not applicable; NS = not significant (p-value < 0.05 is considered significant). Measures Control Group Stuttering Group Group Difference (t-test), p-value Mean (STD) Mean (STD) Number of cases 15 15 NA sex 13 male, 2 Female 13 male, 2 Female NA Age 25.66 (4.47) 27.87 (5.60) 0.24 TIV 1525.33 (141.89) 1526.33 (98.87) 0.98 Stuttering Severity NA 79.44 (18.10) NA 2.2 Imaging acquisitions MR images were acquired using a Siemens Prisma 3.0 Tesla MRI scanner at the National Brain Mapping Lab in Tehran, Iran. Foam pads were utilized to minimize head movements, and participants wore fitted earplugs to reduce scanner noise. During fMRI scanning, all subjects were instructed to keep their eyes closed, relax, and minimize any movements. Sagittal three-dimensional T1-weighted images were obtained with a resolution of 1×1×1 mm³ using a magnetization prepared rapid gradient echo (MP-RAGE) sequence. The imaging parameters were as follows: repetition time = 1810 ms, echo time = 3.470 ms, flip angle = 7°, and matrix size = 256×256. 2.3 Data Analysis 2.3.1 Preprocessing The CAT12 toolbox, integrated into SPM12, was used for processing and analyzing the images in this study. This toolbox offers voxel-based and surface-based morphometry capabilities. The processing and analysis followed a standardized protocol with pre-defined parameters, as specified in the CAT12 Online Manual ( http://www.neuro.uni-jena.de/cat12/CAT12-Manual.pdf ). Previous morphometric studies on various neurological and neurodegenerative diseases have validated the CAT12 toolbox. To ensure data quality, a two-step quality control process was implemented. Initially, a visual examination of all images was conducted to identify any artifacts before proceeding with pre-processing. Second, a statistical quality assurance step was performed using the "check homogeneity" function within the CAT12 toolbox after segmentation. This step assessed inter-subject homogeneity and overall image quality, including a visual inspection to detect potential artifacts introduced during the process. The data underwent spatial normalization and segmentation, resulting in three voxel categories: GM, WM, and cerebrospinal fluid (CSF). Segmentation was achieved using an adaptive maximum a posteriori (MAP) approach as a technique for partial volume segmentation. Furthermore, the total intracranial volume (TIV) was calculated for all subjects. Modulated normalized GM maps were used to explore regional variations in GM volume (GMV), which were then smoothed utilizing a 6 mm full width at half maximum (FWHM) kernel for subsequent analysis. Finally, an absolute masking threshold of 0.1 was employed to enhance the quality of the voxel-based morphometry (VBM) data. 2.3.2 Statistical analysis The imaging data underwent statistical analysis utilizing the CAT12/SPM12 statistical module. We conducted independent two-sample t-tests for each of the two morphometric measures: GM and WM volume (WMV), using the VBM method. In these analyses, age, gender, and total intracranial volume (TIV) were included as covariates to account for their potential influence. To identify group differences, we applied a significance threshold of p < 0.005 with a false discovery rate (FDR) correction to account for multiple comparisons. 3 Results 3.1 Grey matter volume abnormalities in PDS The VBM analysis was employed in this part to investigate if the impaired connections between brain regions in individuals with stuttering investigated in our previous work [ 1 ] were accompanied by structural changes or abnormalities. Table 2 and Figs. 2 – 3 present the brain regions that exhibited significant differences in GMV concentration between individuals with PDS and the control group. We observed an increase in GMVs in two distinct regions in adults with PDS: the right Superior Frontal Gyrus (SFG) and the left Middle Temporal Gyrus (MTG). In contrast, in this group, a decrease in GMV was observed in the left SFG, paracentral lobule (both left and right), the right cuneus, and the right cerebellum. Table 2 Regions of significantly different GMV for adults with PDS relative to the control group from the whole-brain VBM analysis at p = 0.005 corrected, FDR = 0.05, FWHM = 6mm, Cluster size = 50. Regions BA Laterality Increase /Decrease MNI Coordinate Peak difference Intensity Cluster size Right Cerebellum NA Right D [52.5, -52.5, -46.5] 3.27 108 Cuneus 19 Right D [28.5, -93, 24] 4.25 80 Superior Frontal Gyrus 10 Left D [-16.5, 60, 30] 3.25 70 Paracentral_Lobule 6 Left/Right D [0, -28.5, 73.5] 3.70 74 Temporal_Mid_L 21 Left I [-52.5, -18, -15] -3.99 129 Postcentral 2 Right I [36, -25.5, 40.5] -3.35 113 3.2 White matter volume abnormalities in PDS Table 3 and Fig. 4 present the brain regions that exhibited significant differences in WMV concentration between adults with PDS and the control group. We observed decreased WM in the left cerebellum. When applying a smaller cluster size threshold of 30 voxels, additional findings become apparent. We observed increased WMV in the right-hemispheric thalamus and hippocampus. Conversely, decreased WMV was observed in the left inferior temporal region, as well as in the left and right cerebellum. Table 3 Regions of significantly different WMV for adults with PDS relative to the control group from the whole-brain VBM analysis at p = 0.005 corrected, FDR = 0.05, FWHM = 6mm, Cluster size = 50. Regions BA Laterality Increase /Decrease MNI Coordinate Peak Intensity Cluster size Cerebellum NA Left D [-24, -73.5, -37.5] 