YNIMG-11041; No. of pages: 10; 4C: 6, 5, 7 NeuroImage xxx (2014) xxx–xxx

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Full Length Article

Road work on memory lane—Functional and structural alterations to the learning and memory circuit in adults born very preterm Piergiorgio Salvan a,1, Seán Froudist Walsh a,⁎,1, Matthew P.G. Allin a, Muriel Walshe a, Robin M. Murray a, Sagnik Bhattacharyya a, Philip K. McGuire a, Steven C.R. Williams b, Chiara Nosarti a a b

Department of Psychosis Studies, Institute of Psychiatry, King's Health Partners, King's College London, De Crespigny Park, London SE5 8AF, UK Department of Neuroimaging, Institute of Psychiatry, King's Health Partners, King's College London, De Crespigny Park, London SE5 8AF, UK

a r t i c l e

i n f o

Article history: Accepted 10 December 2013 Available online xxxx Keywords: Preterm fMRI DTI Hippocampus Fornix Thalamus

a b s t r a c t Very preterm (VPT) birth is considered a risk factor not only for neurological impairment, but also for reduced function in several cognitive domains in childhood and later in life. Individuals who were born VPT are more likely to demonstrate learning and memory difficulties compared to term-born controls. These problems contribute to more VPT-born children repeating grades and underachieving in school. This, in turn, affects their prospects in adult life. Here we aimed to 1) study how the VPT-born adult brain functionally recruited specific areas during learning, i.e. encoding and recall across four repeated blocks of verbal stimuli, and to investigate how these patterns of activation differed from term-born subjects; and 2) probe the microstructural differences of white-matter tracts connecting these areas to other parts of the learning and memory network. To investigate these functional–structural relationships we analyzed functional and diffusion-weighted MRI. Functional-MRI and a verbal paired associate learning (VPAL) task were used to extract Blood Oxygenation Level Dependent (BOLD) activity in 21 VPT-born adults (b33 weeks of gestation) (mean age: 19.68 years ± 0.85; IQ: 99.86 ± 11.20) and 10 term-born controls (mean age: 19.87 years ± 2.04; IQ: 108.9 ± 13.18). Areas in which differences in functional activation were observed between groups were used as seed regions for tractography. Fractional anisotropy (FA) of the tract-skeleton was then compared between groups on a voxel-wise basis. Results of functional MRI analysis showed a significantly different pattern of activation between groups during encoding in right anterior cingulate–caudate body, and during retrieval in left thalamus, hippocampus and parts of left posterior parahippocampal gyrus. The number of correctly recalled word pairs did not statistically differ between individuals who were born VPT and controls. The VPT-born group was found to have reduced FA in tracts passing through the thalamic/hippocampal region that was differently activated during the recall condition, with the hippocampal fornix, inferior longitudinal fasciculus and inferior fronto-occipital fasciculus particularly affected. Young adults who were born very preterm display a strikingly different pattern of activation during the process of learning in key structures of the learning and memory network, including anterior cingulate and caudate body during encoding and thalamus/parahippocampal gyrus during cued recall. Altered activation in thalamus/ parahippocampal gyrus may be explained by reduced connections between these areas and the hippocampus, which may be a direct consequence of neonatal hypoxic/ischemic injury. These results could reflect the effect of adaptive plastic processes associated with high-order cognitive functions, at least when the cognitive load remains relatively low, as ex-preterm young adults displayed unimpaired performance in completing the verbal paired associate learning task. © 2013 Elsevier Inc. All rights reserved.

Introduction ⁎ Corresponding author at: Department of Psychosis Studies, Institute of Psychiatry, 16 De Crespigny Park, London SE5 8AF, UK. E-mail addresses: [email protected] (P. Salvan), [email protected] (S.F. Walsh), [email protected] (M.P.G. Allin), [email protected] (M. Walshe), [email protected] (R.M. Murray), [email protected] (S. Bhattacharyya), [email protected] (P. McGuire), [email protected] (S.C.R. Williams), [email protected] (C. Nosarti). 1 These authors contributed equally to this work.

Very preterm birth (b 32 weeks of gestation) and particularly extremely preterm birth (b26 weeks) are considered risk factors not only for neurobehavioral impairment in childhood (Bhutta et al., 2002), but also for reduced function in several cognitive domains later in life (Nosarti et al., 2007). Although advances in neonatal intensive care have helped to considerably reduce mortality rates, cognitive and behavioral deficits have been documented in up to 50% of surviving ex-preterm children (Delobel-Ayoub et al., 2009). Understanding how

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Please cite this article as: Salvan, P., et al., Road work on memory lane—Functional and structural alterations to the learning and memory circuit in adults born very preterm, NeuroImage (2014), http://dx.doi.org/10.1016/j.neuroimage.2013.12.031

