Henning Boecker

Extensive and interrelated subcortical white and gray matter alterations in preterm-born adults.

Preterm birth is a leading cause for impaired neurocognitive development with an increased risk for persistent cognitive deficits in adulthood. In newborns, preterm birth is associated with interrelated white matter (WM) alterations and deep gray matter (GM) loss; however, little is known about thexa0persistence and relevance of these subcortical brain changes. We tested the hypothesis that the pattern of correspondent subcortical WM and GM changes is present in preterm-born adults and has a brain-injury-like nature, i.e., it predicts lowered general cognitive performance. Eighty-five preterm-born and 69 matched term-born adults were assessed by diffusion- and T1-weighted MRI and cognitive testing. Main outcome measures were fractional anisotropy of water diffusion for WM property, GM volume for GM property, and full-scale IQ for cognitive performance. In preterm-born adults, reduced fractional anisotropy was widely distributed ranging from cerebellum to brainstem to hemispheres. GM volume was reduced in the thalamus, striatum, temporal cortices, and increased in the cingulate cortices. Fractional anisotropy reductions were specifically associated with GM loss in thalamus and striatum, with correlation patterns for both regions extensively overlapping in the WM of brainstem and hemispheres. For overlap regions, fractional anisotropy was positively related with both gestational age and full-scale IQ. Results provide evidence for extensive, interrelated, and adverse WM and GM subcortical changes in preterm-born adults. Data suggest persistent brain-injury-like changes of subcortical–cortical connectivity after preterm delivery.

Working memory in preterm-born adults: Load-dependent compensatory activity of the posterior default mode network

Premature birth is associated with an increased risk of cognitive performance deficits that are dependent on working memory (WM) load in childhood. Less clear is whether preterm‐born adults show similar WM impairments, or develop compensatory brain mechanisms that help to overcome prematurity‐related functional deficits, for example, by a workload‐dependent over‐recruitment of WM‐typical areas, and/or engagement of alternative brain networks. In this functional magnetic resonance imaging study, 73 adults born very preterm and/or with very low birth weight (VP/VLBW) and 73 term‐born controls (CON, mean age: 26.5 years) performed a verbal N‐Back paradigm with varying workload (0‐back, 1‐back, 2‐back). Generally, both groups showed similar performance accuracy and task‐typical patterns of brain activations (especially in fronto‐cingulo‐parietal, thalamic, and cerebellar areas) and deactivations (especially in mesial frontal and parietal aspects of the default mode network [DMN]). However, VP/VLBW adults showed significantly stronger deactivations (Pu2009<u20090.05, cluster‐level corrected) than CON in posterior DMN regions, including right ventral precuneus, and right parahippocampal areas (with adjacent cerebellar areas), which were specific for the most demanding 2‐back condition. Consistent with a workload‐dependent effect, VP/VLBW adults with stronger deactivations (1‐backu2009>u20092‐back) in the parahippocampal/cerebellar cluster also presented a greater slowing of response latencies with increasing WM load (2‐backu2009>u20091‐back), indicative of higher effort. In conclusion, VP/VLBW adults recruited similar anatomical networks as controls during N‐back performance, but showed an enhanced suppression of posterior DMN regions during higher workload, which may reflect a temporary suppression of stimulus‐independent thoughts that helps to maintain adequate task performance with increasing attentional demands. Hum Brain Mapp 36:1121–1137, 2015.

Visual attention in preterm born adults: Specifically impaired attentional sub-mechanisms that link with altered intrinsic brain networks in a compensation-like mode

Although pronounced and lasting deficits in selective attention have been observed for preterm born individuals it is unknown which specific attentional sub-mechanisms are affected and how they relate to brain networks. We used the computationally specified Theory of Visual Attention together with whole- and partial-report paradigms to compare attentional sub-mechanisms of pre- (n=33) and full-term (n=32) born adults. Resting-state fMRI was used to evaluate both between-group differences and inter-individual variance in changed functional connectivity of intrinsic brain networks relevant for visual attention. In preterm born adults, we found specific impairments of visual short-term memory (vSTM) storage capacity while other sub-mechanisms such as processing speed or attentional weighting were unchanged. Furthermore, changed functional connectivity was found in unimodal visual and supramodal attention-related intrinsic networks. Among preterm born adults, the individual pattern of changed connectivity in occipital and parietal cortices was systematically associated with vSTM in such a way that the more distinct the connectivity differences, the better the preterm adults storage capacity. These findings provide first evidence for selectively changed attentional sub-mechanisms in preterm born adults and their relation to altered intrinsic brain networks. In particular, data suggest that cortical changes in intrinsic functional connectivity may compensate adverse developmental consequences of prematurity on visual short-term storage capacity.

