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. Author manuscript; available in PMC: 2025 Jul 1.
Published in final edited form as: J Child Neurol. 2025 Feb 17;40(6):403–414. doi: 10.1177/08830738251316406

Thalamic volume reduction in Cerebral Visual Impairment: Relationship to visual dysfunction

Marie Drottar a,b, Chan-Mi Kim a,b, Negin Nadvar a,b, Howard J Cabral c, Corinna M Bauer a,b,d,*
PMCID: PMC12092204  NIHMSID: NIHMS2049861  PMID: 39962823

Abstract

The thalamus is critical for the relay and modulation of visual information. As such, injury to the developing thalamus may result in cerebral visual impairment (CVI). This study investigated quantitative volume reductions of the thalamus in CVI compared to controls and probed the association between thalamic volume and the severity of CVI-related visual dysfunctions. Thalamic volumes were quantified using T1-weighted MRI data from 23 participants with CVI and 42 controls. Nineteen participants with CVI also completed the CVI Questionnaire. CVI was associated with significant volume reductions of the global thalami, anterior, lateral, and ventral thalamic regions, as well as several nuclei, particularly in those with CVI due to periventricular leukomalacia. Within the CVI group, smaller volumes of the right thalamus and lateral pulvinar were significantly associated with more reported difficulties moving through space. Together, these results provide empirical evidence supporting aberrant thalamic development as a potential mechanism underlying CVI.

Keywords: Cerebral (cortical) visual impairment – CVI, Thalamus, CVI questionnaire, Visual perception, Periventricular leukomalacia, Prematurity

Introduction

Survivors of early brain injury and/or preterm birth are at an increased risk for developing cerebral visual impairment (CVI); a leading cause of visual impairment and dysfunction in children.1–5 CVI is associated with a spectrum of visual difficulties,6 including impairments in visual function (i.e., reduced acuity, poor contrast sensitivity, restricted visual fields, etc.)7–11 that may be accompanied by perceptual visual dysfunctions (i.e., object and face recognition difficulties, visual inattention, simultanagnosia, and challenges with visual motion perception).9,12–21. Together, the manifestations of CVI impact health-related quality of life.12,22–25 Despite the complex presentation of CVI and its frequency across a range of associated etiologies, the underlying neural mechanisms remain elusive. Due to its central role in vision and visual perception, 26–32 aberrant development of the thalamus is one potential candidate.

The thalamus may be particularly susceptible to permanent damage following injury in the third trimester,33 with as many as 59% of infants with periventricular leukomalacia (PVL) demonstrating neuronal loss in thalamic nuclei, including those implicated in vision, such as the lateral geniculate (LGN).34–36 While the role of the thalamus in sensory and visual functions has been documented since the 1800s,37 it is now recognized as an integral part of the visual system, acting not only as a relay station for sensory information entering the brain from the retina, but actively modulating this information based on feedback loops with cortical, subcortical, and cerebellar regions38. Thus, injury to these nuclei has the potential to interrupt visual development perception.

In the context of individuals with and at-risk for CVI, qualitative 39 and semiquantitative 40 assessments suggest a link between thalamic injury and the severity of visual dysfunction, whereby visible atrophy or lesions to the thalamus were associated with greater visual dysfunction in CVI. Along these lines, smaller global thalamic volumes have been reported in individuals born preterm or with PVL (common causes associated with CVI),36,41–45 however, the correlation with visual impairments was not investigated in these studies. Additionally, it remains unclear whether neuronal loss occurs uniformly across all thalamic nuclei 35 and how the thalamus is impacted in individuals with CVI that is not caused by PVL.

To this end, the current study investigated quantitative differences in volume of the global thalamus, with secondary analyses of the subregions and nuclei that comprise the thalamus to determine whether certain regions are more impacted than others in the case of CVI due to heterogeneous etiologies. Additionally, using partial correlation analysis, we determined the relationship between thalamic volume and extent of visual dysfunctions as reported using the CVI Questionnaire.46,47 The results provide evidence for thalamic volume reduction in those with CVI, whereby the extent of volume reduction is associated with the degree of visual dysfunction. Notably, greater reductions in volume were observed in the group of individuals with CVI due to PVL, suggesting a potential differential impact of etiology on the thalamus.

