Towards neurophysiological biomarkers to assess the repetitive transcranial magnetic stimulation treatment for patients with
schizophrenia and auditory verbal hallucinations
PhD in Clinical Neurophysiology, Dissertation
PhD Candidate: Examiner:
Ovidiu C. Banea, MD Giorgio Di Lorenzo, MD, PhD
Department of Engineering, Reykjavik University Laboratory of Psychophysiology and Cognitive Neuroscience
Clinical Neurophysiology Unit, Landspítali Associate Professor and Chair of Psychiatry
Department of Systems Medicine
University of Rome Tor Vergata, Italy
Place: Reykjavík University, Room M35
Date: 31st of January 2022
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). Lifetime prevalence 0.5-1% (Keshavan et al, 2019)
In Iceland, during the period 2012-2018, a total number of 567 patients were diagnosed with SCZ (Jónasson et al, 2019) 348,450 inhabitants (2018).
Multifactorial origin: It is thought that an interaction between genes, a range of environmental and probably psychosocial factors may cause schizophrenia.
�
Schizophrenia
Onset between 16-30 year old, found more in migrant / local, urban / rural. Much higher incidence at higher latitudes (Saha et al, 2005).
Symptoms: positive, negative, and cognitive (Patel et al., 2014)
Schizophrenia
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
Schizophrenia & Sensory Gating
How to quantify Sensory Gating?
Contrary to expectations, schizophrenic patients who reported perceptual anomalies exhibited P50 ratios that did not differ from normal controls.
Schizophrenia: Structural findings: THALAMUS (MRI)
MRI from 39 male patients and 47 male controls were transformed with a "bounding box" to produce an "average schizophrenic brain" and an "average normal brain." Image subtraction –
Specific regional abnormalities were observed in the (R) thalamus and adjacent white matter. Interpreted as result from a defect in filtering or gating sensory input, which is one of the primary functions of the thalamus in the human brain.
Source: (Andreasen et al., 1994) Science
Schizophrenia: Structural findings: THALAMUS (PET)
Patients with SCZ (20 never medicated) showed a diminished metabolic rate in the right thalamus, with a loss of the normal pattern of right greater than left asymmetry (compared with 15 HC).
The area of the thalamus was smaller in the patients than in the volunteers, and this difference was greatest in the left anterior region.
Deficit in sensory filtering in schizophrenia. (Buchsbaum et al., 1996)
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)
Biomarker - definition (FDA-NIH Biomarker Group 2016)
Biomarkers
Biomarkers
Endophenotype - definition
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).
Spectral EEG endophenotype (Kropotov, 2009)
7 days test-retest reliability (left) and heritability of spectral EEG in monozigotic versus dizigotic twins (right) (Kropotov, 2009).
Neuroanatomy (MRI)
Despite that both Kraepelin and Bleuler were convinced that schizophrenia would ultimately be linked to an organic brain disorder the neuropathology of SCZ remains difficult to understand.
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.)
Left temporoparietal site T3P3 (TPJ)
The dorsal edge of the principal sulcus,
- mainly the supramarginal gyrus (BA40)
-The angular gyrus (BA39)
-Superior temporal cortex (BA 22)
(Wernicke area) language reception and processing
STG includes primary (Heschl's gyrus) and secondary auditory cortices, processing auditory signals, and the planum temporale (PT) in the posterior STG is a language-related area.
Source: Brain Anatomy (Columbia University, NY)
Network disease
Diagnostic of SCZ, ICD-11 (2018) January 2022
Diagnostic of SCZ, ICD-11 (2018) January 2022
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.
"Paradoxical" brain activation in relation to AVHs (Kompus et al, 2011).
MRI studies examining patients with schizophrenia during the processing of auditory stimuli showed overlapping:
Auditory Verbal Hallucinations
Transcranial magnetic stimulation
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
Auditory Verbal Hallucinations
Levels of Evidence:�IA Evidence from meta-analysis of randomized controlled trials�� Grades of Recommendations:�A Directly based on Level I evidence���
Auditory Verbal Hallucinations
Levels of Evidence:
�DROPPED left TP LF-RTMS in SCZ with AVH from LEVEL A (2011) to LEVEL C (2020)
NEW FRENCH GUIDELINES (Lefaucheur et al., 2020)
�“Highly controversial results were reported concerning the effect of LF-rTMS applied to the left STG/TPJ on auditory hallucinations, with as many ‘‘positive” studies showing rTMS efficacy as many ‘‘negative” studies showing RTMS inefficacy.”
“However, considering effect size calculated in various meta-analyses, literature data appeared to be in favor of a possible efficacy of LF RTMS of the left TPC on auditory hallucinations (Level C).” (Lefaucheur et al., 2020)
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
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.
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 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.
EEG pre-processing
EEG was recorded using a 256-channel system (ANT Neuro, Netherlands ) with EOG electrode placed below the right eye, and a ground electrode placed on the left side of the neck.
The data were sampled at 1024 Hz and re-referenced to the average of L and R mastoid electrodes (R19R, L19L).
A bandpass filter was set between 0.1-80 Hz and a notch filter from 49-51 Hz Bad channels were removed when EEG voltage was greater than ±80 μV; if more than 10% of the channels showed too much noise or bad signal, the whole trial was rejected.
Epochs:
P50, 500 ms starting 100 ms prior to the presentation of each auditory stimulus (-100 ms to +400 ms)
P300 epoch: 1000 ms starting 100 ms prior to the presentation of auditory stimulus (-100 to +900 ms).
Baseline correction was performed using a pre-stimulus 100 ms window.
“Bad “channels were removed and interpolated. Individual trials were visually inspected and rejected when indicative of excessive muscle activity, eye movements, or other artifacts.
