Introduction

Obsessive-compulsive disorder (OCD) is a chronic mental disorder characterized by obsession and/or compulsion that affects 2–3% of the world’s population [1]. As one of the most common mental disorders according to the World Health Organization (WHO), OCD causes huge damage on patients’ social function and life quality. The traditional neurobiological model of OCD has been associated with dysfunction in cortico-striatal-thalamo-cortical (CSTC) circuits, but more and more evidence showed that fronto-parietal and cerebellar circuits also play a critical role in the neural mechanisms of OCD, which is highly connected by white matter in relevant brain regions [2, 3].

Diffusion tensor imaging (DTI) offers a powerful tool to investigate white matter integrity non-invasively with multiple parameters, including fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD) and axial diffusivity (AD). Accumulated evidence using DTI with voxel-based methods indicated that disrupted white matter integrity plays a critical role in neurobiological mechanism of OCD. For example, meta-analyses of DTI studies in OCD demonstrated the most consistent change for FA in the genu and anterior body of corpus callosum [4,5,6]. The largest study to date from the OCD workgroup of Enhancing Neuro Imaging Genetics Through Meta-Analysis (ENIGMA) revealed lower FA in the corpus callosum, uncinate fasciculus (UF), sagittal stratum (SS) and posterior thalamic radiation (PTR) [7]. Despite extensive efforts to identify white matter integrity alterations in OCD, whole-brain white matter abnormalities especially at the tract-level still remain largely unknown, primarily due to challenges with image registration inherent in voxel-based methods. Moreover, most previous studies have predominantly included OCD patients undergoing pharmacological treatment, further compounding the challenge of isolating the true impact of OCD on white matter microstructure as medication could also have potential impact [8]. Neuroimaging studies have shown that medication can reverse abnormalities in white matter microstructure [8, 9] in patients with OCD. Specifically, the medication led to a decrease in MD and RD values in striatum and midbrain [9], which suggests the use of medication is associated with significant structural differences in the brain.

Tractography allows for evaluating white matter alterations at specific tract level which addresses the limitations of the voxel-based methods. Previous tractography studies had revealed lower FA in the middle portion of cingulum bundle [10], forceps minor and UF, which are correlated with anxiety symptoms in OCD [11, 12]. However, these studies focused on the white matter integrity of a limited number of tracts in OCD [12, 13]. Due to the challenges caused by fiber intersections and overlaps, previous tractography studies were unable to assess the integrity of key tracts such as the acoustic radiation and optic radiation, which are critical structural connections of the auditory and visual systems, respectively [14, 15]. Abnormalities in these systems have been associated with OCD, yet the integrity of these tracts remains unclear. Another limitation of previous tractography methods is the insufficient segmentation of the corpus callosum, which prevents researchers from evaluating the microstructural integrity of its subregions (e.g., the rostrum, the splenium), thereby constraining our understanding of interhemispheric connectivity in OCD. The newly developed tool named TRActs Constrained by UnderLying Anatomy (TRACULA) provides a more detailed and accurate framework of reconstructing a set of major white matter pathways in human brain from DTI data [16]. TRACULA provides segmentation of the acoustic radiation, optic radiation, extreme capsule for the first time, and subdivides the corpus callosum into eight parts based on its topographic organization. TRACULA has been widely used and validated in studying white matter on patients with amyotrophic lateral sclerosis [17] and mild cognitive impairment [18], but not on OCD yet.

Thus, in current study, we applied this new tractography tool to explore alteration of white matter tracts in medication free patients with OCD, and to further identify the relationships between diffusion parameters and OCD clinical symptom severity.

Materials and methods

Participants

The study was approved by the Ethics Review Committee of West China Hospital, Sichuan University. Written informed consent was given by all the participants. A total of 54 medication-free OCD patients without comorbidity (female/male: 19/35) and 39 age- and gender-matched healthy controls (female/male: 20/19) were enrolled in the present study. Among the 54 OCD patients, 26 were medication-naïve and the other 28 were medication-free.

