text:
@article{van_veenendaal_chronic_2017,
	title = {Chronic antiepileptic drug use and functional network efficiency: {A} functional magnetic resonance imaging study},
	volume = {9},
	copyright = {CC0 1.0 Universal Public Domain Dedication},
	issn = {1949-8470},
	doi = {10.4329/wjr.v9.i6.287},
	abstract = {AIM: To increase our insight in the neuronal mechanisms underlying cognitive side-effects of antiepileptic drug (AED) treatment.
METHODS: The relation between functional magnetic resonance-acquired brain network measures, AED use, and cognitive function was investigated. Three groups of patients with epilepsy with a different risk profile for developing cognitive side effects were included: A "low risk" category (lamotrigine or levetiracetam, n = 16), an "intermediate risk" category (carbamazepine, oxcarbazepine, phenytoin, or valproate, n = 34) and a "high risk" category (topiramate, n = 5). Brain connectivity was assessed using resting state functional magnetic resonance imaging and graph theoretical network analysis. The Computerized Visual Searching Task was used to measure central information processing speed, a common cognitive side effect of AED treatment.
RESULTS: Central information processing speed was lower in patients taking AEDs from the intermediate and high risk categories, compared with patients from the low risk category. The effect of risk category on global efficiency was significant (P {\textless} 0.05, ANCOVA), with a significantly higher global efficiency for patient from the low category compared with the high risk category (P {\textless} 0.05, post-hoc test). Risk category had no significant effect on the clustering coefficient (ANCOVA, P {\textgreater} 0.2). Also no significant associations between information processing speed and global efficiency or the clustering coefficient (linear regression analysis, P {\textgreater} 0.15) were observed.
CONCLUSION: Only the four patients taking topiramate show aberrant network measures, suggesting that alterations in functional brain network organization may be only subtle and measureable in patients with more severe cognitive side effects.},
	language = {eng},
	number = {6},
	journal = {World Journal of Radiology},
	author = {van Veenendaal, Tamar M. and IJff, Dominique M. and Aldenkamp, Albert P. and Lazeron, Richard H. C. and Hofman, Paul A. M. and de Louw, Anton J. A. and Backes, Walter H. and Jansen, Jacobus F. A.},
	month = jun,
	year = {2017},
	pmid = {28717415},
	pmcid = {PMC5491656},
	keywords = {Antiepileptic drugs, Brain networks, Cognitive side effects, Functional magnetic resonance imaging, Graph analysis, Resting state},
	pages = {287--294}
}

@article{mikkelsen_big_2017,
	title = {Big {GABA}: {Edited} {MR} spectroscopy at 24 research sites},
	volume = {159},
	copyright = {CC0 1.0 Universal Public Domain Dedication},
	issn = {1095-9572},
	doi = {10.1016/j.neuroimage.2017.07.021},
	abstract = {Magnetic resonance spectroscopy (MRS) is the only biomedical imaging method that can noninvasively detect endogenous signals from the neurotransmitter γ-aminobutyric acid (GABA) in the human brain. Its increasing popularity has been aided by improvements in scanner hardware and acquisition methodology, as well as by broader access to pulse sequences that can selectively detect GABA, in particular J-difference spectral editing sequences. Nevertheless, implementations of GABA-edited MRS remain diverse across research sites, making comparisons between studies challenging. This large-scale multi-vendor, multi-site study seeks to better understand the factors that impact measurement outcomes of GABA-edited MRS. An international consortium of 24 research sites was formed. Data from 272 healthy adults were acquired on scanners from the three major MRI vendors and analyzed using the Gannet processing pipeline. MRS data were acquired in the medial parietal lobe with standard GABA+ and macromolecule- (MM-) suppressed GABA editing. The coefficient of variation across the entire cohort was 12\% for GABA+ measurements and 28\% for MM-suppressed GABA measurements. A multilevel analysis revealed that most of the variance (72\%) in the GABA+ data was accounted for by differences between participants within-site, while site-level differences accounted for comparatively more variance (20\%) than vendor-level differences (8\%). For MM-suppressed GABA data, the variance was distributed equally between site- (50\%) and participant-level (50\%) differences. The findings show that GABA+ measurements exhibit strong agreement when implemented with a standard protocol. There is, however, increased variability for MM-suppressed GABA measurements that is attributed in part to differences in site-to-site data acquisition. This study's protocol establishes a framework for future methodological standardization of GABA-edited MRS, while the results provide valuable benchmarks for the MRS community.},
	language = {eng},
	journal = {NeuroImage},
	author = {Mikkelsen, Mark and Barker, Peter B. and Bhattacharyya, Pallab K. and Brix, Maiken K. and Buur, Pieter F. and Cecil, Kim M. and Chan, Kimberly L. and Chen, David Y.-T. and Craven, Alexander R. and Cuypers, Koen and Dacko, Michael and Duncan, Niall W. and Dydak, Ulrike and Edmondson, David A. and Ende, Gabriele and Ersland, Lars and Gao, Fei and Greenhouse, Ian and Harris, Ashley D. and He, Naying and Heba, Stefanie and Hoggard, Nigel and Hsu, Tun-Wei and Jansen, Jacobus F. A. and Kangarlu, Alayar and Lange, Thomas and Lebel, R. Marc and Li, Yan and Lin, Chien-Yuan E. and Liou, Jy-Kang and Lirng, Jiing-Feng and Liu, Feng and Ma, Ruoyun and Maes, Celine and Moreno-Ortega, Marta and Murray, Scott O. and Noah, Sean and Noeske, Ralph and Noseworthy, Michael D. and Oeltzschner, Georg and Prisciandaro, James J. and Puts, Nicolaas A. J. and Roberts, Timothy P. L. and Sack, Markus and Sailasuta, Napapon and Saleh, Muhammad G. and Schallmo, Michael-Paul and Simard, Nicholas and Swinnen, Stephan P. and Tegenthoff, Martin and Truong, Peter and Wang, Guangbin and Wilkinson, Iain D. and Wittsack, Hans-Jörg and Xu, Hongmin and Yan, Fuhua and Zhang, Chencheng and Zipunnikov, Vadim and Zöllner, Helge J. and Edden, Richard A. E.},
	month = jul,
	year = {2017},
	pmid = {28716717},
	keywords = {Editing, GABA, MEGA-PRESS, MRS, Multi-site study},
	pages = {32--45}
}

@article{freeze_pericortical_2017,
	title = {Pericortical {Enhancement} on {Delayed} {Postgadolinium} {Fluid}-{Attenuated} {Inversion} {Recovery} {Images} in {Normal} {Aging}, {Mild} {Cognitive} {Impairment}, and {Alzheimer} {Disease}},
	copyright = {CC0 1.0 Universal Public Domain Dedication},
	issn = {1936-959X},
	doi = {10.3174/ajnr.A5273},
	abstract = {BACKGROUND AND PURPOSE: Breakdown of BBB integrity occurs in dementia and may lead to neurodegeneration and cognitive decline. We assessed whether extravasation of gadolinium chelate could be visualized on delayed postcontrast FLAIR images in older individuals with and without cognitive impairment.
MATERIALS AND METHODS: Seventy-four individuals participated in this study (15 with Alzheimer disease, 33 with mild cognitive impairment, and 26 with normal cognition). We assessed the appearance of pericortical enhancement after contrast administration, MR imaging markers of cerebrovascular damage, and medial temporal lobe atrophy. Three participants who were positive for pericortical enhancement (1 with normal cognition and 2 with mild cognitive impairment) were followed up for approximately 2 years. In vitro experiments with a range of gadolinium concentrations served to elucidate the mechanisms underlying the postcontrast FLAIR signals.
RESULTS: Postcontrast pericortical enhancement was observed in 21 participants (28\%), including 6 individuals with Alzheimer disease (40\%), 10 with mild cognitive impairment (30\%), and 5 with normal cognition (19\%). Pericortical enhancement was positively associated with age (P {\textless} .02) and ischemic stroke (P {\textless} .05), but not with cognitive status (P = .3). Foci with enhanced signal remained stable across time in all follow-up cases. The in vitro measurements confirmed that FLAIR imaging is highly sensitive for the detection of low gadolinium concentrations in CSF, but not in cerebral tissue.
CONCLUSIONS: Postcontrast pericortical enhancement on FLAIR images occurs in older individuals with normal cognition, mild cognitive impairment, and dementia. It may represent chronic focal superficial BBB leakage. Future longitudinal studies are needed to determine its clinical significance.},
	language = {eng},
	journal = {AJNR. American journal of neuroradiology},
	author = {Freeze, W. M. and Schnerr, R. S. and Palm, W. M. and Jansen, J. F. and Jacobs, H. I. and Hoff, E. I. and Verhey, F. R. and Backes, W. H.},
	month = jul,
	year = {2017},
	pmid = {28684457}
}

@article{van_de_haar_subtle_2017,
	title = {Subtle blood-brain barrier leakage rate and spatial extent: {Considerations} for dynamic contrast-enhanced {MRI}},
	volume = {44},
	copyright = {CC0 1.0 Universal Public Domain Dedication},
	issn = {2473-4209},
	doi = {10.1002/mp.12328},
	abstract = {PURPOSE: Dynamic contrast-enhanced (DCE) MRI can be used to measure blood-brain barrier (BBB) leakage. In neurodegenerative disorders such as small vessel disease and dementia, the leakage can be very subtle and the corresponding signal can be rather noisy. For these reasons, an optimized DCE-MRI measurement and study design is required. To this end, a new measure indicative of the spatial extent of leakage is introduced and the effects of scan time and sample size are explored.
METHODS: Dual-time resolution DCE-MRI was performed in 16 patients with early Alzheimer's disease (AD) and 17 healthy controls. The leakage rate (Ki ) and volume fraction of detectable leaking tissue (vL ) to quantify the spatial extent of BBB leakage were calculated in cortical gray matter and white matter using noise-corrected histogram analysis of leakage maps. Computer simulations utilizing realistic Ki histograms, mimicking the strong effect of noise and variation in Ki values, were performed to understand the influence of scan time on the estimated leakage.
RESULTS: The mean Ki was very low (order of 10(-4) min(-1) ) and highly influenced by noise, causing the Ki to be increasingly overestimated at shorter scan times. In the white matter, the Ki was not different between patients with early AD and controls, but was higher in the cortex for patients, reaching significance after 14.5 min of scan time. To detect group differences, vL proved more suitable, showing significantly higher values for patients compared with controls in the cortex after 8 minutes of scan time, and in white matter after 15.5 min.
CONCLUSIONS: Several ways to improve the sensitivity of a DCE-MRI experiment to subtle BBB leakage were presented. We have provided vL as an attractive and potentially more time-efficient alternative to detect group differences in subtle and widespread blood-brain barrier leakage compared with leakage rate Ki . Recommendations on group size and scan time are made based on statistical power calculations to aid future research.},
	language = {eng},
	number = {8},
	journal = {Medical Physics},
	author = {van de Haar, Harm J. and Jansen, Jacobus F. A. and Jeukens, Cécile R. L. P. N. and Burgmans, Saartje and van Buchem, Mark A. and Muller, Majon and Hofman, Paul A. M. and Verhey, Frans R. J. and van Osch, Matthias J. P. and Backes, Walter H.},
	month = aug,
	year = {2017},
	pmid = {28493613},
	keywords = {Alzheimer's disease, blood-brain barrier, brain MRI, dynamic contrast-enhanced MRI, leakage, pharmacokinetic modeling},
	pages = {4112--4125}
}

@article{van_bussel_cerebral_2017,
	title = {Cerebral {Pathology} and {Cognition} in {Diabetes}: {The} {Merits} of {Multiparametric} {Neuroimaging}},
	volume = {11},
	copyright = {CC0 1.0 Universal Public Domain Dedication},
	issn = {1662-4548},
	doi = {10.3389/fnins.2017.00188},
	abstract = {Type 2 diabetes mellitus is associated with accelerated cognitive decline and various cerebral abnormalities visible on MRI. The exact pathophysiological mechanisms underlying cognitive decline in diabetes still remain to be elucidated. In addition to conventional images, MRI offers a versatile set of novel contrasts, including blood perfusion, neuronal function, white matter microstructure, and metabolic function. These more-advanced multiparametric MRI contrasts and the pertaining parameters are able to reveal abnormalities in type 2 diabetes, which may be related to cognitive decline. To further elucidate the nature of the link between diabetes, cognitive decline, and brain abnormalities, and changes over time thereof, biomarkers are needed which can be provided by advanced MRI techniques. This review summarizes to what extent MRI, especially advanced multiparametric techniques, can elucidate the underlying neuronal substrate that reflects the cognitive decline in type 2 diabetes.},
	language = {eng},
	journal = {Frontiers in Neuroscience},
	author = {van Bussel, Frank C. G. and Backes, Walter H. and Hofman, Paul A. M. and van Oostenbrugge, Robert J. and van Boxtel, Martin P. J. and Verhey, Frans R. J. and Steinbusch, Harry W. M. and Schram, Miranda T. and Stehouwer, Coen D. A. and Wildberger, Joachim E. and Jansen, Jacobus F. A.},
	year = {2017},
	pmid = {28424581},
	pmcid = {PMC5380729},
	keywords = {cognition, functional MRI, magnetic resonance imaging, multiparametric MRI, type 2 diabetes mellitus},
	pages = {188}
}

