Larry Rifkin

Brain structure and neurocognitive and behavioural function in adolescents who were born very preterm

BACKGROUND Infants born very preterm (<33 weeks) are at increased risk of neurocognitive deficits. Their neurodevelopmental outcome up to age 8 years can be predicted by neonatal ultrasonography, but little is known of their later function. We investigated the effect of very preterm birth on brain structure and neurocognitive and behavioural functioning in adolescence. METHODS A cohort of 105 infants born before 33 weeks of gestation in 1979-80 had ultrasonographic scans at University College Hospital, London, and were prospectively examined at 1, 4, and 8 years. At age 14-15 years, 72 of those who remained in UK (cases) and 21 age-matched full-term controls underwent brain magnetic resonance imaging (MRI), as well as neurological, cognitive, and behavioural assessment. MRI images were assessed by two neuroradiologists unaware of ultrasonographic findings or case or control status. FINDINGS Of the 72 cases, 40 had unequivocally abnormal MRI and 15 had equivocal scans. Of the 21 controls, one had abnormal and five equivocal MRI. Abnormalities of ventricles, corpus callosum, and white matter were especially common in cases. More brain lesions were identified by MRI than by neonatal ultrasonography. The cases had significantly more reading, adjustment, and neurological impairments than controls, but their behaviour was significantly related to MRI abnormality. INTERPRETATION Individuals born very preterm show an excess of neurocognitive and behavioural problems in adolescence, and more than half have abnormal MRI brain scans.

Neuropsychological outcome at adolescence of very preterm birth and its relation to brain structure.

Neuropsychological outcome at 14 to 15 years of age of a cohort of 75 participants (39 male, 36 female) born at <33 weeks’gestation was investigated. Research was conducted parallel to a recent MRI study by Stewart and colleagues which reported that 55% of this cohort had evidence of brain abnormality. One aim of the study was to compare neuropsychological function in those very preterm children with and without MRI abnormality. Compared to a control sample of term adolescents, very preterm participants had impairment only on a measure of word production. On measures of attention, memory, perceptual skill, and visuomotor and executive function, the adolescents born very preterm performed in the normal range, whether or not they had evidence of MRI abnormality. Our findings are encouraging as the neuropsychological consequences of damage to the very preterm brain, still evident on MRI at 14 to 15 years of age, appear to be minor.

Effects of very low birthweight on brain structure in adulthood

Very-low-birthweight (VLBW) individuals are at high risk of brain injury in the perinatal period. We wished to determine how such early brain lesions affect brain structure in adulthood. Thirty-two VLBW adults (20 female, 12 male) and 18 term, normal birthweight sibling control individuals (nine female, nine male) underwent structural MRI at a mean age of 23 years 4 months (range 17 to 33 years; SD 3.4). Images were analyzed using an automated tissue segmentation algorithm in order to estimate whole brain tissue class volumes in native space. Images were then warped to a template image in standard space. There was no significant between-group difference in whole brain, grey matter, white matter, or total cerebral spinal fluid (CSF) volumes. However, lateral ventricular volume was significantly increased by 41% in those with VLBW. The ratio of grey to white matter was also significantly increased (by 10%) in those with VLBW. Group comparison maps showed widespread changes in the distribution of grey and white matter, and relative excess of ventricular CSF, in the brains of VLBW individuals. Increased ventricular volume predicted decreased grey matter in subcortical nuclei and limbic cortical structures, and decreased periventricular white matter. We conclude that these diffuse abnormalities of grey and white matter are a consequence of the interaction of perinatal brain injury and ongoing neurodevelopmental processes.