3.9 182 4 Discussion and conclusion The main aim of this study was to investigate potential neuroanatomical variations in individuals with PDS compared to control group, with the goal of identifying neural correlates associated with stuttering. Structural MRI scans were conducted on adults with PDS and age, sex, hand preference, and education-matched controls. By utilizing the whole brain voxel-based morphometry technique, we compared the WM and GM volume differences between adults with PDS and healthy controls. Our findings revealed multiple regional abnormalities in GM volume across the speech production network in individuals with PDS, while fewer WMV abnormalities were observed in the cerebellum compared to the fluent control group. In our VBM results, adults with PDS showed increased GMV concentration in two distinct regions: the right SFG and the left MTG. In contrast, a decrease in GMV was observed in the left SFG, paracentral lobule (both left and right), the right cuneus (a region situated in the occipital lobe responsible for visual processing), and the right cerebellum. Certainly, investigations conducted on children and adults who stutter have indeed provided evidence of abnormalities in the volume of grey matter in the frontal and temporal gyri, which are regions known to be involved in speech production. These abnormalities have been observed bilaterally, indicating alterations in both hemispheres of the brain [ 14 ] [ 15 ]. One of our notable findings is a reduction in GMV in the left SFG, accompanied by an increase in GMV in the right SFG in adults with PDS compared to the control group. Indeed, the SFG, particularly Broca's area, is crucial for the production and comprehension of speech and plays a significant role in various language-related functions. It contributes to language comprehension, grammar processing, syntactic analysis, and the integration of meaning in sentences [ 16 ] [ 17 ]. As suggested in previous studies, increased volume in the right frontal and prefrontal regions can be considered as a compensatory mechanism in adults with PDS as a compensatory mechanism [ 18 ]. This can explain the differential SFG volume changes in our group of adults with PDS (i.e. decrease left SFG and increase right SFG volume) compared to the control group. Another significant finding of our study indicates that individuals with PDS exhibit an increase in GM volume in left MTG. The primary auditory cortex, located in the temporal lobe, is responsible for processing the meaning of both spoken words and visual stimuli in humans. Wernicke's area, positioned between the temporal and parietal lobes, plays a crucial role in understanding speech, working together with Broca's area in the frontal lobe. It's worth noting that the functions of the left temporal lobe go beyond basic perception, encompassing comprehension, naming, and verbal memory [ 19 ]. While the reported results in the literature regarding the directionality of findings are inconsistent, there exists a substantial body of evidence that supports our own findings [ 20 ]. Notably, previous researches have demonstrated that adults who stutter exhibit higher GMV in the left inferior frontal gyrus, as well as the bilateral pre- and post-central gyri, superior temporal gyri, and MTG [ 21 ][ 22 ]. Conversely, regional decreases in GMV have also been observed in PDS, specifically in the left SFG, left inferior frontal gyrus, and bilateral middle frontal gyrus [ 22 ] [ 23 ]. Regarding our finding related to decreased GMV in the paracentral lobe, we could not find any supporting evidence. The paracentral lobe plays a crucial role in motor control and coordination, particularly in the lower limbs and pelvic region. In relation to stuttering, the involvement of the paracentral lobe has been a topic of interest in neuroimaging studies that suggested a potential dysfunction in motor planning and execution processes associated with stuttering [ 24 ]. However, there is limited research specifically linking GM volume impairments in the paracentral lobe to stuttering [ 25 ]. While some studies have reported alterations in GMV in brain regions associated with motor control and coordination, including the paracentral lobe, other studies have not found significant differences in GMV in this specific region among individuals who stutter. The findings regarding GM/WM volume in the cerebellum and stuttering are not yet fully conclusive and require further investigation [ 24 ]. The cerebellum is a brain region involved in motor coordination and timing, and it has been implicated in speech production. We observed that adults with PDS have decreased GM and WM volume in the right and left cerebellum, respectively; however, additional research using larger sample sizes and more refined methodologies is needed to gain a better understanding of the potential role of cerebellum alterations in stuttering. It is important to acknowledge a limitation of this study, which is the small number of participants. While several MRI studies with similar sample sizes have been published in the literature, the small sample size in our study may introduce higher variability in the data, potentially reducing the reliability of the findings. Interestingly, it is worth noting that not all studies have observed differences in GM/ WM among adults who stutter [ 26 ]. This suggests that the relationship between GMV and stuttering may be complex and influenced by various factors, such as sample