@article{gupta_wavelet_2017,
	title = {Wavelet entropy of {BOLD} time series: {An} application to {Rolandic} epilepsy},
	copyright = {CC0 1.0 Universal Public Domain Dedication},
	issn = {1522-2586},
	doi = {10.1002/jmri.25700},
	abstract = {PURPOSE: To assess the wavelet entropy for the characterization of intrinsic aberrant temporal irregularities in the time series of resting-state blood-oxygen-level-dependent (BOLD) signal fluctuations. Further, to evaluate the temporal irregularities (disorder/order) on a voxel-by-voxel basis in the brains of children with Rolandic epilepsy.
MATERIALS AND METHODS: The BOLD time series was decomposed using the discrete wavelet transform and the wavelet entropy was calculated. Using a model time series consisting of multiple harmonics and nonstationary components, the wavelet entropy was compared with Shannon and spectral (Fourier-based) entropy. As an application, the wavelet entropy in 22 children with Rolandic epilepsy was compared to 22 age-matched healthy controls. The images were obtained by performing resting-state functional magnetic resonance imaging (fMRI) using a 3T system, an 8-element receive-only head coil, and an echo planar imaging pulse sequence ( T2*-weighted). The wavelet entropy was also compared to spectral entropy, regional homogeneity, and Shannon entropy.
RESULTS: Wavelet entropy was found to identify the nonstationary components of the model time series. In Rolandic epilepsy patients, a significantly elevated wavelet entropy was observed relative to controls for the whole cerebrum (P = 0.03). Spectral entropy (P = 0.41), regional homogeneity (P = 0.52), and Shannon entropy (P = 0.32) did not reveal significant differences.
CONCLUSION: The wavelet entropy measure appeared more sensitive to detect abnormalities in cerebral fluctuations represented by nonstationary effects in the BOLD time series than more conventional measures. This effect was observed in the model time series as well as in Rolandic epilepsy. These observations suggest that the brains of children with Rolandic epilepsy exhibit stronger nonstationary temporal signal fluctuations than controls.
LEVEL OF EVIDENCE: 2 J. Magn. Reson. Imaging 2017.},
	language = {eng},
	journal = {Journal of magnetic resonance imaging: JMRI},
	author = {Gupta, Lalit and Jansen, Jacobus F. A. and Hofman, Paul A. M. and Besseling, René M. H. and de Louw, Anton J. A. and Aldenkamp, Albert P. and Backes, Walter H.},
	month = mar,
	year = {2017},
	pmid = {28295824},
	keywords = {BOLD time series, discrete wavelet transform, frequency structure, Rolandic epilepsy, wavelet entropy}
}

@article{zhang_intravoxel_2017,
	title = {Intravoxel {Incoherent} {Motion} {Imaging} in {Small} {Vessel} {Disease}: {Microstructural} {Integrity} and {Microvascular} {Perfusion} {Related} to {Cognition}},
	volume = {48},
	copyright = {CC0 1.0 Universal Public Domain Dedication},
	issn = {1524-4628},
	doi = {10.1161/STROKEAHA.116.015084},
	abstract = {BACKGROUND AND PURPOSE: Cerebral small vessel disease (SVD) is associated with cognitive impairment. This may be because of decreased microstructural integrity and microvascular perfusion, but data on these relationships are scarce. We determined the relationship between cognition and microvascular perfusion and microstructural integrity in SVD patients, using intravoxel incoherent motion imaging-a diffusion-weighted magnetic resonance imaging technique designed to determine microvascular perfusion and microstructural integrity simultaneously.
METHODS: Seventy-three patients with SVD and 39 controls underwent intravoxel incoherent motion imaging and neuropsychological assessment. Parenchymal diffusivity D (a surrogate measure of microstructural integrity) and perfusion-related measure fD* were calculated for the normal appearing white matter, white matter hyperintensities, and cortical gray matter. The associations between cognitive performance and D and fD* were determined.
RESULTS: In SVD patients, multivariable analysis showed that lower fD* in the normal appearing white matter and cortical gray matter was associated with lower overall cognition (P=0.03 and P=0.002, respectively), lower executive function (P=0.04 and P=0.01, respectively), and lower information-processing speed (P=0.04 and P=0.01, respectively). D was not associated with cognitive function. In controls, no association was found between D, fD*, and cognition.
CONCLUSIONS: In SVD patients, lower cognitive performance is associated with lower microvascular perfusion in the normal appearing white matter and cortical gray matter. Our results support recent findings that both cortical gray matter and normal appearing white matter perfusion may play a role in the pathophysiology of cognitive dysfunction in SVD.
CLINICAL TRIAL REGISTRATION: URL: http://www.trialregister.nl. Unique identifier: NTR3786.},
	language = {eng},
	number = {3},
	journal = {Stroke},
	author = {Zhang, C. Eleana and Wong, Sau May and Uiterwijk, Renske and Staals, Julie and Backes, Walter H. and Hoff, Erik I. and Schreuder, Tobien and Jeukens, Cécile R. L. P. N. and Jansen, Jacobus F. A. and van Oostenbrugge, Robert J.},
	month = mar,
	year = {2017},
	pmid = {28196940},
	keywords = {cognition, Aged, Aged, 80 and over, cerebral blood flow, cerebral small vessel disease, Cerebral Small Vessel Diseases, Cognitive Dysfunction, Diffusion Magnetic Resonance Imaging, Female, Gray Matter, Humans, Male, Microvessels, Middle Aged, White Matter},
	pages = {658--663}
}

@article{wong_simultaneous_2017,
	title = {Simultaneous investigation of microvasculature and parenchyma in cerebral small vessel disease using intravoxel incoherent motion imaging},
	volume = {14},
	copyright = {CC0 1.0 Universal Public Domain Dedication},
	issn = {2213-1582},
	doi = {10.1016/j.nicl.2017.01.017},
	abstract = {INTRODUCTION: Cerebral small vessel disease (cSVD) is associated with microvascular and parenchymal alterations. Intravoxel incoherent motion (IVIM) MRI has been proposed to simultaneously measure both the microvascular perfusion and parenchymal diffusivity. This study aimed to evaluate the application of IVIM in cSVD to assess the microvasculature and parenchymal microstructure.
METHODS: Seventy-three patients with cSVD (age 70 ± 11 y) and thirty-nine controls (age 69 ± 12 y) underwent IVIM imaging (3T). Group differences of the perfusion volume fraction f and the parenchymal diffusivity D were investigated using multivariable linear regression accounted for age, sex and cardiovascular factors. To examine the relation between the IVIM measures and the disease severity on structural MRI, white matter hyperintensity (WMH) load served as surrogate measure of the disease severity.
RESULTS: Patients had a larger f (p {\textless} 0.024) in the normal appearing white matter (NAWM) than controls. Higher D (p {\textless} 0.031) was also observed for patients compared with controls in the NAWM and grey matter. Both f (p {\textless} 0.024) and D (p {\textless} 0.001) in the NAWM and grey matter increased with WMH load.
CONCLUSIONS: The increased diffusivity reflects the predicted microstructural tissue impairment in cSVD. Unexpectedly, an increased perfusion volume fraction was observed in patients. Future studies are needed to reveal the precise nature of the increased perfusion volume fraction. IVIM imaging showed that the increases of f and D in cSVD were both related to disease severity, which suggests the potential of IVIM imaging to provide a surrogate marker for the progression of cSVD.},
	language = {eng},
	journal = {NeuroImage. Clinical},
	author = {Wong, Sau May and Zhang, C. Eleana and van Bussel, Frank C. G. and Staals, Julie and Jeukens, Cécile R. L. P. N. and Hofman, Paul A. M. and van Oostenbrugge, Robert J. and Backes, Walter H. and Jansen, Jacobus F. A.},
	year = {2017},
	pmid = {28180080},
	pmcid = {PMC5288390},
	keywords = {BMI, body mass index, Brain parenchyma, Cerebral small vessel disease, cSVD, cerebral small vessel disease, DGM, deep grey matter, Diffusion weighted imaging, DW, diffusion weighted, FLAIR, fluid attenuated inversion recovery, FOV, field of view, Intravoxel incoherent motion imaging, IVIM, intravoxel incoherent motion imaging, LS, lacunar stroke, Microvasculature, mVCI, mild vascular cognitive impairment, NAWM, normal appearing white matter, Perfusion MR imaging, PVS, perivascular spaces, ROI, region of interest, SNR, signal-to-noise ratio, WMH, white matter hyperintensity},
	pages = {216--221}
}

@article{wong_measuring_2017,
	title = {Measuring subtle leakage of the blood-brain barrier in cerebrovascular disease with {DCE}-{MRI}: {Test}-retest reproducibility and its influencing factors},
	volume = {46},
	copyright = {CC0 1.0 Universal Public Domain Dedication},
	issn = {1522-2586},
	doi = {10.1002/jmri.25540},
	abstract = {PURPOSE: Increased blood-brain barrier (BBB) permeability has been shown to play a significant role in the pathophysiology of cerebrovascular disease and it may provide an early functional marker of progression or treatment effects. The aim of the study was to investigate the test-retest reproducibility and influencing factors of dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) in measuring subtle leakage in patients with cerebrovascular disease.
MATERIAL AND METHODS: DCE-MRI (3T) was performed on two separate days in 16 patients (age 66 ± 9 years) with cerebrovascular disease, prospectively. The leakage rate was quantified for white matter (WM) and gray matter (GM) using the Patlak graphical approach with individual vascular input functions (VIFs). Furthermore, the influence of session-averaged VIFs, the average of the VIFs obtained on two days, and shorter scan times (range 5-25 minutes) on the reproducibility were evaluated in WM and GM.
RESULTS: Coefficients of variation (CV) ≤14.4\% (WM and GM), intraclass correlation coefficients (ICCs) of 0.77 (WM) and 0.49 (GM), were observed for the leakage rate. Session-averaged VIFs hardly affected these results (CV ≤13.4\%). The repeatability coefficients (RCs) of the leakage rate decreased from 2.7·10(-3) to 0.4·10(-3) min(-1) in WM (P {\textless} 0.01) and 4.4·10(-3) to 0.9·10(-3) min(-1) in GM (P {\textless} 0.01) with increasing scan time (range 5-25 minutes).
CONCLUSION: Based on the moderate CVs and moderate-to-excellent ICCs, we demonstrate that measuring subtle BBB leakage using DCE-MRI is moderate-to-excellent reproducible. Longer scan times improve the reproducibility. The provided RCs at various scan times may assist future clinical studies investigating BBB leakage using DCE-MRI.
LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 2 J. MAGN. RESON. IMAGING 2017;46:159-166.},
	language = {eng},
	number = {1},
	journal = {Journal of magnetic resonance imaging: JMRI},
	author = {Wong, Sau May and Jansen, Jacobus F. A. and Zhang, C. Eleana and Staals, Julie and Hofman, Paul A. M. and van Oostenbrugge, Robert J. and Jeukens, Cécile R. L. P. N. and Backes, Walter H.},
	month = jul,
	year = {2017},
	pmid = {28160347},
	keywords = {blood-brain barrier, cerebrovascular disease, dynamic contrast-enhanced magnetic resonance imaging, permeability, reproducibility},
	pages = {159--166}
}

@article{van_de_haar_blood-brain_2017,
	title = {Blood-{Brain} {Barrier} {Leakage} in {Patients} with {Early} {Alzheimer} {Disease}},
	volume = {282},
	copyright = {CC0 1.0 Universal Public Domain Dedication},
	issn = {1527-1315},
	doi = {10.1148/radiol.2017164043},
	language = {eng},
	number = {2},
	journal = {Radiology},
	author = {van de Haar, Harm J. and Burgmans, Saartje and Jansen, Jacobus F. A. and van Osch, Matthias J. P. and van Buchem, Mark A. and Muller, Majon and Hofman, Paul A. M. and Verhey, Frans R. J. and Backes, Walter H.},
	month = feb,
	year = {2017},
	pmid = {28099097},
	pages = {615}
}

@article{gupta_towards_2017,
	title = {Towards prognostic biomarkers from {BOLD} fluctuations to differentiate a first epileptic seizure from new-onset epilepsy},
	volume = {58},
	copyright = {CC0 1.0 Universal Public Domain Dedication},
	issn = {1528-1167},
	doi = {10.1111/epi.13658},
	abstract = {OBJECTIVE: The diagnosis of epilepsy cannot be reliably made prior to a patient's second seizure in most cases. Therefore, adequate diagnostic tools are needed to differentiate subjects with a first seizure from those with a seizure preceding the onset of epilepsy. The objective was to explore spontaneous blood oxygen level-dependent (BOLD) fluctuations in subjects with a first-ever seizure and patients with new-onset epilepsy (NOE), and to find characteristic biomarkers for seizure recurrence after the first seizure.
METHODS: We examined 17 first-seizure subjects, 19 patients with new-onset epilepsy (NOE), and 18 healthy controls. All subjects underwent clinical investigation and received electroencephalography and resting-state functional magnetic resonance imaging (MRI). The BOLD time series were analyzed in terms of regional homogeneity (ReHo) and fractional amplitude of low-frequency fluctuations (fALFFs).
RESULTS: We found significantly stronger amplitudes (higher fALFFs) in patients with NOE relative to first-seizure subjects and healthy controls. The frequency range of 73-198 mHz (slow-3 subband) appeared most useful for discriminating patients with NOE from first-seizure subjects. The ReHo measure did not show any significant differences.
SIGNIFICANCE: The fALFF appears to be a noninvasive measure that characterizes spontaneous BOLD fluctuations and shows stronger amplitudes in the slow-3 subband of patients with NOE relative first-seizure subjects and healthy controls. A larger study population with follow-up is required to determine whether fALFF holds promise as a potential biomarker for identifying subjects at increased risk to develop epilepsy.},
	language = {eng},
	number = {3},
	journal = {Epilepsia},
	author = {Gupta, Lalit and Janssens, Rick and Vlooswijk, Mariëlle C. G. and Rouhl, Rob P. W. and de Louw, Anton and Aldenkamp, Albert P. and Ulman, Shrutin and Besseling, René M. H. and Hofman, Paul A. M. and van Kranen-Mastenbroek, Vivianne H. and Hilkman, Danny M. and Jansen, Jacobus F. A. and Backes, Walter H.},
	month = mar,
	year = {2017},
	pmid = {28098938},
	keywords = {Functional magnetic resonance imaging, BOLD time series, Aged, Aged, 80 and over, Female, Humans, Male, Middle Aged, Adolescent, Adult, Brain, Electrocardiography, Electroencephalography, Epilepsy, First-seizure, Follow-Up Studies, Image Processing, Computer-Assisted, Low frequency oscillations, Magnetic Resonance Imaging, New-onset epilepsy, Oxygen, Regional homogeneity, Retrospective Studies, Young Adult},
	pages = {476--483}
}

