Conditional associative learning examined in a paralyzed patient with amyotrophic lateral sclerosis using brain-computer interface technology
© Iversen et al; licensee BioMed Central Ltd. 2008
Received: 09 July 2008
Accepted: 24 November 2008
Published: 24 November 2008
Brain-computer interface methodology based on self-regulation of slow-cortical potentials (SCPs) of the EEG (electroencephalogram) was used to assess conditional associative learning in one severely paralyzed, late-stage ALS patient. After having been taught arbitrary stimulus relations, he was evaluated for formation of equivalence classes among the trained stimuli.
A monitor presented visual information in two targets. The method of teaching was matching to sample. Three types of stimuli were presented: signs (A), colored disks (B), and geometrical shapes (C). The sample was one type, and the choice was between two stimuli from another type. The patient used his SCP to steer a cursor to one of the targets. A smiley was presented as a reward when he hit the correct target. The patient was taught A-B and B-C (sample – comparison) matching with three stimuli of each type. Tests for stimulus equivalence involved the untaught B-A, C-B, A-C, and C-A relations. An additional test was discrimination between all three stimuli of one equivalence class presented together versus three unrelated stimuli. The patient also had sessions with identity matching using the same stimuli.
The patient showed high accuracy, close to 100%, on identity matching and could therefore discriminate the stimuli and control the cursor correctly. Acquisition of A-B matching took 11 sessions (of 70 trials each) and had to be broken into simpler units before he could learn it. Acquisition of B-C matching took two sessions. The patient passed all equivalence class tests at 90% or higher.
The patient may have had a deficit in acquisition of the first conditional association of signs and colored disks. In contrast, the patient showed clear evidence that A-B and B-C training had resulted in formation of equivalence classes. The brain-computer interface technology combined with the matching to sample method is a useful way to assess various cognitive abilities of severely paralyzed patients, who are without reliable motor control.
Forming relations among arbitrary stimuli is the hallmark of human learning. For example, we readily learn that a picture of an object can represent the object and that a printed word can represent both. Such relational learning among stimuli is formally studied as conditional associations or conditional relations, and the formation of equivalence classes among the stimuli is a highly relevant topic in both research and education (e.g., [1, 2]). Given the ubiquity of equivalence class formation, recent studies have examined neural correlates of class formation [3, 4]. Deficiencies in equivalence class formation have been examined in children with developmental disorders (e.g., ). Here we report on a method for assessment of equivalence class formation in one severely paralyzed patient with amyotrophic lateral sclerosis (ALS).
ALS can lead to motor disability so severe that the patient enters the "locked-in" syndrome. The patient can neither move nor speak and has therefore lost customary means of communication . The general literature on ALS suggests that some patients have cognitive deficits and frontal lobe deterioration [6–8], but some studies find only few cognitive deficits and only in some tasks [9, 10]. Assessing the cognitive abilities of patients at the late stage of paralysis is difficult because of their lack of reliable control of a motor response. Some late-stage ALS patients can learn to communicate reliably using only their EEG [11, 12]. Patients can learn to control certain components of their EEG after biofeedback training and through a brain-computer interface can direct the movement of a cursor on a computer screen by regulating their EEG. Thus, the patient can use the EEG to make a voluntary response that requires no neuromuscular control but which can nonetheless be observed in the form of the visual feedback of the EEG change. The basic EEG-control task was used previously to teach ALS patients to compose words, letter by letter, using cursor movement to select characters of the alphabet [12–14]. The task has been described in detail elsewhere .
Using this EEG-control task, Iversen et al.  trained two severely paralyzed ALS patients to respond with high accuracy in a two-choice task so that they could answer questions relating to their cognitive skills. For example, a noun and a verb were presented, one in each choice target, and the patients were given the verbal instruction to steer the cursor to the noun on each trial. Similarly, other tasks assessed basic abilities such as: odd/even number discrimination, and discrimination of larger/smaller numbers. Performance was also assessed using a matching-to-sample paradigm , which was used to examine the ability to discriminate numbers, letters, colors, and to perform simple calculations. The two patients in Iversen et al.  performed above 90% correct on most tasks and thereby demonstrated that they understood the instructions, discriminated the stimuli, and could control the cursor by their EEG. Importantly, the method also detected that both patients had a possible deficit in tasks related to numerical computation, and one patient tested on delayed matching to sample showed inability to remember the sample stimulus at intervals longer than 5 s.