characteristics, methodology, and other variables. Further research is needed to better understand the neurobiological underpinnings of stuttering and the potential involvement of structural alterations. It is crucial to recognize that our understanding of the underlying mechanisms of stuttering is still in its early stages. As research progresses in investigating the neural and genetic foundations of stuttering, scientists may eventually discover an objective biomarker for PDS disorder and identify brain changes associated with effective rehabilitation from this condition. These future advancements would significantly improve clinical assessment methods and bring researchers closer to pinpointing targets for successful treatment. As our understanding of the underlying causes of stuttering deepens, we move closer to the prospect of discovering a lasting cure for this speech condition. Declarations Declaration of interests “The authors declare no competing interests.” Author Contribution S.Sh., Data analysis; S.Sh., N.R., Conceptualization and methodology; S.Sh., N.R., M.T., Validation; S.Sh., Original draft preparation; S.Sh., N.R., Review and editing. 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J Fluen Disord 55:6–45 Watkins KE, Smith SM, Davis S, Howell P (2008) Structural and functional abnormalities of the motor system in developmental stuttering. Brain 50–59. 10.1093/brain/awm241 Jäncke SH, Hänggi L (2004) Morphological brain differences between adult stutterers and nonstutterers. BMC Neurol 4(1):23 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted 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. 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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-4106515","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":281519678,"identity":"1b2a1749-1437-49e9-8a98-b08900ff9241","order_by":0,"name":"Seyedehsamaneh Shojaeilangari","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAzklEQVRIie3PMQrCMBTG8VcKdfls1xSLXiEi6GavYvEYDlYK7dIDtHiZlg4uXkBchIJz3Bw6mIqCk8komH/IEHg/eCEymX4zhwjyDHbx+6lLUPeE65I+tqInUTaJB9eLCJaB57epEF1H7qj6TniFxbTAGv4+SsoylYu5KwUhOCPABj9HiT2MJYHGYpJsEZ7qxEanQaiiuSQNOLMkcTQIbzD3CxzAjlFilekM6sWy7Mpu+Sb0skNLohuPJ7lqMVte62NK+ZNXd805k8lk+s8epoAxZREZZ7YAAAAASUVORK5CYII=","orcid":"","institution":"Iranian Research Organization for Science and Technology (IROST)","correspondingAuthor":true,"prefix":"","firstName":"Seyedehsamaneh","middleName":"","lastName":"Shojaeilangari","suffix":""},{"id":281519679,"identity":"2133fe32-51a5-431e-bd6b-e48688797d8d","order_by":1,"name":"Mohammad Ehsan Taghizadeh","email":"","orcid":"","institution":"Payame Noor University","correspondingAuthor":false,"prefix":"","firstName":"Mohammad","middleName":"Ehsan","lastName":"Taghizadeh","suffix":""},{"id":281519680,"identity":"f6bfc705-6d76-4f91-9817-61ba315ea042","order_by":2,"name":"Narges Radman","email":"","orcid":"","institution":"Institute for Research in Fundamental Sciences (IPM)","correspondingAuthor":false,"prefix":"","firstName":"Narges","middleName":"","lastName":"Radman","suffix":""}],"badges":[],"createdAt":"2024-03-15 09:14:43","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4106515/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4106515/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":53200649,"identity":"8b907e9b-67f4-4854-b0d4-42e0e909b787","added_by":"auto","created_at":"2024-03-21 19:28:32","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":783021,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eRegions of significantly decreased GMV for adults with PDS relative to the control group. (a) Right Cerebellum; (b) Cuneus; (c) Left Superior Frontal Gyrus; (d) Paracentral_Lobule.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4106515/v1/d7de3033d92693f5e16ed6f2.jpeg"},{"id":53201392,"identity":"f3075784-d337-4fd5-a9ab-5a370cb7dc7d","added_by":"auto","created_at":"2024-03-21 19:36:32","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":433356,"visible":true,"origin":"","legend":"\u003cp\u003eRegions of significantly increased GMV for adults with PDS relative to the control group. (a) left Middle Temporal Gyrus (MTG); (b) right Superior Frontal Gyrus (SFG).\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4106515/v1/b4f3c255dd3f74c7563b6817.jpeg"},{"id":53200651,"identity":"88451ef7-b6a5-4115-991c-3eac8e46d4d6","added_by":"auto","created_at":"2024-03-21 19:28:32","extension":"jpeg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":212591,"visible":true,"origin":"","legend":"\u003cp\u003eRegions of significantly decreased WMV for adults with PDS relative to the control group.\u003c/p\u003e","description":"","filename":"floatimage3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4106515/v1/fd1699b186b2ff43354ea4d9.jpeg"},{"id":74379916,"identity":"0b9b4c01-9e9a-4465-beca-feaadccf4b0d","added_by":"auto","created_at":"2025-01-21 18:12:26","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2042086,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4106515/v1/d2a518aa-16a5-450f-b551-c27764df60e4.