# Visual dysfunction of superior colliculus and lateral geniculate nucleus in idiopathic blepharospasm

Sara Meoni, Michel Dojat, Michael Hutchinson, Pierre Pelissier, Christophe

Chiquet, Elena Moro

► To cite this version:

Sara Meoni, Michel Dojat, Michael Hutchinson, Pierre Pelissier, Christophe Chiquet, et al. Visual dysfunction of superior colliculus and lateral geniculate nucleus in idiopathic blepharospasm. Journal of the neurological sciences, 2024, 466, pp.123272. 10.1016/j.jns.2024.123272. inserm-04737019

HAL Id: inserm-04737019

https://inserm.hal.science/inserm-04737019v1

Submitted on 15 Oct 2024

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_1.png" /></figure>

Distributed under a Creative Commons Attribution 4.0 International License
<figure><img src="image_2.png" /></figure>

<figure><img src="image_3.png" /></figure>

# Visual dysfunction of superior colliculus and lateral geniculate nucleus in idiopathic blepharospasm

Sara Meoni<sup>a,b,*†</sup>, Michel Dojat<sup>a,†</sup>, Michael Hutchinson<sup>c</sup>, Pierre Pelissier<sup>b</sup>, Christophe Chiquet<sup>d</sup>, Elena Moro<sup>a,b</sup>

## ARTICLE INFO

**Keywords:**
Brainstem
Dystonia
Eye-blinking
Human vision
Neuroimaging

## ABSTRACT

**Background:** The etiology and pathophysiology of idiopathic blepharospasm (BP) are still largely unknown. It has been hypothesized that BP is the consequence of a dysfunction of the basal ganglia loop, although cortical areas, cerebellum, and other brainstem structures may be involved. There is some evidence that the superior colliculus (SC), a sensorimotor brainstem structure, is involved in another adult-onset focal dystonia, the cervical dystonia. To date, there is no data concerning the implication of the SC in BP.

**Objectives:** Our study aims to investigate the role of the SC in people with idiopathic BP compared to controls using fMRI and a visual stimulation paradigm based on luminance contrast variations.

**Methods:** People with idiopathic BP and controls underwent brain fMRI using a standardized protocol, allowing modulation of visual activity in the SC, the lateral geniculate nucleus (LGN), and the primary visual cortex (V1), at increasing luminance levels (1 %, 3 %, 5 %, 9 %).

**Results:** Ten BP women and ten sex- and age-matched controls were enrolled. Compared to controls, the BP group showed no modulation of visual responses at all luminance levels (p < 0.05) in both SC and LGN. In BP, BOLD responses in V1 were significantly lower at 5 % (p = 0.001), and 9 % (p = 0.002) luminance level.

**Conclusions:** Our findings support the concept of SC and LGN dysfunction in idiopathic BP. Brain fMRI, targeting these sub-cortical visual structures, could play a future important role both as a biomarker and in our understanding of the pathophysiology of adult-onset focal dystonias.

## 1. Introduction

Idiopathic blepharospasm (BP) is an isolated, adult-onset, focal dystonia (AOIFD) characterized by twitching of the eyelids, involuntary closure of the eyes, and increased spontaneous blinking, which can be highly disabling [1-6].

To date, the etiology and pathophysiology of idiopathic BP remain unknown. Similar to other AOIFD phenotypes, it has been hypothesized that BP is the consequence of an impaired inhibition of both sensory and motor levels in a network involving the basal ganglia loop, although other cortical, cerebellar, and brainstem structures may participate in its etiology [7-13].

The superior colliculus (SC) is a complex midbrain sensorimotor

structure involved in the integration of multimodal (visual, tactile, and auditory) stimuli, and the rapid generation of adaptive motor responses of gaze, head, and limbs [14-16]. It has wide connections with the midbrain, the pons, the optic nerve, the visual cortex and the basal ganglia [14,15,17,18].

The SC's implication in the pathophysiology of some movement disorders has been proved so far in both Parkinson's disease (PD) [16,19,20] and cervical dystonia (CD) [21-23]. Specifically in dystonia, people with CD and their unaffected first-degree relatives with abnormal temporal discrimination thresholds (TDTs, i.e. the ability to differentiate two sequential stimuli as being separate in time) have been found with reduced SC activation in brain functional MRI (fMRI) studies, in response to a salient looming visual stimulus, when compared to healthy

<footnote><sup>a</sup> Grenoble-Alpes University, INSERM, U1216, University Hospital of Grenoble-Alpes, Grenoble Institut Neurosciences, Grenoble, France</footnote>

<footnote><sup>b</sup> Movement Disorders Unit, Department of Neurology, University Hospital of Grenoble-Alpes, Grenoble, France</footnote>

<footnote><sup>c</sup> Department of Neurology, St. Vincent's University Hospital, Dublin, Ireland; School of Medicine and Medical Science, University College Dublin, Dublin, Ireland</footnote>

<footnote><sup>d</sup> Department of Ophthalmology, University Hospital of Grenoble-Alpes, HP2 Laboratory, INSERM U1300, Grenoble, France</footnote>

<footnote>* Corresponding author at: Division of Neurology, Centre Hospitalier Universitaire Grenoble Alpes, BP217 38043, Grenoble CEDEX 09, France.
E-mail address: smeoni@chu-grenoble.fr (S. Meoni).</footnote>

<footnote n="1">¹ These Authors equally contributed to the manuscript.</footnote>
subjects and unaffected first-degree relatives with normal TDTs [23]. Therefore, we hypothesize that BP shares similar pathogenic mechanisms with CD and possibly other AOIFD [24], especially concerning the SC dysfunction.