Methods

Participants:

Twenty-three participants with CVI (13 M, 10 F, mean age: 18.49 years, 5.52 s.d. range: 10-30) and 42 controls (17 M, 25 F, mean age: 19.26 years, 4.85 s.d., range 10-28 years) were enrolled in the study. Participants with CVI were previously diagnosed by eyecare professionals with extensive clinical expertise working with CVI. One participant with PVL had suspected CVI.

Additional details can be found elsewhere. 48 Briefly, CVI was diagnosed prior to enrollment in the study based on a thorough examination of their ocular structures, medical history, and visual behaviours including objective assessments of visual function (i.e., visual acuity, ocular motor functions, visual field perimetry) and functional vision (i.e., through direct observation and assessment, questionnaires, and surveys). A diagnosis was made when the visual dysfunction was greater than could be expected based on ocular findings alone. In the CVI group, best corrected binocular visual acuity ranged from 20/15 to 20/75 Snellen (−0.12 to 0.57 logMAR equivalent). Control participants (including those born preterm) were excluded if they had any known history of an ocular disorder (including high grade retinopathy of prematurity), visual field restriction, visual acuity (or best corrected visual acuity) worse than LogMAR 0.0 (i.e., 20/20 Snellen), or any known neurologic condition. Additional participant details can be found in Table 1.

Table 1.

Participant demographics.

Participant Group Sex Age Visual Acuity (Snellen)* Scanner Preterm Controls & Suspected CVI Etiology Visual history
1 control Female 21 20/20 Achieva
2 control Female 17 20/20 Achieva
3 control Female 22 20/20 Achieva
4 control Female 15 20/20 Achieva
5 control Female 15 20/20 Achieva
6 control Female 17 20/20 Achieva
7 control Female 17 20/20 Achieva
8 control Female 24 20/20 Achieva
9 control Female 22 20/20 Achieva
10 control Female 23 20/20 Achieva
11 control Female 23 20/20 Achieva
12 control Male 19 20/20 Achieva
13 control Male 18 20/20 Achieva
14 control Male 15 20/20 Achieva
15 control Male 18 20/20 Achieva
16 control Male 25 20/20 Achieva
17 control Male 14 20/20 Achieva
18 control Male 17 20/20 Achieva
19 control Male 11 20/20 Elition X
20 control Female 12 20/20 Elition X
21 control Female 21 20/20 Elition X
22 control Female 25 20/20 Elition X
23 control Female 25 20/20 Elition X
24 control Female 21 20/20 Elition X
25 control Female 28 20/20 Elition X
26 control Female 19 20/20 Elition X
27 control Female 25 20/20 Elition X
28 control Female 23 20/20 Elition X
29 control Female 20 20/20 Elition X
30 control Female 19 20/20 Elition X
31 control Female 25 20/20 Elition X
32 control Female 25 20/20 Elition X
33 control Male 28 20/20 Elition X
34 control Male 20 20/20 Elition X
35 control Male 18 20/20 Elition X
36 control Male 12 20/20 Elition X
37 control Male 24 20/20 Elition X
38 control Male 18 20/20 Elition X
39 control Female 12 20/20 Elition X Preterm no reported ocular conditions
40 control Male 12 20/20 Elition X preterm no reported ocular conditions
41 control Male 10 20/20 Elition X preterm no reported ocular conditions
42 control Male 14 20/20 Elition X preterm no reported ocular conditions
43 CVI Female 19 20/25 Achieva seizure disorder Intermittent esotropia
44 CVI Male 16 20/75 Achieva genetic disorder Optic nerve atrophy, some visual field restriction
45 CVI Female 14 20/25 Elition X in utero stroke, preterm birth Photophobia, mild right visual field restriction
46 CVI Female 25 20/20 Elition X polymicrogyria Corrected strabismus, lower left field restriction, depth perception difficulty
47 CVI Female 23 20/40 Elition X hypoxia, preterm birth Right visual field restriction
48 CVI Female 20 20/70 Elition X meningitis, stroke (infancy) N/A
49 CVI Female 12 20/20 Elition X perinatal head injury, potential anoxia, infant hypoglycemia Optic ataxia, convergence and accommodative insufficiency
50 CVI Female 20 20/20 Elition X birth complications N/A
51 CVI Female 23 20/70 Elition X low birth weight Left visual field restriction, poor depth perception, nystagmus
52 CVI Male 21 20/40 Elition X seizure N/A
53 CVI Male 22 20/20 Elition X preterm birth Central visual field impairment
54 CVI Male 18 20/20 Elition X unknown Convergence insufficiency
55 CVI Male 17 20/25 Elition X anoxia Restricted visual fields
56 CVI Male 10 20/20 Elition X genetic disorder, delayed myelination Lower and peripheral field restriction, exotropia
57 CVI Male 27 20/20 Elition X Unknown, suspected CVI Convergence insufficiency
58 CVI Female 17 20/40 Achieva PVL Lower and peripheral field restriction, subtle optic atrophy, latent nystagmus, corrected strabismus
59 CVI Male 17 not provided in record Achieva PVL, suspected CVI No details provided
60 CVI Male 10 20/20 Elition X hypoxia, PVL Lower visual field restriction, esotropia
61 CVI Male 15 20/20 Elition X PVL Lower visual field restriction
62 CVI Male 30 20/50 Elition X PVL Lower and left peripheral field restriction, lack of depth perception, optic nerve pallor
63 CVI Male 12 20/30 Elition X PVL Lower visual field restriction, corrected strabismus
64 CVI Male 25 20/20 Elition X PVL Strabismus
65 CVI Female 12 20/60 Elition X PVL Lower field restriction, latent nystagmus, pale optic nerve, intermittent exotropia
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*

