Neurocognitive function EEG measurement method and system

• US 20030013981A1
• Filed: 04/15/2002
• Published: 01/16/2003
• Est. Priority Date: 06/26/2000
• Status: Active Grant

• Current Assignee: Alan Gevins, Michael Smith
• Original Assignee: Alan Gevins, Michael Smith
• Inventors: Smith, Michael, Gevins, Alan
• Granted Patent: US 6,947,790 B2
• Time in Patent Office: Days
• US Class Current: 600/544
• CPC Class Codes: A61B 5/16 Devices for psychotechnics using teaching or educational appliances G09B1/00 - G09B7/00; Testing reaction times ; Devices for evaluating the psychological state
• CPC Class Codes: A61B 5/377 using evoked responses
• CPC Class Codes: A61B 5/4076 Diagnosing or monitoring particular conditions of the nervous system A61B5/4821, A61B5/4824 take precedence
• CPC Class Codes: A61B 5/411 Detecting or monitoring allergy or intolerance reactions to an allergenic agent or substance
• CPC Class Codes: A61B 5/7264 Classification of physiological signals or data, e.g. using neural networks, statistical classifiers, expert systems or fuzzy systems neural networks per se G06N3/00; expert systems per se G06N5/00
• CPC Class Codes: G16H 20/70 relating to mental therapies, e.g. psychological therapy or autogenous training
• CPC Class Codes: G16H 50/20 for computer-aided diagnosis, e.g. based on medical expert systems
• CPC Class Codes: G16H 50/30 for calculating health indices; for individual health risk assessment

Abstract

An efficient, objective testing method and system for evaluating changes in mental function is described. The method and system are based on measuring an individual'"'"'s behavioral responses and brain function during a brief cognitive test battery and passive control conditions. The method and system is designed to assess an individual'"'"'s fundamental cognitive functions, and whether those functions have been significantly affected by a variety of factors such as progressive disease processes, medication, stress, fatigue, training, or the passage of time. The method and system can be used to determine whether drugs being evaluated to treat diseases or conditions affecting cognitive brain function have a significant positive effect on delaying or improving the symptoms of such a disease or condition, especially during clinical trials for drug approval and subsequent marketing. The method and system may also be employed as part of the successful diagnosis or ongoing treatment of neurological diseases or conditions that directly or indirectly affect human neurocognitive performance. The method and system may also be used to determine transitory changes in overall cognitive function due to emotional stress or fatigue, and more long lasting changes in overall cognitive function following training and educational programs.

Claims

1. The method of measuring changes in a human subject'"'"'s fundamental cognitive brain functions, the changes, for example, being due to disease, injury, remedial treatment, the utilization of medicines and normal variation within and between days and over a period of time, including the steps of:

(a) presenting an attention-demanding task to the subject, which engages one or more of the subject'"'"'s fundamental cognitive functions, and, simultaneously;

(b) at least once, measuring the subject'"'"'s behavioral responses to the task, and neuroelectric activity at the subject'"'"'s scalp using a set of electroencephalograph (EEG) electrodes and amplifier and analog/digital converters, to provide a set of baseline digital data representing the subject'"'"'s baseline state behavioral responses and neuroelectric activity in response to the task;

(c) at least once again, measuring the subject'"'"'s behavioral responses to the task, and neuroelectric activity at the subject'"'"'s scalp using a set of electroencephalograph (EEG) electrodes and amplifier and analog/digital converters, to provide a set of possibly altered state digital data representing the subject'"'"'s possibly altered state behavioral responses and neuroelectric activity in response to the task;

(d) in a computer system, comparing the subject'"'"'s baseline state and possibly altered state digital data using a mathematical function derived from behavioral responses and EEG derived neuroelectric activity responses of a reference group of subjects performing the same task recorded in their baseline and altered state conditions, the mathematical function combining measures of task performance with brain function measures, and

(e) deriving one or more scores for the subject based on the comparison described in (d) and determining the significance of those scores.

2. The method of claim 1 wherein the digital data measures of behavioral responses and neuroelectric activity are grouped into one or more classes, called for example, Behavioral Performance, Neurophysiological Cognitive and Neurophysiological Alertness;

and rules, based on expert neuropsychological and neurophysiological knowledge, are applied to each of the measures within each of the classes to determine if the measures differ in an expected manner between each subject'"'"'s baseline and subsequent, possibly altered, states.

3. The method of claims 1 and 2 wherein the function is computed using a neural network, or other statistical classification algorithm, that combines the outputs of the classes into a score, called for example the Neurocognitive Function Change (NCFC) score, that distinguishes baseline and altered states.

