Description of the AVH TMS Icelandic study and preliminary results: Changes of intracortical and motoneuronal inhibition in patients with schizophrenia and auditory verbal hallucinations
Representative and Author: Aron Dalin Jónasson
Author(s): Aron D. Jónasson1Ovidiu C. Banea1,2, Eysteinn Ívarsson1,2, Sara Marcu2,3, Paolo Gargiulo2, Viktor D. Jónasson4, Brynja B. Magnúsdóttir4, Eric Wassermann5 
1 Clinical Neurophysiology Unit, Neurology Department, National University Hospital of Iceland, Reykjavik, Iceland
2 School of Science and Engineering, Reykjavik University, Reykjavik, Iceland
3 University of Padua, Padua Italy
4 Department of Psychology, School of Business, Reykjavik University, Reykjavik, Iceland,
5 Behavioral Neurology Unit, National Institute of Neurological Disorders and Stroke, Bethesda MD, U.S.A.
Organization: ESAT - STADIUS, Katholieke Universiteit Leuven
E-mail address:
Background: Auditory verbal hallucination (AVH) is the most common positive symptom of schizophrenia. It correlates with hyperactivity at auditory area of the brain as shown by Javitt D.C. and A. R. Sweet (2015). In a recent meta-analysis on repetitive TMS as compared to sham-treatment for treatment-resistant AVH, which included 17 randomized, sham-controlled trials, the results showed that rTMS directed at the left temporoparietal area for AVH has decreased, although the effect is still significant (Slotema et al. 2012). At this moment there is not a definite consensus on the effectiveness of the rTMS treatment and the rTMS parameters to be used for the AVH drug resistant patients. The duration of the effect of rTMS may be less than one month. The authors concluded that more research is needed in order to optimize parameters and further evaluate the clinical relevance of this intervention. We aimed to identify changes in psychometric scales and neurophysiological measurements between baseline and in three different times after the treatment with repetitive transcranial magnetic stimulation applied to the left posterior temporal lobe area to patients with AVH. The research will compare a patient-treatment group (TG) which receives real rTMS treatment with a patient-control group (CG) that receives false rTMS treatment with same parameters of frequency, output intensity, number of sessions and duration (but with other localization) and a third group of healthy subjects - control group (HS). Positive symptom, stress, anxiety, depression, and quality of life will be measured before and after treatment in both the treatment group and the patient-control group. The patients are recruited from the psychiatric wards and outpatient clinics at the University Hospital of Iceland. 
Inclusion criteria: 1) Patients between 18-55 years of age, 2) with treatment resistant AVH due to schizophrenia or schizoaffective disorder. 3) for at least 1 year, and 4) experiences AVH at least once per hour. Treatment resistance AVH refers to two pharmacotherapy attempts that used recommended dosage for at least 6-8 weeks. 
Exclusion criteria: 1) History of epilepsy, 2) daily Cannabis use, 3) Use of other hard drugs within one month prior to the study or during the study, 4) drinks more than three units of alcohol daily, 5) uses benzodiazepine daily, 6) uses antiepileptic agents, 7) meet any of the exclusion criteria on the rTMS safety screening list or 8) left handedness, which we will assess with Edinburgh Handedness Inventory. Patients that meet the inclusion criteria will be offered to take part in the study. The rTMS protocol will be clearly explained to them both orally and in a written form. Written informed consent will be obtained before proceeding further. All patients will be able to discontinue the treatment at any point during the study without any influence on their current treatment at the University Hospital of Iceland. Permission from the Ethics committee of the National University Hospital was obtained in April 2018. Neurophysiological measurements P50, P300, QEEG with auditory motor task and cortical silent period (CSP) will be extensively assessed in the healthy-control group at the beginning of the study and compared with the parameters obtained in patients before, during and after the treatment: at the beginning of the study – baseline (T1), within one week after the treatment (T2), one month after the treatment (T3) and 3 months after the treatment (T4). The neurophysiological hypotheses are that rTMS treatment: 1) decreases P50 second response (sensory gating improvement), 2) increases the amplitude and reduces the latency of P300, 3) increases gamma band oscillation synchrony, and 4) increases the duration of cortical silent period (CSP) a gamma-aminobutyric acid receptors B (GABAB) mediated inhibitory activity. Changes of intracortical and motoneuronal inhibition in patients with schizophrenia and auditory verbal hallucinations We describe here the CSP/CuSP ratio as expression of intracortical GABAB intracortical inhibition and spinal motor neuron inhibition in HS group and we will compare the results with pretreatment baseline conditions for both CG (control patients group) and TG (treatment patients group). 
The voluntary contraction of the abductor pollicis brevis (APB) muscle can be suppressed cortically with a suprathreshold TMS pulse (CSP - cortical silent period) and by cutaneous noxious stimulus (CuSP - cutaneous silent period). CSP measures the intracortical inhibition produced by the activation of GABAB interneurons that synapse on pyramidal neurons and CuSP is a spinal reflex mediated by A-delta afferents that inhibits the C7-T1 motoneurons postsynaptically, through an oligosynaptic spinal circuit. We aimed to characterize both CSP and CuSP in APB muscle. 
Methods: In 6 healthy subjects, we assessed the APB silent period to cortical magnetic single pulse stimulation at 140%RMT applied on the contralateral APB motor primary cortex region while the participants performed submaximal isometric contraction. CuSP was recorded after 2nd finger dermatome electrical stimulation (10x sensory threshold) using ring electrodes. Results: The CSP showed the average duration of 160 ms (SD 20) larger than CuSP duration of 44 ms (SD 4) with average CSP end latency of 180 ms in comparison with CuSP end latency of 124 ms. Conclusions: The CSP shows larger end latency and duration in APB muscle compared to CuSP, with a duration ratio between CSP and CuSP of more than 3 to 1 (3.64).