Neurophysiological Targets for Cognitive Training in Schizophrenia

• Sponsor: VA Office of Research and Development (U.S. Fed)
• Overall Status: Completed
• CT.gov ID: NCT00923078
• Collaborator: (none)
• Enrollment: 60
• Location: 1
• Arms: 2
• Duration (Months): 47
• Patients Per Site Per Month: 1.3

Study Details

Study Description

Brief Summary

The purpose of this study is to determine whether computer-based training of auditory and visual processing results in corresponding improvement in brain function in individuals with schizophrenia.

Condition or Disease	Intervention/Treatment	Phase
Schizophrenia	Behavioral: Auditory Cognitive Training; Behavioral: Visual Cognitive Training	N/A

Detailed Description

Schizophrenia is recognized as one of the leading causes of medical disability worldwide, ranked 9th overall by the World Health Organization, and affects more than 2 million Americans per year. There is considerable evidence to suggest that disability status in schizophrenia relates more directly to cognitive Impairment, involving attention, reasoning, and memory, than to characteristic symptoms of psychosis. Accordingly, the evaluation and advancement of interventions designed to restore cognitive function, generally termed cognitive remediation, is of critical importance to our rehabilitation mission. Recent randomized controlled trials of cognitive remediation in schizophrenia have found moderate gains in cognitive function and improved outcomes in important areas of community living. However, despite these encouraging findings, there remains sparse evidence in support of assumptions that (1) cognitive outcomes represent benefits of training-induced adaptive learning, (2) that training effects are specific to method of intervention, or (3) that change in cognitive test performance occurs through restoration of impaired neural circuitry in schizophrenia. This project will begin to address these issues by examining modality-specific effects of computer-based cognitive training on psychophysiological measures of sensory information processing. Training will be administered using two commercially available computer-based software packages, separately targeting auditory and visually-mediated processes using principles of bottom-up perceptual learning. Two psychophysiological paradigms, mismatch negativity (MMN) and P300 generation, will be administered as tests of early visual and auditory processing. MMN and P300 have been studied extensively in human neuroscience as probes of sensory echoic memory and attention engagement to contextually relevant information. Furthermore, reductions in MMN and P300 generation are reliably observed in schizophrenia, follow the course of a progressive neuropathological process, and correlate with severity of cognitive impairment. The specific aims of this study are to determine: (1) whether training selectively influences bottom-up (MMN) or top-down (P300) information processing, (2) whether training effects are modality (auditory vs. visual) specific, (3) whether baseline MMN and P300 predict, or rate-limit, training progress, and (4) whether pre-post change in cognitive test performance is mediated by neural-level change in MMN and P300 generation. Answers to these questions will provide information needed to structure cognitive training for maximum benefit in schizophrenia.

Study Design

• Study Type: Interventional
• Actual Enrollment: 60 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Single (Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Neurophysiological Targets for Cognitive Training in Schizophrenia
• Study Start Date: Nov 1, 2010
• Actual Primary Completion Date: Oct 1, 2014
• Actual Study Completion Date: Oct 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Auditory-Visual Train Order 4 weeks (20 sessions) of auditory cognitive training (Brain Fitness) followed by 4 weeks (20 sessions) of visual cognitive training (Insight)	Behavioral: Auditory Cognitive Training; The program entails six computer-based exercises that are designed to be very easy to use and require no computer experience. The exercises are calibrated to individual performance at the onset of training and adapt in difficulty to individual performance, giving constant feedback about progress. Each of the six exercises focuses on a distinct process: (1) auditory processing speed, (2) discriminating sounds, (3) sound precision, (4) sound sequencing, (5) working memory, and (6) narrative memory. Training was administered in a supervised clinical laboratory setting at a frequency of five 60-minute sessions per week over 4 weeks.; Other Names: Brain Fitness by Posit Science ; Behavioral: Visual Cognitive Training; The program entails five computer-based exercises that are designed to be very easy to use and require no computer experience. The exercises are calibrated to individual performance at the onset of training and, following our laboratory procedures, calibration testing is repeated every 5th session. Exercises adapt in difficulty to individual performance, giving constant feedback about progress. Each of the five exercises focuses on a distinct process: (1) visual precision, (2) visual processing speed, (3) divided attention, (4) visual working memory, and (5) useful field of view. Training was administered in a supervised clinical laboratory setting at a frequency of five 40-minute sessions per week over 4 weeks.; Other Names: Cortex with Insight by Posit Science
Experimental: Visual-Auditory Train Order 4 weeks (20 sessions) of visual cognitive training (Insight) followed by 4 weeks (20 sessions) of auditory cognitive training (Brain Fitness)	Behavioral: Auditory Cognitive Training; The program entails six computer-based exercises that are designed to be very easy to use and require no computer experience. The exercises are calibrated to individual performance at the onset of training and adapt in difficulty to individual performance, giving constant feedback about progress. Each of the six exercises focuses on a distinct process: (1) auditory processing speed, (2) discriminating sounds, (3) sound precision, (4) sound sequencing, (5) working memory, and (6) narrative memory. Training was administered in a supervised clinical laboratory setting at a frequency of five 60-minute sessions per week over 4 weeks.; Other Names: Brain Fitness by Posit Science ; Behavioral: Visual Cognitive Training; The program entails five computer-based exercises that are designed to be very easy to use and require no computer experience. The exercises are calibrated to individual performance at the onset of training and, following our laboratory procedures, calibration testing is repeated every 5th session. Exercises adapt in difficulty to individual performance, giving constant feedback about progress. Each of the five exercises focuses on a distinct process: (1) visual precision, (2) visual processing speed, (3) divided attention, (4) visual working memory, and (5) useful field of view. Training was administered in a supervised clinical laboratory setting at a frequency of five 40-minute sessions per week over 4 weeks.; Other Names: Cortex with Insight by Posit Science

