Cortico-basal ganglia white matter microstructure is linked to restricted repetitive behavior in autism spectrum disorder

Introduction

 

Autism spectrum disorder (ASD) is a developmental condition that affects how people communicate and interact with others. One of the main features of ASD is restricted repetitive behavior (RRB), which refers to various types of behaviors that are repeated over and over, such as rocking, hand flapping, lining up objects, or following rigid routines. RRB can interfere with daily functioning and cause distress to individuals with ASD and their families.

 

But what causes RRB in ASD? And how can we measure it objectively? A recent study published in Molecular Autism sheds some light on these questions by using advanced brain imaging techniques to examine the structure and function of brain regions involved in RRB.

 

The role of the basal ganglia in RRB

The basal ganglia are a group of structures located deep in the brain that are involved in various functions, such as movement, learning, motivation, and reward. The basal ganglia receive inputs from different parts of the cortex, the outer layer of the brain that processes sensory, motor, and cognitive information, and send outputs back to the cortex through a complex network of white matter tracts, which are bundles of nerve fibers that connect different brain regions.

 

Previous studies have suggested that the basal ganglia play a key role in RRB, as they are responsible for selecting and executing appropriate actions, suppressing unwanted impulses, and switching between different tasks. Dysfunction of the basal ganglia, either due to genetic mutations, environmental factors, or brain injury, can lead to disorders characterized by RRB, such as obsessive-compulsive disorder, Tourette syndrome, and Parkinson’s disease.

 

However, the exact relationship between the basal ganglia and RRB in ASD is not well understood. Some studies have found differences in the size or shape of the basal ganglia in individuals with ASD compared to typically developing (TD) individuals, while others have not. Similarly, some studies have found differences in the activity or connectivity of the basal ganglia in individuals with ASD, while others have not. These inconsistencies may be due to methodological limitations, such as small sample sizes, heterogeneous diagnostic criteria, or variable measures of RRB.

 

A new approach to study the basal ganglia in ASD

To overcome these limitations, a team of researchers used a large and well-characterized dataset from the National Institute of Mental Health Data Archive, which contains brain imaging and behavioral data from hundreds of children and adolescents with ASD and TD controls. The researchers focused on two types of brain imaging: structural MRI, which measures the shape and size of brain regions, and diffusion MRI, which measures the movement of water molecules along white matter tracts.

 

The researchers used a novel technique called free-water imaging, which allows them to separate the effects of water molecules that are inside the nerve fibers (which reflect the integrity and organization of the white matter tracts) from those that are outside the nerve fibers (which reflect the amount of fluid or inflammation in the brain tissue). This technique can provide more accurate and sensitive measures of white matter microstructure than conventional methods.

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The researchers also used standardized and validated scales to measure RRB in the participants, such as the Repetitive Behavior Scale-Revised (RBS-R) and the Autism Diagnostic Observation Schedule (ADOS). They also examined the interaction of biological sex and ASD diagnosis on brain structure and function, as sex differences have been reported in both ASD and RRB.

 

The main findings of the study

The study found that individuals with ASD had significantly lower free-water corrected fractional anisotropy (FA T) and higher free-water (FW) in cortico-basal ganglia white matter tracts, compared to TD individuals. FA T is a measure of how well-aligned and coherent the nerve fibers are, while FW is a measure of how much water is outside the nerve fibers. These results suggest that individuals with ASD have less organized and more inflamed white matter tracts connecting the basal ganglia and the cortex.

 

Moreover, the study found that both FA T and FW in basal ganglia white matter tracts significantly correlated with measures of RRB, such that lower FA T and higher FW were associated with more severe RRB. These correlations were stronger for FA T than for FW, indicating that FA T may be a more reliable marker of RRB. In contrast, the study found no significant difference in basal ganglia or cerebellar gray matter volumes between ASD and TD individuals, nor any significant interaction between ASD diagnosis and sex-related differences in brain structure.

 

These findings demonstrate that cortico-basal ganglia white matter microstructure is altered in ASD and linked to RRB. FW in cortico-basal ganglia and intra-basal ganglia white matter was more sensitive to group differences in ASD, whereas cortico-basal ganglia FA T was more closely linked to RRB. In contrast, basal ganglia and cerebellar volumes did not differ in ASD. There was no interaction between ASD diagnosis and sex-related differences in brain structure.

 

The implications and limitations of the study

The study provides new insights into the neural mechanisms underlying RRB in ASD, and suggests that free-water imaging may be a useful tool to study white matter abnormalities in ASD and other neuropsychiatric disorders. The study also highlights the importance of considering both the structure and function of the basal ganglia, as well as the interactions between the basal ganglia and other brain regions, in understanding RRB.