The neurodevelopmental progress of infants less than 33 weeks into adolescence

Background: Several studies have shown an increased incidence of neurodevelopmental impairment in very preterm survivors at school age compared with controls. Aim: To compare findings in the same cohort at 8 years and 15 years. Methods: A total of 151 of the 224 eligible infants born before 33 weeks of gestation from 1979 to 1982, and who were living in the UK, were assessed at 8 and 15 years. Items common to both assessments were compared to evaluate changes in neurodevelopmental function. The assessment included a structured neurological examination, psychometric tests using the WISC-R (in subjects born in 1981–82), a test of visuomotor integration (Beery), and a school questionnaire. Results: There was a significant increase in the proportion of subjects classified as impaired with disability from 11% at 8 to 22% at 14–15 years of age. The proportion of subjects classified as impaired without disability increased from 16% at 8 to 26% at 14–15 years of age. Full scale IQ decreased from 104 to 95 from childhood to adolescence, and more adolescents (24%) were requiring extra educational provision than they had at the age of 8 years (15%). Conclusion: Results indicate that between the ages of 8 and 15 years in this cohort of very preterm survivors there is an apparent deterioration in neurodevelopmental outcome category, cognitive function, and extra educational support. It is not clear whether this represents a genuine deterioration in neurocognitive function or whether it represents the expression of pre-existing cerebral pathology in an increasingly complex environment.

Cognitive maturation in preterm and term born adolescents

Background: Adolescence is a critical period of brain structural reorganisation and maturation of cognitive abilities. This relatively late developmental reorganisation may be altered in individuals who were born preterm. Methods: We carried out longitudinal neuropsychological testing in 94 very preterm individuals (VPT; before 33 weeks’ gestation) and 44 term born individuals at mean ages of 15.3 years (adolescence) and 19.5 years (young adulthood). Results: Full scale, verbal and performance IQ and phonological verbal fluency were significantly lower in the VPT group than the term group at both ages. Repeated measures ANOVA showed only one group by time point interaction for semantic verbal fluency (F = 10.25; df = 107; p = 0.002). Paired-sample t tests showed that semantic verbal fluency increased significantly in the term group over adolescence (t = −5.10; df = 42; p<0.001), but did not increase in the VPT group (t = 0.141; df = 69; p = 0.889). For verbal IQ, there was a significant interaction between time point and sex (F = 4.48; df = 1; p = 0.036) with paired-sample t tests showing that verbal IQ decreased in males between adolescence and adulthood (t = 3.35; df = 71; p = 0.001), but did not change significantly in females (t = 0.20; df = 52; p = 0.845). Conclusion: Decrements of intellectual functioning in VPT individuals persist into adulthood. Additionally, there is a deficit in the adolescent maturation of semantic verbal fluency in individuals born VPT.

Altered functional neuroanatomy of response inhibition in adolescent males who were born very preterm

Event‐related functional magnetic resonance imaging (fMRI) was used to investigate the hypothesis that males who were born very preterm may show differences in relative strength of blood oxygen level dependent (BOLD) signals in selective brain areas during performance of a simple response inhibition task compared with term‐born controls. Participants were eight males (mean gestational age at birth 28wks, [SD 2]; mean age at testing 16y, [SD 1] and 14 controls matched for sex, age (mean age 17y, [SD 1]), and IQ. A ‘go‐no‐go’ task was used to assess response selection and motor response inhibition in response to a visual stimulus. When the ‘no‐go’ condition was contrasted with an attentional control condition, preterm participants showed reduced BOLD signal response bilaterally in the cerebellum, right caudate nucleus, and thalamus, and prefrontal areas including left inferior prefrontal and left anterior cingulate gyri. They also showed increased response mainly in temporal regions. These results suggest that despite good task performance, individuals who were born very preterm exhibit different BOLD signal responses in selective brain areas compared with controls which may underline the use of alternative strategies when challenged with motor response inhibition processing.

Diffusion tensor MRI of the corpus callosum and cognitive function in adults born preterm

Very preterm birth (before 33 weeks gestation) is associated with the white matter damage, and a common sequel is reduced size and altered shape of the corpus callosum. We used diffusion tensor MRI to assess the corpus callosum in 63 very preterm and 45 term-born young adults. Indices of white matter microstructure [fractional anisotropy (FA) and mean diffusivity (MD)] were obtained for the genu, body and splenium. Very preterm females had higher MD in the genu than term-born females, indicating altered white matter microstructure. This was associated with lower performance IQ. The groups demonstrated different patterns of correlations between verbal learning and tract-specific FA and MD, consistent with the reorganization of white matter structure in adults born very preterm.