@article{zhang_blood-brain_2017,
	title = {Blood-brain barrier leakage is more widespread in patients with cerebral small vessel disease},
	volume = {88},
	copyright = {CC0 1.0 Universal Public Domain Dedication},
	issn = {1526-632X},
	doi = {10.1212/WNL.0000000000003556},
	abstract = {OBJECTIVE: As blood-brain barrier (BBB) dysfunction may occur in normal aging but may also play a pivotal role in the pathophysiology of cerebral small vessel disease (cSVD), we used dynamic contrast-enhanced (DCE)-MRI to quantify the rate and the spatial extent of BBB leakage in patients with cSVD and age- and sex-matched controls to discern cSVD-related BBB leakage from aging-related leakage.
METHODS: We performed structural brain MRI and DCE-MRI in 80 patients with clinically overt cSVD and 40 age- and sex-matched controls. Using the Patlak pharmacokinetic model, we calculated the leakage rate. The mean leakage rate and relative leakage volume were calculated using noise-corrected histogram analysis. Leakage rate and leakage volume were compared between patients with cSVD and controls for the normal-appearing white matter (NAWM), white matter hyperintensities (WMH), cortical gray matter (CGM), and deep gray matter.
RESULTS: Multivariable linear regression analyses adjusting for age, sex, and cardiovascular risk factors showed that the leakage volume of the NAWM, WMH, and CGM was significantly larger in patients with cSVD compared with controls. No significant difference was found for leakage rate in any of the tissue regions.
CONCLUSION: We demonstrated a larger tissue volume with subtle BBB leakage in patients with cSVD than in controls. This was shown in the NAWM, WMH, and CGM, supporting the generalized nature of cSVD.},
	language = {eng},
	number = {5},
	journal = {Neurology},
	author = {Zhang, C. Eleana and Wong, Sau May and van de Haar, Harm J. and Staals, Julie and Jansen, Jacobus F. A. and Jeukens, Cécile R. L. P. N. and Hofman, Paul A. M. and van Oostenbrugge, Robert J. and Backes, Walter H.},
	month = jan,
	year = {2017},
	pmid = {28031395},
	keywords = {Aged, Cerebral Small Vessel Diseases, Female, Gray Matter, Humans, Male, White Matter, Magnetic Resonance Imaging, Aging, Blood-Brain Barrier, Capillary Permeability, Cardiovascular Diseases, Contrast Media, Image Interpretation, Computer-Assisted, Linear Models, Multivariate Analysis, Plasma Volume, Severity of Illness Index, Sex Characteristics},
	pages = {426--432}
}

@article{jansen_cerebral_2016,
	title = {Cerebral blood flow, blood supply, and cognition in {Type} 2 {Diabetes} {Mellitus}},
	volume = {6},
	copyright = {CC0 1.0 Universal Public Domain Dedication},
	issn = {2045-2322},
	doi = {10.1038/s41598-016-0003-6},
	abstract = {We investigated whether type 2 diabetes (T2DM) and the presence of cognitive impairment are associated with altered cerebral blood flow (CBF). Forty-one participants with and thirty-nine without T2DM underwent 3-Tesla MRI, including a quantitative technique measuring (macrovascular) blood flow in the internal carotid artery and an arterial spin labeling technique measuring (microvascular) perfusion in the grey matter (GM). Three analysis methods were used to quantify the CBF: a region of interest analysis, a voxel-based statistical parametric mapping technique, and a 'distributed deviating voxels' method. Participants with T2DM exhibited significantly more tissue with low CBF values in the cerebral cortex and the subcortical GM (3.8-fold increase). The latter was the only region where the hypoperfusion remained after correcting for atrophy, indicating that the effect of T2DM on CBF, independent of atrophy, is small. Subcortical CBF was associated with depression. No associations were observed for CBF in other regions with diabetes status, for carotid blood flow with diabetes status, or for CBF or flow in relation with cognitive function. To conclude, a novel method that tallies total 'distributed deviating voxels' demonstrates T2DM-associated hypoperfusion in the subcortical GM, not associated with cognitive performance. Whether a vascular mechanism underlies cognitive decrements remains inconclusive.},
	language = {eng},
	number = {1},
	journal = {Scientific Reports},
	author = {Jansen, Jacobus F. A. and van Bussel, Frank C. G. and van de Haar, Harm J. and van Osch, Matthias J. P. and Hofman, Paul A. M. and van Boxtel, Martin P. J. and van Oostenbrugge, Robert J. and Schram, Miranda T. and Stehouwer, Coen D. A. and Wildberger, Joachim E. and Backes, Walter H.},
	year = {2016},
	pmid = {27920431},
	pages = {10}
}

@article{van_bussel_erratum._2017,
	title = {Erratum. {Functional} {Brain} {Networks} {Are} {Altered} in {Type} 2 {Diabetes} and {Prediabetes}: {Signs} for {Compensation} of {Cognitive} {Decrements}? {The} {Maastricht} {Study}. {Diabetes} 2016;65:2404-2413},
	volume = {66},
	copyright = {CC0 1.0 Universal Public Domain Dedication},
	issn = {1939-327X},
	doi = {10.2337/db17-er02a},
	language = {eng},
	number = {2},
	journal = {Diabetes},
	author = {van Bussel, Frank C. G. and Backes, Walter H. and van Veenendaal, Tamar M. and Hofman, Paul A. M. and van Boxtel, Martin P. J. and Schram, Miranda T. and Sep, Simone J. S. and Dagnelie, Pieter C. and Schaper, Nicolaas and Stehouwer, Coen D. A. and Wildberger, Joachim E. and Jansen, Jacobus F. A.},
	month = feb,
	year = {2017},
	pmid = {27908916},
	pmcid = {PMC5248990},
	pages = {560}
}

@article{besseling_abnormal_2016,
	title = {Abnormal {Profiles} of {Local} {Functional} {Connectivity} {Proximal} to {Focal} {Cortical} {Dysplasias}},
	volume = {11},
	copyright = {CC0 1.0 Universal Public Domain Dedication},
	issn = {1932-6203},
	doi = {10.1371/journal.pone.0166022},
	abstract = {INTRODUCTION: Focal cortical dysplasia (FCD) is a congenital malformation of cortical development that often leads to medically refractory epilepsy. Focal resection can be an effective treatment, but is challenging as the surgically relevant abnormality may exceed the MR-visible lesion. The aim of the current study is to develop methodology to characterize the profile of functional connectivity around FCDs using resting-state functional MRI and in the individual patient. The detection of aberrant connectivity may provide a means to more completely delineate the clinically relevant lesion.
MATERIALS AND METHODS: Fifteen FCD patients (age, mean±SD: 31±11 years; 11 males) and 16 matched healthy controls (35±9 years; 7 males) underwent structural and functional imaging at 3 Tesla. The cortical surface was reconstructed from the T1-weighted scan and the registered functional MRI data was spatially normalized to a common anatomical standard space employing the gyral pattern. Seed-based functional connectivity was determined in all subjects for all dysplasia locations. A single patient was excluded based on an aberrant FCD seed time series. Functional connectivity as a function of geodesic distance (along the cortical surface) was compared between the individual patients and the homotopic normative connectivity profiles derived from the controls.
RESULTS: In 12/14 patients, aberrant profiles of functional connectivity were found, which demonstrated both hyper- and hypoconnectivity as well as combinations. Abnormal functional connectivity was typically found (also) beyond the lesion visible on structural MRI, while functional connectivity profiles not related to a lesion appeared normal in patients.
CONCLUSION: This novel functional MRI technique has potential for delineating functionally aberrant from normal cortex beyond the structural lesion in FCD, which remains to be confirmed in future research.},
	language = {eng},
	number = {11},
	journal = {PloS One},
	author = {Besseling, René M. H. and Jansen, Jacobus F. A. and de Louw, Anton J. A. and Vlooswijk, Mariëlle C. G. and Hoeberigs, M. Christianne and Aldenkamp, Albert P. and Backes, Walter H. and Hofman, Paul A. M.},
	year = {2016},
	pmid = {27861502},
	pmcid = {PMC5115673},
	keywords = {Female, Humans, Male, Adult, Brain, Image Processing, Computer-Assisted, Magnetic Resonance Imaging, Young Adult, Image Interpretation, Computer-Assisted, Brain Mapping, Case-Control Studies, Connectome, Malformations of Cortical Development, Rest},
	pages = {e0166022}
}

@article{van_de_weijer_parkinplay_2016,
	title = {The {Parkin}'{Play} study: protocol of a phase {II} randomized controlled trial to assess the effects of a health game on cognition in {Parkinson}'s disease},
	volume = {16},
	copyright = {CC0 1.0 Universal Public Domain Dedication},
	issn = {1471-2377},
	doi = {10.1186/s12883-016-0731-z},
	abstract = {BACKGROUND: In Parkinson's disease (PD), cognitive impairment is an important non-motor symptom heralding the development of dementia. Effective treatments to slow down the rate of cognitive decline in PD patients with mild cognitive impairment are lacking. Here, we describe the design of the Parkin'Play study, which assesses the effects of a cognitive health game intervention on cognition in PD.
METHODS/DESIGN: This study is a multicentre, phase-II, open-randomized clinical trial that aims to recruit 222 PD patients with mild cognitive impairment. Eligible patients have PD, Hoehn \& Yahr stages I-III, are aged between 40 and 75 years, and have cognitive impairment but no dementia. The intervention group (n = 111) will be trained using a web-based health game targeting multiple cognitive domains. The control group (n = 111) will be placed on a waiting list. In order to increase compliance the health game adapts to the subjects' performance, is enjoyable, and can be played at home. From each group, 20 patients will undergo fMRI to test for potential functional brain changes underlying treatment. The primary outcome after 12 weeks of training is cognitive function, as assessed by a standard neuropsychological assessment battery and an online cognitive assessment. The neuropsychological assessment battery covers the following domains: executive function, memory, visual perception, visuoconstruction and language. A compound score for overall cognitive function will be calculated as the mean score of all test Z-scores based on the distribution of scores for both groups taken together. Secondary outcomes at follow-up visits up to 24 weeks include various motor and non-motor symptoms, compliance, and biological endpoints (fMRI).
DISCUSSION: This study aims at evaluating whether a cognitive intervention among PD patients leads to an increased cognitive performance on targeted domains. Strengths of this study are a unique web-based health game intervention, the large sample size, a control group without intervention and innovations designed to increase compliance.
TRIAL REGISTRATION: NTR5637 on 7-jan-2016.},
	language = {eng},
	number = {1},
	journal = {BMC neurology},
	author = {van de Weijer, Sjors C. F. and Duits, Annelien A. and Bloem, Bastiaan R. and Kessels, Roy P. and Jansen, Jacobus F. A. and Köhler, Sebastian and Tissingh, Gerrit and Kuijf, Mark L.},
	month = nov,
	year = {2016},
	pmid = {27809791},
	pmcid = {PMC5093943},
	keywords = {Aged, Cognitive Dysfunction, Humans, Middle Aged, Adult, Cognitive functions, Executive Function, Health game, Language, Memory, Mild cognitive impairment, Neuropsychological Tests, Parkinson disease, Parkinson Disease, RCT, Treatment Outcome, Video Games, Visual Perception},
	pages = {209}
}

@article{van_de_haar_blood-brain_2016,
	title = {Blood-{Brain} {Barrier} {Leakage} in {Patients} with {Early} {Alzheimer} {Disease}},
	volume = {281},
	copyright = {CC0 1.0 Universal Public Domain Dedication},
	issn = {1527-1315},
	doi = {10.1148/radiol.2016152244},
	abstract = {Purpose To investigate whether the blood-brain barrier (BBB) leaks blood-circulating substances in patients with early forms of Alzheimer disease (AD), and if so, to examine the extent and pattern of leakage. Materials and Methods This study was approved by the local medical ethical committees of the Maastricht University Medical Center and Leiden University Medical Center, and written informed consent was obtained from all subjects. For this pilot study, 16 patients with early AD and 17 healthy age-matched control subjects underwent dynamic contrast material-enhanced magnetic resonance (MR) imaging sequence with dual time resolution for 25 minutes. The Patlak graphical approach was used to quantify the BBB leakage rate and local blood plasma volume. Subsequent histogram analysis was used to determine the volume fraction of the leaking brain tissue. Differences were assessed with linear regression analysis, adjusted for confounding variables. Results The BBB leakage rate was significantly higher in patients compared with that in control subjects in the total gray matter (P {\textless} .05) and cortex (P = .03). Patients had a significantly higher volume fraction of the leaking brain tissue in the gray matter (P = .004), normal-appearing white matter (P {\textless} .04), deep gray matter (P = .01), and cortex (P = .004). When all subjects were considered, scores on the Mini-Mental State Examination decreased significantly with increasing leakage in the deep gray matter (P = .007) and cortex (P {\textless} .05). Conclusion The results of this study showed global BBB leakage in patients with early AD that is associated with cognitive decline. A compromised BBB may be part of a cascade of pathologic events that eventually lead to cognitive decline and dementia. (©)RSNA, 2016 Online supplemental material is available for this article.},
	language = {eng},
	number = {2},
	journal = {Radiology},
	author = {van de Haar, Harm J. and Burgmans, Saartje and Jansen, Jacobus F. A. and van Osch, Matthias J. P. and van Buchem, Mark A. and Muller, Majon and Hofman, Paul A. M. and Verhey, Frans R. J. and Backes, Walter H.},
	month = nov,
	year = {2016},
	pmid = {27243267},
	keywords = {Aged, Aged, 80 and over, Female, Humans, Male, Middle Aged, Magnetic Resonance Imaging, Blood-Brain Barrier, Contrast Media, Case-Control Studies, Alzheimer Disease, Blood Volume, Pilot Projects},
	pages = {527--535}
}