Results
Results��P50 gating in �one patient in T2
Results N100-P300 baseline (HC-N4, SCZ-N5)
At baseline, healthy subjects 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 schizophrenia 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
Exploratory Study 2. A Novel Technique to Trigger High Beta and Low Gamma Activity in Patients with�Schizophrenia (E. Ívarsson et al., 2020)
RESEARCH QUESTION
It has been suggested that schizophrenic symptoms can be explained by over-arousal causing depression in neural activity or inverted-U relationship between performance and arousal (Grossberg, 2000; Yerkes & Dodson, 1908).
Our study followed this suggestion and we expected that in schizophrenia the high-beta and gamma activity will break up in clusters and decrease during a task requiring attention, whereas in normal subjects these bands activity will be increased.
A cognitively driven auditory-motor task was suggested as “triggering beta and gamma neural synchrony” in the cortical regions involved in the working memory and auditory-motor cortices.
Method
The auditory-motor task (AMT) was employed in a sound-attenuated room, and each patient was awake, un-sedated, and comfortably seated on a chair during the tasks.
Subjects held a button in one hand and placed the hand on the thigh. We instructed each subject to press the button using the thumb when the pre-recorded verbal command “press” was given and not to press the button when the verbal command “no press” was given fig.
Subsequently, each subject completed two auditory-motor tasks (one for each hand). The AMT task contained 40 trials: 20 auditory-verbal “press” commands and 20 “no press” commands. The interstimulus interval was 3 seconds (Nagasawa et al., 2010).
The commands were presented in a pseudorandom sequence during each task. The AMT was performed with the dominant hand (AMT-r), and non-dominant hand (AMT-l) one time in HC and two times in the patients (SCZ), before the RTMS treatment (SCZ-T1) and within one week after completing ten sessions of RTMS treatment (SCZ-T2).
Method
First, we analyzed 40 ± 10 sec resting-state EEG with eyes closed for three patients with schizophrenia and we compared it with the EEG of three healthy control participants.
For the auditory-motor task, epochs related to the cognitively driven “motor cortical activation” (MCA) were segmented between -500 ms to +500 ms (1000 ms) relative to the onset of the button code (hand reaction) seen in the EEG trace. The reference period was set between +1500 ms to +2500 ms post-verbal command or auditory stimulus onset (1000 ms). Finally, the remaining artifact free trials were analyzed.
Here are presented the results of motor cortical activation (MCA) for one HS and one patient with auditory verbal hallucinations (AVH), using power spectral density (PSD) and topographical frequency maps including both hands sensory-motor regions.
Method
First, we analyzed 40 ± 10 sec resting-state EEG with eyes closed for three patients with schizophrenia and we compared it with the EEG of three healthy control participants.
For the auditory-motor task, epochs related to the cognitively driven “motor cortical activation” (MCA) were segmented between -500 ms to +500 ms (1000 ms) relative to the onset of the button code (hand reaction) seen in the EEG trace. The reference period was set between +1500 ms to +2500 ms post-verbal command or auditory stimulus onset (1000 ms). Finally, the remaining artifact free trials were analyzed.
Method
Later, ACA, MCA, and NCA epochs were modified (Study 6) to avoid overlapping of the EEG data.
We looked at specific frequencies related to the motor reaction: low beta (13–20 Hz), high beta (20–30 Hz), low gamma (30–45 Hz), and high gamma (45-80 Hz).
We compared data with the reference period and with the resting state EEG.
Right Hand
Post TMS
Results
Exploratory Study 3. The cortical and cutaneous silent period in patients with schizophrenia and AVH
RESEARCH QUESTION
Results pertaining to CSP in schizophrenia patients are controversial. Prolonged CSP was observed among both first-episode patients and clozapine medicated chronic patients compared with healthy controls, suggesting alterations within the GABAB-mediated neurotransmitter system (Daskalakis et al., 2002).
One study found no significant differences in CSP between SCZ patients and healthy controls, and others have reported a shortened CSP in either the chronic or unmedicated patients (Fitzgerald et al., 2002; S.-K. Liu et al., 2009).
Based on these findings, the working hypothesis was that CSP will be prolonged after RTMS as a signal of improvement in the inhibitory system related to sensory gating. Additionally, we looked to cutaneous silent period, which was expected to be prolonged, too. Both data are presented as case studies
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.
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 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.
EEG pre-processing
EEG was recorded using a 256-channel system (ANT Neuro, Netherlands ) with EOG electrode placed below the right eye, and a ground electrode placed on the left side of the neck.
The data were sampled at 1024 Hz and re-referenced to the average of L and R mastoid electrodes (R19R, L19L).
A bandpass filter was set between 0.1-80 Hz and a notch filter from 49-51 Hz Bad channels were removed when EEG voltage was greater than ±80 μV; if more than 10% of the channels showed too much noise or bad signal, the whole trial was rejected.
Epochs:
P50, 500 ms starting 100 ms prior to the presentation of each auditory stimulus (-100 ms to +400 ms)
P300 epoch: 1000 ms starting 100 ms prior to the presentation of auditory stimulus (-100 to +900 ms).
Baseline correction was performed using a pre-stimulus 100 ms window.
“Bad “channels were removed and interpolated. Individual trials were visually inspected and rejected when indicative of excessive muscle activity, eye movements, or other artifacts.
Results
Results��P50 gating in �one patient in T2
Results N100-P300 baseline (HC-N4, SCZ-N5)
At baseline, healthy subjects 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 schizophrenia 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
Exploratory Study 2. A Novel Technique to Trigger High Beta and Low Gamma Activity in Patients with�Schizophrenia (E. Ívarsson et al., 2020)
RESEARCH QUESTION
It has been suggested that schizophrenic symptoms can be explained by over-arousal causing depression in neural activity or inverted-U relationship between performance and arousal (Grossberg, 2000; Yerkes & Dodson, 1908).