visual acuity is reported based on best corrected binocular vision

Informed consent (or assent in the case of minors) was obtained from all participants prior to enrollment in accordance with ethical approval from the Massachusetts General Brigham Institutional Review Board and the Declaration of Helsinki.

MRI acquisition and preprocessing

T1-weighted structural MRI was acquired on 65 participants total. Of these, data from 22 (4 CVI, 18 control) participants was acquired on a Philips 3T Achieva prior to a new scanner installation at the MRI center, and the 43 participants (19 CVI, 24 control) were scanned on a Philips 3T Elition X. The scanning parameters were as follows: Achieva TE = 3.1ms, TR = 6.8 ms, voxel size 0.98*0.98*1.20 mm3, flip angle 9 deg; Elition X: TE = 2.9 ms, TR = 6.5 ms, acquired voxel size 1 mm isotropic, reconstructed voxel size 0.47*0.47*1 mm3, flip angle 8 deg.

All data were processed in FreeSurfer 7.4.1, as described elsewhere. 49–51 As part of the processing stream, data were intensity normalized, skull stripped, and segmented into tissue classes, including white matter, cortex, and subcortical grey matter. Pial surfaces and grey/white matter boundaries were examined for all subjects and manually edited as needed to ensure accurate tissue classifications. Following the standard FreeSurfer pipeline, the thalamus was divided into 23 different nuclei per hemisphere based on a probabilistic atlas derived from histological data.52 Nuclei were then grouped into anterior, lateral, medial, ventral, intralaminar, pulvinar, and geniculate subdivisions (Table 2). Volumes for the total thalamus, major subdivisions, and 25 individual nuclei were exported into SAS OnDemand for Academics for statistical analysis. Representative parcellations are shown in Figure 1.

Table 2.

Thalamic subdivisions and associated nuclei.

Thalamic sub-division Nuclei FreeSurfer Abbreviation
Anterior Anteroventral AV
Lateral Laterodorsal LD
Lateral posterior LP
Ventral Ventral anterior VA
Ventral anterior magnocellular VAmc
Ventral lateral anterior VLa
Ventral lateral posterior VLp
Ventromedial VM
Ventral posterolateral VPL
Intralaminar Central medial CeM
Central lateral CL
Centromedian CM
Parafascicular Pf
Medial Reuniens medial ventral MV(re)
Mediodorsal lateral parvocellular MDl
Mediodorsal lateral magnocellular MDm
Geniculate Lateral geniculate nucleus LGN
Medial geniculate nucleus MGN
Limitans - suprageniculate L-SG
Pulvinar Anterior pulvinar PuA
Inferior pulvinar PuI
Lateral pulvinar PuL
Medial pulvinar PuM
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Figure 1.