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neural circuits associated with cognitive processes are differently engaged in this population may help in the development of early therapeutic interventions designed to minimize the negative impact on its lifelong outcome. Very preterm born individuals tend to have lower IQ and to perform worse than aged-matched, full-term born controls in several cognitive areas such as executive functioning, language processing and working memory, from early childhood through to late adolescence (Bhutta et al., 2002; Nosarti et al., 2007). Such cognitive deficits are more pronounced in those individuals who were born extremely preterm (Bhutta et al., 2002). Underperforming in multiple cognitive domains may significantly affect academic performance (Deary et al., 2007; Mulder et al., 2010) and put very preterm individuals at increased risk for special education and lower levels of academic achievement (Luu et al., 2009), which in turn has implications for later professional development and quality of life (Mathiasen et al., 2009). In the past decade several studies have attempted to increase our understanding of the biological bases of the neurodevelopmental sequelae associated with very preterm birth by using structural and functional magnetic resonance imaging (MRI and fMRI, respectively). We previously studied the neuroanatomy of memory and executive processes in adults born very preterm and controls and observed strikingly different neural activation between the groups, in the absence of significant differences in ‘on-line’ task performance (Lawrence et al., 2010; Narberhaus et al., 2009; Nosarti et al., 2009). These results led us to speculate that satisfactory task performance, at least during completion of relatively easy tasks, can be underlined by differential neuroanatomy, possibly due to differences in neurodevelopment. Some of the differences in functional activation in our previous studies cited above were related to participants' underlying brain anatomy. Analysis of structural and fMRI data from a verbal episodic memory task showed that a reduction in hippocampal volume was associated with an increase in Blood Oxygenation Level Dependent (BOLD) activation in the neighboring parahippocampal gyrus (Lawrence et al., 2010). In another study, striatal volume was found to correlate with reduced functional activation during completion of a verbal fluency task (Nosarti et al., 2009). Recently, we used a different approach to look at structure/function relationships and investigated with fMRI preterm-born adults with varying degrees of neonatal brain injury (as assessed by neonatal ultrasound). We found that areas in the middle frontal gyrus and posterior cingulate gyrus showed decreased activation during a paired associate learning task as the severity of neonatal brain injury increased (Kalpakidou et al., 2012). Although these studies point towards a relationship between BOLD activation and gray matter structure, other studies in psychiatric and neurological disorders have investigated associations between BOLD signal and white matter microstructure using diffusion MRI (Schlosser et al., 2007; Sui et al., 2011; Zhou et al., 2008). These approaches may allow for description of the constraints that structural connectivity places on functional brain activation (Stephan et al., 2009). By linking measures of white matter structural connectivity and BOLD-activation we may begin to disentangle the cause of greatly altered functional patterns in ex-very preterm individuals. To the best of our knowledge, no study has yet investigated possible links between white matter microstructure and functional activation in VPT-born populations in adult life. This approach could be particularly important as the most common neuropathology in preterm infants is white matter injury and its accompanying effect on the cerebral cortex and deep gray matter nuclei (Counsell et al., 2007; Eikenes et al., 2011; Inder et al., 1999, 2005). Aberration in white matter microstructure causes abnormal neurodevelopment, with white matter injuries detectible until at least age 19 (Allin et al., 2007; Eikenes et al., 2011), indicating that the sequelae of prematurity may be lifelong and have a significant impact

on functional outcome (Counsell and Boardman, 2005; Skranes et al., 2007). These most common neuropathologies have been described under the umbrella term “encephalopathy of prematurity”, in which white and gray matter abnormalities lead to disrupted development of the basal ganglia, thalamus, related cortical areas and the white matter connecting these areas (Volpe, 2009). In order to investigate the influence of underlying white matter pathology on learning and memory ability in adults born very preterm we 1) studied the effects of learning across 4 encoding and recall blocks of a verbal paired associate learning fMRI task we previously used (Lawrence et al., 2010) and 2) used diffusion-weighted MRI tractography in order to examine the microstructure of tracts connecting parts of the learning/memory network that were found to be differentially activated in VPT-born adults and controls. Here we were interested not in the average effects of encoding and recall of verbal stimuli as in Lawrence et al. (2010), but rather the effects of learning and adaptation of neural resources to task demands as the structure of the task becomes clear (Bhattacharyya et al., 2009). We attempted to explore if the memory deficits previously reported in VPT-born populations may in fact be due to differences in learning ability and style. For this reason we analyzed BOLD signal that progressively increased or decreased across four blocks of repeated stimuli, in both encoding and recall conditions, and the areas in which these patterns differed between VPT-born participants and controls. As participants become more familiar with the task, we posited that they would alter their strategy to make the most efficient use of neural resources available. We hypothesized that areas that are specialized in the memory of paired associates, such as the left hippocampus and prefrontal cortex, would be progressively more activated as the task progressed, and areas that have more generalized cognitive and attentional functions, such as the anterior cingulate and dorsolateral prefrontal cortex, would decrease in activity in the control group (Chein and Schneider, 2005; Kelly and Garavan, 2005). We further hypothesized that, due to altered functional circuitry shown in various fMRI tasks of cognitive function, the VPT-born adults would recruit different cortical and subcortical regions compared to controls. Based on the results of a number of structural and functional studies implicating hippocampal damage in VPT-born populations (Nosarti et al., 2002) and recent studies showing the importance of white matter surrounding the hippocampus to verbal learning (Meinzer et al., 2010), we hypothesized that a differential functional activation pattern may be in part explained by an altered structural connectivity pattern between the hippocampus and the rest of the verbal paired associate learning circuit. In addition, we explored possible effects of gender on structure–function relationships and behavioral scores.

Material and methods Subjects 21 individuals who were born at less than 33 weeks of gestation and admitted within 5 days of birth to the Neonatal Unit at University College London Hospital participated in this study (gestational age 28.24 weeks (SD: 2.28; range: 24–32 weeks); mean age at time of study 20.85 years (SD: 1.77). Exclusion criteria were: history of cerebral palsy, grade 3/4 intraventricular hemorrhage, or cystic periventricular leukomalacia. Ten control subjects were recruited from advertisements in the local press and universities (mean age 20.00 years (SD: 1.91). Inclusion criteria were full-term birth (37–42 completed weeks of gestation) and English as a first language. Exclusion criteria included birth complications (eg, low birth weight defined as b2500 g, endotracheal mechanical ventilation), prolonged gestation (greater than 42 weeks), history of psychiatric illness, and severe hearing and motor impairment.