Our study followed this suggestion and we expected that in schizophrenia the high-beta and gamma activity will break up in clusters and decrease during a task requiring attention, whereas in normal subjects these bands activity will be increased.
A cognitively driven auditory-motor task was suggested as “triggering beta and gamma neural synchrony” in the cortical regions involved in the working memory and auditory-motor cortices.
Method
The auditory-motor task (AMT) was employed in a sound-attenuated room, and each patient was awake, un-sedated, and comfortably seated on a chair during the tasks.
Subjects held a button in one hand and placed the hand on the thigh. We instructed each subject to press the button using the thumb when the pre-recorded verbal command “press” was given and not to press the button when the verbal command “no press” was given fig.
Subsequently, each subject completed two auditory-motor tasks (one for each hand). The AMT task contained 40 trials: 20 auditory-verbal “press” commands and 20 “no press” commands. The interstimulus interval was 3 seconds (Nagasawa et al., 2010).
The commands were presented in a pseudorandom sequence during each task. The AMT was performed with the dominant hand (AMT-r), and non-dominant hand (AMT-l) one time in HC and two times in the patients (SCZ), before the RTMS treatment (SCZ-T1) and within one week after completing ten sessions of RTMS treatment (SCZ-T2).
Method
First, we analyzed 40 ± 10 sec resting-state EEG with eyes closed for three patients with schizophrenia and we compared it with the EEG of three healthy control participants.
For the auditory-motor task, epochs related to the cognitively driven “motor cortical activation” (MCA) were segmented between -500 ms to +500 ms (1000 ms) relative to the onset of the button code (hand reaction) seen in the EEG trace. The reference period was set between +1500 ms to +2500 ms post-verbal command or auditory stimulus onset (1000 ms). Finally, the remaining artifact free trials were analyzed.
Here are presented the results of motor cortical activation (MCA) for one HS and one patient with auditory verbal hallucinations (AVH), using power spectral density (PSD) and topographical frequency maps including both hands sensory-motor regions.
Method
First, we analyzed 40 ± 10 sec resting-state EEG with eyes closed for three patients with schizophrenia and we compared it with the EEG of three healthy control participants.
For the auditory-motor task, epochs related to the cognitively driven “motor cortical activation” (MCA) were segmented between -500 ms to +500 ms (1000 ms) relative to the onset of the button code (hand reaction) seen in the EEG trace. The reference period was set between +1500 ms to +2500 ms post-verbal command or auditory stimulus onset (1000 ms). Finally, the remaining artifact free trials were analyzed.
Method
Later, ACA, MCA, and NCA epochs were modified (Study 6) to avoid overlapping of the EEG data.
We looked at specific frequencies related to the motor reaction: low beta (13–20 Hz), high beta (20–30 Hz), low gamma (30–45 Hz), and high gamma (45-80 Hz).
We compared data with the reference period and with the resting state EEG.
Right Hand
Post TMS
Results
Exploratory Study 3. The cortical and cutaneous silent period in patients with schizophrenia and AVH
RESEARCH QUESTION
Results pertaining to CSP in schizophrenia patients are controversial. Prolonged CSP was observed among both first-episode patients and clozapine medicated chronic patients compared with healthy controls, suggesting alterations within the GABAB-mediated neurotransmitter system (Daskalakis et al., 2002).
One study found no significant differences in CSP between SCZ patients and healthy controls, and others have reported a shortened CSP in either the chronic or unmedicated patients (Fitzgerald et al., 2002; S.-K. Liu et al., 2009).
Based on these findings, the working hypothesis was that CSP will be prolonged after RTMS as a signal of improvement in the inhibitory system related to sensory gating. Additionally, we looked to cutaneous silent period, which was expected to be prolonged, too. Both data are presented as case studies
Methods
Cortical silent period (CuSP) duration was measured in sub-maximally contracted abductor pollicis brevis muscle by stimulating the motor cortex using TMS with an intensity of 140% resting motor threshold (RMT). Calculations of CSP were determined from the motor evoked potential (MEP) onset to the recovery of any voluntary EMG activity.
Three to five trials were repeated to obtain the average CSP duration for each subject.
To obtain cutaneous silent period (CuSP) electrical stimuli were delivered to the ipsilateral dermatome of the 2nd digit from the dominant hand.
Stimuli were delivered with ring electrodes at 10 times x sensory threshold. Surface EMG electrodes recorded CuSP from abductor pollicis brevis muscle while the patient was requested to continuously sustain a submaximal contraction. When the stimulus produced a clear and visible silent period, three trials were collected for each subject.
RESULTS CSP
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.
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.
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.
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 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.
EEG pre-processing
EEG was recorded using a 256-channel system (ANT Neuro, Netherlands ) with EOG electrode placed below the right eye, and a ground electrode placed on the left side of the neck.
The data were sampled at 1024 Hz and re-referenced to the average of L and R mastoid electrodes (R19R, L19L).
A bandpass filter was set between 0.1-80 Hz and a notch filter from 49-51 Hz Bad channels were removed when EEG voltage was greater than ±80 μV; if more than 10% of the channels showed too much noise or bad signal, the whole trial was rejected.
Epochs:
P50, 500 ms starting 100 ms prior to the presentation of each auditory stimulus (-100 ms to +400 ms)
P300 epoch: 1000 ms starting 100 ms prior to the presentation of auditory stimulus (-100 to +900 ms).
Baseline correction was performed using a pre-stimulus 100 ms window.
