Increased Thalamocortical Connectivity in Tdcs-potentiated Generalization of Cognitive Training
Trial Snapshot
- Phase
- Not Applicable
- Status
- Completed
- Sponsor
- University of Minnesota
- Enrollment
- 12
- Locations
- 1
- Primary Endpoint
- Changes in Thalamocortical Functional Connectivity (FC)
Study Overview
Brief Summary
Non-invasive neuromodulation, such as transcranial direct current stimulation ( tDCS) , is emerging as an important therapeutic tool with documented effects on brain circuitry, yet little is understood about h ow it changes cognition. In particular, tDCS may have a critical role to play in generalization, that is how training in one domain generalizes to unlearned or unpracticed domains. This problem has resonance for disorders with cognitive deficits, such as schizophrenia.
Understanding how tDCS affects brain circuity is critical to the design and application of effective interventions, especially if the effects are different for healthy vs. psychiatric populations. In previous research, one clue to the mechanism underlying increased learning and generalization with tDCS was provided by neuroimaging data from subjects with schizophrenia undergoing cognitive training where increases in thalamocortical (prefrontal) functional connectivity (FC) predicted greater generalization.
The premise of this proposal is that increases in thalamocortical FC are associated with the generalization of cognitive training, and tDCS facilitates these increases. The overarching goals of this proposal are to deploy neuroimaging and cognitive testing to understand how tDCS with cognitive training affect thalamocortical circuitry in individuals with and without psychosis and to examine variability in response within both groups.
Study 1(NCT03896425) will compare right prefrontal, left prefrontal and sham tDCS during concurrent cognitive training over 12 weeks in 90 healthy controls. Study 2 will be similar in all aspects but will examine 90 patients with schizophrenia or schizoaffective disorder and include clinical assessments. Results of the study will provide crucial information about location of stimulation, length of treatment, modeled dosage, trajectory and durability needed to guide future research and interventions for cognitive impairments.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- Triple (Participant, Investigator, Outcomes Assessor)
Eligibility Criteria
- Ages
- 18 Years to 60 Years (Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Ability to provide consent and comply with study procedures.
- •Age 18 - 60 years old.
- •Estimated IQ range within the range: 70 ≤ IQ ≤
- •Schizophrenia or schizoaffective disorder as assessed by the MINI (Mini International Neuropsychiatric Interview)(Sheehan et al., 1998).
- •Not having a current addictive disorder as measured by MINI (Mini International Neuropsychiatric Interview), or a sleep disorder.
- •Ability to participate in three weekly 45' training sessions over 12 weeks and participate in four assessments.
- •Clinically stable and on stable medications for at least one month before start of study.
Exclusion Criteria
- •Any medical condition or treatment with neurological sequelae (e.g. stroke, tumor, loss of consciousness > 30 min, HIV).
- •Contraindications for tDCS or MRI scanning (tDCS contraindication: history of seizures; MRI contraindications: The research team will utilize the CMRR Center's screening tools and adhere to the screening SOP during enrollment of all research participants in this protocol. The CMRR Center's screening tools and SOP are IRB approved under the CMRR Center Grant (HSC# 1406M51205) and information regarding screening procedures is publicly available on the CMRR website (CMRR Policies / Procedures).
Arms & Interventions
right active-tDCS
2-3 times/week for 12 weeks: ramp-up for 30 seconds, 2mA right (AF4 anode - AF3 cathode) for 20 min, and then ramp-down for 30 seconds.
Intervention: Transcranial Direct Current Stimulation (tDCS) (Device)
left active-tDCS
2-3 times/week for 12 weeks: ramp-up for 30 seconds, 2mA left (AF3 anode - AF4 cathode) for 20 min, and then ramp-down for 30 seconds.
Intervention: Transcranial Direct Current Stimulation (tDCS) (Device)
sham tDCS
Current will be turned off immediately after the initial 30-second ramp-up period.
Intervention: Transcranial Direct Current Stimulation (tDCS) (Device)
Outcomes
Primary Outcomes
Changes in Thalamocortical Functional Connectivity (FC)
Time Frame: post-test (week 12)
Most participants completed MRI sessions on a 3T scanner located in the Center for Magnetic Resonance Research (CMRR) at the University of Minnesota. FC measures how different brain regions change in activation together. We characterized FC using global connectivity from graph theory analysis. We extracted the fMRI time courses from 454 parcellations defined by the 400 S4 Schaefer Atlas (Schaefer et al., 2018) combined with the Melbourne Subcortex Atlas (Tian et al., 2020). We computed the absolute value of the Pearson's correlation for all possible pairs of time series, creating a 454x454 (N x N) connectivity matrix, which was then reduced to 10% most significant connections by subject. We estimated the FC by calculating the node strength for each parcellation, which is the weighted mean of all significant connections, from these connectivity matrices. Finally, we averaged node strength across parcellations to calculate global node strength. Higher values indicate more brain-wide FC.