Outcome Measures

Primary Outcome Measures

1. Visual Target Detection (P300 Event-related Potential Amplitude) Change [Baseline; Post 4 weeks (treatment crossover); Post 8 weeks]

   Visual P300 was measured in a 3-stimulus target detection task with target stimuli (10%; large circle) presented in pseudo random order amidst a series of novel (10%; fractal), and standard (80%; small circle) images on a 24" LCD monitor at 100cm viewing distance. Subjects are instructed to press a reaction time button with the preferred hand to Targets only, giving equal importance to speed and accuracy. Primary analysis are based on Target "P300b" identified as the most positive amplitude deflection within the window of 250-550ms post stimulus at posterior midline electrode Pz. The P300b component is thought to reflect cognitive processes involved in memory updating and decision making. P300 reported as difference scores from baseline with negative values indicating increased P300.

2. Auditory Mismatch Negativity (MMN) Amplitude Change [Baseline; Post 4 weeks (treatment crossover); Post 8 weeks]

   Auditory MMN is a fronto-central, mid-latency, potential generated by the auditory cortex in response to deviation in a repetitive stimulus sequence. MMN was assessed using a 3-deviant paradigm in which a series of standard tones (633 Hz, 50ms duration,90%) is interrupted by deviants (10%) that differ either by (1) pitch (1000Hz, 50ms), (2) duration (633 Hz, 100ms), or (3) both (1000Hz, 100ms). MMN was tested concurrently with Visual P300 using a combined task in which subjects were instructed to ignore the auditory stimuli and focus on the visual stimuli. MMN is scored by subtracting each deviant ERP waveform from the standard waveform and measuring the most negative deflection in a window of 50 to 265ms post-stimulus from the resulting difference wave. Primary analysis is based on the combined deviant condition scored at the frontal midline (Fz) electrode site. MMN reported as difference scores from baseline with positive values indicating increased MMN.

3. MCCB Cognitive Composite Score Change [Baseline; Post 4 weeks (treatment crossover); Post 8 weeks]

   The Cognitive Composite score is derived from the MATRICS Consensus Cognitive Battery (MCCB). The MCCB consists of 10 tests and provides standard scores for each according to seven cognitive domains: (1) speed of processing, (2) attention/vigilance, (3) working memory (verbal and visual), (4) verbal learning, (5) visual learning, (6) reasoning and problem solving, and (7) social cognition. The primary dependent measures derived from the MCCB for purpose of this study is the cognitive composite score, computed as the average of standard (t-scores) scores from each domain excluding social cognition. MCCB Composite reported as difference scores from baseline with negative values indicating higher test performance.

Secondary Outcome Measures

1. Visual Learning (BVMT-R) Change [Baseline; Post 4 weeks (treatment crossover); Post 8 weeks]

   The visual learning domain of the MCCB is assessed using the Brief Visuospatial Memory Test-Revised (BVMT-R). In three Learning Trials, the respondent views a stimulus display for 10 seconds and is then asked to draw as many of the figures as possible in their correct location on a page in the response booklet. Scores represent overall accuracy across the three trials, with higher scores indicating better learning. Analysis is based on age- and gender-corrected t-scores. BVMT-R reported as difference scores from baseline with negative values indicating higher test performance.

2. Verbal Learning (HVLT-R) Change [Baseline; Post 4 weeks (treatment crossover); Post 8 weeks]

   The verbal learning domain of the MCCB is assessed using the Hopkins Verbal Learning Test-Revised (HVLT-R). In three Learning Trials, the respondent listens to a 12-item word list read by an examiner and is then asked to recall as many of the words as possible from memory. Scores represent overall accuracy across the three trials, with higher scores indicating better learning. Analysis is based on age- and gender-corrected t-scores. HVLT-R reported as difference scores from baseline with negative values indicating higher test performance.