Please cite this article as: Salvan, P., et al., Road work on memory lane—Functional and structural alterations to the learning and memory circuit in adults born very preterm, NeuroImage (2014), http://dx.doi.org/10.1016/j.neuroimage.2013.12.031

P. Salvan et al. / NeuroImage xxx (2014) xxx–xxx

Participants included in this study took part in other fMRI studies (Kalpakidou et al., 2012; Lawrence et al., 2010; Nosarti et al., 2009). Here we chose all subjects who had completed a verbal paired associate learning task (Lawrence et al., 2010) and had received diffusion-weighted MRI (Kontis et al., 2009). IQ was assessed with the Mean Wechsler Abbreviated Scale of Intelligence Full Scale IQ (Wechsler, 1999). Ethical approval for the study was obtained from King's College Hospital Research Ethics Committee. Written informed consent for the assessment, including MRI, was obtained from all participants. Verbal paired associate learning task

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episodic memory task was studied with a gradient-echo sequence (repetition time 5000 msec, echo time 40 msec, flip angle 70°), with each acquisition compressed into the first 1500 msec of the repetition time, leaving 3500 msec when the scanner was silent to allow for the verbal response. A total of 148 7-mm T2-weighted images were acquired at each of 16 near-axial 7-mm-thick planes parallel to the intercommissural (AC–PC) plane to include the whole brain (FOV 24 × 24 cm and matrix 64). For the DT-MRI image acquisition the sequence provided isotropic voxels (2.5 mm × 2.5 mm × 2.5 mm, reconstructed as 1.875 mm ×1.875 mm × 2.5 mm) with coverage of the whole head, gated to the cardiac cycle, with an echo time of 107 ms, and effective repetition time of 15 R–R intervals. The duration of the diffusion encoding gradients was 17.3 ms, giving a maximum diffusion weighting of 1300 s/mm 2 . At each location, seven images without a diffusion gradient (i.e., b = 0 s/mm 2 ) were acquired, along with 64 diffusion-weighted images (1300 s/mm 2), with the latter having gradient directions distributed uniformly in space.

Subjects performed a verbal paired associate learning task inside the imaging system. The task was adapted from the paired associate learning subtest of the Wechsler Memory Scale-Revised (Wechsler, 1987), as previously used (Bhattacharyya et al., 2009; Lawrence et al. 2010; Kalpakidou et al, 2012). It comprised 3 conditions (encoding, recall, and baseline), with stimuli presented visually in blocks. The accuracy of responses during each condition was recorded online. During encoding, subjects were shown pairs of words and were required to decide whether they went well together (to promote encoding), saying yes or no aloud after each pair. The same word pairs were presented in the encoding condition 4 times so that the associations could be learned over repeated blocks. During recall, a word from previously presented pairs was shown and participants were asked to give the word that it was previously associated with. Subjects were asked to say “pass” if they could not recall the missing word. In the baseline condition, subjects were shown pairs of words printed with the same or different fonts. They were required to say whether the same fonts were used for both words in the pair or not, saying yes or no aloud after each pair. The words were different from those presented during the encoding condition, and word pairs were not repeated across blocks to minimize learning. In the ‘blanks’ low-level baseline condition participants were simply shown 2 blue rectangles with no words displayed on them, and this was subtracted from all subsequent analyses. Stimuli were presented in 40-second blocks of 8 stimulus pairs, with 3 conditions presented in the same order (encoding, recall, and baseline) on 4 occasions. Within each encoding block, the order of the word pairs was randomized. A visual prompt preceded each encoding (“Do these words go well together?”), recall (“Which word was associated with this?”), and baseline block (“Are the fonts of these 2 words the same?”). Presenting the same encoding stimulus pairs 4 times across repeated blocks permitted assessment of the effect of learning on activation and recall accuracy. The words presented were taken from the Medical Research Council Psycholinguistic Database (Coltheart, 1981) and were similar in terms of number of letters, familiarity (Kučera and Francis, 1967) written frequency, concreteness, imageability, and meaningfulness. Participants were familiarized with the task during a training session with a set number of trials outside of the imaging system using different words from those presented during imaging.

The analysis was hypothesis-driven, and modeled patterns of increase or decrease of activation across the four blocks during encoding, and separately, during recall. In the analysis, ‘blanks’ low-level baseline condition was subtracted from all other conditions. To reduce the possible confounding effects of differential task performance between the groups on blood oxygen level-dependent signal, in each recall block of 8 responses each, only activation related to correct responses was modeled. Functional magnetic resonance imaging data from the verbal paired associate learning task were analyzed using software developed at the Institute of Psychiatry (XBAM version 4.1) using a non-parametric approach to minimize assumptions (http://www.brainmap.it). The non-parametric approach is important to achieve rigorous statistical inference given the difficulty of establishing normality in fMRI data (Hayasaka and Nichols, 2003). Images were realigned and smoothed using an 8-mm full-width-athalf-maximum Gaussian filter. Individual activation maps were created using 2 gamma-variate functions to model the blood oxygen leveldependent response. Following least-squares fitting of this model, a sum of squares (SSQ) statistic was estimated at each voxel. This consisted of the ratio of the SSQ of deviations from the mean image intensity due to the model (over the whole time series) to the SSQ of deviations due to the residuals. These data were then permuted to determine significantly activated voxels specific to each condition (Bullmore et al., 2000). The SSQ ratio maps for each individual were transformed into standard stereotactic space (Talairach and Tournoux, 1988), and SSQ values were extracted from cluster local maxima where differential activation across blocks between groups for each condition was significant. These maps were compared using nonparametric repeatedmeasures analysis of covariance. The statistical analysis used type I error control to obtain less than 1 false-positive cluster over the whole map.