@article{van_veenendaal_glutamate_2016,
	title = {Glutamate concentrations vary with antiepileptic drug use and mental slowing},
	volume = {64},
	copyright = {CC0 1.0 Universal Public Domain Dedication},
	issn = {1525-5069},
	doi = {10.1016/j.yebeh.2016.08.027},
	abstract = {OBJECTIVE: Although antiepileptic drugs (AEDs) are effective in suppressing epileptic seizures, they also induce (cognitive) side effects, with mental slowing as a general effect. This study aimed to assess whether concentrations of MR detectable neurotransmitters, glutamate and GABA, are associated with mental slowing in patients with epilepsy taking AEDs.
METHODS: Cross-sectional data were collected from patients with localization-related epilepsy using a variety of AEDs from three risk categories, i.e., AEDs with low, intermediate, and high risks of developing cognitive problems. Patients underwent 3T MR spectroscopy, including a PRESS (n=55) and MEGA-PRESS (n=43) sequence, to estimate occipital glutamate and GABA concentrations, respectively. The association was calculated between neurotransmitter concentrations and central information processing speed, which was measured using the Computerized Visual Searching Task (CVST) and compared between the different risk categories.
RESULTS: Combining all groups, patients with lower processing speeds had lower glutamate concentrations. Patients in the high-risk category had a lower glutamate concentration and lower processing speed compared with patients taking low-risk AEDs. Patients taking intermediate-risk AEDs also had a lower glutamate concentration compared with patients taking low-risk AEDs, but processing speed did not differ significantly between those groups. No associations were found between the GABA concentration and risk category or processing speed.
CONCLUSIONS: For the first time, a relation is shown between glutamate concentration and both mental slowing and AED use. It is suggested that the reduced excitatory action, reflected by lowered glutamate concentrations, may have contributed to the slowing of information processing in patients using AEDs with higher risks of cognitive side effects.},
	language = {eng},
	number = {Pt A},
	journal = {Epilepsy \& Behavior: E\&B},
	author = {van Veenendaal, Tamar M. and IJff, Dominique M. and Aldenkamp, Albert P. and Lazeron, Richard H. C. and Puts, Nicolaas A. J. and Edden, Richard A. E. and Hofman, Paul A. M. and de Louw, Anton J. A. and Backes, Walter H. and Jansen, Jacobus F. A.},
	month = nov,
	year = {2016},
	pmid = {27744245},
	keywords = {Cognitive side effects, GABA, Female, Humans, Male, Middle Aged, Adult, Epilepsy, Neuropsychological Tests, Anticonvulsant, Anticonvulsants, Cognition, Cross-Sectional Studies, gamma-Aminobutyric Acid, Glutamate, Glutamic Acid, Magnetic Resonance Spectroscopy, MR spectroscopy, Occipital Lobe},
	pages = {200--205}
}

@article{drenthen_altered_2016,
	title = {Altered neurotransmitter metabolism in adolescents with high-functioning autism},
	volume = {256},
	copyright = {CC0 1.0 Universal Public Domain Dedication},
	issn = {1872-7123},
	doi = {10.1016/j.pscychresns.2016.09.007},
	abstract = {Previous studies have suggested that alterations in excitatory/inhibitory neurotransmitters might play a crucial role in autism spectrum disorder (ASD). Proton magnetic resonance spectroscopy ((1)H-MRS) can provide valuable information about abnormal brain metabolism and neurotransmitter concentrations. However, few (1)H-MRS studies have been published on the imbalance of the two most abundant neurotransmitters in ASD: glutamate (Glu) and gamma-aminobutyric acid (GABA). Moreover, to our knowledge none of these published studies is performed with a study population consisting purely of high-functioning autism (HFA) adolescents. Selecting only individuals with HFA eliminates factors possibly related to intellectual impairment instead of ASD. This study aims to assess Glu and GABA neurotransmitter concentrations in HFA. Occipital concentrations of Glu and GABA plus macromolecules (GABA+) were obtained using (1)H-MRS relative to creatine (Cr) in adolescents with HFA (n=15 and n=13 respectively) and a healthy control group (n=17). Multiple linear regression revealed significantly higher Glu/Cr and lower GABA+/Glu concentrations in the HFA group compared to the controls. These results imply that imbalanced neurotransmitter levels of excitation and inhibition are associated with HFA in adolescents.},
	language = {eng},
	journal = {Psychiatry Research},
	author = {Drenthen, Gerhard S. and Barendse, Evelien M. and Aldenkamp, Albert P. and van Veenendaal, Tamar M. and Puts, Nicolaas A. J. and Edden, Richard A. E. and Zinger, Svitlana and Thoonen, Geert and Hendriks, Marc P. H. and Kessels, Roy P. C. and Jansen, Jacobus F. A.},
	month = oct,
	year = {2016},
	pmid = {27685800},
	pmcid = {PMC5385138},
	keywords = {Glutamate, Gamma-aminobutyric acid, Magnetic resonance spectroscopy},
	pages = {44--49}
}

@article{freeze_white_2017,
	title = {White {Matter} {Hyperintensities} {Potentiate} {Hippocampal} {Volume} {Reduction} in {Non}-{Demented} {Older} {Individuals} with {Abnormal} {Amyloid}-β},
	volume = {55},
	copyright = {CC0 1.0 Universal Public Domain Dedication},
	issn = {1875-8908},
	doi = {10.3233/JAD-160474},
	abstract = {Cerebral small vessel disease (cSVD) and amyloid-β (Aβ) deposition often co-exist in (prodromal) dementia, and both types of pathology have been associated with neurodegeneration. We examined whether cSVD and Aβ have independent or interactive effects on hippocampal volume (HV) in a memory clinic population. We included 87 individuals with clinical diagnoses of Alzheimer's disease (AD) (n = 24), mild cognitive impairment (MCI) (n = 26), and subjective cognitive complaints (SCC) (n = 37). cSVD magnetic resonance imaging markers included white matter hyperintensity (WMH) volume, lacunar infarct presence, and microbleed presence. Aβ pathology was assessed as cerebrospinal fluid-derived Aβ1 - 42 levels and dichotomized into normal or abnormal, and HV was determined by manual volumetric measurements. A linear hierarchical regression approach was applied for the detection of additive or interaction effects between cSVD and Aβ on HV in the total participant group (n = 87) and in the non-demented group (including SCC and MCI individuals only, n = 63). The results revealed that abnormal Aβ and lacunar infarct presence were independently associated with lower HV in the non-demented individuals. Interestingly, Aβ and WMH pathology interacted in the non-demented individuals, such that WMH had a negative effect on HV in individuals with abnormal CSF Aβ42 levels, but not in individuals with normal CSF Aβ42 levels. These associations were not present when individuals with AD were included in the analyses. Our observations suggest that relatively early on in the disease process older individuals with abnormal Aβ levels are at an increased risk of accelerated disease progression when concomitant cSVD is present.},
	language = {eng},
	number = {1},
	journal = {Journal of Alzheimer's disease: JAD},
	author = {Freeze, Whitney M. and Jacobs, Heidi I. L. and Gronenschild, Ed H. and Jansen, Jacobus F. A. and Burgmans, Saartje and Aalten, Pauline and Clerx, Lies and Vos, Stephanie J. and van Buchem, Mark A. and Barkhof, Frederik and van der Flier, Wiesje M. and Verbeek, Marcel M. and Rikkert, Marcel Olde and Backes, Walter H. and Verhey, Frans R. and {LeARN project}},
	year = {2017},
	pmid = {27662299},
	keywords = {cerebral small vessel disease, Amyloid-beta, dementia, neurodegeneration},
	pages = {333--342}
}

@article{van_bussel_increased_2016,
	title = {Increased {GABA} concentrations in type 2 diabetes mellitus are related to lower cognitive functioning},
	volume = {95},
	copyright = {CC0 1.0 Universal Public Domain Dedication},
	issn = {1536-5964},
	doi = {10.1097/MD.0000000000004803},
	abstract = {Type 2 diabetes mellitus is associated with accelerated cognitive decline. The underlying pathophysiological mechanisms still remain to be elucidated although it is known that insulin signaling modulates neurotransmitter activity, including inhibitory γ-aminobutyric acid (GABA) and excitatory glutamate (Glu) receptors. Therefore, we examined whether levels of GABA and Glu are related to diabetes status and cognitive performance.Forty-one participants with type 2 diabetes and 39 participants without type 2 diabetes underwent detailed cognitive assessments and 3-Tesla proton MR spectroscopy. The associations of neurotransmitters with type 2 diabetes and cognitive performance were examined using multivariate regression analyses controlling for age, sex, education, BMI, and percentage gray/white matter ratio in spectroscopic voxel.Analysis revealed higher GABA+ levels in participants with type 2 diabetes, in participants with higher fasting blood glucose levels and in participants with higher HbA1c levels, and higher GABA+ levels in participants with both high HbA1c levels and less cognitive performance.To conclude, participants with type 2 diabetes have alterations in the GABAergic neurotransmitter system, which are related to lower cognitive functioning, and hint at the involvement of an underlying metabolic mechanism.},
	language = {eng},
	number = {36},
	journal = {Medicine},
	author = {van Bussel, Frank C. G. and Backes, Walter H. and Hofman, Paul A. M. and Puts, Nicolaas A. J. and Edden, Richard A. E. and van Boxtel, Martin P. J. and Schram, Miranda T. and Stehouwer, Coen D. A. and Wildberger, Joachim E. and Jansen, Jacobus F. A.},
	month = sep,
	year = {2016},
	pmid = {27603392},
	pmcid = {PMC5023915},
	keywords = {Aged, Cognitive Dysfunction, Female, Gray Matter, Humans, Male, Middle Aged, White Matter, Magnetic Resonance Imaging, Case-Control Studies, Neuropsychological Tests, Cognition, gamma-Aminobutyric Acid, Glutamic Acid, Magnetic Resonance Spectroscopy, Blood Glucose, Diabetes Mellitus, Type 2, Hemoglobin A, Glycosylated},
	pages = {e4803}
}

@article{ijff_cognitive_2016,
	title = {The {Cognitive} {Profile} of {Ethosuximide} in {Children}},
	volume = {18},
	copyright = {CC0 1.0 Universal Public Domain Dedication},
	issn = {1179-2019},
	doi = {10.1007/s40272-016-0187-z},
	abstract = {INTRODUCTION: Although ethosuximide is one of the oldest antiepileptic drugs (AEDs), little information is available about the cognitive side effects of ethosuximide.
OBJECTIVE: The aim of this study was to investigate the cognitive profile of ethosuximide.
METHODS: In this cross-sectional study, we used an extensive neuropsychological test battery in patients with epilepsy aged 6-16 years who were treated with monotherapy ethosuximide. We evaluated the efficacy of the drug by seizure frequency (seizure free or not).
RESULTS: We included 61 patients with a mean age of 9.4 years [standard deviation (SD) 2.7] who used on average 686 mg/day (SD 245) ESM as monotherapy. ESM was effective in the majority of the patients (70 \% were seizure free for at least 6 months at moment of inclusion). The total study population showed impairments of intelligence, visuomotor, and attentional function including activation/alertness. Comparisons between the well-controlled patients and patients who were not in remission showed significantly lower intelligence values and lower performance on the visual-perceptual and attentional tasks for the group with ongoing seizures. Our results suggested that the higher order cognitive dysfunctions (such as intelligence and visual-perceptual functions) may be regarded as seizure or aetiology effects and that the impaired fluid cognitive functions, such as activation/alertness, sustained auditory attention and attentional control or switching, were due to ESM.
CONCLUSION: This study suggests the attentional dysfunction resulting in psychomotor slowing and alertness deficits may be regarded as effects of ethosuximide. Although no untreated baseline assessment was available, these effects are comparable to those of other AEDs, and ethosuximide may therefore be considered an AED with only mild effects on cognition. As ethosuximide is a first-line therapy for absence seizures in childhood, and drug-induced cognitive impairment may interfere with development, learning, and academic achievement, these findings are of interest to clinicians who prescribe this drug, especially when informing parents.},
	language = {eng},
	number = {5},
	journal = {Paediatric Drugs},
	author = {IJff, Dominique M. and van Veenendaal, Tamar M. and Debeij-van Hall, Mariette H. and Jansen, Jacobus F. A. and de Louw, Anton J. A. and Majoie, Marian H. J. M. and Aldenkamp, Albert P.},
	month = oct,
	year = {2016},
	pmid = {27557905},
	keywords = {Female, Humans, Male, Adolescent, Retrospective Studies, Anticonvulsants, Cognition, Cross-Sectional Studies, Child, Epilepsy, Absence, Ethosuximide, Seizures},
	pages = {379--385}
}

@article{van_de_haar_neurovascular_2016,
	title = {Neurovascular unit impairment in early {Alzheimer}'s disease measured with magnetic resonance imaging},
	volume = {45},
	copyright = {CC0 1.0 Universal Public Domain Dedication},
	issn = {1558-1497},
	doi = {10.1016/j.neurobiolaging.2016.06.006},
	abstract = {The neurovascular unit, which protects neuronal cells and supplies them with essential molecules, plays an important role in the pathophysiology of Alzheimer's Disease (AD). The aim of this study was to noninvasively investigate 2 linked functional elements of the neurovascular unit, blood-brain barrier (BBB) permeability and cerebral blood flow (CBF), in patients with early AD and healthy controls. Therefore, both dynamic contrast-enhanced magnetic resonance imaging and arterial spin labeling magnetic resonance imaging were applied to measure BBB permeability and CBF, respectively. The patients with early AD showed significantly lower CBF and local blood volume in the gray matter, compared with controls. In the patients, we also found that a reduction in CBF is correlated with an increase in leakage rate. This finding supports the hypothesis that neurovascular damage, and in particular impairment of the neurovascular unit constitutes the pathophysiological link between CBF reduction and BBB impairment in AD.},
	language = {eng},
	journal = {Neurobiology of Aging},
	author = {van de Haar, Harm J. and Jansen, Jacobus F. A. and van Osch, Matthias J. P. and van Buchem, Mark A. and Muller, Majon and Wong, Sau May and Hofman, Paul A. M. and Burgmans, Saartje and Verhey, Frans R. J. and Backes, Walter H.},
	month = sep,
	year = {2016},
	pmid = {27459939},
	keywords = {Alzheimer's disease, Blood–brain barrier, Cerebral hemodynamics, Dementia, Magnetic resonance imaging},
	pages = {190--196}
}

