Real-time fMRI neurofeedback (rtfMRI-nf)^1,2 is a promising technique for studies and researching novel treatments of neuropsychiatric disorders^3-5. EEG performed simultaneously with rtfMRI-nf allows investigation of electrophysiological correlates of the rtfMRI-nf training⁵. Frontal EEG asymmetry (FEA) at rest has been shown to inversely correlate with PTSD severity⁶. FEA changes during emotional stimuli have been shown to reflect PTSD patients’ response to CBT treatment⁷. Here we describe the first study using rtfMRI-nf with simultaneous EEG in PTSD patients. We show that FEA changes during a happy emotion induction task with rtfMRI-nf targeting the left amygdala (LA)⁸ provide information about the PTSD patients’ individual response to the emotion regulation training.

Fifteen male patients with a primary diagnosis of PTSD related to combat trauma have completed the study in the experimental group. The study included eight sessions (visits): an initial psychological assessment, an initial Clinician-Administered PTSD Scale for DSM-IV (CAPS) evaluation, an MRI session (structural MRI, resting fMRI, emotional Stroop task), three rtfMRI-nf training sessions with simultaneous EEG (Fig. 1A-D), a repeat MRI session, and a final CAPS evaluation (Fig. 1F). Severity of co-morbid depression was evaluated using the Hamilton Depression Rating Scale (HDRS).

The experiments were performed on a GE Discovery MR750 3T MRI scanner with an 8-channel receive-only head coil. A single-shot gradient echo EPI sequence with FOV/slice=240/2.9 mm, TR/TE=2000/30 ms, SENSE R=2, image matrix 96×96, flip=90°, 34 axial slices, was employed for fMRI. Simultaneous EEG recordings (Fig. 1B) were performed using a 32-channel MR-compatible EEG system (Brain Products GmbH) in 0.016−250 Hz band with 0.1 µV resolution and 5 kS/s sampling. The rtfMRI-nf was implemented using a custom real-time system with a neurofeedback GUI (Fig. 1A). The nf signal was based on fMRI activation in the LA target ROI⁸ (Fig. 1C). The rtfMRI-nf session protocol (Fig. 1D) included seven runs, and each run (except Rest) consisted of 40-s blocks of Rest, Happy Memories, and Count conditions. For each Happy Memories condition, the participant was asked to feel happy by evoking happy autobiographical memories, while trying to raise the level of the red bar on the screen.

EEG data analysis was performed using BrainVision Analyzer 2 as described previously⁵. Artifacts were removed using the average artifact subtraction and ICA. Time-frequency analysis was conducted with 8 ms temporal and 0.25 Hz frequency resolution using a continuous wavelet transform. The upper alpha EEG band was defined individually for each subject as [IAF…IAF+2] Hz, where IAF is the individual alpha peak frequency. Signals from frontal EEG channels F3 and F4 with Cz reference (Fig. 1E) were used to define FEA = ln(P(F4))−ln(P(F3)), where P is EEG power in the upper alpha band. Average FEA changes between Happy Memories and Rest conditions across four rtfMRI-nf runs (Practice, Runs 1-3) in each rtfMRI-nf session were computed.

Session-to-session variations in the average individual Happy vs Rest FEA changes significantly correlated with the corresponding variations in CAPS ratings (Fig. 2A) and HDRS ratings (Fig. 2B). Our interpretation of these results is illustrated in Fig. 2C. A multiple regression analysis for ∆FEA vs ∆CAPS and ∆HDRS showed a significant main effect (F(2,12)=14.7, p=0.001, R²=0.711). The partial correlation ∆FEA vs ∆CAPS when controlling for ∆HDRS: r(12)=0.71, p=0.004. The partial correlation ∆FEA vs ∆HDRS when controlling for ∆CAPS: r(12)=0.58, p=0.031. These partial correlations are close to the corresponding zero-order correlations in Figs. 2A,B.The average individual FEA changes during the rtfMRI-nf task are sensitive to severity of PTSD symptoms. This effect is similar to the one observed in patients with depression⁵. The session-to-session variations in the FEA changes provide a measure of an individual response to emotion regulation training, reflecting reduction in both PTSD severity (CAPS) and co-morbid depression severity (HDRS). The partial correlation analyses suggest that variations in CAPS ratings and variations in HDRS ratings have essentially independent effects on the observed variations in the FEA changes. Our results indicate that the FEA variations associated with the rtfMRI-nf training can serve as a measure of treatment response in PTSD.