3. Visual Working Memory (Spatial Span) Change [Baseline; Post 4 weeks (treatment crossover); Post 8 weeks]

   Visual working memory is assessed in the MCCB using the Spatial Span task of the Wechsler Memory Scales-III. Using a board on which 10 cubes are irregularly spaced, the examiner taps patterns of increasing length. The respondent is asked to follow by tapping the pattern in the same or reverse sequence. Scores represent total accuracy combined over forward and reverse span conditions. Analysis is based on age- and gender-corrected t-scores. Spatial Span reported as difference scores from baseline with negative values indicating higher test performance.

4. Auditory Working Memory (LNS) Change [Baseline; Post 4 weeks (treatment crossover); Post 8 weeks]

   Auditory working memory is assessed in the MCCB using the Letter-Number Sequencing (LNS) task. LNS is an orally administered test in which and examiner reads strings of numbers and letters, of increasing length over trials, and the respondent mentally reorders the string and reports back to the examiner verbally. Scores represent total number of accurate trials. Analysis is based on age- and gender-corrected t-scores. LNS reported as difference scores from baseline with negative values indicating higher test performance.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• DSM-IV diagnosis of schizophrenia or schizoaffective disorder

• Age between 18 & 70

• minimum of 30 days since discharge from last hospitalization

• minimum of 30 days since last change in psychiatric medications

• receiving mental health services

• no housing changes in the past 30 days

Exclusion Criteria:

• current diagnosis of alcohol or substance abuse

• history of brain trauma or neurological disease

• chart diagnosis of mental retardation or premorbid intelligence < 70 based on Wechsler Test of Adult Reading (WTAR) full-scale estimated IQ

• auditory or visual impairment that would interfere with study procedures

• a sample of 20 healthy community volunteers was also recruited according to these criteria and tested, without intervention, as a normative reference sample for MMN and P300 measures

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	VA Connecticut Health Care System (West Haven)	West Haven	Connecticut	United States	06516

Sponsors and Collaborators

• VA Office of Research and Development

Investigators

• Principal Investigator: Jason K Johannesen, PhD, VA Connecticut Health Care System (West Haven)

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: VA Office of Research and Development
• ClinicalTrials.gov Identifier: NCT00923078
• Other Study ID Numbers: D7008-W
• First Posted: Jun 18, 2009
• Last Update Posted: Dec 22, 2017
• Last Verified: Dec 1, 2017

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by VA Office of Research and Development: schizophrenia; cognitive remediation; rehabilitation; electrophysiology; neuropsychology
• Additional relevant MeSH terms: Schizophrenia

Study Results

Participant Flow

Pre-assignment Detail	Healthy comparison subjects completed a single assessment at baseline and did not receive intervention or follow-up testing.

Arm/Group Title	Auditory Then Visual Cognitive Training	Visual Then Auditory Cognitive Training	Healthy Comparison
Arm/Group Description	20 individuals with schizophrenia randomized to 4 weeks (20 sessions) of auditory training (Brain Fitness) followed by 4 weeks (20 sessions) of visual training (Insight).	20 individuals with schizophrenia randomized to 4 weeks (20 sessions) of visual training (Insight) followed by 4 weeks (20 sessions) of auditory training (Brain Fitness).	A sample healthy community volunteers participated in a single test session to provide normative comparison data on neurophysiological (P300, MMN) outcome measures
Period Title: First Intervention (Weeks 1-4)
STARTED	20	20	20
COMPLETED	19	19	0
NOT COMPLETED	1	1	20
Period Title: First Intervention (Weeks 1-4)
STARTED	19	19	0
COMPLETED	19	19	0
NOT COMPLETED	0	0	0

Baseline Characteristics

Arm/Group Title	Auditory-Visual Train Order	Visual-Auditory Train Order	Healthy Comparison	Total
Arm/Group Description	N = 20 participants with schizophrenia randomized to 4 weeks (20 sessions) of auditory training (Brain Fitness) followed by 4 weeks (20 sessions) of visual training (Insight)	N = 20 participants with schizophrenia randomized to 4 weeks (20 sessions) of visual training (Insight) followed by 4 weeks (20 sessions) of auditory training (Brain Fitness)	N = 20 healthy community volunteers participated in a single test session to provide normative comparison data	Total of all reporting groups
Overall Participants	20	20	20	60
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	19 95%	19 95%	20 100%	58 96.7%
>=65 years	1 5%	1 5%	0 0%	2 3.3%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	45.65 (12.26)	46.55 (12.85)	39.15 (13.39)	43.78 (13.05)
Sex: Female, Male (Count of Participants)
Female	7 35%	10 50%	9 45%	26 43.3%
Male	13 65%	10 50%	11 55%	34 56.7%
Region of Enrollment (participants) [Number]
United States	20 100%	20 100%	20 100%	60 100%
IQ (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	95.20 (14.83)	87.70 (12.32)	103.26 (13.86)	95.25 (14.90)
Cognitive Composite Score (t-score) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [t-score]	36.35 (12.86)	30.40 (12.87)	45.95 (13.70)	37.57 (14.45)
Positive and Negative Syndrome Scale (PANSS) (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	56.8 (12.89)	56.8 (13.94)	56.8 (13.25)

