Quantitative EEG and auditory evoked potentials before and after RTMS treatment in patients with schizophrenia
EEG Cantitativ și potențiale auditive evocate înainte și după tratamentul cu stimulare transcraniană magnetică la pacienți cu schizofrenie
Ovidiu C. Banea MD, PhD
Department of Engineering, Reykjavik University
Clinical Neurophysiology Unit, Landspítali
19th of July 2022 Conference
Summary
PART ONE
PART TWO
Schizophrenia
Chronic and severe mental disorder affecting approximately 24 million people or 1 in 300 people worldwide (WHO, 2022).
Median incidence: 15.2 cases per 100,000 persons (McGrath et al, 2004).
Multifactorial origin: It is thought that an interaction between genes, a range of environmental and probably psychosocial factors may cause schizophrenia.
Onset between 16-30 year old, found more in migrant / local, urban / rural. Much higher incidence at higher latitudes (Saha et al, 2005).
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History (The History of Schizophrenia | Pasadena Villa, n.d.)
Word schizophrenia comes from the Greek words schizo = split, and phren = mind, to describe fragmented thinking
History (The History of Schizophrenia | Pasadena Villa, n.d.)
Between physical disease and phenomenology (disorder of consciousness and self-experience)
Schizophrenia & Sensory Gating
Biomarkers and endophenotype candidates
Neuroimage biomarkers (fMRI, MRS): Dopamine hyperactivity, NMDA receptor hypofunction, hippocampal hyperactivity, immune dysregulation, dysconnectivity, cortical gray matter volume loss (Kraguljac et al., 2021)
Neurophysiological Biomarker: TMS as potential method by which sensory processing can be assessed, since TMS paradigms (CSP) can be used to measure GABAB-mediated cortical inhibition that is linked with sensory gating (Kim et al., 2020).
Endophenotypes: Assessment of P50 suppression and PPI of the startle response, eye tracking dysfunction (smooth pursuit), working memory and cognition by dysfunction and abnormality found at DLPFC level (Gottesman & Gould, 2003) , QEEG and spectral analysis (Kropotov, 2009).
Biomarker and endophenotype
The research efforts of Psychiatry must be equally focused on biological processes, psychopathological experiences, psychological - biographical connections, and social interactions,
Instead of being reduced to analyzing processes inside the brain (Thomas Fuchs, 2021)
Neuroanatomy (MRI)
Most studies have shown a grey matter volume reduction of STG but not localized to a particular type of cortex, i.e.,
Both the allocortex including the hippocampus and the isocortex including the superior temporal gyrus (STG) are affected (Psychology and Schizophrenia - Janet E. Pletson - Google Books, n.d.)
Auditory Verbal Hallucinations
Auditory verbal hallucinations is the most common positive symptom in schizophrenia.
The first treatment option for hallucinations in schizophrenia is antipsychotic medication, which can induce a rapid decrease in severity.
Antipsychotic medication does not ameliorate AVH in 20-30% of patients.
TMS
TMS is a technique in which a strong pulse of electrical current is sent through a coil. When the coil is placed over a person’s skull, this induces a magnetic field pulse in a small brain area, depolarizing local neurons up to a depth of 2 cm.
When TMS is applied repetitive, it is thought to induce longer-lasting effects as a result of long-term potentiation or depression at the neuronal level.�
Left T3P3 STG
In 1999, Hoffman and colleagues started to explore RTMS for the treatment of AVH. When the coil was directed at the left temporoparietal cortex, they were able to ameliorate medication-resistant AVH (Hoffman 1999)
Low frequency 1Hz INHIBITORY EFFECT
RTMS and AVH
Slotema et al 2014
Problem
RTMS applied at the left temporoparietal area with a frequency of 1 Hz, how effective in time?
All studies on effectiveness were assessed using psychometric scales before and after treatment.
There is still no consensus for the stimulus parameter or for the effectiveness in time.
No objective measurements as neurophysiological biomarkers were assessed for this kind of treatment
2018 RTMS study to assess efficacy on first episodes (P. Homan)
Hallucination Change Scale
PART TWO ��Towards neurophysiological biomarkers to assess the repetitive transcranial magnetic stimulation treatment for patients with schizophrenia and auditory verbal hallucinations�
The aim
To determine the degree to which repetitive transcranial magnetic stimulation (RTMS) is effective for the treatment of patients with schizophrenia and persistent auditory verbal hallucinations (AVH).