Image acquisition

Diffusion-weighted MRI preprocessing and analysis

Functional and structural MRI data from all 31 subjects were acquired on a 1.5-Tesla GE Signa Neurovascular MR system (GE Medical Systems, Milwaukee, Wisconsin). A quadrature head coil was used for radiofrequency transmission and reception. A high-resolution inversion recovery echo-planar imaging data-set with 3-mm-thick near-axial slices and an in-plane resolution of 1.5 mm was also acquired to facilitate mapping of the functional data into standard space. The verbal

Motion and eddy-current correction were performed using FMRIB's Diffusion Toolbox (FDT), part of the FMRIB Software Library (FSL www. fmrib.ox.ac.uk/fsl/) (Smith et al., 2004; Woolrich et al., 2009). The gradient matrix was then rotated in order to account for the changes made at the last step (Leemans and Jones, 2009). Following this, the brain was virtually separated from the rest of the head using FSL's Brain Extraction Tool (Smith, 2002). Diffusion tensors and fractional

FMRI preprocessing and analysis

Please cite this article as: Salvan, P., et al., Road work on memory lane—Functional and structural alterations to the learning and memory circuit in adults born very preterm, NeuroImage (2014), http://dx.doi.org/10.1016/j.neuroimage.2013.12.031

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anisotropy maps were constructed using Diffusion Toolkit (Ruopeng Wang, Van J. Wedeen, TrackVis.org, Martinos Center for Biomedical Imaging, Massachusetts General Hospital). Probability distributions on fiber direction were calculated at each voxel using methods described by Behrens et al. (2003a, 2003b). Probabilistic tractography was then performed from voxels within seed masks. Definition of seed regions for tractography In order to search for anatomical correlates explaining functional differences between the groups using a data driven method, two different seed masks were generated from the clusters of significant group differences in the encoding and recall fMRI tasks respectively. The aim was to operate at an individual level in order to reduce intersubject variability in locating the seed points for each subject. To do this we back-projected the significant clusters from the common template used in the fMRI analysis to the subject's individual mean fMRI image using XBAM tools (http://www.brainmap.it). Proceeding at individual level, we linearly registered each subject's mean fMRI image to their native diffusion space using FSL's FLIRT (Jenkinson and Smith, 2001). We then applied the fMRI-to-diffusion space registration matrix to the significant clusters from the fMRI group analysis, which were previously aligned into each individual's mean fMRI volume. Group comparison and statistics for DW-MRI data Less probable connections below a chosen threshold (based on the number of streamlines emitted from the seed points) were omitted from further analysis (Ethofer et al., 2012). This threshold was chosen as it found the best balance between reconstructing real anatomical tracts and eliminating false positives. Each person's brain and tract maps (one map of probable tracts was created for each of the two seed regions) were non-linearly coregistered to a standard FA template using FSL's FNIRT (FMRIB58_FA_1mm) (Andersson and Smith, 2007). Each tract map was then binarised and summed to create an atlas of connections from each seed region in controls and VPT-born participants (separately). As the atlas maps were quite similar between groups, we decided to create a binary mask including only those voxels present in at least 60% of all participant's thresholded tract maps (de Zeeuw et al., 2012). In order to search for white matter microstructural differences within the tracts, we then multiplied each of the binary tract masks (including only voxels connected to the seed region in N60% of participants) by the study-specific tract skeleton that was created using FSL's TBSS (Smith et al., 2006). We thus searched for FA differences within the center of the tracts stemming from each seed region in two separate analyses. The group comparisons were performed using nonparametric permutation testing with the FSL Randomise tool (http://fsl.fmrib.ox.ac. uk/fsl/fslwiki/Randomise). Randomise implemented 5000 randomly generated permutations of the data (Nichols and Holmes, 2001). To improve the estimation of variance in the statistical analysis, resulting data were thresholded using a cluster-based thresholding method that corrected for multiple comparisons at p b 0.05. Correlations between FA and gestational age in the voxels that were found to have significantly different FA between the groups were performed in the same way. Non-imaging statistical analysis SPSS version 22 was used for all other statistical analysis. Continuous demographic, health and neuropsychological variables were compared using Student's t-tests (or the non-parametric equivalent). Categorical variables were compared using a chi-square test. Repeated measures analysis of variance and multivariate analysis of variance were used to test for the effects of gender on online behavioral

