While animal studies have demonstrated a unique reproduction-related neuroplasticity, little is known on the effects of pregnancy on the human brain. Here we investigated whether pregnancy is ...associated with changes to resting state brain activity, white matter microstructure, neural metabolite concentrations and grey matter architecture using a comprehensive pre-conception cohort study. We show that pregnancy leads to selective and robust changes in neural architecture and neural network organization, which are most pronounced in the Default Mode Network. These neural changes correlated with pregnancy hormones, primarily third-trimester estradiol, while no associations were found with other factors such as osmotic effects, stress and sleep. Furthermore, the changes related to measures of maternal-fetal bonding, nesting behavior and the physiological responsiveness to infant cues, and predicted measures of mother-infant bonding and bonding impairments. These findings suggest there are selective pregnancy-related modifications in brain structure and function that may facilitate peripartum maternal processes of key relevance to the mother-infant dyad.
Summary The mechanisms underlying the pathogenesis of multiple sclerosis induce the changes that underpin relapse-associated and progressive disability. Disease mechanisms can be investigated in ...preclinical models and patients with multiple sclerosis by molecular and metabolic imaging techniques. Many insights have been gained from such imaging studies: persisting inflammation in the absence of a damaged blood–brain barrier, activated microglia within and beyond lesions, increased mitochondrial activity after acute lesions, raised sodium concentrations in the brain, increased glutamate in acute lesions and normal-appearing white matter, different degrees of demyelination in different patients and lesions, early neuronal damage in grey matter, and early astrocytic proliferation and activation in lesions and white matter. Clinical translation of molecular and metabolic imaging and extension of these techniques will enable the assessment of novel drugs targeted at these disease mechanisms, and have the potential to improve health outcomes through the stratification of patients for treatments.
Grey matter atrophy is common in multiple sclerosis. However, in contrast with other neurodegenerative diseases, it is unclear whether grey matter atrophy in multiple sclerosis is a diffuse 'global' ...process or develops, instead, according to distinct anatomical patterns. Using source-based morphometry we searched for anatomical patterns of co-varying cortical thickness and assessed their relationships with white matter pathology, physical disability and cognitive functioning. Magnetic resonance imaging was performed at 3 T in 208 patients with long-standing multiple sclerosis (141 females; age = 53.7 ± 9.6 years; disease duration = 20.2 ± 7.1 years) and 60 age- and sex-matched healthy controls. Spatial independent component analysis was performed on cortical thickness maps derived from 3D T1-weighted images across all subjects to identify co-varying patterns. The loadings, which reflect the presence of each cortical thickness pattern in a subject, were compared between patients with multiple sclerosis and healthy controls with generalized linear models. Stepwise linear regression analyses were used to assess whether white matter pathology was associated with these loadings and to identify the cortical thickness patterns that predict measures of physical and cognitive dysfunction. Ten cortical thickness patterns were identified, of which six had significantly lower loadings in patients with multiple sclerosis than in controls: the largest loading differences corresponded to the pattern predominantly involving the bilateral temporal pole and entorhinal cortex, and the pattern involving the bilateral posterior cingulate cortex. In patients with multiple sclerosis, overall white matter lesion load was negatively associated with the loadings of these two patterns. The final model for physical dysfunction as measured with Expanded Disability Status Scale score (adjusted R(2) = 0.297; P < 0.001) included the predictors age, overall white matter lesion load, the loadings of two cortical thickness patterns (bilateral sensorimotor cortex and bilateral insula), and global cortical thickness. The final model predicting average cognition (adjusted R(2) = 0.469; P < 0.001) consisted of age, the loadings of two cortical thickness patterns (bilateral posterior cingulate cortex and bilateral temporal pole), overall white matter lesion load and normal-appearing white matter integrity. Although white matter pathology measures were part of the final clinical regression models, they explained limited incremental variance (to a maximum of 4%). Several cortical atrophy patterns relevant for multiple sclerosis were found. This suggests that cortical atrophy in multiple sclerosis occurs largely in a non-random manner and develops (at least partly) according to distinct anatomical patterns. In addition, these cortical atrophy patterns showed stronger associations with clinical (especially cognitive) dysfunction than global cortical atrophy.
