Brain Function Testing System and Device Thereof

Abstract

A system for analyzing eye movement on the basis of brain function and a device using the same, wherein the eye movement analysis system comprises: an eye movement behavior pattern and a plurality of eye movement data collection and data storage modules. The eye movement data collection is used to perform real time analysis on position data of the head and eyes, so as to compensate for the impact of head motion on eye position, thereby ensuring more accurate results. The device using this system is applicable to the diagnosis of neurodegenerative diseases.

Claims

1-10. (canceled)

11. An eye movement analysis system for detecting brain function comprising a vision and eye movement task module, which is configured to perform at least one of the following tasks: 1) Pro-saccade task; 2) Anti-saccade task; 3) Memory-saccade task; and 4) Double-saccade task.

12. The system of claim 11, further comprising: a) a behavior data collection module; or b) a data storage and analysis module.

13. The system of claim 12, wherein the behavior data collection module is configured to perform at least: using computer object recognition and tracking methods to process in real-time image information collected by a fast near-infrared camera; and eliminating in real-time the effect of head movements on the eye position monitoring using an inclinometer.

14. The system of claim 13, wherein the frequency of the fast near-infrared camera is not lower than 1000 Hz.

15. The system of claim 13, wherein the method for eliminating the effect of head movement on eye position monitoring in real time comprises: placing the inclinometer at the rotation point of the subject's head; when saccade and head rotation occur at the same time, the inclinometer recording the current eye movement angle ; obtaining the head movement angle from the inclinometer.

16. The system of claim 15, wherein a response frequency of the inclinometer is not lower than 200 Hz.

17. The system of claim 12, wherein the data storage and analysis module is configured to perform at least: establishing saccade database based on saccade behavior paradigms; and establishing a calculation model and analyzing eye movement parameters.

18. A brain function testing device using the system according to any one of claims 1 to 7.

19. The device of claim 18, wherein the device is used to monitor or test a brain function or a neurodegenerative disease.

20. The device of claim 19, wherein the neurodegenerative disease is one of Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, and cerebellar atrophy.

Description

BRIEF DESCRIPTION OF THE FIGURES

[0132] FIG. 1 shows a block diagram showing the structural principles of a saccade analysis system based on brain function in the present invention.

[0133] FIG. 2 shows the pro-saccade task. The subject first looks at the gaze point (cross), and then when the visual stimulus point (dot) appears, the subject is tasked to make a quick saccade toward the visual stimulus point, whereby the control function of the subject's brain (for example, basal ganglia, superior colliculus) on the reflective saccade is examined.

[0134] FIG. 3 shows the anti-saccade task. The subject first looks at the gaze point (cross), and then when the visual stimulus point appears, the subject is tasked to make a quick saccade to the mirror position of the visual stimulus point (dot), whereby the brain's (e.g., prefrontal cortex, basal ganglia) inhibition of reflective saccades and ability to generate and control correct saccades are examined.

[0135] FIG. 4 illustrates the memory-saccade task. The subject first looks at the gaze point (cross), and then a visual stimulus point (dot) appears at a random position, selected among eight positions evenly distributed with same eccentricity centered at the gaze point, and disappears immediately. After a period of time when the gaze point disappears, the subject is tasked to make a quick saccade to the position where the visual stimulus point once appeared, whereby the spatial memory ability of the subject is examined, and the accuracy of the spatial memory of the subject's brain (for example, the frontal parietal cortex) is determined by analyzing the accuracy of the saccade.

[0136] FIG. 5 shows the double-saccade task. The subject first looks at the gaze point (cross). Then the two visual stimulus points (dots) sequentially appear and disappear. After the gaze point disappears, the subject is tasked to make two saccades to sequentially, in the order of appearance, look at the two positions where the visual stimulus points appeared whereby the ability of the subject's brain (for example, the posterior parietal cortex) to convert visual spatial information is measured.

[0137] FIG. 6 shows a block diagram showing the working principle of the brain function testing device of the present invention.

[0138] FIG. 7 shows a working principle diagram of the behavior data collection device.

[0139] FIG. 8 shows saccadic traces of normal subjects under pro-saccade tasks.

[0140] FIG. 9 shows saccadic traces of subjects with Parkinson's Disease (PD) under pro-saccade tasks.