performance, fMRI activation and fractional anisotropy (in regions found to be different in between group comparisons). Results Behavioral data There were no statistically significant group-differences in age at assessment, sex or IQ scores (see Table 1). Behaviorally, an effect of learning was observed across groups from having the stimulus pairs repeated 4 times, with a significant difference in the number of correctly recalled between the first and second blocks (mean score in block 2 − block 1 = 0.548; SD: 0.888; p = 0.002), and between the third and fourth block (mean block 4 score − block 3 score = 0.354; SD: 0.66; p = 0.006). No between-group differences were observed in the number of correctly recalled items in any of the 4 blocks. fMRI results Within group fMRI results Results of a within-group analysis showed that in controls, during the encoding condition, the BOLD signal progressively increased over repeated trials in the left middle frontal gyrus (BA 47) and the right anterior cingulate (BA 24), and progressively decreased in left middle temporal gyrus (BA 21). In individuals born preterm, the BOLD signal progressively increased over repeated presentation of the encoding blocks in right inferior frontal gyrus (BA 44). In controls during the recall condition, the BOLD signal progressively decreased over repeated trials in the right lentiform nucleus and in the left fusiform gyrus (BA 20); while progressively increasing BOLD signal was observed in left inferior frontal gyrus (BA 44). In preterm born individuals BOLD signal progressively decreased in subsequent recall blocks in left caudate nucleus. Between group fMRI results A statistically significant interaction between group and direction of change of activation during encoding condition was found in a region encompassing parts of the right anterior cingulate cortex (ACC) and superior frontal gyrus (SFG) and part of the caudate nucleus, in which VPT-born participants showed a progressive increase in activation from block 1 to block 4. In contrast, the control group showed a decreasing pattern of activation in this area across the four blocks (See Fig. 1 and Table 2). The same style of analysis was applied to the recall phase of the fMRI task, which revealed the opposite activation pattern across blocks (for the VPT-born group progressive decrease in activation, for the control group increase) in a cluster encompassing parts of left posterior parahippocampal gyrus, posterior hippocampus and thalamus (pulvinar) (Fig. 1 and Table 2). DW-MRI results Probabilistic tractography Probabilistic tractography using the anterior cingulate/caudate region found to be differentially activated during encoding as a seed region revealed a wide range of projection, association and commissural tracts connecting the seed region to frontal, temporal and subcortical regions. Reconstructed tracts are shown in orange in Fig. 2b and included the genu of the corpus callosum, tracts of the internal capsule, anterior thalamic radiations, frontostriatal tracts and the fronto temporal section of the inferior fronto-occipital fasciculus (IFOF), which is also regarded as the ventral language pathway (Saur et al., 2008). Tracking from the hippocampal/thalamic region that was obtained from the analysis of the fMRI recall data revealed a network of tracts including the hippocampal fornix, the inferior fronto-occipital fasciculus,

Please cite this article as: Salvan, P., et al., Road work on memory lane—Functional and structural alterations to the learning and memory circuit in adults born very preterm, NeuroImage (2014), http://dx.doi.org/10.1016/j.neuroimage.2013.12.031

P. Salvan et al. / NeuroImage xxx (2014) xxx–xxx

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Table 1 Neonatal, demographic and neuropsychological data of the study groups.

Gestational age (weeks), mean (SD) Birthweight (g), mean (SD) Age (y), mean (SD) Sex f (m) IQ, mean (SD)

Comparison group (n = 10)

Range (max–min)

Preterm group (n = 21)

Range (max–min)

t

Sig. (2-tailed)

39.33 (1.37) 3145 (558.35) 20.00 (1.91) 6 (4) 108.9 (13.178)

38–42 2490–3910 18–23

28.24 (2.28) 1244.95 (452.01) 20.85 (1.77) 10 (11) 99.86 (11.20)

24–32 552–2390 19–26

14.602 8.638 1.089 Chi-square 0.416 1.987

*0.02 *0.000 0.286 0.704 0.056

90–126

75–123

* = p b 0.05.

the inferior longitudinal fasciculus and the splenium of the corpus callosum (shown in blue in Fig. 2c). Skeleton-based voxelwise FA comparison TBSS analysis revealed no significant differences between preterm born individuals and controls when comparing FA values in the white matter tracts stemming from the right anterior cingulate gyrus/caudate region (in which between group differences were observed in the fMRI interaction analysis during encoding). However, when analyzing FA in the tracts stemming from the white matter between the posterior left hippocampus and left thalamus (the cluster in which between group differences were observed during recall), VPT-born adults displayed statistically significantly lower FA than controls in left hippocampal fornix, splenium of the corpus callosum, inferior longitudinal fasciculus and inferior fronto-occipital fasciculus (P b 0.05 Family-wise error corrected—see Table 3 and Fig. 2c). FA and gestational age in the VPT-group In the VPT-born group a significant correlation between FA and gestational age was found in the inferior fronto-occipital fasciculus/

inferior longitudinal fasciculus (p b 0.05, FWE-corrected), but not in the fornix or splenium of the corpus callosum (p N 0.05, FWEcorrected). On-line task performance, fMRI, DW-MRI results and gender We performed a series of analyses of variance to investigate possible main effects of gender, as well as the interaction between group (preterm born and control) and gender (males and females) in terms of on-line task performance (the number of correct responses in each recall block), mean SSQ values extracted from the fMRI analyses and mean FA values extracted from the significant regions found in the DW-MRI analysis combined. No statistically significant results were noted for any of these analyses. Discussion Several studies have documented structural and functional brain alterations following very preterm birth (Counsell et al., 2003; Constable et al., 2008; Nosarti et al., 2002, 2008; Skranes et al., 2007).

Fig. 1. Functional MRI results. a) The cluster that showed a significantly different pattern of activation across 4 encoding blocks is shown in orange. The blue cluster shows the regions that displayed a significantly different pattern of activation across 4 recall blocks. b) Coronal view of encoding cluster (orange) and the pattern of activation in that cluster across the 4 encoding blocks in both groups. c) Coronal view of the recall cluster (blue) and the pattern of activation in that cluster across the 4 recall blocks in both groups. Y-axis represents sum-of-squared ratio (SSQ) of BOLD-activation and X-axis represents the block number (for encoding and recall respectively).

Please cite this article as: Salvan, P., et al., Road work on memory lane—Functional and structural alterations to the learning and memory circuit in adults born very preterm, NeuroImage (2014), http://dx.doi.org/10.1016/j.neuroimage.2013.12.031

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Fig. 2. Probabilistic tractography results and significant FA differences between groups. a) Seed regions used for tractography. These were derived from fMRI clusters that differed between groups in pattern of activation across four blocks of encoding (orange) and recall (blue); b) and c) show the center of the tracts that were reconstructed from the clusters in a). These are the voxels in which statistical comparisons of between-group FA differences were performed. There were no regions of significantly different FA in the VPT group in the tracts connected to the orange cluster derived from the encoding task b). The red voxels in c) show the areas of significantly decreased FA in the VPT-born group compared to controls.