The neural basis of response inhibition and attention allocation as mediated by gestational age

Children and adolescents born before 33 weeks of gestation, that is very preterm, may experience problems with the inhibitory control of behaviour and the allocation of attention. Previous functional magnetic resonance imaging (fMRI) studies have found preterm‐born adolescents to display altered brain activation in tasks measuring inhibitory control. However, adolescence is a period during which dynamic changes are occurring in the brain, and it is not yet known whether these functional alterations will persist into adulthood, or instead reflect developmental delay. This study used an event‐related fMRI Go/No‐Go motor response inhibition paradigm, which included an oddball task measuring attention allocation to infrequent stimuli, to compare blood‐oxygen‐level‐dependent (BOLD) signal between 26 preterm‐born adults and 21 controls. Group differences in brain activation were observed in inhibition and attention networks during both conditions. During motor response inhibition, preterm‐born participants compared to controls showed increased BOLD signal in medial and right lateral posterior brain regions, including middle temporal/occipital gyrus, posterior cingulate gyrus and precuneus. During oddball trials, preterm‐born young adults displayed attenuated brain activation in a fronto‐parietal‐cerebellar network which is involved in mediating attention allocation. This pattern of reduced brain activation in task‐relevant regions of attention allocation, and increased activation in posterior brain regions during inhibitory control, suggests adult alteration of inhibition and attention processing following very preterm birth, which may reflect a developmental delay. Hum Brain Mapp, 2009.

Hyperactivity in adolescents born very preterm is associated with decreased caudate volume

BACKGROUND Several studies have associated preterm birth with impaired behavioral functioning and attention problems. In addition, preterm individuals have an increased risk of brain injury in the neonatal period. Such early lesions have the potential to disrupt subsequent neurodevelopment. This study explored behavioral functioning, particularly externalizing behavior, in a group of adolescents who were born very preterm and its relationship with volume of the caudate, a brain region particularly vulnerable to damage in the preterm neonate. METHODS We studied 72 adolescents born before 33 weeks and 50 age- and gender-matched full-term control subjects. Behavioral assessment included the Rutter Behavioural Scale and a social adjustment scale. Bilateral caudate volumes were quantified by stereologic methods. RESULTS Preterm adolescents scored significantly higher than control subjects on the Rutter hyperactivity score, and boys scored higher than girls. In preterm boys only, left caudate volume was negatively correlated with hyperactivity score (r = -.43, p = .018) and social adjustment score in childhood (r = -.40, p = .028). CONCLUSIONS Our data suggest that boys born very preterm are more likely to experience nonclinical behavioral problems in adolescence compared with full-term control subjects. Our results indicate that behavioral problems in this group might be associated with reductions in volume of the left caudate nucleus.

Neurological abnormalities and cognitive ability in first-episode psychosis

BACKGROUND It remains unclear if the excess of neurological soft signs, or of certain types of neurological soft signs, is common to all psychoses, and whether this excess is simply an epiphenomenon of the lower general cognitive ability present in psychosis. AIMS To investigate whether an excess of neurological soft signs is independent of diagnosis (schizophrenia v. affective psychosis) and cognitive ability (IQ). METHOD Evaluation of types of neurological soft signs in a prospective cohort of all individuals presenting with psychoses over 2 years (n=310), and in a control group from the general population (n=239). RESULTS Primary (P<0.001), motor coordination (P<0.001), and motor sequencing (P<0.001) sign scores were significantly higher in people with any psychosis than in the control group. However, only primary and motor coordination scores remained higher when individuals with psychosis and controls were matched for premorbid and current IQ. CONCLUSIONS Higher rates of primary and motor coordination signs are not associated with lower cognitive ability, and are specific to the presence of psychosis.