All patients were diagnosed by two trained psychiatrists using the Structured Clinical Interview for DSM-5 (SCID-5). Inclusion criteria for OCD patients: 1) confirmed to the diagnosis of OCD in DSM-5; 2) aged between 12–60; 3) had been unmedicated for at least 4 weeks before inclusion; 4) right-handed; 5) the Han nationality. Exclusion criteria for OCD patients: 1) comorbidity of other psychiatric disorders in DSM-5; 2) history of severe illnesses, such as nervous system disease, cardiovascular disease, endocrine disease, cerebral organic disease and so on; 3) substance abuse or dependence; 4) pregnancy; 5) metal implants, claustrophobia or any other contraindications for magnetic resonance scan. Healthy controls (HCs) were recruited by poster. HCs were interviewed using the Mini-International Neuropsychiatric Interview (M.I.N.I.) by experienced psychiatrists to exclude any psychiatric disorders, and HCs had never been prescribed psychiatric medication. Other criteria of exclusion were consistent with OCD group.

Image acquisition

All MRI data were performed on a 3.0 T MR scanner (Siemens TrioTim, Chengdu, China) equipped with a 32-channel head coil. T1-weighted 3D magnetic resonance images (3D-T1) was scanned with the Time Repetition (TR) = 2400 ms, Echo Time (TE) = 2.01 ms, the flip angle of 8°, inversion time (TI) = 1000 ms, slices = 208, slice thickness = 0.8 mm, no slice gap, field of view (FOV) = 256 × 256 mm², matrix = 320 × 320 and the voxel size = 0.8 × 0.8 × 0.8 mm³. As a result of 80 noncollinear directions with 1000 s/mm² and 10 repetitions with no diffusion weight, two sets of diffusion-weighted images (DWI) were acquired: one with right-to-left and the other with left-to-right diffusion directions. The imaging parameters were as follows: TR = 4200 ms, TE = 104 ms, the flip angle of 80 °, 75 slices with a slice thickness of 1.8 mm and no slice gap, FOV = 216 × 216 mm², matrix = 120 × 120 and the voxel size = 1.8 × 1.8 × 1.8 mm³.

Symptom assessment

Symptom assessments were conducted in all OCD patients. Yale-Brown Obsessive Compulsive Scale (YBOCS) was used to evaluate the severity of OCD symptoms, and Hamilton Depression Rating Scale (HAMD, 24-item version) and Hamilton Anxiety Rating Scale (HAMA) was used to quantify the severity of depression and anxiety.

Data processing

Diffusion-weighted data were processed using the FMRIB Software Library (FSL) 5.0.6 (https://fsl.fmrib.ox.ac.uk/fsl/fslwiki/) [19]. After eddy current distortions and motion correction [20], skull stripping, diffusion tensor model fitting, then cortical reconstruction and volumetric segmentation were performed on T1-weighted images using Freesurfer version7.3 (http://freesurfer.net/) [21].

Freesurfer TRACULA (TRActs Constrained by UnderLying Anatomy) software was then used to reconstruct 42 major white matter pathways using global probabilistic tractography [16, 22]. TRACULA derives tract volume and four diffusion metrics: fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), axial diffusivity (AD). The 42 fibers are divided into three types: commissural pathways, projection pathways, and association pathways (Fig. 1).

Fig. 1: Visualization of 42 white matter pathways reconstructed via TRACULA.
figure 1

The white matter pathways are overlaid on the T1 image of one subject in local space. Generated using probabilistic tractography rendered in left, anterior and superior views. Full titles and abbreviations of these pathways are shown on the left.

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The commissural pathways include the anterior commissure (AC), middle cerebellar peduncle (MCP), fornix (FX) and corpus callosum which was further divided into four sections, including body, genu, rostrum and splenium. Body was further subdivided into 5 components, including central (BOCY-C), prefrontal (BODY-PF), premotor (BODY-PM), parietal (BODY-P), and temporal (BODY-T).

