Methods and systems for assessing a subject - Patents.com

Abstract

A method and system for assessing a subject using fMRI analysis of the subject's brain activity, while the subject performs a set of cognitive tasks. For each task, a first level of performance in completing the task is derived. For at least some of the tasks completed to a satisfactory performance level, it is evaluated whether any of the tasks showed increased activity in brain regions different from the brain regions related to the task that exceeds a threshold. For these tasks, a further fMRI analysis is performed performing a further cognitive task, but with a further cognitive load. The fMRI analysis is compared to the further fMRI analysis. This allows, for example, to determine that the patient is using compensation mechanisms to complete the cognitive tasks.

Description

[Technical field]

[0001] The present invention relates to methods and systems for assessing a subject, and in particular to methods and systems for assessing mild traumatic brain injury. [Background technology]

[0002] Mild traumatic brain injury (mTBI) is period of loss of consciousness, Loss of memory for events immediately before or after the accident Changes in mental state at the time of the accident, and Transient or non-transient temporal focal neurological disorders It can be described as a traumatically induced physiological disruption of brain function manifested by at least one of the following:

[0003] Traumatic brain injury (TBI), particularly mTBI, constitutes a large and rapidly growing public health concern. Approximately 69 million people worldwide sustain a TBI each year. Approximately 85% of these TBIs are diagnosed as mTBI.

[0004] Most mTBI patients develop a range of symptoms including headache, dizziness, fatigue, vertigo, neuropsychiatric symptoms (including behavioral and mood changes, confusion), difficulties with balance, changes in sleep patterns, and cognitive impairment (including impairments in memory, attention, concentration, and executive function).

[0005] In the acute phase, the current diagnosis of mTBI is based on clinical assessment of altered mental status (e.g., using the Glasgow Coma Scale). Cognitive assessment may be performed at a later stage in patients with chronic cognitive symptoms.

[0006] The primary cognitive functions impaired in mTBI are attention and executive functions (e.g., working memory, processing speed). In addition, mTBI patients often have visual and balance problems that may exacerbate cognitive impairment. For the evaluation of patients with mTBI, a thorough assessment of attention, processing speed, executive functions, and memory is necessary to capture any current cognitive impairment. More importantly, these tests need to have high sensitivity, as symptoms are often subtle. Summary of the Invention [Problem to be solved by the invention]

[0007] Standard neuropsychological and cognitive tests used in clinical practice for this purpose are not sensitive enough to detect these subtle cognitive impairments. These standard tests are often characterized by lack of multitasking, absence of distractions in the laboratory, tasks that are too easy, duration of tasks that are too short, inappropriate selection of tasks (e.g., presentation of a memory task during which the patient is more prone to memory problems due to attention deficits), patients putting more effort into the performance of the laboratory tasks compared to tasks in daily life, and compensatory mechanisms used during the laboratory tasks.

[0008] As a result, despite the fact that there is an increased awareness of the incidence angle of mTBI, the current assessment criteria for mTBI remain suboptimal and therefore do not have the required sensitivity. This is mainly because current neuropsychological and cognitive assessments use standard methodologies for all patients. As a result, subtle cognitive impairments that mTBI patients encounter in their daily lives may not be revealed during clinical evaluation. Cognitive impairment in mTBI is characterized by subtle cognitive impairments that impair normal daily functioning, and as a result, limit the ability of mTBI patients to have normal social and work lives.

[0009] The inadequate sensitivity of current tests means that when cognitive deficits in mTBI patients are assessed, cognitive test scores are often within the norm, i.e., indistinguishable from those of healthy individuals. As a result, a high proportion of mTBI patients do not receive an accurate diagnosis and, as a consequence, cannot receive any treatment.

[0010] In other words, although mTBI patients report cognitive impairments in everyday life, these problems are not detected by current methods of assessing cognitive impairment in mTBI.

[0011] "Differential working memory load effects after mild traumatic brain injury" by McAllister T, W et al. (Neuroimage 2001 US, vol. 14, no. 5, pp. 1004-1012) discloses the use of an auditory n-back task with different processing loads, i.e., 0, 1, 2, and 3-back tests. fMRI analysis is performed during the test.