Neural correlates of executive attention in adults born very preterm

Very preterm birth is associated with an increased prevalence of attention problems and may especially impair executive attention, i.e., top-down control of attentional selection in situations where distracting information interferes with the processing of task-relevant stimuli. While there are initial findings linking structural brain alterations in preterm-born individuals with attention problems, the functional basis of these problems are not well understood. The present study used an fMRI adaptation of the Attentional Network Test to examine the neural correlates of executive attention in a large sample of N = 86 adults born very preterm and/or with very low birth weight (VP/VLBW), and N = 100 term-born controls. Executive attention was measured by comparing task behavior and brain activations associated with the processing of incongruent vs. congruent arrow flanker stimuli. Consistent with subtle impairments of executive attention, the VP/VLBW group showed lower accuracy and a tendency for increased response times during the processing of incongruent stimuli. Both groups showed similar activation patters, especially within expected fronto-cingulo-parietal areas, but no significant between-group differences. Our results argue for a maintained attention-relevant network organization in high-functioning preterm born adults in spite of subtle deficits in executive attention. Gestational age and neonatal treatment variables showed associations with task behavior, and brain activation in the dorsal ACC and lateral occipital areas, suggesting that the degree of prematurity (and related neonatal complications) has subtle modulatory influences on executive attention processing.

Reduced Cholinergic Basal Forebrain Integrity Links Neonatal Complications and Adult Cognitive Deficits After Premature Birth.

BACKGROUNDnPrematurely born individuals have an increased risk for long-term neurocognitive impairments. In animal models, development of the cholinergic basal forebrain (cBF) is selectively vulnerable to adverse effects of perinatal stressors, and impaired cBF integrity results in lasting cognitive deficits. We hypothesized that cBF integrity is impaired in prematurely born individuals and mediates adult cognitive impairments associated with prematurity.nnnMETHODSnWe used magnetic resonance imaging-based volumetric assessments of a cytoarchitectonically defined cBF region of interest to determine differences in cBF integrity between 99 adults who were born very preterm and/or with very low birth weight and 106 term-born control subjects from the same birth cohort. Magnetic resonance imaging-derived cBF volumes were studied in relation to neonatal clinical complications after delivery and intelligence measures (IQ) in adulthood.nnnRESULTSnIn adults who were born very preterm and/or with very low birth weight, cBF volumes were significantly reduced compared with term-born adults (-4.5% [F1,202 = 11.82, p = .001]). Lower cBF volume in adults who were born very preterm and/or with very low birth weight was specifically associated with both neonatal complications (rpart,92 = -.35, p < .001) and adult IQ (rpart,88 = .33, p = .001) even after controlling for global gray matter and white matter volume. In a path analytic model, cBF volume significantly mediated the association between neonatal complications and adult cognitive deficits.nnnCONCLUSIONSnWe provide first-time evidence in humans that cBF integrity is impaired after premature birth and links neonatal complications with long-term cognitive outcome. Data suggest that cholinergic system abnormalities may play a relevant role for long-term neurocognitive impairments associated with premature delivery.

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,u2009<u200932 weeks of gestation and/or birth weightu2009<u20091,500 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. Hum Brain Mapp 37:289–299, 2016.

The association of children’s mathematic abilities with both adults’ cognitive abilities and intrinsic fronto-parietal networks is altered in preterm-born individuals

Mathematic abilities in childhood are highly predictive for long-term neurocognitive outcomes. Preterm-born individuals have an increased risk for both persistent cognitive impairments and long-term changes in macroscopic brain organization. We hypothesized that the association of childhood mathematic abilities with both adulthood general cognitive abilities and associated fronto-parietal intrinsic networks is altered after preterm delivery. 72 preterm- and 71 term-born individuals underwent standardized mathematic and IQ testing at 8xa0years and resting-state fMRI and full-scale IQ testing at 26xa0years of age. Outcome measure for intrinsic networks was intrinsic functional connectivity (iFC). Controlling for IQ at age eight, mathematic abilities in childhood were significantly stronger positively associated with adults’ IQ in preterm compared with term-born individuals. In preterm-born individuals, the association of children’s mathematic abilities and adults’ fronto-parietal iFC was altered. Likewise, fronto-parietal iFC was distinctively linked with preterm- and term-born adults’ IQ. Results provide evidence that preterm birth alters the link of mathematic abilities in childhood and general cognitive abilities and fronto-parietal intrinsic networks in adulthood. Data suggest a distinct functional role of intrinsic fronto-parietal networks for preterm individuals with respect to mathematic abilities and that these networks together with associated children’s mathematic abilities may represent potential neurocognitive targets for early intervention.

Neuroimaging findings related to behavioral disturbances in Alzheimer's disease: a systematic review.

