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Is Early Cognitive Training Key to Minimizing Schizophrenia Impact?

24 August 2012. Training in adolescence can offset cognitive deficits in adulthood in a proposed rat model of schizophrenia, reports a study published August 22 in Neuron. Studying rats given ventral hippocampal lesions early in life, researchers led by André Fenton of New York University found that training these rats as adolescents to pay attention to certain cues while ignoring others prevented impairments observed in similar tasks when they were adults. The study casts adolescence as a stage of neurodevelopment when important and lasting changes can be made to promote cognition in adulthood.

Based on these data, the researchers suggest that prophylactic cognitive training in people at risk for schizophrenia, before they’ve had their first psychotic episode, may avoid some of the mental pitfalls of the disorder. Currently, cognitive training is given to people after they’ve become ill, and researchers are still hashing out the merits of the various methods, like cognitive behavioral therapy (see SRF related news story) and cognitive remediation (see SRF Webinar). Some have suggested that earlier training in adolescence may benefit cognitive function later in life, particularly for those skills that would have already matured prior to disease onset (see SRF related news story).

The new study uses the neonatal ventral hippocampus lesion (NVHL) model of schizophrenia, in which lesions given the first week of life give rise to schizophrenia-related abnormalities in adulthood, including enhanced dopamine-dependent responses, disrupted prepulse inhibition, and impaired social behavior, learning, and memory (Lipska, 2004). Though people with schizophrenia do not carry hippocampal lesions dating back to when they were infants, hippocampal abnormalities have been consistently found (Tamminga et al., 2010), and the NVHL model explores the possibility that early problems there could derail development throughout the brain. Like the delayed onset of schizophrenia, the abnormalities in NVHL rats do not emerge until later in life, thus providing a venue for researchers to study how delayed consequences might arise from early abnormalities.

Shock zone
First author Heekyung Lee and colleagues studied the ability of NVHL rats to learn to avoid a region of the test arena that delivered a mild (<0.4 mA) foot shock. The shock zone was defined in terms of the surrounding room, which had visual cues as a reference. The animals had to learn to ignore cues inside the circular arena, which slowly rotated, and pay attention to the room cues in order to avoid the shock zone.

Control adult rats quickly figured this out by the second or third trial, but adult NVHL rats needed about 12 tries. Throughout training, the NVHL rats entered the shock zone about four times as often as did controls, and when the shock zone location was changed on them, they took longer to avoid the new region than controls did. Control experiments suggested that this was not due to hyperactivity, or to impairments in motivation, spatial perception, memory, or navigation.

In adolescence (postnatal day 35), however, NVHL rats readily mastered the task, learning to avoid the shock zone as quickly as controls did. The researchers then found that this experience could serve as training for solving a similar T-maze task, which required focusing on some cues but ignoring others, in adulthood. The T-maze required the rats to learn which arm of the maze—left or right—delivered a shock; after 15 trials, the shock and non-shock arms were switched, requiring the rats to relearn the relevant cues. NVHL adults that had been trained with shock zone avoidance as adolescents performed the T-maze task as well as their control counterparts, which consisted of rats trained on shock zone avoidance as adolescents and rats that weren’t trained, but exposed to the test arena as adolescents without receiving any shocks. In contrast, NVHL rats that were merely exposed to the test arena as adolescents made more mistakes on the T-maze, averaging about one more wrong turn than the others. This difference extended to shock zone avoidance learning in adulthood, too: the NVHL rats trained as adolescents performed at control levels, whereas the NVHL rats that were only exposed to the test arena had difficulty learning the task.

Out of synch
These differences suggested that adolescent training had a lasting influence on the brain, leading the researchers to search for neural correlates of the training. Local field potential recordings in the left and right hippocampus became more synchronized while adult control rats performed the shock zone avoidance task, but this was not as pronounced for adult NVHL rats. Shock avoidance training in adolescence, however, seemed to boost synchrony: trained NVHL rats had increased synchrony across several frequency ranges compared to NVHL rats without training, and were comparable to trained controls. Because of these and other physiologic changes associated with adolescent training (e.g., in synchrony between hippocampus and neocortex, and in parvalbumin labeling in neocortical cells), the authors propose that training exerted its effects on neural circuitry responsible for synchronous brain oscillations, which contribute to cognitive control.

The findings suggest that neurodevelopment can be guided away from an aberrant course, but whether the adolescent brain is particularly pliable remains unclear. As researchers delineate the changes in brain structure and processing in human adolescence, a more complete picture of neurodevelopment will emerge, which may help identify the glitches that preface schizophrenia.—Michele Solis.

