The estimated global incidence of attention-deficit/hyperactivity disorder (ADHD) is approximately 6% (1). ADHD is one of the common neurodevelopmental psychiatric disorders in children and adolescents (2). This disorder is characterized by inattention, excessive impulsivity and hyperactivity. The majority of patients who were diagnosed with ADHD in childhood still suffer from persistent, impairing symptoms in adulthood (3).

There is growing evidence that ADHD is associated with abnormal white matter microstructure (4). Following the advances in analytic techniques of diffusion magnetic resonance imaging (MRI), the use of diffusion MRI in ADHD research has contributed significantly to our understanding of the abnormalities in white matter ultrastructure (5).

At present, studies on white matter changes in ADHD are mostly based on diffusion tensor imaging (DTI) (6–8). Several DTI analytical approaches, such as tract-based spatial statistics (TBSS), voxel-based analysis (VBA), and regions of interest (ROI) analysis, have been widely applied to ADHD (9–11). Nevertheless, the inconsistent outcomes of these approaches can be attributed to variations in analytical techniques and the age disparity among subjects, resulting in diminished white matter integrity across diverse regions and extents. TBSS is a skeleton-based approach which can reduce the effects of local misregistration. A TBSS study showed that there was a decrease in FA in the regions of left genu internal capsule and the right forceps major in ADHD children (12). Unlike this, FA reduction was found to be in the cerebellum, anterior thalamic radiation, and corpus callosum genus in VBA studies (13, 14). In the ROI-based method, ADHD children who were not treated exhibited similar FA values to control children (6). There are advantages and drawbacks to each of these DTI analysis techniques.

It is possible that tissue diffusion characteristics vary along each node of the fiber tract, as diseases injury may occur in some local positions of the bundle. Despite the fact that the majority of studies have found that there are white matter injuries in ADHD, it remains unclear whether the specific properties of white matter abnormalities are different along each fiber tract. Thus, the application of a new automated fiber quantification (AFQ) analysis method is particularly important. Using deterministic tractography, AFQ recreates white matter tracts throughout the brain, so more node-detailed information about white matter changes along each fiber tract could be assessed at an individual level (15). Researchers have recently successfully applied AFQ to many cerebral diseases, such as Alzheimer’s disease. (16–18), epilepsy (19), Cushing disease (20), cerebral small vessel disease (4), and end-stage renal disease (21). To our knowledge, there is currently no AFQ research individually specialized for ADHD in children and adolescents.

Furthermore, crossing fibers can be detected much more accurately with diffusion kurtosis imaging (DKI) than with DTI (22–25). A comparative study found that the DKI parameters were more sensitive to detecting white matter abnormalities with coherent and complex arrangements of fibers than DTI (25). While a few DKI studies have been conducted on ADHD in the past (26, 27), comparative studies between DKI and DTI are lacking. Based on the above factors, we have a hypothesis that there are subtle changes in the microstructure of certain local segments of white matter fibers in ADHD patients. In this study, we plan to perform DKI scans on children with ADHD, and compare white matter fiber changes using TBSS (based on DKI and DTI data) and AFQ (based on DTI data) techniques.

ADHD patients exhibit specific subcortical dysfunction, with prevailing belief that subcortical abnormalities play a role in the onset of ADHD, while cortical plasticity influences the diverse clinical trajectory of the disorder (28). The thalamus, as the largest subcortical structure in the brain, assumes significance as a crucial element within the cortico striato thalamo cortical circuit (29, 30). Dysfunction within this circuit has been recognized as a significant neural correlate of ADHD (31). Additionally, it is worth noting that the ventral and intralaminar thalamus have been identified as potential components of the somatomotor network (32, 33), and they exhibit connectivity with the anterior midcingulate cortex (34, 35). It is plausible that dysfunctions within these interconnected circuits or subcortical structures might play a role in the manifestation of clinical symptoms associated with attention deficit hyperactivity disorder (ADHD). Additional investigation into ADHD could contribute to a comprehensive comprehension of the disorder. This study exclusively focused on the alterations observed in diffusion imaging, thus necessitating future extensive examinations of ADHD from a multimodal standpoint (36–38).