Brain fMRI is a suitable neuroimaging tool for a non-invasively investigation of cortical and subcortical dysfunctions in BP [25-30]. Our group has developed a specific brain fMRI protocol to visualize the SC, and to modulate its functional response to visual stimuli with varying luminance contrasts (by measuring the blood oxygenation level-dependent [BOLD] signal) [31]. We have previously shown that the BOLD responses of the SC, the lateral geniculate nucleus (LGN), and the primary visual cortex (V1) increased linearly with increasing luminance contrast from 1 % to 9 % in healthy subjects [31]. Furthermore, we recently found that SC dysfunctions in de novo PD patients, without improvement after 6 months of a dopaminergic treatment [19].

To date, the role of the SC in the pathogenesis of BP is unknown. In this pilot study, we specifically investigated the SC function using brain fMRI in BP patients compared to healthy subjects.

## 2. Materials and methods

### 2.1. Study design and Participants

People with BP were recruited at the Movement Disorders Unit of the Grenoble University Hospital (Grenoble, France). Inclusion criteria for patients were: diagnosis of idiopathic BP according with the diagnostic criteria [1] of the Movement Disorders Society; Jankovic Rating Scale (JRS) [32] score ≤ 5 (severity score ≤ 3 and frequency score ≤ 2); no dementia or active psychiatric disorders; absence of ophthalmological issues (cataract, retinal pathologies or glaucoma) or other medical conditions interfering with the study; no contraindication to brain MRI. Healthy controls (HC), enrolled in our previous study [31], were matched for age and sex. Inclusion criteria for controls were: absence of neurological conditions; no family history for movement disorders; absence of ophthalmological issues (cataract, retinal pathologies or glaucoma) or other medical conditions, and no contraindication to brain MRI.

All participants provided written informed consent to the study according to the Declaration of Helsinki. The study was approved by the local ethics committee (ID RCB-2012-A00310-43 and 2018-A00438-47), and registered with [ClinicalTrial.gov](NCT03903341).

### 2.2. Clinical assessment

Neurological assessments in both patients and controls were performed by a movement disorders specialist (S.M.). Patients were also assessed with the JRS. Neuroimaging assessment was performed at the peak of the botulin toxin treatment benefit (one to two months after toxin injection), in order to avoid excessive blinking during the brain MRI session which could affect data acquisition.

Ophthalmological evaluation, in both patients and controls, by an ophthalmologist (C.C.), included visual acuity, visual fields, fundus oculi and eye pressure, and contrast discrimination assessments.

### 2.3. Neuroimaging protocol

Neuroimaging assessment included anatomical 3 T brain MRI and fMRI with a visual stimulation protocol. The MRI acquisition technique and fMRI paradigm conditions have been described in detail previously [31]. Here, we have reported the main procedure.

### 2.4. Functional MRI paradigm and procedure

Participants were presented in each visual hemifield with a series of achromatic checkerboards, viewed via a mirror fixed on the head coil, and flashing at a frequency of 4 Hz on a grey background, with four

levels of luminance contrast (1 %, 3 %, 5 %, and 9 %) to avoid SC saturation [33].

In order to maintain attention during the visual task, the participant was instructed to fixate a cross in the center of the screen and to respond by pressing a button, each time the orientation of the cross changed (from + to x and back to +).

A block-design visual paradigm was used with each luminance contrast level presented in four separate 12-s blocks (one block per luminance contrast level), plus five 12-s fixation cross intervals including one at the start, one at the end and one between each main block. The order of luminance contrast levels was randomized within blocks.

### 2.5. MRI acquisition

Structural, functional, and perfusion images were acquired during each MRI session using a whole-body 3 T Philips Achieva MRI scanner equipped with a 32-channel SENSE coil. For structural images, a high-resolution (1mm³) 3D-T1-weighted (MPRAGE) sequence and a T1 inversion recovery sequence (FGATIR, 0.75 × 0.75x1mm³) were acquired to facilitate the manual delineation of our regions of interest (ROI).

For functional images, a standard gradient echo planar imaging (EPI) sequence was used with twenty-five slices (voxel size = 1.5 mm³) to cover SC, LGN, and V1. A whole-brain pseudo-continuous arterial spin labeling (ASL) sequence was used to measure brain tissue perfusion with the following parameters: 1800 ms label, 1634 ms post-label delay and multi-slice single-shot EPI readout (3.5 × 3.5 × 5 mm3, 20 slices, TE/TR = 4230/12 ms). During the acquisition, the subject was comfortably placed in a supine position.