@article{van_bussel_functional_2016,
	title = {Functional {Brain} {Networks} {Are} {Altered} in {Type} 2 {Diabetes} and {Prediabetes}: {Signs} for {Compensation} of {Cognitive} {Decrements}? {The} {Maastricht} {Study}},
	volume = {65},
	copyright = {CC0 1.0 Universal Public Domain Dedication},
	issn = {1939-327X},
	doi = {10.2337/db16-0128},
	abstract = {Type 2 diabetes is associated with cognitive decrements, accelerated cognitive decline, and increased risk for dementia. Patients with the metabolic syndrome, a major risk factor for diabetes, may display comparable cognitive decrements as seen in type 2 diabetes. Currently, the impact of diabetes and prediabetes on cognition and the underlying organization of functional brain networks still remain to be elucidated. This study investigated whether functional brain networks are affected in type 2 diabetes and prediabetes. Forty-seven participants with diabetes, 47 participants with prediabetes, and 45 control participants underwent detailed cognitive testing and 3-Tesla resting state functional MRI. Graph theoretical network analysis was performed to investigate alterations in functional cerebral networks. Participants with diabetes displayed altered network measures, characterized by a higher normalized cluster coefficient and higher local efficiency, compared with control participants. The network measures of the participants with prediabetes fell between those with diabetes and control participants. Lower processing speed was associated with shorter path length and higher global efficiency. Participants with type 2 diabetes have altered functional brain networks. This alteration is already apparent in the prediabetic stage to a somewhat lower level, hinting at functional reorganization of the cerebral networks as a compensatory mechanism for cognitive decrements.},
	language = {eng},
	number = {8},
	journal = {Diabetes},
	author = {van Bussel, Frank C. G. and Backes, Walter H. and van Veenendaal, Tamar M. and Hofman, Paul A. M. and van Boxtel, Martin P. J. and Schram, Miranda T. and Sep, Simone J. S. and Dagnelie, Pieter C. and Schaper, Nicolaas and Stehouwer, Coen D. A. and Wildberger, Joachim E. and Jansen, Jacobus F. A.},
	month = aug,
	year = {2016},
	pmid = {27217484},
	keywords = {Aged, Female, Humans, Male, Middle Aged, Brain, Magnetic Resonance Imaging, Brain Mapping, Cognition, Cross-Sectional Studies, Diabetes Mellitus, Type 2, Cognition Disorders, Prediabetic State},
	pages = {2404--2413}
}

@article{jansen_texture_2016,
	title = {Texture analysis on parametric maps derived from dynamic contrast-enhanced magnetic resonance imaging in head and neck cancer},
	volume = {8},
	copyright = {CC0 1.0 Universal Public Domain Dedication},
	issn = {1949-8470},
	doi = {10.4329/wjr.v8.i1.90},
	abstract = {AIM: To investigate the merits of texture analysis on parametric maps derived from pharmacokinetic modeling with dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) as imaging biomarkers for the prediction of treatment response in patients with head and neck squamous cell carcinoma (HNSCC).
METHODS: In this retrospective study, 19 HNSCC patients underwent pre- and intra-treatment DCE-MRI scans at a 1.5T MRI scanner. All patients had chemo-radiation treatment. Pharmacokinetic modeling was performed on the acquired DCE-MRI images, generating maps of volume transfer rate (K(trans)) and volume fraction of the extravascular extracellular space (ve). Image texture analysis was then employed on maps of K(trans) and ve, generating two texture measures: Energy (E) and homogeneity.
RESULTS: No significant changes were found for the mean and standard deviation for K(trans) and ve between pre- and intra-treatment (P {\textgreater} 0.09). Texture analysis revealed that the imaging biomarker E of ve was significantly higher in intra-treatment scans, relative to pretreatment scans (P {\textless} 0.04).
CONCLUSION: Chemo-radiation treatment in HNSCC significantly reduces the heterogeneity of tumors.},
	language = {eng},
	number = {1},
	journal = {World Journal of Radiology},
	author = {Jansen, Jacobus Fa and Lu, Yonggang and Gupta, Gaorav and Lee, Nancy Y. and Stambuk, Hilda E. and Mazaheri, Yousef and Deasy, Joseph O. and Shukla-Dave, Amita},
	month = jan,
	year = {2016},
	pmid = {26834947},
	pmcid = {PMC4731352},
	keywords = {Dynamic contrast-enhanced magnetic resonance imaging, Head and neck squamous cell carcinomas, Image texture analysis, Tumor heterogeneity},
	pages = {90--97}
}

@article{van_bussel_altered_2016,
	title = {Altered {Hippocampal} {White} {Matter} {Connectivity} in {Type} 2 {Diabetes} {Mellitus} and {Memory} {Decrements}},
	volume = {28},
	copyright = {CC0 1.0 Universal Public Domain Dedication},
	issn = {1365-2826},
	doi = {10.1111/jne.12366},
	abstract = {Type 2 diabetes mellitus is associated with cognitive decrements. Specifically affected cognitive domains are learning and memory, for which the hippocampus plays an essential role. The pathophysiological mechanism remains to be revealed. The present study examined whether local hippocampal microstructure and white matter connectivity are related to type 2 diabetes and memory performance. Forty participants with type 2 diabetes and 38 participants without type 2 diabetes underwent detailed cognitive assessment and 3-Tesla diffusion magnetic resonance imaging (MRI). Diffusion MRI was performed to assess microstructure (fractional anisotropy and mean diffusivity) and white matter connectivity (tract volume) of the hippocampus, which were compared between participants with and without type 2 diabetes. No differences in hippocampal microstructure were observed. Participants with type 2 diabetes had fewer white matter connections between the hippocampus and frontal lobe (P = 0.017). Participants who scored lower on memory function, regardless of type 2 diabetes, had fewer white matter connections between the hippocampus and temporal lobe (P = 0.017). Taken together, type 2 diabetes and memory decrements appear to be associated with altered hippocampal white matter connectivity.},
	language = {eng},
	number = {3},
	journal = {Journal of Neuroendocrinology},
	author = {van Bussel, F. C. G. and Backes, W. H. and Hofman, P. a. M. and van Boxtel, M. P. J. and Schram, M. T. and Stehouwer, C. D. A. and Wildberger, J. E. and Jansen, J. F. A.},
	month = mar,
	year = {2016},
	pmid = {26791354},
	keywords = {cognition, Aged, Female, Humans, Male, Middle Aged, White Matter, Magnetic Resonance Imaging, Case-Control Studies, Memory, Diabetes Mellitus, Type 2, Cognition Disorders, diffusion, Diffusion Tensor Imaging, hippocampus, Hippocampus, memory, Nerve Net, white matter connectivity},
	pages = {12366}
}

@article{van_der_kruijs_autonomic_2016,
	title = {Autonomic nervous system functioning associated with psychogenic nonepileptic seizures: {Analysis} of heart rate variability},
	volume = {54},
	copyright = {CC0 1.0 Universal Public Domain Dedication},
	issn = {1525-5069},
	doi = {10.1016/j.yebeh.2015.10.014},
	abstract = {OBJECTIVE: Psychogenic nonepileptic seizures (PNESs) resemble epileptic seizures but originate from psychogenic rather than organic causes. Patients with PNESs are often unable or unwilling to reflect on underlying emotions. To gain more insight into the internal states of patients during PNES episodes, this study explored the time course of heart rate variability (HRV) measures, which provide information about autonomic nervous system functioning and arousal.
METHODS: Heart rate variability measures were extracted from double-lead electrocardiography data collected during 1-7days of video-electroencephalography monitoring of 20 patients with PNESs, in whom a total number of 118 PNESs was recorded. Heart rate (HR) and HRV measures in time and frequency domains (standard deviation of average beat-to-beat intervals (SDANN), root mean square of successive differences (RMSSD), high-frequency (HF) power, low-frequency (LF) power, and very low-frequency (VLF) power) were averaged over consecutive five-minute intervals. Additionally, quantitative analyses of Poincaré plot parameters (SD1, SD2, and SD1/SD2 ratio) were performed.
RESULTS: In the five-minute interval before PNES, HR significantly (p{\textless}0.05) increased (d=2.5), whereas SDANN (d=-0.03) and VLF power (d=-0.05) significantly decreased. During PNES, significant increases in HF power (d=0.0006), SD1 (d=0.031), and SD2 (d=0.016) were observed. In the five-minute interval immediately following PNES, SDANN (d=0.046) and VLF power (d=0.073) significantly increased, and HR (d=-5.1) and SD1/SD2 ratio (d=-0.14) decreased, compared to the interval preceding PNES.
CONCLUSION: The results suggest that PNES episodes are preceded by increased sympathetic functioning, which is followed by an increase in parasympathetic functioning during and after PNES. Future research needs to identify the exact nature of the increased arousal that precedes PNES.},
	language = {eng},
	journal = {Epilepsy \& Behavior: E\&B},
	author = {van der Kruijs, Sylvie J. M. and Vonck, Kristl E. J. and Langereis, Geert R. and Feijs, Loe M. G. and Bodde, Nynke M. G. and Lazeron, Richard H. C. and Carrette, Evelien and Boon, Paul A. J. M. and Backes, Walter H. and Jansen, Jacobus F. A. and Aldenkamp, Albert P. and Cluitmans, Pierre J. M.},
	month = jan,
	year = {2016},
	pmid = {26615481},
	keywords = {Female, Humans, Male, Middle Aged, Adult, Electrocardiography, Young Adult, Seizures, Arousal, Autonomic nervous system, Autonomic Nervous System, Conversion disorder, Emotions, Heart Rate, Heart rate variability, Psychogenic nonepileptic seizures, Psychophysiologic Disorders, Vagal tone},
	pages = {14--19}
}

@article{jansen_evaluation_2016,
	title = {Evaluation of {Head} and {Neck} {Tumors} with {Functional} {MR} {Imaging}},
	volume = {24},
	copyright = {CC0 1.0 Universal Public Domain Dedication},
	issn = {1557-9786},
	doi = {10.1016/j.mric.2015.08.011},
	abstract = {Head and neck cancer is one of the most common cancers worldwide. MR imaging-based diffusion and perfusion techniques enable the noninvasive assessment of tumor biology and physiology, which supplement information obtained from standard structural scans. Diffusion and perfusion MR imaging techniques provide novel biomarkers that can aid monitoring in pretreatment, during treatment, and posttreatment stages to improve patient selection for therapeutic strategies; provide evidence for change of therapy regime; and evaluate treatment response. This review discusses pertinent aspects of the role of diffusion and perfusion MR imaging and computational analysis methods in studying head and neck cancer.},
	language = {eng},
	number = {1},
	journal = {Magnetic Resonance Imaging Clinics of North America},
	author = {Jansen, Jacobus F. A. and Parra, Carlos and Lu, Yonggang and Shukla-Dave, Amita},
	month = feb,
	year = {2016},
	pmid = {26613878},
	pmcid = {PMC4663682},
	keywords = {Diffusion Magnetic Resonance Imaging, Humans, Data processing, Diffusion, Head and neck cancer, Head and Neck Neoplasms, Magnetic Resonance Angiography, MR imaging, Multimodal Imaging, Neovascularization, Pathologic, Perfusion},
	pages = {123--133}
}

@article{van_veenendaal_metabolic_2015,
	title = {Metabolic and functional {MR} biomarkers of antiepileptic drug effectiveness: {A} review},
	volume = {59},
	copyright = {CC0 1.0 Universal Public Domain Dedication},
	issn = {1873-7528},
	doi = {10.1016/j.neubiorev.2015.10.004},
	abstract = {As a large number of patients with epilepsy do not respond favorably to antiepileptic drugs (AEDs), a better understanding of treatment failure and the cause of adverse side effects is required. The working mechanisms of AEDs also alter neurotransmitter concentrations and brain activity, which can be measured using MR spectroscopy and functional MR imaging, respectively. This review presents an overview of clinical research of MR spectroscopy and functional MR imaging studies to the effects of AEDs on the brain. Despite the scarcity of studies associating MR findings to the effectiveness of AEDs, the current research shows clear potential regarding this matter. Several GABAergic AEDs have been shown to increase the GABA concentration, which was related to seizure reductions, while language problems due to topiramate have been associated with altered activation patterns measured with functional MR imaging. MR spectroscopy and functional MR imaging provide biomarkers that may predict individual treatment outcomes, and enable the assessment of mechanisms of treatment failure and cognitive side effects.},
	language = {eng},
	journal = {Neuroscience and Biobehavioral Reviews},
	author = {van Veenendaal, Tamar M. and IJff, Dominique M. and Aldenkamp, Albert P. and Hofman, Paul A. M. and Vlooswijk, Marielle C. G. and Rouhl, Rob P. W. and de Louw, Anton J. and Backes, Walter H. and Jansen, Jacobus F. A.},
	month = dec,
	year = {2015},
	pmid = {26475992},
	keywords = {Cognitive side effects, Humans, Brain, Epilepsy, Treatment Outcome, Anticonvulsant, Anticonvulsants, MR spectroscopy, Animals, Biomarkers, Functional MRI, Neurotransmitter Agents, Treatment failure},
	pages = {92--99}
}