Changes in Task-dependent Thalamocortical Functional Connectivity (fMRI) During the N-back Task.
Time Frame: post-test (week 12)
Task-dependent thalamocortical connectivity associated with the N-back task was calculated by modeling the block task design together with the thalamic regressor using psychophysiological interaction analysis (PPI). The thalamic regressor is the time series of the mediodorsal thalamus from the Melbourne atlas. The primary analysis focused on the 2-back conditions alone. The PPI analysis calculates the functional connectivity between the mediodorsal thalamus and all other brain regions specifically during 2-back trials. Neural activation related to the thalamic regressor was compared to neural activation during the fixation (no choices made) to normalize the relative activation (z-score). Positive values indicate increased functional connectivity with the thalamus during the 2-back choices. A z-score of zero represents no difference compared to the fixation cross (no choices). We report the average z-score of the PPI regressor within the control network (Yeo et al., 2011).
Changes in Task-dependent Thalamocortical Functional Connectivity (fMRI) During the DPX Task.
Time Frame: post-test (week 12)
PPI regressor (z-score) within Control Network associated with B-cue Task-dependent thalamocortical connectivity associated with the DPX task demands will be identified by analyzing cue and probe events together with the thalamic regressor using psychophysiological interaction analysis (PPI). The thalamic regressor is the time series of the mediodorsal thalmus from the Melbourne atlas (THA-DAm; Tian et al., 2020). Preliminary analysis for the DPX task will examine B-cue related connectivity alone. We report the average z-score of the PPI regressor within the control network (Yeo et al., 2011). Neural activation was normed to calculated z-scores, such that postive values indicate increased connectivity with the thalamus, and negative values indicate decreased connectivity with the thalamus.
Change in N-back Performance
Time Frame: post-test (week 12)
The n-back task measures working memory capacity. The participant is presented with a series of stimuli and instructed to indicate with a button press when the current stimulus matches the stimulus that appeared a pre-determined number (n) of trials before. d' (d prime) will be calculated as a measure of signal detection, which indicates the normalized rate of hits to false positives (d' = z(H) - z(F)). Increase in d' signifies improved signal detection, i.e. a better outcome. A d' near zero indicates a performance at chance, i.e., a poor performance. The range is -4.65 to 4.65
Change in DPX Performance
Time Frame: post-test (week 12)
The Dot Pattern Expectancy (DPX) task is an adaptation of the expectancy AX task that uses pairs of simple dot patterns rather than letter pairs as stimuli. The DPX task will be performed in 3 blocks. Each trial consists of a cue dot pattern followed by a probe dot pattern. Different combinations of cues and probes enable the identification of a specific deficit in a subject's ability to maintain goal-relevant information throughout a trial. Timing will be jittered and each block of the DPX task will consist of 40 trials: 24 AX (60%), 6 AY (15%), 6 BX (15%) and 4 BY (10%). Each block will last 6 minutes. d'-context will be calculated as a measure of signal detection, which indicates the normalized rate of AX hits to BX false positives (d' = z(H) - z(F)). Increase in d' -context signified improved signal detection, i.e. a better outcome. A d' near zero indicates a performance at chance, i.e., a poor performance. The range is -4.65 to 4.65.
Change in Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) Composite Score
Time Frame: follow-up (week 24)
MCCB Composite T-Score Intends to provide a relatively brief evaluation of key cognitive domains relevant to schizophrenia and related disorders. The composite score is reported as a T-score, with a mean of 50 and standard deviation of 10. Higher values indicate greater cognitive functioning.
Changes in Thalamocortical Functional Connectivity (FC)
Time Frame: baseline
Most participants completed MRI sessions on a 3T scanner located in the Center for Magnetic Resonance Research (CMRR) at the University of Minnesota. FC measures how different brain regions change in activation together. We characterized FC using global connectivity from graph theory analysis. We extracted the fMRI time courses from 454 parcellations defined by the 400 S4 Schaefer Atlas (Schaefer et al., 2018) combined with the Melbourne Subcortex Atlas (Tian et al., 2020). We computed the absolute value of the Pearson's correlation for all possible pairs of time series, creating a 454x454 (N x N) connectivity matrix, which was then reduced to 10% most significant connections by subject. We estimated the FC by calculating the node strength for each parcellation, which is the weighted mean of all significant connections, from these connectivity matrices. Finally, we averaged node strength across parcellations to calculate global node strength. Higher values indicate more brain-wide FC.
Changes in Task-dependent Thalamocortical Functional Connectivity (fMRI) During the N-back Task.
