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Back to Reality: Computerized Cognitive Training Lends a Hand to Schizophrenia

26 February 2012. Intensive cognitive training can aid neural and cognitive impairments found in schizophrenia, according to a study published on February 23 in Neuron. A team of researchers, led by Sophia Vinogradov of the University of California, San Francisco, found that 80 hours of computerized cognitive training improved reality monitoring (the ability to distinguish information generated internally from external experiences), increased medial prefrontal cortex (mPFC) activation, and the boost to mPFC activity was associated with improved social functioning six months later.

Although antipsychotics are useful in improving positive symptoms of schizophrenia, they have little effect on the cognitive deficits that most strongly predict functional outcome (Green et al., 2000). To improve cognition, many researchers are exploring non-pharmacological “cognitive remediation” strategies that seek to strengthen a person’s capacity to think. These approaches can improve cognitive functioning (McGurk et al., 2007) and induce changes in brain activity (Haut et al., 2010) in schizophrenia, and are the subject of a recent SRF Webinar that included a presentation by Vinogradov.

Detecting the internal versus the external
Reality monitoring is a higher-order cognitive process that depends, in part, on the activity of the mPFC (Frith and Frith, 1999). Individuals with schizophrenia have difficulty recognizing self-generated items during reality monitoring, and exhibit mPFC hypofunction, even when they can accurately identify the source of information (Vinogradov et al., 2008). Abnormal reality monitoring in the illness is associated with deficits in more basic cognitive components such as attention, memory, executive function, and social cognition, suggesting that tuning up these elementary aspects of cognition may improve higher-order processes such as reality monitoring (Fisher et al., 2008).

First author Karuna Subramaniam administered a baseline reality monitoring task during fMRI to 31 schizophrenia patients and 15 healthy controls. Prior to the task, subjects were presented with simple sentences (noun-verb-noun) in which the final noun was either created by the subject or provided by the experimenter. Once inside the scanner, the subjects were required to differentiate between the words they had provided (internally generated) from those given by the experimenter (externally generated). Consistent with prior data, schizophrenia subjects exhibited impaired reality monitoring: they were significantly worse at identifying the source of the words than were healthy subjects. In addition, also similar to previous studies, while healthy controls exhibited greater mPFC activation during identification of self-generated words than those that were externally generated, this increase in mPFC activity was absent in schizophrenia subjects.

Restored reality and pumped-up PFC
The schizophrenia subjects were then randomly assigned to one of two groups who each received 80 hours of computer training over 16 weeks: one group received active cognitive training while the control condition played computer games. The active training comprised three modules, each focused on a different component cognitive process: auditory processing exercises for 10 weeks, visual processing exercises for six weeks, and emotion identification exercises throughout. All exercises became progressively harder as a subject’s performance improved.

After 16 weeks of this, both groups and the healthy controls performed the reality monitoring fMRI task a second time. Only the subjects who had received cognitive training improved their accuracy, correctly identifying the source of more words than at baseline. In contrast, neither the healthy controls nor the schizophrenia subjects who played computer games exhibited significant improvement, arguing that the improved reality monitoring was specific to those who received the targeted cognitive training.

Activation of the mPFC was also improved by cognitive training. Although healthy controls and the computer game-playing subjects did not exhibit differences in activation between the two scans, subjects who received cognitive training exhibited significantly more mPFC activity than at baseline.

Improved cognition and enhanced social functioning
Subramaniam and colleagues also tested all schizophrenia subjects on clinical and cognitive measures at baseline and after training. No change emerged in the Positive and Negative Syndrome Scale (PANSS) symptoms ratings between the two time points; however, consistent with prior results from the authors (see SRF related news story; Fisher et al., 2010), improvements in cognitive functioning were picked up. Active training subjects (but not those who played computer games) exhibited significant improvement on a test of delayed verbal memory recall from the Neuropsychological Test Battery relative to baseline. Importantly, delayed verbal memory recall performance was significantly correlated with both the accuracy of source word identification on the reality monitoring task, and with mPFC activity, only after active training. No such correlations were present in the subjects who played computer games. Active training also improved executive functioning, as measured by the Tower of London task, which probes planning skills, and reality monitoring performance after training was significantly correlated with Tower of London performance, but not at baseline. In contrast, no correlations were observed between mPFC activity and executive functioning.