For more technical details about MRI sequences, see Moro et al., 2020 [19], Neuroimaging assessment section.

### 2.6. MRI Data analysis: Individual region-of-interest

Functional data analysis was performed with SPM12 (Wellcome Department of Imaging Neuroscience, London, U.K.) implemented in Matlab. First, for each individual, a rigid body transformation was applied to correct for possible head movements. A spatial smoothing (2 mm Gaussian kernel) was applied to each functional volume. A general linear model (GLM) was constructed with five regressors, i.e. the five conditions of interest (1 %, 3 %, 5 %, 9 %, and fixation) and movement parameter estimates as additional nuisance factors. The conditions of interest were modeled as boxcar functions (block-design paradigm) convolved with a canonical hemodynamic response function. A region-of-interest (ROI) analysis was performed in SC, LGN, and V1, individually and manually defined using ITK-Snap [34]. Based on MPRAGE sequence, V1 was defined as the part of the occipital lobe that lay in and around the calcarine. SC and LGN were manually delineated using MPRAGE and FGATIR respectively. To smooth the manual ROIs, a 3D dilation operator was applied with a two voxels kernel. In realigning each individual structural image to a reference space (MNI) with a non-linear high degree of freedom transformation [35], we verified that our ROIs individual coordinates (see Supplementary Material, Table 1) were in accordance with those reported in the literature (for more details see Bellot et al., 2016 [31], Supplementary Material, Table 1). Differential contrast images were computed based on the GLM relative to each stimulus condition compared to the baseline (fixation) across all experimental runs. Each voxel for each ROI (SC, LGN, and V1) was considered as responsive according their *t* value (t-statistic maps). We considered as significant a lower *t* value for BP patients than for HC (respectively *p* < 0.01 vs *p* < 0.001 uncorrected) due to the weak BOLD level for the former.
**Table 1**

<table><caption>Mean BOLD Response (Arbitrary Units) for each luminance contrast level for the three Regions of Interest for controls and BP patients.</caption><thead><tr><th rowspan="2">Luminance contrast, %</th><th colspan="2">SC</th><th colspan="2">LGN</th><th colspan="2">V1</th></tr><tr><th>Mean</th><th>95 % CI</th><th>Mean</th><th>95 % CI</th><th>Mean</th><th>95 % CI</th></tr></thead><tbody><tr><td colspan="7">HC, n = 10</td></tr><tr><td>1 %</td><td>0.14</td><td>0.13-0.15</td><td>0.16</td><td>0.17-0.16</td><td>0.02</td><td>0.02-0.02</td></tr><tr><td>3 %</td><td>0.21</td><td>0.20-0.21</td><td>0.22</td><td>0.22-0.22</td><td>0.16</td><td>0.15-0.16</td></tr><tr><td>5 %</td><td>0.29</td><td>0.28-0.29</td><td>0.28</td><td>0.27-0.28</td><td>0.34</td><td>0.34-0.35</td></tr><tr><td>9 %</td><td>0.40</td><td>0.39-0.41</td><td>0.35</td><td>0.35-0.36</td><td>0.48</td><td>0.47-0.48</td></tr><tr><td colspan="7">BP patients, n = 10</td></tr><tr><td>1 %</td><td>0.08</td><td>0.07-0.09</td><td>0.05</td><td>0.04-0.05</td><td>0.02</td><td>0.02-0.03</td></tr><tr><td>3 %</td><td>0.07</td><td>0.05-0.09</td><td>0.05</td><td>0.04-0.06</td><td>0.13</td><td>0.11-0.14</td></tr><tr><td>5 %</td><td>0.06</td><td>0.05-0.07</td><td>0.08</td><td>0.07-0.09</td><td>0.18</td><td>0.17-0.19</td></tr><tr><td>9 %</td><td>0.06</td><td>0.04-0.07</td><td>0.09</td><td>0.08-0.11</td><td>0.25</td><td>0.23-0.27</td></tr></tbody></table>

BOLD = blood oxygenation level dependent; BP = blepharospasm; CI = confidence interval, HC = healthy controls; LGN = lateral geniculate nucleus; ROI = region of interest; SC = superior colliculus; V1 = primary visual area.

**2.7. Statistical analysis**

In this study, we were first interested in the comparison of SC BOLD response following luminance modulation between BP and HC. The successive steps of visual processing in LGN and V1 were also studied. Then, a Friedman analysis with luminance contrasts as within-subjects factor for each ROI, both hemispheres together, was performed for HC and BP patients.

To test whether the luminance contrast level modified the BOLD response, in each group we performed post hoc comparisons using Wilcoxon test for each ROI. The Mann-Whitney test was used to compare between groups the response of each ROI for each luminance contrast.

We decided not to adopt a two-factor repeat model to analyze the main effect and interaction effect for the statistical analysis involving factors of between-group and within-subjects, due to the small sample size.