Figure 1.

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Thalamic parcellations for representative CVI-nonPVL (A), CVI-PVL (B), and control (C) participants. In the online version, colour coding for each nuclei group is on the right.

Visual Assessments

The Flemish CVI Questionnaire (FCVIQ)47 was completed by 19 participants with CVI (all scanned on the Elition X) or their caregiver based on their visual functioning from the previous six months. For each item in the FCVIQ, a binary yes/no response was provided. Questions referencing chocolate spread were substituted with “peanut butter jar (or favourite food)”, to be more relevant to our test population. The number of items marked as ‘yes’ were summed and a score for each of the five factors was generated according to Ben Itzhak et al. 46

Statistical Analysis

Statistical analyses were completed using SAS Studio. All volumes were adjusted for overall brain size using residuals and the estimated total intracranial volume estimate from FreeSurfer. Shapiro-Wilke tests and visual inspection confirmed distribution of the data. Differences in volume between CVI and control groups were determined using a general linear model adjusting for the potential effects of age, sex, and scanner. As a secondary analysis, we investigated the potential effect of CVI etiology on the thalamus. The CVI group was then divided into those with a diagnosis of PVL and those without. The models were then re-run according to the presence of PVL, comparing control, CVI-PVL, and CVI-nonPVL groups. Similarly, results were adjusted for age, sex, scanner, and intracranial volume. Based on the distribution of the data, Pearson partial correlations were used to investigate the potential relationship between thalamic volume and the extent of visual dysfunction as measured by the FCVIQ. Although neither age nor sex showed significant correlations with the behavioural measures, both were included as nuisance variables in the correlations to account for any potential effect that they may have had. Because all participants who completed the FCVIQ were scanned on the Elition, scanner was not included as a covariate. For all results, significance threshold was set at p < 0.05 with Bonferroni correction for multiple comparisons.

Results

There was no significant difference in ages between groups (t(63) = −0.59, p = 0.56) and there was no difference in the distribution of males and females between groups (chi square = 1.54, p = 0.21). Severity of visual dysfunction based on the FCVIQ and sub-factors were not significantly different between CVI sub-groups of PVL and non-PVL. (Figure 2)

Figure 2.

Figure 2.

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Differences between CVI subgroups for the FCVIQ total score (A) and factor scores (B). No significant differences between PVL and non-PVL subgroups of CVI were observed, indicating that functional vision was not differently impacted based on etiology. Light grey CVI-nonPVL, dark grey CVI-PVL

Global thalamus volume

A significant reduction in volume of the left (F(1, 60) = 8.79, p = 0.0043) and right (F(1, 60) = 7.63, p = 0.0076) thalami were observed between CVI and control groups after adjusting for the potential effects of age, sex, and scanner. There was a significant overall effect of PVL-status on global thalamic volume bilaterally (left: F(3, 58) = 17.40, p < 0.0001; right: F(3, 58) = 21.25, p < 0.0001). Tukey’s posthoc comparisons revealed that volumes for the CVI-PVL group were significantly smaller than the CVI-nonPVL (bilaterally: p < 0.0001), control preterm (left: p = 0.0054, right: p = 0.0005), and control term (bilaterally: p < 0.0001). Additionally, a trend for reduced volume of the left thalamus in preterm controls compared to term-born controls (p = 0.071) was also observed. Within the CVI group we observed significant negative correlations between volume of the right thalamus and impairments moving in space (r = −0.625, p = 0.0074) and between volume of the left thalamus and clutter and distance viewing impairments (r = −0.622, p = 0.0077), which nearly survived correction for multiple comparisons. (Figure 3)

Figure 3.

Figure 3.