Recent evidence suggests that cardiovascular fitness and gross motor skill performance are related to neurocognitive functioning by influencing brain structure and functioning. This study ...investigates the role of resting‐state networks (RSNs) in the relation of cardiovascular fitness and gross motor skills with neurocognitive functioning in healthy 8‐ to 11‐year‐old children (n = 90, 45 girls, 10% migration background). Cardiovascular fitness and gross motor skills were related to brain activity in RSNs. Furthermore, brain activity in RSNs mediated the relation of both cardiovascular fitness (Frontoparietal network and Somatomotor network) and gross motor skills (Somatomotor network) with neurocognitive functioning. The results indicate that brain functioning may contribute to the relation between both cardiovascular fitness and gross motor skills with neurocognitive functioning.
Aims/hypothesis
Glucagon-like peptide (GLP)-1-based therapies have been suggested to improve hepatic steatosis. We assessed the effects of the GLP-1 receptor agonist liraglutide and the dipeptidyl ...peptidase (DPP)-4 inhibitor sitagliptin on hepatic steatosis and fibrosis in patients with type 2 diabetes.
Methods
In this 12 week, parallel, randomised, placebo-controlled trial, performed at the VU University Medical Center between July 2013 and August 2015, 52 overweight patients with type 2 diabetes treated with metformin and/or sulphonylurea agent (mean ± SD age 62.7 ± 6.9 years, HbA
1c
7.3 ± 0.7% or 56 ± 1 mmol/mol) were allocated to once daily liraglutide 1.8 mg (
n
= 17), sitagliptin 100 mg (
n
= 18) or matching placebos (
n
= 17) by computer generated numbers. Both participants and researchers were blinded to group assignment. Hepatic fat content was measured using proton magnetic resonance spectroscopy (
1
H-MRS). Hepatic fibrosis was estimated using three validated formulae.
Results
One patient dropped out in the sitagliptin group owing to dizziness, but no serious adverse events occurred. At week 12, no between-group differences in hepatic steatosis were found. Liraglutide reduced steatosis by 10% (20.9 ± 3.4% to 18.8 ± 3.3%), sitagliptin reduced steatosis by 12.1% (23.9 ± 3.0% to 21.0 ± 2.7%) and placebo lessened it by 9.5% (18.7 ± 2.7% to 16.9 ± 2.7%). Neither drug affected hepatic fibrosis scores compared with placebo.
Conclusions/interpretation
Twelve-week liraglutide or sitagliptin treatment does not reduce hepatic steatosis or fibrosis in type 2 diabetes.
Trial registration
ClinicalTrials.gov NCT01744236
Funding
Funded by the European Community’s Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 282521 – the SAFEGUARD project.
Hypomyelinating leukodystrophies represent a genetically heterogeneous but clinically overlapping group of heritable disorders. Current management approaches in the care of the patient with a ...hypomyelinating leukodystrophy include use of serial magnetic resonance imaging (MRI) to establish and monitor hypomyelination, molecular diagnostics to determine a specific etiology, and equally importantly, careful attention to neurologic complications over time. Emerging research in oligodendrocyte biology and neuroradiology with bedside applications may result in the possibility of clinical trials in the near term, yet there are significant gaps in knowledge in disease classification, characterization, and outcome measures in this group of disorders. Here we review the biological background of myelination, the clinical and genetic variability in hypomyelinating leukodystrophies, and the insights that can be obtained from current MRI techniques. In addition, we discuss ongoing research approaches to define potential outcome markers for future clinical trials. Ann Neurol 2014;76:5–19
The success of epilepsy surgery in patients with refractory epilepsy depends upon correct identification of the epileptogenic zone (EZ) and an optimal choice of the resection area. In this study we ...developed individualized computational models based upon structural brain networks to explore the impact of different virtual resections on the propagation of seizures. The propagation of seizures was modelled as an epidemic process susceptible-infected-recovered (SIR) model on individual structural networks derived from presurgical diffusion tensor imaging in 19 patients. The candidate connections for the virtual resection were all connections from the clinically hypothesized EZ, from which the seizures were modelled to start, to other brain areas. As a computationally feasible surrogate for the SIR model, we also removed the connections that maximally reduced the eigenvector centrality (EC) (large values indicate network hubs) of the hypothesized EZ, with a large reduction meaning a large effect. The optimal combination of connections to be removed for a maximal effect were found using simulated annealing. For comparison, the same number of connections were removed randomly, or based on measures that quantify the importance of a node or connection within the network. We found that 90% of the effect (defined as reduction of EC of the hypothesized EZ) could already be obtained by removing substantially less than 90% of the connections. Thus, a smaller, optimized, virtual resection achieved almost the same effect as the actual surgery yet at a considerably smaller cost, sparing on average 27.49% (standard deviation: 4.65%) of the connections. Furthermore, the maximally effective connections linked the hypothesized EZ to hubs. Finally, the optimized resection was equally or more effective than removal based on structural network characteristics both regarding reducing the EC of the hypothesized EZ and seizure spreading. The approach of using reduced EC as a surrogate for simulating seizure propagation can suggest more restrictive resection strategies, whilst obtaining an almost optimal effect on reducing seizure propagation, by taking into account the unique topology of individual structural brain networks of patients.
