Psychosis, Schizophrenia
Conditions
Keywords
tDCS, cognitive control, EEG, gamma oscillations
Brief summary
Cognitive impairments in schizophrenia are the most debilitating aspect of the illness and poorly treated by current medications. This study investigates transcranial direct current stimulation (tDCS) - a safe, noninvasive weak electrical current delivery to stimulate brain function - as a novel therapeutic for cognition in schizophrenia. Integrating neurostimulation, electrophysiology and neuroimaging, this project aims to study tDCS effects on cognition by verifying therapeutic target engagement, evaluating the tolerability of tDCS sessions, and optimizing treatment parameters.
Detailed description
Cognitive deficits are a strong predictor of functional outcome in schizophrenia, yet poorly remediated by current treatments. Disturbances in dorsolateral prefrontal cortex (DLPFC) function underlie core impairments such as in cognitive control and thus represent a critical target for novel therapeutics. Initial studies indicate transcranial direct-current stimulation (tDCS) may be effective in reducing symptoms due to DLPFC dysfunction. While tDCS potentially represents an exciting, novel therapeutic advance, a number of basic questions should be addressed prior to conducting larger-scale clinical trials, including: verifying therapeutic target engagement, optimizing treatment parameters, and evaluating for meaningful clinical effects. Recent studies employing tDCS to enhance prefrontal cortical function in schizophrenia applied stimulating electrodes over the left frontal scalp region, putatively targeting the left DLPFC. However, explicit confirmation of such target engagement is lacking. Further, EEG studies have demonstrated close links of frontal cortical gamma oscillations to cognitive control processes but modulation of this critical physiologic process has not been investigated. Accordingly, the primary aim of this study is to employ multimodal imaging to explicitly test for the assumed DLPFC engagement (fMRI) and modulation of frontal gamma activity (EEG) by tDCS. This study will also investigate the optimization of tDCS application parameters. Analogous to dose-finding investigations in drug studies, we will conduct a parametric investigation of optimal current strengths. Also, while there is extensive evidence for tolerability of single session tDCS, confirmation of feasibility of multisession optimized protocols in schizophrenia is lacking and so will be explicitly evaluated. In summary, a successful outcome of this study would provide tDCS the sound mechanistic and methodologic basis for more definitive testing in large-scale clinical trials as a highly innovative therapeutic intervention for cognitive impairments in schizophrenia.
Interventions
DEVICEtranscranial direct current stimulation
transcranial direct current stimulation (tDCS) is a safe, noninvasive, weak electrical current delivery that stimulates brain function. It is a novel therapeutic for cognition in schizophrenia.
Sponsors
National Institute of Mental Health (NIMH)
Baylor College of Medicine
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 35 Years
Healthy volunteers
No
Inclusion criteria
1. ages 18-35 years; 2. within first five years of antipsychotic treatment; 3. on stable doses of antipsychotic medication for at least one month; 4. Clinically stable as defined by Clinical Global Impression-Severity scale (CGI-S) less than or equal to 4 (moderately ill); 5. Mild to severe cognitive impairment in MATRICS Consensus Cognitive Battery (composite scores \<40); 6. DSM-5 MINI 7.0.2 criteria for schizophrenia or schizoaffective by patient SCID
Exclusion criteria
1. Mental retardation as defined by pre-morbid IQ by Wechsler Test of Adult Reading at screening \<70 or Spanish Word Accentuation Test; 2. significant head injury; 3. History of severe medical or neurological illnesses 4. pregnancy or postpartum (\<6 weeks after delivery or miscarriage); 5. inability to provide informed consent; 6. significant color blindness that affects task performance; 7. Positive urine drug screen (exception for marijuana) or presence of substance use disorder within 1 month; 8. Currently on benzodiazepines or mood stabilizers affecting GABA
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| tDCS Engagement of DLPFC Activity Indexed by fMRI BOLD Imaging | 1 week | Change from Baseline to week 1 as measured by modulation of fMRI BOLD signal in DLPFC in the context of cognitive control task performance. |
| tDCS Engagement of DLPFC Activity Indexed by Modulation of Frontal Cortical Gamma Oscillations | 1 week | Change from Baseline to week 1 as measured by EEG frontal gamma oscillations in the context of cognitive control task performance |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Optimal tDCS Strength for DLPFC Engagement | 1 Week | Change from baseline to 1 week in DLPFC engagement across conditions (1.5 vs 2.0 vs 2.5 mA) |
| Tolerability and Feasibility of Multi-session tDCS in Schizophrenia | 1 week | The percentage of participants able to complete the full study. |
Countries
United States
Participant flow
Recruitment details
The reason we have fewer subjects randomized than enrolled is that some participants did not meet criteria to be randomized. These subjects were consented and completed many assessments, but were ultimately not randomized due to how they scored on some assessments. For instance, some peoples MCCB score was too high to be randomized into the study.
Pre-assignment details
The primary reasons for ineligibility were not meeting the early psychosis criterion (\< 5 years of treatment), not taking any medication, and drug use. There were also many who did not even enter screening due to the assessment that they would highly likely not meet the threshold of requirement cognitive impairment (MATRICS score 40).