Lee H, Dvorak D, Kao HY, Duffy AM, Scharfman HE, Fenton AA. Early Cognitive Experience Prevents Adult Deficits in a Neurodevelopmental Schizophrenia Model. Neuron. 2012 Aug 22. Abstract

Comments on News and Primary Papers
Comment by:  Til Wykes
Submitted 24 August 2012 Posted 24 August 2012

The notion that cognitive remediation is effective in producing cognitive and functional gains in established schizophrenia (Wykes et al., 2011), and produces other gains such as changes identified in brain imaging (e.g., Wykes et al., 2002) is unsurprising. But the paper on remediation in adolescent rats by Lee and colleagues provides results that the authors do consider surprising, and could lead to further extensions of cognitive remediation to those who are "at risk" for disorders such as schizophrenia. This is because of the procognitive effects of providing training in youthful rats.

Procognitive effects of experience-based training are not, however, surprising. The authors quote research showing that there are functional changes with training—the one that springs to my mind is London taxi drivers whose hippocampi are larger following their "training" for The Knowledge—an all-roads-in-London test. So why are the authors surprised? Perhaps it is because the results...  Read more

View all comments by Til Wykes

Comment by:  Angus MacDonald, SRF Advisor
Submitted 24 August 2012 Posted 24 August 2012

In their new Neuron article, Lee and colleagues from Andre Fenton’s group at NYU report that spatial cognitive control deficits in a rat model of schizophrenia can be prevented through a ratish analogue of cognitive remediation therapy during adolescence. The importance of early intervention has been one of the hottest debates in applied schizophrenia research; the current findings suggest a basic mechanism in support of such efforts.

What is remarkable about the Fenton study is how small a training “dosage” was required to lead to markedly different adult performance. Two days of training about five weeks after birth led to marked changes in the rats’ capacity to use spatial cognitive control eight to nine weeks after birth.

Rats were sacrificed at the end of the experiment, allowing the researchers to examine the extent to which the initial lesion had affected brain development. The initial lesions dramatically altered hippocampal development. Despite this, lesioned rats who received training did not show any observable difference in brain morphology in adulthood...  Read more

View all comments by Angus MacDonald

Comment by:  Patrick McGorry, SRF Advisor
Submitted 27 August 2012 Posted 27 August 2012

I am always a little skeptical of animal models of psychosis or schizophrenia, which are pretty high-order disturbances and seem very specific to humans. If this model has some validity, the preventive therapy in humans would be more akin to cognitive remediation therapy rather than cognitive therapy per se, which has more CBT links or connotations.

View all comments by Patrick McGorry

Comment by:  Barbara K. Lipska
Submitted 27 August 2012 Posted 27 August 2012

Lee et al. report exciting new data in support of the neurodevelopmental hypothesis of schizophrenia and the plausibility of the early intervention that might prevent the emergence of schizophrenia symptoms. Lee and colleagues used a neonatal ventral hippocampal lesion in rats as a model of schizophrenia.

First, using the active place avoidance task with carefully designed control tasks, they showed that the animals with neonatal lesions are cognitively impaired as adults, consistent with the results of the previous studies (see Tseng et al., 2009, for review). Next, they examined whether training of the lesioned animals in adolescence would prevent the emergence of these abnormalities. They exposed the animals to a series of cognitive tests and found that, indeed, the neonatally lesioned rats that acquired additional training as adolescents showed improved cognition in adulthood. Moreover, specific measures of neural function were also improved. The authors recorded local field potentials in the hippocampi and found that the...  Read more

View all comments by Barbara K. Lipska

Primary Papers: Early cognitive experience prevents adult deficits in a neurodevelopmental schizophrenia model.

Comment by:  Patricio O'Donnell, SRF Advisor
Submitted 4 September 2012 Posted 5 September 2012
  I recommend this paper

Can cognitive training restore function in a developmentally compromised neural circuit? This is a critical question that may open the door to novel preventive strategies for disorders with a developmental component but adult onset, such as schizophrenia. Lee et al. used rats with a neonatal ventral hippocampal lesion to test whether cognitive experience could prevent the emergence of typical schizophrenia-related deficits in adulthood in this model. The study is elegant, the data quite convincing, and the implications are vast. This is indeed a perfect example of what the field of schizophrenia research needs: the use of animal models as tools to test specific hypotheses.

Animal models of schizophrenia have been around for quite some time, and new ones keep being proposed. The data obtained from pharmacological, developmental, environmental, and genetic models over the past decade have been critical for shaping current thoughts about possible pathophysiological scenarios. But the field is still caught in the trap of trying to think of models as reproducing the disease,...  Read more

View all comments by Patricio O'Donnell
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