Edited by: Martijn Arns, Research Institute Brainclinics, Netherlands
Reviewed by: Sarah N. Wyckoff, Sense Labs, USA; Kerstin Mayer, University of Tübingen, Germany
*Correspondence: Holger Gevensleben, Child and Adolescent Psychiatry, University Medical Center (UMG), Von-Siebold-Str.5, D-37075 Göttingen, Germany e-mail:
This article was submitted to the journal Frontiers in Human Neuroscience.
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To elucidate basic mechanisms underlying neurofeedback we investigated neural mechanisms of training of slow cortical potentials (SCPs) by considering EEG- and fMRI. Additionally, we analyzed the feasibility of a double-blind, placebo-controlled design in NF research based on regulation performance during treatment sessions and self-assessment of the participants. Twenty healthy adults participated in 16 sessions of SCPs training: 9 participants received regular SCP training, 11 participants received sham feedback. At three time points (pre, intermediate, post) fMRI and EEG/ERP-measurements were conducted during a continuous performance test (CPT). Performance-data during the sessions (regulation performance) in the treatment group and the placebo group were analyzed. Analysis of EEG-activity revealed in the SCP group a strong enhancement of the CNV (electrode Cz) at the intermediate assessment, followed by a decrease back to baseline at the post-treatment assessment. In contrast, in the placebo group a continuous but smaller increase of the CNV could be obtained from pre to post assessment. The increase of the CNV in the SCP group at intermediate testing was superior to the enhancement in the placebo group. The changes of the CNV were accompanied by a continuous improvement in the test performance of the CPT from pre to intermediate to post assessment comparable in both groups. The change of the CNV in the SCP group is interpreted as an indicator of neural plasticity and efficiency while an increase of the CNV in the placebo group might reflect learning and improved timing due to the frequent task repetition. In the fMRI analysis evidence was obtained for neuronal plasticity. After regular SCP neurofeedback activation in the posterior parietal cortex decreased from the pre- to the intermediate measurement and increased again in the post measurement, inversely following the U-shaped increase and decrease of the tCNV EEG amplitude in the SCP-trained group. Furthermore, we found a localized increase of activity in the anterior cingulate cortex (ACC). Analyses of the estimation of treatment assignment by the participants indicate feasibility of blinding. Participants could not assess treatment assignment confidently. Participants of the SCP-group improved regulation capability during treatment sessions (in contrast to the participants of the placebo-group), although regulation capability appeared to be instable, presumably due to diminished confidence in the training (SCP- or sham-training). Our results indicate that SCP training in healthy adults might lead to functional changes in neuronal circuits serving cognitive preparation even after a limited number of sessions.
Local cortical oscillations shape sensory, motor, and cognitive processes (Rothenberger,
The generation of a contingent negative variation (CNV), a characteristic negative SCP representing anticipatory attention, motivation, and motor preparation (Walter et al.,
Regulation of SCPs appears to be attenuated in children with ADHD, as indicated by a reduced CNV during CPT tasks (Banaschewski et al.,
Beyond neurobiological considerations, psychological (cognitive behavioral) operators or mechanisms of neurofeedback are hypothesized, but not empirical validated. Generation of SCP regulation capability (learning of neuro-regulation of SCPs) is assumed to rely on operant learning mechanisms, sharing pathways with skill motor acquisition (Strehl, this issue; Birbaumer et al.,
In order to investigate neurobiological and psychological mechanisms of action of SCP training, we analyzed the impact of SCP training on the tCNV and conducted fMRI-whole brain analysis (parietal cortex ACC) in a CPT with long ISI. Using electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) enabled us to investigate neural correlates of late anticipation (related to negative SCPs) at high temporal resolution (EEG) and at high spatial resolution (fMRI).
A second aim was to analyze the relation between the treatment evaluation (believe to get through a SCP- or placebo-training) and the acquisition of neuro-regulation capability during the training sessions.
