An analysis of MRI derived cortical complexity in premature-born adults : regional patterns, risk factors, and potential significance

Premature birth bears an increased risk for aberrant brain development concerning its structure and function. Cortical complexity (CC) expresses the fractal dimension of the brain surface and changes during neurodevelopment. We hypothesized that CC is altered after premature birth and associated with long-term cognitive development. One-hundred-and-one very premature-born adults (gestational age <32 weeks and/or birth weight <1500 ​g) and 111 term-born adults were assessed by structural MRI and cognitive testing at 26 years of age. CC was measured based on MRI by vertex-wise estimation of fractal dimension. Cognitive performance was measured based on Griffiths-Mental-Development-Scale (at 20 months) and Wechsler-Adult-Intelligence-Scales (at 26 years). In premature-born adults, CC was decreased bilaterally in large lateral temporal and medial parietal clusters. Decreased CC was associated with lower gestational age and birth weight. Furthermore, decreased CC in the medial parietal cortices was linked with reduced full-scale IQ of premature-born adults and mediated the association between cognitive development at 20 months and IQ in adulthood. Results demonstrate that CC is reduced in very premature-born adults in temporoparietal cortices, mediating the impact of prematurity on impaired cognitive development. These data indicate functionally relevant long-term alterations in the brain’s basic geometry of cortical organization in prematurity

Sequelae of premature birth in young adults

Background and Purpose Qualitative studies about the abnormalities appreciated on routine magnetic resonance imaging (MRI) sequences in prematurely born adults are lacking. This article aimed at filling this knowledge gap by (1) qualitatively describing routine imaging findings in prematurely born adults, (2) evaluating measures for routine image interpretation and (3) investigating the impact of perinatal variables related to premature birth. Methods In this study two board-certified radiologists assessed T1-weighted and FLAIR-weighted images of 100 prematurely born adults born very preterm (VP <32 weeks) and/or at very low birth weight (VLBW <1500 g) and 106 controls born at full term (FT) (mean age 26.8 ± 0.7 years). The number of white matter lesions (WML) was counted according to localization. Lateral ventricle volume (LVV) was evaluated subjectively and by measurements of Evans’ index (EI) and frontal-occipital-horn ratio (FOHR). Freesurfer-based volumetry served as reference standard. Miscellaneous incidental findings were noted as free text. Results The LVV was increased in 24.7% of VP/VLBW individuals and significantly larger than in FT controls. This was best identified by measurement of FOHR (AUC = 0.928). Ventricular enlargement was predicted by low gestational age (odds ratio: 0.71, 95% CI 0.51–0.98) and presence of neonatal intracranial hemorrhage (odds ratio: 0.26, 95% CI 0.07–0.92). The numbers of deep and periventricular WML were increased while subcortical WMLs were not. Conclusion Enlargement of the LVV and deep and periventricular WMLs are typical sequelae of premature birth that can be appreciated on routine brain MRI. To increase sensitivity of abnormal LVV detection, measurement of FOHR seems feasible in clinical practice

Neurometabolic correlates of depression and disability in episodic cluster headache

A close association between pain, depression and disability has been shown. However, the neurometabolic correlates of this association have been barely investigated in disease states. Episodic cluster headache is a severe headache syndrome and represents a suitable disease model for the investigation of episodic pain. The aim of this study was to explore the relationship between depression and disability as well as pain scores and brain metabolism in patients with cluster headache during the disease period with repetitive pain attacks, but outside an acute attack. Thirteen patients with cluster headache underwent 2-[fluorine-18]-fluoro-2-deoxy-d-glucose positron emission (FDG-PET) and completed questionnaires on depression and disability as well as a pain visual analogue rating scale (VAS). A positive correlation between the depression scores and glucose metabolism was observed in the insular cortex. A positive correlation between the pain disability scores and brain metabolism was detected in the amygdala. The same applied to the pain visual analogue rating scores. Our data underline the association between severe episodic pain, depression and disability. In addition to this clinical observation, our results stress the importance of the insula and amygdala in pain processing and suffering

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 restingstate 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 rsfMRI 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

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 8 years and resting-state fMRI and full-scale IQ testing at 26 years 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

Results from the DELCODE study

Previous studies have demonstrated increased tau plasma levels in patients with Alzheimer’s disease (AD) and mild cognitive impairment (MCI) due to AD. Much less is known whether increased tau plasma levels can already be detected in the pre-MCI stage of subjective cognitive decline (SCD). In the present study we measured tau plasma levels in 111 SCD patients and 134 age- and gender-matched cognitively healthy controls participating in the DZNE (German Center for Neurodegenerative Diseases) longitudinal study on cognition and dementia (DELCODE). Tau plasma levels were measured using ultra-sensitive, single-molecule array (Simoa) technology. We found no significant different tau plasma levels in SCD (3.4 pg/ml) compared with healthy controls (3.6 pg/ml) after controlling for age, gender, and education (p = 0.137). In addition, tau plasma levels did not correlate with Aβ42 (r = 0.073; p = 0.634), tau (r = −0.179; p = 0.240), and p-tau181 (r = −0.208; p = 0.171) cerebrospinal fluid (CSF) levels in a subgroup of 45 SCD patients with available CSF. In conclusion, plasma tau is not increased in SCD patients. In addition, the lack of correlation between tau in plasma and CSF in the examined cohort suggests that tau levels are affected by different factors in both biofluids