 

However, the study also has some limitations that need to be addressed in future research. First, the study used a cross-sectional design, which means that it cannot establish causal relationships between brain structure and RRB, nor account for developmental changes over time. Longitudinal studies are needed to examine how brain structure and RRB change as individuals with ASD grow and mature. Second, the study used a relatively broad definition of ASD, which may include individuals with different subtypes or comorbidities that could affect brain structure and RRB. More fine-grained analyses are needed to identify specific factors that modulate brain structure and RRB in ASD. Third, the study used a limited set of brain regions, namely the basal ganglia and the cerebellum, which were selected based on previous hypotheses. Other brain regions, such as the prefrontal cortex, the temporal lobe, or the insula, may also be involved in RRB, and should be investigated in future studies.

 

The take-home message

RRB is a common and challenging feature of ASD that affects the quality of life of individuals with ASD and their families. This study shows that RRB is associated with altered white matter microstructure in the brain, especially in the cortico-basal ganglia network, which is responsible for action selection and inhibition. This study also shows that free-water imaging is a promising technique to measure white matter abnormalities in ASD and other disorders. These findings may have implications for the diagnosis, prognosis, and treatment of RRB in ASD, and may inspire new avenues of research to understand the brain basis of RRB.

 

FAQ

About free-water imaging

What is free-water imaging and why is it useful for studying white matter in ASD?

 

Free-water imaging is a technique that separates the effects of water molecules that are inside the nerve fibers (which reflect the integrity and organization of the white matter tracts) from those that are outside the nerve fibers (which reflect the amount of fluid or inflammation in the brain tissue). This technique can provide more accurate and sensitive measures of white matter microstructure than conventional methods, which can be confounded by the presence of free-water. Free-water imaging can help us better understand how white matter is affected in ASD and how such measures are linked to RRB.

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What is the difference between fractional anisotropy (FA) and free-water corrected fractional anisotropy (FA T)?

 

Fractional anisotropy (FA) is a measure of how well-aligned and coherent the nerve fibers are in a white matter tract. FA ranges from 0 to 1, where 0 means that the water molecules can move equally in all directions (isotropic diffusion), and 1 means that the water molecules can only move along one direction (anisotropic diffusion). FA is affected by both the intrinsic properties of the nerve fibers, such as their diameter, density, and myelination, and the extrinsic factors, such as the amount of water or inflammation in the brain tissue. Free-water corrected fractional anisotropy (FA T) is a measure of FA that removes the effects of the extrinsic factors, by separating the water molecules that are inside the nerve fibers (tissue water) from those that are outside the nerve fibers (free water). FA T is more specific and sensitive to the microstructural changes in the nerve fibers than FA.

 

How does free-water imaging differ from conventional diffusion imaging methods?

 

Conventional diffusion imaging methods, such as diffusion tensor imaging (DTI), assume that the water molecules in the brain tissue move in a single-compartment model, meaning that they are only affected by the intrinsic properties of the nerve fibers. However, this assumption may not hold true in some brain regions or conditions, where there may be water molecules that are outside the nerve fibers, such as in the extracellular space or in the cerebrospinal fluid. These water molecules can move more freely and randomly than those inside the nerve fibers, and can affect the diffusion measures, such as fractional anisotropy (FA) or mean diffusivity (MD). Free-water imaging is a technique that accounts for this possibility, by using a two-compartment model, meaning that it separates the water molecules that are inside the nerve fibers (tissue water) from those that are outside the nerve fibers (free water). This technique can provide more accurate and sensitive measures of white matter microstructure, such as free-water corrected fractional anisotropy (FA T) or free-water (FW).

 

About RRB in ASD

What are the main types of RRB and how are they measured in this study?

 

RRB can be divided into two main types: lower-order RRB and higher-order RRB. Lower-order RRB refers to motor behaviors, such as rocking, hand flapping, or spinning, that are often stereotyped and repetitive. Higher-order RRB refers to cognitive behaviors, such as following rigid routines, having narrow interests, or being resistant to change, that are often inflexible and compulsive. In this study, the researchers used two standardized and validated scales to measure RRB: the Repetitive Behavior Scale-Revised (RBS-R) and the Autism Diagnostic Observation Schedule (ADOS). The RBS-R is a parent-report questionnaire that assesses six subtypes of RRB: stereotyped behavior, self-injurious behavior, compulsive behavior, ritualistic behavior, sameness behavior, and restricted behavior. The ADOS is a semi-structured observation that evaluates four domains of ASD symptoms, including RRB.

 

How does biological sex affect brain structure and RRB in ASD?

 

Biological sex is an important factor to consider in ASD, as there are sex differences in the prevalence, presentation, and diagnosis of ASD. Previous studies have suggested that sex may also influence brain structure and function in ASD, as well as the severity and type of RRB. However, the results of these studies have been inconsistent and inconclusive. In this study, the researchers did not find any significant interaction between ASD diagnosis and sex-related differences in brain structure, nor any significant sex difference in RRB. This suggests that sex may not have a strong effect on the relationship between brain structure and RRB in ASD, at least in the regions and measures examined in this study. However, more research is needed to explore the role of sex in other brain regions and measures, as well as other factors that may modulate sex differences in ASD, such as age, IQ, or hormonal levels.