Exploratory objectives
Subjects
Ten patients (mean age 32.4, SD = 6.85) and six HC aged between (mean age 30.3, SD = 7.5) participated in the studies.
Inclusion criteria
18-55 years of age and had treatment resistant AVH for at least 1 year (lack of clinically meaningful response to two trials of pharmacotherapy at the recommended dosage, lasting at least 6 weeks)
Exclusion criteria
History of epilepsy, cannabis or other illegal drugs use within one month prior to the study or during the study, drinking more than 3 units of alcohol daily, or RTMS contraindication
The study was approved by the Ethics Committee of the National University Hospital of Iceland (Approval No 21. 2018).
Methods
Clinical outcome
Quality of Life (QoL) is a self-report scale consisting of five conceptual domains of quality of life: material and physical well-being, relationships with other people, social community and civic activities, personal development, and fulfillment, and recreation. The scale maximum score is 112 (Flanagan, 1978).
Depression Anxiety Stress Scales (DASS) is a measure of mental health focusing on three traits of depression, anxiety, and stress. Maximum score is 126 (Brown et al., 1997).
Psychotic Symptom Rating Scales (PSYRATS) The score of the PSYRATS auditory hallucinations subscale (AHS) is a structured interview that measures auditory hallucinations (11 items) The maximum score of AHS is 44 (Drake et al., 2007; Haddock et al., 1999).
Methods
Neurophysiological assessment
Protocol design
Exploratory Study 1. Using high-density EEG to assess TMS treatment in patients with schizophrenia (Marcu et al., 2020)
Sensory gating is impaired in patients with schizophrenia (Adler et al., 1985; Olincy et al., 2010) and P300 showed decreased amplitude in patients when compared to healthy controls (Turetsky et al., 2015).
RESEARCH QUESTION
We looked mostly to reproduce paired-click, and oddball auditory paradigms in healthy controls and patients with schizophrenia and to develop a quantitative method with dense-array 256 channel EEG.
Methods
The S1 response was identified as the most prominent peak in the 40 to 80 ms post-stimulus windows.
The preceding negative trough was used to calculate the S1 amplitude. For the S2 response, the positive peak with latency closest to that of the S1 peak was selected.
P50 suppression was calculated as the ratio of the mean value of the S2 amplitude to the mean value of the S1 amplitude (S2:S1).
The difference of S1 minus S2 amplitude was also used as a comparison.
Methods
The regions of interest (ROI) were defined using a MATLAB script as follow: Left Anterior (LA), Left Posterior (LP), Medial Anterior (MA), Medial Central (MC), Medial Posterior (MP), Right Anterior (RA) and Right Posterior (RP)
Fifteen electrodes were selected from 3 parallel lines for each region (105 electrodes).
Methods
N100-P300 complex values for each ROI were calculated as the difference between the most negative voltage value and the most positive voltage value within the time range of 80-500 ms.
Results
Results��P50 gating in �one patient in T2
Results N100-P300 baseline (HC-N4, SCZ-N5)
At baseline, HC showed better topographical representation from left and right anterior regions which are located over the frontal lobes and midline, MA, and MC regions, while the patients with SCZ showed better representation over LA, RA and posterior regions and less amplitude from the midline.
Results N100-P300 after RTMS (HC-N4, SCZ-N5)
All patients (TG + CG) showed reduced N100-P300 complex voltage at the mid posterior region, with TG patients (n2) showing the major global difference with reduced voltages in all regions
Individual data showed reduced P300 amplitude in all patients after RTMS treatment, with the S15 subject showing no values after RTMS
Passive task
Study 4. Effects of transcranial magnetic stimulation on AVH and mid latency auditory evoked potentials in patients with schizophrenia
RESEARCH QUESTION
We expected that RTMS would reduce AVH severity (hypothesis H1), that stress and anxiety would be reduced, and that QoL would be increased after the RTMS treatment in patients with SCZ and AVH (hypothesis H2).
Based on the assumption that there is impaired triggering of attention in patients with schizophrenia, as made evident by reduced N100 amplitude we expected that N100 amplitude would be higher after the RTMS (hypothesis H3) and that N100 and P200 sensory gating which appeared to be impaired in patients with schizophrenia and AVH will improve (hypothesis H4).