4. The method of claims 1-3 wherein the attention-demanding task is a brief cognitive test battery.

5. The method of claims 1-4 wherein at least some of the behavioral performance measures from the attention-demanding tasks combine measures of task performance, for example the subject'"'"'s speed and accuracy of response to each task trial.

6. The method of claims 1-5 in which the test battery tests the subject'"'"'s attention and/or memory, and/or language functions.

7. The method of claims 1-6 wherein the subject performs a series of repetitions of easy and more difficult versions of at least some of the tasks.

8. The method of claims 1-7 wherein in (a) of claim 1 a passive control condition is presented to the subject for comparison to the attention-demanding tasks.

9. The method of claims 1-8 wherein in (a) of claim 1 the attention-demanding task is presented by a digital computer.

10. The method of claims 1-9 and determining the various ways of determining the baseline (prior) state and /or possibly altered (subsequent) state selected from the group of:

(i) the subject'"'"'s first recording, (ii) the subject'"'"'s most recent recording, (iii) a weighted average of all the subject'"'"'s prior recordings, (iv) a particular prior recording before initiation of a drug or other therapy, (v) a specified subset of prior recordings from the subject, and (vi) baseline states previously determined from a normative reference group of subjects with demographic or health characteristics similar to those of the subject.

11. The method of claims 1-10 and determining one or more of the following to determine whether a Neurocognitive Function Change (NCFC) score represents a sufficiently significant change from the baseline state (to be called an altered state) by:

(i) statistical comparison of a subject'"'"'s NCFC score on a particular test day or days with the normal range of variation of the subject'"'"'s NCFC score resulting from comparing the subject'"'"'s prior baseline states to each other using the mathematical function of claim 1(d);

(ii) statistical comparison of a subject'"'"'s NCFC score on a particular test day or days with a typical normal range of variation of the NCFC scores of a normative reference group of subjects resulting from comparing each member of the group'"'"'s baseline states to each other using the mathematical function of claim 1(d).

12. The method of claim 11 wherein a subsequent state that was determined to be an altered state is further analyzed to determine how the state is altered by statistically comparing the outputs of each class in the subject'"'"'s NCFC function to the normal range of variation of the outputs of each class, and if an output for a class is significant, examining the outputs of the individual rules and measures within each class;

wherein the normal range of variation of the outputs of each class is determined by one or more of the following;

(i) analysis of the outputs of the individual rules of the subject'"'"'s NCFC functions resulting from comparing the subject'"'"'s prior baseline states to each other using the mathematical function of claim 1(d);

(ii) analysis of the outputs of the individual rules of a normative group of subjects'"'"' NCFC functions resulting from comparing each member of the group'"'"'s prior baseline states to each other using the mathematical function of claim 1(d).

13. The method of claims 1-12 employed to test the effect of medicine on a subject in which at least one set of baseline digital data is obtained before administration of the medicine to the subject and at least one set of possibly altered state digital data is obtained after administration of the medicine to the subject.

14. The method of claims 1-12 employed to test the effectiveness of a remedial program to improve cognitive functioning in which at least one set of baseline digital data is obtained before administration of the remedial program to the subject and at least one set of possibly altered state digital data is obtained after administration of the remedial program.

15. The method of claims 1-12 employed to measure the effect of fatigue on a subject in which at least one set of baseline digital data is obtained when the subject is in an alert, rested state and at least one set of possibly altered state digital data is obtained after the subject has been deprived of a normal amount of sleep or is otherwise fatigued.

16. The method of claims 1-12 employed to measure the effect of injury or disease on a subject in which at least one set of baseline digital data is obtained when the subject is in a healthy, uninjured state and at least one set of possibly altered state digital data is obtained after the subject has been injured or contracted a disease.

17. The method of claims 1-12 and comparing a possibly injured or diseased baseline state of a subject with baseline data from a normal reference group.

18. The method of claims 1-12 employed to measure recovery from injury or disease in which at least one set of baseline digital data is obtained after the subject has been injured or contracted a disease and at least another set of possibly altered digital data is subsequently obtained.

19. The method of claims 1-18, alone or in concert with symptomatic or asymptomatic blood borne or other measurable marker shown to be associated with a disease or condition, in order allow early detection of impairment or improvement due to that disease or condition or a treatment, thus being able to speedily predict and evaluate efficacy of a treatment.

20. The method of claims 1-19 wherein the task is not culturally biased, as it does not involve reading a language.

21. The method of claims 1-19 and additionally presenting the subject with control conditions in which the subject sits passively with eyes opened and then with eyes closed.