A task that is used for examination of acquisition of novel relations among stimuli is the so-called conditional-associative learning task, which tests the acquisition of arbitrary associations among visual stimuli (e.g., ). For example, Röttig et al.  presented a task to 15 non-bulbar ALS patients where the participants had to learn to associate each of six pictures with a meaningless pattern; the response was a distinct motor response of pointing to the correct design; none of the patients showed a deficit in this conditional-associative learning task. In general, performance on tasks that relate behavior to stimuli has been studied for a variety of brain injuries, including early work with aphasia patients (e.g., ).
One male patient with advanced ALS participated in the study. Patient ER had sporadic ALS with disease onset at age 38 and was 44 at the time of the study. He had tetraplegia and respiratory weakness with incomprehensible speech. He had control over eye movements and rudimentary control of one foot. He was not artificially ventilated or fed. Patient ER was fluent in Turkish and could understand but not read German. The patient lived at home being cared for by family members and professional caregivers. Prior to the present study he had participated in EEG training for several months and had learned efficient control of cursor movement. Patient ER had been taught to use a program to communicate messages to his caregivers [19, 20]. Using the same general method, he had also participated in a study that examined cognitive abilities with a matching to sample method similar to the one used in the present study . In the present study, the patient was trained or tested once each or every other week in his home environment. Each training day usually lasted 2–3 h and consisted of several 5–10 min training sessions separated by 5–10 min breaks during which the patient relaxed and the trainer checked equipment. On a given training day, patient ER also had other training sessions unrelated to the present experiment.
Apparatus and recording
EEG was recorded from the vertex referenced to linked mastoids at a sampling rate of 256 Hz. The EEG signal was amplified using a conventional 16-channel amplifier (EEG 8, Contact Precision Instruments) with a low-pass filter of 40 Hz, and a high-pass filter of 0.01 Hz corresponding to a time constant of 16 s. Electrodes were 8 mm Ag/AgCl electrodes fixed with elefix cream at an impedance of less than 5 kOhm. Vertical eye movement was recorded with electrodes attached above and below one of the eyes. Slow cortical potentials (SCPs) were extracted from the on-line EEG signal and corrected for eye movement artifacts . The criterion SCP amplitude changes were usually in the 30–50 μV range and were converted to visual feedback in the form of vertical movement of a small cursor on the monitor of a notebook computer (Toshiba Satellite 210CT), which was placed about 1 m from the patient's face .
When the study began, the patient had prior experience in controlling the cursor on the computer screen by means of SCP changes in his EEG. Specifically, the patient had experience in controlling the cursor in matching to sample tasks using identical stimuli such as signs, colored disks, and geometrical shapes . Thus, the patient had a prerequisite skill of identity matching with these stimuli at above 90% correct, with several sessions at 100% correct. Therefore, it was known that he understood the task, could control the cursor by his EEG, and that he could discriminate the stimuli that were to be used in the present experiment. Given this demonstration that these basic abilities were intact for this patient, possible performance decrements on the conditional relation task or in the formation of equivalence classes could be interpreted as indicative of possible deficits of the specific cognitive abilities related to formation of conditional relations.
The sample and the choices differed from trial to trial, and the location of the correct target varied randomly between the upper or lower position from trial to trial as well. Thus, the patient had to look at both the sample and the choice stimuli on each trial to solve the task correctly.
The stimuli were all within the size frame of 2 cm high and wide. Specifically, we used three types of stimuli with three elements of each type: three signs $, &, and #; three disks colored blue, red, and green; and three geometrical shapes triangle, square, and diamond (e.g., Fig 1). On each trial, one stimulus was presented as a sample on the left side of the monitor and two stimuli were presented as choices, with each choice stimulus centered in one choice box. The two choice stimuli were always of the same type (i.e., two signs, two colored disks, or two shapes), and the sample was always a different type. There was no requirement to make an observing response to the sample (which is a common requirement in research with conditional relations [2, 16]); however, the patient obviously had to look at the sample to be able to solve the task. The patient had to learn which of the two choice stimuli was correct for a given sample stimulus. Because the symbolic stimulus relations were arbitrary (i.e., $ to Blue, & to Red, and # to Green), the task was different from the identity matching tasks that the patient was familiar with. The patient was instructed for both training and test sessions that he had to figure out by himself what was the correct stimulus.