Methods
Clinical symptoms were used as primary outcomes.
Additionally, we measured N1 component (N100) and P2 component (P200) neurophysiological markers as a secondary outcome. A paired-click paradigm was performed to elicit the P50, N100, and P200 components. In this study, we focused on N100 and P200 responses.
Variables
The largest negative deflection between 80 and 150 ms was identified as the N100 or N1, and the largest positive deflection between 150 and 250 ms was identified as the P200 or P2.
Methods
Results
TG and CG neurophysiological data measured separately in pre-post RTMS conditions didn´t show significant changes.
Clinical symptoms showed a similar change direction for all psychometric scales: PSYRATS AHS decreased in both groups, QoL improved in both groups and DASS decreased in both groups.
The null hypotheses H1 and H2 were not true (type 1 error), and the alternative hypotheses could not be tested because of type 2 error (e.g., for PSYRATS the pre-study calculated N to achieve statistical power was 16).
We calculated pre-post RTMS changes for all 72 metrics in all patients (N=10). Two variables showed the most marked changes after the treatment with small-medium effect size: N1S1BmLP or N100 to S1 measured “baseline to peak” in left posterior region, which changed from -0.57 μV (SD 0.97) to -2.39 μV (SD 1.59), (p = 0.006, η2 = 0.346) and N1S1BmMP or N100 to S1 measured “baseline to peak” in medial posterior region (p = 0.038, η2 = 0.218). The p-values after Bonferroni correction should be < 0.00714 (7 variables).
Results�HS
Results�T3P3�S25 in T1
Results�T3P3�S25 in T2
Study 5. P300 Analysis Using HD EEG to Decipher Neural Response to RTMS in Patients with SCZ and AVH (Aubonnet et al., 2020)
RESEARCH QUESTION
We looked at the N100-P300 complex voltage before and after the treatment expecting that after the treatment the amplitude of P300 will be higher in patients receiving RTMS at T3-P3 EEG location.
The question was if P300 related oscillations and local connectivity participation index derived from a dense-array 256 channel EEG system can be considered as candidates for biomarkers of the patients with schizophrenia
Methods
Results
The individual analysis revealed general consistent results.
The analysis of the psychometric tests revealed that four out of five subjects in TG and three out of five subjects in CG felt improved condition after the treatment, whereas the other subjects remained neutral or reported worse psychometric scores.
In the time domain analysis, the N1-P3 amplitude was globally higher post-treatment than pre-treatment, for six subjects, two in TG and four in CG.
The PSD increased post-treatment mainly for the alpha band and beta band globally, for six subjects as well, two in TG and four in CG. No trends were detectable for the gamma and theta bands. In several subjects, the right temporal area showed an opposite behavior compared to the other regions.
The connectivity results showed an increased network integration (increase in participation coefficient) during post-treatment for frequent, for the beta band especially, for seven subjects, four in CG, three in TG.
Improvement in clinical outcome��S17 TG S23 CG
The yellow areas in frequency analysis are related to a higher PSD in T2, whereas the blue ones are related to a higher PSD in T1. Amount of increase (green) or decrease (orange) participation coefficient (PC) values. The positive bars in time analysis are related to a higher N1-P3 amplitude in T2 (Red Rare)
Stagnation or worse in psychometric scales��S26 CG S15 TG
The yellow areas in frequency analysis are related to a higher PSD in T2, whereas the blue ones are related to a higher PSD in T1. Amount of increase (green) or decrease (orange) participation coefficient (PC) values. The positive bars in time analysis are related to a higher N1-P3 amplitude in T2 (Red Rare)
Study 6. Network signatures of RTMS treatment in patients with SCZ and AVH during an auditory-motor task using HD-EEG (Ovidiu C. Banea et al., 2021)
RESEARCH QUESTION
Following our observations that the cortical distribution of the relative power in different EEG bands showed topographical EEG fragmentation the question
was if there will be increasing values of the relative power after the RTMS, especially for beta and gamma bands.
Auditory-motor task results were compared with the resting state. We expected that network organization measured with the graph theory and small worldness will show an improved small world effect.