This study examines the precise modifications in white matter microstructure in children with ADHD through the utilization of AFQ and TBSS. While previous neuroimaging investigations of ADHD have evaluated the integrity of the white matter, the TBSS study outcomes based on voxels did not survive following multiple comparison corrections in this particular study of children. One plausible explanation is that TBSS may be better suited for detecting significant white matter abnormalities (39). For instance, it exhibits sensitivity towards long-term exposure-induced structural alterations (40) or structural changes linked to severe injuries like Traumatic Brain Injury (41). However, the focus of the research cohort pertained predominantly to children who had recently received a diagnosis of ADHD. These individuals are of a tender age and presently in the nascent phases of the disorder, potentially exhibiting alterations solely at a microscopic scale in the white matter fiber bundles. Another possible explanation for the observed outcome could be attributed to the limited scope of the investigation. However, the AFQ analysis revealed the presence of abnormalities in the CB_R, which were more effectively detected by the AFQ method as compared to TBSS. The AD and MD values of CB_R exhibited significant increases at the node-wise level, while only AD values of CB_R showed a significant increase in the entire fiber tract, as per the AFQ study. These findings suggest that AFQ may serve as a complementary method to TBSS, offering a novel approach and providing new insights into ADHD. Notably, node-wise analysis is crucial as it can reveal local anomalies that may be obscured by the whole. Previous research has demonstrated an increase in AD in the right cingulum bundle (42). Our study similarly found a significant increase in the mean AD value of the CB_R fiber tract in individuals with ADHD. AD reflects diffusion coefficients parallel to fiber orientation and is known to be sensitive to axonal damage (43). Therefore, our findings suggest that the observed microstructure changes in the CB_R of individuals with ADHD may be primarily attributed to axonal damage.

The cingulum bundle is a white matter pathway that extends longitudinally from the anterior cingulate cortex (ACC) to the posterior cingulate cortex (PCC), linking the components of the default mode network (DMN) and providing important limbic connections, including those to supplementary motor and primary motor regions (44). This large-scale white matter system (45) is responsible for processing attention and controlling executive functions (46). An amygdala, hippocampus, and insular cortex receive projections from it (47).

There exists a substantial body of evidence indicating that ADHD is linked to deficiencies in various neurocognitive domains. Neuropsychological theories posit that ADHD is chiefly marked by executive dysfunction (48) and anomalous function of the default mode network (DMN) (49). The cingulum bundle is implicated in both executive dysfunction and the DMN theory of ADHD, as supported by these two theories. First, previous studies have shown that executive function processes play a critical role in ADHD (48, 50–52). In executive functioning, the cingulum bundle plays a key role. The cingulum bundle is strongly connected to the cingulate gyrus, which is associated with executive function (53, 54). Second, DMN nodes are connected by various white matter tracts, including anterior and posterior cingulum bundles. Previous studies have demonstrated a correlation between reduced functional connectivity of the cingulum bundle and ADHD. Specifically, researchers using rs-fMRI found that functional connectivity in the DMN and between the dorsal anterior cingulate and posterior region of the DMN was decreased in ADHD adults (55). Additionally, a reduction in brain connectivity has been observed in the anterior cingulate and temporal regions of the brain, which are associated with inattention (56).