But could these lab-based improvements generalize to real-world function? To explore this, the researchers also assessed social functioning of the schizophrenia subjects six months after training. The Social Functioning Subscale of the Quality of Life Scale revealed no change in social function between the groups. However, mPFC activity immediately after training was significantly correlated with ratings of social functioning six months after training, though this correlation was absent at baseline. These data suggest that cognitive training provided some improvement in patients’ functional outcome and quality of life, key outcomes of any successful cognitive remediation strategy.

The promise of cognitive training
The findings suggest, tantalizingly, that a non-pharmacological treatment can contribute to improvements in higher-order cognitive function, mPFC activity, and social functioning in schizophrenia. Worth noting is the fact that subjects did not receive training on the specific reality monitoring task on which they improved, indicating that they were able to generalize their training on specific cognitive components to the more complex task of reality monitoring. Moreover, the mean length of illness of the schizophrenia subjects included in this study was 19 years, demonstrating that cognitive improvements are possible in chronically ill patients with appropriate training.

Just how this cognitive training improved patients’ behavioral and neural functioning, and what specific components of the training were most beneficial, remains to be determined. In the meantime, the broader implications of this study offer hope and, as noted by the authors, suggest that “neural impairments in schizophrenia—and undoubtedly other neuropsychiatric illnesses—are not immutably fixed, but instead may be amenable to well-designed interventions that target restoration of neural system functioning.”—Allison A. Curley.

Reference:
Subramaniam K, Luks TL, Fisher M, Simpson GV, Nagarajan S, Vinogradov S. Computerized Cognitive Training Restores Neural Activity within the Reality Monitoring Network in Schizophrenia. Neuron . 2012 Feb 23 ; 73(4):842-53. Abstract

Comments on News and Primary Papers
Comment by:  Philip Harvey
Submitted 27 February 2012
Posted 27 February 2012

This is a fabulous study for several reasons.

The authors use cognitive training to enhance cognition and measure both cognitive functioning and the intactness of a neural network that they previous discovered. They find that they enhance cognition and improve regional brain activation. Further, social functioning is improved at a six-month follow-up.

Since the authors measured cognition and functionally relevant outcomes, these data again provide support for the usefulness of cognitive remediation for cognition and functioning, as well as show that these interventions directly impact critical neural networks. The integration of brain, cognition, and functioning makes a strong argument for the universal application of cognitive remediation in people with schizophrenia.

View all comments by Philip HarveyComment by:  James Gold, SRF Advisor
Submitted 27 February 2012
Posted 27 February 2012

Dr. Subramaniam and colleagues deserve congratulations on an impressive study demonstrating that an extensive computerized cognitive training intervention appears to have effects on both brain physiology and performance on an untrained reality monitoring task—important evidence that the training does not only “teach to the test.” Further, the training appears to normalize the relationship between medial frontal activity and reality monitoring in patients, suggesting that the training has resulted in a reorganization of how patients are able to mobilize neural systems to meet the cognitive challenge. This result is important and adds to the evidence that the Posit Science approach may be valuable for people with schizophrenia. Adding to the importance of this result is the fact that, to date, there is no compelling, replicated evidence that any available pharmacological approach provides effective treatment for the cognitive impairments of schizophrenia. Indeed, given the apparent exodus of multiple major pharmaceutical companies from psychiatric treatment development research, the need to better understand the utility of psychosocial interventions is increasing as we search for answers for today’s patients and likely tomorrow’s as well.

