Liam Davenport

March 15, 2016

MADRID — Adults who were born very prematurely have an increased risk for interpersonal and behavioral problems that significantly correlate with brain imaging evidence.

Investigators at King's College London, in the United Kingdom, found that 30-year-olds who were born very preterm, defined by the World Health Organization as birth at 28 to <32 weeks' gestation, have interpersonal and behavioral problems that are significantly negatively associated with corticostriatal tract volume in the brain.

Study investigator Chiara Nosarti, PhD, King's College London, told delegates attending the European Psychiatric Association (EPA) 24th Congress that because behavioral problems are partly moderated by intelligence quotient (IQ), the findings suggest there is an underlying mechanism that connects both phenomena.

Significant Differences

Previous studies have shown that preterm children have an increased risk of developing a psychiatric disorder before age 18 years and are more likely to be hospitalized with any psychiatric diagnosis.

Moreover, an earlier investigation by Dr Nosarti and colleagues found that the risks for psychosis, bipolar disorder, and depression at 16 years of age were moderately increased among those who were born at 32 to 36 weeks' gestation but were substantially increased in those born at less than 32 weeks' gestation.

For the current analysis, the researchers conducted a follow-up study of the University College London Hospital cohort, which includes 473 infants born at <33 weeks' gestation from 1979 to 1984 and 268 control participants.

Dr Chiara Nosarti

The participants were previously followed-up at 14 and 18 years of age. The latter follow-up revealed that 12% of teenagers who were born very preterm had received a psychiatric diagnosis, compared with 5% of control individuals.

The current assessment returned to the participants at an average age of 30 years, at which point 126 very preterm individuals and 83 control persons were available for analysis. Dr Nosarti pointed out that 40 individuals have yet to be assessed, so the results are preliminary.

There were some significant differences between the very preterm and control groups, with the very preterm participants more likely to be male (65% vs 46%) and to have a lower average IQ (103.57 vs 111.57). The very preterm participants were also less likely to be employed (85% vs 95%).

Negative Correlations

The researchers found that there was no difference in the prevalence of self-reported psychiatric diagnoses and history of psychiatric medication use between the groups.

However, the team did find differences between the very preterm and control groups on the interviewer-rated Comprehensive Assessment of At Risk Mental States.

Specifically, there were significant differences between the groups on the negative-interpersonal dimension (NID) and communicational-cognitive-behavioral disorganization (CCBD) scales (P = .018 and P = .013, respectively).

The difference on the NID scale remained significant after controlling for age, sex, and IQ (P = .008), suggesting that differences in scores on the CCBD are at least partly due to differences in IQ between the groups.

Hypothesizing that these differences in NID and CCBD scores between very preterm individuals and control persons could be associated with structural changes in the corticostriatal tracts, which have been previously linked to developmental delays, the team performed diffusion MRI.

The results showed significant negative correlations between NID scale scores and the volumes of the striatal working memory/attention (r = -0.20, P = .045), striatal sensorimotor (r = -0.33, P = .004), and striatal default mode network tracts (r = -0.30, P = .013).

Moreover, there were significant negative correlations between CCBD scores and the volumes of the striatal frontal (r = -0.21, P = .038) and striatum limbic (r = -0.21, P = .033) tracts.

The team also found that the volumes of the striatal default mode network, sensorimotor, frontal, and limbic tracts were all significantly smaller in very preterm individuals compared with control persons (P < .05 in all cases).

Network Deficits

Dr Nosarti told Medscape Medical News that the connectivity problems identified within the corticostriatal tracts explain the link between CCBD scores and IQ revealed in her study, in particular, because the tracts connect "very large-scale networks."

"Deficits in these networks are not only pertinent to the behavioral manifestation of psychiatric disorders but also to the cognitive manifestations as well," she said.

"IQ explains to an extent the type of behavioral problems that are experienced, but they don't account totally for them. So there are two concomitant, co-occurring problems that affect both the cognitive and the behavioral profiles of preterm adults," Dr Nosarti added.

To try to anticipate, and prevent, some of the psychopathology seen in adults who were born very preterm, Dr Nosarti and colleagues are offering cognitive training to children aged 8 years.

These consist of very simple cognitive control exercises. The idea is that "if you strengthen the connections that you know will be perhaps partly responsible for future problems, then you might prevent or attenuate the problems from developing."

Dr Nosarti also pointed out that the connectivity problems she found are also present in persons with neurodegenerative conditions, and so she would like to continue to monitor this group of very preterm individuals to determine whether they show neurodegenerative problems as they grow older.

"One thing that we have noticed in terms of both functional and structural imaging studies is that you tend to have these heteronodal networks that are more affected [by connectivity issues] than others, and these are the first ones that become defective with normal aging, but also in Alzheimer's disease," she said.

"So it's very much about targeting developmental delays, adult psychiatric outcomes, and perhaps building protective mechanisms for future aging."

Clinically Relevant?

Session cochair Romuald Brunner, MD, Centre of Psychosocial Medicine, University Hospital Heidelberg, Germany, was not sure, however, of the clinical relevance of Dr Nosarti's findings.

Dr Romuald Brunner

Describing the results as "very subtle" and only pertaining to brain morphology, he said that he is "a little bit skeptical" of their importance, because the researchers did not find any differences in psychiatric outcomes between the very preterm individuals and the control persons.

Pointing out that the differences highlighted in the study between very preterm and control individuals were small, Dr Brunner noted that, today, preterm children are currently performing "better than expected" compared with those born in previous generations, suggesting that "probably the services have much better developed in the last 10, 20 years to support education and so on."

Furthermore, although there is indeed a measurable difference in intelligence between preterm children and control children, "there's nearly no negative outcome, so perhaps it's more related to social aspects than to really biological aspects," he noted.

In summarizing, Dr Brunner said that the sorts of findings that were presented by Dr Nosarti have to be judged "very, very carefully," adding: "If you can show an example of disturbed brain maturation, you could probably find a mechanism of disturbed basic function, like working memory or something like that.

"It's still very interesting to investigate these preterm samples to develop models, but I think that's all."

The study was funded by the Medical Research Council, the March of Dimes, Athena Swan, Newlife Foundation for Disabled Children, the Biomedical Research Centre at Guy's and St Thomas's, the NHS Foundation Trust, King's College London, and the National Institute for Health Research. The investigators and Dr Brunner report no relevant financial relationships.

European Psychiatric Association (EPA) 24th Congress: Presented March 13, 2016.


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