Using neuro-cognitive modelling to link attention deficits to structural and functional brain changes

‘Visual attention’ is an emerging property of interconnected neural networks, in which the interconnections are biased to promote targets over distracting stimuli. It has been shown that efficiency of the attention system is lost after many kinds of brain damage, with each presumably effecting different aspects of basic visual attention functions. Yet, our understanding of these processes is limited by the methodological shortcomings of classical neuropsychological assessment. The overarching goal of the current thesis was to overcome these constrains and thereby extend the link between attention deficits and underlying brain changes. The here used approach incorporates parametric measurement of visual attention derived from the computational Theory of Visual Attention (TVA, Bundesen, 1990) and modern magnetic resonance imaging techniques. Project 1 of the current thesis applied a combined TVA–neuroimaging analysis in a neurodevelopmental model (preterm birth) to relate attention deficits with changes in functional connectivity networks. We found that pre- versus full-term born adults show a selective reduction of visual short-term memory capacity. The remarkable changes we observed in attention-related large-scale brain networks of the occipital and posterior parietal cortices were most pronounced in those preterm born individuals with the most preserved attention functions. This finding was interpreted as evidence for a compensatory reorganization of functional connectivity in order to ameliorate the advert consequences of preterm birth on visual short-term memory. Project 2 of this thesis applied a combined TVA-neuroimaging analysis in a neurodegenerative model (posterior cortical atrophy) to relate attention deficits with structural changes in grey and white matter morphometry. Compared to healthy control participants, patients with posterior cortical atrophy suffered from a selective disturbance of visual processing speed. The individual rate of processing speed slowing was a valid predictor for the severity of simultanagnosia, the core symptom in this clinical condition. We further found wide-spread atrophy in occipital as well as parietal and to a smaller degree in temporal brain areas. White matter degeneration in the superior parietal lobe, rather than atrophy of any grey matter cluster, was significantly associated with patients’ impaired processing speed. Based on these results we propose that disruption of white matter pathways especially within the superior parietal lobe leads to reduced processing speed which then results in the overt clinical symptoms of simultanagnosia. Altogether, projects of the current thesis expanded the link between specific attention deficits and underlying brain damage by using neuro-cognitive modelling. We demonstrated that parametric measurements of attention facilitate, in the role of intermediate cognitive constructs, the mapping between etiological factors and behavioral outcomes. Identifying predictable behavior-brain relationships in attention disorders may offer new perspectives for diagnosis and treatment. The clinical application of an integrated TVA-neuroimaging analysis could additionally compliment insights from healthy participants toward understanding the principles of normal visual attention as well as identifying their neuronal basis

Impaired structural connectivity between dorsal attention network and pulvinar mediates the impact of premature birth on adult visual–spatial abilities

The dorsal attention network (DAN), including frontal eye fields and posterior parietal cortices, and its link with the posterior thalamus, contribute to visual–spatial abilities. Very premature birth impairs both visual–spatial abilities and cortico‐thalamic structural connectivity. We hypothesized that impaired structural DAN‐pulvinar connectivity mediates the effect of very premature birth on adult visual–spatial abilities. Seventy very premature (median age 26.6 years) and 57 mature born adults (median age 26.6 years) were assessed with cognitive tests and diffusion tensor imaging. Perceptual organization (PO) index of the Wechsler Adult Intelligence Scale‐III was used as a proxy for visual–spatial abilities, and connection probability maps in the thalamus, derived from probabilistic tractography from the DAN, were used as a proxy for DAN‐thalamic connectivity. Premature born adults showed decreases in both PO‐index and connection probability from DAN into the pulvinar, with both changes being positively correlated. Moreover, path analysis revealed that DAN‐pulvinar connectivity mediates the relationship between very premature birth and PO‐index. Results provide evidence for long‐term effects of very premature birth on structural DAN‐pulvinar connectivity, mediating the effect of prematurity on adult visual–spatial impairments. Data suggest DAN‐pulvinar connectivity as a specific target of prognostic and diagnostic procedures for visual–spatial abilities after premature birth

Using neuro-cognitive modelling to link attention deficits to structural and functional brain changes