The number of successful detections of the central cross changes during the attentional task between the control and patients was analyzed using the Mann-Whitney test.

With respect to the sample size, based on our previous results [19,31], we considered that the effect size was sufficient to allow a reliable statistical analysis of the BOLD signal modulation in the visual structures of interest when using our specific fMRI paradigm. Consequently, we calculated a similar number of patients and controls to conduct this new fMRI study.

A p value <0.05 was considered significant. Mean and SD were used to calculate the clinical characteristics and the treatment dose of the study population. The analysis was done using the statistical software Statistica for PC version 12 and the open source software R (R Core Team, 2015).

**2.8. Data availability statement**

Anonymous data are available on reasonable request and can be provided by the guarantor author (S.M.) following the EU General Data Protection Regulation.

**3. Results**

**3.1. Study population**

Eleven women with idiopathic BP (mean ± [SD] age at the inclusion: 66.10 ± 10.00 years) were recruited between March 2019 and June

2022. One patient was excluded from the analysis because she could not perform the neuroimaging assessment. Ten age- (mean age ± [SD] 57.10 ± 12.00 years) and sex- matched HC were selected for the analysis from our previous study [31]. The two groups did not differ in terms of age (two-sample *t*-test; *p* = 0.07).

At the time of the study, the mean ± [SD] disease duration was 2.80 ± 0.52 years. All patients had a mild to moderate BP according to the JRS (mean ± [SD] severity score, 2.70 ± 0.48 and frequency score, 1.80 ± 0.42). All patients were regularly treated with botulin neurotoxin A (mean ± [SD] dose, 44.10 ± 10.50 International Units, IU). The mean ± [SD] interval from botulin toxin treatment to neuroimaging was 1.60 ± 0.35 months.

**3.2. BOLD signal responses to luminance contrast change**

The variations of the BOLD signal in function of luminance contrast for the three ROIs for HC and BP patients are shown in Table 1.

In the control group, the Friedman test showed a main effect of luminance for each ROI (SC, LGN, V1: *p* < 10⁻⁶). For BP patients, a luminance effect was observed for V1 (*p* = 10⁻⁵) but not for LGN (*p* = 0.26) and SC (*p* = 0.09).

To test whether the luminance contrast level modified the BOLD response, a post hoc comparisons using Wilcoxon test for each ROI (Table 2) was performed for each group. For HC, BOLD responses were significantly modulated for SC (*p* < 0.0002 but for 1 % vs 3 %, *p* = 0.02), for LGN (*p* < 0.00005 but for 1 % vs 3 %, *p* = 0.001), and V1 (1 % vs 3 % vs 5 % vs 9 %, *p* < 0.00005).

In the BP group, BOLD responses were significantly modulated only for V1 (1 % vs 3 % vs 5 %, *p* < 0.003, excepted for 5 % vs 9 %, *p* = 0.14).

*Controls vs patients.* When analyzing differences for each luminance contrast between controls and patients, BP people had significantly lower stimulus-induced BOLD responses at all luminance levels in both SC (1 %, *p* = 0.002; 3 %, *p* = 0.003; 5 %, *p* = 0.002; 9 %, *p* = 0.003) and LGN (1 %, *p* = 0.001; 3 %, *p* = 0.003; 5 %, *p* = 0.004; 9 %, *p* = 0.003, see Fig. 1 and Fig. 2). Concerning V1, BOLD responses were significantly lower at 5 % (*p* = 0.001) and at 9 % (*p* = 0.002) luminance level in BP patients compared to HC (Fig. 1 and Fig. 2).

Overall, in the BP group, the detected BOLD activity was lower than in the control group for the three ROIs (SC, *p* = 0.008; LGN, *p* = 0.007; V1, *p* = 0.008, Fig. 2).

**3.3. Attentional task**

The BP group performed more errors at the attentional task, i.e., no detection or misdetection of the fixation cross orientation changes, compared to controls (mean ± standard error of mean [SEM] of performance in percentage for BP patients: 11.78 ± 7.10 % vs controls = 3.90 ± 0.90 %, *p* < 0.05).

**Table 2**

<table><caption>Comparisons of mean BOLD response (Arbitrary Units) between each luminance contrast level for the three Regions of Interest for controls and BP patients.</caption><thead><tr><th rowspan="2">Luminance contrast, %</th><th colspan="2">SC</th><th colspan="2">V1</th></tr><tr><th>p</th><th></th><th>p</th><th></th></tr></thead><tbody><tr><td colspan="5">HC, n = 10</td></tr><tr><td>1 vs 3</td><td>0.02</td><td>0.001</td><td></td><td></td></tr><tr><td>3 vs 5</td><td>&lt; 0.0002</td><td>&lt; 0.00005</td><td></td><td></td></tr><tr><td>5 vs 9</td><td>&lt; 0.0002</td><td>&lt; 0.00005</td><td></td><td></td></tr><tr><td colspan="5">BP patients, n = 10</td></tr><tr><td>1 vs 3</td><td>0.02</td><td>0.5</td><td></td><td></td></tr><tr><td>3 vs 5</td><td>0.05</td><td>0.11</td><td></td><td></td></tr><tr><td>5 vs 9</td><td>0.5</td><td>0.6</td><td></td><td></td></tr></tbody></table>