To investigate whether extent and severity of white matter (WM) damage, as measured with diffusion tensor imaging (DTI), can distinguish cognitively preserved (CP) from cognitively impaired (CI) ...multiple sclerosis (MS) patients.
Conventional MRI and DTI data were acquired from 55 MS patients (35 CP, 20 CI) and 30 healthy controls (HC). Voxelwise analyses were used to investigate fractional anisotropy (FA), mean diffusivity, radial diffusivity, and axial diffusivity of a WM skeleton. Regional gray matter volume was quantified and lesion probability maps were generated.
Compared to HCs, decreased FA was found in 49% of the investigated WM skeleton in CP patients and in 76% of the investigated WM in CI patients. Several brain areas that showed reduced FA in both patient groups were significantly worse in CI patients, i.e, corpus callosum, superior and inferior longitudinal fasciculus, corticospinal tracts, forceps major, cingulum, and fornices. In CI patients, WM integrity damage was additionally seen in cortical brain areas, thalamus, uncinate fasciculus, brainstem, and cerebellum. These findings were independent of lesion location and regional gray matter volume, since no differences were found between the groups.
CI patients diverged from CP patients only on DTI metrics. WM integrity changes were found in areas that are highly relevant for cognition in the CI patients but not in the CP patients. These WM changes are therefore thought to be related to the cognitive deficits and suggest that DTI might be a powerful tool when monitoring cognitive impairment in MS.
To prospectively compare the depiction of intracortical lesions by using multislab three-dimensional (3D) double inversion-recovery (DIR), multislab 3D fluid-attenuated inversion-recovery (FLAIR), ...and T2-weighted spin-echo (SE) magnetic resonance (MR) imaging in patients with multiple sclerosis.
Local ethics review board approval and informed consent were obtained. Conventional T2-weighted SE and multislab 3D FLAIR and DIR images were acquired in 10 patients with multiple sclerosis (five women, five men) and 11 age-matched healthy control subjects (seven women, four men). Mean age was 40 years (range, 25-54 years) in patients and 34 years (range, 24-55 years) in control subjects. Lesions were classified according to seven anatomic regions: intracortical, mixed white matter-gray matter, juxtacortical, deep gray matter, periventricular white matter, deep white matter, and infratentorial lesions. The numbers of lesions per category were compared between techniques (Dunnett-corrected analysis of variance). Gain or loss (with 95% confidence intervals CIs) of numbers of lesions detected at 3D DIR imaging was calculated in comparison with those detected at T2-weighted SE and 3D FLAIR imaging.
Total number of lesions did not differ between 3D DIR and 3D FLAIR sequences, but the 3D DIR sequence showed a gain of 21% (95% CI: 4%, 41%) in comparison with the T2-weighted SE sequence. Because of high gray matter-white matter contrast, DIR images depicted more intracortical lesions (80 lesions in 10 patients) than both SE (10 lesions) and FLAIR (31 lesions) images; gains with DIR were 538% (95% CI: 191%, 1297%) and 152% (95% CI: 15%, 453%) compared with SE and FLAIR, respectively. Only four intracortical lesions were detected in control subjects. Also, DIR imaging enabled a better definition of mixed white matter-gray matter lesions because of greater contrast between the lesion and its surroundings.
MR imaging with 3D DIR enables increased intracortical lesion detection in the multiple sclerosis brain, as well as improved distinction between juxtacortical and white matter-gray matter lesions.
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