“Bad “channels were removed and interpolated. Individual trials were visually inspected and rejected when indicative of excessive muscle activity, eye movements, or other artifacts.
Results
Results��P50 gating in �one patient in T2
Results N100-P300 baseline (HC-N4, SCZ-N5)
At baseline, healthy subjects 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 schizophrenia 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
Exploratory Study 2. A Novel Technique to Trigger High Beta and Low Gamma Activity in Patients with�Schizophrenia (E. Ívarsson et al., 2020)
RESEARCH QUESTION
It has been suggested that schizophrenic symptoms can be explained by over-arousal causing depression in neural activity or inverted-U relationship between performance and arousal (Grossberg, 2000; Yerkes & Dodson, 1908).
Our study followed this suggestion and we expected that in schizophrenia the high-beta and gamma activity will break up in clusters and decrease during a task requiring attention, whereas in normal subjects these bands activity will be increased.
A cognitively driven auditory-motor task was suggested as “triggering beta and gamma neural synchrony” in the cortical regions involved in the working memory and auditory-motor cortices.
Method
The auditory-motor task (AMT) was employed in a sound-attenuated room, and each patient was awake, un-sedated, and comfortably seated on a chair during the tasks.
Subjects held a button in one hand and placed the hand on the thigh. We instructed each subject to press the button using the thumb when the pre-recorded verbal command “press” was given and not to press the button when the verbal command “no press” was given fig.
Subsequently, each subject completed two auditory-motor tasks (one for each hand). The AMT task contained 40 trials: 20 auditory-verbal “press” commands and 20 “no press” commands. The interstimulus interval was 3 seconds (Nagasawa et al., 2010).
The commands were presented in a pseudorandom sequence during each task. The AMT was performed with the dominant hand (AMT-r), and non-dominant hand (AMT-l) one time in HC and two times in the patients (SCZ), before the RTMS treatment (SCZ-T1) and within one week after completing ten sessions of RTMS treatment (SCZ-T2).
Method
First, we analyzed 40 ± 10 sec resting-state EEG with eyes closed for three patients with schizophrenia and we compared it with the EEG of three healthy control participants.
For the auditory-motor task, epochs related to the cognitively driven “motor cortical activation” (MCA) were segmented between -500 ms to +500 ms (1000 ms) relative to the onset of the button code (hand reaction) seen in the EEG trace. The reference period was set between +1500 ms to +2500 ms post-verbal command or auditory stimulus onset (1000 ms). Finally, the remaining artifact free trials were analyzed.
Here are presented the results of motor cortical activation (MCA) for one HS and one patient with auditory verbal hallucinations (AVH), using power spectral density (PSD) and topographical frequency maps including both hands sensory-motor regions.
Method
First, we analyzed 40 ± 10 sec resting-state EEG with eyes closed for three patients with schizophrenia and we compared it with the EEG of three healthy control participants.
For the auditory-motor task, epochs related to the cognitively driven “motor cortical activation” (MCA) were segmented between -500 ms to +500 ms (1000 ms) relative to the onset of the button code (hand reaction) seen in the EEG trace. The reference period was set between +1500 ms to +2500 ms post-verbal command or auditory stimulus onset (1000 ms). Finally, the remaining artifact free trials were analyzed.
Method
Later, ACA, MCA, and NCA epochs were modified (Study 6) to avoid overlapping of the EEG data.
We looked at specific frequencies related to the motor reaction: low beta (13–20 Hz), high beta (20–30 Hz), low gamma (30–45 Hz), and high gamma (45-80 Hz).
We compared data with the reference period and with the resting state EEG.
Right Hand
Post TMS
Results
Exploratory Study 3. The cortical and cutaneous silent period in patients with schizophrenia and AVH
RESEARCH QUESTION
Results pertaining to CSP in schizophrenia patients are controversial. Prolonged CSP was observed among both first-episode patients and clozapine medicated chronic patients compared with healthy controls, suggesting alterations within the GABAB-mediated neurotransmitter system (Daskalakis et al., 2002).
One study found no significant differences in CSP between SCZ patients and healthy controls, and others have reported a shortened CSP in either the chronic or unmedicated patients (Fitzgerald et al., 2002; S.-K. Liu et al., 2009).
Based on these findings, the working hypothesis was that CSP will be prolonged after RTMS as a signal of improvement in the inhibitory system related to sensory gating. Additionally, we looked to cutaneous silent period, which was expected to be prolonged, too. Both data are presented as case studies
Methods
Cortical silent period (CuSP) duration was measured in sub-maximally contracted abductor pollicis brevis muscle by stimulating the motor cortex using TMS with an intensity of 140% resting motor threshold (RMT). Calculations of CSP were determined from the motor evoked potential (MEP) onset to the recovery of any voluntary EMG activity.
Three to five trials were repeated to obtain the average CSP duration for each subject.
To obtain cutaneous silent period (CuSP) electrical stimuli were delivered to the ipsilateral dermatome of the 2nd digit from the dominant hand.
Stimuli were delivered with ring electrodes at 10 times x sensory threshold. Surface EMG electrodes recorded CuSP from abductor pollicis brevis muscle while the patient was requested to continuously sustain a submaximal contraction. When the stimulus produced a clear and visible silent period, three trials were collected for each subject.
RESULTS CSP
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.
EEG pre-processing
EEG was recorded using a 256-channel system (ANT Neuro, Netherlands ) with EOG electrode placed below the right eye, and a ground electrode placed on the left side of the neck.
The data were sampled at 1024 Hz and re-referenced to the average of L and R mastoid electrodes (R19R, L19L).
A bandpass filter was set between 0.1-80 Hz and a notch filter from 49-51 Hz Bad channels were removed when EEG voltage was greater than ±80 μV; if more than 10% of the channels showed too much noise or bad signal, the whole trial was rejected.