[0141] FIG. 10 shows saccadic traces of subjects with mild cognitive impairment (MCI) and Alzheimer's Disease (AD) under pro-saccade tasks.

[0142] FIG. 11 shows saccadic traces of normal subjects under anti-saccade tasks.

[0143] FIG. 12 shows saccadic traces of subjects with Parkinson's Disease under anti-saccade tasks.

[0144] FIG. 13 shows saccadic traces of subjects with mild cognitive impairment and Alzheimer's Disease under anti-saccade tasks.

[0145] FIG. 14 shows saccadic traces of normal subjects under memory-saccade tasks.

[0146] FIG. 15 shows saccadic traces of subjects with Parkinson's Disease under memory-saccade tasks.

[0147] FIG. 16 shows saccadic traces of subjects with mild cognitive impairment and Alzheimer's Disease under memory-saccade tasks.

[0148] FIG. 17 shows saccadic traces of normal subjects under double-saccade tasks.

[0149] FIG. 18 shows saccadic traces of subjects with Parkinson's Disease under double-saccade tasks.

[0150] FIG. 19 shows saccadic traces of subjects with mild cognitive impairment and Alzheimer's Disease under double-saccade tasks.

[0151] FIG. 20 shows the group mean error rates under the four tasks of subjects in the normal, PD, and AD groups.

[0152] FIG. 21 shows the saccadic traces of two subjects (normal, suspected patient) under the pro-saccade task.

[0153] FIG. 22 shows the saccadic traces of two subjects (normal, suspected patient) under the anti-saccade task.

[0154] FIG. 23 shows the saccadic traces of two subjects (normal, suspected patient) under the memory-saccade task.

[0155] FIG. 24 shows the saccadic traces of two subjects (normal, suspected patient) under the double-saccade task.

[0156] FIG. 25 shows the saccadic traces under the saccade tasks of the present invention of a subject that is determined to be normal by the classic methods. The saccade tasks of the present invention indicate that the subject's saccadic traces are abnormal, and after detailed clinical review, the subject is diagnosed with essential tremor.

[0157] FIG. 26 shows the saccadic traces under the saccadic tasks of the present invention of a subject that is determined to be normal by the classic methods. The saccade tasks of the present invention indicate that the subject's saccadic traces are abnormal, and after detailed clinical review, the subject is diagnosed with mild cognitive impairment.

[0158] FIG. 27 shows the error rates of the normal group subjects and suspected patients under the four tasks.

[0159] FIG. 28 shows the accuracy of the normal group subjects and suspected patients under the pro-saccade task.

[0160] FIG. 29 shows the accuracy of the normal group subjects and suspected patients under the anti-saccade task.

DETAILED WORKING DESCRIPTION

[0161] The present invention is further described below through specific working embodiments and experimental data. Although technical terms are used hereinafter for clarity, these terms are not meant to define or limit the scope of the invention.

[0162] As used herein, the term subject comprises any human or non-human animal. The term non-human animal comprises all vertebrates, for example, mammals and non-mammals, such as non-human primates, sheep, dogs, cats, horses, cattle, chickens, amphibians, reptiles, etc. Unless specifically stated, the terms patient and subject are used interchangeably.

[0163] The terms treatment and treatment method refer to both therapeutic treatment and preventative measures. Those in need of treatment include individuals who already have a specific medical condition, as well as those who may eventually acquire the condition.

[0164] The term neurodegenerative disease refers to a disease state in which neurons of the brain and spinal cord are lost. Neurodegenerative diseases are caused by the loss of neurons or their myelin sheaths, where the diseases deteriorate over time to cause dysfunction. Neurodegenerative diseases are divided into two groups according to phenotype: one group affects motor movement, such as cerebellar ataxia; the other group affects memory and includes related dementia.

[0165] The term eye movement refers to eye movements, including but not limited to the eye staying on the processed object (called gaze), the rapid movement of the eye between two gaze points or between gaze point and stimulus point (called saccade), and the eye movement following a moving object (called following movement). The eye movement parameters of the present invention include, but are not limited to, at least one of error rate of saccadic traces, saccade latency, saccade velocity, and saccade accuracy.

[0166] The term saccade is a type of eye movements, which is the rapid movement of the eye between two gaze points or between a gaze point and a stimulus point.

[0167] Unless otherwise specified, the experimental methods in the following Working Examples are conventional methods.