[0012] US Patent Application Publication No. 2012 / 083688 discloses a system and method for detecting the effects of a concussion, where an MRI analysis is performed while a subject performs a task that exercises one or more functional centers of the brain. [Means for solving the problem]

[0013] The invention is defined by the claims.

[0014] According to an embodiment of the present invention,

[0015] 1. A method for evaluating a subject, comprising: performing a functional MRI (fMRI) analysis of the subject's brain activity while performing a set of cognitive tasks, each cognitive task being associated with activity of a specific region or network of brain regions; receiving or identifying, for each task, an indication of a first level of competence in completing the task; for at least some of the tasks completed to a threshold level of performance, identifying any tasks for which there is increased activity above a threshold in a distinct region or network of brain regions relative to the particular region or network of brain regions associated with the task; performing a further fMRI analysis of the subject's brain activity while performing a further cognitive task for the identified task, in which an additional cognitive load is provided to the subject, but which is related to activity of the specific regions or networks of the same brain regions as the identified task; for each additional cognitive task, receiving or identifying an indication of a second level of performance in completing the task for comparison with the first level of performance. A method is provided comprising:

[0016] This method addresses the problem that subjects (i.e., patients) are routinely screened using cognitive tests and are often underdiagnosed because cognitive tests cannot detect subtle impairments in cognitive function.

[0017] The method provides a two-step approach that allows for the detection of subtle impairments by having the patient perform a number of cognitive tasks covering most cognitive domains inside an MR scanner. Analysis of the MR scan data looks at the expected brain regions and networks associated with each task that should normally be activated while performing a particular task (i.e., there is task A to test for cognitive domain A, and this task is designed to activate brain regions associated with domain A).

[0018] If brain regions and networks related to cognitive domain A are activated (as detected by fMRI) during performance of a cognitive task related to cognitive domain A, and the task is performed to a satisfactory level, then there is no problem with that cognitive domain and its associated functional domains.

[0019] Conversely, if the relevant brain regions and networks are not activated as expected, but the patient still functions to a satisfactory level, i.e., without serious performance impairment, the patient is likely to have affected brain regions, but the brain is still using other regions and networks so that it can perform the task. Thus, the brain is utilizing its reserve capacity. Although this type of response is typically missed, the method of the present invention still allows to detect brain disorders.

[0020] In particular, if an expected brain region associated with cognitive domain A, e.g., cognitive domain A, is not activated while performing a cognitive task associated with cognitive domain A, but the behavioral measures are still within expected values, the subject is given additional workload. This may deplete (other) cognitive resources, which provides an indication of subtle cognitive impairment in a particular cognitive domain.

[0021] If there is still no significant decline in performance, it can be concluded that the patient is able to perform well but uses cognitive reserve. This may lead to problems in the long term. If there is a significant decline in performance (compared to testing the same cognitive domain at a lower workload test), it can be concluded that the subject has a cognitive problem in that particular cognitive domain and treatment and care pathways can be tailored accordingly.

[0022] Thus, based on the comparison, it is possible to determine whether the subject is using compensatory mechanisms to complete the cognitive task.

[0023] The method may involve determining, for each task completed to a threshold level of performance, that activity in a particular area or network of areas associated with the task is below an expected level, and then only identifying those tasks where activity is increasing.

[0024] A reduction or even absence of activity in the expected area or network is an indicator of brain trauma as explained above. It indicates a suboptimal or non-functioning area or network, already providing insight that the cognitive area relevant to the task is affected, at least anatomically. An increase in activity in a different area or network is then a further second indicator of the affected cognitive area.

[0025] The cognitive tasks may include, for example, one or more of an executive function task, an attention task, a planning task, and a memory task.

[0026] The cognitive tasks may include, for example, one or more of a vigilance task, a flanker task, and a Posner cue task.

[0027] A variety of possible additional cognitive load methods can be used, for example the additional cognitive load can include one or both of an eye movement load and a pupil measurement load.

[0028] In another example, the additional cognitive load includes an autonomic nervous system (ANS) regulatory load.

[0029] Multiple ANS functions are also known to be susceptible to mTBI-related dysregulation: for example, it has been shown that mTBI reduces cerebrovascular reactivity and that mTBI individuals exhibit higher heart rate, reduced heart rate variability, and reduced skin conductance compared to healthy individuals.