Epochs:
P50, 500 ms starting 100 ms prior to the presentation of each auditory stimulus (-100 ms to +400 ms)
P300 epoch: 1000 ms starting 100 ms prior to the presentation of auditory stimulus (-100 to +900 ms).
Baseline correction was performed using a pre-stimulus 100 ms window.
“Bad “channels were removed and interpolated. Individual trials were visually inspected and rejected when indicative of excessive muscle activity, eye movements, or other artifacts.
Results
Results��P50 gating in �one patient in T2
Results N100-P300 baseline (HC-N4, SCZ-N5)
At baseline, healthy subjects 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 schizophrenia 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
Exploratory Study 2. A Novel Technique to Trigger High Beta and Low Gamma Activity in Patients with�Schizophrenia (E. Ívarsson et al., 2020)
RESEARCH QUESTION
It has been suggested that schizophrenic symptoms can be explained by over-arousal causing depression in neural activity or inverted-U relationship between performance and arousal (Grossberg, 2000; Yerkes & Dodson, 1908).
Our study followed this suggestion and we expected that in schizophrenia the high-beta and gamma activity will break up in clusters and decrease during a task requiring attention, whereas in normal subjects these bands activity will be increased.
A cognitively driven auditory-motor task was suggested as “triggering beta and gamma neural synchrony” in the cortical regions involved in the working memory and auditory-motor cortices.
Method
The auditory-motor task (AMT) was employed in a sound-attenuated room, and each patient was awake, un-sedated, and comfortably seated on a chair during the tasks.
Subjects held a button in one hand and placed the hand on the thigh. We instructed each subject to press the button using the thumb when the pre-recorded verbal command “press” was given and not to press the button when the verbal command “no press” was given fig.
Subsequently, each subject completed two auditory-motor tasks (one for each hand). The AMT task contained 40 trials: 20 auditory-verbal “press” commands and 20 “no press” commands. The interstimulus interval was 3 seconds (Nagasawa et al., 2010).
The commands were presented in a pseudorandom sequence during each task. The AMT was performed with the dominant hand (AMT-r), and non-dominant hand (AMT-l) one time in HC and two times in the patients (SCZ), before the RTMS treatment (SCZ-T1) and within one week after completing ten sessions of RTMS treatment (SCZ-T2).
Method
First, we analyzed 40 ± 10 sec resting-state EEG with eyes closed for three patients with schizophrenia and we compared it with the EEG of three healthy control participants.
For the auditory-motor task, epochs related to the cognitively driven “motor cortical activation” (MCA) were segmented between -500 ms to +500 ms (1000 ms) relative to the onset of the button code (hand reaction) seen in the EEG trace. The reference period was set between +1500 ms to +2500 ms post-verbal command or auditory stimulus onset (1000 ms). Finally, the remaining artifact free trials were analyzed.
Here are presented the results of motor cortical activation (MCA) for one HS and one patient with auditory verbal hallucinations (AVH), using power spectral density (PSD) and topographical frequency maps including both hands sensory-motor regions.
Method
First, we analyzed 40 ± 10 sec resting-state EEG with eyes closed for three patients with schizophrenia and we compared it with the EEG of three healthy control participants.
For the auditory-motor task, epochs related to the cognitively driven “motor cortical activation” (MCA) were segmented between -500 ms to +500 ms (1000 ms) relative to the onset of the button code (hand reaction) seen in the EEG trace. The reference period was set between +1500 ms to +2500 ms post-verbal command or auditory stimulus onset (1000 ms). Finally, the remaining artifact free trials were analyzed.
Method
Later, ACA, MCA, and NCA epochs were modified (Study 6) to avoid overlapping of the EEG data.
We looked at specific frequencies related to the motor reaction: low beta (13–20 Hz), high beta (20–30 Hz), low gamma (30–45 Hz), and high gamma (45-80 Hz).
We compared data with the reference period and with the resting state EEG.
Right Hand
Post TMS
Results
Exploratory Study 3. The cortical and cutaneous silent period in patients with schizophrenia and AVH
RESEARCH QUESTION
Results pertaining to CSP in schizophrenia patients are controversial. Prolonged CSP was observed among both first-episode patients and clozapine medicated chronic patients compared with healthy controls, suggesting alterations within the GABAB-mediated neurotransmitter system (Daskalakis et al., 2002).
One study found no significant differences in CSP between SCZ patients and healthy controls, and others have reported a shortened CSP in either the chronic or unmedicated patients (Fitzgerald et al., 2002; S.-K. Liu et al., 2009).
Based on these findings, the working hypothesis was that CSP will be prolonged after RTMS as a signal of improvement in the inhibitory system related to sensory gating. Additionally, we looked to cutaneous silent period, which was expected to be prolonged, too. Both data are presented as case studies
Methods
Cortical silent period (CuSP) duration was measured in sub-maximally contracted abductor pollicis brevis muscle by stimulating the motor cortex using TMS with an intensity of 140% resting motor threshold (RMT). Calculations of CSP were determined from the motor evoked potential (MEP) onset to the recovery of any voluntary EMG activity.
Three to five trials were repeated to obtain the average CSP duration for each subject.
To obtain cutaneous silent period (CuSP) electrical stimuli were delivered to the ipsilateral dermatome of the 2nd digit from the dominant hand.
Stimuli were delivered with ring electrodes at 10 times x sensory threshold. Surface EMG electrodes recorded CuSP from abductor pollicis brevis muscle while the patient was requested to continuously sustain a submaximal contraction. When the stimulus produced a clear and visible silent period, three trials were collected for each subject.
RESULTS CSP
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.