Results from the DELCODE study

Previous studies have demonstrated increased tau plasma levels in patients with Alzheimer’s disease (AD) and mild cognitive impairment (MCI) due to AD. Much less is known whether increased tau plasma levels can already be detected in the pre-MCI stage of subjective cognitive decline (SCD). In the present study we measured tau plasma levels in 111 SCD patients and 134 age- and gender-matched cognitively healthy controls participating in the DZNE (German Center for Neurodegenerative Diseases) longitudinal study on cognition and dementia (DELCODE). Tau plasma levels were measured using ultra-sensitive, single-molecule array (Simoa) technology. We found no significant different tau plasma levels in SCD (3.4 pg/ml) compared with healthy controls (3.6 pg/ml) after controlling for age, gender, and education (p = 0.137). In addition, tau plasma levels did not correlate with Aβ42 (r = 0.073; p = 0.634), tau (r = −0.179; p = 0.240), and p-tau181 (r = −0.208; p = 0.171) cerebrospinal fluid (CSF) levels in a subgroup of 45 SCD patients with available CSF. In conclusion, plasma tau is not increased in SCD patients. In addition, the lack of correlation between tau in plasma and CSF in the examined cohort suggests that tau levels are affected by different factors in both biofluids

Inter-ictal assay of peripheral circulating inflammatory mediators in migraine patients under adjunctive cervical non-invasive vagus nerve stimulation (nVNS) : A proof-of-concept study

Objective: To assay peripheral inter-ictal cytokine serum levels and possible relations with non-invasive vagus nerve stimulation (nVNS) responsiveness in migraineurs. Methods: This double-blinded, sham-controlled study enrolled 48 subjects and measured headache severity, frequency [headache days/month, number of total and mild/moderate/severe classified attacks/month], functional state [sleep, mood, body weight, migraine-associated disability] and serum levels of inflammatory markers [inter-ictal] using enzyme-linked immunoassays at baseline and after 2 months of adjunctive nVNS compared to sham stimulation and suitably matched controls. Results: No significant differences were observed at baseline and after 2 months for headache severity, total attacks/month, headache days/month and functional outcome [sleep, mood, disability] between verum and sham nVNS. However, the number of severe attacks/month significantly decreased in the verum nVNS group and circulating pro-inflammatory IL-1 beta was elevated significantly in the sham group compared to nVNS. Levels of anti-inflammatory IL-10 were significantly higher at baseline in both groups compared to healthy controls, but not at 2 months follow-up [p 0.05]. No severe device-/stimulation-related adverse events occurred. Conclusion: 2 months of adjunctive cervical nVNS significantly declined the number of severe attacks/month. Pro-inflammatory IL-1 beta plasma levels [inter-ictal] were higher in sham-treated migraine patients compared to verum nVNS. However, pro- [IL-6, HMGB-1, TNF-alpha, leptin] and anti-inflammatory [IL-10, adiponectin, ghrelin] mediators did not differ statistically. Profiling of neuroinflammatory circuits in migraine to predict nVNS responsiveness remains an experimental approach, which may be biased by pre-analytic variables warranting large-scale biobank-based systematic investigations [omics]. (C) 2019 Elsevier Inc. All rights reserved.Peer reviewe

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

Reduced cholinergic basal forebrain integrity links neonatal complications and adult cognitive deficits after premature birth

Background Premature-born individuals have an increased risk for long-term neurocognitive impairments. In animal models, the 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 in premature-born individuals cBF integrity is impaired and mediates adult cognitive impairments associated with prematurity. Methods We used MRI-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 (VP/VLBW) and 106 term born controls from the same birth cohort. MRI-derived cBF volumes were studied in relation to neonatal clinical complications after delivery as well as intelligence measures (IQ) in adulthood. Results In VP/VLBW adults, cBF volumes were significantly reduced compared to term-born adults (-4.5%, F(1, 202) = 11.82, p = 0.001). Lower cBF volume in VP/VLBW adults was specifically associated with both neonatal complications (rpart(92) = -0.35, p < 0.001) and adult IQ (rpart(88) = 0.33, p = 0.001) even after controlling for global gray matter and white matter volume. In an additional path analytic model, cBF volume significantly mediated the association between neonatal complications and adult cognitive deficits. Conclusions Results 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