Schizophrenia Research Forum - A Catalyst for Creative Thinking


Lee H, Dvorak D, Kao HY, Duffy ŃM, Scharfman HE, Fenton AA. Early cognitive experience prevents adult deficits in a neurodevelopmental schizophrenia model. Neuron. 2012 Aug 23 ; 75(4):714-24. Pubmed 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 may have further implications for treatment and prevention, but only if followed up in those who are ďat risk,Ē a notion that has produced much heat and not much light in the annals of SRF. We have been optimistic about the possibility of change in prodromal patients using cognitive behavioral therapy, but that hope has not yet been justified in the current research. It may be that this form of experience-based learning is of greater help in the prodromal group than the traditional cognitive behavioral therapies. It may also be that we need to begin our interventions in school by identifying those who are cognitively at risk for many different future problems, not just schizophrenia.

The results also suggest that even when there is a known lesion, it is possible to normalize behavior as well as produce some correlated neuronal change. This is exciting, as it opens up the possibility of finding cures, if not for the whole disorder at least for some of the problems or symptoms of schizophrenia. All this can be produced by a non-pharmacological intervention. This is something that will surely excite the providers of healthcare, as the cost-benefit would be very high if the future health costs for these patients were reduced through such means.

References:

Wykes T, Brammer M, Mellers J, Bray P, Reeder C, Williams C, Corner J. Effects on the brain of a psychological treatment: cognitive remediation therapy: functional magnetic resonance imaging in schizophrenia. Br J Psychiatry. 2002 Aug;181:144-52. Abstract

Wykes T, Huddy V, Cellard C, McGurk SR, Czobor P. A meta-analysis of cognitive remediation for schizophrenia: methodology and effect sizes. Am J Psychiatry . 2011 May ; 168(5):472-85. Abstract

View all comments by Til WykesComment by:  Angus MacDonald, SRF Advisor
Submitted 24 August 2012
Posted 24 August 2012

In their new Neuron article, Lee and colleagues from Andre Fentonís 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 ďdosageĒ was required to lead to markedly different adult performance. Two days of training about five weeks after birth led to marked changes in the ratsí 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 compared to lesioned rats who did not receive training. That is to say, the integrity of the hippocampus measured grossly did not predetermine that rats would perform poorly on the spatial cognitive control task—if they received training. However, subsequent analysis demonstrated that phase synchronization between the hippocampus and prefrontal cortex (which rats possess, albeit not in extremis) was compromised in the lesioned rats who did not receive training, but was recovered in those that did receive training.

Thus, the data suggest that fundamentally important circuitry can be guided through training that is relevant for later cognitive functioning.

What is absent is evidence for the specialness of adolescent intervention. This seems to be assumed from previous work rather than the result of comparisons of implementing the intervention at different ages.

Itís also interesting to note that hippocampal lesion models are generally evaluated using memory-related tasks. Fentonís task presents something of a hybrid. The spatial cognitive control paradigm used is appropriately adapted to the species in question, but in the abstract it has features similar to that of the Stroop task. In Fentonís active place avoidance task, there is a dominant channel for responding on which the rat is over-trained, like the Stroop task's word reading component on which most people reading this text have been over-training. There is also a subordinate channel for responding, with which the rat is familiarized, something like color naming on the Stroop task. However, a key aspect of the manipulation is the inability to learn a new zone to avoid, which may be more akin to perseveration than to Stroop performance. Rotation of shock zone to a new location is described as task transference, but since the original learning was a source of interference (and needed to be inhibited) in the subsequent task, Iím not sure I agree with this description.

This work will be warmly received by a large number of advocates who are pushing for interventions earlier in the risk period. One advantage the authors had compared to those in the clinical schizophrenia field is that they knew which of their rats were strongly exposed and were therefore at the highest risk. While our screening tools have been honed over the past decade, they still have a high false-positive rate. One can take some solace, though, that cognitive remediation is unlikely to have extensive negative side effects. Except, perhaps, boredom.