Twenty healthy adults (age 18–29) participated in a SCP or sham NF-training, as well as in fMRI and EEG assessments. All experimental procedures conformed fully the institutional guidelines. The trial was approved by the local ethics committee of the University Medical Center Göttingen (UMG). Participants were informed about the purposes of the study and gave written informed consent. They were paid 85€ for the completion of the study. All participants were screened for mental/psychiatric disorders with the SKID-I screening questionnaire (Wittchen et al.,
Sample | SCP ( |
Placebo ( |
---|---|---|
23.2 (2.91) | 22.9 (2.98) | |
7/2 | ||
10 (2.56) | 10.30 (1.44) | |
21.44 (9.15) | 16.45 (4.30) | |
0.15 (0.14) | 0.29 (0.34) |
The study consisted of a SCP training and pre-, intermediate-, and post- training EEG and fMRI measurements. Subjects were, in a double-blind procedure, pseudo-randomly assigned to either real-SCP or sham-SCP training. Both trainings consisted of 16 training units of about 45 min each. Two units, divided by a short break, were conducted in each training session. The 8 training sessions were spread across 3 weeks, with generally two to three sessions per week depending on the schedule of the participants.
EEG- and fMRI-measurement were conducted before the first session (pre-test), after 4 sessions (intermediate-test), and after the final session (post-test). EEG measurements were performed in the EEG laboratory of the Department of Child and Adolescent Psychiatry, University Medical Center, Göttingen (UMG). FMRI measurements were performed at the Biomedizinische NMR Forschungs GmbH, Max Planck Institute for Biophysical Chemistry, Göttingen. The EEG and fMRI measurements at each time point were conducted within a week.
The neurofeedback program SAM (“Self-regulation and Attention Management”) was used for both the SCP and the sham training. The SAM-system has been developed by our study group for scientific purposes and has been employed effectively in different previous NF studies (Heinrich et al.,
Within the SAM training units, participants were asked to direct a ball on a computer screen upwards (negative SCP trials) or downwards (positive SCP trials) by generating negative or positive SCPs. All participants were instructed to get into an attentive (negative SCP trials) or relaxed state (positive SCP trials). Negative SCP and positive SCP trials were presented with equal probability in random order. One trial lasted for 8 s (baseline period: 2 s, feedback period: 6 s), inter-trial-interval was set to 5 ± 1 s. During the feedback phase, the mean SCP amplitude (moving time window: 1 s) was calculated at a rate of 10 Hz (10 times per second). Each SCP training unit presented approximately 120 trials and lasted 25–30 min. At least 1/3 transfer trials were conducted, where no feedback was provided. Transfer trials are thought to facilitate generalization (Heinrich et al.,
Feedback was calculated from the Cz electrode, which is standard for SCP training (Heinrich et al.,
In placebo training, the feedback data of participants of a previous study were used, providing an appropriate range of different feedback curves. These curves were weighted by coefficients to control the development of positive and negative SCPs in the course of the training such that participants should have the impression of the development of poor, average or good regulation skills over the course of the training. Three subjects (one third) of the placebo group were assigned to each of this “skill impression” group. Different approaches were taken to guarantee the blindness of the participants as well as of the trainers towards the training condition. Trainers did not see the online recorded EEG signal, but only the (real or simulated) feedback curve. Participants also saw the (real or simulated) feedback curve. For all participants (SCP and sham) the online recorded EOG signal was shown on the screen during the trials and the artifact detection was based in both training groups on the actual online EEG and EOG signals. This is considered to be an essential component to guarantee blindness of trainer and participant in a placebo-controlled study.
On a five-point-scale (0 = “I strongly agree”; 1 = “I rather agree; 2 = “I don’t know; 3 = I rather disagree; 4 = “I strongly disagree”) participants rated their estimation of group assignment (“I’m involved in a regular neurofeedback training”) following each training sessions. The assessment controls for blinding and/or differences in the evaluation/estimation of the training. Furthermore the analysis of the guessed treatment assignment allowed investigating a potential relation between the estimation of the training and the development of regulation capability in the SCP group.