The projection pathways include the acoustic radiation (AR), anterior thalamic radiation (ATR), corticospinal tract (CST) and optic radiation (OR).

The association pathways include the arcuate fasciculus (AF), the dorsal part of the cingulum bundle (CBD), the ventral part of the cingulum bundle (CBV), extreme capsule (EMC), frontal aslant tract (FAT), inferior, middle and superior longitudinal fasciculus (ILF, MLF&SLF) and uncinate fasciculus (UF). The SLF was divided into 3 components, including I, II and III. All projection and association pathways were dissected in the left and right hemisphere.

Additionally, to examine structural abnormalities across the brain more comprehensively, we leveraged the structural segmentation from Freesurfer to investigate grey matter alterations in cortical and subcortical regions in OCD. We calculated four structural measures (surface area, thickness, volume, and mean curvature) across 34 cortical structures per hemisphere which were delineated by the Desikan-Killiany atlas [23, 24]. Subcortical segmentation was applied to obtain 7 grey matter structures per hemisphere including thalamus, caudate, putamen, pallidum, hippocampus, amygdala, and nucleus accumbens. Volumes of these subcortical regions were extracted for analysis.

Statistical approach

Statistical analyses were carried out using Statistical Package for the Social Sciences (SPSS, version 26.0, Windows). The age differences between OCD patients and HCs were assessed using the independent sample t-test, and for sex differences between two groups using the Chi-square test (significant level p < 0.05).

White matter analyses

Tract volume, FA, MD, RD, and AD were compared using an analysis of covariance (ANCOVA) with age and sex included as covariates. We applied the same analysis on adult OCD group with age- and sex-matched HCs. To assess the potential impact of medication history on white matter integrity, we conducted an additional analysis to compare differences in diffusion measures between medication-free and medication-naïve subgroups. P-values were corrected for multiple comparisons across all performed tests {N = 5 measures (FA, MD, RD, AD, volume) * 42 white matter tracts = 210} using the false discovery rate (FDR) method (significance level p_fdr < 0.05).

Grey matter analyses

Structural measures, including surface area, thickness, volume, and mean curvature, were compared between OCD patients and HCs across 34 cortical regions per hemisphere, with age, sex, and intracranial volume (ICV) as covariates. Besides, volumes of 7 subcortical regions per hemisphere were compared between OCD patients and HCs, controlling for age, sex, and ICV. P-values were corrected for multiple comparisons across all performed tests {N1 = 4 measures (surface area, thickness, volume, mean curvature) * 68 cortical regions = 272; N2 = subcortical volume * 14 subcortical regions = 14} using the FDR method (significance level p_fdr < 0.05).

Correlation analyses

Additionally, we performed a partial correlation analysis between diffusion measures and clinical characteristics in whole OCD patients with age, sex, and education years included as covariates. P-values were corrected for multiple comparisons across all performed tests {N = 5 measures (FA, MD, RD, AD, volume) * 42 white matter tracts * 5 clinical characteristics (YBOCS, obsession sub-score, compulsion sub-score, HAMA, HAMD) = 1050} using the FDR method (significance level p_fdr < 0.05).

Results

Demographics and clinical characteristics

The demographic and clinical characteristcis of the patients (age: 23.37 ± 5.53; male/female: 35/19) and HCs (age: 23.26 ± 2.15; male/female: 19/20) are summarized in Table 1. There were no significant differences between the patients and HCs in the distributions of age and gender. The adult OCD subgroup included 36 patients (age: 23.92 ± 3.30; male/female: 25/11) and 33 HCs (age: 23.70 ± 2.04; male/female: 19/14), and there were no significant differences in age or gender between patients and HCs. Details of adult group are shown in Supplementary Table 1.