‘Visual attention’ is an emerging property of interconnected neural networks, in which the interconnections are biased to promote targets over distracting stimuli. It has been shown that efficiency of the attention system is lost after many kinds of brain damage, with each presumably effecting different aspects of basic visual attention functions. Yet, our understanding of these processes is limited by the methodological shortcomings of classical neuropsychological assessment. The overarching goal of the current thesis was to overcome these constrains and thereby extend the link between attention deficits and underlying brain changes. The here used approach incorporates parametric measurement of visual attention derived from the computational Theory of Visual Attention (TVA, Bundesen, 1990) and modern magnetic resonance imaging techniques. Project 1 of the current thesis applied a combined TVA–neuroimaging analysis in a neurodevelopmental model (preterm birth) to relate attention deficits with changes in functional connectivity networks. We found that pre- versus full-term born adults show a selective reduction of visual short-term memory capacity. The remarkable changes we observed in attention-related large-scale brain networks of the occipital and posterior parietal cortices were most pronounced in those preterm born individuals with the most preserved attention functions. This finding was interpreted as evidence for a compensatory reorganization of functional connectivity in order to ameliorate the advert consequences of preterm birth on visual short-term memory. Project 2 of this thesis applied a combined TVA-neuroimaging analysis in a neurodegenerative model (posterior cortical atrophy) to relate attention deficits with structural changes in grey and white matter morphometry. Compared to healthy control participants, patients with posterior cortical atrophy suffered from a selective disturbance of visual processing speed. The individual rate of processing speed slowing was a valid predictor for the severity of simultanagnosia, the core symptom in this clinical condition. We further found wide-spread atrophy in occipital as well as parietal and to a smaller degree in temporal brain areas. White matter degeneration in the superior parietal lobe, rather than atrophy of any grey matter cluster, was significantly associated with patients’ impaired processing speed. Based on these results we propose that disruption of white matter pathways especially within the superior parietal lobe leads to reduced processing speed which then results in the overt clinical symptoms of simultanagnosia. Altogether, projects of the current thesis expanded the link between specific attention deficits and underlying brain damage by using neuro-cognitive modelling. We demonstrated that parametric measurements of attention facilitate, in the role of intermediate cognitive constructs, the mapping between etiological factors and behavioral outcomes. Identifying predictable behavior-brain relationships in attention disorders may offer new perspectives for diagnosis and treatment. The clinical application of an integrated TVA-neuroimaging analysis could additionally compliment insights from healthy participants toward understanding the principles of normal visual attention as well as identifying their neuronal basis

White matter alterations of the corticospinal tract in adults born very preterm and/or with very low birth weight

White matter (WM) injury, either visible on conventional magnetic resonance images (MRI) or measurable by diffusion tensor imaging (DTI), is frequent in preterm born individuals and often affects the corticospinal tract (CST). The relation between visible and invisible white mater alterations in the reconstructed CST of preterm subjects has so far been studied in infants, children and up to adolescence. Therefore, we probabilistically tracked the CST in 53 term-born and 56 very preterm and/or low birth weight (VP/VLBW, < 32 weeks of gestation and/or birth weight < 1,500 g) adults (mean age 26 years) and compared their DTI parameters (axial, radial, mean diffusivity—AD, RD, MD, fractional anisotropy—FA) in the whole CST and slice-wise along the CST. Additionally, we used the automatic, tract-based-spatial-statistics (TBSS) as an alternative to tractography. We compared control and VP/VLBW and subgroups with and without CST WM lesions visible on conventional MRI. Compared to controls, VP/VLBW subjects had significantly higher diffusivity (AD, RD, MD) in the whole CST, slice-wise along the CST, and in multiple regions along the TBSS skeleton. VP/VLBW subjects also had significantly lower (TBSS) and higher (tractography) FA in regions along the CST, but no different mean FA in the tracked CST as a whole. Diffusion changes were weaker, but remained significant for both, tractography and TBSS, when excluding subjects with visible CST lesions. Chronic CST injury persists in VP/VLBW adults even in the absence of visible WM lesions, indicating long-term structural WM changes induced by premature birth

Relationship between stereoscopic vision, visual perception, and microstructure changes of corpus callosum and occipital white matter in the 4-year-old very low birth weight children

Aim. To assess the relationship between stereoscopic vision, visual perception, and microstructure of the corpus callosum (CC) and occipital white matter, 61 children born with a mean birth weight of 1024 g (SD 270 g) were subjected to detailed ophthalmologic evaluation, Developmental Test of Visual Perception (DTVP-3), and diffusion tensor imaging (DTI) at the age of 4. Results. Abnormal stereoscopic vision was detected in 16 children. Children with abnormal stereoscopic vision had smaller CC (CC length: 53±6 mm versus 61±4 mm; p<0.01; estimated CC area: 314±106 mm2 versus 446±79 mm2; p<0.01) and lower fractional anisotropy (FA) values in CC (FA value of rostrum/genu: 0.7±0.09 versus 0.79±0.07; p<0.01; FA value of CC body: 0.74±0.13 versus 0.82±0.09; p=0.03). We found a significant correlation between DTVP-3 scores, CC size, and FA values in rostrum and body. This correlation was unrelated to retinopathy of prematurity. Conclusions. Visual perceptive dysfunction in ex-preterm children without major sequelae of prematurity depends on more subtle changes in the brain microstructure, including CC. Role of interhemispheric connections in visual perception might be more complex than previously anticipated