[0030] A method of eliciting ANS function is to induce hypoxia (a reversible, temporary decrease in oxygen levels). Measures of ANS function are sensitive to hypoxia, as the literature has shown the presence of differences in pulse oximetry, aspects of cerebrovascular regulatory responses, heart rate, electrodermal activity, and cardiovascular responses.

[0031] Affected ANS function, in turn, is known to have a negative effect on cognitive function, disproportionately in mTBI patients.

[0032] In another example, the additional cognitive load includes additional tests involving working memory or attention.

[0033] In another example, the additional cognitive load includes additional time constraints on the task, degraded stimulation quality, or increased stimulation frequency.

[0034] In all cases, the level of additional cognitive load can be variable based on the level of real-time brain activity obtained by fMRI analysis, and therefore the additional load can be adapted using feedback from the brain activity analysis.

[0035] The method further includes, for example, monitoring the subject's vital signs. Some vital signs may be used as a measure of cognitive effort and may be indicative of a patient having an mTBI.

[0036] The method may include assessing cognitive load using eye-tracking.

[0037] The invention also provides a computer program comprising computer program code adapted to carry out the method defined above, when said program is run on a computer.

[0038] The present invention also provides a processor programmed with a computer program.

[0039] The present invention also provides 1. A system for assessing cognitive ability, comprising: an input for receiving fMRI images of the subject's brain activity while performing a set of cognitive tasks; the processor for delivering tasks to the subject and controlling an output device for processing the fMRI images; The present invention provides a system having:

[0040] The present invention also provides 1. An MRI system comprising: fMRI scanner and an output device for delivering a task to a subject; A system for evaluating the cognitive abilities described above; The present invention provides an MRI system comprising:

[0041] These and other aspects of the invention will be apparent from and elucidated with reference to the embodiments described hereinafter.

[0042] For a better understanding of the invention and to show more clearly how it may be carried into effect, reference will now be made, by way of example only, to the accompanying drawings in which: [Brief description of the drawings]

[0043] [Figure 1] An MRI system is shown. [Diagram 2] A method for evaluating a subject is shown. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0044] The present invention will now be described with reference to the drawings.

[0045] It should be understood that the detailed description and specific examples, while indicating exemplary embodiments of the devices, systems, and methods, are for purposes of illustration only and are not intended to limit the scope of the invention. These and other features, aspects, and advantages of the devices, systems, and methods of the present invention will become better understood from the following description, appended claims, and accompanying drawings. It should be understood that the figures are merely schematic and are not drawn to scale. It should also be understood that the same reference numerals are used throughout the figures to denote the same or similar parts.

[0046] The present invention provides a method and system for assessing a subject performing a set of cognitive tasks using fMRI analysis of the subject's brain activity. For each task, a first level of performance in completing the task is derived. For at least some of the tasks completed to a satisfactory performance level, it is evaluated whether any of the tasks showed increased activity in brain regions different from the brain regions related to the task that exceeds a threshold. For these tasks, a further fMRI analysis is performed performing a further cognitive task, but with a further cognitive load. The fMRI analysis is compared to the further fMRI analysis. This allows, for example, to determine that the patient is using compensation mechanisms to complete the cognitive tasks.

[0047] The approach of the present invention can be considered similar to cardiac Vmax testing (e.g., bicycle testing to test maximum physical performance). The additional cognitive load serves as additional cognitive stress that challenges the patient in a manner similar to stress during daily routines by requiring additional effort in the form of additional cognitive load or resource loss. The present invention can thus provide an effective method for discovering potential or hidden brain damage and associated cognitive impairment in mTBI.

[0048] 1 shows an MRI system 100 comprising an fMRI scanner 102 and an output device 104 for delivering tasks to a subject. The fMRI scanner comprises an advanced functional MR imaging unit and an fMRI scanning unit.

[0049] The output device 104 is, for example, a display screen or a virtual reality system for providing visual stimuli integrated into the MR bore.

[0050] A system 106 for assessing cognitive performance is provided, comprising an input 108 for receiving fMRI images of the subject's brain activity while performing a task delivered to the subject, and a processor 110. The processor 110 performs an analysis of the fMRI images and determines (or is advised of) the subject's performance level in performing the task. This performance information may be determined by the system 106. For example, the subject may provide input to the system as part of the cognitive task (e.g., via speech, using a keyboard, via a touch-sensitive input, or via any other user interface device), or the system may determine performance based on information collected using sensors. The level of performance is a measure of how well the subject performed the task, i.e., a measure of the subject's performance in performing the task.