BACKGROUNDnBehavioral and psychological symptoms of dementia (BPSD) associated with Alzheimers Disease (AD) have been linked to structural and functional alterations in fronto-temporal circuits and cortical abnormalities. However, little is known on how specific volumetric and functional brain changes may be associated with the frequency, severity and pattern of BPSD.nnnMETHODSnA systematic review of the literature regarding neuroimaging and BPSD changes in AD was performed through Pubmed/Medline, ISI, and EMBASE electronic databases from January 2000 to May 2015. Eligible references (n=40) included clinical studies in which structural or functional neuroimaging assessment was performed in AD subjects presenting BPSD features.nnnRESULTSnBPSD symptoms, particularly apathy and psychosis have been associated in most of studies with either volume reductions or decreased metabolism in the prefrontal cortex (orbital and dorsolateral portions), anterior cingulate, insula and temporal lobes (middle portion). WM lacunes associated with AD progression have been associated with depressive symptoms.nnnCONCLUSIONnThe sum of evidence highlights the importance of BPSD-related imaging findings for the understanding of the non-cognitive symptom spectrum in AD. Results suggest that structural and functional changes in fronto-limbic areas may lead to emotional deregulation and symptom unawareness. As these findings may be present early on the AD clinical course, they may have a relevance for the development of imaging markers that could be used in diagnosis, disease monitoring and prediction of therapeutic response.

Decreased BOLD fluctuations in lateral temporal cortices of premature born adults

Lasting volume reductions in subcortical and temporal‐insular cortices after premature birth suggest altered ongoing activity in these areas. We hypothesized altered fluctuations in ongoing neural excitability and activity, as measured by slowly fluctuating blood oxygenation of resting‐state functional MRI (rs‐fMRI), in premature born adults, with altered fluctuations being linked with underlying brain volume reductions. To investigate this hypothesis, 94 very preterm/very low birth weight (VP/VLBW) and 92 full‐term born young adults underwent structural and rs‐fMRI data acquisition with voxel‐based morphometry and amplitude of low‐frequency fluctuations (ALFF) as main outcome measure. In VP/VLBW adults, ALFF was reduced in lateral temporal cortices, and this reduction was positively associated with lower birth weight. Regions of reduced ALFF overlapped with reduced brain volume. On the one hand, ALFF reduction remained after controlling for volume loss, supporting the functional nature of ALFF reductions. On the other hand, ALFF decreases were positively associated with underlying brain volume loss, indicating a relation between structural and functional changes. Furthermore, within the VP/VLBW group, reduced ALFF was associated with reduced IQ, indicating the behavioral relevance of ALFF decreases in temporal cortices. These results demonstrate long‐term impact of premature birth on ongoing BOLD fluctuations in lateral temporal cortices, which are linked with brain volume reductions. Data suggest permanently reduced fluctuations in ongoing neural excitability and activity in structurally altered lateral temporal cortices after premature birth.

P118. White matter macro- and microstructure alterations in preterm born adults

Introduction White matter (WM) injury, both macroscopic (visible on conventional MRI) and microscopic (detectable by diffusion tensor imaging, DTI) is frequent among preterm born infants investigated in later life ( Volpe, 2009 ). Degree and localization vary, but the corticospinal tract (CST) is often affected ( Eikenes et al., 2011 ). The relation between the micro- and macroscopic CST alterations has only been studied to our knowledge up to adolescence ( Bassi et al., 2011 , Estep et al., 2014 , Groeschel et al., 2014 ) but not in adults. We aimed to assess group differences in micro- and macroscopic WM integrity of the CST between preterm and full-term born adults and to evaluate the impact of macroscopic lesions onto the DTI parameters in and along the CST. Methods As part of a prospective study of preterm birth (Bavarian Longitudinal Study), we investigated adults at 26xa0years of age by means of MRI. Artifact-free DTI data were available from 51 full-term and 55 preterm born subjects ( Giorgio et al., 2010 ) and extracted DTI parameters (mean, axial, radial diffusivity - MD, AD, RD, and fractional anisotropy, FA) in the CST and slice-wise along the CST. On FLAIR-MRI images we identified macroscopic WM lesions as hyperintensities, noted their relation to the CST and correlated their presence with the DTI. Results and discussion WM hyperintensities, periventricular or in the corona radiata, were present in 9 of 51 (18%) full-term and 26 of 55 (47%) preterm born subjects. In 3 of 51 (6%) full-term and 17 of 55 (30%) preterm born subjects these ”lesions” affected the CST. Compared to full-term individuals, the preterm born subjects had significantly higher diffusivity (MD, AD, RD) in and along the CST but no difference in FA. These changes were weaker, but nevertheless remained significant when excluding subjects with macroscopic lesions. This suggests chronic CST injury with increased tissue water content ( Aung et al., 2013 ) even in the absence of visible WM lesions and points towards a high susceptibility of the CST after preterm birth.