EEG pre-processing
EEG was recorded using a 256-channel system (ANT Neuro, Netherlands ) with EOG electrode placed below the right eye, and a ground electrode placed on the left side of the neck.
The data were sampled at 1024 Hz and re-referenced to the average of L and R mastoid electrodes (R19R, L19L).
A bandpass filter was set between 0.1-80 Hz and a notch filter from 49-51 Hz Bad channels were removed when EEG voltage was greater than ±80 μV; if more than 10% of the channels showed too much noise or bad signal, the whole trial was rejected.
Epochs:
P50, 500 ms starting 100 ms prior to the presentation of each auditory stimulus (-100 ms to +400 ms)
P300 epoch: 1000 ms starting 100 ms prior to the presentation of auditory stimulus (-100 to +900 ms).
Baseline correction was performed using a pre-stimulus 100 ms window.
“Bad “channels were removed and interpolated. Individual trials were visually inspected and rejected when indicative of excessive muscle activity, eye movements, or other artifacts.
Results
Results��P50 gating in �one patient in T2
Results N100-P300 baseline (HC-N4, SCZ-N5)
At baseline, healthy subjects 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 schizophrenia 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
Exploratory Study 2. A Novel Technique to Trigger High Beta and Low Gamma Activity in Patients with�Schizophrenia (E. Ívarsson et al., 2020)
RESEARCH QUESTION
It has been suggested that schizophrenic symptoms can be explained by over-arousal causing depression in neural activity or inverted-U relationship between performance and arousal (Grossberg, 2000; Yerkes & Dodson, 1908).
Our study followed this suggestion and we expected that in schizophrenia the high-beta and gamma activity will break up in clusters and decrease during a task requiring attention, whereas in normal subjects these bands activity will be increased.
A cognitively driven auditory-motor task was suggested as “triggering beta and gamma neural synchrony” in the cortical regions involved in the working memory and auditory-motor cortices.
Method
The auditory-motor task (AMT) was employed in a sound-attenuated room, and each patient was awake, un-sedated, and comfortably seated on a chair during the tasks.
Subjects held a button in one hand and placed the hand on the thigh. We instructed each subject to press the button using the thumb when the pre-recorded verbal command “press” was given and not to press the button when the verbal command “no press” was given fig.
Subsequently, each subject completed two auditory-motor tasks (one for each hand). The AMT task contained 40 trials: 20 auditory-verbal “press” commands and 20 “no press” commands. The interstimulus interval was 3 seconds (Nagasawa et al., 2010).
The commands were presented in a pseudorandom sequence during each task. The AMT was performed with the dominant hand (AMT-r), and non-dominant hand (AMT-l) one time in HC and two times in the patients (SCZ), before the RTMS treatment (SCZ-T1) and within one week after completing ten sessions of RTMS treatment (SCZ-T2).
Method
First, we analyzed 40 ± 10 sec resting-state EEG with eyes closed for three patients with schizophrenia and we compared it with the EEG of three healthy control participants.
For the auditory-motor task, epochs related to the cognitively driven “motor cortical activation” (MCA) were segmented between -500 ms to +500 ms (1000 ms) relative to the onset of the button code (hand reaction) seen in the EEG trace. The reference period was set between +1500 ms to +2500 ms post-verbal command or auditory stimulus onset (1000 ms). Finally, the remaining artifact free trials were analyzed.
Here are presented the results of motor cortical activation (MCA) for one HS and one patient with auditory verbal hallucinations (AVH), using power spectral density (PSD) and topographical frequency maps including both hands sensory-motor regions.
Method
First, we analyzed 40 ± 10 sec resting-state EEG with eyes closed for three patients with schizophrenia and we compared it with the EEG of three healthy control participants.
For the auditory-motor task, epochs related to the cognitively driven “motor cortical activation” (MCA) were segmented between -500 ms to +500 ms (1000 ms) relative to the onset of the button code (hand reaction) seen in the EEG trace. The reference period was set between +1500 ms to +2500 ms post-verbal command or auditory stimulus onset (1000 ms). Finally, the remaining artifact free trials were analyzed.
Method
Later, ACA, MCA, and NCA epochs were modified (Study 6) to avoid overlapping of the EEG data.
We looked at specific frequencies related to the motor reaction: low beta (13–20 Hz), high beta (20–30 Hz), low gamma (30–45 Hz), and high gamma (45-80 Hz).
We compared data with the reference period and with the resting state EEG.
Right Hand
Post TMS
Results
Exploratory Study 3. The cortical and cutaneous silent period in patients with schizophrenia and AVH
RESEARCH QUESTION
Results pertaining to CSP in schizophrenia patients are controversial. Prolonged CSP was observed among both first-episode patients and clozapine medicated chronic patients compared with healthy controls, suggesting alterations within the GABAB-mediated neurotransmitter system (Daskalakis et al., 2002).
One study found no significant differences in CSP between SCZ patients and healthy controls, and others have reported a shortened CSP in either the chronic or unmedicated patients (Fitzgerald et al., 2002; S.-K. Liu et al., 2009).
Based on these findings, the working hypothesis was that CSP will be prolonged after RTMS as a signal of improvement in the inhibitory system related to sensory gating. Additionally, we looked to cutaneous silent period, which was expected to be prolonged, too. Both data are presented as case studies
Methods
Cortical silent period (CuSP) duration was measured in sub-maximally contracted abductor pollicis brevis muscle by stimulating the motor cortex using TMS with an intensity of 140% resting motor threshold (RMT). Calculations of CSP were determined from the motor evoked potential (MEP) onset to the recovery of any voluntary EMG activity.
Three to five trials were repeated to obtain the average CSP duration for each subject.
