Primary blepharospasm (BSP) is a common focal dystonia disorder characterized by intermittent or persistent involuntary eye closure (1). Although recognized as a movement disorder, various studies have shown that abnormal sensory processing plays an important role in the pathophysiology of BSP (2). Local sensory symptoms, such as burning sensation in the eye, photophobia and dry eye, may precede the onset of motor symptoms (3). Patients with BSP show an increased somatosensory temporal discrimination threshold (STDT) (4). The increased STDT values remain unmodified with worsened disease severity (5). Sensory tricks, also called “geste antagoniste,” are voluntary maneuvers that alleviate the severity of abnormal movement or postures in dystonia patients (6). Sensory tricks are a cardinal feature of many forms of focal dystonia, especially common in cervical dystonia but also present in BSP, oromandibular dystonia, and writer's cramp (7). According to a survey, sensory tricks can occur in up to 71.2% of patients with BSP (8). A more frequently reported trick is using the index finger and/or thumb to touch the upper eyelid (6). Other tricks include wearing tinted lenses, singing, talking, or chewing gum (9). In animal experiments, altering the sensory input by a peripheral injury can elicit involuntary blinking and eyelid spasms in predisposed animals (10), further indicating the regulatory role of the sensory system in BSP.

The pathophysiological mechanisms of BSP are not clear. Alterations of synaptic plasticity, including disruption of homeostatic plasticity, widespread facilitation of synaptic potentials, and loss of synaptic inhibitory processes, are currently considered endophenotypic features of focal dystonia (11, 12). Abnormal sensorimotor integration functions may be related to maladaptive plasticity phenomena, which can contribute to the co-contraction of antagonistic muscle groups involved in the onset of dystonic movements (13, 14).

The startle reflex is a rapid and involuntary motor response triggered by a sudden and intense sensory stimulus (e.g., sound, electricity, or touch) (15). The startle reflex typically manifests as an eyeblink response (blink reflex) in humans and as a whole-body motor response in animals (16, 17). Prepulse inhibition (PPI) occurs when a weak prestimulus (prepulse) 30–500 ms before the startling stimulus significantly inhibits the startle reflex (18). PPI of the blink reflex causes inhibition of the R₂ magnitude, while short interstimulus intervals (ISIs) increase the amplitude of R₁ (19). Prepulse inhibition is believed to be a model of sensorimotor gating across taxa (20). Numerous studies have confirmed that PPI impairment is an important feature of several psychiatric disorders, including schizophrenia and obsessive-compulsive disorder (21, 22). In recent years, PPI impairment has also been observed in movement disorders such as Parkinson's disease (23), cervical dystonia (24), and BSP (25). Previous studies have shown that PPI is most pronounced at 120 ms in healthy populations (26, 27), but no studies have been conducted in healthy populations and patients with dystonia in China or Asia.

Therefore, in the present study, we analyzed PPI at different ISIs in healthy Chinese populations, compared PPI impairment characteristics between BSP patients and healthy controls, and examined the correlations of PPI impairment with disease duration and motor symptom severity in BSP patients. We aimed to elucidate the neurophysiological mechanisms of sensorimotor gating impairment in BSP patients and to provide an objective basis for identifying biological markers, guiding treatment, and evaluating the prognosis.

Trials with artifacts were excluded. In each trial, we identified the ipsilateral R₁, R₂, and the contralateral R_2c of the blink reflex.

We used the area under the curve to represent the magnitude of the R₂ and R_2c components of each blink reflex. Following the baseline and prepulse trials, we recorded the R₁ latency and peak-to-peak amplitude as well as the bilateral R₂ latencies and areas under the curve. The percentage change in R₂ area was the magnitude of the PPI effect (hereafter, PPI size), and the formula was PPI size (in %) = [1 – R₂ area at prepulse trials (120, 200, or 300 ms)/R₂ area at baseline trials] × 100%.

Data analysis was performed using SPSS 25.0 (SPSS, Chicago, IL, USA). The normality of data was tested using the Shapiro-Wilk test. Age, gender, and sensory thresholds for supraorbital nerve stimulation and prepulse stimulus were compared between the BSP and HC groups using the independent-sample t-test for quantitative data and Mann-Whitney U-test for qualitative data and non-normally distributed data. The presence of sensory tricks was expressed as a percentage of the total number of BSP patients. Disease duration and JRS score were presented as the mean ± standard deviation (SD).

We compared PPI size at different ISIs in HCs using the one-way analysis of variance. The ipsilateral R₁ latency and amplitude, bilateral R₂ latencies and areas at baseline and prepulse trials, and PPI size at different ISIs were compared separately between BSP patients and HCs with the Mann-Whitney U-test for non-normally distributed data, and the independent-sample t-test for normally distributed data. We also used the Wilcoxon rank-sum test for non-normally distributed data and a paired-sample t-test for normally distributed data to compare within-group differences in the ipsilateral R₁ latency and amplitude, bilateral R₂ latencies and areas at baseline and prepulse trials.

We further divided BSP patients into those with sensory tricks (ST group) and those without sensory tricks (NST group) and compared the PPI size of two subgroups. All data obtained above were expressed as the mean ± SD. The correlations of PPI size with disease duration and JRS score in the BSP group were analyzed with Pearson correlation analysis.

All p-values < 0.05 was considered a significant difference.