[0051] Alternatively, the clinician can manually enter the performance results into the system 106 .

[0052] The processor, for example, determines behavioral responses to cognitive test stimuli under varying cognitive load levels and then evaluates the cognitive performance data according to predetermined quality rules.

[0053] The processor 110 also controls the output device 104 to deliver tasks to the subject.

[0054] The database 112 is a database of cognitive tests to be applied to the subject. Sensor devices 114 are also shown and include, for example, systems for performing eye movement measurements and / or systems for performing pupil measurements and / or vital signs sensors, for example for blood pressure monitoring.

[0055] In using the system, the clinician selects the test to be applied, the system, for example, providing guidance to this end.

[0056] The cognitive effort required by the subject, i.e., the additional effort compared to the previous resting state, is evaluated from the analysis of fMRI images while the subject is performing each cognitive task. In this way, the brain regions (i.e., specific brain regions or networks of regions) stimulated by a specific task are identified. The term "brain region" is used to mean a single region or network of brain regions, and optionally also the switching mechanism between neural networks. Indeed, fMRI studies suggest a higher cognitive control network that includes the lateral prefrontal cortex (DLPFC), the anterior cingulate cortex (dACC) and the dorsal area of ​​the parietal cortex (DPC).

[0057] Different brain regions are associated with different types of cognitive tasks, and therefore each task has expected brain regions that are stimulated during performance of the task.

[0058] For a discussion of the various cognitive domains, associated cognitive tasks, relevant functional neurological structures, and further cognitive load, see MJ Cook et al., “Task-related functional magnetic resonance imaging activation in patient with acute and subacute mild traumatic brain injury” (A coordinate-based meta-analysis, 2020;25;102129).

[0059] If a subject is unable to complete a task to the expected performance level, this is an indication of a possible mTBI, as detected by conventional fMRI-based cognitive testing. However, if the task is completed to the expected performance level, the present invention provides for further analysis to determine whether cognitive impairment may still be present, even for brain regions associated with successfully completed tasks. In particular, the present invention allows brain regions used for compensation to perform cognitive tasks to be identified.

[0060] The usage method is shown in Figure 2.

[0061] The method 200 includes, at step 202, receiving a first fMRI image and performing an fMRI analysis of a subject's brain activity while performing a set of cognitive tasks (1-n), each of which is associated with activity in a particular region of the brain.

[0062] In step 204, for each task 1-n, a first level of performance P1 in completing the task is obtained. This performance may be sensed (e.g., by the user's movements, or gaze, or voice / speech recognition), or may be input by a clinician, or may be derived from user input (e.g., by touching a screen to follow the commands of a cognitive task).

[0063] Some tasks, e.g., a number k of n tasks (k<=n), are performed to a satisfactory level. These tasks are identified in step 206. For some of the k tasks that are completed to a threshold level of performance, there is a subset of tasks, e.g., a number m of those tasks (m<=k) for which the fMRI analysis exceeds a threshold and shows increased activity in distinct regions of the brain relative to brain regions related to the task. These m tasks are identified in step 208.

[0064] For the identified task, a further (second) fMRI analysis of the subject's brain activity is performed in step 210, while the subject performs a further cognitive task related to the activity of the same brain regions as the identified task, but with an additional cognitive load. This additional cognitive load may be of the same type as the original task (but requiring additional brain resources), such that an increased amount of compensation is required to perform the task as a result of the additional cognitive load. However, the cognitive load may be implemented, for example, as a different type of task targeting a different brain region that has been identified as being used for compensation. In that case, the additional cognitive load will affect the subject's ability to compensate, which again results in a difference in performance that can be analyzed.

[0065] For each additional task, a second level of performance P2 in completing the task is obtained. In step 214, a comparison is made between the first and second levels of a pair of tasks (i.e., tasks targeting the same brain regions with or without additional cognitive load).

[0066] Once the k tasks that are completed to a threshold level of performance are identified in step 206, a further selection can be made prior to selection in step 208 to determine when activity in a particular brain region falls below an expected level. Thus, a task is selected to which additional cognitive load is applied only if the relevant brain region is stimulated less than expected.