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What are the clinical implications of finding lower FA T and higher FW in cortico-basal ganglia white matter tracts in ASD?

 

Lower FA T and higher FW in cortico-basal ganglia white matter tracts in ASD suggest that there is less organization and more inflammation in these tracts, which may impair the communication and coordination between the basal ganglia and the cortex. The basal ganglia are involved in various functions, such as movement, learning, motivation, and reward, and they receive inputs from different parts of the cortex, such as the prefrontal cortex, the temporal cortex, or the parietal cortex. These functions and regions are also implicated in RRB, which is one of the main features of ASD. Therefore, lower FA T and higher FW in cortico-basal ganglia white matter tracts may reflect the severity and type of RRB in ASD, and may also indicate the risk or prognosis of developing RRB. Moreover, lower FA T and higher FW in cortico-basal ganglia white matter tracts may suggest the potential targets or biomarkers for interventions for RRB in ASD, such as pharmacological, behavioral, or neuromodulatory therapies.

 

What are the limitations of using clinical scales to measure RRB in ASD?

 

Clinical scales are commonly used to measure RRB in ASD, as they provide standardized and validated methods to assess the severity and type of RRB. However, clinical scales also have some limitations, such as the reliance on subjective reports from parents, caregivers, or clinicians, which may introduce bias or inconsistency. Moreover, clinical scales may not capture the full spectrum of RRB, as they may focus on certain subtypes or domains of RRB, or use different definitions or criteria for RRB. Furthermore, clinical scales may not reflect the dynamic and contextual nature of RRB, as they may not account for the frequency, duration, intensity, or variability of RRB, or the factors that trigger or maintain RRB. Therefore, clinical scales may need to be complemented by other measures of RRB, such as behavioral observations, self-reports, or biomarkers.

 

About the basal ganglia network and the default mode network

How does the basal ganglia network differ from the default mode network in ASD and RRB?

 

The basal ganglia network is a brain network that consists of the basal ganglia and their connections to the cortex and other brain regions. The basal ganglia network is involved in various functions, such as action selection, inhibition, switching, learning, and reward. The default mode network is another brain network that consists of regions in the medial prefrontal cortex, the posterior cingulate cortex, the precuneus, and the inferior parietal lobule. The default mode network is involved in functions such as self-referential thinking, social cognition, memory, and imagination. Previous studies have suggested that both the basal ganglia network and the default mode network are altered in ASD and RRB. However, the basal ganglia network may be more directly related to RRB, as it regulates the execution and suppression of actions, while the default mode network may be more indirectly related to RRB, as it modulates the cognitive and emotional aspects of RRB. Moreover, the basal ganglia network may be more sensitive to the microstructural changes in white matter, as measured by free-water imaging, while the default mode network may be more sensitive to the functional changes in brain activity, as measured by functional MRI.

 

About the cerebellum

How does the cerebellum relate to RRB in ASD?

 

The cerebellum is a brain structure located at the back of the brain that is involved in motor coordination, learning, and cognition. Previous studies have suggested that the cerebellum may also be involved in RRB, as it is connected to the basal ganglia and other brain regions that regulate RRB. Moreover, some studies have found abnormalities in the cerebellum in individuals with ASD, such as reduced size, altered shape, or impaired function. However, in this study, the researchers did not find any significant difference in cerebellar gray matter volume or white matter microstructure between ASD and TD individuals, nor any significant correlation with RRB. This suggests that the cerebellum may not play a major role in RRB in ASD, at least in the measures examined in this study. However, more research is needed to explore the role of the cerebellum in other aspects of RRB, such as timing, sequencing, or learning.

 

About the dataset

What are the advantages and disadvantages of using a large and well-characterized dataset from the National Institute of Mental Health Data Archive?

 

 

The National Institute of Mental Health Data Archive is a repository of brain imaging and behavioral data from various studies on ASD and other mental disorders. The researchers used this dataset to access a large and diverse sample of individuals with ASD and TD controls, which increases the statistical power and generalizability of their findings. Moreover, the dataset provides standardized and validated measures of RRB and other clinical variables, which reduces the variability and bias that may arise from different methods or instruments. However, the dataset also has some limitations, such as the lack of information on some important factors that may affect brain structure and RRB, such as medication use, comorbidities, or genetic variants. Moreover, the dataset does not include longitudinal data, which limits the ability to examine the developmental trajectories of brain structure and RRB in ASD. Therefore, the researchers acknowledge that their findings need to be replicated and extended in future studies that can address these limitations.

 

Source:

https://molecularautism.biomedcentral.com/articles/10.1186/s13229-023-00581-2

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