Outcome Measures

1. Primary Outcome

Title	Visual Target Detection (P300 Event-related Potential Amplitude) Change
Description	Visual P300 was measured in a 3-stimulus target detection task with target stimuli (10%; large circle) presented in pseudo random order amidst a series of novel (10%; fractal), and standard (80%; small circle) images on a 24" LCD monitor at 100cm viewing distance. Subjects are instructed to press a reaction time button with the preferred hand to Targets only, giving equal importance to speed and accuracy. Primary analysis are based on Target "P300b" identified as the most positive amplitude deflection within the window of 250-550ms post stimulus at posterior midline electrode Pz. The P300b component is thought to reflect cognitive processes involved in memory updating and decision making. P300 reported as difference scores from baseline with negative values indicating increased P300.
Time Frame	Baseline; Post 4 weeks (treatment crossover); Post 8 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Auditory Cognitive Training	Visual Cognitive Training
Arm/Group Description	4 weeks (20 sessions) of auditory cognitive training (Brain Fitness) completed either before or following 4 weeks (20 sessions) of visual cognitive training (Insight)	4 weeks (20 sessions) of visual cognitive training (Insight) completed either before or following 4 weeks (20 sessions) of auditory cognitive training (Brain Fitness)
Measure Participants	38	38
Mean (Standard Error) [microvolts (uV)]	2.20 (1.02)	-0.72 (1.02)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Auditory Cognitive Training
	Comments	Null hypothesis is that there is no difference between baseline and post-training scores. Linear mixed models tested fixed effects of period (3 levels; baseline, post 4-weeks, post 8 weeks), condition (3 levels; baseline, Auditory Cognitive Training, Visual Cognitive Training) and the period x condition interaction. Final model parameters were selected according to Bayesian Information Criteria. Alpha=.05 (2-sided)
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.05
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	2.20
	Confidence Interval	(2-Sided) 95%; 0.17 to 4.23
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.02
	Estimation Comments	contrast calculated as baseline minus Auditory Training

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Visual Cognitive Training
	Comments	Null hypothesis is that there is no difference between baseline and post-training scores. Linear mixed models tested fixed effects of period (3 levels; baseline, post 4-weeks, post 8 weeks), condition (3 levels; baseline, Auditory Cognitive Training, Visual Cognitive Training) and the period x condition interaction. Final model parameters were selected according to Bayesian Information Criteria. Alpha=.05 (2-sided)
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.48
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.72
	Confidence Interval	(2-Sided) 95%; -2.75 to 1.31
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.02
	Estimation Comments	contrast calculated as baseline minus Visual Training

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Auditory Cognitive Training, Visual Cognitive Training
	Comments	Null hypothesis is that there is no difference between post-training scores in Auditory vs. Visual Cognitive Training conditions. Linear mixed models tested fixed effects of period (3 levels; baseline, post 4-weeks, post 8 weeks), condition (3 levels; baseline, Auditory Cognitive Training, Visual Cognitive Training) and the period x condition interaction. Final model parameters were selected according to Bayesian Information Criteria. Alpha=.05 (2-sided)
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.01
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.92
	Confidence Interval	(2-Sided) 95%; -4.95 to -0.90
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.02
	Estimation Comments	contrast calculated as Auditory Training minus Visual Training

2. Primary Outcome

Title	Auditory Mismatch Negativity (MMN) Amplitude Change
Description	Auditory MMN is a fronto-central, mid-latency, potential generated by the auditory cortex in response to deviation in a repetitive stimulus sequence. MMN was assessed using a 3-deviant paradigm in which a series of standard tones (633 Hz, 50ms duration,90%) is interrupted by deviants (10%) that differ either by (1) pitch (1000Hz, 50ms), (2) duration (633 Hz, 100ms), or (3) both (1000Hz, 100ms). MMN was tested concurrently with Visual P300 using a combined task in which subjects were instructed to ignore the auditory stimuli and focus on the visual stimuli. MMN is scored by subtracting each deviant ERP waveform from the standard waveform and measuring the most negative deflection in a window of 50 to 265ms post-stimulus from the resulting difference wave. Primary analysis is based on the combined deviant condition scored at the frontal midline (Fz) electrode site. MMN reported as difference scores from baseline with positive values indicating increased MMN.
Time Frame	Baseline; Post 4 weeks (treatment crossover); Post 8 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Auditory Cognitive Training	Visual Cognitive Training
Arm/Group Description	4 weeks (20 sessions) of auditory cognitive training (Brain Fitness) completed either before or following 4 weeks (20 sessions) of visual cognitive training (Insight)	4 weeks (20 sessions) of visual cognitive training (Insight) completed either before or following 4 weeks (20 sessions) of auditory cognitive training (Brain Fitness)
Measure Participants	38	38
Mean (Standard Error) [microvolts (uV)]	0.67 (0.29)	0.51 (0.29)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Auditory Cognitive Training
	Comments	Null hypothesis is that there is no difference between baseline and post-training scores. Linear mixed models tested fixed effects of period (3 levels; baseline, post 4-weeks, post 8 weeks), condition (3 levels; baseline, Auditory Cognitive Training, Visual Cognitive Training) and the period x condition interaction. Final model parameters were selected according to Bayesian Information Criteria. Alpha=.05 (2-sided)
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.05
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.67
	Confidence Interval	(2-Sided) 95%; 0.08 to 1.25
	Parameter Dispersion	Type: Standard Error of the Mean; Value: .295
	Estimation Comments	contrast calculated as baseline minus Auditory Training