Table 1 Demographic and clinical characteristics of participants.
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White matter alterations in OCD

Comparing to HCs, we found widespread decreased FA in OCD group with 28 among 42 reconstructed tracts, involving commissural, projection and association pathways. Moreover, most of the FA changes were accompanied by increased MD and RD, while AD alterations were only detected in left AR (decrease) and left SLF-III (increase). Furthermore, OCD patients showed enlarged volume of white matter bundles in bilateral AF, left MLF, bilateral SLF-I, bilateral SLF-II, left SLF-III and right UF. Details of whole group analyses are shown in Fig. 2. Adult OCD group showed lower FA, higher MD and RD in similar regions, which were shown in Supplementary Fig. 1. Group differences of diffusion measures and tract volume between medication-free and medication-naïve OCD were not significant (Supplementary Table 2).

Fig. 2: Group differences in diffusion measures (FA, MD, RD, AD) and white matter volumes between OCD and HC.
figure 2

A. FA reduction in OCD compared with HCs. The colour of each tract represents adjusted p values using false discovery rate. B. The colour blocks of each diffusion measures of pathways show the significance of group differences. FA fractional anisotropy, MD mean diffusivity, RD radial diffusivity, AD axial diffusivity, L left hemisphere, R right hemisphere, p_fdr p values adjusted using false discovery rate (FDR), ACOMM anterior commissure, MCP middle cerebellar peduncle, CC corpus callosum, ROSTRUM the rostrum of Corpus Callosum, GENU the genu of Corpus Callosum, BODYPF the prefrontal part of body of Corpus Callosum, BODYPM the premotor part of body of Corpus Callosum, BODYC the central part of body of Corpus Callosum, BODYT the temporal part of body of Corpus Callosum, BODYP the parietal part of body of Corpus Callosum, SPLENIUM the splenium of Corpus Callosum, AR acoustic radiation, ATR anterior thalamic radiation, CST corticospinal tract, OR optic radiation, AF arcuate fasciculus, CBD the dorsal part of the cingulum bundle, CBV the ventral part of the cingulum bundle, EMC extreme capsule, FAT frontal aslant tract, ILF inferior longitudinal fasciculus, MLF middle longitudinal fasciculus, SLF-I superior longitudinal fasciculus-I, SLF-II superior longitudinal fasciculus-II, SLF-III superior longitudinal fasciculus-III, UF uncinate fasciculus.

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Grey matter alterations in OCD

We found grey matter changes linking to the detected white matter changes, including abnormalities in the medial orbital frontal cortex, superior frontal gyrus, pars opercularis, precentral gyrus, postcentral gyrus, lingual gyrus, and Heschl’s Gyrus (Table 2). In addition, patients with OCD demonstrated larger volumes in the left hippocampus and bilateral amygdala compared to HCs, as illustrated in Table 3.

Table 2 Group comparisons of surface area, thickness, volume, and mean curvature across 34 cortical regions (each hemisphere) between OCD and healthy controls.
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Table 3 Group comparisons of volume across 7 subcortical regions (each hemisphere) between OCD and healthy controls.
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Correlation between diffusion measures and clinical characteristics

There are negative correlations between FA of left FAT and obsession sub-score (r = −0.304, p = 0.030), as well as between FA of right FAT and YBOCS total score (r = -0.291, p = 0.040). Moreover, there are negative correlations between FA of right CST (r = −0.280, p = 0.046), left ILF (r = −0.310, p = 0.027) and YBOCS total score. We also found correlations between MD, RD and OCD symptoms. No correlation survives the multiple comparison correction. All correlation results are shown in Supplementary Table 3.