BOLD = blood oxygenation level dependent; BP = blepharospasm; HC = healthy controls; LGN = lateral geniculate nucleus; ROI = region of interest; SC = superior colliculus; V1 = primary visual area.
<figure><img src="image_4.png" /><figcaption>**Fig. 1.** Average variations of the BOLD signal in the ROIs (superior colliculus: SC; lateral geniculate nucleus: LGN; and primary visual area: V1) according to the luminance contrast changes versus fixation for healthy controls (HC, *n* = 9) and blepharospasm patients (BP, *n* = 10). Left and right parts of each ROI were combined. Vertical bars indicate standard error mean. A.U. = Arbitrary Unit. \* *p* < 0.05.</figcaption></figure>

<figure><img src="image_5.png" /><figcaption>**Fig. 2.** Mean BOLD response in the ROIs (superior colliculus: SC; lateral geniculate nucleus: LGN; and primary visual area: V1) according to the luminance contrast change vs fixation for each group for healthy controls (HC, *n* = 9) and blepharospasm patients (BP, *n* = 10). Left and right parts of each ROI were combined. Vertical bars indicate standard error mean. A.U. = Arbitrary Unit. \* *p* < 0.05.</figcaption></figure>

## 4. Discussion

Using an established brain fMRI protocol, we found that there was no modulation of both the SC and LGN responses while increasing luminance contrast in people with BP compared to controls (Fig. 1 and Fig. 2). To our knowledge, this is the first brain fMRI study reporting on visual dysfunction in the SC and the LGN in BP patients.

Small brainstem structures as SC and LGN are challenging to investigate in patients, due to the difficulty in localizing them accurately with conventional brain MRI and the poor access even with functional

neurosurgery and neurophysiological techniques [36]. Indeed, the SC function in people with AOIFD has been investigated mostly indirectly, using neurophysiological studies assessing TDTs [22,37–39], and by a few brain fMRI studies in CD [23,24].

Our results are consistent with the recent hypothesis about the pathophysiology of another AOIFD such as CD, in which the SC dysfunction has been demonstrated [21–24]. The SC has a very complex structure composed of the sensory neurons of the superficial layers (SLSC) which receive direct afferents from the retinal ganglion cells through the retinotectal pathway in response to changes in luminance
and movement in the visual field, and by the pre-motor neurons of the deep layers (DLSC) which project to the generating center of the ocular saccades of the brainstem and to the tectospinal and tecto-reticulospinal pathways [40]. Beyond the retina, the SC receives a large array of inputs from cortical visual areas, including the primary visual cortex [41].

The SLSC and the DLSC are modulated by a population of GABA (gamma-aminobutyric acid)-ergic interneurons [42]. Specifically, both the SLSC and DLSC are tonically inhibited by the GABA-ergic outflow from the striatum via the substantia nigra pars reticulata (SNpr) (Fig. 3A) [43,44]. The tecto-reticulospinal and tectospinal pathways that originate at the DLSC could affect the facial, bulbar, arm, and hand muscles [45], and, therefore, be involved in the genesis of cranial and focal hand dystonia. Indeed, abnormal TDT was found in all these focal dystonias, suggesting that similar underlying pathogenic mechanisms may be evoked [37,38,46].

Similarly to the hypothesis advanced for CD [21], we suggest that BP is caused by secondary disinhibition due to a deficit of the GABA-ergic activity both from the SNpr and within the SC, resulting in the hyper-activation of eyelids muscles (Fig. 3B).

Furthermore, patients with BP showed hyperactivity in the orbicu-
laris muscle of the eyelids compared to controls [37]. One reason may be
the abnormal increase in the blink reflex to visual stimuli, which is
controlled by the complex multi-synaptic network of the brainstem-
basal ganglia nuclei, involving the retinotectal and tecto-reticulospinal
pathways. Consequently, the SC could be involved in the networks of
the blink reflex in response to visual stimuli, participating in the path-
ogenesis of BP, given its role as a multimodal sensory-motor integration
structure. Moreover, SC dysfunction could also explain the hyperexcit-
ability of the blink reflex in response to sensory and auditory stimuli that
has been described in BP [47,48].

We also found an abnormal response to the visual stimuli in the LGN of BP patients (see Fig. 1 and Fig. 2). The LGN was not modulated by lower luminance contrasts from 1 % to 3 % in BP, although it showed a trend to modulation from 3 % to 9 %.

To our knowledge, this is the first report of abnormal responses of the
LGN to luminance.

contrast in BP. These findings may suggest that this structure is also
involved in the BP pathophysiology. Brainstem connections of LGN with
SC and basal ganglia loop and with visual cortex [49] may explain LGN
pathological responses mostly secondary to SC dysfunction in BP pa-
tients (Fig. 3B).