During the training sessions subjects were instructed to generate shifts of cortical excitability (SCPs) towards positivity (reduced excitability) or negativity (enhanced excitability). Regulation indices were calculated as the difference between the EEG-activity during positivity trials vs. negativity trials, reflecting a measure of neuro-regulation capability. Due to the slow development of a SCP, only the last 4 s of the 6-s-feedback-interval of a trial were taken into account (Hinterberger et al.,
The difference in the activity between positivity trials and negativity trials of one session in terms of a
The
In the pre-, intermediate-, and post-training EEG and fMRI measurements, a cued version of a continuous performance task (CPT; van Leeuwen et al.,
For the CPT, subjects were presented with the letters O, X, or H. During EEG measurements black letters against a light gray background were shown in the center of a 17-inch CRT monitor with 800 × 600 points resolution against a light gray background at a viewing angle of 1.58 vertically and 1.08 horizontally. For fMRI measurement a dedicated setup was used (Schaefter and Kirchhoff, Hamburg, Germany) to project the stimuli on a screen within the MRI bore. Here black letters against a white background were presented. Two black vertical bars were continuously present above and below the stimulus location, to direct subjects’ attention to the center of the screen.
The letters were presented for 250 ms, with an inter stimulus interval of 5750 ms. The subjects were instructed that the letter O acted as an attentional signal (cue) and that they should press a response button as fast as possible with their right thumb or index finger if the following letter was an X (target) and to refrain from pressing the response button if the following letter was an H (distractor). To encourage fast responses, correct responses (button presses) had to occur within 1000 ms from stimulus onset. After the measurement subjects received visual feedback about the percentage of correct responses, as well as their average reaction time achieved.
A total of 80 stimuli were presented in one measurement (one block, total duration about 8 min.), the probability of an O-X pair (cued target) as well as the O-H pair (cued distractor) was 20% each (16 pairs/measurement). Additionally, there was a 10% chance of an uncued H (non-target) or X being shown. The test consisted of four blocks with a short break between each block.
Electrical activity of the brain was recorded with a BrainAmp amplifier (Brain Products, Munich, Germany) and sintered Ag/AgCl electrodes with Abralyt2000 electrolyte from 23 sites according to an extended 10–20 system (recording reference: FCz, ground electrode: CPz). Electrooculogram electrodes were placed above and below the right eye and at the outer canthi. Impedances of the electrodes were kept below 10 kOhm. Data was sampled at a rate of 500 Hz (bandwidth: 0.016–120 Hz).
Data were processed with Vision Analyzer software (Brain Products, Munich, Germany). Brain electrical activity was re-referenced to the average, and filtered offline with 0.05–30 Hz, 24 dB/oct Butterworth filters. Ocular artifacts were corrected by the methods described by Gratton et al. (
All MRI measurements were conducted at 3T (Siemens Tim Trio, Erlangen, Germany) using a 12-channel receive-only head coil. Individual structural T1-weighted MRI datasets were acquired using a 3D MP-RAGE sequence (1.3 × 1 × 1.3 mm3, interpolated to 1 × 1 × 1 mm3). fMRI was acquired with a single-shot, gradient-echo EPI sequence (TR = 2000 ms, TE = 36 ms, flip angle = 70°, 244 volumes per run) with a spatial resolution of 2 × 2 × 4 mm3 (matrix = 96 × 96, 192 mm FoV, 7/8 parial Fourier, bandwidth = 1336 Hz/pixel, echo spacing = 0.81 ms). 22 slices were acquired without gap in an interleaved fashion, positioned in the transvers-to-coronal plane, approximately parallel to the body of the corpus callosum and covering the whole cerebrum. To facilitate registration of fMRI data to the anatomical 3D image, one EPI volume with the same specifications as the functional series but with additional slices (36 slices) was acquired at the end of each fMRI session.
Evaluation of fMRI data was performed using tools from the FMRIB Software library (FSL).
