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. Author manuscript; available in PMC: 2022 Dec 1.
Published in final edited form as: Cerebellum. 2021 Apr 15;20(6):931–937. doi: 10.1007/s12311-021-01265-4

Contributions of cerebellar white matter microstructure to social difficulty in nonverbal learning disability

Bruce Ramphal a.,a, David Pagliaccio a.,a, Lauren V Thomas a.,a, Xiaofu He a.,a, Amy E Margolis a.,a
PMCID: PMC8530438  NIHMSID: NIHMS1736838  PMID: 33856654

Abstract

Background:

Emerging evidence suggests that the cerebellum may contribute to variety of cognitive capacities, including social cognition. Nonverbal learning disability (NVLD) is characterized by visual-spatial and social impairment. Recent functional neuroimaging studies have shown that children with NVLD have altered cerebellar resting state functional connectivity, which is associated with various symptom domains. However, little is known about cerebellar white matter microstructure in NVLD and whether it contribute to social deficits.

Methods:

Twenty-seven children (12 with NVLD; 15 typically developing (TD)) contributed useable diffusion tensor imaging data. Tract-based spatial statistics (TBSS) were used to quantify fractional anisotropy (FA) in the cerebellar peduncles. Parents completed the Child Behavior Checklist, providing a measure of social difficulty.

Results:

Children with NVLD had greater fractional anisotropy in the left and right inferior cerebellar peduncle. Furthermore, right inferior cerebellar peduncle FA was associated with social impairment as measured by the Child Behavior Checklist Social Problems subscale. Finally, the association between NVLD diagnoses and greater social impairment was mediated by right inferior cerebellar peduncle FA.

Conclusions:

These findings provide additional evidence that the cerebellum contributes both to social cognition and to the pathophysiology of NVLD.

Keywords: neurodevelopment, neuroimaging, diffusion tensor imaging, cerebellum, nonverbal learning disability

Introduction

Nonverbal learning disability (NVLD) is a neurodevelopmental disorder characterized by core deficits in visual-spatial processing in the presence of intact verbal ability. Children with NVLD further exhibit impairment in social and executive functions as well as in motor and math skills. NVLD has an estimated 3–4% prevalence rate among North American youth (Margolis et al., 2020). An emerging literature has identified several neural correlates of NVLD, such as reductions in hippocampal gray matter volume and alterations in resting state functional connectivity (RSFC) of the right posterior cerebellum (Banker, Pagliaccio, et al., 2020; Banker, Ramphal, et al., 2020; Margolis, Pagliaccio, Thomas, Banker, & Marsh, 2019). Specifically, children with NVLD exhibited negative RSFC between the right crus I/II of the cerebellum and the left posterior cingulate cortex (Banker, Ramphal, et al., 2020), while typically developing (TD) children exhibited positive connectivity. Children with NVLD also had positive RSFC between cerebellar right lobule VI and the right hippocampus, while TD children had near-zero connectivity between these regions. Thus, children with NVLD appear to have distinct patterns of posterior cerebellar resting-state functional connectivity.

Posterior cerebellar regions have been found to contribute to social cognition (Van Overwalle, Manto, et al., 2020), which is a key domain of functional impairment in NVLD (Semrud-Clikeman, Walkowiak, Wilkinson, & Minne, 2010). Specifically, crus I and II play a role in anticipation of social interactions, detecting social norm violations, processing social sequences (Heleven, van Dun, & Van Overwalle, 2019), and interpreting nonverbal cues (Van Overwalle, Manto, et al., 2020). Evidence suggests that crus II plays a particularly influential role in mentalizing processes (Van Overwalle, Ma, & Heleven, 2020). Consistent with their roles in social cognition, crus I and II have been implicated in autism spectrum disorder (D’Mello, Crocetti, Mostofsky, & Stoodley, 2015; Olivito et al., 2018; Shukla, Keehn, Lincoln, & Müller, 2010; Stoodley et al., 2017).

Some studies have implicated cerebellar white matter microstructure in disorders characterized by deficits in social cognition. For example, reduced fractional anisotropy (FA) in the cerebellar peduncles has been observed in Asperger syndrome (Catani et al., 2008), autism spectrum disorder (ASD) (Brito et al., 2009; Hanaie et al., 2013; Sivaswamy et al., 2010), and schizophrenia (Okugawa et al., 2006). Interestingly, cerebellar peduncle microstructure has also been found to mediate associations between visual memory and fine motor skill, two domains of difficulty in NVLD (Thomas, Lacadie, Vohr, Ment, & Scheinost, 2017).

Given the role of the role of the posterior cerebellar in social cognition and our previous work demonstrating cerebellar functional differences in NVLD, the current study sought to examine whether cerebellar white matter contributes to the pathophysiology of NVLD. We hypothesized that children with NVLD would have reduced FA in the cerebellar peduncles, and that FA would mediate associations between NVLD and social difficulty.