WORKING EXAMPLES

Example 1: A Saccade Analysis System and Device Based on Brain Degenerative Diseases

[0168] The example specifically comprises the following modules (FIG. 1)

[0169] 1) Experimental environment control module or device: to eliminate the impact of the experimental environment (including light brightness, noise level, etc.) on saccades;

[0170] 2) A head fixation device may be further included to avoid large movements of the subject's head during data collection;

[0171] 3) Vision and saccade task module or device: to collect eye and head position signals and pre-process them under specific behavior tasks (FIGS. 2 to 5);

[0172] 4) Data collection module or device: for real-time collection of eye position signals through a near-infrared fast camera (1000 Hz), real-time collection of head position signals (200 Hz) through a head-mounted inclinometer, real-time analysis and processing of head, position signals, and compensation for the effect of head movement on eye positions (FIG. 3). The adopted calculation method is: the inclinometer needs to be placed on the pivot point of the head as much as possible. When saccade and head rotation occur simultaneously, the current eye movement angle is recorded. Both head movements and saccades contribute to . The head movement angle is obtained by the inclinometer. The true saccade angle can be obtained by subtracting from (FIG. 6);

[0173] 5) Data processing and analysis module or device: real-time processed eye position signals and behavioral task codes are transmitted to a computer server through a network and added to a behavioral database; a computational model is established with the support of big data, and eye movement parameters are analyzed. Analysis are then returned to the user.

[0174] The working principle of a device prepared using this system is shown in FIG. 7. Behavioral data collection instrument sends screen visual stimulation signals (FIGS. 2 to 5). The data collection device (behavioral data collection instrument) collects eye position signals in real-time through a near-infrared fast camera (1000 Hz) and acquires head position signals in real-time through a head-mounted inclinometer (200 Hz) to analyze and integrate the head position signal in real time and compensate for the impact of head movement on the eye position. The processed eye position signal is transmitted to a computer server for data storage and analysis.

[0175] Current representative instruments based on eye movements to test brain function are these following:

[0176] 1. Neurotrack Technologies Inc., a start-up located in Redwood City, Calif., has launched a system based on examining cognitive ability through monitoring the spatial pattern of gaze (fixation) during freely viewing a picture. Specifically, through a browser application program the system has the subjects freely observe pictures on a screen, the user's eyeballs moving accordingly, thereby checking whether the user's cognitive ability shows any signs of decline.

[0177] 2. The DEM-200 eye movement detector produced by Shanghai Dikang Medical Biotechnology Co., Ltd. helps to diagnose mental illnesses clinically by detecting the spatial pattern of gaze (fixation) during freely viewing a picture and pupil changes of the subjects.

[0178] The similarity of the two systems described above is to determine the subject's cognitive ability (for example, memory ability) by detecting eye movement traces (gaze points) when viewing pictures freely. The system of the present invention observes saccades under a specific behavioral task paradigm, and determines physiological and cognitive functions of the brain by analyzing saccade parameters (such as saccade latency, saccade velocity, saccade accuracy, etc.).

TABLE-US-00002 TABLE 1 Eye movement features of different neurodegenerative diseases Neuro- degenerative Clinical eye movement Laboratory eye movement disease characteristics characteristics PD Slightly insufficient upward Decreased voluntary eye amplitude of voluntary eye movement gain (such as movement; insufficient amplitude) Slightly impaired smooth pursuit PD with Increased eye movement dementia velocity; decreased reflex and voluntary eye movement gain; increased reverse eye movement error HD patients Difficult initiation of eye Increased eye movement movements; slow eye velocity and variability; movements (young reduced eye movement veloc- patients); fixation ity; increased eye movement drifting and not continuous direction and precise time error rate of reverse eye movement and memory- guided eye movement; smooth pursuit drifting HD potential Normal Increased eye movement population velocity and variability; reduced eye movement veloc- ity; increased eye movement direction and precise time error rate of anti-saccade and memory-saccade AD patients Visual fixation defect in Increased fixation instability; anti-saccade test increased reflex and voluntary eye movement velocitys; increased anti-saccade errors; decreased anti-saccade error correction

[0179] Table 1 shows the eye movement characteristics of different neurodegenerative diseases. It is apparent that changes in eye movements are caused by Alzheimer's Disease, Parkinson's Disease, and Huntington's Disease. But the core issue of the present invention is what specific eye movement paradigm behavior combinations can be used to determine these diseases. Paradigm behavior combinations are massive, but the specific paradigm behaviors invented by the inventors can well determine these diseases. According to the specific eye movement features of degenerative diseases, the inventor organically combined pro-saccade task, anti-saccade task, memory-saccade task and double-saccade task, and the inventors found that this invention not only applies well to patients who have been identified clinically, but also identifies more sensitively potential patients with deficient brain function who are clinically determined to be normal.