Concerning V1 responses in BP patients, we found a lower BOLD
response at higher luminance contrasts (5 % and 9 %) compared to
controls, suggesting an abnormal activity also in V1 (Fig. 1). The
involvement of V1 mostly at higher luminance levels in our patients
could be downstream of the decreased activation of the LGN and SC.

The significant reduction in BOLD activity in all the three

investigated structures (SC, LGN, and V1), and for each luminance
contrast compared to controls further supports their involvement in the
pathogenesis of BP.

Interestingly, our findings of SC and LGN visual dysfunction in BP are similar to those found in de novo PD patients [19]. This is not surprising since the pathogenesis of both diseases involves basal ganglia network dysfunctions. However, in contrast with BP, V1 responses in PD are similar to controls [50], suggesting a greater implication of V1 in BP than in PD.

Finally, BP patients showed a lower performance in the attentional task compared to controls. This finding further supports the SC dysfunction in BP, as it is also largely involved in several attention and decision making tasks [51].

Our study has some limitations. First, the sample size was small. However, this was a pilot study as no previous data have been published on the SC in BP. Moreover, the minimum number of subjects to be included in an fMRI study is variable and depends on the size of the effect being measured, that is a priori unknown and usually small. We could not separate the activity of the superficial or intermediate/deep SC layers that have different functions and connectivity, due to methodological considerations (i.e., the size and number of the voxels).

Second, data were not collected and analyzed in a blinded fashion. Furthermore, blink-related artefacts during the fMRI session could have affect the data acquisition. Finally, botulin toxin treatment could have modulate the function of the investigated midbrain and cortical structures by altering visual and sensory input [50].

More larger, multicentric studies are needed to confirm our pre-
liminary results.

5. Conclusions

This is the first report, to our knowledge, of visual dysfunction of both SC and LGN in BP. We found a lack of modulation of the SC and LGN BOLD responses to increasing luminance contrasts in BP patients compared to controls. We speculate that SC and LGN dysfunction in idiopathic BP is secondary to a deficit in GABA-ergic activity, both from the SNpr and within the SC. As such, brain fMRI targeting SC and LGN, could play an important role both as a biomarker and in our understanding of the pathophysiology of AOIFD.

Authors’ role

SM and EM contributed to the conception and design of the study; SM, PP, CC, MD contributed to the acquisition and analysis of data; SM, MD, EM, MH contributed to drafting the text and preparing the figures.

<figure><img src="image_6.png" /><figcaption>**Fig. 3.** Illustration of main neuroanatomical networks involving the superior colliculus (SC), the lateral geniculate nucleus (LGN), the cortex and the basal ganglia loop, in the physiological condition (A), and in the pathological condition of blepharospasm (B). BP = blepharospasm; SNpc = substantia nigra pars compacta; SNpr = substantia nigra pars reticulata; V1 = primary visual area.</figcaption></figure>
## Financial disclosures of all authors in the last 12 months

S.M. has received research support from Grenoble Alpes University. M.D., M.H., P.P., C.C have no disclosures.

E.M. has received honoraria from Medtronic as consultant and research support from Ipsen, France Parkinson's and the Grenoble Alpes University.

## Funding sources

No funding sources to declare.

## CRediT authorship contribution statement

**Sara Meoni:** Writing – review & editing, Writing – original draft, Investigation, Conceptualization.
**Michel Dojat:** Writing – original draft, Methodology, Investigation, Formal analysis.
**Michael Hutchinson:** Writing – review & editing.
**Pierre Pelissier:** Data curation.
**Christophe Chiquet:** Investigation.
**Elena Moro:** Writing – review & editing.

## Declaration of competing interest

None.

## Acknowledgments

This work was partly supported by a grant from AMADYS (France). The Grenoble MRI facility IRMaGe was partly funded by the French program ‘Investissement d'Avenir' run by the Agence Nationale pour la Recherche (ANR-11-INBS-0006). We thank all the patients and healthy subjects for their participation to the study.

## Appendix A. Supplementary data

Supplementary data to this article can be found online at https://doi.org/10.1016/j.jns.2024.123272.

## References

[1] A. Albanese, K. Bhatia, S.B. Bressman, et al., Phenomenology and classification of dystonia: a consensus update, Mov. Disord. 28 (7) (2013) 863-873.

[2] G. Defazio, M. Esposito, G. Abbruzzese, et al., The Italian dystonia registry: rationale, design and preliminary findings, Neurol. Sci. 38 (5) (2017) 819-825.

[3] G. Defazio, M. Hallett, H.A. Jinnah, A. Conte, A. Berardelli, Blepharospasm 40 years later, Mov. Disord. 32 (4) (2017) 498-509.

[4] G. Defazio, H.A. Jinnah, A. Berardelli, et al., Diagnostic criteria for blepharospasm: a multicenter international study, Parkinsonism Relat. Disord. 91 (2021) 109-114.