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Visual Cognitive Training
	Comments	Null hypothesis is that there is no difference between baseline and post-training scores. Linear mixed models tested fixed effects of period (3 levels; baseline, post 4-weeks, post 8 weeks), condition (3 levels; baseline, Auditory Cognitive Training, Visual Cognitive Training) and the period x condition interaction. Final model parameters were selected according to Bayesian Information Criteria. Alpha=.05 (2-sided)
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.09
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	.51
	Confidence Interval	(2-Sided) 95%; -0.08 to 1.09
	Parameter Dispersion	Type: Standard Error of the Mean; Value: .295
	Estimation Comments	contrast calculated as baseline minus Visual Training

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Auditory Cognitive Training, Visual Cognitive Training
	Comments	Null hypothesis is that there is no difference between post-training scores in Auditory vs. Visual Cognitive Training conditions. Linear mixed models tested fixed effects of period (3 levels; baseline, post 4-weeks, post 8 weeks), condition (3 levels; baseline, Auditory Cognitive Training, Visual Cognitive Training) and the period x condition interaction. Final model parameters were selected according to Bayesian Information Criteria. Alpha=.05 (2-sided)
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.59
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.16
	Confidence Interval	(2-Sided) 95%; -0.75 to 0.43
	Parameter Dispersion	Type: Standard Error of the Mean; Value: .295
	Estimation Comments	contrast calculated as Auditory Training minus Visual Training

3. Primary Outcome

Title	MCCB Cognitive Composite Score Change
Description	The Cognitive Composite score is derived from the MATRICS Consensus Cognitive Battery (MCCB). The MCCB consists of 10 tests and provides standard scores for each according to seven cognitive domains: (1) speed of processing, (2) attention/vigilance, (3) working memory (verbal and visual), (4) verbal learning, (5) visual learning, (6) reasoning and problem solving, and (7) social cognition. The primary dependent measures derived from the MCCB for purpose of this study is the cognitive composite score, computed as the average of standard (t-scores) scores from each domain excluding social cognition. MCCB Composite reported as difference scores from baseline with negative values indicating higher test performance.
Time Frame	Baseline; Post 4 weeks (treatment crossover); Post 8 weeks

Outcome Measure Data

Analysis Population Description

Of N=40 randomized, analysis was based on 38 who completed intervention and post-testing. Across conditions, participants completed, on average, 14.61 hrs of training in Period 1 (12.53 visual, 16.70 auditory) and 14.41 hrs in Period 2 (13.00 visual, 15.92 auditory)

Arm/Group Title	Auditory Cognitive Training	Visual Cognitive Training
Arm/Group Description	4 weeks (20 sessions) of auditory cognitive training (Brain Fitness) completed either before or following 4 weeks (20 sessions) of visual cognitive training (Insight)	4 weeks (20 sessions) of visual cognitive training (Insight) completed either before or following 4 weeks (20 sessions) of auditory cognitive training (Brain Fitness)
Measure Participants	38	38
Mean (Standard Error) [t-score]	-2.03 (0.75)	-2.45 (0.75)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Auditory Cognitive Training
	Comments	Null hypothesis is that there is no difference between baseline and post-training scores. Linear mixed models tested fixed effects of period (3 levels; baseline, post 4-weeks, post 8 weeks), condition (3 levels; baseline, Auditory Cognitive Training, Visual Cognitive Training) and the period x condition interaction. Final model parameters were selected according to Bayesian Information Criteria. Alpha=.05 (2-sided)
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.01
	Comments	Post-test scores following Auditory Cognitive Training as compared to baseline, tested at alpha = 0.05 (uncorrected).
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-2.03
	Confidence Interval	(2-Sided) 95%; -3.53 to -0.52
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.75
	Estimation Comments	contrast calculated as baseline minus Auditory Training