First level regressors were describing the last 2 s before the presentation of the next letter in the cue (O-X, O-H) and the non-cue (H-O, H-X,) trials. Contrast of interests was set up as cue (32 trials) vs. non-cue trials (24 trials). This contrast emphasizes brain activation associated with anticipation, since subjects prepare for a possible reaction after the cue, but have no need for preparation in the non-cue trials. Contrast images were spatially normalized to the MNI152 template brain by means of their respective anatomical scan. Second-level fixed-effect analysis combined the 4 fMRI measurements within each session on the individual subject level. To summarize results across all subjects, mixed-effects group analysis was performed (Beckmann et al.,
The mean score of the
By comparing the difference of the
The relation between the mean values of
CPT performance data (reaction time) in the EEG lab session and tCNV activation repeated measure ANOVAs (factor time: pre, int, post) was computed with group (SCP, sham) as between-subject factor.
Data analyses were performed using PASW Statistics (v.18).
On a five-point-scale participants rated their estimation of group assignment. The average rating across all 20 participants was
For two subjects of the placebo group, session regulation data were lost due to hard disk problems. The analysis therefore encompassed SCP group = placebo group = 9 subjects. Due to organizational problems two subjects of the placebo group conducted only seven double-sessions. For these cases we chose a last-observation-carried-forward-approach (LOCF).
Find mean positivity and negativity for each session and session regulation indices in Table
Session | Regulation indices (μV) sessions 1–8 | ||||||
---|---|---|---|---|---|---|---|
SCP group ( |
Placebo group ( |
Contrast | |||||
Pos. (SD) | Neg. (SD) | Reg. (SD) | Pos. (SD) | Neg. (SD) | Reg. (SD) | Diff (p) | |
7.83 (7.31) | 3.42 (5.98) | 4.41 (11.37) | 10.16 (8.78) | 13.35 (17.24) | −3.19 (12.48) | 7.60 (0.20) | |
3.29 (9.95) | 0.69 (8.02) | 2.60 (5.23) | 7.45 (13.78) | 6.40 (10.10) | 1.05 (5.81) | 1.55 (0.48) | |
2.15 (5.73) | 1.83 (8.90) | 0.32 (7.36) | 5.58 (13.16) | 8.68 (11.10) | −3.10 (5.95) | 3.42 (0.16) | |
1.12 (8.31) | −3.51 (5.01) | 4.64 (8.63) | 3.06 (10.28) | 5.38 (11.02) | −2.32 (5.05) | ||
4.88 (7.41) | 0.76 (8.23) | 4.12 (5.61) | 10.39 (17.10) | 13.58 (17.05) | −3.19 (11.35) | 7.32 (0.10) | |
−1.53 (3.03) | −1.08 (6.00) | −0.45 (6.87) | 6.97 (11.71) | 7.52 (8.29) | −0.54 (6.07) | 0.09 (0.98) | |
5.40 (5.63) | −1.22 (7.28) | 6.62 (8.12) | 1.96 (8.28) | 4.10 (5.18) | −0.52 (6.82) | 7.14 (0.06) | |
6.84 (8.84) | −0.32 (7.47) | 7.16 (7.86) | 6.35 (7.74) | 5.79 (5.92) | 1.82 (6.69) | 5.34 (0.14) |
Comparison of positivity trials, negativity trials, and session regulation indices (positivity trials − negativity trials) between both training groups for each session. Positive values of the regulation-indices indicate differences between negativity and positivity trials in the desired direction.
Comparing the mean regulation index (positivity—negativity trials across all sessions) reveals a significantly enhanced regulation capability in the SCP group (
Differences in regulation capability primarily result from enhanced activity during negativity trials in the SCP group (illustrated in Figure
No significant relation between general regulation capability (
Rating session 1–8: correlation (p) | ||||||||
---|---|---|---|---|---|---|---|---|
Regulation | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 |
−0.38 (0.32) | 0.50 (0.17) | −0.41 (0.27) | 0.58 (0.10) | 0.40 (0.28) | 0.04 (0.92) | 0.27 (0.49) | ||
0.46 (0.21) | 0.58 (0.10) | −0.18 (0.64) | 0.24 (0.53) | 0.02 (0.95) | 0.27 (0.48) | −0.27 (0.48) | 0.51 (0.16) | |
−0.48 (0.19) | 0.05 (0.89) | −0.10 (0.80) | 0.24 (0.53) | −0.06 (0.88) | 0.27 (0.48) | −0.19 (0.63) |
Pearson correlation coefficients for the SCP group between regulation performance (positivity, negativity, and differentiation = positivity − negativity) and the subjective ratings of the participants guessing the group assignment (SCP vs. placebo condition).