[5] G. Defazio, A.F. Gigante, M. Hallett, et al., Motor and psychiatric features in idiopathic blepharospasm: a data-driven cluster analysis, Parkinsonism Relat. Disord. 104 (2022) 94-98.

[6] L.M. Scorr, H.J. Cho, G. Kilic-Berkmen, et al., Clinical features and evolution of Blepharospasm: a multicenter international cohort and systematic literature review, Dystonia 1 (2022) 10359.

[7] L.M. Levy, M. Hallett, Impaired brain GABA in focal dystonia, Ann. Neurol. 51 (1) (2002) 93-101.

[8] S. Tisch, P. Limousin, J.C. Rothwell, et al., Changes in blink reflex excitability after globus pallidus internus stimulation for dystonia, Mov. Disord. 21 (10) (2006) 1650-1655.

[9] Y.-Z. Huang, J.C. Rothwell, C.-S. Lu, J. Wang, R.-S. Chen, Restoration of motor inhibition through an abnormal premotor-motor connection in dystonia, Mov. Disord. 25 (6) (2010) 696-703.

[10] G. Kranz, E.A. Shamim, P.T. Lin, G.S. Kranz, M. Hallett, Transcranial magnetic brain stimulation modulates blepharospasm: a randomized controlled study, Neurology 75 (16) (2010) 1465-1471.

[11] J. Valls-Sole, G. Defazio, Blepharospasm: update on epidemiology, clinical aspects, and pathophysiology, Front. Neurol. 7 (2016) 45.

[12] M.M. Mascia, S. Dagostino, G. Defazio, Does the network model fits neurophysiological abnormalities in blepharospasm? Neurol. Sci. 41 (8) (2020) 2067-2079.

[13] A. Conte, G. Defazio, M. Mascia, D. Belvisi, P. Pantano, A. Berardelli, Advances in the pathophysiology of adult-onset focal dystonas: recent neurophysiological and neuroimaging evidence, F1000Res 9 (2020) F1000. Faculty Rev-67.

[14] E. Comoli, V. Coizet, J. Boyes, et al., A direct projection from superior colliculus to substantia nigra for detecting salient visual events, Nat. Neurosci. 6 (9) (2003) 974-980.

[15] P.J. May, J.G. McHaffie, T.R. Stanford, et al., Tectonigral projections in the primate: a pathway for pre-attentive sensory input to midbrain dopaminergic neurons, Eur. J. Neurosci. 29 (3) (2009) 575-587.

[16] M. Rolland, C. Carcenac, P.G. Overton, M. Savasta, V. Coizet, Enhanced visual responses in the superior colliculus and subthalamic nucleus in an animal model of Parkinson's disease, Neuroscience 252 (2013) 277-288.

[17] D.A. Hopkins, L.W. Niessen, Substantia nigra projections to the reticular formation, superior colliculus and central gray in the rat, cat and monkey, Neurosci. Lett. 2 (5) (1976) 253-259.

[18] P. Redgrave, V. Coizet, E. Comoli, et al., Interactions between the midbrain superior colliculus and the basal ganglia, Front. Neuroanat. (2010) 4.

[19] E. Moro, E. Bellot, S. Meoni, et al., Visual dysfunction of the superior colliculus in De novo parkinsonian patients, Ann. Neurol. 87 (4) (2020) 533-546.

[20] E. Bellot, L. Kauffmann, V. Coizet, S. Meoni, E. Moro, M. Dojat, Effective connectivity in subcortical visual structures in de novo patients with Parkinson's disease, Neuroimage Clin 33 (2022) 102906.

[21] M. Hutchinson, T. Isa, A. Molloy, et al., Cervical dystonia: a disorder of the midbrain network for covert attentional orienting, Front. Neurol. 5 (2014) 54.

[22] L. Williams, J.S. Butler, M. Thirkettle, et al., Slowed luminance reaction times in cervical dystonia: disordered superior colliculus processing, Mov. Disord. (2020).

[23] E.M. Mc Govern, O. Killian, S. Narasimham, et al., Disrupted superior collicular activity may reveal cervical dystonia disease pathomechanisms, Sci. Rep. 7 (1) (2017) 16753.

[24] S. Rafee, M. Hutchinson, R. Reilly, The Collicular-Pulvinar-amygdala Axis and adult-onset idiopathic focal Dystonasias, Adv Neurobiol 31 (2023) 195-210.

[25] X.-F. Huang, M.-R. Zhu, P. Shan, et al., Multiple neural networks malfunction in primary Blepharospasm: an independent components analysis, Front. Hum. Neurosci. 11 (2017) 235.

[26] M.-F. Ni, X.-F. Huang, Y.-W. Miao, Z.-H. Liang, Resting state fMRI observations of baseline brain functional activities and connectivities in primary blepharospasm, Neurosci. Lett. 660 (2017) 22-28.

[27] G. Battistella, P. Termsarasab, R.A. Ramdhani, S. Fuertinger, K. Simonyan, Isolated focal dystonia as a disorder of large-scale functional networks, Cereb. Cortex 27 (2) (2017) 1203-1215.