[0067] Thus, the method provides a safe, protocolized, in-bore, real-time fMRI, multimodal "stress" module. The additional cognitive load means that cognitive, oculomotor, pupillometric, and whole-body regulatory abilities can be completely exhausted. This can then cause cognitive impairment that is usually hidden. ANS regulatory abilities include, for example, heart rate and electrodermal activity.

[0068] The additional cognitive load causes a decrease in performance in cognitive tests, compared to both non-stressful situations and healthy individuals. It is particularly interesting when fMRI activity shows a lack of normal increases in brain regions expected to be involved in cognitive control, as explained above. Cognitive control is the process of using executive functions such as attention, planning, or working memory to guide appropriate behavior to achieve a specific goal.

[0069] Tests for assessing cognitive abilities can include any standard neuropsychological test, such as tests of executive function and attention. Ideally, cognitive tests from experimental neuropsychology can be used, which are more suitable for measuring subtle cognitive impairments, such as tests like vigilance tasks, flanker tasks, or Posner cueing tasks.

[0070] Additional cognitive load may be provided by adding features or tests that engage working memory or attention. This may be accomplished by increasing the time pressure to complete a task, by degrading stimuli, by decreasing interstimulus intervals, by adding positive or negative reinforcement, by adding multiple tasks, by increasing the number of distracting stimuli, or by increasing the duration of a task.

[0071] Responses to the cognitive tests may be collected under variable additional cognitive load levels, which in this way can be adapted based on real-time performance (e.g., using a working memory task).

[0072] An example will now be presented in more detail.

[0073] This example is based on a test of the working memory cognitive domain. Working memory is the ability to temporarily store and manipulate information used for cognition or behavioral guidance. Previous functional MR imaging studies in healthy subjects have shown that increased working memory load is associated with increased activation in bilateral frontal and parietal regions. These regions are known to be vulnerable to damage in TBI. Working memory malfunctions have been frequently reported in TBI.

[0074] As an example of a suitable cognitive task, the n-back task is a continuous performance task commonly used to measure working memory. In the n-back task, subjects are presented with a sequence of stimuli and the task consists of indicating when the current stimulus matches the one n steps earlier in the sequence. The load factor n can be adjusted to make the task more or less difficult. This can be seen as a further degree of control of cognitive load.

[0075] For example, an auditory 3-back test may consist of the system delivering, or the experimenter reading, the following list of letters to the test subject: TIFF2025502927000002.tif1496

[0076] In order to correspond to the characters read three steps earlier, an acknowledgment response is provided when bold, underlined characters are read.

[0077] The n-back task captures the active part of working memory. When n is 2 or more, it is not enough to simply keep in mind the representation of the most recently presented term; the working memory buffer must also be continuously updated to keep track of what the current stimulus must be compared to. To accomplish this task, subjects must maintain and manipulate information in working memory.

[0078] In healthy subjects, increased activation is found in bilateral frontal and parietal regions, consistent with activation of working memory circuits. Following increases in working memory load (i.e., increases in the value of n), increased brain activation is detected in response to each increase in working memory load.

[0079] In mTBI patients, little difference may be detected in neurological activation in certain brain regions between 3-back and 2-back, providing an indication of when, for example, a maximum (or plateau) has been reached in these patients and those brain regions can no longer be used and need to be returned to other regions (i.e., compensated).

[0080] An example of additional cognition may be presenting a dual-task n-back task, where two independent sequences are presented simultaneously, typically using stimuli of different modalities, such as one auditory and one visual. Thus, one task may use the same brain regions as the original task, but the added task uses other brain resources.

[0081] Adding additional workload can distort the quality of the visual stimulus and increase the effort required to read the text.

[0082] More generally, additional cognitive load can be achieved by shifting from any unimodal stimulus to any multimodal stimulus (e.g., visual and auditory stimuli) presented simultaneously to the patient. However, the visual and auditory stimuli can be presented either congruently or incongruently. Incongruent stimuli demand high attentional resources.

[0083] As explained above, the goal is to detect whether cognitive load activates brain regions other than those expected to be normally activated while performing a cognitive task. In the example of the n-back task, "normal" test levels may not show differences in performance and neuronal activity between healthy subjects and patients with mTBI.