Training and testing steps, brief description of procedure and number of sessions for each step.
Training (A → B Relations)
A1 → B1, A2 → B2, A3 → B3
1, 2, 3, 4, 5
A1 → B1, A2 → B2
A1 → B1, A3 → B3
A2 → B2, A3 → B3
A1 → B1, A2 → B2, A3 → B3
Testing (B → A Symmetry)
B1 → A1, B2 → A2, B3 → A3 probes
Training (B → C Relations)
B1 → C1, B2 → C2, B3 → C3
Testing (C → B Symmetry)
C1 → B1, C2 → B2, C3 → B3 probes
Testing (A → C Transitivity)
A1 → C1, A2 → C2, A3 → C3 probes
18, 19, 20
(Session 19: retraining of all A → B relations, session 11 repeated)
Repetition of steps 2, 3, 4, and 5
21, 22, 23, 24
Relations within sessions:
A → B, B → A, B → C, C → B
Testing (C → A Equivalence)
C1 → A1, C2 → A2, C3 → A3 probes
Steps 2, 3, 4, 5 and 8 repeated
29 – 39
Whole Class Testing
Ax+Bx+Cx versus other combinations
40, 41, 42, 43
Training A → B. The relation A → B was presented for the first five sessions using all three stimuli from each type. Thus, the presentations mixed within each session were A1 → B1 ($ to Blue), A2 → B2 (& to Red), and A3 → B3 (# to Green). Stimuli and their nomenclature are used as in Fig. 1. Because the patient did not learn the relations in these five sessions, the procedure was simplified to two relations each session until the patient achieved at least 90% correct. Thus, we presented A1 → B1 and A2 → B2 for one session, A1 → B1 and A3 → B3 for two sessions, and A2 → B2 and A3 → B3 for two sessions. Then all three relations were presented together again in session 11.
Symmetry testing of B → A. Once the A → B relations (all three relations) were learned, the patient was tested to see if he had also learned the reverse conditional discrimination. That is, the B stimuli were now presented as samples while the A stimuli were comparisons. During the two test sessions (12 and 13), the A → B stimuli from step 1 were presented as baseline trials while the B → A stimuli were presented in 12 probe trials (four for each of B1 → A1, B2 → A2, and B3 → A3). Probe trials were mixed with baseline trials in the symmetry testing sessions.
Training B → C. The relation B → C was presented in two sessions using all three stimuli from each type. The presentations B1 → C1 (Blue to triangle), B2 → C2 (Red to square), and B3 → C3 (Green to diamond) were mixed within each session.
Symmetry testing of C → B. Once the B → C relations in step 3 were learned, the C → B relations were tested by presenting the C stimuli as samples and the B stimuli as comparisons in 12 probe trials while the B → C relations from step 3 were presented as baseline trials.
Transitivity testing of A → C. After the symmetry tests, the transitive relation A → C was tested with an A stimulus as sample and two C stimuli as comparisons. The 12 A → C probe trials were mixed with B → C relations as baseline trials. A procedural error occurred prior to the first transitivity test. The trainer had inadvertently missed to run one session from the protocol with the method of step 1 to reacquaint the patient with the A stimuli as samples, which had been absent during steps 3 and 4. After the first test session of transitivity, the patient therefore had one session with A → B trials; that is, the method from session 11 was repeated in session 19. Then session 20 presented one more transitivity test.
Maintenance training. For four sessions, the training was simply a repetition of sessions from steps 2, 3, 4, and 5.
Maintenance training with mixed relations within sessions. As a preparation for the next equivalence test, trials in a session were mixtures of the A → B, B → A, B → C, and C → B relations.