ROI
First assessment: Eye-bird view maps for RP
Maps for Healthy Subjects (No rTMS) and Patients in T1 (pre TMS) and T2 (post TMS) conditions:
EEG bands: alpha (8-13Hz), beta (13-30Hz), low gamma (30-49Hz) and high gamma (51-100Hz)
Auditory-motor task protocol and windows of Interest
Healthy Subjects (No RTMS)
n e t w o r k o r g a n i z a t i o n
Clustered nodes
N4 - Connector hub
Number of Nodes
Number of Edges
Degree of centrality
Clustering Coefficient
Hub coefficient
Average Path Length
Small-worldness
Global synchrony
SMALL WROLDNESS And GRAPHS Theory
The global impairments in brain connectivity during working memory tasks can also be studied according to graph theory analysis, especially through measures such as small-world (SM) networks that exhibit high clustering and decreased characteristic path length.
The SM network phenomenon is observed when the connectivity among nodes of a given network is in the middle between a completely regular and random network (Watts and Strogatz, 1998).
SCZ show disrupted functional integration expressed by decreases in SM index (Micheloyannis et al., 2006b) with more contribution of frontotemporal networks and occipital regions (van den Heuvel et al., 2008; Zalesky et al., 2011).
1 - 2
1 - 3
1 - 4
…
256 - 255
256 - 256
Matrix with 256
rows and 256 columns
Significant values
Left Frontal
Right Frontal
Left sensory-motor
Right sensory-motor
Left temporo-parietal
Right temporo-parietal
T1 Subject I5 - Left Hand - Non-cortical activity
T2 Subject I5 - Left Hand - Non-cortical activity
Network organization AM Task
RESULTS
Significant improvement on psychotic symptoms as measured by PSYRATS between pre-rTMS (M = 28,6, Std = 4,17) and post-rTMS (M = 23,6, std = 5,27) conditions, F(1, 5) = 23,44,
p < 0,05, ηp² = 0,967.
RTMS modulates gamma PSD in SCZ patients during
Resting state
LTP
LOW Gamma
RTMS modulates gamma PSD
over the
left temporoparietal in SCZ patients during AMT performed with non-dominant hand
Small worldness
Results
10 days of low frequency rTMS did not show significant improvement of neurophysiological parameters in patients with schizophrenia and pharmaco-resistant AVH.
Small worldness index showed changes in patients with schizophrenia and AVH after rTMS similarly to those found in healthy controls suggesting that this might represent an interesting biomarker for rTMS treatment effectiveness.
The sample size and a working memory psychological test as first outcome (we used positive symptoms PSYRATS) are important limitations of this study.
Limitations
Conclusions
This work was a hypothesis-generating research analyzing the influence of RTMS on brain mechanisms in patients with schizophrenia and pharmaco-resistant AVH.
1) Based on the patient´s clinical evaluations and all the neurophysiological measurements it might be suspected that both, left temporoparietal and vertex RTMS induce positive changes in patients with schizophrenia and auditory verbal hallucinations.
2) We were able to observe local changes of N100 amplitude after the RTMS. This finding suggests that this auditory evoked potential of triggering attention might be an interesting marker of RTMS induced neural plasticity to be analyzed in patients with schizophrenia and AVH.
Conclusions
3) P300 evoked EEG oscillations spectral analysis did not show group differences before and after RTMS treatment. It might be that in our study P300 was not elicited and we faced a habituation effect (The passive task elicits P200).
4) Patients with schizophrenia exhibit higher gamma PSD during the auditory-motor task compared to healthy controls, which was modified by RTMS without being significant.
PSD of alpha, beta, and gamma oscillatory EEG activity and network organization showed the most marked changes in the prestimulus period or "delay epoch” compared with “auditory” or “motor” windows.
Conclusions
5) The change of low and high gamma PSD was visible, locally, over the left temporoparietal region, when the auditory-motor task was done with the nondominant hand, showing that during this condition, gamma synchronization can be a marker of “neural effort” and workload during the working memory-related time.
6) Small worldness index of low gamma activity analyzed in patients with schizophrenia and AVH during the WM period of an auditory-motor task, when it is performed with the nondominant hand, showed changes after RTMS similarly to those found in healthy controls. This might represent an interesting biomarker for RTMS treatment effectiveness.
Takk fyrir!�
Mulțumesc!��Thank you!