Targeting Treatment-Resistant Auditory Verbal Hallucinations in Schizophrenia with fMRI-Based Neurofeedback - Exploring Different Cases of Schizophrenia

Abstract

Auditory verbal hallucinations (AVHs) are a hallmark of schizophrenia and can significantly impair patients' emotional, social, and occupational functioning. Despite progress in psychopharmacology, over 25% of schizophrenia patients suffer from treatment-resistant hallucinations. In the search for alternative treatment methods, neurofeedback (NF) emerges as a promising therapy tool. NF based on real-time functional magnetic resonance imaging (rt-fMRI) allows voluntarily change of the activity in a selected brain region - even in patients with schizophrenia. This study explored effects of NF on ongoing AVHs. The selected participants were trained in the self-regulation of activity in the anterior cingulate cortex (ACC), a key monitoring region involved in generation and intensity modulation of AVHs. Using rt-fMRI, three right-handed patients, suffering from schizophrenia and ongoing, treatment-resistant AVHs, learned control over ACC activity on three separate days. The effect of NF training on hallucinations' severity was assessed with the Auditory Vocal Hallucination Rating Scale (AVHRS) and on the affective state - with the Positive and Negative Affect Schedule (PANAS). All patients yielded significant upregulation of the ACC and reported subjective improvement in some aspects of AVHs (AVHRS) such as disturbance and suffering from the voices. In general, mood (PANAS) improved during NF training, though two patients reported worse mood after NF on the third day. ACC and reward system activity during NF learning and specific effects on mood and symptoms varied across the participants. None of them profited from the last training set in the prolonged three-session training. Moreover, individual differences emerged in brain networks activated with NF and in symptom changes, which were related to the patients' symptomatology and disease history. NF based on rt-fMRI seems a promising tool in therapy of AVHs. The patients, who suffered from continuous hallucinations for years, experienced symptom changes that may be attributed to the NF training. In order to assess the effectiveness of NF as a therapeutic method, this effect has to be studied systematically in larger groups; further, long-term effects need to be assessed. Particularly in schizophrenia, future NF studies should take into account the individual differences in reward processing, fatigue, and motivation to develop individualized training protocols.

Keywords: affect; anterior cingulate cortex; auditory hallucinations; brain–computer interface; functional magnetic resonance imaging; neurofeedback; schizophrenia; self-regulation.

Figure 1

Example of a neurofeedback run. Blocks of regulation alternated with blocks of baseline (“counting”). During regulation blocks, the fixed red bar in the upper part of the screen served as a marker of the highest ACC activity as a target. The green moving bar indicated the current level of activity in the ACC, which should be moved toward the red bar. The baseline block was indicated by a static blue bar in the center of the screen.

Figure 2

Rating of subjective control over feedback signal across days. The profiles matched roughly the achieved ACC regulation (compare Figure 6).

Figure 3

Mood ratings according to the Positive and Negative Affect Scale (PANAS) before and after each neurofeedback training. Patient 1 exhibited a trend for continuously improved positive affect. This was similar in the other two participants, except that the third day was associated with reduced positive or increased negative affect.

Figure 4

Regulation during the neurofeedback runs as compared to baseline blocks of counting (p < 0.05, FWE corrected). The activation patterns did not reveal a clear increase in regulation, but the individual clusters appeared more focused on the ACC over the 3 days of neurofeedback training in patients 2 and 3. Please note that absolute T values differ across training days and across patients (adapted color codes). However, the identical thresholds make the cluster sizes directly comparable.

Figure 5

Mapping of linear increase over days (p < 0.05, FWE corrected). The training led to increased activity in clusters encompassing midbrain structures (all patients) and – in patients 2 and 3 – in the ACC.

Figure 6

Region of interest (ROI) analysis (A) in the ACC and (B) in the reward system revealed a general trend for increasing activity over the three training days. However, the interindividual differences are remarkable; a.u., arbitrary units.

Figure 7

Transfer effect in patient 2 (p < 0.05, FWE corrected). ACC regulation emerged also in the absence of feedback after the NF training as compared to before. However, the ACC activation cluster was noticeably smaller than during the neurofeedback training (see Figure 3) and did not yield significance in patient 1. The strong activation changes in the visual system may be related to attention shifts with respect to the visual task.