Univariate and multivariate pattern analysis of preterm subjects: a multimodal neuroimaging study

Background: Widespread lasting functional connectivity (FC) and brain volume changes in cortices and subcortices after premature birth have been researched in recent studies. However, the relationship remains unclear between spontaneously slow blood oxygen dependent level (BOLD) fluctuations and gray matter volume (GMV) changes in specific brain areas, such as temporal insular cortices, and whether classification methods based on MRI could be successfully applied to the identification of preterm individuals. In this thesis I hypothesized that in prematurely born adults 1. Ongoing neural excitability and brain activity, as estimated by regional functional connectivity of resting state functional MRI (rs-fMRI) is accompanied with altered low-frequency fluctuations and neonatal complications; 2. Altered regional functional connectivity is connected with superimposed cerebral structural reductions; and 3. multivariate neuroanatomical and functional brain patterns could be treated as features to identify preterm subjects from term subjects individually. Methods: To investigate these hypotheses, the principal results of structural alterations were measured with voxel-based morphometry (VBM), while rs-fMRI outcomes were estimated with amplitude of low-frequency fluctuations (ALFF) in analysis with ninety-four very preterm/very low birth weight (VP/VLBW) and ninety-two full-term (FT) born young adults. Results: The results of the thesis support the hypotheses by showing that, in univariate results, first in VP/VLBW grownups, ALFF was decreased in the left lateral temporal cortices no matter with global signal regression, and this reduction was closely associated with neonatal complications and cognitive variables. Second overlapped brain regions were found between reduced ALFF and reduced brain volumes in the left temporal cortices, and positively associated with each other, demonstrating a potential relationship between VBM and ALFF in this brain area. In multimodal multivariate pattern recognition analysis (MVPA), the gray matter volume (GMV) classifier displayed a higher accuracy (80.7%) contrast with the ALFF classifier (77.4%). The late fusion of GMV and ALFF did not outperform single GMV modality classification by reaching 80.4% accuracy. Moderator analysis from both rs-fMRI and structural MRI (sMRI) uncovered that the neuro-prematurity performance was predominantly determined by neonatal complications. Conclusions: In conclusion, these outcomes exhibit the long term effects of premature labour on lateral temporal cortices, which changed in both ongoing BOLD fluctuations and decreased cerebral structural volumes. This thesis further provided evidence that multivariate pattern analysis such as support vector machine (SVM) may identify imaging-based biomarkers and reliably detect signatures of preterm birth

Univariate and multivariate pattern analysis of preterm subjects: a multimodal neuroimaging study

Background: Widespread lasting functional connectivity (FC) and brain volume changes in cortices and subcortices after premature birth have been researched in recent studies. However, the relationship remains unclear between spontaneously slow blood oxygen dependent level (BOLD) fluctuations and gray matter volume (GMV) changes in specific brain areas, such as temporal insular cortices, and whether classification methods based on MRI could be successfully applied to the identification of preterm individuals. In this thesis I hypothesized that in prematurely born adults 1. Ongoing neural excitability and brain activity, as estimated by regional functional connectivity of resting state functional MRI (rs-fMRI) is accompanied with altered low-frequency fluctuations and neonatal complications; 2. Altered regional functional connectivity is connected with superimposed cerebral structural reductions; and 3. multivariate neuroanatomical and functional brain patterns could be treated as features to identify preterm subjects from term subjects individually. Methods: To investigate these hypotheses, the principal results of structural alterations were measured with voxel-based morphometry (VBM), while rs-fMRI outcomes were estimated with amplitude of low-frequency fluctuations (ALFF) in analysis with ninety-four very preterm/very low birth weight (VP/VLBW) and ninety-two full-term (FT) born young adults. Results: The results of the thesis support the hypotheses by showing that, in univariate results, first in VP/VLBW grownups, ALFF was decreased in the left lateral temporal cortices no matter with global signal regression, and this reduction was closely associated with neonatal complications and cognitive variables. Second overlapped brain regions were found between reduced ALFF and reduced brain volumes in the left temporal cortices, and positively associated with each other, demonstrating a potential relationship between VBM and ALFF in this brain area. In multimodal multivariate pattern recognition analysis (MVPA), the gray matter volume (GMV) classifier displayed a higher accuracy (80.7%) contrast with the ALFF classifier (77.4%). The late fusion of GMV and ALFF did not outperform single GMV modality classification by reaching 80.4% accuracy. Moderator analysis from both rs-fMRI and structural MRI (sMRI) uncovered that the neuro-prematurity performance was predominantly determined by neonatal complications. Conclusions: In conclusion, these outcomes exhibit the long term effects of premature labour on lateral temporal cortices, which changed in both ongoing BOLD fluctuations and decreased cerebral structural volumes. This thesis further provided evidence that multivariate pattern analysis such as support vector machine (SVM) may identify imaging-based biomarkers and reliably detect signatures of preterm birth