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Structural brain alterations in persistent developmental stuttering: a whole- brain voxel-based morphometry (VBM) analysis of grey and white matter","fulltext":[{"header":"1 Introduction","content":"\u003cp\u003ePersistent developmental stuttering (PDS), also referred to as developmental stuttering or childhood-onset fluency disorder, is a speech disorder that manifests as disruptions or interruptions in the typical rhythm and flow of speech. It typically begins in childhood and may persist into adulthood. People with persistent developmental stuttering often experience repetitions, prolongations, or blocks of sounds, syllables, or words [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eWhile the precise cause of PDS is not completely understood, researchers posit that a multifactorial etiology involving genetic, neurological, and environmental factors may contribute to the development of this disorder. [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. It is not caused by anxiety, stress, or emotional trauma, although these factors can exacerbate stuttering symptoms. Stuttering can vary in severity and can be influenced by factors such as fatigue, excitement, or speaking in certain situations. It can also affect the individual's social interactions, self-esteem, and overall well-being.\u003c/p\u003e \u003cp\u003eMRI (Magnetic Resonance Imaging) studies have been conducted to investigate the structural differences in the brains of individuals with PDS compared to those without the disorder. These studies aim to understand the potential neural basis of stuttering and identify any structural abnormalities that may contribute to the condition.\u003c/p\u003e \u003cp\u003eSeveral MRI studies have documented variations in brain structure and connectivity among individuals with PDS [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e] [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e] [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e] [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. For example, some studies have found differences in the size or activation of certain brain regions involved in speech production and motor control, such as the prefrontal cortex, premotor cortex, and basal ganglia [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAdditionally, evidence suggests that the white matter (WM) tracts connecting different brain regions involved in speech production may be altered in individuals with PDS. Diffusion tensor imaging (DTI) has been used to examine the integrity and connectivity of WM tracts in the brains of people who stutter [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eWithin the WM pathway, the superior longitudinal fasciculus serves as a connection between brain regions associated with speech planning in the inferior frontal region and the auditory regions involved in processing speech sounds. This pathway also involves the motor cortex, which plays a role in executing speech movements. Research has indicated that individuals who stutter, both children and adults, exhibit subtle reductions in WM integrity, specifically within the left superior longitudinal fasciculus [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eHowever, it is important to note that findings from MRI studies on PDS have been somewhat inconsistent, and further research is needed to better understand the structural differences associated with the disorder. The small sample sizes and methodological variations across studies make it challenging to draw definitive conclusions.\u003c/p\u003e \u003cp\u003eIn this study, a whole brain voxel-based morphometry technique was employed to compare the WM and grey matter (GM) differences between individuals who stutter and those who do not.\u003c/p\u003e"},{"header":"2 Method","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Participants\u003c/h2\u003e \u003cp\u003e This study involved a total of thirty participants, consisting of 15 adults with persistent developmental stuttering (PDS) (12 males and 3 females) and a control group of 15 fluent speakers who were matched in terms of age, sex, and education (12 males and 3 females). The mean age of the PDS group was 27.8, ranging from 21 to 41, while the mean age of the control group was 25.66, ranging from 20 to 36. Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e provides detailed demographic information about the participants in both groups.\u003c/p\u003e \u003cp\u003eAll individuals with PDS experienced the onset of stuttering during preadolescence and had not received any treatment for their condition in the year leading up to the study. They were in good physical health and did not have a history of neurological disorders or psychiatric conditions based on their self-report. All participants were native Persian speakers and were right-handed, as confirmed by the Edinburgh-handedness inventory [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. A safety questionnaire was administered prior to the fMRI data acquisition to verify the absence of any contraindications for MRI recording. Informed consent was obtained from each participant prior to the experiment, and the study protocol was approved by the local ethical committees at the \u003cem\u003eInstitute for Research in Fundamental Sciences (IPM) (Ref. No. SCS. REC: 98/60.1/3440)\u003c/em\u003e.\u003c/p\u003e \u003cp\u003eThe PDS group exhibited a range of stuttering severity, spanning from mild to severe, as evaluated by the Stuttering Severity Instrument-3 (SSI3) [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] and the criteria outlined in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eParticipant demographic information. An independent-sample t-test was used: TIV\u0026thinsp;=\u0026thinsp;total intracranial volume; STD\u0026thinsp;=\u0026thinsp;standard deviation; NA\u0026thinsp;=\u0026thinsp;not applicable; NS\u0026thinsp;=\u0026thinsp;not significant (p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 is considered significant).