Webinar presented at SRF December 15, 2011.

1. Neuroplasticity-based cognitive training
in schizophrenia
Sophia Vinogradov, M.D.
University of California, San Francisco; SFVA Medical Center
The brain adapts to salient experiences by representing the relevant sensory
stimuli and action outputs with disproportionately larger and more coordinated
populations of neurons.
Merzenich & Jenkins,1993; Buomomano & Merzenich, 1998; Merzenich & DeCharms, 1996; Merzenich, 2001

2. In schizophrenia…
• Neurons within the brain are not networking
together (mapping together) to support normal
cognitive processes.
• Abnormal signal detection  Abnormal
networking  Abnormal brain functions
Haig et al, 2000
Goldman-Rakic, 1999
Taylor 2002, 2005

3. We know from basic science that…
• The accuracy, fidelity, and efficiency of
brain networks can be improved through
intensive, progressive, heavily rewarded,
perceptual and cognitive training.
Temple et al, 2000
Temple et al, 2003
Merzenich et al, 1999

4. In the impaired brain…
• Training must focus both on relevant
lower level perceptual processes as well
as higher-order cognitions in order to
maximize plastic changes.
Vinogradov, Fisher, de Villers-Sidani, in press

5. Interacting feed-forward and feed-back processes
contribute to cognitive operations

6. Improvements in neural system function
should translate to improved quality of life
Life Function
Work
Social
Leisure
Cognitive Function Attention
Language
Problem Solving
Learning and Memory
Speed of Information Processing
Brain Function
Accuracy of Information Processing
Neuromodulatory Function
6

7. Neuroplasticity-based cognitive training
contains several active ingredients
• Training of relevant perceptual processes
• Use of implicit learning mechanisms
• Highly intensive training schedules
• Carefully controlled and constrained
learning tasks
• Individualized adaptation of task difficulty
• Frequent and repetitive engagement of
attention and reward systems

8. Why auditory systems?
Why verbal learning/memory?
• Schizophrenia = Widespread disturbances in
neural systems subserving verbal memory
operations
• Abnormalities in frontotemporal cortical networks
during auditory and verbal working memory,
word encoding, and recognition1
• Disturbances also present at earliest stages of
auditory processing2
1. Weiss and Heckers 2001
Ragland et al 2002
2. Kasai K, et al 2002
Light et al 2007
Kawakubo et al 2006

9. San Francisco VA Medical Center

10. Cognitive change after Targeted Cognitive Training
(TCT) vs. Computer Games (CG)
TCT (N=40) CG (N=32) *p<.05, **p<.01
0.8
0.6
0.4
Z-Score Change
0.2
0
-0.2
-0.4
-0.6
-0.8
Global Speed of Working Verbal Visual Problem
Cognition** Processing* Memory Learning and Learning and Solving
Memory** Memory
Results of Repeated Measures ANOVA: Relative to the CG group, the TCT group show
significant gains in Global Cognition , Speed of Processing, and Verbal Learning and Memory.
The CG group show a significant decline in Verbal Learning and Memory.

11. Global Cognition at baseline, post-training,
and 6-Months in TCT (N=27) and CG (N=24)
Baseline Post-BFP 6-Months
0.0
-0.2
-0.4
-0.6
Z-Score
-0.8
-1.0
-1.2
-1.4
-1.6
TCT Global Cognition CG Global Cognition
Results of Repeated Measures ANOVA: Relative to the CG group, the TCT group show
significant gains in Global Cognition from Baseline to Post-BFP (p < .01), and significant gains
from baseline to 6-Months Post Training at trend level (p=.08).

12. Association between change in cognition and
change in Quality of Life
Targeted Cognitive Computer Games
Training (TCT) Control Group (CG)
r (p) r (p)
Global Cognition .39 (.05) .02 (.93)
Speed of Processing .50 (.01) .28 (.18)
Working Memory .45 (.02) -.10 (.65)
Verbal Learning and -.09 (.67) -.01 (.97)
Memory
Visual Learning and .15 (.47) -.17 (.44)
Memory
Problem Solving .20 (.51) .29 (.41)
Change scores = 6-Months Post-Training minus Baseline.

13. Serum anticholinergic activity is negatively
correlated with cognitive improvement
2
R = 0.20, p = .02
7
(Square Root Transformed)
6
5
Baseline SAA
4
3
2
1
0
-0.4 -0.2 0 0.2 0.4 0.6 0.8 1 1.2 1.4
Global Cognition (Z-Score Change)
SAA uniquely accounted for 20% of the variance in change in Global Cognition, independent
of the effects of IQ, age, and symptom severity (N=25).
Vinogradov, Fisher, Holland, Kirshner, Pollock, AJP, 2009

14. After training, SZ subjects show
enhanced M100 response
Left hemisphere Right hemisphere
Average Z-amplitude
Brodmann Area 41
50-150ms
LH: -47.14 -26.90 10.10
Session One
Session Two
The enhanced M100 response correlates with
improved executive function
Change: Executive Function
Left hemisphere Right hemisphere
Change: M100 amplitude

15. Frontal cortical activation after training
predicts enhanced social functioning 6
months later
6
rs = .61, p = .05
Social functioning 6 months after
5
computerized training 4
3
2
1
0
-1
-4 -2 0 2 4 6
Mean mPFC signal for self-generated
minus externally-presented items
after 80 hours vs baseline

16. Conclusions
• “Neuroplasticity-based” targeted cognitive training in
schizophrenia appears to result in improved cognitive
performance and “restoration” of neural correlates of
both elemental and complex operations.
• Training-induced increases in frontal cortical activation
patterns predict real-world functional improvement 6
months later.

17. • Open questions:
– What are the necessary and sufficient elements of
training? What neural mechanisms support the
response to training? How can we develop the most
efficient and robust training approaches possible?
– What forms of training result in robust, enduring, and
adaptive changes in neural system functioning