Methods

Participants

Fifty children with suspected NVLD and 21 TD children were recruited for possible inclusion in the current study (7–15 years old). Of the 50 children with suspected NVLD, 15 did not meet diagnostic criteria (Table S1), and five did not complete any MRI scanning, leaving 30 who completed some portion of the scanning protocol. Of these, 12 did not complete the diffusion tensor imaging (DTI) sequence which was at the end of the scan session; six participants were excluded for poor quality DTI data, leaving 12 participants with NVLD who had useable DTI data. Of the 21 TD children who participated in the scan visit, 17 completed the DTI portion; two were excluded for poor quality data, leaving 15 TD children who had useable DTI data. Other MRI data from this sample has been previously published (Banker, Pagliaccio, et al., 2020; Banker, Ramphal, et al., 2020; Davis, Margolis, Thomas, Huo, & Marsh, 2018; Margolis et al., 2019; Ramphal et al., 2020), but the DTI data is novel.

Diffusion tensor imaging acquisition and preprocessing

All DTI data were acquired on a 3-Tesla General Electric (GE) Discovery MR750 scanner with a 32-channel head coil. Whole brain DTI data were acquired with the following parameters: 75 axial slices, each at 2 mm thickness, TR = 95,000 ms, TE = 87.7 ms, FOV = 24 cm, matrix size = 132 × 128 (machine-interpolated to 256 × 256 for post-processing), voxel size = 0.94 mm × 0.94 mm × 2 mm. The diffusion-weighted images were acquired along 25 non-collinear directions, with a b value of 1000 s/mm2, and three baseline images with b = 0 s/mm2. Two trained research assistants visually inspected the raw diffusion-weighted images, eddy current corrected diffusion-weighted images, and color encoded FA images (He et al., 2014).

Images were processed using FMRIB Software Library (FSL) version 5.0.11 (Oxford, UK) (Smith et al., 2004). DTI acquisitions were corrected for subject motion, eddy current-induced distortion, and outlier replacement (Andersson et al., 2017; Andersson & Sotiropoulos, 2016). FSL DTIFIT was used to fit diffusion tensors at each voxel and FA images were derived from the fitted diffusion tensors. We then ran tract-based spatial statistics (TBSS) (Smith et al., 2006). In place of using the default adult-derived target image (FMRIB58_FA), using TBSS, we automatically selected the most representative FA image from our pediatric population as the target image, and the target image was then affine-aligned into MNI152 standard space. A skeleton of white matter tracts that were common to all participants was created by thinning the mean FA image using a threshold of 0.2. The Johns Hopkins University (JHU) white matter tractography atlas (Mori et al., 2008; Wakana et al., 2007) was used to quantify tract average FA from the skeletonized FA image. FA values for the middle and bilateral inferior and superior cerebellar peduncle tracts were extracted.

Social difficulty

Our primary clinical measure was parent report on the Social Problems subscale from the Child Behavior Checklist (CBCL) (Achenbach & Rescorla, 2001). This subscale assesses social difficulties including trouble getting along with peers, difficulty making friends, and getting teased. Parents also completed the Social Responsiveness Scale (SRS, see Supplementary Information for details), which was examined in exploratory analyses (Constantino & Gruber, 2005).

Statistical analyses

All analyses were performed in R v4.0.0. Demographic and social differences between the NVLD and TD groups were identified by t-tests and chi-square proportion tests (Pagliaccio, 2020). Differences in cerebellar white matter microstructure between children with NVLD and TD children were identified using multiple linear regression. Specifically, FA of the middle and bilateral inferior and superior cerebellar peduncle were examined as the dependent variables, group (NVLD or TD) was included as the independent variable of interest, and age was included as a covariate (given group differences in age; Table 1). Exploratory analyses examined group differences in other DTI metrics–mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD)–of the cerebellar peduncles.

Table 1.

Sample demographics and clinical characteristics

TD (N=15) NVLD (N=12) Test Statistic p
Age (Months) 117.87 (14.84) 149.25 (24.37) t=3.92 .001 **
Sex (M) 7 (46.67%) 7 (58.33%) χ2=0.05 .83
Performance IQ 117.73 (12.63) 88.25 (12.37) t=−6.10 <.001 ***
Verbal IQ 123.4 (11.72) 106.25 (11.69) t=−3.78 <.001 ***
IQ Discrepancy (VIQ-PIQ) 5.67 (10.03) 18.00 (12.23) t=2.82 .01 *
CBCL Social Problems 52.64 (3.75) 63.92 (4.5) t=6.87 <.001 ***
SRS Total 44.93 (7.18) 71.67 (15.79) t=5.43 <.001 ***
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Note: N=1 missing CBCL Social Problems.