No study is without problems in interpretation, and some arise here. For example, is it possible that the larger effect on the recognition of self-generated items versus externally presented items might be the result of potential ceiling effects in the externally presented condition? In addition, the interpretation of the social functioning results might have been clearer if change in BOLD signal had been correlated with change in social functioning. The current result: no overall change in social function, but correlation between BOLD signal at the end of training and social functioning level at six months. This makes it hard to interpret training-related improvement in medial prefrontal activity as causing the changes in social functioning, basically missing the link that goes directly from treatment condition to outcome.

Lastly, it remains unclear exactly how the Posit Science program works at a neural level. Clearly the approach was designed to target lower-level sensory-perceptual processes with the goal of increasing the fidelity and precision of the inputs to higher-order systems. It would certainly make sense that the gradual training approach, which titrates difficulty level, does indeed work this way. Other non-incompatible possibilities deserve to be considered. Might the dense training approach serve as a kind of attentional and strategy training just as much as perceptual training? That is, patients learn how to get things “right.” One could imagine that this could occur because specific neural populations involved in task performance become more efficient, their task-relevant “receptive fields” become more precise. Alternatively, it is also be possible that higher-order attentional functions are also becoming trained to more efficiently modulate lower-level systems. And it might be easier to understand the type of generalization effects seen in this study if the training inadvertently also had benefits to task general cognitive systems that may be brought to bear on many untrained tasks. It remains for future work to see which understanding is more accurate.

In the meantime, the contribution of the Vinogradov team deserves recognition for an ambitious study, a potentially important and intriguing finding, and providing a ray of hope in an otherwise pretty dark treatment development landscape.

View all comments by James GoldComment by:  Robert McCarley
Submitted 7 March 2012
Posted 8 March 2012
  I recommend the Primary Papers

Very exciting and hopeful data, especially in this patient population who had been ill nearly 20 years. These data argue strongly for similar trials at other sites.

From a scientific point of view, it will be interesting to see if these functional changes will be accompanied by structural alterations of increased MRI gray matter, compatible with plasticity and increased dendritic and synaptic elements.

View all comments by Robert McCarley

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Comment by:  Lewis Kirshner
Submitted 18 June 2012
Posted 20 June 2012

The field seems to be cautiously returning to look seriously at psychotherapeutic approaches. Paying attention to forms of cognition and affect has been a traditional form of therapy, and it seems foolish to ignore the clinical experiences of its many practitioners, despite conceptual problems of past work. We also have the benefits of studies indicating the effects of trauma on subsequent psychosis and developmental research on attachment and language that may mediate early neglect or trauma. Problems in development of TOM in insecure attachment may point to specific vulnerabilities.

References:

Berry K, Barrowclough C, Wearden A. Attachment theory: a framework for understanding symptoms and interpersonal relationships in psychosis. Behav Res Ther . 2008 Dec ; 46(12):1275-82. Abstract

Fonagy P, Target M. Playing with reality: I. Theory of mind and the normal development of psychic reality. Int J Psychoanal . 1996 Apr ; 77 ( Pt 2)():217-33. Abstract

Heins M, Simons C, Lataster T, Pfeifer S, Versmissen D, Lardinois M, Marcelis M, Delespaul P, Krabbendam L, van Os J, Myin-Germeys I. Childhood trauma and psychosis: a case-control and case-sibling comparison across different levels of genetic liability, psychopathology, and type of trauma. Am J Psychiatry . 2011 Dec ; 168(12):1286-94. Abstract

Lysaker PH, Outcalt SD, Ringer JM. Clinical and psychosocial significance of trauma history in schizophrenia spectrum disorders. Expert Rev Neurother . 2010 Jul ; 10(7):1143-51. Abstract

Read J, Gumley J. Can attachment theory help explain the relationship between childhood adversity and psychosis? Attachment New Directions in Psychotherapy. Relational Analysis. 2008;2:1-35.

View all comments by Lewis Kirshner