@article{van_bussel_interplay_2015,
	title = {On the interplay of microvasculature, parenchyma, and memory in type 2 diabetes},
	volume = {38},
	copyright = {CC0 1.0 Universal Public Domain Dedication},
	issn = {1935-5548},
	doi = {10.2337/dc14-2043},
	abstract = {OBJECTIVE: Type 2 diabetes is associated with accelerated cognitive decline, especially regarding memory for which the hippocampus plays an essential role. The pathophysiological mechanisms still remain to be elucidated. The purpose of this study is to examine whether hippocampal microvascular and microstructural changes are related to type 2 diabetes (based on status or based on fasting blood glucose [FBG] levels) and verbal memory performance.
RESEARCH DESIGN AND METHODS: Thirty-nine participants with type 2 diabetes (64.5 ± 6.1 years old) and 34 participants without type 2 diabetes (58.3 ± 9.2 years old) underwent detailed cognitive assessments and 3-Tesla MRI using intravoxel incoherent motion (IVIM) MRI. Multivariate regression analyses controlling for age, sex, education level, BMI, systolic blood pressure, hematocrit level, and relative hippocampal volume were performed to examine associations between hippocampal IVIM measures, type 2 diabetes (status and FBG), and memory performance.
RESULTS: For the microvasculature, blood perfusion volume (f) was larger in participants with type 2 diabetes, f and blood flow (fD*) increased with higher FBG levels, and microvascular pseudodiffusion (D*) and fD*, which are indicative of altered microvasculature, were higher in participants with both relatively high FBG levels and low memory performance. In addition, fD* increased with lower memory performance. For the parenchymal microstructure, the diffusion (D), indicative of injured microstructure, was higher with reduced memory performance.
CONCLUSIONS: In addition to the parenchymal microstructure, especially the microvascular properties of the hippocampus are altered in participants with both type 2 diabetes and memory problems and possibly hint at an underlying vascular mechanism.},
	language = {eng},
	number = {5},
	journal = {Diabetes Care},
	author = {van Bussel, Frank C. and Backes, Walter H. and Hofman, Paul A. and van Oostenbrugge, Robert J. and Kessels, Alfons G. and van Boxtel, Martin P. and Schram, Miranda T. and Stehouwer, Coen D. and Wildberger, Joachim E. and Jansen, Jacobus F.},
	month = may,
	year = {2015},
	pmid = {25690006},
	keywords = {Aged, Female, Humans, Male, Microvessels, Middle Aged, Adult, Case-Control Studies, Memory, Diabetes Mellitus, Type 2, Cognition Disorders, Hippocampus, Magnetic Resonance Angiography, Memory Disorders, Prospective Studies},
	pages = {876--882}
}

@article{ijff_cognitive_2015,
	title = {Cognitive effects of lacosamide as adjunctive therapy in refractory epilepsy},
	volume = {131},
	copyright = {CC0 1.0 Universal Public Domain Dedication},
	issn = {1600-0404},
	doi = {10.1111/ane.12372},
	abstract = {BACKGROUND: Lacosamide (LCM) is a novel antiepileptic drug (AED) with potential benefit as adjunctive treatment in patients with partial-onset seizures. As yet, limited information on cognitive effects of LCM is available, especially in real-life settings.
AIMS: In this open clinical prospective study, the cognitive effects of LCM were evaluated when used as adjunctive antiepileptic therapy in patients with refractory epilepsy.
METHODS: We included 33 patients aged between 16 and 74 years (mean: 37 years). All patients had a localization-related epilepsy. Patients were assessed at baseline before starting LCM treatment and during follow-up when the optimal clinical dose was achieved.
MATERIALS: Subjective complaints were evaluated using the SIDAED; effects on cognition were evaluated using the computerized visual searching task (CVST).
RESULTS: The CVST showed significant faster information processing reaction times at the second evaluation (P = 0.013), which was not correlated with seizure control, type of epilepsy, age, gender, drug load, number of concomitant drugs, dose or duration of LCM treatment. On the SIDAED, patients complained more about their cognitive function at the second evaluation (P = 0.005). For the SIDAED, a positive correlation at follow-up was found between the total severity score and higher age (r = 0.375, P = 0.031), but not with epilepsy factors or treatment characteristics.
DISCUSSION/CONLUSION: Screening of the cognitive effects of LCM showed that LCM does not have negative effects on information processing speed. As this is the most sensitive function for cognitive side effects of AEDs, LCM does not seem to induce the common negative cognitive effects. Remarkably, patients complained more, especially about their cognitive function, which is possible the 'doing better, feeling worse phenomenon'.},
	language = {eng},
	number = {6},
	journal = {Acta Neurologica Scandinavica},
	author = {IJff, D. M. and van Veenendaal, T. M. and Majoie, H. J. M. and de Louw, A. J. A. and Jansen, J. F. A. and Aldenkamp, A. P.},
	month = jun,
	year = {2015},
	pmid = {25630655},
	keywords = {cognition, Aged, Female, Humans, Male, Middle Aged, Adolescent, Adult, Epilepsy, Treatment Outcome, Anticonvulsants, Cognition, Prospective Studies, Acetamides, adverse effects, anti-epileptic drug, epilepsy},
	pages = {347--354}
}

@article{van_de_haar_blood-brain_2015,
	title = {Blood-brain barrier impairment in dementia: current and future in vivo assessments},
	volume = {49},
	copyright = {CC0 1.0 Universal Public Domain Dedication},
	issn = {1873-7528},
	doi = {10.1016/j.neubiorev.2014.11.022},
	abstract = {Increasing evidence indicates that blood-brain barrier (BBB) impairment may play a role in the pathophysiology of cognitive decline and dementia. In vivo imaging studies are needed to quantify and localize the BBB defects during life, contemplating the circulatory properties. We reviewed the literature for imaging studies investigating BBB impairment in patients suffering from dementia. After selection, 11 imaging studies were included, of which 6 used contrast-enhanced magnetic resonance imaging (MRI), 2 used contrast-enhanced computed tomography (CT), and 3 positron emission tomography (PET). Primarily the MRI studies hint at a subtle increasing permeability of the BBB, particularly in patients already exhibiting cerebrovascular pathology. More elaborate studies are required to provide convincing evidence on BBB impairment in patients with various stages of dementia with and without obvious cerebrovascular pathology. In the future, dynamic contrast enhanced MRI techniques and transport specific imaging using PET may further detail the research on the molecular nature of BBB defects.},
	language = {eng},
	journal = {Neuroscience and Biobehavioral Reviews},
	author = {van de Haar, Harm J. and Burgmans, Saartje and Hofman, Paul A. M. and Verhey, Frans R. J. and Jansen, Jacobus F. A. and Backes, Walter H.},
	month = feb,
	year = {2015},
	pmid = {25524876},
	keywords = {Alzheimer's disease, Humans, Blood-Brain Barrier, Blood–brain barrier, Dementia, Animals, Contrast-enhanced, CT, DCE-MRI, PET, Vascular dementia},
	pages = {71--81}
}

@article{besseling_delayed_2014,
	title = {Delayed convergence between brain network structure and function in rolandic epilepsy},
	volume = {8},
	copyright = {CC0 1.0 Universal Public Domain Dedication},
	issn = {1662-5161},
	doi = {10.3389/fnhum.2014.00704},
	abstract = {INTRODUCTION: Rolandic epilepsy (RE) manifests during a critical phase of brain development, and has been associated with language impairments. Concordant abnormalities in structural and functional connectivity (SC and FC) have been described before. As SC and FC are under mutual influence, the current study investigates abnormalities in the SC-FC synergy in RE.
METHODS: Twenty-two children with RE (age, mean ± SD: 11.3 ± 2.0 y) and 22 healthy controls (age 10.5 ± 1.6 y) underwent structural, diffusion weighted, and resting-state functional magnetic resonance imaging (MRI) at 3T. The probabilistic anatomical landmarks atlas was used to parcellate the (sub)cortical gray matter. Constrained spherical deconvolution tractography and correlation of time series were used to assess SC and FC, respectively. The SC-FC correlation was assessed as a function of age for the non-zero structural connections over a range of sparsity values (0.01-0.75). A modularity analysis was performed on the mean SC network of the controls to localize potential global effects to subnetworks. SC and FC were also assessed separately using graph analysis.
RESULTS: The SC-FC correlation was significantly reduced in children with RE compared to healthy controls, especially for the youngest participants. This effect was most pronounced in a left and a right centro-temporal network, as well as in a medial parietal network. Graph analysis revealed no prominent abnormalities in SC or FC network organization.
CONCLUSION: Since SC and FC converge during normal maturation, our finding of reduced SC-FC correlation illustrates impaired synergy between brain structure and function. More specifically, since this effect was most pronounced in the youngest participants, RE may represent a developmental disorder of delayed brain network maturation. The observed effects seem especially attributable to medial parietal connections, which forms an intermediate between bilateral centro-temporal modules of epileptiform activity, and bear relevance for language function.},
	language = {eng},
	journal = {Frontiers in Human Neuroscience},
	author = {Besseling, René M. H. and Jansen, Jacobus F. A. and Overvliet, Geke M. and van der Kruijs, Sylvie J. M. and Ebus, Saskia C. M. and de Louw, Anton J. A. and Hofman, Paul A. M. and Aldenkamp, Albert P. and Backes, Walter H.},
	year = {2014},
	pmid = {25249968},
	pmcid = {PMC4158874},
	keywords = {brain maturation, functional connectivity, graph theory, rolandic epilepsy, structural connectivity, structure-function correlation},
	pages = {704}
}

@article{braakman_aetiology_2015,
	title = {Aetiology of cognitive impairment in children with frontal lobe epilepsy},
	volume = {131},
	copyright = {CC0 1.0 Universal Public Domain Dedication},
	issn = {1600-0404},
	doi = {10.1111/ane.12283},
	abstract = {OBJECTIVES: Cognitive impairment is frequent in children with frontal lobe epilepsy (FLE), but its aetiology is unknown. MRI scans often reveal no structural brain abnormalities that could explain the cognitive impairment. This does not exclude more subtle morphological abnormalities that can only be detected by automated morphometric techniques.
AIMS: With these techniques, we investigate the relationship between cortical brain morphology and cognitive functioning in a cohort of children with FLE and healthy controls.
MATERIALS AND METHODS: Thirty-four children aged 8-13 years with FLE of unknown cause and 41 healthy age-matched controls underwent neuropsychological assessment and structural brain MRI. Patients were grouped as cognitively impaired or unimpaired. Intracranial volume, white matter volume, lobular cortical volume, cortical thickness and volumes of cortex structures were compared between patients and controls, and potential correlations with cognitive status were determined.
RESULTS: The group of cognitively impaired children with FLE had significantly smaller left temporal cortex volumes, specifically middle temporal grey matter volume and entorhinal cortex thickness. In addition, cognitively impaired children with FLE had smaller volumes of structures in the left and right frontal cortex, right temporal cortex and the left subcortical area.
CONCLUSION: Cognitively impaired children with FLE have smaller volumes of various cortex structures within the frontal lobes and in extra-frontal regions, most notably temporal cortex volumes. These findings might well explain the broad scale of cognitive domains affected in children with FLE complicated by cognitive impairment and highlight that FLE impacts on areas beyond the frontal lobe.},
	language = {eng},
	number = {1},
	journal = {Acta Neurologica Scandinavica},
	author = {Braakman, H. M. H. and Vaessen, M. J. and Jansen, J. F. A. and Debeij-van Hall, M. H. J. A. and de Louw, A. and Hofman, P. a. M. and Vles, J. S. H. and Aldenkamp, A. P. and Backes, W. H.},
	month = jan,
	year = {2015},
	pmid = {25208759},
	keywords = {Female, Humans, Male, Adolescent, Brain, Magnetic Resonance Imaging, Neuropsychological Tests, Child, Cognition Disorders, all epilepsy/seizures, all paediatric, Epilepsy, Frontal Lobe, MRI, neuropsychological assessment, volumetric MRI},
	pages = {17--29}
}

@article{gupta_spatial_2014,
	title = {Spatial heterogeneity analysis of brain activation in {fMRI}},
	volume = {5},
	copyright = {CC0 1.0 Universal Public Domain Dedication},
	issn = {2213-1582},
	doi = {10.1016/j.nicl.2014.06.013},
	abstract = {In many brain diseases it can be qualitatively observed that spatial patterns in blood oxygenation level dependent (BOLD) activation maps appear more (diffusively) distributed than in healthy controls. However, measures that can quantitatively characterize this spatial distributiveness in individual subjects are lacking. In this study, we propose a number of spatial heterogeneity measures to characterize brain activation maps. The proposed methods focus on different aspects of heterogeneity, including the shape (compactness), complexity in the distribution of activated regions (fractal dimension and co-occurrence matrix), and gappiness between activated regions (lacunarity). To this end, functional MRI derived activation maps of a language and a motor task were obtained in language impaired children with (Rolandic) epilepsy and compared to age-matched healthy controls. Group analysis of the activation maps revealed no significant differences between patients and controls for both tasks. However, for the language task the activation maps in patients appeared more heterogeneous than in controls. Lacunarity was the best measure to discriminate activation patterns of patients from controls (sensitivity 74\%, specificity 70\%) and illustrates the increased irregularity of gaps between activated regions in patients. The combination of heterogeneity measures and a support vector machine approach yielded further increase in sensitivity and specificity to 78\% and 80\%, respectively. This illustrates that activation distributions in impaired brains can be complex and more heterogeneous than in normal brains and cannot be captured fully by a single quantity. In conclusion, heterogeneity analysis has potential to robustly characterize the increased distributiveness of brain activation in individual patients.},
	language = {eng},
	journal = {NeuroImage. Clinical},
	author = {Gupta, Lalit and Besseling, René M. H. and Overvliet, Geke M. and Hofman, Paul A. M. and de Louw, Anton and Vaessen, Maarten J. and Aldenkamp, Albert P. and Ulman, Shrutin and Jansen, Jacobus F. A. and Backes, Walter H.},
	year = {2014},
	pmid = {25161893},
	pmcid = {PMC4141984},
	keywords = {Functional magnetic resonance imaging, Female, Humans, Male, Adolescent, Brain, Magnetic Resonance Imaging, Image Interpretation, Computer-Assisted, Brain Mapping, Child, Activation patterns, Algorithms, BOLD activation maps, Co-occurrence Matrix, Epilepsy, Rolandic, Fractal dimensions, Lacunarity, Spatial Analysis, Spatial heterogeneity},
	pages = {266--276}
}