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Visual Cognitive Training
	Comments	Null hypothesis is that there is no difference between baseline and post-training scores. Linear mixed models tested fixed effects of period (3 levels; baseline, post 4-weeks, post 8 weeks), condition (3 levels; baseline, Auditory Cognitive Training, Visual Cognitive Training) and the period x condition interaction. Final model parameters were selected according to Bayesian Information Criteria. Alpha=.05 (2-sided)
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.01
	Comments	Post-test scores following Visual Cognitive Training as compared to baseline, tested at alpha = 0.05 (uncorrected).
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-2.45
	Confidence Interval	(2-Sided) 95%; -3.95 to -0.94
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.75
	Estimation Comments	contrast calculated as baseline minus Visual Training

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Auditory Cognitive Training, Visual Cognitive Training
	Comments	Null hypothesis is that there is no difference between post-training scores in Auditory vs. Visual Cognitive Training conditions. Linear mixed models tested fixed effects of period (3 levels; baseline, post 4-weeks, post 8 weeks), condition (3 levels; baseline, Auditory Cognitive Training, Visual Cognitive Training) and the period x condition interaction. Final model parameters were selected according to Bayesian Information Criteria. Alpha=.05 (2-sided)
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.58
	Comments	Post-test scores following Auditory Cognitive Training as compared to Visual Cognitive Training, tested at alpha = 0.05 (uncorrected).
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.42
	Confidence Interval	(2-Sided) 95%; -1.93 to 1.08
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.75
	Estimation Comments	contrast calculated as Auditory Training minus Visual Training

4. Secondary Outcome

Title	Visual Learning (BVMT-R) Change
Description	The visual learning domain of the MCCB is assessed using the Brief Visuospatial Memory Test-Revised (BVMT-R). In three Learning Trials, the respondent views a stimulus display for 10 seconds and is then asked to draw as many of the figures as possible in their correct location on a page in the response booklet. Scores represent overall accuracy across the three trials, with higher scores indicating better learning. Analysis is based on age- and gender-corrected t-scores. BVMT-R reported as difference scores from baseline with negative values indicating higher test performance.
Time Frame	Baseline; Post 4 weeks (treatment crossover); Post 8 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Auditory Cognitive Training	Visual Cognitive Training
Arm/Group Description	4 weeks (20 sessions) of auditory cognitive training (Brain Fitness) completed either before or following 4 weeks (20 sessions) of visual cognitive training (Insight)	4 weeks (20 sessions) of visual cognitive training (Insight) completed either before or following 4 weeks (20 sessions) of auditory cognitive training (Brain Fitness)
Measure Participants	38	38
Mean (Standard Error) [t-score]	-2.92 (1.55)	-3.24 (1.55)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Auditory Cognitive Training
	Comments	Null hypothesis is that there is no difference between baseline and post-training scores. Linear mixed models tested fixed effects of period (3 levels; baseline, post 4-weeks, post 8 weeks), condition (3 levels; baseline, Auditory Cognitive Training, Visual Cognitive Training) and the period x condition interaction. Final model parameters were selected according to Bayesian Information Criteria. Alpha=.05 (2-sided)
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.06
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-2.92
	Confidence Interval	(2-Sided) 95%; -6.02 to 0.18
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.55
	Estimation Comments	contrast calculated as baseline minus Auditory Training

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Visual Cognitive Training
	Comments	Null hypothesis is that there is no difference between baseline and post-training scores. Linear mixed models tested fixed effects of period (3 levels; baseline, post 4-weeks, post 8 weeks), condition (3 levels; baseline, Auditory Cognitive Training, Visual Cognitive Training) and the period x condition interaction. Final model parameters were selected according to Bayesian Information Criteria. Alpha=.05 (2-sided)
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	< 0.05
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-3.24
	Confidence Interval	(2-Sided) 95%; -6.34 to -0.14
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.55
	Estimation Comments	contrast calculated as baseline minus Visual Training

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Auditory Cognitive Training, Visual Cognitive Training
	Comments	Null hypothesis is that there is no difference between post-training scores in Auditory vs. Visual Cognitive Training conditions. Linear mixed models tested fixed effects of period (3 levels; baseline, post 4-weeks, post 8 weeks), condition (3 levels; baseline, Auditory Cognitive Training, Visual Cognitive Training) and the period x condition interaction. Final model parameters were selected according to Bayesian Information Criteria. Alpha=.05 (2-sided)
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.84
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.32
	Confidence Interval	(2-Sided) 95%; -3.42 to 2.78
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.55
	Estimation Comments	contrast calculated as Auditory Training minus Visual Training