Time Frame: baseline
Task-dependent thalamocortical connectivity associated with the N-back task was calculated by modeling the block task design together with the thalamic regressor using psychophysiological interaction analysis (PPI). The thalamic regressor is the time series of the mediodorsal thalamus from the Melbourne atlas. The primary analysis focused on the 2-back conditions alone. The PPI analysis calculates the functional connectivity between the mediodorsal thalamus and all other brain regions specifically during 2-back trials. Neural activation related to the thalamic regressor was compared to neural activation during the fixation (no choices made) to normalize the relative activation (z-score). Positive values indicate increased functional connectivity with the thalamus during the 2-back choices. A z-score of zero represents no difference compared to the fixation cross (no choices). We report the average z-score of the PPI regressor within the control network (Yeo et al., 2011).
Changes in Task-dependent Thalamocortical Functional Connectivity (fMRI) During the DPX Task.
Time Frame: mid-test (week 6)
PPI regressor (z-score) within Control Network associated with B-cue Task-dependent thalamocortical connectivity associated with the DPX task demands will be identified by analyzing cue and probe events together with the thalamic regressor using psychophysiological interaction analysis (PPI). The thalamic regressor is the time series of the mediodorsal thalmus from the Melbourne atlas (THA-DAm; Tian et al., 2020). Preliminary analysis for the DPX task will examine B-cue related connectivity alone. We report the average z-score of the PPI regressor within the control network (Yeo et al., 2011). Neural activation was normed to calculated z-scores, such that postive values indicate increased connectivity with the thalamus, and negative values indicate decreased connectivity with the thalamus.
Changes in Task-dependent Thalamocortical Functional Connectivity (fMRI) During the DPX Task.
Time Frame: baseline
Task-dependent thalamocortical connectivity associated with the Dot Pattern Expectancy (DPX) task demands will be identified by analyzing cue and probe events together with the thalamic regressor using psychophysiological interaction analysis (PPI). The thalamic regressor is the time series of the mediodorsal thalamus from the Melbourne atlas. We examined B-cue related connectivity. The PPI analysis calculates the functional connectivity between the mediodorsal thalamus and all other brain regions specifically during B-cue trials. Neural activation related to the thalamic regressor was compared to neural activation during the fixation (no choices made) to normalize the relative activation (z-score). Positive values indicate increased functional connectivity with the thalamus during the B-cue responses. A z-score of zero represents no difference compared to the fixation cross (no choices). We report the average z-score of the PPI regressor within the control network.
Change in N-back Performance
Time Frame: baseline
The n-back task measures working memory capacity. The participant is presented with a series of stimuli and instructed to indicate with a button press when the current stimulus matches the stimulus that appeared a pre-determined number (n) of trials before. d' (d prime) will be calculated as a measure of signal detection, which indicates the normalized rate of hits to false positives (d' = z(H) - z(F)). Increase in d' signifies improved signal detection, i.e. a better outcome. A d' near zero indicates a performance at chance, i.e., a poor performance. The range is -4.65 to 4.65
Change in DPX Performance
Time Frame: baseline
The Dot Pattern Expectancy (DPX) task is an adaptation of the expectancy AX task that uses pairs of simple dot patterns rather than letter pairs as stimuli. The DPX task will be performed in 3 blocks. Each trial consists of a cue dot pattern followed by a probe dot pattern. Different combinations of cues and probes enable the identification of a specific deficit in a subject's ability to maintain goal-relevant information throughout a trial. Timing will be jittered and each block of the DPX task will consist of 40 trials: 24 AX (60%), 6 AY (15%), 6 BX (15%) and 4 BY (10%). Each block will last 6 minutes. d'-context will be calculated as a measure of signal detection, which indicates the normalized rate of AX hits to BX false positives (d' = z(H) - z(F)). Increase in d' -context signified improved signal detection, i.e. a better outcome. A d' near zero indicates a performance at chance, i.e., a poor performance. The range is -4.65 to 4.65.
Change in Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) Composite Score
Time Frame: baseline
Intends to provide a relatively brief evaluation of key cognitive domains relevant to schizophrenia and related disorders. The composite score is reported as a T-score, with a mean of 50 and standard deviation of 10. Higher values indicate greater cognitive functioning.