\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eMeasures\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eControl Group\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eStuttering Group\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eGroup Difference (t-test), p-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMean (STD)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMean (STD)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNumber of cases\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003esex\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13 male, 2 Female\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13 male, 2 Female\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25.66 (4.47)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e27.87 (5.60)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.24\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTIV\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1525.33 (141.89)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1526.33 (98.87)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.98\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eStuttering Severity\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e79.44 (18.10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Imaging acquisitions\u003c/h2\u003e \u003cp\u003eMR images were acquired using a Siemens Prisma 3.0 Tesla MRI scanner at the National Brain Mapping Lab in Tehran, Iran. Foam pads were utilized to minimize head movements, and participants wore fitted earplugs to reduce scanner noise. During fMRI scanning, all subjects were instructed to keep their eyes closed, relax, and minimize any movements. Sagittal three-dimensional T1-weighted images were obtained with a resolution of 1\u0026times;1\u0026times;1 mm\u0026sup3; using a magnetization prepared rapid gradient echo (MP-RAGE) sequence. The imaging parameters were as follows: repetition time\u0026thinsp;=\u0026thinsp;1810 ms, echo time\u0026thinsp;=\u0026thinsp;3.470 ms, flip angle\u0026thinsp;=\u0026thinsp;7\u0026deg;, and matrix size\u0026thinsp;=\u0026thinsp;256\u0026times;256.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Data Analysis\u003c/h2\u003e \u003cdiv id=\"Sec6\" class=\"Section3\"\u003e \u003ch2\u003e2.3.1 Preprocessing\u003c/h2\u003e \u003cp\u003eThe CAT12 toolbox, integrated into SPM12, was used for processing and analyzing the images in this study. This toolbox offers voxel-based and surface-based morphometry capabilities. The processing and analysis followed a standardized protocol with pre-defined parameters, as specified in the CAT12 Online Manual (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.neuro.uni-jena.de/cat12/CAT12-Manual.pdf\u003c/span\u003e\u003cspan address=\"http://www.neuro.uni-jena.de/cat12/CAT12-Manual.pdf\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e). Previous morphometric studies on various neurological and neurodegenerative diseases have validated the CAT12 toolbox.\u003c/p\u003e \u003cp\u003eTo ensure data quality, a two-step quality control process was implemented. Initially, a visual examination of all images was conducted to identify any artifacts before proceeding with pre-processing. Second, a statistical quality assurance step was performed using the \"check homogeneity\" function within the CAT12 toolbox after segmentation. This step assessed inter-subject homogeneity and overall image quality, including a visual inspection to detect potential artifacts introduced during the process.\u003c/p\u003e \u003cp\u003eThe data underwent spatial normalization and segmentation, resulting in three voxel categories: GM, WM, and cerebrospinal fluid (CSF). Segmentation was achieved using an adaptive maximum a posteriori (MAP) approach as a technique for partial volume segmentation.\u003c/p\u003e \u003cp\u003eFurthermore, the total intracranial volume (TIV) was calculated for all subjects. Modulated normalized GM maps were used to explore regional variations in GM volume (GMV), which were then smoothed utilizing a 6 mm full width at half maximum (FWHM) kernel for subsequent analysis.\u003c/p\u003e \u003cp\u003eFinally, an absolute masking threshold of 0.1 was employed to enhance the quality of the voxel-based morphometry (VBM) data.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section3\"\u003e \u003ch2\u003e2.3.2 Statistical analysis\u003c/h2\u003e \u003cp\u003eThe imaging data underwent statistical analysis utilizing the CAT12/SPM12 statistical module. We conducted independent two-sample t-tests for each of the two morphometric measures: GM and WM volume (WMV), using the VBM method.\u003c/p\u003e \u003cp\u003eIn these analyses, age, gender, and total intracranial volume (TIV) were included as covariates to account for their potential influence. To identify group differences, we applied a significance threshold of p\u0026thinsp;\u0026lt;\u0026thinsp;0.005 with a false discovery rate (FDR) correction to account for multiple comparisons.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"3 Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e3.1 Grey matter volume abnormalities in PDS\u003c/h2\u003e \u003cp\u003eThe VBM analysis was employed in this part to investigate if the impaired connections between brain regions in individuals with stuttering investigated in our previous work [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e] were accompanied by structural changes or abnormalities. Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and Figs.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e3\u003c/span\u003e present the brain regions that exhibited significant differences in GMV concentration between individuals with PDS and the control group. We observed an increase in GMVs in two distinct regions in adults with PDS: the right Superior Frontal Gyrus (SFG) and the left Middle Temporal Gyrus (MTG). In contrast, in this group, a decrease in GMV was observed in the left SFG, paracentral lobule (both left and right), the right cuneus, and the right cerebellum.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eRegions of significantly different GMV for adults with PDS relative to the control group from the whole-brain VBM analysis at p\u0026thinsp;=\u0026thinsp;0.005 corrected, FDR\u0026thinsp;=\u0026thinsp;0.05, FWHM\u0026thinsp;=\u0026thinsp;6mm, Cluster size\u0026thinsp;=\u0026thinsp;50.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026minus;\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRegions\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBA\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLaterality\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eIncrease\u003c/p\u003e \u003cp\u003e/Decrease\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMNI Coordinate\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePeak difference Intensity\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eCluster size\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRight Cerebellum\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRight\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026minus;\" colname=\"c5\"\u003e \u003cp\u003e[52.5, -52.5, -46.5]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e3.27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e108\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCuneus\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRight\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026minus;\" colname=\"c5\"\u003e \u003cp\u003e[28.5, -93, 24]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e4.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e80\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSuperior Frontal Gyrus\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLeft\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026minus;\" colname=\"c5\"\u003e \u003cp\u003e[-16.5, 60, 30]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e3.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e70\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParacentral_Lobule\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLeft/Right\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026minus;\" colname=\"c5\"\u003e \u003cp\u003e[0, -28.5, 73.5]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e3.70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e74\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTemporal_Mid_L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLeft\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026minus;\" colname=\"c5\"\u003e \u003cp\u003e[-52.5, -18, -15]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e-3.99\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e129\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePostcentral\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRight\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026minus;\" colname=\"c5\"\u003e \u003cp\u003e[36, -25.5, 40.5]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e-3.35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e113\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003e3.2 White matter volume abnormalities in PDS\u003c/h2\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e and Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e4\u003c/span\u003e present the brain regions that exhibited significant differences in WMV concentration between adults with PDS and the control group. We observed decreased WM in the left cerebellum.\u003c/p\u003e \u003cp\u003eWhen applying a smaller cluster size threshold of 30 voxels, additional findings become apparent. We observed increased WMV in the right-hemispheric thalamus and hippocampus. Conversely, decreased WMV was observed in the left inferior temporal region, as well as in the left and right cerebellum.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eRegions of significantly different WMV for adults with PDS relative to the control group from the whole-brain VBM analysis at p\u0026thinsp;=\u0026thinsp;0.005 corrected, FDR\u0026thinsp;=\u0026thinsp;0.05, FWHM\u0026thinsp;=\u0026thinsp;6mm, Cluster size\u0026thinsp;=\u0026thinsp;50.