Equivalence testing of C → A. The reversed transitivity relation C → A was tested by having the C stimuli serve as samples for choices between A stimuli in 12 probe trials. The baseline trials were as in step 7 except that the C → B relations were omitted.
Maintenance training. The procedures from steps 2, 3, 4, 5 and 8 were repeated for 11 sessions.
Distribution of sessions over the 10 days that the patient was trained and tested.
3 – 11
13 – 20
21 – 28
29 – 35
39 – 41
During the first five training days where the patient had identity matching sessions using the same stimuli as in the conditional relation procedures, the patient maintained a high level of accuracy ranging from 88.6% to 100%, with an average of 96.3% (N = 19 sessions); six sessions were at 100%.
After the B → A symmetry test, the patient was taught the B → C relations (all three at the same time) in sessions 14 and 15 and learned all three in those two sessions in contrast to the slow learning of the A → B relations in sessions 1 though 11. On the C → B symmetry probe trials, patient ER scored 92% and 98% correct indicating that the taught B → C relations were symmetric. The A → C test for transitivity was given prematurely on session 18 by mistake (see procedure), and the patient scored at chance level on probe trials while maintaining the baseline at close to 100% correct. Because the patient had not been exposed to the A → B relations for some sessions, this relation was reintroduced in session 19. A new A → C transitivity test in the following session 20 showed nearly 100% correct on both baseline and probe trials indicating that the taught A → B and B → C relations were transitive.
To prepare the patient for the C → A equivalence test, two sessions presented all the necessary trial types (see Table 1) in mixed order for sessions 25 and 26, and the overall accuracy was above 90%. On the two C → A equivalence tests, the patient scored 90% and 100% correct, respectively, indicating that the taught A → B and B → C relations were equivalent; the baseline accuracy was close to 95% in both sessions.
After the equivalence test, steps 2, 3, 4, 5 and 8 were repeated as step 9 over 11 sessions (sessions 29 – 39) to maintain the overall performance. Accuracy on baseline and probe trials was above 90% on each of these sessions, and data are not shown to save space.
The last test involved a choice between groups of stimuli; one group showed three equivalence class-related stimuli together while the other group showed three stimuli that did not constitute an equivalence class. All trials in these test sessions were of this type (two test types were presented, see procedure). Each test was presented twice. For the first two sessions, the accuracy was 94.4% and 98.3% for Test 1 and Test 2, respectively. For the next two sessions, the percent correct was 98.3 for both Test 1 and Test 2. That the overall correct selection was very close to 100% on all four sessions indicates that the patient easily identified and selected the group of stimuli that formed an equivalence class.
The patient reliably matched correctly when the stimuli were used in identity matching indicating that he understood the task, could discriminate the stimuli, and could control the cursor with the SCP of his EEG. When instructed to learn on his own the arbitrary conditional associations between the stimuli from type A and B, the A → B relations, he showed no learning after five sessions, and the task had to be broken into simpler steps of only two different associations per session before he could learn it. The next B → C relations were learned much faster in two sessions with all three associations presented within each session.
When tested for symmetry, transitivity, and equivalence, the patient scored at or above 90% indicating that A → B and B → C training had formed equivalence classes of the trained stimuli. However, on the first transitivity test (A → C) he scored at chance level. Because of a logistic mistake, the patient was not given a reminder session of the A → B relations (after B → C training and C → B symmetry testing) before the A → C transitivity test, and that may have resulted in the low score because his transitivity test was at high accuracy after the reminder session. The patient was also tested for discrimination of whole classes in a novel test. He could easily select the group of stimuli that formed a class over a group of stimuli that did not form a class. Whole class tests may resemble a few cases of reported sorting or categorization of equivalence class stimuli (e.g., [23, 24]). Such tests may be useful supplements to customary equivalence testing.