Example 2: Eye Movement Parameters of Alzheimer's Disease and Parkinson's Disease Patients

[0180] By using the saccade analysis system and device of the present invention, it is verified that the system can accurately distinguish between patients with neurodegenerative diseases and normal people:

[0181] (1) Different neurodegenerative diseases can cause specific changes in eye movement parameters in the four aforementioned behavioral paradigms. As follows:

[0182] Alzheimer's Disease (AD): Increased gaze instability; increased saccade latency and variability; decreased saccade velocity, increased error rate of saccade direction and precise time of anti-saccade task and memory-saccade task; decreased anti-saccade correction.

[0183] Parkinson's Disease (PD): Decreased voluntary eye movement gain (such as insufficient stretching); there are obvious defects in the initiation of memory-saccades and anti-saccades; inhibition of saccade amplitude can be detected early in PD, and may be related to basal ganglia function; but elongation of eye movement velocity usually occurs in the late stage of the disease, and is related to the impairment of cognitive ability, which may be caused by the impairment of the function of the diffuse non-dopamine system in the late stage of the disease.

[0184] Huntington's Disease (HD): Increased saccade velocity and variability; decreased saccade velocity, increased error rate of saccade direction and precise time of anti-saccade task and memory-saccade task; vertical saccades are more prone to be affected than horizontal saccades.

[0185] (2) specific data are as follows:

[0186] The eye movement parameters of AD and PD patients are significantly different from those of the normal control group under the four aforementioned behavioral paradigms. In the data analysis, in addition to comparing the eye movement parameters of the same age subjects under the same eye movement task and identifying abnormal eye movements, we also took the eye movement parameters during the pro-saccade task of each subject as baseline. The baseline reference was compared with same eye movement parameters in the other three kinds of tasks and the relative changes of each subject's eye movement parameters could reflect the specific cognitive function of the brain. By analyzing and comparing the execution of the above-mentioned four types of saccade tasks (for example, error rate, saccade latency, saccade velocity, saccade accuracy), the subjects' vision, movement, and cognitive status can be understood.

[0187] Taking three subjects as examples, among the saccadic traces under the four behavioral task paradigms, FIGS. 8-10 show the saccadic traces of the subjects (normal, PD, and AD) under the pro-saccade task. The pro-saccade task is mainly used to determine basic vision-saccade information processing function; different colors indicate four different saccade directions. Compared with normal controls, the saccadic traces of patients with PD and AD are disordered, especially in the patient with PD.

[0188] FIGS. 11-13 show the saccadic traces of subjects (normal, PD, and AD) under the anti-saccade task. The anti-saccade task is mainly used to detect the brain's ability to suppress reflex motions; different colors indicate four different saccade directions. Compared with normal controls, the saccadic traces of patients with PD and AD are disordered, especially in the patient with AD.

[0189] FIGS. 14-16 show the saccadic traces of subjects (normal, PD, and AD) under a memory-saccade task. The memory-saccade task is mainly used to determine the brain's function of short-term (working) memory; different colors indicate four different saccade directions. Compared with the normal control, the saccadic traces of the PD patient are disordered, and the AD patient cannot perform this task (very high error rate).

[0190] FIGS. 17-19 show the saccadic traces of three subjects (normal, PD, and AD) under a double-saccade task. The double-saccade task is mainly used to determine the spatial cognitive ability of the brain; different colors indicate different saccade directions. Compared with the normal control, the saccadic traces of the PD patient are disordered, and the AD patient cannot perform this task (very high error rate).