The event-related potential following cue stimuli showed the expected slow negative tCNV with a maximum at central leads that terminates with the onset of the next stimulus (see Figure
Eight of nine subjects of the SCP group (but only the half of the placebo group) exhibited an enhancement of the CNV in the intermediate testing compared to initial measurement (pre-training testing), indicating that the intermediate CNV enhancement in the SCP group does not result from separate outliers.
Moderate to strong relations (correlation coefficients between 0.5 and 0.6) between the regulation performance (SCP during negativity trials) during single training session and the tCNV in the EEG-lab sessions developed, which however did not turn out to be significant due to the small sample size.
Response speed of correct responses showed a steady increase from pre to intermediate to the post assessment (Time:
Response speed variability (RT-SD) was lower in the first compared to the later three blocks (Block:
fMRI BOLD-activation of the last two seconds of the CPT anticipation phase was compared between SCP-trained and placebo-trained group for the three time points (pre, intermediate, post). All three analyses (pre vs. intermediate, intermediate vs. post, pre vs. post) showed no significant TIME × GROUP interaction in brain activation. However, computing within-group contrasts, three different BOLD-activation patterns became visible within the group of SCP-trained subjects (Figure
At the electrophysiological level we found a result somehow contrary to our primary expectations. The pre- to intermediate assessment in the SCP group revealed—according to our expectations—a strong increase of the tCNV during the CPT in the EEG-lab sessions. This increase in the SCP group significantly exceeded the increase of the tCNV in the placebo group. This enhancement of the parameter targeted by the SCP training (primarily related to negativity trials) was followed by a coequal tCNV decrease in the post-training assessment in the SCP group (back to baseline). Interestingly, this inverted U-like shift of the tCNV in the SCP group was accompanied by a continuing decrease in reaction time during CPT performance from pre- to intermediate assessment and from intermediate to post assessment. The continuing improvement in reaction time was comparable to the decrease of the reaction time in the placebo group. In contrast, in the placebo group the tCNV (as the assumed associated parameter of the performance on the neurophysiological level) showed a continuing increase in accordance with the decreasing reaction time. It appears that in the placebo group the increasing mobilization of neurophysiological resources (enhancement of the tCNV) is accompanied by coinciding improvement in the test performance (decreasing reaction time). Obviously the participants of the sham-group learned to optimize their CPT-performance, mobilizing more neurophysiological resources to continuously improve performance (learning/repetition effects). On the other hand, in the SCP group, the continuing improvement in reaction time is accompanied by an initial increase in the mobilization of neurophysiological resources in case of an enhanced tCNV in the intermediate testing, followed by reduction of neurophysiological effort accompanied by a further enhancement of the performance. Hence, it may be that subjects conducting SCP training require less neurophysiological resources to achieve a comparable performance in the long run (at post-training assessment).