We aimed to analyze the patterns of functional adaptation and learning during a verbal paired associate learning task in VPT-born adults and controls and to discover what, if any, neuroanatomical differences could be associated with the hypothesized functional alterations. VPT-born participants and term-born controls differed in the pattern of functional activation across four blocks in both encoding of word pairs and in retrieval of previously presented words (when cued with that word's pair). fMRI and DW-MRI analysis of VPAL encoding network We found that VPT-born subjects showed a progressive increase in activation in an area encompassing the right ACC and parts of the right caudate and SFG during repeated presentation of the stimuli to be encoded. This sharply contrasted with the term-born group, which showed a decrease in activation in the same area while performing the same task (encoding blocks 1–4). The control group's progressive decrease in activation across blocks is a pattern that is often seen in fMRI tasks that require repeated performance of the same action (Larsson and Smith, 2012) and resembles a reduction in activation in domain-general cognitive and attentional areas often seen when learning takes place (Chein and Schneider, 2005; Kelly and Garavan, 2005). The increase in activation across the

blocks in the VPT-born group may be due to increasing cognitive effort required to perform the task at a control level. Anterior cingulate and right caudate are thought to be involved in suppression of undesired actions and activation in brain areas that may interfere with the language task at hand (Crosson et al., 2007; Moore et al., 2012; Price, 2012). An increase in activation in the VPT-born group as the task continues may represent the increasing effort required to maintain attention and concentration on the stimuli being processed at a given time and to suppress irrelevant thoughts and actions. We have previously found fronto-striatal functional alterations in VPT-born adolescents and young adults in other executive tasks (e.g. attention allocation and response inhibition) and in a verbal fluency task (Nosarti et al., 2006, 2009) and activation in these areas has been found to correlate with gestational age (Nosarti et al., 2009). Probabilistic tractography from the ACC/caudate cluster revealed direct connections to ipsilateral basal ganglia and inferior frontal gyrus, as well as to the pre-SMA region bilaterally. We found that there were no significant differences between groups in FA or probability of connection to the seed point within the tracts connecting to the ACC/caudate region. These results may then reflect a more general attention deficit in VPT-born adults rather than a specific white matter deficit in frontostriatal circuits important for the encoding of verbal paired associates.

Table 2 Significant between group differences in brain activation during encoding and recall conditions. Anatomical location

Hemisphere

Cluster size (in mm3)

Encoding condition Anterior cingulate, caudate and superior frontal gyrus

Right

35,669

Recall condition Posterior parahippocampal gyrus, posterior hippocampus and thalamus (pulvinar)

Left

37,807

p-Value

Cluster center of gravity in MNI space (mm) X

Y

Z

0.0039

22

12

27

0.0037

−19

−32

−4

Please cite this article as: Salvan, P., et al., Road work on memory lane—Functional and structural alterations to the learning and memory circuit in adults born very preterm, NeuroImage (2014), http://dx.doi.org/10.1016/j.neuroimage.2013.12.031

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Table 3 Index of clusters with significantly reduced FA in the VPT-born group. Anatomical location

Splenium of corpus callosum Fornix Posterior division inferior longitudinal fasciculus Posterior part inferior fronto-occipital fasciculus Posterior division inferior longitudinal fasciculus

Hemisphere

Left Left Left Left Left

fMRI and DW-MRI analysis of VPAL recall network When we probed the activation across the four blocks in which participants were asked to recall the paired associate of the word presented on the screen, we found that VPT-born adults and controls differed in activation in a posterior area encompassing parts of the left hippocampus, parahippocampal gyrus and the thalamus (mainly pulvinar). Controls had an increase in BOLD activation across the four blocks which contrasted significantly to a corresponding decrease of activation in the same area observed in VPT-born participants. The pattern of activation observed here for controls is consistent with activation observed in volunteers under placebo conditions studied by Bhattacharyya et al. (2009), who used the same fMRI task we administered and reported a gradual increase in activation across subsequent recall blocks in a large cluster with local maxima in left ventral striatum and anterior thalamus. These results could reflect a progressive increase in efficiency in selection of semantic associations between words, permitted by increased specialization of neural function in the retrieval process in a specific area (Gauthier et al., 1999). We previously reported an increased activation in left parahippocampal gyrus in VPT born young adults compared to controls during encoding of verbal paired associates (i.e. mean activation across blocks rather than across successive blocks as analyzed here) and interpreted the results as reflecting process of neuronal organization after early brain injury as participants with the youngest gestational age also showed the greatest increases in volume of left parahippocampal region, which was positively correlated with functional activation in the region (Lawrence et al., 2010). Probabilistic tractography from this region revealed white matter connections to prefrontal, occipital and temporal cortices, with the IFOF, inferior longitudinal fasciculus (ILF) and hippocampal fornix clearly defined parts of the network. Comparison between the two groups revealed that the VPT-born group had lower FA in the hippocampal fornix and the occipital white matter bundle through which the IFOF, ILF and optic radiations all pass (Fernandez-Miranda et al., 2008). A recent study of white matter alterations in psychotic disorders found that individuals with psychosis had lower FA in the left IFOF and left ILF than people at high risk of developing the disorder, who in turn had lower FA in these areas than controls (Carletti et al., 2012). Tract-specific FA (i.e., in the left IFOF/ILF) could therefore be investigated as a marker of risk for psychiatric disorders, which are known to be associated with altered neurodevelopment (Nosarti et al., 2012). The hippocampal fornix, IFOF the ILF connect occipital, prefrontal and subcortical structures to the hippocampus and medial temporal lobe and also link language-related areas of posterior temporal and posterior frontal lobe (Catani and Thiebaut de Schotten, 2008; Catani et al., 2003; Fernandez-Miranda et al., 2008). Although there is much controversy over the role of the hippocampus in such tasks (Staresina and Davachi, 2009), the prevailing view is that it is critical to successful retrieval of associative and episodic memories (Eldridge et al., 2000; Mayes et al., 2007) and interactions between the hippocampus and other areas involved in associative learning are likely to be crucial to successful performance of the task. The fornix carries a large amount of connections both to and from the hippocampal formation to the prefrontal cortex, anterior thalamus,