22. The method of claims 1-21 and measuring the subject'"'"'s neuroelectric activity in (b) and/or (c) of claim 1 while performing the task of (a) to determine one, or more, of the group selected from:

i. characterizing the subject'"'"'s level of alertness;

ii. characterizing the subject'"'"'s mental efforts and brain utilization;

iii. characterizing the subject'"'"'s sustained focused attention and working memory;

iv. characterizing the subject'"'"'s sustained divided attention;

v. characterizing the subject'"'"'s preparatory attention and neurocognitive strategy;

vi. characterizing the subject'"'"'s perceptual and cognitive speed;

vii. characterizing the subject'"'"'s selective attention and transient focused attention;

viii. characterizing the subject'"'"'s intermediate term memory;

ix. characterizing how the subject'"'"'s brain and behavior respond to changes in mental workload by presenting more and less difficult versions of a task during the same test session;

x. characterizing the subjects quickness to adapt by presenting repeated trials of the same task during one test session.

23. The method of claims 1-22 and measuring the subject'"'"'s neuroelectric activity in (b) and/or (c) of claim 1 while performing the task of (a) to determine one, or more, of the group selected from:

i. characterizing the subject'"'"'s level of alertness by EEG measurement of the subject'"'"'s frontal delta power associated with slow horizontal eye movements, posterior theta and delta power, and ratios of posterior theta to alpha and delta to alpha powers;

ii. characterizing the subject'"'"'s level of alertness from the passive eyes-open and eyes-closed EEG, and/or evoked potential measures such as N100 and P300;

iii. characterizing the subject'"'"'s mental effort and brain utilization by EEG measurement of the subject'"'"'s parietal and prefrontal alpha powers;

iv. characterizing the subject'"'"'s sustained focused attention and sustained divided attention by EEG measurement of the subject'"'"'s frontal midline theta power;

v. characterizing the subject'"'"'s preparatory attention and neurocognitive strategy respectively by EEG measurement of the subject'"'"'s Contingent Negative Variation evoked potential, and left to right and anterior to posterior ratios of the subject'"'"'s alpha powers;

vi. characterizing the subject'"'"'s perceptual and cognitive speed by EEG measurement of the subject'"'"'s evoked potential peak latencies such as N100, P200 and P300;

vii. characterizing the subject'"'"'s selective and transient focused attention by EEG measurement of the subject'"'"'s N100, P300 and Slow Wave evoked potential amplitudes;

viii. characterizing the subject'"'"'s working memory by EEG measurement of the subject'"'"'s parietal and prefrontal alpha powers, frontal midline theta power, and P300 and Slow Wave evoked potential amplitude during a working memory task;

ix. characterizing the subject'"'"'s intermediate term memory by measurement of differences between previously studied and newly presented information in the subject'"'"'s N400, P600, Slow Wave, and other evoked potential amplitudes during an intermediate term memory task;

x. characterizing how the subject'"'"'s brain and behavior respond to changes in mental workload by presenting more and less difficult versions of the same task during the same test session and measuring differences between the difficulty levels, and the difficulty levels and resting, in neural activity measures i-ix; and

xi. characterizing the subject'"'"'s quickness to adapt by measuring changes in the neural activity measures i-ix as the subject continues to perform the attention demanding tasks during the same test session.

24. The method of measuring changes in a human subject'"'"'s fundamental cognitive brain functions, the changes, for example, being due to disease, injury, remedial treatment, the testing of medicines and normal variation within and between days and over a period of time, including the steps of:

(a) presenting an attention-demanding task to the subject, which engages the subject'"'"'s fundamental cognitive functions, and, simultaneously;

(b) at least once, measuring the subject'"'"'s behavioral responses to the task, and associated brain function using functional magnetic resonance imaging (fMRI), alone or in combination with EEG, to provide a set of baseline digital data representing the subject'"'"'s behavioral responses and brain activity in response to the task;

(c) at least once again, measuring the subject'"'"'s behavioral responses to the task, and associated brain function using functional magnetic imaging (fMRI), alone or in combination with EEG, to provide a set of possibly altered state digital data representing the subject'"'"'s behavioral responses and brain activity in response to the task;

(d) in a computer system, comparing the subject'"'"'s baseline state and possibly altered state digital data using a mathematical function derived from the behavioral responses and fMRI derived brain activity responses, alone or in combination with EEG derived neuroelectric activity responses, of a reference group of subjects performing the same task recorded in their baseline and altered state conditions, the mathematical function combining measures of task performance with brain function measures; and

(e) deriving one or more scores for the subject based on the comparison described in (d) and determining the significance of those scores.

