Effect of Neuroplasticity Modulation in tDCS Treatment Response Among Schizophrenia Patients With Auditory Hallucination

Schizophrenia Clinical Trial

Official title:

Examining Neuroplasticity Modulation as Mechanistic Basis of tDCS Treatment Effects on Auditory Verbal Hallucination in Schizophrenia

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04629352
• Other study ID #: IA/CPHE/19/1/504591
• Status: Recruiting
• Phase: N/A
• Start date: December 1, 2020
• Est. completion date: August 31, 2025

Study information

• Verified date: April 2024
• Source: National Institute of Mental Health and Neuro Sciences, India
• Contact: Anushree Bose, PhD
• Phone: +91-8026995366
• Email: anushree.cp[@]gmail.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Schizophrenia is a severe neuropsychiatric disorder of the brain and is also one of the top ten disabling diseases. A common symptom of schizophrenia (SCZ) is hearing voices inside one's heads which others do not. Despite adequate medication, SCZ patients may continue to hear voices that are often rude or unfriendly and cause distress to the patients. Transcranial direct current stimulation (tDCS) is a safe, non-invasive brain stimulation technique that reduces 'hearing voices'. However, how and why add-on tDCS works is unclear. The brain can change itself in response to its environment; this is called neuroplasticity. tDCS possibly changes the brain's environment and/or enhances the brain's ability to respond favourably to its environment. This theory will be examined here by studying changes in brain functions before and after giving tDCS to schizophrenia patients hearing voices. The aim of this study is to examine the brain's neuroplasticity potential as the biological phenomena driving treatment effects of tDCS in Schizophrenia patients with clinically significant and persistent auditory verbal hallucinations. The secondary aims are to answer whether the brain's neuroplasticity potential in schizophrenia patients can predict their responsivity to tDCS treatment for auditory verbal hallucinations, and if chronicity of illness effects tDCS treatment response.

The brain's neuroplasticity potential will be examined using neuroimaging and neurophysiological techniques that give information about the integrity of the brain's signal processing efficiency, the chemical concentration of certain bio-molecules within it, and how well different areas of the brain communicate with each other. With this information, the potential role of the brain's neuroplasticity potential in facilitating treatment effects of tDCS can be better understood. With this knowledge, it could be possible personalize tDCS treatment, profile tDCS responders and non-responders based on demographic and biological factors, and prescribe tDCS at the appropriate time within the illness course for maximal benefit to the SCZ patients.

Description:

20-30% schizophrenia (SCZ) patients struggle with auditory verbal hallucinations (AVH) minimally responsive to pharmaceutical treatments. An add-on fronto-temporoparietal transcranial direct current stimulation (tDCS) is suggested to address persistent AVH in SCZ patients. High heterogeneity among existing randomized control trials for AVH treatment in SCZ and the lack of empirical studies investigating the tDCS action mechanism warrants a systematic investigation into the mechanistic basis of tDCS action.

This proposal aims to examine the potential for neuroplasticity modulation as the mechanistic factor behind the therapeutic effects of left fronto-temporo-parietal tDCS for treating clinically significant AVH in early-course and chronic SCZ patients. It has been proposed and demonstrated that more tDCS sessions over a shorter interval lead to rapid plasticity induction. Accelerated tDCS protocol delivers a higher number of tDCS sessions over a shorter duration. Accelerated protocol (5 sessions/day for 2 days, inter-session interval~20 minutes) for the treatment of AVH in SZ showed clinical improvement with concurrent changes in neurophysiological correlates of auditory hallucination pathophysiology. Specifically, this study will examine neuroplasticity potential as a biomarker for tDCS treatment response with an accelerated tDCS (acctDCS) protocol. Using a randomized, double-blind, sham-controlled parallel-arm, pre-post design, changes in neuroplasticity potential with tDCS treatment for AVH in SCZ will be assessed. The four composite primary outcome measures of this study are:

1. changes in N100-derived event-related-potential waveforms (neurophysiological),

2. changes glutamine-glutamate levels (neurochemical),

3. changes in resting-state functional connectivity (neuroimaging), and

4. reduction in AVH severity (clinical).