*

p<.05,

**

p<.01,

***

p<.001

For tracts exhibiting group differences in FA, the association between FA and CBCL Social Problems was examined in regressions, controlling for diagnostic group and age. Follow-up exploratory analyses examined whether FA was associated with SRS scores.

A bootstrap-based mediation model (R mediation package version 4.5.0) was tested to examine whether associations between NVLD diagnosis and social impairment (Table 1) was mediated by cerebellar peduncle FA metrics identified in our primary analysis. Briefly, the average causal mediation effect (ACME) was calculated as the product (a*b) of the regression coefficient (a) representing group differences (NVLD vs. TD) in FA and the regression coefficient (b) relating FA to social impairment, controlling for diagnostic group. A null distribution was generated by 5000 random permutations of the data to determine a p-value for the ACME. All statistical tests were two-sided, alpha was set at .05, and standardized regression coefficients are presented.

Results

Sample characteristics

Sample characteristics are presented in Table 1. Children with NVLD were older than TD children and had lower verbal IQ (VIQ). Consistent with our diagnostic criteria, relative to TD children, children with NVLD exhibited lower performance IQ (PIQ), greater discrepancy between VIQ and PIQ, and more social impairment (CBCL and SRS).

NVLD and cerebellar peduncle fractional anisotropy

Relative to TD children, those with NVLD had significantly greater left and right inferior cerebellar peduncle (ICP) FA (β= 1.02, t(24)=2.18, p=.040 and β=1.17, t(24)=2.51 p=.019, respectively; Figure 1), controlling for age (Table S2). Age terms were nonsignificant (p>.18), and age was not associated with left (r=.14, p=.47) or right ICP FA (r=.05, p=.80) in bivariate analyses, suggesting that between group differences in age did not drive associations between NVLD diagnosis and FA. Children with NVLD did not differ from TD children with respect to middle or superior cerebellar peduncle FA (p’s>.81; Table S2). In exploratory analyses, children with NVLD also did not differ in MD, RD, or AD of any cerebellar peduncles (p’s>.10; Table S3).

Figure 1.

Figure 1.

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Relative to TD children, children with NVLD had higher FA in the A) left and B) right inferior cerebellar peduncles. Gray points depict group means. FA = fractional anisotropy. NVLD = Nonverbal Learning Disability. TD = typically developing.

NVLD, ICP FA, and social difficulty

Greater FA of the right (β=0.33, t(22)=3.7, p=.008), but not the left ICP (β=0.24, t(22)=2.0, p=.060), was associated with higher CBCL Social Problems scores, controlling for NVLD diagnosis and age (Figure 2). FA of the right (average causal mediation effect (ACME)=0.38, p=.03; proportion mediated=0.26), but not the left ICP (ACME=0.25, p=.14; proportion mediated=.17) mediated the association between NVLD diagnosis and CBCL Social Problems scores. In exploratory analyses, right ICP FA was associated with the Cognition subscale of the Social Responsiveness subscale (β=0.32, p=.043), which measures the ability to understand social cues, but not other subscales (Table S4).

Figure 2.

Figure 2.

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Right inferior cerebellar peduncle (RICP) fractional anisotropy (FA) A) was positively associated with CBCL Total Problems, residualized for age and diagnostic group (NVLD vs. typically developing) and B) mediated the association between NVLD diagnosis and CBCL Total Problems. The regression coefficient a relates NVLD diagnosis to RICP FA, and the regression coefficient b relates RICP FA to CBCL Social Problems, controlling for NVLD diagnosis. The total effect is defined as the regression coefficient relating NVLD diagnosis to CBCL Social Problems; the direct effect is defined as the regression coefficient relating NVLD diagnosis to CBCL Social Problems, controlling for the effects of RICP FA. *p<.05, **p<.01, ***p<.001. CBCL= Child Behavior Checklist. NVLD = nonverbal learning disability.

Discussion

Summary of results

In the current study, we identified differences in cerebellar white matter microstructure between typically developing (TD) children and children with nonverbal learning disability (NVLD). Children with NVLD exhibited higher FA in the bilateral inferior cerebellar peduncles (ICP), which mediated associations between NVLD diagnosis and parent-reported social problems. In exploratory analyses, we showed that ICP FA was specifically associated with social cognition, rather than other aspects of social responsiveness.

