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. 2017 Dec 1;7(1):16753.
doi: 10.1038/s41598-017-17074-x.

Disrupted Superior Collicular Activity May Reveal Cervical Dystonia Disease Pathomechanisms

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Free PMC article

Disrupted Superior Collicular Activity May Reveal Cervical Dystonia Disease Pathomechanisms

Eavan M Mc Govern et al. Sci Rep. .
Free PMC article

Abstract

Cervical dystonia is a common neurological movement disorder characterised by muscle contractions causing abnormal movements and postures affecting the head and neck. The neural networks underpinning this condition are incompletely understood. While animal models suggest a role for the superior colliculus in its pathophysiology, this link has yet to be established in humans. The present experiment was designed to test the hypothesis that disrupted superior collicular processing is evident in affected patients and in relatives harbouring a disease-specific endophenotype (abnormal temporal discrimination). The study participants were 16 cervical dystonia patients, 16 unaffected first-degree relatives with abnormal temporal discrimination, 16 unaffected first-degree relatives with normal temporal discrimination and 16 healthy controls. The response of participant's superior colliculi to looming stimuli was assessed by functional magnetic resonance imaging. Cervical dystonia patients and relatives with abnormal temporal discrimination demonstrated (i) significantly reduced superior collicular activation for whole brain and region of interest analysis; (ii) a statistically significant negative correlation between temporal discrimination threshold and superior collicular peak values. Our results support the hypothesis that disrupted superior collicular processing is involved in the pathogenesis of cervical dystonia. These findings, which align with animal models of cervical dystonia, shed new light on pathomechanisms in humans.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Figure 1
Figure 1
Participants’ temporal discrimination threshold Z-scores: Temporal discrimination threshold (TDT) Z-scores in 16 patients, 32 relatives and 16 healthy controls. The black open circles represent individual TDT Z-scores. An abnormal TDT Z-score was defined ≥2.5 standard deviations above the age- and sex- matched population mean. The dashed-red line denotes a TDT Z-score of 2.5. All sixteen cervical dystonia patients had TDT Z-scores ≥ 2.5, 16 unaffected relatives had a TDT Z-score ≥ 2.5 (relatives with abnormal TDT), 16 unaffected relatives had a TDT Z-score ≤ 2.5 (relatives with normal TDT) and all 16 healthy controls had a TDT Z-score ≤ 2.5.
Figure 2
Figure 2
Whole brain analysis of superior collicular activation to visual stimuli: (A) Whole brain, whole group 2nd level general linear model (GLM) analysis in all 64 participants (16 patients, 32 unaffected relatives, 16 healthy controls) for the following basic contrasts: loom, recede, random, structured movement (loom & recede) and all visual (loom, recede & random). Coronal brain images are displayed. Slices were selected to highlight peak superior collicular activity. A Family wise error corrected p-value < 0.05 is used. K = cluster size. A significant and focal activation of both superior colliculi is seen for the loom condition (K = 69, p < 0.002). The recede random and structured movement conditions failed to demonstrate statistically significant clusters at superior collicular level. (B) Segmented group 2nd level GLM analysis brain analysis in 32 participants with abnormal temporal discrimination thresholds (TDTs) (16 cervical dystonia patients and 16 relatives with abnormal TDTs) and 32 participants with normal TDTs (16 relatives and 16 control participants with normal TDTs). A statistically significant cluster at superior collicular level is observed for the looming condition in the normal TDT group. In the abnormal TDT group, no statistically significant clusters were observed within the superior colliculus boundary for the loom, recede or random condition.
Figure 3
Figure 3