The secondary objectives of this study are:

1. exploring the correlation between neurobiological measures of neuroplasticity changes induced by tDCS and clinical improvement in AVH to indicate the nature and strength of the relationship between the two;

2. exploring the effect of verum (active) tDCS on early course versus late course SCZ patients will uncover if illness chronicity is a potential barrier to tDCS responsivity; and

3. utilizing disorder-related (age at illness onset, medication, the severity of the symptom, etc.) and biographic (age, sex, years of education, etc.) features of the study sample towards predicting neuroplasticity modulation in the study sample.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 72
• Est. completion date: August 31, 2025
• Est. primary completion date: July 31, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 45 Years

Eligibility

INCLUSION CRITERIA

• Diagnosis of schizophrenia DSM-5 (American Psychiatric Association, 2013)

• Clinically Significant Auditory Verbal Hallucinations

• Right Handedness

• Written informed consent

EXCLUSION CRITERIA

• Features suggestive of psychiatric emergency

• Any contraindication to MRI or tDCS procedures

• Any co-morbid psychiatric diagnosis

• Pregnancy or post-partum status

• Left/Mixed Handedness

Related Conditions & MeSH terms

• Hallucinations
• Schizophrenia

Intervention

Device:
• Verum Accelerated Transcranial Direct Current Stimulation (acctDCS)
In verum transcranial direct current stimulation (tDCS), patient will receive five sessions daily for two days, a 10-session course of tDCS [anode: left-DLPFC (at F3) and cathode: left-TPJ (midway between C3 and P3); electrode size: 35cm2]. For Verum-tDCS condition, 2-mA of constant current will be delivered for 20-minutes, additional ramp-up and ramp-down of 20 seconds each.
• Sham Accelerated Transcranial Direct Current Stimulation (acctDCS)
In sham transcranial direct current stimulation (tDCS), each SCZ patient will receive five sessions daily for two days, a 10-session course of tDCS [anode: left-DLPFC (at F3) and cathode: left-TPJ (midway between C3 and P3); electrode size: 35cm2]. However, no current will be delivered beyond initial ramp-up time though the tDCS device display will indicate that 2mA current is being applied.

Locations

Country	Name	City	State
India	Department of Psychiatry, National Institute of Mental Health And Neuro Sciences (NIMHANS), Bengaluru, Karnataka	Bengaluru	Karnataka

Sponsors (1)

Lead Sponsor	Collaborator
National Institute of Mental Health and Neuro Sciences, India

Country where clinical trial is conducted

India, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	In a posthoc analysis, a prediction model for the potential of neuroplasticity modulation with tDCS will be attempted using machine learning algorithms and Bayesian approaches.	Disorder-related (age at illness onset, medication, severity of symptom, etc.) and biographic features (age, sex, years of education, etc.) of the study sample will be used to develop a prediction model for neuroplasticity modulation in this study sample. This model will be optimized further at one-month to take into account the changes in auditory verbal hallucination severity at follow-up among SCZ patients responsive to tDCS.	Day-6: After 10 sessions of RCT tDCS, One-month follow-up
Primary	Neurophysiological Measure: Change in amplitude of N100-related waveforms	Event-related potential (N100) based indices of changes in early auditory processing and adaptive plasticity in response to tDCS treatment.	Baseline: Day-1, After single session of tDCS: Day-1, Day-6: After 10 sessions of RCT tDCS
Primary	Neuro-Chemical Measure: Change in concentration of glutamate-glutamine levels	Spectroscopy based indices of glutamate-glutamine levels at left temporo-parietal junction (TPJ) and left prefrontal cortex (PFC) in response to tDCS treatment.	Baseline: Day-1, Day-6: After 10 sessions of RCT tDCS
Primary	Neuro-haemodynamic Measure: Change in strength of resting-state-functional-connectivity among brain areas	Neuroimaging based indices of seed-based resting-state-functional-connectivity (rs-FC) of the left-TPJ with left-PFC in response to tDCS treatment.	Baseline: Day-1, Day-6: After 10 sessions of RCT tDCS
Primary	Clinical Measure: Change in auditory verbal hallucination score	Change in auditory hallucination severity as indicated by Auditory Hallucination Rating Scale (AHRS) scores. Minimum score is 2 and maximum score is 41. Higher the score more severe the symptom.	Baseline: Day-1, Day-6: After 10 sessions of RCT tDCS, One month Follow-up, Three-months follow-up
Secondary	Change in auditory hallucination severity in responsive schizophrenia patients (with =25% reduction in auditory hallucination severity at post RCT time point) at 1-month and 3-month follow-up	Change in auditory hallucination severity as indicated by Auditory Hallucination Rating Scale at (AHRS) scores at clinical follow-up. Minimum score is 2 and maximum score is 41. Higher the score more severe the symptom.	One-month Follow-up, Three-month follow-up
Secondary	Change in auditory hallucination score in early course and late course schizophrenia patients	Both Early course (illness duration =2 years; n=36) and Late course (illness duration =5 years; n=36) schizophrenia patients will be recruited to explore the influence of illness chronicity on neuroplasticity potential and tDCS responsivity. Change in auditory hallucination severity as indicated by Auditory Hallucination Rating Scale at (AHRS) scores. Minimum score is 2 and maximum score is 41. Higher the score more severe the symptom.	Baseline: Day-1, Day-6: After 10 sessions of RCT tDCS