Distinctly altered cerebellar white matter microstructure in NVLD

We hypothesized that children with NVLD would have reduced FA in the cerebellar peduncles, consistent with other disorders characterized by social difficulties, such as autism spectrum disorder (ASD) and schizophrenia (Brito et al., 2009; Catani et al., 2008; Hanaie et al., 2013; Okugawa et al., 2006; Sivaswamy et al., 2010). Contrary to this hypothesis, children with NVLD had increased FA. Furthermore, while many of the studies examining cerebellar peduncle FA in ASD have primarily implicated the superior peduncles, our current study implicates the inferior peduncles. In the context of ongoing debate about whether NVLD represents a discrete clinical entity, we add to the literature delineating its unique pathophysiology. For example, in a previous study, we demonstrated that, although children with NVLD and children with ASD both had social problems and associated alterations in salience network functional connectivity, the locus of disruption was disorder-specific (Margolis et al., 2019). Here, we similarly suggest that, although NVLD and ASD may both be characterized by disruption in cerebellar peduncle microstructure, the direction and location of disruption appears to be disorder specific. Notably, increased FA is not synonymous with improved structural integrity, but may rather represent differences in axonal orientation, density, myelination, diameter, or other microstructural properties (Jones, Knösche, & Turner, 2013).

Inferior cerebellar peduncles

The inferior cerebellar peduncles are composed of both afferent and efferent tracts linking the cerebellum to portions of the brainstem, such as the inferior olive and the vestibular nucleus. The olivocerebellar tract consists of climbing fibers, which synapse on cerebellar Purkinje cells. One line of thought asserts that the olivocerebellar tract communicates prediction error signals, which contribute to motor coordination (Ebner, Hewitt, & Popa, 2011; Kitazawa, Kimura, & Yin, 1998; Lang et al., 2017; Ohmae & Medina, 2015). Indeed, a recent study demonstrated that higher FA in the inferior cerebellar peduncle was associated with worse motor adaptation in humans (Jossinger, Mawase, Ben-Shachar, & Shmuelof, 2020). Furthermore, it has been specifically proposed that cerebellar mechanisms of motor prediction error and adaptation may contribute to social cognition, given the importance of prediction in social reciprocity (Sokolov, Miall, & Ivry, 2017; Van Overwalle, Manto, Leggio, & Delgado-García, 2019). Relatedly, the cerebellar cognitive affective syndrome, which results from posterior cerebellar damage is characterized by dysmetria in non-motor functions, including social cognition (Hoche, Guell, Vangel, Sherman, & Schmahmann, 2018; Schmahmann, Guell, Stoodley, & Halko, 2019; Schmahmann & Sherman, 1998). Thus, it is possible that altered prediction error processes involving the inferior cerebellar peduncle may contribute to social cognitive deficits in NVLD. Future studies should investigate this potential pathway as it may provide novel targets for behavioral intervention against the social problems present in many individuals with NVLD.

A second line of thought suggests that the olivocerebellar system contributes to timing in domains including, but not limited to, the motor domain (Jacobson, Rokni, & Yarom, 2008; Liu, Xu, Ashe, & Bushara, 2008; Wu, Ashe, & Bushara, 2011; Xu, Liu, Ashe, & Bushara, 2006). Given the role of synchrony in social interaction, it is possible that disruptions in the neural representation of timing might alter social behavior (Hove & Risen, 2009; LaFrance, 1979; Miles, Nind, & Macrae, 2009; Mogan, Fischer, & Bulbulia, 2017). Thus, disruptions in ICP-mediated processes, whether related to prediction error or timing, may contribute to the social deficits observed in NVLD.

Although we demonstrated that ICP FA mediated NVLD-related social cognitive difficulty, our study was small and cross-sectional. Furthermore, our parent-reported measures of social deficits rendered us unable to parse the specific, putative functions of the ICP, such as processing of social prediction and timing. The current study nevertheless provides direction for further inquiry into the neural bases and behavioral nuances of NVLD. Indeed, future, longitudinal studies are required to replicate our findings. Additionally, experimental psychological paradigms would offer the ability to more definitively delineate the aspects of social cognition that may cascade from altered ICP FA. In the absence of such studies, the current study provides further evidence that NVLD may be characterized by cerebellar differences.

Supplementary Material

Contributions of cerebellar white matter microstructure to social difficulty in nonverbal learning disability Supplement

Acknowledgments

This work was supported by NIEHS grant K23ES026239 (to AEM), The NVLD Project (to AEM), and the Promise Project.

Footnotes

The authors report no biomedical financial interests or potential conflicts of interest.

All research protocols conform to the recognized standards outlined in the Declaration of Helsinki and the US Federal Policy for the Protection of Human Subjects.

All participating children and guardians provided written informed assent and consent, respectively.

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Contributions of cerebellar white matter microstructure to social difficulty in nonverbal learning disability Supplement
NIHMS1736838-supplement-Contributions_of_cerebellar_white_matter_microstructure_to_social_difficulty_in_nonverbal_learning_disability_Supplement.pdf (67.6KB, pdf)

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