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRegions\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBA\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLaterality\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eIncrease\u003c/p\u003e \u003cp\u003e/Decrease\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMNI Coordinate\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePeak Intensity\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eCluster size\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCerebellum\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLeft\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e[-24, -73.5, -37.5]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e182\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"4 Discussion and conclusion","content":"\u003cp\u003eThe main aim of this study was to investigate potential neuroanatomical variations in individuals with PDS compared to control group, with the goal of identifying neural correlates associated with stuttering. Structural MRI scans were conducted on adults with PDS and age, sex, hand preference, and education-matched controls. By utilizing the whole brain voxel-based morphometry technique, we compared the WM and GM volume differences between adults with PDS and healthy controls. Our findings revealed multiple regional abnormalities in GM volume across the speech production network in individuals with PDS, while fewer WMV abnormalities were observed in the cerebellum compared to the fluent control group.\u003c/p\u003e \u003cp\u003eIn our VBM results, adults with PDS showed increased GMV concentration in two distinct regions: the right SFG and the left MTG. In contrast, a decrease in GMV was observed in the left SFG, paracentral lobule (both left and right), the right cuneus (a region situated in the occipital lobe responsible for visual processing), and the right cerebellum.\u003c/p\u003e \u003cp\u003eCertainly, investigations conducted on children and adults who stutter have indeed provided evidence of abnormalities in the volume of grey matter in the frontal and temporal gyri, which are regions known to be involved in speech production. These abnormalities have been observed bilaterally, indicating alterations in both hemispheres of the brain [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e] [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eOne of our notable findings is a reduction in GMV in the left SFG, accompanied by an increase in GMV in the right SFG in adults with PDS compared to the control group. Indeed, the SFG, particularly Broca's area, is crucial for the production and comprehension of speech and plays a significant role in various language-related functions. It contributes to language comprehension, grammar processing, syntactic analysis, and the integration of meaning in sentences [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e] [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. As suggested in previous studies, increased volume in the right frontal and prefrontal regions can be considered as a compensatory mechanism in adults with PDS as a compensatory mechanism [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. This can explain the differential SFG volume changes in our group of adults with PDS (i.e. decrease left SFG and increase right SFG volume) compared to the control group.\u003c/p\u003e \u003cp\u003eAnother significant finding of our study indicates that individuals with PDS exhibit an increase in GM volume in left MTG. The primary auditory cortex, located in the temporal lobe, is responsible for processing the meaning of both spoken words and visual stimuli in humans. Wernicke's area, positioned between the temporal and parietal lobes, plays a crucial role in understanding speech, working together with Broca's area in the frontal lobe. It's worth noting that the functions of the left temporal lobe go beyond basic perception, encompassing comprehension, naming, and verbal memory [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eWhile the reported results in the literature regarding the directionality of findings are inconsistent, there exists a substantial body of evidence that supports our own findings [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Notably, previous researches have demonstrated that adults who stutter exhibit higher GMV in the left inferior frontal gyrus, as well as the bilateral pre- and post-central gyri, superior temporal gyri, and MTG [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e][\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Conversely, regional decreases in GMV have also been observed in PDS, specifically in the left SFG, left inferior frontal gyrus, and bilateral middle frontal gyrus [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e] [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eRegarding our finding related to decreased GMV in the paracentral lobe, we could not find any supporting evidence. The paracentral lobe plays a crucial role in motor control and coordination, particularly in the lower limbs and pelvic region. In relation to stuttering, the involvement of the paracentral lobe has been a topic of interest in neuroimaging studies that suggested a potential dysfunction in motor planning and execution processes associated with stuttering [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. However, there is limited research specifically linking GM volume impairments in the paracentral lobe to stuttering [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. While some studies have reported alterations in GMV in brain regions associated with motor control and coordination, including the paracentral lobe, other studies have not found significant differences in GMV in this specific region among individuals who stutter.\u003c/p\u003e \u003cp\u003eThe findings regarding GM/WM volume in the cerebellum and stuttering are not yet fully conclusive and require further investigation [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. The cerebellum is a brain region involved in motor coordination and timing, and it has been implicated in speech production. We observed that adults with PDS have decreased GM and WM volume in the right and left cerebellum, respectively; however, additional research using larger sample sizes and more refined methodologies is needed to gain a better understanding of the potential role of cerebellum alterations in stuttering.