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Children With Early Psychotic Symptoms Lag in Cognition

February 17, 2014. Children who report psychotic-like experiences lag behind their peers in their cognitive development, according to a study published online February 5 in JAMA Psychiatry. Led by Ruben Gur and Raquel Gur of the University of Pennsylvania in Philadelphia, the study evaluated psychiatric symptoms and cognition in more than 9,000 children between eight and 21 years old. Over 15 percent of these reported some kind of experiences that are characteristic of psychosis, and this subset fell short in measures of complex cognition and social cognition, as early as eight years of age.

A second study from the same group reports cognitive deficits across childhood in those with 22q11.2 deletion syndrome, which increases risk for schizophrenia (see SRF related news report). Published online January 21 in Molecular Psychiatry, the study found that those with 22q11.2 deletions were one to three years behind in measures of complex and social cognition, and that these lags were apparent as early as eight years of age.

Both studies suggest that cognitive deficits in childhood may flag those at risk for psychosis. Though a link between cognitive impairments and psychosis has been observed in young adults at their first full-blown episode of psychosis, or with prodromal symptoms of psychosis (Saykin et al., 1994; Seidman et al., 2010), the new studies begin to outline how and when these deficits emerge in childhood. Finding impairments at the earliest ages, the studies suggest that the brain systems supporting cognition are disturbed early on.

“These studies cover new territory by showing evidence of an association between cognition and psychotic symptoms from very early in development,” SRF advisor Jim Gold of the University of Maryland wrote in an email. Gold was not involved in either study.

Both studies also confirm problems with reasoning and other aspects of complex cognition recognized later in development, but also finger for the first time the domain of social cognition, which included emotion recognition tests.

The Philadelphia Neurodevelopmental Cohort
The JAMA Psychiatry study also raises the possibility of routinely screening cognition in the general population as a way to identify those at risk for psychosis. Study participants were drawn from over 50,000 patients who had, during a visit to the doctor, agreed for their blood to be collected for genetic studies of pediatric disorders by Children’s Hospital of Philadelphia. “Their medical records have a lot of information about their physical health, but they stopped where a psychiatrist might become interested,” Ruben Gur told SRF.

Gur and colleagues have begun to fill this gap. Over the past two years they have re-contacted nearly 10,000 of these children to evaluate them with structured psychiatric interviews and a computerized neurocognitive battery of tests. As in a previous study, psychotic symptoms were relatively common in the general population (e.g., Kelleher et al., 2012), though they did not compel a visit to a psychiatrist.

Much like the height and weight growth charts used by pediatricians to compare a child’s growth with what is expected at any given age, the study came up with neurocognitive growth charts that map out standard developmental trajectories of different aspects of cognition, including executive functions such as attention or working memory, complex cognition, social cognition, memory, and processing speed. Deviations from the standard curve indicate people whose cognitive development is slower or faster than expected for someone their age.

“I can see in the future that, when you go to a pediatrician, a child can take the test on any Web-enabled computer while waiting outside, and the result will give their [sic] mental age,” Gur said.

A previous population-based longitudinal study has found that cognitive declines precede schizophrenia (see SRF related news report), but whether the cognitive deficits highlighted in the new study will predict psychosis isn’t clear.

“Because this is a cross-sectional study and there is no information (yet) on longer-term outcome, there is no ability of the current results to comment on the prediction of psychosis, nor do the authors make this claim,” writes Tyrone Cannon of Yale University in an accompanying perspective.

Gur has plans to do this kind of follow-up. Longitudinal data, combined with genetic results and some brain imaging, promise to make the cohort, called the Philadelphia Neurodevelopmental Cohort, a useful resource for understanding psychiatric disease.

“I think this study can potentially do for the brain what the Framingham Study did for the heart,” Gur said, referring to the landmark study following citizens of Framingham, Massachusetts, to look for contributors to cardiovascular disease.