View all comments by Angus MacDonaldComment 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 McGorryComment 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 neonatally lesioned animals showed deficits in interhippocampal synchrony, the findings similar to the changes reported in patients with schizophrenia. Adolescent cognitive training normalized interhippocampal synchrony and improved performance on the cognitive tasks in the neonatally hippocampally lesioned rats. Finally, to gain more insight into the mechanisms of these changes, the authors measured cortical thickness and parvalbumin protein content, but these parameters were not informative about the benefits of cognitive training in this animal model of schizophrenia.

The results of this study support the notion that schizophrenia is a neurodevelopmental disorder characterized by discoordinated neural networks, and provide critical evidence for the benefits of early behavioral intervention. Although we still do not fully understand the pathophysiological mechanisms underlying schizophrenia, or the mechanisms responsible for the improvements due to cognitive training, this work certainly offers a potential new therapeutic tool in the form of preemptive cognitive therapy.

References:

Tseng KY, Chambers RA, Lipska BK. The neonatal ventral hippocampal lesion as a heuristic neurodevelopmental model of schizophrenia. Behav Brain Res . 2009 Dec 7 ; 204(2):295-305. Abstract

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, and therefore in need of validity assessments. In all honesty, seeking a schizophrenic rat or mouse is misguided, as this is a uniquely human disorder. However, animal models are fantastic tools to test specific hypotheses regarding predisposing factors, the role of neurochemical or circuit pathways during development, etc., on neural processes that may be associated with the disease. In this case, Lee and colleagues used a widely used model that, independent of real or perceived validity issues, does allow them to test whether cognitive experience can rescue the effect of a developmentally impaired circuit. This is indeed a wise, hypothesis-driven use of an animal model that can help the field move forward.

Adult rats with a neonatal ventral hippocampal lesion exhibit a number of cognitive deficits, including altered working memory, set shifting, and reversal learning (Brady et al., 2010; Gruber et al., 2010; McDannald et al., 2011), along with altered prefrontal cortical oscillatory activity during goal-directed behaviors (Gruber et al., 2010) and altered function in prefrontal cortical interneurons (Tseng et al., 2008). In their manuscript, Lee et al. report deficits in cognitive control and altered interhippocampal synchrony in adult NVHL rats. Cognitive control was tested using a place-avoidance task in which the animals had to use relevant cues (and ignore irrelevant ones) to avoid receiving an electric shock; NVHL rats showed impairment when they were challenged to dissociate relevant from irrelevant cues, despite being proficient at the task when only relevant cues were presented. When NVHL rats were trained in the task as adolescents, their performance as adults improved dramatically. This training also yielded improved hippocampal synchrony and changes in parvalbumin staining compared to non-trained rats.

In short, the data strongly argue that the behavioral and circuit connectivity consequences of a developmentally altered prefrontal cortex can be prevented by engaging those circuits in cognitive training. It will be important to extend these observations to other models that also produce cognitive deficits and altered prefrontal cortical function.

There is a strong resurgence of cognitive-based therapies and other cognitive approaches in schizophrenia. The work by Lee at al. suggests that these approaches would be better utilized at early stages, and perhaps could be optimal tools for high-risk populations. But perhaps the most important aspect of this work is how it illuminates the use of animal models to address specific questions, allowing the field to gain useful information without falling into the validity traps.

References:

Brady AM, Saul RD, Wiest MK (2010) Selective deficits in spatial working memory in the neonatal ventral hippocampal lesion rat model of schizophrenia. Neuropharmacology 59:605-611. Abstract

Gruber AJ, Calhoon GG, Shusterman I, Schoenbaum G, Roesch MR, O'Donnell P (2010) More is less: a disinhibited prefrontal cortex impairs cognitive flexibility. J Neurosci 30:17102-17110. Abstract

McDannald MA, Whitt JP, Calhoon GG, Piantadosi PT, Karlsson RM, O'Donnell P, Schoenbaum G (2011) Impaired reality testing in an animal model of schizophrenia. Biol Psychiatry 70:1122-1126. Abstract

Tseng KY, Lewis BL, Hashimoto T, Sesack SR, Kloc M, Lewis DA, O'Donnell P (2008) A neonatal ventral hippocampal lesion causes functional deficits in adult prefrontal cortical interneurons. J Neurosci 28:12691-12699. Abstract

View all comments by Patricio O'Donnell