Background: Repetitive transcranial magnetic stimulation (RTMS) has been suggested as a possible therapeutic alternative for patients with schizophrenia (SCZ) and treatment-resistant auditory verbal hallucinations (AVH). The aim of the studies presented here was to investigate how RTMS affects clinical symptoms, electroencephalographic responses, and brain functional networks. We suspected improvement of symptoms accompanied by changes in EEG activity, event-related potentials, and sensory gating.
Subjects and methods: Ten patients with schizophrenia (mean age 32.4, SD = 6.85, 7m, 3f) and six healthy controls (mean age 30.3, SD = 7.5, 4m, 2f) participated in this study. Nine patients were on antipsychotic medication. The patients were randomly selected into two groups, the treatment group (TG) and the control group (CG). The active low-frequency 1Hz RTMS was delivered in ten daily sessions of 900 pulses at two different EEG locations: T3-P3 (TG) and Cz (CG). Clinical symptoms were investigated with psychometric scales like Quality of Life (QoL), Depression Anxiety Stress Scales (DASS), and Psychotic Symptom Rating Scale with Auditory Hallucinations Subscale (PSYRATS AHS). The neurophysiological tests employed were cortical and cutaneous silent period, mid-latency auditory evoked potentials (P50, N100, P200) using a paired click paradigm, P300 obtained with an auditory oddball paradigm, and the cognitively driven auditory-motor task (AMT). Time, frequency domains, and functional network organization of different neurophysiological markers were analyzed. P300 oscillatory activity was analyzed with EEG source connectivity (e.g., participation coefficient) and for the auditory-motor task-induced oscillations, we used network integration parameters of graph theory (i.e., characteristic path length - CPL and small worldness - SW). The patient's results obtained after the treatment (T2) were compared with data obtained at baseline condition (T1) and with data from the third group of healthy controls (HC).
Results: There were no significant changes between TG and CG on QoL, DASS, and PSYRATS AHS scores or neurophysiological data after the RTMS treatment. We also calculated pre-post RTMS changes for all patients. N100 showed the most marked changes after RTMS in left temporoparietal region, from -0.57 μV (SD 0.97) to -2.39 μV (SD 1.59), (p = 0.006, η2 = 0.346) and in medial posterior region (p = 0.038, η2 = 0.218) suggesting a modulation of this marker over both stimulation sites. After RTMS, N100-P300 voltage increased for six patients, two in TG and four in CG, but also decreased in patients from TG who showed the best clinical outcome. The EEG power spectral density (PSD) during the auditory oddball paradigm increased in T2, mainly for the alpha band and beta band globally, for six subjects, two in TG and four in CG. The connectivity results for the frequent stimuli of the auditory oddball paradigm showed increased network segregation during T2 for the beta band, in seven patients, four in CG, and three in TG. The study revealed that patients with schizophrenia exhibit higher gamma PSD in a period between two auditory commands of AMT, compared to HC, which was modified by RTMS without being significant. The change was visible, locally, over the left temporoparietal region, when the task was done with the non-dominant hand, showing that during this condition, gamma synchronization is a marker of “neural effort” and workload during the working memory-related time and not during the auditory or motor cortical activation. Graph theory analyzed for low-gamma EEG activity elicited in between the auditory stimuli, an epoch of the auditory-motor task we called “non-cortical activation” and which is related to the working memory, showed a decreased SW index after RTMS when the task was performed with the non-dominant hand. This SW effect observed in the patients was similar to that of the HC group. Kendall's tau-b correlation showed a strong, negative correlation between the SW index of low-gamma phase oscillations and PSYRATS AHS scores in T1, which was statistically significant (τb = −0.788, p = 0.032). After RTMS (T2) the correlation was strongly positive (τb = 0.733, p = 0.039).
Discussion: The sample size of this study was small to achieve TG-CG statistical significance (e.g., PSYRATS AHS pre-calculated N was 16). Individual data showed controversial results, sometimes with the improvement of AVH severity and neurophysiological data in patients treated at the Cz EEG location. N100 from the paired click paradigm showed the most marked changes at the left temporoparietal region. P300 was performed with a passive auditory oddball paradigm by “automatic” discrimination between two tones without asking the subject to move the finger or count the target stimuli. The findings we obtained with P300 amplitude, which in most cases decreased after RTMS, might be in direct relation to a habituation effect, which is seen in healthy subjects (Polich, 1989).
Conclusion: Based on the patient ́s clinical evaluations and all the neurophysiological measurements presented in the studies of this thesis we cannot affirm that left temporoparietal (T3-P3) RTMS is more effective than vertex (Cz) RTMS in patients with schizophrenia and auditory verbal hallucinations. Some interesting neurophysiological observations were made, particularly changes of N100 amplitude at the left temporoparietal region and low gamma activity during the period in between auditory commands of a cognitively driven task. N100 amplitude measured from a paired click paradigm and low gamma activity measured in-between auditory stimuli of AMT performed with the non-dominant hand might be of interest to assess the neuromodulatory aftereffects of RTMS in patients with SCZ and AVH. The small-world network of low gamma activity showed a significant main effect of the condition (AMT and resting state) for HC and SCZ-T2 suggesting that RTMS might have influenced the network by restoring the SW index. Further, studies with a multimodal neurophysiological approach are necessary to assess RTMS effectiveness for patients with SCZ and AVH.