測定・頸部ジストニアに適用される時間の弁別閾値の解析

Measurement and analysis of the temporal discrimination threshold applied to cervical dystonia. Detection of environmental change is key to survival. Our ability to perceive such change and react quickly depends on a network within the midbrain.

This important network issues motor commands and responds to environmental change and directs our attention in a reflexive manner. The term temporal discrimination describes a person's ability to discriminate or perceive rapid changes in their environment. The goal of this article is to present two methods for the measurement and analysis of temporal discrimination and to demonstrate the application of this technique to the study of cervical dystonia.

The temporal discrimination threshold is the shortest time interval at which an observer can discriminate between two asynchronous stimuli and perceives them as occurring separately. Temporal discrimination has been shown to be abnormal or prolonged in disorders affecting the basal ganglia including dystonia. Dystonia is the third most common movement disorder after Parkinson's disease and essential tremor.

It is characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive movements or postures. The pathogenesis of cervical dystonia remains unknown. Dystonia can affect any part of the body.

When it affects one body part, it is known as focal dystonia. Dystonia affecting the neck muscles is known as cervical dystonia and is the most common form of adult-onset focal dystonia. The temporal discrimination threshold is being measured in individuals with cervical dystonia, their unaffected relatives, and healthy controls.

It is believed that this technique can provide insight into the activity of the visual sensory neurons in the superficial layers of the superior colliculus and that this insight can perhaps provide clues as to the underlying pathomechanisms of cervical dystonia. The visual stimuli, two yellow LEDs, are encased in custom-built hardware solutions that enable the stimuli to be presented with the desired millisecond interstimulus intervals. Two hardware options have been developed.

The first is the traditional laboratory-based tabletop method in which the LEDs are positioned seven degrees from the subject's center point on the left and right sides. This experiment is conducted in a darkened room. The second hardware solution is a portable headset which enables testing at any location.

This hardware solution provides consistency in distance and angles between stimuli and participant. Following presentation of each stimulus pair, the participant responds same or different depending on whether they perceive the stimuli to be synchronous or asynchronous. The standard approach to stimulus presentation is a staircase approach.

This method involves presenting the individual with progressively asynchronous stimuli. Stimuli are presented every five seconds with the interstimulus interval increasing by five milliseconds each time. The trial ends when a participant responds different for three consecutive pairs of stimuli.

The experiment is repeated four times on the left and right resulting in a total of eight runs. The temporal discrimination threshold is calculated by taking the median of the thresholds from each of the eight runs for that individual. Due to a potential learning effect in the staircase method, we developed a method of randomized presentation order.

The stimuli pairs are still presented every five seconds, but the interstimulus interval varies in a randomized fashion from zero to 100 milliseconds. The standard method of analyzing temporal discrimination data results in a single value expressed in milliseconds. We use this value to calculate the zed score for each individual.

The zed score is defined as the difference between the participant's Temporal Discrimination Threshold or TDT value and the mean TDT from an age-matched control population divided by the standard deviation of the TDT values for that control population. TDT values resulting in zed scores above 2.5 are deemed to be abnormal. While this approach has been widely used and the TDT has been shown to be a strong and selective endophenotype, it is nonetheless a single value.

To fully characterize a participant's data, we expanded our analysis to fit their data to a cumulative Gaussian distribution. The mean of this distribution represents the point at which participants are equally likely to respond same or different. This point is referred to as the Point of Subjective Equality.

The standard deviation of the Gaussian distribution, also referred to as the Just Noticeable Difference, indicates how sensitive participants are to changes in temporal asynchrony around their mean. The method is strengthened by submitting the data to a non-parametric bootstrap analysis to get 95%confidence intervals for each participant. Both metrics correlate with the temporal discrimination threshold, but are independent of each other.

This analysis method has the potential to reveal subtle differences between the patient and control group that may not be apparent from the standard method. Causative genes have been identified in less than 1%of adult-onset focal dystonia cases. An endophenotype is a subclinical marker of genetic carriage which can help us to understand disease pathomechanisms.

The temporal discrimination threshold, a potential endophenotype for adult-onset focal dystonia, is abnormal in up to 97%of patients and approximately 50%of their clinically unaffected relatives. In addition, an abnormal TDT follows an age and sex-related pattern similar to that of cervical dystonia. These findings suggest autosomal-dominant inheritance and support the use of the TDT as an endophenotype for adult-onset focal dystonia and in particular cervical dystonia.

An abnormal TDT can be interpreted as an impaired ability to detect or discriminate environmental change. The superior colliculus located at the back of the midbrain plays a critical role in detecting and reacting to salient stimuli. Let's take a closer look at this structure.

The superior colliculus is a paired laminated structure situated in the dorsal midbrain. It is the primary brainstem center for transforming spatial information of target location and to orienting head and eye movement. The superior colliculus consists of several layers with distinct organization.

However, it can be functionally separated into a superficial and deep layer. The superficial layer receives direct input from the visual system and contains a topographic map of the surrounding world in retinotopic coordinates. The visio-sensory neurons respond to salient environmental stimuli which in turn encode the location of objects in a retinotopic map.

The premotor neurons in the deep layer project to other brain regions which when they become excited fire at high frequencies generating quick eye movements known as saccades in the direction of the target. The deep layer also contains motor neurons which project to the upper cervical cord via the tectospinal pathway. When these neurons are activated, the head turns towards the target.

Superior collicular activity is modulated by gamma-aminobutyric acid or GABA, an inhibitory neurotransmitter. Inhibitory GABAergic activity limits the duration of the transient response in both the visual sensory neurons in the superficial layer and the premotor neurons in the deep layer of the superior colliculus. In response to a visual stimulus, most of the neurons in the superficial layer exhibit a transient on response.

GABAergic inhibition then silences this response enabling the neurons to be ready to respond again when the visual stimulus is turned off. If there is insufficient GABA, these neurons may become dysfunctionally active. It is hypothesized that insufficient GABAergic inhibition results in prolonged duration firing of visio-sensory neurons giving rise to abnormal temporal discrimination.

In addition, the abnormal movements characteristic of cervical dystonia are hypothesized to also result in insufficient GABAergic inhibition causing prolonged firing of the motor neurons in the deep layers of the superior colliculus. We have demonstrated that temporal discrimination can be measured in a straightforward and efficient manner and that this simple tool is a reliable endophenotype for cervical dystonia. In addition, it can potentially provide insight into the pathomechanisms of this disorder.