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A. Group differences in volume (adjusted for intracranial volume- ICV) for the left and right global thalamus. Volume was significantly reduced in the CVI group compared to controls bilaterally. B. Partial correlation plots between right thalamic volume and the FCVIQ factor score for impairments moving in space. C. Partial correlation plots showing a trend for the relationship between left thalamic volume and the FCVIQ factor score for impairments with clutter and distance viewing.

Thalamic Regions

Next, we investigated specific regions within the thalamus. Volume was significantly smaller in the CVI group compared to controls for several subregions (Figure 4), of which the right anterior, left lateral, and bilateral ventral thalamic areas survived correction for multiple comparisons (i.e., p < 0.00357).

Figure 4.

Figure 4.

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Group differences in volume (adjusted for intracranial volume- ICV) for the left and right thalamic subregions. Volume was significantly reduced in the CVI group compared to controls bilaterally for a number of regions. Group differences surviving Bonferroni correction for multiple comparisons are indicated with an *.

As a secondary analysis, we examined for each of the thalamic regions the overall significant effect of group when examining the impact of PVL, CVI, and preterm birth. Post-hoc Tukey’s t-tests revealed that the CVI-PVL group had significantly smaller volumes compared to both the CVI-nonPVL and control groups for each region. (Figure 5) Additionally, the CVI-PVL group had significantly smaller volumes than the preterm control group for multiple regions as well, including the right anterior, geniculate, medial, and ventral areas. CVI-nonPVL was not significantly different from the control group (Supplemental Information)

Figure 5.

Figure 5.

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Subgroup differences in volume for the left and right global thalamus. Volume was significantly smaller in the CVI-PVL group (blue) compared to all other groups bilaterally. ICV: Intracranial volume

Within the CVI group, no significant Pearson partial correlations between volume of thalamic regions and the FCVIQ survived correction for multiple comparisons (i.e., p < 0.000595; Figure 6). However, a negative correlation between volume of the left geniculate region and impairments moving in space (r = −0.744, p = 0.0006) nearly survived our conservative Bonferroni adjustment.

Figure 6.

Figure 6.

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R-values associated with Pearson partial correlations between volume of thalamic regions, CVIQ total score, and the CVIQ factor scores. * indicates p < 0.05, ** indicates correlations with p < 0.005. Imp = impairments

Specific thalamic nuclei

As an exploratory analysis, we investigated whether volume differences between groups could be observed in specific thalamic nuclei with age, sex, and scanner as covariates. A number of thalamic nuclei survived Bonferroni correction for multiple comparisons (i.e., p < 0.00109). Specifically, CVI was associated with significantly smaller volume of the right AV (F(1, 59) = 15.25, p = 0.0002), bilateral LP (left: F(1, 59) = 17.61, p < 0.0001), right: F(1, 59) = 11.9, p = 0.001), right VA (F(1, 59) = 20.51, p < 0.0001), right VAmc (F(1, 59) = 13.3, p = 0.0006), right VLa (F(1, 59) = 13.88, p = 0.0004), right Pc (F(1, 59) = 12.91, p = 0.0007), right MDl (F(1, 59) = 14.98, p = 0.0003), and right MGN (F(1, 59) = 13.79, p = 0.0005), as well as left VLP (F(1, 59) = 12.31, p = 0.0009) and left Pt (F(1, 59) = 12.02, p = 0.001). Full details can be found in the supplemental material.

For each of the thalamic nuclei there was an overall significant effect of group when examining the impact of PVL, CVI, and preterm birth. However, the right LD, left VM, left Pf, bilateral PuL, bilateral PuI, left MGN, and bilateral LSg nuclei did not survive correction for multiple comparisons. Post hoc Tukey’s t-tests revealed that the CVI-PVL group had significantly smaller volumes compared to both the CVI-nonPVL and control groups for each region. Additionally, the CVI-PVL group had significantly smaller volumes than the preterm control group for multiple nuclei throughout the thalamus. Volumes of the CVI-nonPVL group were only significantly smaller than controls for a number of regions as well (Supplemental material).

Within the CVI group, Pearson partial correlations between total difficulties scores on the FCVIQ were significantly correlated with volume of the right LSg (r = −0.814, p = 0.0001). We also investigated correlations with each of the 5 factors and observed a significant correlation between severity of impairments moving in space and volume of the right lateral pulvinar (PuL, r = −0.842, p < 0.0001). (Figure 7)

Figure 7.