To obtain cutaneous silent period (CuSP) electrical stimuli were delivered to the ipsilateral dermatome of the 2nd digit from the dominant hand.
Stimuli were delivered with ring electrodes at 10 times x sensory threshold. Surface EMG electrodes recorded CuSP from abductor pollicis brevis muscle while the patient was requested to continuously sustain a submaximal contraction. When the stimulus produced a clear and visible silent period, three trials were collected for each subject.
RESULTS CSP
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.
EEG pre-processing
EEG was recorded using a 256-channel system (ANT Neuro, Netherlands ) with EOG electrode placed below the right eye, and a ground electrode placed on the left side of the neck.
The data were sampled at 1024 Hz and re-referenced to the average of L and R mastoid electrodes (R19R, L19L).
A bandpass filter was set between 0.1-80 Hz and a notch filter from 49-51 Hz Bad channels were removed when EEG voltage was greater than ±80 μV; if more than 10% of the channels showed too much noise or bad signal, the whole trial was rejected.
Epochs:
P50, 500 ms starting 100 ms prior to the presentation of each auditory stimulus (-100 ms to +400 ms)
P300 epoch: 1000 ms starting 100 ms prior to the presentation of auditory stimulus (-100 to +900 ms).
Baseline correction was performed using a pre-stimulus 100 ms window.
“Bad “channels were removed and interpolated. Individual trials were visually inspected and rejected when indicative of excessive muscle activity, eye movements, or other artifacts.
Results
Results��P50 gating in �one patient in T2
Results N100-P300 baseline (HC-N4, SCZ-N5)
At baseline, healthy subjects 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 schizophrenia 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
Exploratory Study 2. A Novel Technique to Trigger High Beta and Low Gamma Activity in Patients with�Schizophrenia (E. Ívarsson et al., 2020)
RESEARCH QUESTION
It has been suggested that schizophrenic symptoms can be explained by over-arousal causing depression in neural activity or inverted-U relationship between performance and arousal (Grossberg, 2000; Yerkes & Dodson, 1908).
Our study followed this suggestion and we expected that in schizophrenia the high-beta and gamma activity will break up in clusters and decrease during a task requiring attention, whereas in normal subjects these bands activity will be increased.
A cognitively driven auditory-motor task was suggested as “triggering beta and gamma neural synchrony” in the cortical regions involved in the working memory and auditory-motor cortices.
Method
The auditory-motor task (AMT) was employed in a sound-attenuated room, and each patient was awake, un-sedated, and comfortably seated on a chair during the tasks.
Subjects held a button in one hand and placed the hand on the thigh. We instructed each subject to press the button using the thumb when the pre-recorded verbal command “press” was given and not to press the button when the verbal command “no press” was given fig.
Subsequently, each subject completed two auditory-motor tasks (one for each hand). The AMT task contained 40 trials: 20 auditory-verbal “press” commands and 20 “no press” commands. The interstimulus interval was 3 seconds (Nagasawa et al., 2010).
The commands were presented in a pseudorandom sequence during each task. The AMT was performed with the dominant hand (AMT-r), and non-dominant hand (AMT-l) one time in HC and two times in the patients (SCZ), before the RTMS treatment (SCZ-T1) and within one week after completing ten sessions of RTMS treatment (SCZ-T2).
Method
First, we analyzed 40 ± 10 sec resting-state EEG with eyes closed for three patients with schizophrenia and we compared it with the EEG of three healthy control participants.
For the auditory-motor task, epochs related to the cognitively driven “motor cortical activation” (MCA) were segmented between -500 ms to +500 ms (1000 ms) relative to the onset of the button code (hand reaction) seen in the EEG trace. The reference period was set between +1500 ms to +2500 ms post-verbal command or auditory stimulus onset (1000 ms). Finally, the remaining artifact free trials were analyzed.
Here are presented the results of motor cortical activation (MCA) for one HS and one patient with auditory verbal hallucinations (AVH), using power spectral density (PSD) and topographical frequency maps including both hands sensory-motor regions.
Method
First, we analyzed 40 ± 10 sec resting-state EEG with eyes closed for three patients with schizophrenia and we compared it with the EEG of three healthy control participants.
For the auditory-motor task, epochs related to the cognitively driven “motor cortical activation” (MCA) were segmented between -500 ms to +500 ms (1000 ms) relative to the onset of the button code (hand reaction) seen in the EEG trace. The reference period was set between +1500 ms to +2500 ms post-verbal command or auditory stimulus onset (1000 ms). Finally, the remaining artifact free trials were analyzed.
Method
Later, ACA, MCA, and NCA epochs were modified (Study 6) to avoid overlapping of the EEG data.
We looked at specific frequencies related to the motor reaction: low beta (13–20 Hz), high beta (20–30 Hz), low gamma (30–45 Hz), and high gamma (45-80 Hz).
We compared data with the reference period and with the resting state EEG.
Right Hand
Post TMS
Results
Exploratory Study 3. The cortical and cutaneous silent period in patients with schizophrenia and AVH
RESEARCH QUESTION
Results pertaining to CSP in schizophrenia patients are controversial. Prolonged CSP was observed among both first-episode patients and clozapine medicated chronic patients compared with healthy controls, suggesting alterations within the GABAB-mediated neurotransmitter system (Daskalakis et al., 2002).
One study found no significant differences in CSP between SCZ patients and healthy controls, and others have reported a shortened CSP in either the chronic or unmedicated patients (Fitzgerald et al., 2002; S.-K. Liu et al., 2009).