Discussion

Using the novel tractography toolbox capable of reconstructing 42 white matter tracts, we found that there were widespread decreased FA in OCD group comparing to HCs, and more importantly, (1) alterations in specific tracts including rostrum of CC, frontal aslant tract (FAT), optic radiation (OR), inferior longitudinal fasciculus (ILF); (2) disrupted integrity in acoustic radiation (AR) and extreme capsule (EMC) for the first time; and (3) the reduction in FA in these tracts was consistently accompanied by increases in MD and RD in OCD; (4) abnormalities in multiple grey matter regions that were associated with the observed white matter alterations. These findings demonstrated that OCD had structural disconnection not only within the traditional frontal-limbic networks but also extended to the visual and auditory systems, thereby advancing our understanding of the neurobiological mechanisms underlying OCD.

In the present study, we observed widespread FA reductions, accompanied by increased MD and RD, in the white matter tracts connecting various brain regions in OCD patients (Supplementary Fig. 2). Lower FA values signify altered white matter integrity [25], which has been widely reported in OCD [26, 27]. Increased MD values are generally thought to reflect larger extracellular volumes or reduced cellular density [28, 29], while increased RD values are conventionally interpreted as indicative of myelin degeneration [30]. According to the concurrent decreases in FA and increases in MD and RD across extensive white matter tracts, we speculate that the widespread cellular alterations and myelin degeneration may contribute to the pathophysiology of OCD, particularly in tracts involved in emotional regulation along with auditory and visual systems.

Our results replicate previous findings that highlight the involvement of frontal-limbic networks in OCD. The UF connects the orbitofrontal cortex and the prefrontal cortex to the anterior temporal lobes and amygdala, serving as an important structural connection within the fronto-limbic circuit. We found lower FA in the UF of OCD patients, which is consistent with previous DTI studies [11, 12, 31]. These results are in line with altered functional connectivity in this circuit in OCD [32,33,34]. Impairment in this circuit may affect emotional processing in patients with OCD, leading to neurocognitive alterations including dysregulated fear and intolerance of uncertainty [2]. Another tract involved in the frontal-limbic network, EMC, also showed altered integrity in the current study. The EMC consists of streamlines connecting the superior frontal gyrus and the middle temporal gyrus, and located lateral to the UF. To the best of our knowledge, this is the first study to segment EMC in OCD patients and we found lower FA, along with higher MD and RD in the bilateral EMC. However, the EMC may not be a primary association fiber tract, but rather a bottleneck for the ventral pathways, including the UF [35]. In the present study, we observed simultaneous abnormalities in both the EMC and UF. Thus, we suggest that the disrupted integrity of the EMC reflects regional alterations in the UF. Future study could use tractometry to determine whether these alterations are shared by both tracts [36]. Additionally, compared to HCs, OCD patients exhibit structural alterations in the medial orbital frontal and superior frontal regions, which are structural connected to the UF and EMC. These cortical regions are critical nodes within the Default Mode Network (DMN), a network implicated in the pathophysiology of OCD [37, 38]. The concurrence of abnormalities across these grey matter regions and white matter tracts suggests a structural basis underlying the functional dysconnectivity between DMN and frontal-limbic circuit [39, 40].

CC is the largest commissural pathway connecting the cerebral hemispheres and has been consistently shown to be affected in OCD [5, 6]. In our study, we observed reduced FA in the rostrum, body (including the parietal, prefrontal, and temporal sections), and splenium of the CC in patients with OCD compared to HCs. The rostrum, located at the foremost of the CC, connects the orbital prefrontal region of both hemispheres. While a few studies have reported FA reduction in this small region of CC in OCD patients [41,42,43], our results replicate and extend these findings by clearly delineating this tract using high-angular-resolution diffusion imaging with ninety directions. The orbital frontal region plays a key role in the neural circuitry of OCD [44]. Previous studies have reported disrupted topological properties of the structural network, increased gray matter volume [45, 46] in this region in OCD patients. Our findings provide robust evidence supporting the involvement of interhemispheric connections in the orbital frontal region in OCD.