"Mental" age
In the JAMA Psychiatry study, first author Raquel Gur and colleagues conducted comprehensive psychiatric evaluations of participants with GOASSESS, a computer-based version of the Schedule for Affective Disorders and Schizophrenia. This probed symptoms related to anxiety, mood, attention deficit, disruptive behavior, and eating disorders, as well as psychosis. A substantial portion of the children—2,321 (15.5 percent)—reported some kind of psychotic symptom, including hearing voices, seeing things other people didn’t see, or being suspicious of others; 1,423 of these were separated into a “psychosis spectrum (PS)” group, whereas 898 with milder symptoms were categorized as “psychosis limited.” Another group of 981 reported “other psychiatric” symptoms that did not involve psychosis.

The participants were also given a one-hour-long computerized test of cognition (Gur et al., 2012). The researchers acknowledge that one hour is too long for routine testing, and they are now trying to trim it down to 30 minutes, Gur said.

From the typically developing children in the cohort, the researchers found the expected correlation between cognitive performance scores and age. Based on this, they developed a formula into which entering a person’s cognitive performance scores gave a predicted age, or “mental age.” When they did this for the psychotic spectrum group, their predicted age was on average six-18 months younger than their actual age—signs of a neurodevelopmental lag. Among boys, statistical differences between the psychosis spectrum group and the typically developing group were found for memory, complex cognition, and social cognition; for girls, differences were limited to complex cognition.

The relationship between mental age and actual age also varied with symptom severity: Those in the psychosis limited group showed a higher mental age than the PS group in measures of complex and social cognition. The lag was also specific to psychosis, as no significant differences emerged between the other psychiatric symptoms group and the typically developing group.

“That’s cool,” Gold said. “So psychiatric symptoms early don’t always mean cognitively worse. It is symptoms suggestive of psychosis that appear to be important for cognition.”

The 22q11.2 syndrome study also supported a special relationship between psychosis and the complex and social cognition domains. Though not assessed for psychosis symptoms, 137 people with 22q11.2 deletions had more pronounced deficits in complex and social cognition than 439 people who did not carry the deletion but were developmentally delayed. This difference was apparent through the entire age range, from eight to 21 years old. This suggests that perturbations to the brain systems involved in these aspects of cognition are somehow related to psychosis. If true, cognitive profiling may eventually flag those at risk for psychosis early and buy time for intervention strategies that could mitigate that risk.—Michele Solis.

Gur RC, Calkins ME, Satterthwaite TD, Ruparel K, Bilker WB, Moore TM, Savitt AP, Hakonarson H, Gur RE. Neurocognitive Growth Charting in Psychosis Spectrum Youths. JAMA Psychiatry. 2014 Feb 5. Abstract

Gur RE, Yi JJ, McDonald-McGinn DM, Tang SX, Calkins ME, Whinna D, Souders MC, Savitt A, Zackai EH, Moberg PJ, Emanuel BS, Gur RC. Neurocognitive development in 22q11.2 deletion syndrome: comparison with youth having developmental delay and medical comorbidities. Mol Psychiatry. 2014 Jan 21. doi: 10.1038/mp.2013.189. Abstract

Cannon TD. Neurocognitive Growth Charts and Psychosis: Is the Relationship Predictive? JAMA Psychiatry. 2014 Feb 5. Abstract

Comments on News and Primary Papers
Comment by:  Philip Harvey
Submitted 25 February 2014
Posted 25 February 2014

The Gurs have done it again. First, they developed the first truly remotely deliverable cognitive assessment with any validity data that would stand the test of peer review. Now they have passed another hurdle: general population screening. For years, those of us interested in this topic have said: "Sure. Those kids look different, but can you go into the community, screen the whole group, and find the outliers who may be impaired?" So these studies are really important because they constitute a true, largely epidemiologically interesting sample of the population. Then the researchers relate psychosis and cognition and find a link. As Ruben said, it may happen that someday we can have high-throughput cognitive (or functional capacity, to give our work a plug) testing that can be administered at a routine clinical visit to a doctor. Any findings could lead to a referral. This could lead to targeted early interventions. The only weak link is the family who never goes to the doctor at all. Are they the ones really at risk? This study does not have to answer that question. The results stand on their own.

View all comments by Philip HarveyComment by:  Michael F. Green, SRF Advisor
Submitted 26 February 2014
Posted 26 February 2014

The very impressive article by Gur et al. on neurocognitive growth charting was already summarized by Michele Solis, so I will just make a couple of additional comments.