Changes in Thalamocortical Functional Connectivity (FC)
Time Frame: mid-test (week 6)
Most participants completed MRI sessions on a 3T scanner located in the Center for Magnetic Resonance Research (CMRR) at the University of Minnesota. FC measures how different brain regions change in activation together. We characterized FC using global connectivity from graph theory analysis. We extracted the fMRI time courses from 454 parcellations defined by the 400 S4 Schaefer Atlas (Schaefer et al., 2018) combined with the Melbourne Subcortex Atlas (Tian et al., 2020). We computed the absolute value of the Pearson's correlation for all possible pairs of time series, creating a 454x454 (N x N) connectivity matrix, which was then reduced to 10% most significant connections by subject. We estimated the FC by calculating the node strength for each parcellation, which is the weighted mean of all significant connections, from these connectivity matrices. Finally, we averaged node strength across parcellations to calculate global node strength. Higher values indicate more brain-wide FC.
Changes in Task-dependent Thalamocortical Functional Connectivity (fMRI) During the N-back Task.
Time Frame: mid-test (week 6)
Task-dependent thalamocortical connectivity associated with the N-back task was calculated by modeling the block task design together with the thalamic regressor using psychophysiological interaction analysis (PPI). The thalamic regressor is the time series of the mediodorsal thalamus from the Melbourne atlas. The primary analysis focused on the 2-back conditions alone. The PPI analysis calculates the functional connectivity between the mediodorsal thalamus and all other brain regions specifically during 2-back trials. Neural activation related to the thalamic regressor was compared to neural activation during the fixation (no choices made) to normalize the relative activation (z-score). Positive values indicate increased functional connectivity with the thalamus during the 2-back choices. A z-score of zero represents no difference compared to the fixation cross (no choices). We report the average z-score of the PPI regressor within the control network (Yeo et al., 2011).
Change in N-back Performance
Time Frame: mid-test (week 6)
The n-back task measures working memory capacity. The participant is presented with a series of stimuli and instructed to indicate with a button press when the current stimulus matches the stimulus that appeared a pre-determined number (n) of trials before. d' (d prime) will be calculated as a measure of signal detection, which indicates the normalized rate of hits to false positives (d' = z(H) - z(F)). Increase in d' signifies improved signal detection, i.e. a better outcome. A d' near zero indicates a performance at chance, i.e., a poor performance. The range is -4.65 to 4.65
Change in DPX Performance
Time Frame: mid-test (week 6)
The Dot Pattern Expectancy (DPX) task is an adaptation of the expectancy AX task that uses pairs of simple dot patterns rather than letter pairs as stimuli. The DPX task will be performed in 3 blocks. Each trial consists of a cue dot pattern followed by a probe dot pattern. Different combinations of cues and probes enable the identification of a specific deficit in a subject's ability to maintain goal-relevant information throughout a trial. Timing will be jittered and each block of the DPX task will consist of 40 trials: 24 AX (60%), 6 AY (15%), 6 BX (15%) and 4 BY (10%). Each block will last 6 minutes. d'-context will be calculated as a measure of signal detection, which indicates the normalized rate of AX hits to BX false positives (d' = z(H) - z(F)). Increase in d' -context signified improved signal detection, i.e. a better outcome. A d' near zero indicates a performance at chance, i.e., a poor performance. The range is -4.65 to 4.65.
Change in Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) Composite Score
Time Frame: mid-test (week 6)
MCCB Composite T-Score Intends to provide a relatively brief evaluation of key cognitive domains relevant to schizophrenia and related disorders. The composite score is reported as a T-score, with a mean of 50 and standard deviation of 10. Higher values indicate greater cognitive functioning.
Change in Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) Composite Score
Time Frame: post-test (week 12)
MCCB Composite T-Score Intends to provide a relatively brief evaluation of key cognitive domains relevant to schizophrenia and related disorders. The composite score is reported as a T-score, with a mean of 50 and standard deviation of 10. Higher values indicate greater cognitive functioning.
Secondary Outcomes
- Change in University of California San Diego Performance-Based Skills Assessment - Brief (UPSA-B)(follow-up (week 24))
- Change in Brief Psychiatric Rating Scale (BPRS) Score(follow-up (week 24))
- Change in Brief Negative Symptom Scale (BNSS) Score(follow-up (week 24))
- Change in University of California San Diego Performance-Based Skills Assessment - Brief (UPSA-B)(baseline)
- Change in Brief Psychiatric Rating Scale (BPRS) Score(baseline)
- Change in Brief Negative Symptom Scale (BNSS) Score(baseline)
- Change in University of California San Diego Performance-Based Skills Assessment - Brief (UPSA-B)(mid-test (week 6))
- Change in University of California San Diego Performance-Based Skills Assessment - Brief (UPSA-B)(post-test (week 12))
- Change in Brief Psychiatric Rating Scale (BPRS) Score(mid-test (week 6))
- Change in Brief Psychiatric Rating Scale (BPRS) Score(post-test (week 12))
- Change in Brief Negative Symptom Scale (BNSS) Score(Mid-test (week 6))
- Change in Brief Negative Symptom Scale (BNSS) Score(post-test (week 12))