Cluster size (mm3)

768 307 201 179 98

p-Value

0.008 0.001 0.035 0.032 0.039

Cluster center of gravity in MNI space (mm) X

Y

Z

−25 −13 −36 −28 −35

−68 −28 −53 −66 −9

17 13 20 0.7 −10

ventral striatum, mammillary bodies and contralateral hippocampal formation (Catani et al., 2002; Vann et al., 2011). This tract has long been associated with episodic memory due to experimental lesion studies in rats and primates and studies in humans with amnesia (Aggleton and Brown, 1999, 2006). A recent case study described a patient with a selective lesion to the left fornix that resulted in a primary deficit in delayed recall, with verbal paired associate learning abilities particularly affected (Korematsu et al., 2010). A diffusion MRI tractography study on the relationship between frontotemporal white matter tracts and aging and episodic memory found that the indices of microstructure of the fornix and not other tracts such as the uncinate fasciculus and cingulum were strongly correlated with episodic memory abilities (Metzler-Baddeley et al., 2011). Precise multidimensional analysis of their data set concluded that microstructure of the fornix was particularly associated with verbal and visual recall abilities, with recognition less reliant on this tract (Metzler-Baddeley et al., 2011). Interestingly, the hippocampal/parahippocampal regions that, in this study, increased in activation across recall blocks are connected via the fornix (Vann et al., 2011) to the ventral striatal and anterior thalamic regions that increased in activation during the same task in Bhattacharyya et al. (2009, 2012). Regional functional differences in different subcortical and cortical areas may in fact all point to a progressive increase in activation of the hippocampal formation–fornix–anterior thalamus–prefrontal cortex recall network in control participants and the abnormal engagement of this network during learning in VPT-born adults (Aggleton and Brown, 1999, 2006). The ILF is thought to be crucial to object identification, discrimination and recognition (Schmahmann & Pandya, 2006; FernandezMiranda et al., 2008) and damage to this tract has been related to visual agnosia (Geschwind, 1965). As the words were presented visually in the verbal paired associate learning task we used, communication between the occipital lobe and the hippocampus is likely to be important for both encoding of new items and comparison of new stimuli with previously stored associative memories. Reduced FA in the ILF in the VPT-born group may require that group to use indirect occipito-hippocampal pathways to access stored verbal associative memories. The medial temporal lobe is also believed to modulate the processing of incoming visual information through the temporo-occipital connections of the ILF (Catani et al., 2003). As such, the hippocampus and/or parahippocampal structures could prime the occipital lobe for processing of recently presented stimuli. There is still much debate about the function of the inferior fronto-occipital fasciculus (Thiebaut de Schotten et al., 2012). It has been suggested that it may be required for conscious recall of learned memory associations (Thiebaut de Schotten et al., 2012; Tomita et al., 1999) and used for top-down modulation of incoming visual stimuli in order to allow for easier recognition and processing of items that are likely to be seen (Bar et al., 2006; Pins and Ffytche, 2003). Semantic paraphasias are induced in most patients in whom this bundle is stimulated intraoperatively (Duffau et al., 2009; Mandonnet et al., 2007) and it is thus likely that damage to this bundle would damage the ability to create semantic associations between words during encoding and to prime visual areas for processing of words in specific semantic categories through top-down connections from the prefrontal cortex.

Please cite this article as: Salvan, P., et al., Road work on memory lane—Functional and structural alterations to the learning and memory circuit in adults born very preterm, NeuroImage (2014), http://dx.doi.org/10.1016/j.neuroimage.2013.12.031