At a point-wise level, the AFQ technique enables the measurement of diffusion at 100 equidistant nodes along the fiber tract. In contrast to prior methodologies, this approach affords a more precise analysis of tracts, yielding more accurate identification of damage segments and greater sensitivity to abnormalities in other indicators. The present investigation revealed significant alterations primarily in the AD (nodes 36–38, nodes 83–97) and MD (nodes 92–95) of CB_R. The findings of our study suggest that ADHD patients exhibit injury predominantly in the anterior and posterior regions of the CB_R fiber tract, which is manifested by elevated AD and MD values. Prior research has demonstrated that changes in AD and MD may be indicative of axonal damage (57) and myelin degradation (58). An elevated AD in the CC_R is significantly associated with a decrease in neuronal branching (59). Additionally, the MD metric reflects the diffusion rates of water throughout the brain, and an increase in MD values is indicative of a loss of axons, dendrites, and neuronal cell bodies, ultimately leading to structural alterations at the macroscopic level (60). There is evidence that a reduction in axonal density is linked to heightened MD values (61). Collectively, these findings suggest that the observed microstructural changes in the CB_R are primarily attributed to damage to myelin and axons. Previous research has indicated that the anterior portion of the cingulum bundles plays a crucial role in facilitating communication between limbic regions (62). Furthermore, lesions in this area have been shown to disrupt performance on the 5-Choice Serial Reaction Time Task, which is closely linked to cholinergic activity (63). Given that cholinergic activity is known to be associated with attention, these findings suggest that the anterior cingulum bundles may be involved in attentional processes. Additionally, a recent study has suggested that ADHD may be associated with alterations in the functional connectivity of the right posterior cingulate (64), which may indicate damage to the white matter microstructure of ADHD patients. Drawing upon extant research findings, our investigation uncovered significant alterations in the AD and MD values of CB_R in specific regions, suggesting that increased AD and MD of CB_R may represent early-phase abnormalities in ADHD. Our conjecture is that CB_R plays a pivotal role in the initial stages of ADHD, particularly in its anterior and posterior components. By means of AFQ analyses, more precise localization data can be ascertained regarding damaged fiber segments.

Furthermore, our study revealed no statistically significant alterations in FA along fiber tracts. Our findings are consistent with previous research, which has demonstrated that there are no significant differences in FA within the white matter structure of the cingulum tract between individuals with ADHD and healthy controls (65–68). However, prior investigations have produced inconsistent results, with some diffusion studies indicating reduced FA in the right cingulum bundle among individuals with ADHD in comparison to healthy controls (69, 70). The inconsistency of studies may be attributed to the ADHD subtype or study age range, as well as the potential influence of varying research methods and subject ages. Amlien’s review demonstrated that an increase in AD led to a reduction in FA differences between groups (71). It is plausible that a significant increase in AD may have impacted the FA results in our study, necessitating a larger sample size and replication of the study.

The results of our study indicate that the altered white matter parameters observed in individuals with ADHD were not found to be significantly correlated with clinical test scores. However, the ADHD group exhibited significantly higher scores in attention deficit and hyperactivity, as well as in the areas of inhibition, shifting, emotional control, initiation, working memory, planning, organization of materials, and monitoring, thereby confirming the presence of executive function deficits in this population.

An AFQ analysis of adults with ADHD found that there were no differences between ADHD and HC, and the ADHD group showed no significant association (72), this correlation result is consistent with our findings. Future research is needed to explore the relationship between changes in white matter microstructure and executive function.

According to the AFQ method, capable of detecting mild changes in white matter, we identified white matter abnormalities in fiber tracts with a greater degree of spatial precision. As a surveillance tool for ADHD, the AFQ method can detect ADHD-related white matter abnormalities with greater sensitivity, and the CB_R played a critical role in furthering our understanding of ADHD-related white matter abnormalities. Our findings may be helpful in further studying the relationship between focal white matter abnormalities and ADHD.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving humans were approved by Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei. The studies were conducted in accordance with the local legislation and institutional requirements. Written informed consent for participation in this study was provided by the participants’ legal guardians/next of kin.

RH and FT: study design, data collection and curation, image scanning and post-processing, formal analysis, visualization, and writing-original draft. WC, YW, YJ, WD, YZ, and BG: case collection, investigation, data curation, image post-processing, software application, formal analysis. QS: scanning specification, technical guidance, supervision. YM: conceptualization, study design, funding acquisition, supervision, and writing – review and editing. All authors contributed to the article and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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