[28] J. Wei, S. Wei, R. Yang, et al., Voxel-mirrored homotopic connectivity of resting-state functional magnetic resonance imaging in Blepharospasm, Front. Psychol. 9 (2018) 1620.

[29] P. Nguyen, D. Kelly, A. Glickman, et al., Abnormal neural responses during reflexive blinking in Blepharospasm: an event-related functional MRI study, Mov. Disord. 35 (7) (2020) 1173-1180.

[30] A. Glickman, P. Nguyen, E. Shelton, D.A. Peterson, B.D. Berman, Basal ganglia and cerebellar circuits have distinct roles in blepharospasm, Parkinsonism Relat. Disord. 78 (2020) 158-164.

[31] E. Bellot, V. Coizet, J. Warnking, K. Knoblauch, E. Moro, M. Dojat, Effects of aging on low luminance contrast processing in humans, Neuroimage 139 (2016) 415-426.

[32] J. Jankovic, J. Orman, Botulinum a toxin for cranial-cervical dystonia: a double-blind, placebo-controlled study, Neurology 37 (4) (1987) 616-623.

[33] K.A. Schneider, S. Kastner, Visual responses of the human superior colliculus: a high-resolution functional magnetic resonance imaging study, J. Neurophysiol. 94 (4) (2005) 2491-2503.

[34] P.A. Yushkevich, J. Piven, H.C. Hazlett, et al., User-guided 3D active contour segmentation of anatomical structures: significantly improved efficiency and reliability, Neuroimage 31 (3) (2006) 1116-1128.

[35] J. Ashburner, K.J. Friston, Unified segmentation, Neuroimage 26 (3) (2005) 839-851.

[36] W. Thevathasan, E. Moro, What is the therapeutic mechanism of pedunculopontine nucleus stimulation in Parkinson's disease? Neurobiol. Dis. 128 (2019) 67-74.

[37] M. Fiorio, M. Tinazzi, L. Bertolasi, S.M. Aglioti, Temporal processing of visuotactile and tactile stimuli in writer's cramp, Ann. Neurol. 53 (5) (2003) 630-635.

[38] M. Fiorio, M. Tinazzi, A. Scontrini, et al., Tactile temporal discrimination in patients with blepharospasm, J. Neurol. Neurosurg. Psychiatry 79 (7) (2008) 796-798.

[39] A. Conte, E.M. McGovern, S. Narasimham, et al., Temporal discrimination: mechanisms and relevance to adult-onset dystonia, Front. Neurol. 8 (2017) 625.

[40] B.J. White, S.E. Boehnke, R.A. Marino, L. Itti, D.P. Munoz, Color-related signals in the primate superior colliculus, J. Neurosci. 29 (39) (2009) 12159-12166.

[41] C.M. Cerkevich, D.C. Lyon, P. Balaram, J.H. Kaas, Distribution of cortical neurons projecting to the superior colliculus in macaque monkeys, Eye Brain 2014 (2014) 121-137.

[42] Y. Okada, The distribution and function of gamma-aminobutyric acid (GABA) in the superior colliculus, Prog. Brain Res. 90 (1992) 249-262.

[43] O. Hikosaka, R.H. Wurtz, Visual and oculomotor functions of monkey substantia nigra pars reticulata. IV. Relation of substantia nigra to superior colliculus, J. Neurophysiol. 49 (5) (1983) 1285-1301.

[44] G. Chevalier, J.M. Deniau, Disinhibition as a basic process in the expression of striatal functions, Trends Neurosci. 13 (7) (1990) 277-280.

[45] E. Perkins, S. Warren, P.J. May, The mesencephalic reticular formation as a conduit for primate collicular gaze control: tectal inputs to neurons targeting the spinal cord and medulla, Anat Rec (Hoboken) 292 (8) (2009) 1162-1181.

[46] O. Kimmich, D. Bradley, R. Whelan, et al., Sporadic adult onset primary torsion dystonia is a genetic disorder by the temporal discrimination test, Brain 134 (Pt 9) (2011) 2656-2663.
[47] J. Müller, M. Rinnerthaler, W. Poewe, M. Kofler, Auditory startle reaction in primary blepharospasm, Mov. Disord. 22 (2) (2007) 268–272.

[48] G. Benbir, M.E. Kiziltan, Blink reflex studies in postparalytic facial syndrome and blepharospasm: trigeminal and extratrigeminal somatosensory stimulation, J. Clin. Neurophysiol. 31 (6) (2014) 535–540.

[49] W.M. Usrey, H.J. Alitto, Visual functions of the thalamus, Annu Rev Vis Sci 1 (2015) 351–371.

[50] A. Jochim, Y. Li, G. Gora-Stahlberg, et al., Altered functional connectivity in blepharospasm/orofacial dystonia, Brain Behav. 8 (1) (2018) e00894.

[51] M.A. Basso, P.J. May, Circuits for action and cognition: a view from the superior colliculus, Annu Rev Vis Sci 3 (2017) 197–226.