5. Secondary Outcome

Title	Verbal Learning (HVLT-R) Change
Description	The verbal learning domain of the MCCB is assessed using the Hopkins Verbal Learning Test-Revised (HVLT-R). In three Learning Trials, the respondent listens to a 12-item word list read by an examiner and is then asked to recall as many of the words as possible from memory. Scores represent overall accuracy across the three trials, with higher scores indicating better learning. Analysis is based on age- and gender-corrected t-scores. HVLT-R reported as difference scores from baseline with negative values indicating higher test performance.
Time Frame	Baseline; Post 4 weeks (treatment crossover); Post 8 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Auditory Cognitive Training	Visual Cognitive Training
Arm/Group Description	4 weeks (20 sessions) of auditory cognitive training (Brain Fitness) completed either before or following 4 weeks (20 sessions) of visual cognitive training (Insight)	4 weeks (20 sessions) of visual cognitive training (Insight) completed either before or following 4 weeks (20 sessions) of auditory cognitive training (Brain Fitness)
Measure Participants	38	38
Mean (Standard Error) [t-score]	0.62 (1.04)	0.03 (1.03)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Auditory Cognitive Training
	Comments	Null hypothesis is that there is no difference between baseline and post-training scores. Linear mixed models tested fixed effects of period (3 levels; baseline, post 4-weeks, post 8 weeks), condition (3 levels; baseline, Auditory Cognitive Training, Visual Cognitive Training) and the period x condition interaction. Final model parameters were selected according to Bayesian Information Criteria. Alpha=.05 (2-sided)
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.55
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.62
	Confidence Interval	(2-Sided) 95%; -1.45 to 2.69
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.04
	Estimation Comments	contrast calculated as baseline minus Auditory Training

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Visual Cognitive Training
	Comments	Null hypothesis is that there is no difference between baseline and post-training scores. Linear mixed models tested fixed effects of period (3 levels; baseline, post 4-weeks, post 8 weeks), condition (3 levels; baseline, Auditory Cognitive Training, Visual Cognitive Training) and the period x condition interaction. Final model parameters were selected according to Bayesian Information Criteria. Alpha=.05 (2-sided)
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.98
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.03
	Confidence Interval	(2-Sided) 95%; -2.02 to 2.07
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.03
	Estimation Comments	contrast calculated as baseline minus Visual Training

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Auditory Cognitive Training, Visual Cognitive Training
	Comments	Null hypothesis is that there is no difference between post-training scores in Auditory vs. Visual Cognitive Training conditions. Linear mixed models tested fixed effects of period (3 levels; baseline, post 4-weeks, post 8 weeks), condition (3 levels; baseline, Auditory Cognitive Training, Visual Cognitive Training) and the period x condition interaction. Final model parameters were selected according to Bayesian Information Criteria. Alpha=.05 (2-sided)
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.57
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.59
	Confidence Interval	(2-Sided) 95%; -2.66 to 1.47
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.04
	Estimation Comments	contrast calculated as Auditory Training minus Visual Training

6. Secondary Outcome

Title	Visual Working Memory (Spatial Span) Change
Description	Visual working memory is assessed in the MCCB using the Spatial Span task of the Wechsler Memory Scales-III. Using a board on which 10 cubes are irregularly spaced, the examiner taps patterns of increasing length. The respondent is asked to follow by tapping the pattern in the same or reverse sequence. Scores represent total accuracy combined over forward and reverse span conditions. Analysis is based on age- and gender-corrected t-scores. Spatial Span reported as difference scores from baseline with negative values indicating higher test performance.
Time Frame	Baseline; Post 4 weeks (treatment crossover); Post 8 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Auditory Cognitive Training	Visual Cognitive Training
Arm/Group Description	4 weeks (20 sessions) of auditory cognitive training (Brain Fitness) completed either before or following 4 weeks (20 sessions) of visual cognitive training (Insight)	4 weeks (20 sessions) of visual cognitive training (Insight) completed either before or following 4 weeks (20 sessions) of auditory cognitive training (Brain Fitness)
Measure Participants	38	38
Mean (Standard Error) [t-score]	-0.60 (1.27)	-0.92 (1.27)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Auditory Cognitive Training
	Comments	Null hypothesis is that there is no difference between baseline and post-training scores. Linear mixed models tested fixed effects of period (3 levels; baseline, post 4-weeks, post 8 weeks), condition (3 levels; baseline, Auditory Cognitive Training, Visual Cognitive Training) and the period x condition interaction. Final model parameters were selected according to Bayesian Information Criteria. Alpha=.05 (2-sided)
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.63
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.60
	Confidence Interval	(2-Sided) 95%; -3.14 to 1.93
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.27
	Estimation Comments	contrast calculated as baseline minus Auditory Training

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Visual Cognitive Training
	Comments	Null hypothesis is that there is no difference between baseline and post-training scores. Linear mixed models tested fixed effects of period (3 levels; baseline, post 4-weeks, post 8 weeks), condition (3 levels; baseline, Auditory Cognitive Training, Visual Cognitive Training) and the period x condition interaction. Final model parameters were selected according to Bayesian Information Criteria. Alpha=.05 (2-sided)
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.47
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.92
	Confidence Interval	(2-Sided) 95%; -3.45 to 1.61
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.27
	Estimation Comments	contrast calculated as baseline minus Visual Training