Automated quantitative evaluation of brain MRI may be more accurate for discriminating preterm born adults

Objective To investigate the structural brain abnormalities and their diagnostic accuracy through qualitative and quantitative analysis in term born and very preterm birth or with very low birth weight (VP/VLBW) adults. Methods We analyzed 3-T MRIs acquired in 2011–2013 from 67 adults (27 term born controls, mean age 26.4 years, 8 females; 40 VP/VLBWs, mean age 26.6 years, 16 females). We compared automatic segmentations of the white matter, deep gray matter and cortical gray matter, manual corpus callosum measurements and visual ratings of the ventricles and white matter with t tests, logistic regression, and receiver operator characteristic (ROC) curves. Results Automatic segmentation correctly classified 84% of cases; visual ratings correctly classified 63%. Quantitative volumetry based on automatic segmentation revealed higher ventricular volume, lower posterior corpus callosum, and deep gray matter volumes in VP/VLBW subjects compared to controls (p < 0.01). Visual rating and manual measurement revealed a thinner corpus callosum in VP/VLBW adults (p = 0.04) and deformed lateral ventricles (p = 0.03) and tendency towards more “dirty” white matter (p = 0.06). Automatic/manual measures combined with visual ratings correctly classified 87% of cases. Stepwise logistic regression identified three independent features that correctly classify 81% of cases: ventricular volume, deep gray matter volume, and white matter aspect. Conclusion Enlarged and deformed lateral ventricles, thinner corpus callosum, and “dirty” white matter are prevalent in preterm born adults. Their visual evaluation has low diagnostic accuracy. Automatic volume quantification is more accurate but time consuming. It may be useful to ask for prematurity before initiating further diagnostics in subjects with these alterations

A Multivariate Surface-Based Analysis of the Putamen in Premature Newborns: Regional Differences within the Ventral Striatum

Many children born preterm exhibit frontal executive dysfunction, behavioral problems including attentional deficit/hyperactivity disorder and attention related learning disabilities. Anomalies in regional specificity of cortico-striato-thalamo-cortical circuits may underlie deficits in these disorders. Nonspecific volumetric deficits of striatal structures have been documented in these subjects, but little is known about surface deformation in these structures. For the first time, here we found regional surface morphological differences in the preterm neonatal ventral striatum. We performed regional group comparisons of the surface anatomy of the striatum (putamen and globus pallidus) between 17 preterm and 19 term-born neonates at term-equivalent age. We reconstructed striatal surfaces from manually segmented brain magnetic resonance images and analyzed them using our in-house conformal mapping program. All surfaces were registered to a template with a new surface fluid registration method. Vertex-based statistical comparisons between the two groups were performed via four methods: univariate and multivariate tensor-based morphometry, the commonly used medial axis distance, and a combination of the last two statistics. We found statistically significant differences in regional morphology between the two groups that are consistent across statistics, but more extensive for multivariate measures. Differences were localized to the ventral aspect of the striatum. In particular, we found abnormalities in the preterm anterior/inferior putamen, which is interconnected with the medial orbital/prefrontal cortex and the midline thalamic nuclei including the medial dorsal nucleus and pulvinar. These findings support the hypothesis that the ventral striatum is vulnerable, within the cortico-stiato-thalamo-cortical neural circuitry, which may underlie the risk for long-term development of frontal executive dysfunction, attention deficit hyperactivity disorder and attention-related learning disabilities in preterm neonates. © 2013 Shi et al

Diffusion Tensor Imaging is associated with motor outcomes of very preterm born children at 11 years of age

Abstract Aim Very preterm children born less than 32 weeks of gestation are at risk for motor difficulties such as cerebral palsy and developmental coordination disorder. This study explores the association between diffusion tensor imaging metrics at term and motor outcomes at 11 years of age. Methods A cohort of 37 very preterm infants (mean gestational age 29 4/7, SD 2 0/7) born in 2004-2006 in Turku University Hospital underwent diffusion tensor imaging at term. A region-of-interest analysis of fractional anisotropy and mean diffusivity was performed. Motor outcomes at 11 years of age were measured with the Movement Assessment Battery for Children ? Second Edition. Results The diffusion metrics of the corpus callosum (genu p=0.005, splenium p=0.049), the left corona radiata (p=0.035) and the right optic radiation (p=0.017) were related to later motor performance. Mean diffusivity decreased and fractional anisotropy increased in proportion to the improving performance. Conclusion The diffusion metrics of the genu and splenium of the corpus callosum, the left corona radiata and the right optic radiation at term were associated with motor skills at 11 years of age. Diffusion tensor imaging should be further studied as a potential tool in recognising children at risk for motor impairment.Peer reviewe