Figure 7.

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Partial correlation plots between volume of the right lateral pulvinar and the FCVIQ factor score for impairments moving in space for the CVI group.

A number of additional correlations were observed, however they did not survive Bonferroni correction for multiple comparisons (p < 0.00018; Figure 8).

Figure 8.

Figure 8.

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R-values associated with Pearson partial correlations between volume of thalamic nuclei, CVIQ total score, and the CVIQ factor scores. * indicates p < 0.05, ** indicates correlations with p < 0.005. Imp = impairments

Discussion

In addition to serving as the primary relay center for visual information from the retina to the cortex, the thalamus is a key hub for many aspects of visual perceptual processing through a series of feed-forward and feed-back cortico-thalamo-cortical projections.53 Because of its high degree of interconnectedness with cortical networks implicated in higher order cognitive and perceptual functions, injury to the thalamus may result in behavioural impairments similar to those observed in the case of focal cortical injury.35 The developing thalamus is particularly vulnerable to early brain injury, 54,55 making it an important target for investigation in the case of CVI. Thus, this study investigated the potential for altered volume of the thalamus and sub-regions and specific nuclei therein in individuals with CVI compared to a typically-sighted and developing control group. As a follow-up analysis, we investigated the correlation between thalamic volume and severity of visual impairments as determined from the Flemish CVI questionnaire.

We observed significant bilateral reductions in global thalamic volume in CVI compared to the control group. While to the best of our knowledge this is one of the first studies to provide a detailed empirical quantification of global and regional thalamic volume reduction in participants with CVI, our results support previous reports of global thalamic reduction in individuals with CVI using qualitative 39 and semi-quantitative methods 40.

In our regional analysis we observed significantly smaller volumes of the left lateral, right anterior, and bilateral ventral thalamic regions in CVI compared to controls. Notably, the lateral thalamus was associated with the reported severity of visual disinterest, particularly in the left hemisphere, although this did not survive correction for multiple comparisons. The lateral thalamus is involved with multiple functions, including somatosensory processing, spatial learning, memory, and visual processes, such as visually-guided behaviour. 56–58 While volumes of the anterior and ventral thalamic regions were not associated with the extent of visual dysfunction reported in the FCVIQ following correction for multiple comparisons, they are implicated in other behaviours and cognitive abilities that may not be covered by the FCVIQ, as it is specifically investigating vision. For example, the anterior thalamus is implicated in spatial navigation and memory, 59,60 while the ventral thalamus is implicated in sensorimotor control.61

Our correlation analysis in the CVI group revealed a significant negative correlation between impairments moving in space and volume of the global right thalamus and the right lateral pulvinar. The clinical significance of the right thalamic association with CVI-related impairments moving in space is a little unclear. However, isolated right thalamic strokes have been associated with impairments in visuo-spatial processes, including spatial cognitive tasks and hemi-spatial neglect.62,63 The pulvinar is thought to be one of the most prominent nuclei in the thalamus for processing visual information, with a high degree of reciprocal connections with the cortex.64–67 First, the pulvinar receives input directly from the retina, which feeds the information forward to motion-sensitive MT,21,68,69 although these connections may diminish in strength during childhood.69,70 The lateral pulvinar has connections to both dorsal and ventral visual networks.66 As such, the lateral pulvinar plays a particularly important role in a number of aspects of visually-guided processes, including motion perception,64 visual attention, 71,72 and spatial awareness. 72–74 Thus, it is not surprising that reduced volume of the lateral pulvinar was associated with greater difficulties in impairments moving in space and spatial navigation in the current study.

Due to its role and proximity to the germinal matrix and subventricular zone, the thalamus and developing thalamo-cortical connections are particularly susceptible to ramifications of preterm birth, including periventricular leukomalacia.35 Indeed, global thalamic volume is reduced in PVL 75 and those born preterm 41,76, with the extent of thalamic volume reduction being associated with cognitive impairments during childhood. 45 In this study, we also observed a significant reduction in thalamic volume in the preterm group, both with and without the presence of PVL. Notably, ex-preterms with PVL and CVI demonstrated more severe volume reductions in virtually all thalamic regions and nuclei as compared to ex-preterms without PVL (i.e., the preterm control group) and the non-PVL CVI group. Together, these results indicate that the effects of PVL on thalamic volume were greater than that of preterm birth alone, but that prematurity is associated with long-term reductions in thalamic volume.