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Auditory Cognitive Training, Visual Cognitive Training
	Comments	Null hypothesis is that there is no difference between post-training scores in Auditory vs. Visual Cognitive Training conditions. Linear mixed models tested fixed effects of period (3 levels; baseline, post 4-weeks, post 8 weeks), condition (3 levels; baseline, Auditory Cognitive Training, Visual Cognitive Training) and the period x condition interaction. Final model parameters were selected according to Bayesian Information Criteria. Alpha=.05 (2-sided)
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.80
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.32
	Confidence Interval	(2-Sided) 95%; -2.85 to 2.22
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.27
	Estimation Comments	contrast calculated as Auditory Training minus Visual Training

7. Secondary Outcome

Title	Auditory Working Memory (LNS) Change
Description	Auditory working memory is assessed in the MCCB using the Letter-Number Sequencing (LNS) task. LNS is an orally administered test in which and examiner reads strings of numbers and letters, of increasing length over trials, and the respondent mentally reorders the string and reports back to the examiner verbally. Scores represent total number of accurate trials. Analysis is based on age- and gender-corrected t-scores. LNS reported as difference scores from baseline with negative values indicating higher test performance.
Time Frame	Baseline; Post 4 weeks (treatment crossover); Post 8 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Auditory Cognitive Training	Visual Cognitive Training
Arm/Group Description	4 weeks (20 sessions) of auditory cognitive training (Brain Fitness) completed either before or following 4 weeks (20 sessions) of visual cognitive training (Insight)	4 weeks (20 sessions) of visual cognitive training (Insight) completed either before or following 4 weeks (20 sessions) of auditory cognitive training (Brain Fitness)
Measure Participants	38	38
Mean (Standard Error) [t-score]	-1.10 (0.98)	-1.47 (0.97)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Auditory Cognitive Training
	Comments	Null hypothesis is that there is no difference between baseline and post-training scores. Linear mixed models tested fixed effects of period (3 levels; baseline, post 4-weeks, post 8 weeks), condition (3 levels; baseline, Auditory Cognitive Training, Visual Cognitive Training) and the period x condition interaction. Final model parameters were selected according to Bayesian Information Criteria. Alpha=.05 (2-sided)
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.26
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-1.10
	Confidence Interval	(2-Sided) 95%; -3.06 to 0.85
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.98
	Estimation Comments	contrast calculated as baseline minus Auditory Training

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Visual Cognitive Training
	Comments	Null hypothesis is that there is no difference between baseline and post-training scores. Linear mixed models tested fixed effects of period (3 levels; baseline, post 4-weeks, post 8 weeks), condition (3 levels; baseline, Auditory Cognitive Training, Visual Cognitive Training) and the period x condition interaction. Final model parameters were selected according to Bayesian Information Criteria. Alpha=.05 (2-sided)
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.13
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-1.47
	Confidence Interval	(2-Sided) 95%; -3.41 to 0.46
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.97
	Estimation Comments	contrast calculated as baseline minus Visual Training

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Auditory Cognitive Training, Visual Cognitive Training
	Comments	Null hypothesis is that there is no difference between post-training scores in Auditory vs. Visual Cognitive Training conditions. Linear mixed models tested fixed effects of period (3 levels; baseline, post 4-weeks, post 8 weeks), condition (3 levels; baseline, Auditory Cognitive Training, Visual Cognitive Training) and the period x condition interaction. Final model parameters were selected according to Bayesian Information Criteria. Alpha=.05 (2-sided)
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.71
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.37
	Confidence Interval	(2-Sided) 95%; -2.32 to 1.58
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.98
	Estimation Comments	contrast calculated as Auditory Training minus Visual Training

Adverse Events

Time Frame	Events were monitored during the active study period of 60 days
Arm/Group Title	Auditory Cognitive Training		Visual Cognitive Training		Healthy Comparison
Arm/Group Description	Individuals with schizophrenia randomized to 4 weeks (20 sessions) of auditory training (Brain Fitness)		Individuals with schizophrenia randomized to 4 weeks (20 sessions) of visual training (Insight)		N = 20 healthy community volunteers participated in a single test session to provide normative comparison data
All Cause Mortality
	Auditory Cognitive Training		Visual Cognitive Training		Healthy Comparison
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Auditory Cognitive Training		Visual Cognitive Training		Healthy Comparison
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/40 (0%)		0/40 (0%)		0/20 (0%)
Other (Not Including Serious) Adverse Events
	Auditory Cognitive Training		Visual Cognitive Training		Healthy Comparison
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/40 (0%)		0/40 (0%)		0/20 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.