Additionally, we found that OCD patients exhibited reduced FA in the bilateral FAT. FAT connects the inferior frontal gyrus (IFG) and pre-supplementary motor area (pre-SMA) [47]. FAT may serve as a unique structural fingerprint underlying individual cognitive capability, and altered microstructure in FAT was associated with the severity of obsessive-compulsive symptoms [48]. Previous study has revealed increased functional connectivity between IFG and pre-SMA, correlating with motor response inhibition in OCD [49]. These results collectively provide structural evidence for abnormal connectivity between these regions. In addition, we found reduced surface area and volume, along with increased mean curvature, in the pars opercularis. This region is located in the anterior part of the IFG and is structurally connected to the FAT. Previous study has found that a larger relative cortical surface area in this region is associated with better response inhibition in typically developing children and adolescents [50]. The reduced surface area observed in the present study may help explain the impaired response inhibition in patients with OCD. Furthermore, a prior study found that in adult women, a greater relative surface area in the pars opercularis is associated with increased intolerance of uncertainty (IU) [51]. IU, defined as the reduced ability to cope with uncertainty or to respond with impulsive behaviors, is a characteristic feature of the OCD clinical profile [2]. However, due to the lack of IU assessment in our study, we were unable to investigate the relationship between IU and structural measures, which should be a focus of future research.

Another tract frequently reported as abnormal in OCD is the CST. The CST originates from the primary motor cortex (M1) and the supplementary motor area (SMA), passes through the internal capsule, and projects to the brainstem. Diffusion studies have revealed FA alterations in this tract in OCD patients using voxel-based analyses [43, 52, 53]. Consistent with these findings, our study observed reduced FA, along with higher MD and RD in the bilateral CST of individuals with OCD. As a critical pathway transmitting fibers from M1 and SMA to the internal capsule, alterations in the CST suggest structural disconnection within the sensorimotor circuit in OCD [2]. Our grey matter analysis also revealed abnormalities in brain regions associated with the sensorimotor circuit. Specifically, the OCD group showed reduced surface area, thickness, and volume, along with increased mean curvature in the precentral and postcentral gyrus. This circuit plays a key role in the generation and control of motor behaviors and integration of sensory information [2]. Alterations within this circuit may be related to sensory phenomena, habit formation, or the experience of uncomfortable tactile sensations in patients with OCD [2, 54, 55]. Neuroimaging evidence from the ENIGMA-OCD consortium has shown significant hypo-connectivity within the sensorimotor network [56], and our findings suggest a potential structural basis underlying the altered connectivity in this circuit, providing additional support for this pathophysiological model of OCD.

More importantly, our study extends previous findings by identifying structural disconnections in tracts related to visual and auditory systems in OCD for the first time. As an important visual pathway, ILF connects the occipital lobe to anterior temporal lobe. In the current study, we found decreased FA and increased RD in the bilateral ILF, consistent with prior DTI studies [43, 46]. Additionally, we found reduced thickness and volume in the bilateral lingual gyrus in OCD patients compared to HCs. As part of the occipital lobe, the lingual gyrus has been shown to be involved in the regulation of visual recognition [57]. These structural abnormalities in the lingual gyrus provide additional support of visual processing deficits in patients with OCD. We also observed lower FA in other visual pathways, including the optic radiation and the splenium of CC. The OCD global study has revealed abnormalities in posterior thalamic radiation (including optic radiation), which supports the role of the thalamus, its afferent tracts and visual attentional processes in the pathophysiology of OCD [15]. The splenium of CC also connects the occipital to parietal regions, serving as an structural connection in the visual network. Specifically, the forceps major, which comprises fibers originating from the splenium and extending to the occipital regions, has been associated with increased RD in patients with OCD [13, 58]. Furthermore, fMRI study has also shown that dynamic functional connectivity of visual network correlates with symptom severity in patients with OCD [59]. Our results suggest that disruption in multiple tracts within visual pathway may contribute to the impaired visual-spatial memories in OCD [60,61,62].