25. The method of measuring changes in a human subject'"'"'s fundamental cognitive brain functions, the changes, for example, being due to disease, injury, remedial treatment, the testing of medicines and normal variation within and between days and over a period of time, including the steps of:

(a) presenting an attention-demanding task to the subject, which engages the subject'"'"'s fundamental cognitive functions, and, simultaneously;

(b) at least once, measuring the subject'"'"'s behavioral responses to the task, and associated brain function using magnetoencephalograms (MEG), alone or in combination with EEG, to provide a set of baseline digital data representing the subject'"'"'s behavioral responses and brain activity in response to the task;

(c) at least once again, measuring the subject'"'"'s behavioral responses to the task, and associated brain function using magnetoencephalograms (MEG), alone or in combination with EEG, to provide a set of possibly altered state digital data representing the subject'"'"'s behavioral responses and brain activity in response to the task;

(d) in a computer system, processing the subject'"'"'s baseline state and possibly altered state digital data to derive an overall score using a mathematical function derived from the behavioral responses and MEG derived brain activity responses, alone or in combination with EEG derived neuroelectric activity responses, of a reference group of subjects performing the same task recorded in their baseline and altered state conditions, the mathematical function combining measures of task performance with brain function measures; and

(e) deriving one or more scores for the subject based on the comparison described in (d) and determining the significance of those scores.

26. The method of measuring changes in a human subject'"'"'s fundamental cognitive brain functions, the changes, for example, being due to disease, injury, remedial treatment, the testing of medicines and normal variation within and between days and over a period of time, including the steps of:

(a) presenting an attention-demanding task to the subject, which engages the subject'"'"'s fundamental cognitive functions, and, simultaneously;

(b) at least once, measuring the subject'"'"'s behavioral responses to the task, and neuroelectric activity at the subject'"'"'s scalp using a set of electroencephalograph (EEG) electrodes and amplifier and analog/digital converters, to provide a set of baseline digital data representing the subject'"'"'s behavioral responses and neuroelectric activity in response to the task;

(c) at least once again, measuring the subject'"'"'s behavioral responses to the task, and neuroelectric activity at the subject'"'"'s scalp using a set of electroencephalograph (EEG) electrodes and amplifier and analog/digital converters, to provide a set of possibly altered state digital data representing the subject'"'"'s behavioral responses and neuroelectric activity in response to the task;

(d) in a computer system, comparing the subject'"'"'s baseline state and possibly altered state digital data to behavioral responses and EEG derived neuroelectric activity responses of a reference group of subjects performing the same task recorded in their baseline and altered states, the comparison using a multivariate statistical method combining measures of task performance with brain function measures in a single comparison, and

(e) deriving a score for the subject based on the comparison of (d) and determining the significance of the score.

27. The method of measuring changes in a human subject'"'"'s fundamental cognitive brain functions, the changes, for example, being due to disease, injury, remedial treatment, the testing of medicines and normal variation within and between days and over a period of time, including the steps of:

(a) presenting an attention-demanding task to the subject, which engages one or more of the subject'"'"'s fundamental cognitive functions, and, simultaneously;

(b) at least once, measuring the subject'"'"'s behavioral responses to the task, and neuroelectric activity at the subject'"'"'s scalp using a set of electroencephalograph (EEG) electrodes and amplifier and analog/digital converters, to provide a set of baseline digital data representing the subject'"'"'s baseline state behavioral responses and neuroelectric activity in response to the task;

(c) at least once again, measuring the subject'"'"'s behavioral responses to the task, and neuroelectric activity at the subject'"'"'s scalp using a set of electroencephalograph (EEG) electrodes and amplifier and analog/digital converters, to provide a set of possibly altered state digital data representing the subject'"'"'s possibly altered state behavioral responses and neuroelectric activity in response to the task;

(d) computing measures from the baseline and possibly altered state sets of digital data and grouping the measures into one or more classes, called for example, Behavioral Performance, Neurophysiological Cognitive and Neurophysiological Alertness; and

applying rules, based on expert neuropsychological and neurophysiological knowledge, to each of the measures within each of the classes to determine if the measures differ in an expected manner between each subject'"'"'s baseline and subsequent, possibly altered, states;

.

(e) in a computer system, comparing the subject'"'"'s data analyzed as in (d) to identically analyzed data of a reference group of subjects performing the same task recorded in their baseline and altered state conditions, the comparison using a multivariate statistical method combining measures of task performance with brain function measures in a single comparison; and

(f) deriving a score for the subject based on the comparison of (e) and determining the significance of the score.