Neural substrates of letter fluency processing in young adults who were born very preterm: Alterations in frontal and striatal regions
Introduction
Selective language impairments have been observed in individuals who were born very preterm (VPT; e.g., less than 33 weeks of gestation) and very low birth weight (VLBW; e.g., less than 1500 g at birth). From infancy onwards the described deficits have involved verbal delays in language development (Largo et al., 1986), as well as specific problems in articulation and correct use of grammar (Largo et al., 1990), receptive language (Vohr et al., 1989), language comprehension, naming, auditory discrimination (Jansson-Verkasalo et al., 2004), expressive language and sentence repetition (Wolke and Meyer, 1999), rapid word retrieval and comprehension of relative concepts (Luoma et al., 1998), lexical morphology (Le Normand and Cohen, 1999) and auditory memory (Briscoe et al., 1998). Slight delays in the development of lexicon and grammar have been observed in a study of VPT-born two years old children, but only in those individuals who had an extremely low birth weight, whereas a typical linguistic development was reported in healthy VPT-born participants (Sansavini et al., 2006). At school age, developmental language delays (Magill-Evans et al., 2002), as well as deficits in reading skills (Hall et al., 1995), naming (Saavalainen et al., 2006), speech, motor function, interaction and motivation (Jennische and Sedin, 2003) have been observed. As differences in processing speed have been observed between VPT-born individuals and controls (Faust et al., 1999), it remains to be established whether these may be one of the underlying mechanisms associated with the observed language deficits.
In adolescence and early adulthood, we have shown that the performance of VPT-born individuals on a verbal fluency task was poor compared to controls, in the absence of differences in reading and spelling scores (Rushe et al., 2001), and after controlling for IQ (Nosarti et al., 2007). Verbal fluency scores were positively associated with the size of the corpus callosum in very preterm boys (Nosarti et al., 2004), in line with other studies which reported phonological processing disruptions associated with developmental callosal damage (Temple and Ilsley, 1993). The volume of other brain structures has been associated with verbal fluency performance in preterm-born adolescents, for example the thalamus (Gimenez et al., 2006b). These results indicate that structural brain abnormalities observed in VPT and VLBW populations may be at least partly responsible for the neuropsychological impairments which are common in these cohorts, and we recently demonstrated that both grey matter and white alterations were associated with length of gestation and mediated adolescent neurodevelopmental impairment (Nosarti et al., 2008).
However, the relationship between neuropsychological performance and perinatal brain insult is not always as clear as in children born at term (Nosarti et al., 2002, Cooke and Abernethy, 1999). The most likely explanation is that the presence of any very early brain injury has resulted in compensatory alterations in brain development, such that the brain areas typically underlying cognitive functions differ between populations who are developmentally compromised and controls (Stiles et al., 2003). A few functional magnetic resonance imaging studies (fMRI) have addressed these points by comparing the neuronal activation of very preterm individuals and controls during language tasks. An investigation of preterm-born children identified a pattern of brain activity during semantic processing which was similar to the pattern of activity displayed during a phonologic processing task in controls (Peterson et al., 2002). We observed that preterm adolescent boys with neurodevelopmental thinning of the corpus callosum, exhibited differential lateralisation of phonological and orthographic processing, compared to full term controls (Rushe et al., 2004).
The current study used fMRI to investigate the neuronal activation in young adults, who were born very preterm, during the performance of a phonemic verbal fluency task. This task was chosen on the basis of previously reported deficits in verbal fluency in a group of VPT-born adolescents and adults recruited from a similar cohort (Rushe et al., 2001, Nosarti et al., 2007, Nosarti et al., 2008). As far as we are aware, has never been studied with fMRI in VPT-born individuals. Verbal fluency refers to the willed or intrinsic generation of words predicated on cues (Friston et al., 1991), which in our study were lexical, and assesses the ‘executive system’ that involves sustained attention, initiation of response, error monitoring, response selection, and the use of working memory in order to update and compare previous responses and remember the rules (Indefrey and Levelt, 2000, Ruff et al., 1997). Other cognitive components of verbal fluency include mental flexibility, as the task not only requires lexical word generation, but also the capacity to quickly switch to a different sub-category once another is exhausted. This process involves convergence of cognitive speed and strategic thinking (capacity to quickly organise information, formulate recall strategies and switch between categories) (Bolla et al., 1990). The current study used overt verbal responses in the absence of acoustic scanner noise, which could interfere with the measurement of performance during on-line testing. Furthermore, we varied the task demands by examining subjects performance during two levels of difficulty; using “easy” and “hard” letters, which differ in the number of words that subjects can normally generate (Fu et al., 2002).
As there is evidence that high-order executive functions such as verbal fluency may be underpinned by neuronal activity in frontal–striatal circuits (Rubia et al., 2006, Woodward et al., 2005), we hypothesized that the preterm group would show altered neuronal activity in frontal and striatal brain regions compared to controls, as previously reported in another executive task involving response inhibition and attention allocation (Nosarti et al., 2006, Lawrence et al., 2009). We further predicted that gestational age at birth would be linearly associated with altered patterns of peak blood-oxygenated-level-dependent (BOLD) signal, in line with previous studies which have reported statistically significant relationships between quantitative structural MRI changes and gestational age (Gimenez et al., 2006a, Partridge et al., 2004, Nosarti et al., 2008). Finally, as we have previously identified extensive structural cortical changes in adolescence (Nosarti et al., 2008), we acquired and analyzed structural volumetric MRI data in the same subjects to clarify whether any functional changes were associated with structural brain volume changes.
Section snippets
Participants
In 1983–84, 252 infants born at less than 33 weeks gestation and admitted consecutively to the Neonatal Unit at University College London Hospital (UCLH), within 5 days of birth, survived and were discharged (Nosarti et al., 2008). Of this cohort, all individuals born at 28 or less weeks of gestation were enrolled for long term follow up, as well as a random sample of those born from 29 to 33 weeks of gestation. One hundred and forty-seven (40% of the entire sample) adolescents were selected
Behavioural data
VPT-born participants and controls did not differ in age (F = 0.10(53), p > 0.05) or gender distribution (χ2 = 1.51, p > 0.05). Both VPT-born and control participants generated more accurate responses in the “easy” compared to the “hard” letter condition (repeated measures, F = 42.66(1,53), p < 0.0001), but there were no significant differences between the groups in terms of correct responses generated in both conditions (“easy and “hard”) (F = 0.74(1,53), p > 0.05). No significant interaction between task
Discussion
This study describes differential patterns of brain activation in young adults who were born very preterm compared to controls during a verbal fluency task. Group membership, level of task difficulty (“easy” and “hard” letter trials) and gestational age had significant effects on BOLD signal. Between group differences and degree of immaturity at birth seemed to predominantly affect activation in two brain areas: the caudate nucleus and the anterior cingulate gyrus. These results support our
Acknowledgments
The study was funded by the March of Dimes Birth Defects Foundation, USA (12-FY03-41) and the Health Foundation, UK (1206/2063). The authors would like to thank Mr Chris Andrews, Dr Emma Lawrence, and Dr Vincent Giampietro for help with data analysis and Dr Colin O'Carroll for assistance with participant's recruitment and assessment.
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