\u003c/p\u003e \u003cp\u003eIt is important to acknowledge a limitation of this study, which is the small number of participants. While several MRI studies with similar sample sizes have been published in the literature, the small sample size in our study may introduce higher variability in the data, potentially reducing the reliability of the findings.\u003c/p\u003e \u003cp\u003eInterestingly, it is worth noting that not all studies have observed differences in GM/ WM among adults who stutter [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. This suggests that the relationship between GMV and stuttering may be complex and influenced by various factors, such as sample characteristics, methodology, and other variables. Further research is needed to better understand the neurobiological underpinnings of stuttering and the potential involvement of structural alterations.\u003c/p\u003e \u003cp\u003eIt is crucial to recognize that our understanding of the underlying mechanisms of stuttering is still in its early stages. As research progresses in investigating the neural and genetic foundations of stuttering, scientists may eventually discover an objective biomarker for PDS disorder and identify brain changes associated with effective rehabilitation from this condition. These future advancements would significantly improve clinical assessment methods and bring researchers closer to pinpointing targets for successful treatment. As our understanding of the underlying causes of stuttering deepens, we move closer to the prospect of discovering a lasting cure for this speech condition.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eDeclaration of interests\u003c/h2\u003e \u003cp\u003e\u0026ldquo;The authors declare no competing interests.\u0026rdquo;\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eS.Sh., Data analysis; S.Sh., N.R., Conceptualization and methodology; S.Sh., N.R., M.T., Validation; S.Sh., Original draft preparation; S.Sh., N.R., Review and editing.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eShojaeilangari S, Radman N, Taghizadeh ME, Soltanian-Zadeh H (2021) rsfMRI based evidence for functional connectivity alterations in adults with developmental stuttering. 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BMC Neurol 4(1):23\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"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":"Persistent developmental stuttering, voxel-based morphometry, Structural brain alterations, MRI, speech fluency disorder","lastPublishedDoi":"10.21203/rs.3.rs-4106515/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4106515/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003ePersistent developmental stuttering (PDS), known as childhood-onset speech fluency disorder involves, significant involuntary problems in normal fluency such as repetition and prolongation of sounds, syllables, or words, as well as silence for certain syllables or words, or pauses within a word. Given the significance of brain morphological abnormalities in unraveling the origins of various neurological disorders, the scientific community has displayed a longstanding fascination with the advancement of structural neuroimaging methods like voxel-based morphometry (VBM). Despite numerous investigations using structural neuroimaging techniques to examine alterations in brain structure associated with stuttering, the precise brain regions predominantly affected by this speech disorder remain unclear. Here, adults with PDS (n\u0026thinsp;=\u0026thinsp;15) and fluent speakers (n\u0026thinsp;=\u0026thinsp;15) carefully matched based on age, sex, education, and hand preference were examined utilizing MRI scans to detect possible brain volumetric abnormalities in the stuttering group compared to the healthy control group. Using a whole-brain VBM technique, the brains of adults with PDS and normal subjects were compared concerning grey matter (GM) and white matter (WM) volume differences. Our investigation revealed a reduction in WM volume within the cerebellum. Moreover, we observed increased GM volumes in two specific regions: the right Superior Frontal Gyrus (SFG) and the left Middle Temporal Gyrus (MTG). Conversely, a decrease in GM volume was observed in the left SFG, bilateral paracentral lobule, the right cuneus and the right cerebellum. These findings strengthen the potential significance of brain structures in persistent stuttering.\u003c/p\u003e","manuscriptTitle":"Structural brain alterations in persistent developmental stuttering: a whole- brain voxel-based morphometry (VBM) analysis of grey and white matter","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-03-21 19:28:27","doi":"10.21203/rs.3.rs-4106515/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":"26ec3631-f71f-4974-a4cd-af8782614328","owner":[],"postedDate":"March 21st, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-01-21T18:04:19+00:00","versionOfRecord":[],"versionCreatedAt":"2024-03-21 19:28:27","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4106515","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4106515","identity":"rs-4106515","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}