Comprehensive Error Rate Under Four Behavioral Task Paradigms

[0191] FIG. 20 shows the group mean error rates under the four tasks of subjects in the normal, PD, and AD groups. Compared with the normal control group, PD and AD patients have significantly higher error rates under the four tasks. In both the PD and AD groups, the total error rates were both more than doubled compared with the normal group, especially for AD group. From the data in Table 2, it is apparent that interrupted gaze has a greater contribution to the error rate in the disease groups, and the error rate of interrupted gaze has increased most in the disease groups in the memory-saccade task, which means the memory-saccade task is more sensitive to determine PD or AD, followed by the double-saccade task and the anti-saccade task. Therefore, these four saccade tasks are not randomly generated. Instead, the applicant determined and considered the error rate of different tasks and the vision and modules composed of different saccade tasks in the experiment, and finally formed these tasks through multi-aspect exploration and coordination. Products produced using this behavioral paradigm, such as testing devices, can achieve the function of more sensitive and accurate screening of neurological diseases.

TABLE-US-00003 TABLE 2 Error Rate Interrupt No Wrong direc- Total gaze saccade tion saccade error rate Pro- Normal 0.083 0.030 0.033 0.147 saccade task PD 0.223 0.023 0.064 0.309 AD 0.305 0.128 0.053 0.486 Anti- Normal 0.125 0.173 0.075 0.373 saccade task PD 0.300 0.370 0.124 0.794 AD 0.364 0.260 0.122 0.746 Memory- Normal 0.165 0.109 0.034 0.308 saccade task PD 0.492 0.240 0.023 0.755 AD 0.526 0.241 0.022 0.788 Double- Normal 0.025 0.110 0.040 0.175 saccade task PD 0.372 0.366 0.018 0.756 AD 0.338 0.404 0.020 0.762

Example 3: Early Detection

[0192] One subject sought clinical help because of paroxysmal mild tremor of the limb. Clinical examination found that the patient's other nervous system detection indicators were within the normal ranges, the brain magnetic resonance scan results were normal, and clinical diagnosis was difficult. The clinicians performed the aforementioned four eye-movement task tests for the patient and listed the experimental results in the control group (as opposed to patients with apparent PD and AD). However, when we analyzed the data, we found that many of the eye movement parameters of the subject were significantly different from those of other control subjects and were closer to the test results of PD and AD patients (FIGS. 21-24 and 27-29). Based on this, the clinician followed up the subject and carried out a number of clinical tests for 3 months, and the current initial diagnosis is essential tremor (suspected Parkinson's disease). FIGS. 21-24 show the saccadic traces of the subject and a subject from the healthy group under four saccadic tasks. Compared with the normal control, the subject's saccadic traces were significantly disordered.

[0193] FIG. 27 shows the error rates of normal subjects and the above-mentioned subject under four tasks. Compared with the normal control group, the above-mentioned subject's error rates under the four tasks were significantly higher, and the total error rate was more than twice that of the normal subjects, and the contribution of the interrupted gaze error rate in each paradigm behavior is still the largest, further proving the core role of memory-saccade task. FIGS. 28-29 show the saccade accuracy (saccade landing point) of normal subject and the above-mentioned subject.

[0194] Similarly, FIG. 25 shows the saccadic traces under the saccadic tasks of the present invention of a subject who was identified as normal by classic methods. The clinical examination found that the patient's nervous system detection indicators were within the normal ranges, but after testing, the saccade tasks in the present invention indicated that the subject's saccadic traces were abnormal. After a detailed clinical review, he was finally diagnosed with essential tremor. FIG. 26 shows the saccadic traces under the saccadic tasks of the present invention of a subject who was identified as normal by classic methods. The clinical examination found that the patient's nervous system detection indicators were within the normal range, but after testing, the saccade tasks in the present invention indicated that the subject's saccadic traces were abnormal. After a detailed clinical review, he was finally diagnosed with mild cognitive impairment (MCI). The above results show that the paradigm behavior of the present invention is of great significance for the early detection of neurological diseases.

INCORPORATION BY REFERENCE

[0195] The entire disclosure of each patent document and scientific document cited herein is incorporated herein by reference for all purposes.

EQUIVALENCY

[0196] The present invention may be implemented in other specific forms without departing from its basic characteristics. Accordingly, the foregoing embodiments are to be considered illustrative and not restrictive of the invention described herein. The scope of the present invention is indicated by the appended claims rather than the foregoing description and is intended to include all changes that fall within the meaning and scope of equivalents of the claims.