In the auditory system, we segmented the AR and for the first time, demonstrated disruption of this fiber in OCD patients, characterized by lower FA in bilateral AR. Additionally, we detected higher MD and RD, along with lower AD in this tract, indicating increased extracellular volume or lower cellular density, myelin injury, and axonal damage, respectively. The AR is an important tract in the auditory system, conveying auditory signals from the medial geniculate nucleus (MGN) of the thalamus to the transverse temporal gyrus of Heschl (HG) [63, 64], a core region of the auditory network. Specifically, we also found reduced thickness and volume in bilateral HG in OCD patients compared to HCs. Increased connectivity [65] and alterations in cortical temporal dynamics of the auditory network [14] have been detected in OCD patients using resting-state fMRI. However, no studies have explored the underlying white matter tracts connecting this region. This finding provides evidence for structural connectivity abnormalities within the auditory network in OCD, which aligns with functional alterations revealed by fMRI.

Furthermore, another tract of the auditory system, the AF, which connects inferior frontal to posterior temporal regions [66, 67], also showed disrupted integrity in OCD group. We found that OCD patients showed lower FA in the left AF, along with increased volume in the bilateral AF. Altered integrity of the AF has been reported in pediatric patients with OCD compared to those with attention deficit hyperactivity disorder [27]. For the first time, we observed disruption of the AF also existed in adult patients compare with HCs, as adult subgroup showed alterations in this tract consistent with the results of whole group analysis.

Finally, in the current study, we recruited only patients of Han nationality in Chengdu, Sichuan Province, a region with multiple minority groups. While cultural and dietary differences, which could potentially confound the investigation of white matter integrity due to environmental influences, were considered [68,69,70,71], this approach ensures homogeneity in the sample. However, it may hinder the generalization of the results. Since there may be not only differences in white matter integrity across populations but also in OCD diagnosis, future studies with a more diverse population of OCD patients may help reveal robust biosignatures of core OCD features across countries and cultures.

Limitations

Several limitations are worth noting. First, we recruited well controlled OCD patients who are medication-free and without comorbidity, but limiting the sample size. Second, the exclusion of comorbidity contributes to identify OCD-specific features but reduce the generalizability of our results. Future studies with more varied OCD population and larger sample size may be needed to verify our results. Third, the education data for healthy controls were not collected in the present study, which may affect the covariate analysis in group comparisons. Fourth, due to the DWI data acquisition, we did not employ advanced models like diffusion kurtosis imaging (DKI) or neurite orientation dispersion and density imaging (NODDI) which could provide a more nuanced understanding of the white matter microstructure. Future studies should acquire multi-shell DWI data with higher b-values to investigate white matter integrity using DKI or NODDI model. Fifth, the subgroup analyses were exploratory and no prior power calculation was conducted, which limits the ability to detect differences between the subgroups. Finally, similar to the other automated tractography toolboxes, TRACULA could not reconstruct fibers from specific brain regions, such as the thalamus or striatum, which constrains its applicability in studying circuits particularly relevant to OCD. Region-of interest (ROI)-based tractography, which tracks white matter pathways between specific brain regions, may address this limitation in future studies by enabling the investigation of relevant circuits.

Conclusion

Using the newly developed tractography tool to reconstruct 42 major white-matter pathways of brain, we comprehensively characterized alterations in white matter intergrity in medication-free OCD patients. We found widespread decreased FA in white matter in OCD patients, including uncinate fasciculus, frontal aslant tract, inferior and middle longitudinal fasciculus, rostrum of the corpus callosum, acoustic radiation and optic radiation. In addition, we discovered abnormalities in multiple grey matter regions that were associated with the observed white matter alterations. Our findings not only replicate the involvement of frontal-limbic networks in OCD but also extend to the visual and auditory systems, thereby enhancing our understanding of the neurobiological mechanisms underlying OCD.