Maximizing the Impact of Neuroplasticity Using Transcranial Electrical Stimulation Study 2 (MINUTES)

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 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.

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.

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.

Three different stimulation montages will be programmed: right, left and sham. During the Ramp periods, 2 mA current will be delivered to both AF3 and AF4 with an ascending (RampUp) and descending ramp (RampDown) over 30 sec via two saline soaked electrode sponges (~ 25cm²; current density = 0.08 mA/cm²). In this way, all subjects experience the same sensation on both sides to blind them to condition. During the Constant period, current will be set based on the Condition: Right - 2mA AF4 anode-AF3 cathode; Left - 2mA applied to AF3 anode-AF4 cathode; Sham - current turned off.

Most participants will complete MRI sessions on a 3T scanner located in the Center for Magnetic Resonance Research (CMRR) at the University of Minnesota. To calculate FC, we will characterize the global and local network connectivity using a graph theory analysis. This will be formed by extracting the fMRI time courses from ninety regions of interest, based on ROIs defined by the freesurfer T1 parcellation. We will focus on low frequency (0.06-0.125 Hz) oscillations in the BOLD signal. We will estimate the functional connectivity by computing the absolute value of the Pearson's correlation between all possible pairs of time series, creating a 90 x 90 (N x N) connectivity matrix. The network topology metrics, characteristic path length and clustering coefficient, will be computed from the connectivity matrix, averaged over a threshold range representing .1 to .3 of the maximum possible number of edges in the graph. We will also measure global strength and diversity of the nodes.

Task-dependent thalamocortical connectivity associated with the N-back task will be identified by modeling the block task design together with the thalamic regressor . The primary analysis for the N-Back tasks will consider the 2-back conditions alone. Subsequent analyses will examine the 2 > 0-back contrast to strengthen interpretation of any observed changes in task-dependent thalamocortical connectivity. Main effects of hemisphere (right active-tDCS vs left active-tDCS and sham-tDCS ), length of treatment , and modeled dosage will be examined for the N-back fMRI dataset . Group x Time (pre, mid, and post-intervention) interactions will also be examined for the N-back fMRI dataset.

Task-dependent thalamocortical connectivity associated with the DPX task demands will be identified by analyzing cue and probe events together with the thalamic regressor. Preliminary analysis for the DPX task will examine B-cue related connectivity alone. Subsequent analyses will strengthen interpretation by examining both B-cue > A-cue related connectivity, as well as connectivity changes associated with response-related, or reactive, control (during the AY condition). Main effects of hemisphere (right active vs . left active and sham-tDCS ), length of treatment , and modeled dosage will be examined for the DPX fMRI dataset . Group x Time interactions will also be examined for the DPX fMRI dataset.

The n-back 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. Both accuracy (percentage of correct responses) and reaction time (milliseconds) will be recorded, and d' (d prime) will be calculated as a measure of signal detection. Increase in d' signifies improved signal detection, i.e. a better outcome.

The DPX task is an adaptation of the expectancy AX task that uses pairs of simple dot patterns rather than letter pairs as stimuli. 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. Increase in d' -context signified improved signal detection, i.e. a better outcome.

Change in Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) composite score

Intends to provide a relatively brief evaluation of key cognitive domains relevant to schizophrenia and related disorders. The composite score is calculated as a sum of T scores from the battery's available sub tests. Composite scores range from 213 (0.1 %tile) to 487 (99.9 %tile).

Measures functional capacity by assessing skills involved in everyday tasks important to daily living. Points are scored for each of two sub scales based on the participant's correct performance of items in the sub scale (incorrect: 0 points, correct: 1 or 2 points). Points are used to derive a sub scale score by dividing points scored by the number of items in the sub scale (percentage correct) and multiplied by 50. The two sub scale scores are then added to derive the total score, with a possible range of 0-100. Higher scores represent better outcomes.

Measures symptom severity in patients with schizophrenia. Scores are assigned for symptom categories based on a semi-structured clinical interview with anchored severity scales (1-7) for each symptom category. Total score is derived by adding up individual symptom scores, resulting in a total score range of 24-168. Higher scores indicate greater symptom severity. A decrease in scores over time would indicate symptom reduction, i.e. a better outcome.

Measures of symptom severity in patients with schizophrenia with an emphasis on negative symptoms. Scores are assigned to symptom categories based on a semi-structured clinical interview with anchored severity scales (0-6 or 0-9). Total score is derived by adding up individual symptom scores, resulting in a total score range of 0-90. Higher scores indicate greater symptom severity. A decrease in scores over time would indicate symptom reduction, i.e. a better outcome.

Inclusion Criteria: Ability to provide consent and comply with study procedures. Age 18 - 60 years old. Estimated IQ range within the range: 70 ≤ IQ ≤ 115. 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).