Based on these findings, the working hypothesis was that CSP will be prolonged after RTMS as a signal of improvement in the inhibitory system related to sensory gating. Additionally, we looked to cutaneous silent period, which was expected to be prolonged, too. Both data are presented as case studies
Methods
Cortical silent period (CuSP) duration was measured in sub-maximally contracted abductor pollicis brevis muscle by stimulating the motor cortex using TMS with an intensity of 140% resting motor threshold (RMT). Calculations of CSP were determined from the motor evoked potential (MEP) onset to the recovery of any voluntary EMG activity.
Three to five trials were repeated to obtain the average CSP duration for each subject.
To obtain cutaneous silent period (CuSP) electrical stimuli were delivered to the ipsilateral dermatome of the 2nd digit from the dominant hand.
Stimuli were delivered with ring electrodes at 10 times x sensory threshold. Surface EMG electrodes recorded CuSP from abductor pollicis brevis muscle while the patient was requested to continuously sustain a submaximal contraction. When the stimulus produced a clear and visible silent period, three trials were collected for each subject.
RESULTS CSP
RESULTS CuSP
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
We divided the cortical EEG 256 channels in seven regions of interest (ROI), each of them with an averaged signal derived from 15 electrodes selected from 3 parallel lines (105 electrodes out of a total of 256). At the end, we measured 9 metrics for each ROI and for the average of all electrodes (AA and AVG) providing 72 (63 + 9) variables.
The patient groups were compared to the healthy control group at baseline and the two patient groups were also compared against each other at baseline.
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
PSD has been performed from the event-related oscillations and we looked to the network organization and the difference between T2 (postTMS) and T1 (pre-TMS) conditions. Network organization was analyzed with participation coefficient, a metric of functional segregation.
Methods
The connectivity has been computed at the cortical level using the "EEG source connectivity" method. It consists of estimating the brain sources (over 68 regions of interest - ROI) and then computing the statistical coupling between these reconstructed sources. The weighted minimum norm estimate (wMNE) and the Phase Locking Value (PLV) was used to solve the inverse problem and compute the functional connectivity, respectively.
The analysis has been performed on the beta and gamma bands. To quantify the network integration, we used the participation coefficient (PC), to calculate the interactions between brain modules (distant sub-networks), on the threshold connectivity matrices (here 20%). We used the brain connectivity toolbox (BCT) to compute the PC (Rubinov & Sporns, 2010).
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.
Methods
Intervention: 10 session rTMS at 1Hz (900 pulses) at 100%RMT
Tests:
HD EEG (256 channels) gamma & beta cortical activation in resting condition and during auditory motor task before and after rTMS
Pshychometrics: PSYRATS AHS (11 items)
Patients | Gender | Diagnostic | Medication |
TG1 | M | Paranoid Schizophrenia | Clozapine, Fluoxetine, Wellbutrin, Metformin |
TG2 | M | Paranoid Schizophrenia | Clozapine, Olanzapine, Perphenazine, Alprazolam, Levomepromazine, Oxazepam and Melatonin |
TG3 | M | Paranoid Schizophrenia | Clozapine and Flupenthixol |
CG1 | F | Paranoid Schizophrenia | Aripiprazole, Olanzapine, Chlorprothixene and Pregabalin |
TG4 | M | Paranoid Schizophrenia | Non-medicated |
CG2 | M | Hebephrenic schizophrenia | Clozapine, Pregabalin, Amisulpride |
Six patients (mean age = 30.2, SD 2.9, 5 males and 1 female) diagnosed with schizophrenia following the ICD-10 schizophrenia classification (F20) (SCZ group) and six healthy controls (HC) (mean age = 28.7, SD 4.3, 4 males and 2 females) were included in this study.
Hypotheses - AM task
Previous studies showed that pre-stimulus baseline (NCA) gamma activity is elevated (Gandal M) and that task-driven “evoked” gamma-band responses are reduced in schizophrenia (Gandal MJ, Edgar JC, Klook K, Siegel SJ.2012) Leicht et al., 2011). On the other hand, during working memory tasks, where there is a need for increased effort, it was observed that an efficient network organization is expressed by a higher SM index (Micheloyannis et al., 2006a).
Based on Gandal review and Micheloyannis findings (Gandal. Et al 2012, Micheloyannis et al., 2006a) we hypothesized
(1) that 10 days of rTMS will increase beta and gamma PSD over sensorimotor and temporoparietal cortices after auditory triggering of the hand-motor task,
(2) that rTMS will decrease gamma PSD during pre-stimulus baseline period and
(3) that small worldness index will improve after the rTMS.
ROI
RESTING STATE EEG HS, eyes closed (Power Spectral Density & Frequency map) / 60 seconds
RESTING STATE EEG HS, eyes opened (Power Spectral Density & Frequency map) / 60 seconds
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)
NCA
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.
Summary
Summary
Conclusions
This thesis dissertation is 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) By dividing the scalp regions and analyzing ERP data in seven regions of interest 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). However, the results suggest that brain connectivity, through the participation coefficient, and PSD, were highly related to the psychometric score and that N1-P3 complex, despite the variability, should be further investigated.
4) This report revealed for the first time that patients with schizophrenia exhibit higher gamma power spectral density 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 working memory 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.
Limitations
Brain Ecology �to understand mental illness
Thomas Fuchs 2005, Der Nervenarzt
Brain, Organism and Environment = Dynamic Unity
Ecological conception�has consequences for:
Fuchs, 2021 Psychiatry Between Psyche and Brain Chapter in Book
Schizophrenia - ECOLOGICAL VIEW
Schizophrenia
A key cognitive symptom in patients with schizophrenia is impaired sensory gating, defined as reduced ability to suppress processing of irrelevant and uninformative sensory input (Fröhlich, 2016)
„Just one more thing“
Takk fyrir!�
Mulțumesc!��Thank you!��Grazie!