Whole brain, whole group analysis for the three different contrasts. Whole brain, whole group 2nd level general linear model (GLM) analysis in 32 participants with normal temporal discrimination threshold (TDT) and 32 participants with abnormal TDT for the following three contrasts are presented; Aa = Loom > Random (normal TDT); Ab = Loom > Random (abnormal TDT); Ba = Loom > Recede (normal TDT); Bb = Loom > Recede (abnormal TDT); Ca = Recede > Random (normal TDT); Recede > Random (abnormal TDT). A Family wise error corrected p-value < 0.05 is used. TDT = temporal discrimination threshold. K = cluster size. BA = Broadmann’s area. Statistically significant clusters were observed in the following areas for each of the contrasts: Aa = Left BA19 (K = 1151, p < 0.000), Right visual association cortex (K- 757, p < 0.001), Right superior colliculus (K=299, p < 0.05). Ab = Left fusiform gyrus (K = 5374, p < 0.000), Right BA19 (K = 2122, p < 0.000), Right thalamus (K = 312, p < 0.018). Ba = Right BA7 (K = 5196, p < 0.000), Left occipital cortex (K = 372, p < 0.038) Left visual association cortex (K = 372, p < 0.038). Bb = Left sensory association area (K = 27, p < 0.001), Right BA39 (K = 95, p < 0.000), Right BA7 (K = 27, p < 0.001). Ca = Right visual association cortex (K = 16078, p < 0.000), Cb = Right visual association cortex (K = 427, p < 0.000).
Figure 4
Figure 4
Event related time courses: (A) Event-related time course for the superior colliculus during the loom and random condition in two candidate subjects: one relative with abnormal temporal discrimination threshold (TDT) and one relative normal TDT. Red solid line = looming condition in a relative with normal TDT; black solid line = looming condition in a relative with normal TDT; red dashed line = random condition in a relative with abnormal TDT; black dashed line = random condition in a relative with abnormal TDT. In the relative with normal TDT, the peak percent signal change is observed at 4 seconds for the loom condition. This peak percent signal change for the loom condition was reversed in the relative with an abnormal TDT. (B) Loom > random peak signal in all 64 participants: 32 participants with abnormal TDT (patients and unaffected relatives) and 32 participants with normal TDT (unaffected relatives and healthy controls). Each circle represents an individual’s peak signal for the loom > random contrast. A significant difference was observed in the peak signal for the loom > random contrast between the abnormal TDT group (M = −0.092, SD = 0.266) and the normal TDT group [M = 0.076, SD = 0.17; t(52) = 3.0, p = 0.004]. The magnitude of the differences in the means was very large (eta squared = 0.14).
Figure 5
Figure 5
Correlation analysis: Pearson’s product moment correlation-coefficient analysis examining the relationship between superior collicular peak percent signal change for the loom > random contrast and temporal discrimination threshold (TDT) Z-score. Each open black circle represents one of the 64 participants; TDT Z-scores are plotted on the x-axis; the peak percent signal change observed for the loom > random contrast is plotted on the y-axis. The analysis shows a statistically significant negative correlation between the loom > random contrast and TDT Z-score [r = − 0.25, n = 62, p < 0.04], with lower levels of superior collicular activation associated with a higher (abnormal) TDT Z-score.
Figure 6
Figure 6
Experimental visual stimulus paradigm. Screen capture of the sequence of events that occurs during each of the three conditions incorporated into the experimental paradigm. The colour of the vertical lines indicates the trial type: loom (green), recede (yellow), random (blue). In the looming-motion condition, the size of the sphere expands during motion towards the outer vertical lines before disappearing. The receding-motion condition is the reverse of the looming-motion condition; the sphere begins at its maximum diameter and contracts towards the inner vertical lines before disappearing. The random-motion condition consists of an unchanging sphere volume with randomly moving points that maintain the same velocity of the previous conditions.
Figure 7
Figure 7
Region of interest anatomical definition: (A) Human cadaver brainstem specimen used during a neuro-pathological dissection. A consultant neuropathologist dissected the brainstem specimen and identified the anatomical landmarks of the left and right superior colliculi. The diameter of each superior colliculus was measured and noted to be 7 mm. (B) Superior collicular 3-D regions of interest on T1-weighted structural brain images. Three radiological views are shown; axial, coronal and sagittal respectively. Mango image processing software (Lancaster, Martinez; www.ric.uthscsa.edu/mango) was used to create the 3-D regions of interest using pre-defined anatomical boundaries from the neuro-pathological dissection.

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