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It is possible that, as a result of learning through the repeated presentation of the same stimuli, controls participants make increasing use of hippocampal–thalamic prefrontal pathways and possibly topdown prefrontal–occipital and temporo-occipital pathways in order to facilitate recognition and recall of words pairs. These pathways may however be damaged or less developed in VPT-born adolescents due to the long term effects of preterm birth on white matter maturation (Anjari et al., 2007; Counsell et al., 2003). This hypothesis would explain the fMRI results showing an increase in activation in left hippocampal formation and parts of the thalamus that are thought to be specialized in semantic language functions in the control group (Llano, 2012), and a decrease in the VPT-born group as they seek alternative strategies for successful task completion (Kelly and Garavan, 2005). Analysis on gender moderation When possible gender-dependent effects were explored in relation to the functional and structural neuroimaging results, as well as to the behavioral scores, no significant gender effects were noted. Our results therefore are not consistent with the findings of other investigations, which reported gender differences in very preterm-born samples in FA in right anterior frontal fasciculus, splenium of corpus callosum and right posterior limb of internal capsule (Constable et al., 2008; Rose et al., 2009). A possible explanation for this discrepancy could be that the analysis performed in this study considered FA values extracted from a mask comprising all the significant regions found in the DWMRI analysis (left hippocampal fornix, splenium of corpus callosum, inferior longitudinal fasciculus and inferior fronto-occipital fasciculus). We cannot therefore exclude the possibility that a more detailed region-specific analysis would have revealed significant gender effects, and this will be the focus of future studies with larger samples. Regarding the fMRI data, as far as we are aware, there are no published studies to date suggesting significant effects of gender on BOLD signal in VPT populations associated with language processing and visual learning (Narberhaus et al., 2009; Peterson et al., 2002). Significance for the very preterm birth literature Aside from reductions in FA and volume in the cerebral white matter, alterations in gray matter volume have been reported in several cortical and subcortical regions in very preterm-born individuals in their second decade of life (Nosarti et al., 2008). Periventricular regions that are likely to be affected by perinatal hypoxia/ischemia are often found to have volumetric and functional differences in VPT-born subjects compared to controls (Allin et al., 2007; Nosarti et al., 2006, 2008). Reduction in hippocampal gray matter volume has been shown repeatedly, while the thalamus and its cortical connections are affected in both preterm and very preterm born populations at various ages (Boardman et al., 2006; Counsell et al., 2007; Gimenez et al., 2006; Nosarti et al., 2008). As a result of reduced gray matter volume in structures crucial for the successful storage and retrieval of associative memories and damage to the normal circuits that facilitate improved and quicker task response, VPT-born adults may be forced to recruit other circuits, which are normally involved in unrelated tasks in order to perform at a control level (Kelly and Garavan, 2005; Lawrence et al., 2010). Functional BOLD-activation differences have been found on various tasks involving VPT-born adolescents and adults (Gimenez et al., 2005; Kalpakidou et al., 2012; Nosarti et al., 2006, 2009), but we believe this is the first study to show that altered neuroanatomy in adults born preterm can affect their ability to adapt to task demands and adopt advantageous strategies as the structure of tasks becomes clear. Similar results have been found however when comparing controls and mild-cognitive impairment patients after repeated exposure to a verbal encoding and retrieval task (Belleville et al., 2011).

Better understanding of the neuroanatomical causes of learning difficulties experienced by individuals born VPT will allow for the development of focused neuroscience-based interventions and schooling, which have found success in other clinical groups (Berthier and Pulvermuller, 2011; Bradshaw et al., 2012; Wolf et al., 2006).

Limitations and conclusions The limitations of this study include the small size of the control group, and the resolution of the fMRI data. Another limitation is the fact that we are not able to obtain the direction of axonal information flow from our tractography data, thus our assertion of the role of topdown or bottom-up connections is entirely based on theoretical grounds. Preterm birth is associated with alterations in brain development, which may result in plastic reorganization of structure in response to early brain lesions, so that the end-state functional architecture of developmentally altered systems may be characterized by “different functional structures” (Thomas and Karmiloff-Smith, 2002). The modulation of fronto-striatal and hippocampal formation/ thalamic function during a verbal paired associate task in expreterm young adults may reflect the long-lasting effects of altered neurodevelopment, enabling the compromised individuals to maintain competent performance of specific learning tasks, at least when the cognitive load remains relatively low. The differential patterns of brain activation during a learning task observed in the VPT group could represent a long term effect of impaired white matter structures (fornix, IFOF and ILF) resulting in less exploitation of networks with highly specialized functions (such as the recall-fornix network and the semantic-IFOF network) during learning. A corollary of this is seen in the increasing activation in domain-general frontal ‘executive’ networks during encoding of semantic associations between words. Although in the current study we found no significant gender differences in fMRI and DW-MRI data, the possibility that gender may be at least partially influencing the results cannot be excluded, due to our limited sample size. Future studies using multimodal neuroimaging in VPT populations should be conducted with larger samples to further investigate the possible effects of gender, which have been shown in other structural neuroimaging studies (Reiss et al., 2004; Rose et al., 2009). This study contributes to the understanding of the relationship between brain function and structure following preterm birth with the identification of white matter microstructural alterations linked to functional differences during a verbal memory task, which were also directly associated with gestational age (i.e. significant correlation between FA and gestational age in inferior fronto-occipital fasciculus). These results could reflect the effect of adaptive plastic processes associated with high-order cognitive functions.

Acknowledgments The study was funded by the March of Dimes Birth Defects Foundation, USA (12-FY03-41) and the Health Foundation, UK (1206/ 2063). We would like to thank the NIHR Biomedical Research Centre for their continuing support. We would also like to thank Vincent Giampietro, Kie-Woo Nam and Thanomjit Phanichrat for the help with data analysis. Conflict of interest The authors report no conflicts of interest.

Please cite this article as: Salvan, P., et al., Road work on memory lane—Functional and structural alterations to the learning and memory circuit in adults born very preterm, NeuroImage (2014), http://dx.doi.org/10.1016/j.neuroimage.2013.12.031

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Please cite this article as: Salvan, P., et al., Road work on memory lane—Functional and structural alterations to the learning and memory circuit in adults born very preterm, NeuroImage (2014), http://dx.doi.org/10.1016/j.neuroimage.2013.12.031

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Please cite this article as: Salvan, P., et al., Road work on memory lane—Functional and structural alterations to the learning and memory circuit in adults born very preterm, NeuroImage (2014), http://dx.doi.org/10.1016/j.neuroimage.2013.12.031

Road work on memory lane--functional and structural alterations to the learning and memory circuit in adults born very preterm.

Very preterm (VPT) birth is considered a risk factor not only for neurological impairment, but also for reduced function in several cognitive domains ...
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