Cercetări cu marcatori neurofiziologici pentru evaluarea tratamentului

cu stimulare transcranială magnetică la pacienţii cu schizofrenie

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Ovidiu C. Banea

Neurofiziologie Clinică, MD, PhD

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Department of Engineering, Reykjavik University , Iceland

National University Hospital, Landspítali, Iceland

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Hospital Vall d´Hebron, Barcelona Spain

Hospital Sant Juan de Deu “Althaia” Manresa, Spain

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Data: 15 aprilie 2022

Sibiu, România

Summary

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PART ONE

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• Schizophrenia & AVH

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• TMS

PART TWO

• The present work
• Studies
• Conclusions
• Ecology of the brain

Schizophrenia

Chronic and severe mental disorder affecting approximately 24 million people or 1 in 300 people worldwide (WHO, 2022).

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Multifactorial origin: It is thought that an interaction between genes, a range of environmental and probably psychosocial factors may cause schizophrenia.

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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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Symptoms: positive, negative, and cognitive (Patel et al., 2014)

Schizophrenia

P: Hallucinations, Delusions, Thought disorders, Movement disorders (agitated body movements.

N: Disruptions to normal emotions and behaviors “Flat affect”, Reduced feelings of pleasure in everyday life, Difficulty beginning and sustaining activities, reduced speaking.

C: Poor “executive functioning” (the ability to understand information and use it to make decisions). Problems with “working memory” (the ability to use information immediately after learning it). Trouble focusing or paying attention (sensory gating dysfunction).

Between physical disease and phenomenology

• Kraepelin (1890s): product of neural processes and physical origin „progressive disorder and described deteriorated brain cells that underlie the disorder”

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• Bleuler (1911): “physical disease process but considered it “not absolutely necessary.” He agreed with Freud, Jung, and Janet, that the understanding of schizophrenia requires the study of unconscious psychological processes

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• Karl Jaspers (1913): “General Psychopathology” analyzing a symptom by form rather than by their content, biographical understanding and phenomenological approach, distinction between neurosis and psychosis

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• McGhie and Chapman (1961): proposed that symptoms of schizophrenia indicate a primary deficit in mechanisms of attention related to selection and inhibition (McGHIE & CHAPMAN, 1961)

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How to quantify Sensory Gating?

• Psychometrically sound self-report rating scale such as Sensory Gating Inventory (SGI) (Hetrick et al., 2012)
• Using auditory evoked potentials (P50 suppression)
• MRI or PET scan

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 –

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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).

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The area of the thalamus was smaller in the patients than in the volunteers, and this difference was greatest in the left anterior region.

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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,

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Instead of being reduced to analyzing processes inside the brain (Thomas Fuchs, 2021)

Biomarker - definition (FDA-NIH Biomarker Group 2016)

• A defined characteristic that is measured as an indicator of normal biological processes, pathogenic processes, or responses to an exposure or intervention, including therapeutic interventions. Types: Histologic, molecular (glucose), radiographic (tumor size), and physiologic (blood pressure) characteristics.

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Endophenotype - definition

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• Biomarkers that are genetically correlated with disease liability, can be measured in all individuals (both affected and unaffected), and that provide greater power to identify disease-related genes than does disease “yes/no” status alone

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.

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• At the onset of illness, acquiring an MRI scan could be part of the routine evaluation to determine the disease progression.

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• The practice is not recognized by the American Psychiatric Association in any of its guidelines on the treatment of schizophrenia (DeLisi, 2020).
• Most studies have shown a grey matter volume reduction of STG

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Left temporoparietal site T3P3 (TPJ)

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)

Auditory Verbal Hallucinations

Auditory verbal hallucinations is the most common positive symptom in schizophrenia.

The first treatment option for hallucinations 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. MRI studies examining patients with schizophrenia during the processing of auditory stimuli showed (Kompus et al, 2011)

increased activation in the absence of an external stimulus !

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.���

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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)

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Low frequency 1Hz INHIBITORY EFFECT

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RTMS and AVH

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).

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Exploratory objectives

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• To determine if the symptoms of patients with schizophrenia change after intervention with 10 days of low-frequency 1Hz RTMS

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• To explore if neurophysiological tests like quantifying auditory event-related responses (P50 suppression, N100-P300 complex), EEG (electroencephalography) relative power, functional connectivity, and the cortical silent period (CSP) show changes after the RTMS treatment.

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.

The study was approved by the Ethics Committee of the National University Hospital of Iceland (Approval No 21. 2018).

Protocol

design

Methods

Clinical outcome

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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).

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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).

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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).

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Methods

Neurophysiological assessment

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• EEG recordings in three conditions: Resting-state (RS), auditory-motor task with the left hand (AMT-l), auditory-motor task with the right hand (AMT-r)

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• Auditory paired-click paradigm

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• Oddball auditory paradigm

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• Cortical silent period

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• Cutaneous silent period

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Methods

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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)

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Fifteen electrodes were selected from 3 parallel lines for each region (105 electrodes).

Methods P50, N100

The S1 response was identified as the most prominent peak in the 40 to 80 ms post-stimulus windows.

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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.

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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).

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The difference of S1 minus S2 amplitude was also used as a comparison.

Methods P300 (N100-P300)

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 *expl 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.

Exploratory Study. 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).

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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).

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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

RESULTS CSP

RESULTS CuSP

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.

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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.

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.

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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

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.

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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)

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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)

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

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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 (CPL).

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

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• For Healthy Subjects we would expect higher clustering (existence of motifs, modules and hubs) with shorter path length for gamma band activity during working memory than during resting state

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• In Patients Group we expect higher global SWN organization after 10 days rTMS

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• Reference period (NCA): we would expect increased connectivity

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,

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p < 0,05, ηp² = 0,967.

RTMS modulates gamma PSD

over the

left temporoparietal in SCZ patients during AMT performed with non-dominant hand

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Small worldness

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.

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Conclusions

This work was a hypothesis-generating research analyzing the influence of RTMS on brain mechanisms in patients with schizophrenia and pharmaco-resistant AVH.

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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.

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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.

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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.

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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

• The weaknesses of the works presented here are that they are based on a small sample size. The patients were also undergoing their usual treatment, including antipsychotic and sedative medications. This did not change between pre-and-post RTMS conditions but might have influenced the background neural activity and the generation of the ERPs (Javitt et al., 2008).
• The experimental procedure was long (1 hour) and tiring and some patients had difficulty cooperating and maintaining tasks engagement, which may have affected data quality.
• Muscle and movement artifacts added noise to the EEG signal, requiring a thorough pre-processing and the exclusion of many trials.

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“

Source: https://ecosystembiomes.files.wordpress.com/2015/07/niveles.jpg

Takk fyrir!�

Mulțumesc!��Thank you!��Grazie!

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Email: ovidiubanea@gmail.com

fb: @brainecology

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