This interpretation is in accordance with observations concerning e.g., professional musicians or elite athletes engaged in highly over-learned motor skill tasks. Long term practicing motor performance might lead to a more efficient generation of neural activity (reduced or more focused activity accompanying improvements in performance). In professional piano players motor areas were activated to a lesser degree during finger tapping tasks than in non-musicians (Jäncke et al.,
The decrease of the tCNV in the SCP group in the post-training assessment (compared to the intermediate testing) therefore might reflect the lesser effort which is needed after NF training to fulfill the same task with comparable adequacy. For the same task lesser neurons need to be activated (Krings et al.,
Generally, the tCNV is considered to be associated with the negative SCPs which have to be generated during the SCP-sessions (Heinrich et al.,
The development of the tCNV in the time course of this trial reveals results from previous trials studying the effects of SCP training in children with ADHD in a different light. The usual finding of SCP trials with children with ADHD is an enhanced (or less reduced) CNV after SCP training (Heinrich et al.,
The additional whole brain data of the complementary fMRI CPT measurements may provide additional indications for the interpretation of the EEG results. Even if no significant difference in the GROUP × TIME interaction of the BOLD-activation could be detected between the groups of SCP- and placebo-trained subjects, significant changes in brain activation can be seen in the SCP-group across the time course of the training (within group contrasts) but not in the placebo-group. In the posterior parietal cortex activation, peaking at the right postcentral sulcus, decreases from the pre- to the intermediate measurement and, in the posterior parietal cortex of both hemispheres, increases again in the post measurement. This pattern inversely follows the U-shaped increase and decrease of the tCNV EEG amplitude in the SCP-trained group. Since the posterior parietal cortex is a multisensory motor association area, involved in motor planning (Andersen and Buneo,
Taken together, for the SCP trained group, these BOLD-activation changes in two different areas of the brain, although being on the level of indications, provide some incidence that a successful training could not only involve multiple brain areas, but also encompass changes in different brain networks at different levels of optimization.
There is controversy about the feasibility of placebo-controlled trials in NF research. Firstly, previous trials failed to keep up blinding throughout the training and blinding came into question in placebo controlled NF (Holtmann et al.,
The estimations of our participants concerning the guessing of the treatment assignment display successful blinding. The estimation does not differ between SCP- and sham-training. The mean rating close to the middle of the rating scale reflects indecisiveness of the participants with little variance in the estimation. No significant correlation between estimation of group assignment and regulation performance could be obtained, making a significant influence of the estimation of the participants (as expected) quite improbable. However, there was not much variance in the estimations, making it hard to obtain an assumed connectivity between estimation and regulation capability. In further trials we would prefer to manipulate the estimation of the treatment directly (e.g., via opposed instructions).
Anecdotally we would like to note, that at least one participant (of the placebo-group) reported after completion of the trial that he was quite sure, that he had practiced placebo-training. He delineated his strategy that he once in a while reversed his regulation strategies but could not observe any systematic change in his displayed feedback following his switch of strategy. Additionally this underlines possible problems inherent in placebo-control in NF-research, participants spending effort in elucidating treatment assignment rather than struggling for enhanced regulation capability.
As expected, regulation capability developed differently in the SCP- compared to the placebo-group. While there was no difference in the generation of positivity during positivity trials between groups, the SCP-group learned to enhance negativity during the negativity trials (in contrast to the placebo-group). However there resulted no linear increase in regulation capability. Regulation performance in the SCP-group appeared to be instable with no significant differences in the regulation indices between SCP- and placebo-group for most of the sessions. However, acquisition of SCP-regulation capability is difficult (Neumann and Birbaumer,
The generalization of our results is limited by different factors among which we consider the most important the small sample size, which hardly allows for parametric testing. We consider the results as very relevant but preliminary and like to underline the need for replication with stronger sample sizes. The design of the study is compromised by the many repetitions of the CPT, due to the separated assessment of the EEG and fMRI measurement. This makes the test susceptible for learning processes overwriting or influencing systematic but sensible effects of the training. A combined EEG-fMRI assessment would significantly reduce the test repetitions and allow to directly put the EEG- in relation to the fMRI activity.
Nevertheless we consider these results a further step in understanding mechanisms of change in NF training, indicating neuronal plasticity even after a short number of SCP sessions although learning of SCP regulation does not appear to be optimal, probably due to blinding and uncertainty about the training condition (SCP or placebo).
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
The authors thank Christa Dahlmann and all student assistants for their valuable support. This study was supported by the German Research Foundation (with a joint grant to Hartmut Heinrich, G.H.M, and Aribert Rothenberger; HE 4536/2, MO 726/2, RO 698/4) and the Open Access Publication Funds of the Göttingen University.
1
2This provides empirical evidence for the general impression that professional soccer players often do not make much use of their mental resources (at least while executing their complex movement patterns).