[0084] However, when applying cognitive load, one would expect similar areas to be activated in healthy subjects, but if an area is (subtly) damaged, but not enough to show cognitive decline at a "normal" level of the task, one would expect areas other than those where cognitive load would be expected to be activated. This would indicate that the patient had to return to areas of cognitive reserve.

[0085] An example of an area that may be activated compensatory is the anterior cingulate cortex, a more attention-related area.

[0086] Cognitive load can be measured using eye tracking (e.g., saccadic response time), which is known to be sensitive to cognitive load.

[0087] Variations to the disclosed embodiments can be understood and effected by those skilled in the art in practicing the claimed invention, from a study of the drawings, the disclosure, and the appended claims. In the claims, the word "comprising" does not exclude other elements or steps, and the indefinite article "a" or "an" does not exclude a plurality.

[0088] A single processor or other unit may fulfill the functions of several items recited in the claims.

[0089] The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage.

[0090] The computer program may be stored / distributed on a suitable medium, such as an optical storage medium or a solid-state medium, provided together with or as part of other hardware, but may also be distributed in other forms, such as over the Internet or other wired or wireless telecommunications systems.

[0091] It should be noted that when the term "adapted for" is used in the claims or description, it is intended to be equivalent to the term "configured for." When the term "apparatus" is used in the claims or description, it is intended to be equivalent to the term "system," and vice versa.

[0092] Any reference signs in the claims should not be construed as limiting the scope.

Claims

1. 1. A method for evaluating a subject, comprising: performing a functional MRI (fMRI) analysis of the subject's brain activity while performing a set of cognitive tasks, each cognitive task being associated with activity of a specific region or network of brain regions; for each task, receiving or identifying an indication of a first level of capability in completing the task associated with the subject's level of capability in performing the task; and the method further comprises: for at least some of the tasks completed to a threshold level of performance, identifying any tasks for which there is increased activity above a threshold in a distinct region or network of brain regions relative to the particular region or network of brain regions associated with the task; performing a further fMRI analysis of the subject's brain activity while performing a further cognitive task for the identified task, in which an additional cognitive load is provided to the subject, but which is related to activity of the specific regions or networks of the same brain regions as the identified task; for each additional cognitive task, receiving or identifying an indication of a second level of performance in completing the task associated with the subject's level of performance in performing the additional task for comparison with the first level of performance; The method comprising:

2. 2. The method of claim 1, further comprising the step of: determining, for each task completed to a threshold level of performance, that activity in the particular region or network of regions related to the task is below an expected level; and then identifying any tasks for which there is increased activity.

3. 3. The method of claim 1 or 2, wherein the cognitive tasks include one or more of an executive function task, an attention task, a planning task, and a memory task.

4. 4. The method of claim 3, wherein the cognitive tasks include one or more of a vigilance task, a flanker task, and a Posner cueing task.

5. The method of claim 1 , wherein the additional cognitive load comprises one or both of an eye movement load and a pupil measurement load.

6. The method of claim 1 , wherein the additional cognitive load comprises an autonomic nervous system (ANS) regulatory load.

7. 7. The method according to claim 1, wherein the additional cognitive load comprises additional tests involving working memory or attention.

8. 8. The method of claim 1, wherein the additional cognitive load comprises an additional time constraint for the task, a degraded stimulation quality, or an increased stimulation frequency.

9. 9. The method of claim 1, wherein the additional cognitive load is variable based on a level of real-time brain activity obtained by fMRI analysis.

10. The method of claim 1 , further comprising monitoring vital signs of the subject.

11. 11. The method of claim 1, further comprising assessing cognitive load using eye-tracking.

12. A computer program having a computer program code adapted to perform the method according to any one of claims 1 to 11, when the program is run on a computer.

13. A processor programmed with the computer program of claim 12.

14. 1. A system for assessing cognitive ability, comprising: an input for receiving fMRI images of the subject's brain activity while performing a set of cognitive tasks; 14. The processor of claim 13 for delivering tasks to the subject and for controlling an output device for processing the fMRI images. The system has:

15. 1. An MRI system comprising: fMRI scanner and an output device for delivering a task to a subject; A system for assessing cognitive ability according to claim 14; 1. An MRI system comprising:

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