Our results support previous reports in the literature indicating a link between thalamic volume reduction and damage with severity of visual impairments. Specifically, in a sample of 72 children with bilateral cerebral palsy due to PVL, injury to the thalamus was positively associated with the extent of impairments in visual function (i.e., ocular control, acuity, visual fields, colour perception, and stereopsis).40 Similar relationships between visual function and thalamic volume reduction have been reported by Ricci and colleagues.39 In our study, volume of specific thalamic regions and nuclei was associated with the number of reported visual dysfunctions. Notably, although thalamic volumes were significantly reduced in CVI-PVL as compared to non-PVL causes of CVI, there were no differences in the extent of visual dysfunctions between the two sub-groups of participants with CVI. Together, this evidence suggests that maldevelopment of the thalamus is likely not the only driving factor underlying the challenges with functional vision.

One of the main limitations of this study is the relatively small sample size. While CVI is a leading cause of childhood visual impairment, 1–5 it remains a relatively uncommon diagnosis in comparison to other neurodevelopmental conditions such as autism spectrum disorder (1 in 36)77 or attention deficit hyperactivity disorder (1 in 9)78. Despite the small sample size and heterogeneous etiologies represented, several thalamic volume differences and correlations survived correction for multiple comparisons, indicating that it is likely a key region associated with the presence and severity of visual dysfunctions experienced by those with CVI, particularly for those with PVL or encephalopathy of prematurity. In turn, these results provide targets for future interventions aimed at modulating the thalamocortical circuits associated with visual perception. In this study, we were not able to distinguish between primary injury to the thalamus and secondary retrograde degeneration (as discussed in 37,79). As such, it will be important to investigate the integrity of associated thalamocortical white matter pathways and the optic tracts, which may be impacted following early brain injury.80 Additionally, we acknowledge the inherent limitations in segmentation of the thalamic nuclei using automated approaches, such as FreeSurfer. 81 Alternative segmentation methods, such as those implementing the Morel atlas in MNI space, 82 require initially nonlinear transformation of the data into MNI stereotaxic space, which may itself be problematic in the case of atypical morphology due to neonatal brain injury. Nevertheless, previous reports indicate that estimates of thalamic volume provided by FreeSurfer shows good agreement with stereology in both healthy participants and neurological patients.83

Overall, these results demonstrate that there are reductions in volume of the thalamus and specific nuclei and sub-regions in CVI compared to controls, but that these differences are more pronounced in CVI due to PVL as compared to other underlying causes. The results also provide evidence for the role of the pulvinar and right thalamus in difficulties with proprioception and moving through space reported in individuals with CVI. The role of trans-synaptic retrograde degeneration and thalamocortical white matter pathways in CVI remain important areas for future investigation.

Supplementary Material

1

Acknowledgements

We wish to thank our participants and their families for their invaluable contribution to this work.

Funding

This work is supported by the National Institutes of Health (EY030877 to C.M.B.).

Abbreviations

CVI

Cerebral visual impairment

PVL

periventricular leukomalacia

FCVIQ

Flemish Cerebral Visual Impairment Questionnaire

Footnotes

Ethical Considerations

The study was approved by the Investigative Review Board at Massachusetts General Hospital, Boston, MA (2022P000532, 2019P003229) and conducted in accordance with the Declaration of Helsinki for research involving humans.

Consent to Participate

Written informed consent was obtained from all participants or a parent/legal guardian along with participant assent (in the case of a minor).

Declaration of Conflicting Interest

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data Availability

De-identified data is available following a data use agreement and approval from the local institutional review board.

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Associated Data

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Supplementary Materials

1
NIHMS2049861-supplement-1.pdf (148.9KB, pdf)

Data Availability Statement

De-identified data is available following a data use agreement and approval from the local institutional review board.

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