The smiley was presented after a correct selection for all session types, including test probes. Customarily in testing for equivalence classes, subjects are not informed during testing whether they are correct or not . This is done to avoid teaching the new relations during testing. Ideally that should also have been the case in the present experiment. However, at the time when the experiment was carried out it was impractical to modify the existing, hardwired feedback procedure of presenting a smiley after a correct selection. Evidence in our data suggests that the patient most likely did not learn the tested relations during testing. First, the acquisition of the A → B relations took 11 sessions and the acquisition of the B → C relations took two sessions. This indicates that for this patient, learning new relations was not instantaneous after just a few correct trials. Second, an analysis of performance on individual probe trials suggested that the patient selected correctly from the beginning of probe test sessions, which indicates that the relations were acquired as a result of learning in prior training sessions. Third, on the first test session for transitivity (A → C relations), the patient did poorly on probe trials throughout the session indicating that he did not learn quickly from just a few correct trials. Thus, collectively, these pieces of evidence suggest that in the present experiment, the equivalence classes did form during training and not during testing.
The diagnostic instrument developed here is for use with severely paralyzed persons, who cannot be adequately examined for possible cognitive deficits with traditional neuropsychological instruments that require a reliable motor skill of some form. The tasks presented here required pretraining to learn to use the SCP of the EEG to control the brain-computer interface. Control participants were not used. Instead, a within-subject design was used to compare the patient to himself as a control . Thus, when the patient was excellent on one task (e.g., identity matching) but performed poorly on a second similar task (e.g., conditional relation of A → B) on the same training day, using the same stimuli, the inference can be drawn that the patient did not lack the skill to discriminate the stimuli or the skill to control the cursor; instead he lacked some ability to process information for the second task. Thus, with this single-subject design, the tentative conclusion could be reached that the late-stage ALS patient we tested may have had some selected cognitive deficits, specifically in terms of ability to acquire simple conditional associate learning relations.
The same patient was tested with delayed identity matching using geometrical forms as stimuli . Without delay between sample and comparisons, the patient was close to 100% correct but with a delay between sample of comparison of 5 s or longer, the patient scored at chance level indicating a possible severe deficit in short-term memory. It is conceivable that the deficit in acquisition of the A → B relation in the present experiment, which the patient did not learn at all within five sessions of exposure to the task, reflects the same deficit he showed in the short-term memory test. To learn arbitrary associations between stimuli, the participant has to remember what happened on previous trials within the past few minutes in a given session to learn from the feedback. The literature indicates that healthy subjects can acquire very complex conditional associations within a time span much shorter than it took the patient in the present experiment (e.g., ). Once a relation is acquired, and once relations form equivalence classes during training, then responding correctly during equivalence testing may, loosely speaking, be a matter of long-term memory [26, 27], for which the patient showed no deficit.
Studies of equivalence class formation in brain-injured patients are relevant for an understanding of brain mechanisms and also for the development of teaching methods for patients who may have lost skills due to injury or disease. Thus, conditional-relations training can be used to teach more relations than are presented in training. In the present experiment only two relations were explicitly taught, the A → B and the B → C relations, while the remaining relations actually emerged through the training . Thus, this type of training can be used to teach new skills to patients with brain injury. For example, similar conditional-relation training was used to teach emotion naming  or face naming  to adults who had lost such skills due to brain injuries.
One limitation of the present study is that the ability to control the SCP of the EEG is a prerequisite skill for responding correctly in the two-choice task. Such training to control the SCP may take weeks, and some ALS patients do not learn the skill [12, 22]. An alternative approach would be to use a different type of BCI which operates on the basis of event-related potentials (P300) and allows for presentation of at least four choices [29–31]. This method does not require lengthy training.
The main impetus of the present research was to develop a method that could assess cognitive function in late-stage paralyzed ALS patients with no remaining reliable motor control. With only one patient, the present results should be considered preliminary. Thus, while there may be cognitive deficits associated with ALS, such as slowness in acquiring new conditional associations, it should be reemphasized that the patient did form equivalence classes of the stimuli, as healthy human subjects ordinarily do. Thus, even late-stage, locked-in patients, who may appear completely separated from their world in terms of communication, actually still may have considerable cognitive abilities and can be enabled to express their thoughts and wishes by means of brain-computer interfaces [31–33].
amyotrophic lateral sclerosis
The first author was funded by a grant from Deutsche Forschungsgemeinschaft (DFG). The project was funded by a grant to N. Birbaumer (SFB 550/B5).
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