To our knowledge, this is the first study of PPI impairment in BSP patients from a Chinese population. Previous European studies have shown that PPI size in healthy populations is generally above 60% (24, 31). In contrast, the present study reported a smaller PPI of about 40%. Additionally, previous studies have shown that PPI is most pronounced at 120 ms in healthy populations (26, 27), but in our research, PPI size appeared to be greater at 200 ms. The differences in ethnicity may contribute to the discrepancy of results, in addition to age and gender structures (27, 32, 33). Furthermore, we found that impaired PPI in BSP patients also occurred at ISIs of 200 and 300 ms, and the R₁ amplitude facilitation and bilateral R₂ latencies prolongation were absent in BSP patients, which above was not explored in previous studies (25, 34).

A supraorbital nerve stimulation induces two primary responses in the orbicularis oculi: an early ipsilateral component (R₁) and a late bilateral component (R₂) (35). The R₁ originates from an oligosynaptic pontine circuit, while the R₂ is mediated by multisynaptic pontomedullary connections (36). The main anatomical structures responsible for PPI are located in the brainstem, as PPI can still be observed in decerebrate animals (37). The central structure may be the connection between the pedunculopontine tegmental nucleus (PPTN) and the caudal pontine reticular nucleus (38). Although PPI occurs in the brainstem, it is also subject to top-down modulation by forebrain regions (39, 40). In the present study, the unconditioned blink reflex did not differ between BSP patients and HCs, indicating the integrity of the brainstem circuits. Abnormal top-down modulation from the prefrontal lobe projections to the pontine reflex circuits may be the reason for impaired PPI. Previous studies have found an abnormal blink reflex recovery cycle in BSP patients, confirming hyperexcitability of the trigemino-facial circuits (41). In our study, impaired PPI in BSP patients suggests abnormal inhibitory modulation at the cortical and subcortical levels may also contribute to the hyperexcitability of the trigemino-facial circuits.

Early animal studies have identified a cortico-subcortical pathway from the brainstem that mediates PPI, called the cortico-pallidum-thalamic (CSPT) circuit (42). Neuroimaging studies demonstrated the involvement of the frontal and parietal cortical regions, striatum, hippocampus and thalamus in PPI (43). In recent years, studies have reported abnormal activation and functional connectivity in the frontal and parietal cortex, basal ganglia, and cerebellar in BSP (44). In addition, cerebellar continuous theta burst stimulation can improve motor symptoms in patients with dystonia (45, 46). It has been suggested that PPTN had a reciprocal association with basal ganglia (47). The PPTN also participated in muscle tone regulation (48). Therefore, PPTN may play a role in the dysregulation of PPI in BSP. Our previous studies also showed abnormal functional connectivity of sensorimotor networks and regulatory networks involving the frontal lobe in BSP (49). Thus, impairment of central nervous system inhibition may lead to excessive motor output, and abnormal cortical and subcortical regulation may also contribute to the abnormal PPI in BSP.

We demonstrated that PPI impairment is greater in BSP patients without sensory tricks, similar to the results of previous studies (25). Gomez-Wong et al. found that the R₂ magnitude of the blink reflex was reduced when a sensory trick was induced by a light touch on the eyelids and periorbital areas of the face in BSP patients, suggesting that sensory tricks may serve as a prepulse stimulus to modulate the activity of the trigeminal-facial circuits and thus ameliorate spasm (50). According to the “sensory-motor integration” theory, the abnormal excitation in the primary motor cortex may be due to excessive signal afferents in the primary somatosensory cortex, a phenomenon known as “sensory overflow (51).” PPI may inhibit sensory information overload through sensorimotor gating mechanisms (20). Our previous functional magnetic resonance imaging study reported a relatively preserved function of the supplementary motor in BSP patients with sensory tricks (49). Thus, the relatively normal PPI in BSP patients with sensory tricks reflects the relative preservation of sensory information processing and the ability to regulate abnormal trigemino-facial circuits excitability.

Additionally, we showed that PPI was not associated with the severity or duration of BSP, indicating abnormal PPI may represent a premorbid feature. Such PPI impairment was found not only in BSP but in cervical dystonia (24), thus may be a potential pathogenesis of dystonia.

Although we found that PPI seemed to be more pronounced at 200 ms, there was no significant difference. Besides, our study has some other limitations. We failed to explore PPI at ISIs lower than 100 ms due to equipment limitations. Considering the small sample size, we were unable to provide a subgroup analysis according to the variability of clinical symptoms, such as increased blinking and apraxia of eyelids opening.

In conclusion, we found that PPI was impaired in BSP patients at three different ISIs. Patients with sensory tricks had better PPI than those without sensory tricks. The sensory tricks phenomenon may represent either the relative integrity of sensorimotor gating pathways or a compensatory mechanism. We may thus speculate that the underlying pathophysiology of abnormal cortical/subcortical regulation mechanisms of sensorimotor gating and abnormal brainstem excitatory pathways may play an important role in BSP.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by the Ethics Committee of the First Affiliated Hospital of Dalian Medical University [identification number: PJ-KS-KY-2022-134(X)]. The patients/participants provided their written informed consent to participate in this study.

ZL and CS were responsible for recruiting and screening eligible subjects. XY and HYW completed the study registration and obtained informed consent. RL collected clinical information. XHa and XHu designed and conducted the experiment. XHa wrote the paper, designed the tables, and drew the images. All authors have made meaningful revisions to the paper.