Participants by arm
| Arm | Count |
|---|---|
| 2.5mA Active stimulation group will receive 20 minutes of 2.5 mA transcranial direct current stimulation.
transcranial direct current stimulation: transcranial direct current stimulation (tDCS) is a safe, noninvasive, weak electrical current delivery that stimulates brain function. It is a novel therapeutic for cognition in schizophrenia. | 1 |
| 2.0mA Active stimulation group will receive 20 minutes of 2.0 mA transcranial direct current stimulation.
transcranial direct current stimulation: transcranial direct current stimulation (tDCS) is a safe, noninvasive, weak electrical current delivery that stimulates brain function. It is a novel therapeutic for cognition in schizophrenia. | 2 |
| 1.5mA Active stimulation group will receive 20 minutes of 1.5 mA transcranial direct current stimulation.
transcranial direct current stimulation: transcranial direct current stimulation (tDCS) is a safe, noninvasive, weak electrical current delivery that stimulates brain function. It is a novel therapeutic for cognition in schizophrenia. | 1 |
| 0mA (Active Placebo) This will be an active sham involving transcranial direct current stimulation, though stimulation will be brief (15 msec) and have low current (0.11 mA) pulses every 550 ms.
transcranial direct current stimulation: transcranial direct current stimulation (tDCS) is a safe, noninvasive, weak electrical current delivery that stimulates brain function. It is a novel therapeutic for cognition in schizophrenia. | 4 |
| Total | 8 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 | 1 | 0 |
Baseline characteristics
| Characteristic | 2.5mA | 2.0mA | 1.5mA | 0mA (Active Placebo) | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants | 2 Participants | 1 Participants | 4 Participants | 8 Participants |
| Age, Continuous | 22 years STANDARD_DEVIATION 0 | 26 years STANDARD_DEVIATION 3.65 | 22 years STANDARD_DEVIATION 0 | 23 years STANDARD_DEVIATION 2.44 | 24 years STANDARD_DEVIATION 2.66 |
| MCCB Score | 15 units on a scale STANDARD_DEVIATION 0 | 17.5 units on a scale STANDARD_DEVIATION 4.95 | 35 units on a scale STANDARD_DEVIATION 0 | 32 units on a scale STANDARD_DEVIATION 12.72 | 26.6 units on a scale STANDARD_DEVIATION 11.94 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 0 Participants | 3 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Region of Enrollment United States | 1 participants | 2 participants | 1 participants | 4 participants | 8 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Sex: Female, Male Male | 1 Participants | 2 Participants | 0 Participants | 3 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 1 | 0 / 2 | 0 / 1 | 0 / 4 |
| other Total, other adverse events | 0 / 1 | 1 / 2 | 0 / 1 | 0 / 4 |
| serious Total, serious adverse events | 0 / 1 | 1 / 2 | 0 / 1 | 0 / 4 |
Outcome results
Primary
tDCS Engagement of DLPFC Activity Indexed by fMRI BOLD Imaging
Change from Baseline to week 1 as measured by modulation of fMRI BOLD signal in DLPFC in the context of cognitive control task performance.
Time frame: 1 week
Population: Our analytic strategy involved defining regions of interest (ROI) derived from group averages across all study subjects but due to unforeseen circumstances, we recruited far too few subjects to derive meaningful group averages. Individual subject and by extension, condition-specific averages that are based on such ROIs, could therefore not be derived. However, we will upload our raw data to the National Data Archive to be accessed for any potential analyses with data pooled from other studies.
Primary
tDCS Engagement of DLPFC Activity Indexed by Modulation of Frontal Cortical Gamma Oscillations
Change from Baseline to week 1 as measured by EEG frontal gamma oscillations in the context of cognitive control task performance
Time frame: 1 week
Population: Our analytic strategy involved defining regions of interest (ROI) derived from group averages across all study subjects but due to unforeseen circumstances, we recruited far too few subjects to derive meaningful group averages. Individual subject and by extension, condition-specific averages that are based on such ROIs, could therefore not be derived. However, we will upload our raw data to the National Data Archive to be accessed for any potential analyses with data pooled from other studies.
Secondary
Optimal tDCS Strength for DLPFC Engagement
Change from baseline to 1 week in DLPFC engagement across conditions (1.5 vs 2.0 vs 2.5 mA)
Time frame: 1 Week
Population: Our analytic strategy involved defining regions of interest (ROI) derived from group averages across all study subjects but due to unforeseen circumstances, we recruited far too few subjects to derive meaningful group averages. Individual subject and by extension, condition-specific averages that are based on such ROIs, could therefore not be derived. However, we will upload our raw data to the National Data Archive to be accessed for any potential analyses with data pooled from other studies.
Secondary
Tolerability and Feasibility of Multi-session tDCS in Schizophrenia
The percentage of participants able to complete the full study.
Time frame: 1 week
Population: Due to unforeseen circumstances, we were unable to sufficiently recruit enough subjects to complete the originals plans for analysis. The percentages below are the percent of subjects who completed each condition.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 2.5mA | Tolerability and Feasibility of Multi-session tDCS in Schizophrenia | 0 percentage of participants completed |
| 2.0mA | Tolerability and Feasibility of Multi-session tDCS in Schizophrenia | 50 percentage of participants completed |
| 1.5mA | Tolerability and Feasibility of Multi-session tDCS in Schizophrenia | 0 percentage of participants completed |
| 0mA (Active Placebo) | Tolerability and Feasibility of Multi-session tDCS in Schizophrenia | 100 percentage of participants completed |