@article{jansen_quantitative_2014,
	title = {Quantitative {MR} and cognitive impairment in cryptogenic localisation-related epilepsy},
	volume = {16},
	copyright = {CC0 1.0 Universal Public Domain Dedication},
	issn = {1294-9361},
	doi = {10.1684/epd.2014.0665},
	abstract = {For patients with chronic cryptogenic localisation-related epilepsy (CLRE), conventional MRI does not provide measures to discern between patients with or without cognitive complaints. We investigated, in a preliminary study, whether it is possible to detect cerebral biomarkers of cognitive impairment in patients with CLRE using sensitive quantitative MRI techniques. Neuropsychological assessment and quantitative 3.0 T MRI, comprising T2 relaxometry, diffusion tensor imaging, and spectroscopic imaging, were applied to 35 patients with CLRE and 21 healthy controls. Analysis included the left and right hippocampi, and frontal and temporal lobes. Differences between the groups and correlations with cognitive and clinical characteristics were assessed. Patients with epilepsy scored significantly worse on cognitive tasks compared to healthy controls. Significantly larger CSF fractions in the hippocampi and left temporal lobe, a longer T2 relaxation time in the left hippocampus, and a significantly higher concentration of glutamate/glutamine in the left frontal lobe were observed in patients with epilepsy. Moreover, poor memory performance was significantly correlated with larger CSF fractions in the right hippocampus and left temporal lobe in patients. In the temporal lobe, an association between subtle changes in morphology (indicative of atrophy) and memory performance was found, consistent with previous literature. These results may help to explain the alterations in brain functioning in patients with epilepsy.},
	language = {eng},
	number = {3},
	journal = {Epileptic Disorders: International Epilepsy Journal with Videotape},
	author = {Jansen, Jacobus Fa and van der Kruijs, Sylvie Jm and Vlooswijk, Mariëlle Cg and Majoie, Hj Marian and Hofman, Paul Am and Aldenkamp, Albert P. and Backes, Walter H.},
	month = sep,
	year = {2014},
	pmid = {25036856},
	keywords = {cognition, Female, Humans, Male, Middle Aged, Adult, Epilepsy, Image Processing, Computer-Assisted, Neuropsychological Tests, Cognition, Magnetic Resonance Spectroscopy, MR spectroscopy, Cognition Disorders, Diffusion Tensor Imaging, memory, diffusion tensor imaging, localization-related epilepsy, MRI-negative},
	pages = {318--327}
}

@article{van_der_kruijs_resting-state_2014,
	title = {Resting-state networks and dissociation in psychogenic non-epileptic seizures},
	volume = {54},
	copyright = {CC0 1.0 Universal Public Domain Dedication},
	issn = {1879-1379},
	doi = {10.1016/j.jpsychires.2014.03.010},
	abstract = {OBJECTIVE: Psychogenic non-epileptic seizures (PNES) are epilepsy-like episodes which have an emotional rather than organic origin. Although PNES have often been related to the process of dissociation, the psychopathology is still poorly understood. To elucidate underlying mechanisms, the current study applied independent component analysis (ICA) on resting-state fMRI to investigate alterations within four relevant networks, associated with executive, fronto-parietal, sensorimotor, and default mode activation, and within a visual network to examine specificity of between-group differences.
METHODS: Twenty-one patients with PNES without psychiatric or neurologic comorbidities and twenty-seven healthy controls underwent resting-state functional MR imaging at 3.0T (Philips Achieva). Additional neuropsychological testing included Raven's Matrices test and dissociation questionnaires. ICA with dual regression was used to identify resting-state networks in all participants, and spatial maps of the networks of interest were compared between patients and healthy controls.
RESULTS: Patients displayed higher dissociation scores, lower cognitive performance and increased contribution of the orbitofrontal, insular and subcallosal cortex in the fronto-parietal network; the cingulate and insular cortex in the executive control network; the cingulate gyrus, superior parietal lobe, pre- and postcentral gyri and supplemental motor cortex in the sensorimotor network; and the precuneus and (para-) cingulate gyri in the default-mode network. The connectivity strengths within these regions of interest significantly correlated with dissociation scores. No between-group differences were found within the visual network, which was examined to determine specificity of between-group differences.
CONCLUSIONS: PNES patients displayed abnormalities in several resting-state networks that provide neuronal correlates for an underlying dissociation mechanism.},
	language = {eng},
	journal = {Journal of Psychiatric Research},
	author = {van der Kruijs, Sylvie J. M. and Jagannathan, Sridhar R. and Bodde, Nynke M. G. and Besseling, René M. H. and Lazeron, Richard H. C. and Vonck, Kristl E. J. and Boon, Paul A. J. M. and Cluitmans, Pierre J. M. and Hofman, Paul A. M. and Backes, Walter H. and Aldenkamp, Albert P. and Jansen, Jacobus F. A.},
	month = jul,
	year = {2014},
	pmid = {24703187},
	keywords = {Female, Humans, Male, Middle Aged, Adult, Brain, Image Processing, Computer-Assisted, Magnetic Resonance Imaging, Oxygen, Brain Mapping, Rest, Neuropsychological Tests, Seizures, Magnetic resonance imaging, Psychophysiologic Disorders, Dissociation, Dissociative Disorders, Independent component analysis, Psychogenic non-epileptic seizures, Resting-state networks, Statistics as Topic, Surveys and Questionnaires},
	pages = {126--133}
}

@article{vaessen_functional_2014,
	title = {Functional and structural network impairment in childhood frontal lobe epilepsy},
	volume = {9},
	copyright = {CC0 1.0 Universal Public Domain Dedication},
	issn = {1932-6203},
	doi = {10.1371/journal.pone.0090068},
	abstract = {In childhood frontal lobe epilepsy (FLE), cognitive impairment and educational underachievement are serious, well-known co-morbidities. The broad scale of affected cognitive domains suggests wide-spread network disturbances that not only involves, but also extends beyond the frontal lobe. In this study we have investigated whole brain connectional properties of children with FLE in relation to their cognitive impairment and compared them with healthy controls. Functional connectivity (FC) of the networks was derived from dynamic fluctuations of resting state fMRI and structural connectivity (SC) was obtained from fiber tractograms of diffusion weighted MRI. The whole brain network was characterized with graph theoretical metrics and decomposed into modules. Subsequently, the graph metrics and the connectivity within and between modules were related to cognitive performance. Functional network disturbances in FLE were related to increased clustering, increased path length, and stronger modularity compared to healthy controls, which was accompanied by stronger within- and weaker between-module functional connectivity. Although structural path length and clustering appeared normal in children with FLE, structural modularity increased with stronger cognitive impairment. It is concluded that decreased coupling between large-scale functional network modules is a hallmark for impaired cognition in childhood FLE.},
	language = {eng},
	number = {3},
	journal = {PloS One},
	author = {Vaessen, Maarten J. and Jansen, Jacobus F. A. and Braakman, Hilde M. H. and Hofman, Paul A. M. and De Louw, Anton and Aldenkamp, Albert P. and Backes, Walter H.},
	year = {2014},
	pmid = {24594874},
	pmcid = {PMC3942412},
	keywords = {Humans, Adolescent, Magnetic Resonance Imaging, Aging, Case-Control Studies, Child, Cognition Disorders, Nerve Net, Epilepsy, Frontal Lobe},
	pages = {e90068}
}

@article{besseling_reduced_2013,
	title = {Reduced structural connectivity between sensorimotor and language areas in rolandic epilepsy},
	volume = {8},
	copyright = {CC0 1.0 Universal Public Domain Dedication},
	issn = {1932-6203},
	doi = {10.1371/journal.pone.0083568},
	abstract = {INTRODUCTION: Rolandic epilepsy (RE) is a childhood epilepsy with centrotemporal (rolandic) spikes, that is increasingly associated with language impairment. In this study, we tested for a white matter (connectivity) correlate, employing diffusion weighted MRI and language testing.
METHODS: Twenty-three children with RE and 23 matched controls (age: 8-14 years) underwent structural (T1-weighted) and diffusion-weighted MRI (b = 1200 s/mm(2), 66 gradient directions) at 3T, as well as neuropsychological language testing. Combining tractography and a cortical segmentation derived from the T1-scan, the rolandic tract were reconstructed (pre- and postcentral gyri), and tract fractional anisotropy (FA) values were compared between patients and controls. Aberrant tracts were tested for correlations with language performance.
RESULTS: Several reductions of tract FA were found in patients compared to controls, mostly in the left hemisphere; the most significant effects involved the left inferior frontal (p = 0.005) and supramarginal (p = 0.004) gyrus. In the patient group, lower tract FA values were correlated with lower language performance, among others for the connection between the left postcentral and inferior frontal gyrus (p = 0.043, R = 0.43).
CONCLUSION: In RE, structural connectivity is reduced for several connections involving the rolandic regions, from which the epileptiform activity originates. Most of these aberrant tracts involve the left (typically language mediating) hemisphere, notably the pars opercularis of the inferior frontal gyrus (Broca's area) and the supramarginal gyrus (Wernicke's area). For the former, reduced language performance for lower tract FA was found in the patients. These findings provide a first microstructural white matter correlate for language impairment in RE.},
	language = {eng},
	number = {12},
	journal = {PloS One},
	author = {Besseling, René M. H. and Jansen, Jacobus F. A. and Overvliet, Geke M. and van der Kruijs, Sylvie J. M. and Ebus, Saskia C. M. and de Louw, Anton and Hofman, Paul A. M. and Vles, Johannes S. H. and Aldenkamp, Albert P. and Backes, Walter H.},
	year = {2013},
	pmid = {24376719},
	pmcid = {PMC3871667},
	keywords = {Female, Humans, Male, White Matter, Adolescent, Case-Control Studies, Language, Child, Diffusion Tensor Imaging, Epilepsy, Rolandic, Anisotropy, Language Tests, Sensorimotor Cortex},
	pages = {e83568}
}

@article{matulewicz_anatomic_2014,
	title = {Anatomic segmentation improves prostate cancer detection with artificial neural networks analysis of 1H magnetic resonance spectroscopic imaging},
	volume = {40},
	copyright = {CC0 1.0 Universal Public Domain Dedication},
	issn = {1522-2586},
	doi = {10.1002/jmri.24487},
	abstract = {PURPOSE: To assess whether an artificial neural network (ANN) model is a useful tool for automatic detection of cancerous voxels in the prostate from (1)H-MRSI datasets and whether the addition of information about anatomical segmentation improves the detection of cancer.
MATERIALS AND METHODS: The Institutional Review Board approved this HIPAA-compliant study and waived informed consent. Eighteen men with prostate cancer (median age, 55 years; range, 36-71 years) who underwent endorectal MRI/MRSI before radical prostatectomy were included in this study. These patients had at least one cancer area on whole-mount histopathological map and at least one matching MRSI voxel suspicious for cancer detected. Two ANN models for automatic classification of MRSI voxels in the prostate were implemented and compared: model 1, which used only spectra as input, and model 2, which used the spectra plus information from anatomical segmentation. The models were trained, tested and validated using spectra from voxels that the spectroscopist had designated as cancer and that were verified on histopathological maps.
RESULTS: At ROC analysis, model 2 (AUC = 0.968) provided significantly better (P = 0.03) classification of cancerous voxels than did model 1 (AUC = 0.949).
CONCLUSION: Automatic analysis of prostate MRSI to detect cancer using ANN model is feasible. Application of anatomical segmentation from MRI as an additional input to ANN improves the accuracy of detecting cancerous voxels from MRSI.},
	language = {eng},
	number = {6},
	journal = {Journal of magnetic resonance imaging: JMRI},
	author = {Matulewicz, Lukasz and Jansen, Jacobus F. A. and Bokacheva, Louisa and Vargas, Hebert Alberto and Akin, Oguz and Fine, Samson W. and Shukla-Dave, Amita and Eastham, James A. and Hricak, Hedvig and Koutcher, Jason A. and Zakian, Kristen L.},
	month = dec,
	year = {2014},
	pmid = {24243554},
	pmcid = {PMC4306557},
	keywords = {Aged, Humans, Male, Middle Aged, Adult, Magnetic Resonance Imaging, Algorithms, Biomarkers, Tumor, computer-aided diagnosis, Image Enhancement, magnetic resonance spectroscopic imaging, neural networks, Neural Networks (Computer), pattern recognition, Pattern Recognition, Automated, prostate cancer, Prostatic Neoplasms, Proton Magnetic Resonance Spectroscopy, Reproducibility of Results, Sensitivity and Specificity},
	pages = {1414--1421}
}

@article{besseling_aberrant_2013,
	title = {Aberrant functional connectivity between motor and language networks in rolandic epilepsy},
	volume = {107},
	copyright = {CC0 1.0 Universal Public Domain Dedication},
	issn = {1872-6844},
	doi = {10.1016/j.eplepsyres.2013.10.008},
	abstract = {INTRODUCTION: Rolandic epilepsy (RE) is an idiopathic focal childhood epilepsy with a well-established neuropsychological profile of language impairment. The aim of this study is to provide a functional correlate that links rolandic (sensorimotor) pathology to language problems using functional MRI.
MATERIALS AND METHODS: Twenty-three children with RE (8-14 years old) and 21 matched controls underwent extensive language assessment (Clinical Evaluation of Language Fundamentals). fMRI was performed at rest and using word generation, reading, and finger tapping paradigms. Since no activation group differences were found, regions of interest (ROIs) were defined at pooled (patients and controls combined) activation maxima and in contralateral homotopic cortex, and used to assess language lateralization as well as for a resting-state connectivity analysis. Furthermore, the association between connection strength and language performance was investigated.
RESULTS: Reduced language performance was found in the children with RE. Bilateral activation was found for both language tasks with some predominance of the left hemisphere in both groups. Compared to controls, patient connectivity was decreased between the left sensorimotor area and right inferior frontal gyrus (p{\textless}0.01). For this connection, lower connectivity was associated with lower language scores in the patient group (r=0.49, p=0.02), but not in the controls.
CONCLUSION: Language laterality analysis revealed bilateral language representation in the age range under study (8-14 years). As a consequence, the connection of reduced functional connectivity we found represents an impaired interplay between motor and language networks, and aberrant functional connectivity associated with poorer language performance. These findings provide a first neuronal correlate in terms of aberrant resting-state functional connectivity for language impairment in RE.},
	language = {eng},
	number = {3},
	journal = {Epilepsy Research},
	author = {Besseling, René M. H. and Overvliet, Geke M. and Jansen, Jacobus F. A. and van der Kruijs, Sylvie J. M. and Vles, Johannes S. H. and Ebus, Saskia C. M. and Hofman, Paul A. M. and de Louw, Anton J. A. and Aldenkamp, Albert P. and Backes, Walter H.},
	month = dec,
	year = {2013},
	pmid = {24210960},
	keywords = {Female, Humans, Male, Adolescent, Magnetic Resonance Imaging, Language, Child, Nerve Net, rolandic epilepsy, Epilepsy, Rolandic, Language Tests, Benign rolandic epilepsy of childhood with centro temporal spikes, Cerebral Cortex, Language impairment, Psychomotor Performance, RE, Resting-state functional MRI, Sensory Gating},
	pages = {253--262}
}