As mentioned in the summary, one of the remarkable contributions of this paper is to extend the link between cognitive impairment and psychosis down to the age of eight. This is uncharted territory, and, despite some variations, the lags in complex cognition and social cognition are relatively consistent from age eight to 20. Some of us would have expected a gradually increasing gap with increasing age, but that did not happen. That is encouraging in itself.

The authors were forward thinking and included a social cognitive domain in the battery. Sometimes people assume that social cognitive tests must be more inherently complex than mundane, non-social cognitive tests (after all, they are social), but that is not always the case. Indeed, the social cognitive tests in this battery can be considered low-level tests that place minimal demands on social inference. That means they are tapping only a subset of social cognitive processes, but they are useful here because they are fully appropriate for children.

What does a 1.5-year delay in social cognition mean for the kids? At these ages—it probably means a lot. The kids with psychosis spectrum are over a year behind in identifying the emotional expressions of their classmates, siblings, and teachers. It is not hard to imagine the social and functional consequences that might accompany the delay. Fortunately, such skills can be trained. Based on this study, we may need to develop training programs for younger participants.

View all comments by Michael F. Green

Comments on Related News

Related News: Forty-Year Study Reveals Patterns of Cognitive Decline in Schizophrenia

Comment by:  Angus MacDonald, SRF Advisor
Submitted 23 September 2013
Posted 23 September 2013

The Dunedin study is not only a rich and rare resource for testing developmental hypotheses, but it has also been mined with ingenuity and resourcefulness over the years by Avshalom Caspi, Terrie Moffitt, and their colleagues to provide a number of provocative findings. In this case, they use the continuity of the sample and its multiple-informant design to test a number of useful hypotheses about the development of cognitive impairments in schizophrenia. Their population-based cohort of over 1,000 children yielded 31 cases of tightly defined schizophrenia by age 38. (The fact that this is over 3 percent of the sample, the authors argue, is explained by the comprehensiveness of their methods, suggesting that lower epidemiological estimates may underrepresent lifetime population risks.)

Their findings provide a particularly clear example of a moderate, generalized deficit in cognitive ability well before the onset of illness that, after onset, leads to further declines in fluid, but not crystalized intelligence. The example is clear because it addresses the diagnostic specificity of the deficit—the pattern was different for children later diagnosed with depression or mild cognitive impairments—and it is corroborated by the reports from others’ throughout their lives. The findings reinforce efforts by the U.S. NIH and FDA to target cognitive impairments as a symptom of interest for patients with schizophrenia.

The findings hold important methodological lessons for schizophrenia researchers, too. As pointed out by Paul Meehl in 1971, psychopathologists who co-vary or control for factors influenced by the illness may make a systematic mistake. This kind of control variable sets up false equivalences by comparing the most able patients to the least able controls.

View all comments by Angus MacDonald

Related News: Forty-Year Study Reveals Patterns of Cognitive Decline in Schizophrenia

Comment by:  James Gold, SRF Advisor
Submitted 25 September 2013
Posted 25 September 2013

The recent paper by Meier et al. is a powerful confirmation of several observations that have been in the literature for many years. First, cognitive impairment is evident from early in development in people who go on to develop schizophrenia. Second, there is a loss of intellectual function that occurs in those people at risk who later become ill. Third, this "illness-associated" impairment appears to maximally impact more "fluid" intellectual functions and largely spares "crystallized" forms of verbal knowledge (however, those functions are not fully spared, as there is evidence of subnormal performance levels from early in development).

Thus, what Meier et al. have shown is not new, but it is the first time that these key findings have all been demonstrated in the same subjects followed over time in a population-based sample. The inclusion of a group of depressed patients as well as a mild cognitive impairment control group are innovations that enhance confidence that this is an effect related to schizophrenia in particular rather than psychopathology or cognitive limitations in general. Unexpectedly, this study also found a very sizeable number of people meeting diagnostic criteria for schizophrenia who appear to have been untreated with antipsychotics for extended time periods but did receive treatment for other mental health problems. It will be interesting to learn more about the life course and treatment history of this unusual group of people.

View all comments by James Gold