@article{overvliet_early_2013,
	title = {Early onset of cortical thinning in children with rolandic epilepsy},
	volume = {2},
	copyright = {CC0 1.0 Universal Public Domain Dedication},
	issn = {2213-1582},
	doi = {10.1016/j.nicl.2013.03.008},
	abstract = {INTRODUCTION: Rolandic epilepsy, a childhood epilepsy associated with language impairments, was investigated for language-related cortical abnormalities.
METHODS: Twenty-four children with rolandic epilepsy and 24 controls (age 8-14 years) were recruited and underwent the Clinical Evaluation of Language Fundamentals test. Structural MRI was performed at 3 T (voxel size 1 × 1 × 1 mm(3)) for fully automated quantitative assessment of cortical thickness. Regression analysis was used to test for differences between patients and controls and to assess the effect of age and language indices on cortical thickness.
RESULTS: For patients the core language score (mean ± SD: 92 ± 18) was lower than for controls (106 ± 11, p = 0.0026) and below the norm of 100 ± 15 (p = 0.047). Patients showed specific impairments in receptive language index (87 ± 19, p = 0.002) and language content index (87 ± 18, p = 0.0016). Cortical thickness was reduced in patients (p {\textless} 0.05, multiple-comparisons corrected) in left perisylvian regions. Furthermore, extensive cortical thinning with age was found in predominantly left-lateralized frontal, centro-parietal and temporal regions. No associations were found between cortical thickness and language indices in the regions of aberrant cortex.
CONCLUSION: The cortical abnormalities described represent subtle but significant pathomorphology in this critical phase of brain development (8-14 years) and suggest that rolandic epilepsy should not be considered merely a benign condition. Future studies employing longitudinal designs are prompted for further investigations into cerebral abnormalities in RE and associations with cognitive impairment and development.},
	language = {eng},
	journal = {NeuroImage. Clinical},
	author = {Overvliet, Geke M. and Besseling, René M. H. and Jansen, Jacobus F. A. and van der Kruijs, Sylvie J. M. and Vles, Johannes S. H. and Hofman, Paul A. M. and Ebus, Saskia C. M. and de Louw, Anton and Aldenkamp, Albert P. and Backes, Walter H.},
	year = {2013},
	pmid = {24179797},
	pmcid = {PMC3777705},
	keywords = {Language impairment, Benign rolandic epilepsy of childhood with centro-temporal spikes, Cortical thickness (quantitative), Developmental trajectory},
	pages = {434--439}
}

@article{besseling_reduced_2013-1,
	title = {Reduced functional integration of the sensorimotor and language network in rolandic epilepsy},
	volume = {2},
	copyright = {CC0 1.0 Universal Public Domain Dedication},
	issn = {2213-1582},
	doi = {10.1016/j.nicl.2013.01.004},
	abstract = {INTRODUCTION: Over the last years, evidence has accumulated that rolandic epilepsy (RE) is associated with serious cognitive comorbidities, including language impairment. However, the cerebral mechanism through which epileptiform activity in the rolandic (sensorimotor) areas may affect the language system is unknown. To investigate this, the connectivity between rolandic areas and regions involved in language processing is studied using functional MRI (fMRI).
MATERIALS AND METHODS: fMRI data was acquired from 22 children with rolandic epilepsy and 22 age-matched controls (age range: 8-14 years), both at rest and using word-generation and reading tasks. Activation map analysis revealed no group differences (FWE-corrected, p {\textless} 0.05) and was therefore used to define regions of interest for pooled (patients and controls combined) language activation. Independent component analysis with dual regression was used to identify the sensorimotor resting-state network in all subjects. The associated functional connectivity maps were compared between groups at the regions of interest for language activation identified from the task data. In addition, neuropsychological language testing (Clinical Evaluation of Language Fundamentals, 4th edition) was performed.
RESULTS: Functional connectivity with the sensorimotor network was reduced in patients compared to controls (p = 0.011) in the left inferior frontal gyrus, i.e. Broca's area as identified by the word-generation task. No aberrant functional connectivity values were found in the other regions of interest, nor were any associations found between functional connectivity and language performance. Neuropsychological testing confirmed language impairment in patients relative to controls (reductions in core language score, p = 0.03; language content index, p = 0.01; receptive language index, p = 0.005).
CONCLUSION: Reduced functional connectivity was demonstrated between the sensorimotor network and the left inferior frontal gyrus (Broca's area) in children with RE, which might link epileptiform activity/seizures originating from the sensorimotor cortex to language impairment, and is in line with the identified neuropsychological profile of anterior language dysfunction.},
	language = {eng},
	journal = {NeuroImage. Clinical},
	author = {Besseling, René M. H. and Jansen, Jacobus F. A. and Overvliet, Geke M. and van der Kruijs, Sylvie J. M. and Vles, Johannes S. H. and Ebus, Saskia C. M. and Hofman, Paul A. M. and Louw, Anton de and Aldenkamp, Albert P. and Backes, Walter H.},
	year = {2013},
	pmid = {24179777},
	pmcid = {PMC3777786},
	keywords = {Rolandic epilepsy, Independent component analysis, Resting-state networks, Language impairment, ICA, independent component analysis, RE, rolandic epilepsy, Resting-state fMRI, Sensorimotor/rolandic network},
	pages = {239--246}
}

@article{braakman_pediatric_2014,
	title = {Pediatric frontal lobe epilepsy: white matter abnormalities and cognitive impairment},
	volume = {129},
	copyright = {CC0 1.0 Universal Public Domain Dedication},
	issn = {1600-0404},
	doi = {10.1111/ane.12183},
	abstract = {OBJECTIVES: Cognitive impairment is frequent in children with frontal lobe epilepsy (FLE). Its etiology remains unknown. With diffusion tensor imaging, we have studied cerebral white matter properties and associations with cognitive functioning in children with FLE and healthy controls.
METHODS: Thirty children aged 8-13 years with FLE of unknown cause and 39 healthy age-matched controls underwent neuropsychological assessment, structural and diffusion-weighted brain MRI. Patients were grouped as cognitively impaired or unimpaired, and their white matter diffusion properties were compared with the controls.
RESULTS: Children with FLE had reduced apparent diffusion coefficients in various posteriorly located tract bundles, a reduced fractional anisotropy (FA) of the white matter tract between the right frontal and right occipital lobe, and smaller volumes of several collections of interlobar bundle tracts, compared with controls. The cognitively impaired patient group demonstrated significant increases in FA of the white matter of both occipital lobes, a reduced FA of white matter tract bundles between the right frontal and both left occipital lobe and subcortical white matter area, and smaller volumes of two collections of tract bundles connecting the frontal lobe with the temporal and parietal lobes, compared with controls.
CONCLUSIONS: Children with FLE had white matter abnormalities mainly in posterior brain regions, not confined to the area of the seizure focus. Cognitively impaired children with FLE showed the most pronounced white matter abnormalities. These possibly reflect disturbed maturation and might be part of the etiology of the cognitive impairment.},
	language = {eng},
	number = {4},
	journal = {Acta Neurologica Scandinavica},
	author = {Braakman, H. M. H. and Vaessen, M. J. and Jansen, J. F. A. and Debeij-van Hall, M. H. J. A. and de Louw, A. and Hofman, P. a. M. and Vles, J. S. H. and Aldenkamp, A. P. and Backes, W. H.},
	month = apr,
	year = {2014},
	pmid = {24112290},
	keywords = {Diffusion Magnetic Resonance Imaging, Female, Humans, Male, Adolescent, Brain, Case-Control Studies, Neuropsychological Tests, Child, Cognition Disorders, epilepsy, Epilepsy, Frontal Lobe, Anisotropy, Analysis of Variance, Leukoencephalopathies, Nerve Fibers, Myelinated, neuroimaging, neuropsychology, pediatric neurology, Pediatrics},
	pages = {252--262}
}

@article{barendse_working_2013,
	title = {Working memory deficits in high-functioning adolescents with autism spectrum disorders: neuropsychological and neuroimaging correlates},
	volume = {5},
	copyright = {CC0 1.0 Universal Public Domain Dedication},
	issn = {1866-1947},
	doi = {10.1186/1866-1955-5-14},
	abstract = {Working memory is a temporary storage system under attentional control. It is believed to play a central role in online processing of complex cognitive information and may also play a role in social cognition and interpersonal interactions. Adolescents with a disorder on the autism spectrum display problems in precisely these domains. Social impairments, communication difficulties, and repetitive interests and activities are core domains of autism spectrum disorders (ASD), and executive function problems are often seen throughout the spectrum. As the main cognitive theories of ASD, including the theory of mind deficit hypotheses, weak central coherence account, and the executive dysfunction theory, still fail to explain the broad spectrum of symptoms, a new perspective on the etiology of ASD is needed. Deficits in working memory are central to many theories of psychopathology, and are generally linked to frontal-lobe dysfunction. This article will review neuropsychological and (functional) brain imaging studies on working memory in adolescents with ASD. Although still disputed, it is concluded that within the working memory system specific problems of spatial working memory are often seen in adolescents with ASD. These problems increase when information is more complex and greater demands on working memory are made. Neuroimaging studies indicate a more global working memory processing or connectivity deficiency, rather than a focused deficit in the prefrontal cortex. More research is needed to relate these working memory difficulties and neuroimaging results in ASD to the behavioral difficulties as seen in individuals with a disorder on the autism spectrum.},
	language = {eng},
	number = {1},
	journal = {Journal of Neurodevelopmental Disorders},
	author = {Barendse, Evelien M. and Hendriks, Marc Ph and Jansen, Jacobus Fa and Backes, Walter H. and Hofman, Paul Am and Thoonen, Geert and Kessels, Roy Pc and Aldenkamp, Albert P.},
	month = jun,
	year = {2013},
	pmid = {23731472},
	pmcid = {PMC3674927},
	pages = {14}
}

@article{lu_comparing_2013,
	title = {Comparing primary tumors and metastatic nodes in head and neck cancer using intravoxel incoherent motion imaging: a preliminary experience},
	volume = {37},
	copyright = {CC0 1.0 Universal Public Domain Dedication},
	issn = {1532-3145},
	doi = {10.1097/RCT.0b013e318282d935},
	abstract = {OBJECTIVE: This study aimed to use intravoxel incoherent motion (IVIM) imaging for investigating differences between primary head and neck tumors and nodal metastases and to evaluate IVIM efficacy in predicting outcome.
METHODS: Sixteen patients with head and neck cancer underwent IVIM diffusion-weighted imaging on a 1.5-T magnetic resonance imaging scanner. The significance of parametric difference between primary tumors and metastatic nodes were tested. Probabilities of progression-free survival and overall survival were estimated using the Kaplan-Meier method.
RESULTS: In comparison with metastatic nodes, the primary tumors had significantly higher vascular volume fraction (f) (P {\textless} 0.0009) and lower diffusion coefficient (D) (P {\textless} 0.0002). Patients with lower SD for D had prolonged progression-free survival and overall survival (P {\textless} 0.05).
CONCLUSIONS: Pretreatment IVIM measures were feasible in investigating the physiologic differences between the 2 tumor tissues. After appropriate validation, these findings might be useful in optimizing treatment planning and improving patient care.},
	language = {eng},
	number = {3},
	journal = {Journal of Computer Assisted Tomography},
	author = {Lu, Yonggang and Jansen, Jacobus F. A. and Stambuk, Hilda E. and Gupta, Gaorav and Lee, Nancy and Gonen, Mithat and Moreira, Andre and Mazaheri, Yousef and Patel, Snehal G. and Deasy, Joseph O. and Shah, Jatin P. and Shukla-Dave, Amita},
	month = jun,
	year = {2013},
	pmid = {23674004},
	pmcid = {PMC3655331},
	keywords = {Diffusion Magnetic Resonance Imaging, Female, Humans, Male, Middle Aged, Adult, Retrospective Studies, Head and Neck Neoplasms, Biopsy, Data Interpretation, Statistical, Echo-Planar Imaging, Lymphatic Metastasis, Survival Analysis},
	pages = {346--352}
}

@article{overvliet_clinical_2013,
	title = {Clinical evaluation of language fundamentals in {Rolandic} epilepsy, an assessment with {CELF}-4},
	volume = {17},
	copyright = {CC0 1.0 Universal Public Domain Dedication},
	issn = {1532-2130},
	doi = {10.1016/j.ejpn.2013.01.001},
	abstract = {BACKGROUND: In clinical practice, Rolandic epilepsy is in many cases associated with developmental language impairment. However, from the literature it is unclear exactly which domains are affected; A wide variety of investigations are reported that each provide a different representation of language performance in these patients.
AIMS: The aim of this study is to compare performance on the language domains between children with Rolandic epilepsy and healthy controls.
METHODS: Prospective study of children with Rolandic epilepsy compared to healthy controls. 25 children (mean age 136.6 months, SD 23.0) with Rolandic epilepsy and 25 age-matched healthy controls were tested on their language function using the CELF-4 (Clinical evaluation of Language Fundamentals, Dutch edition). The healthy control were not matched regard to other important factors, particularly educational attainment and co-morbidity. Expressive language, receptive language, language content, language structure and language working memory were tested.
RESULTS: In children with Rolandic epilepsy, the core language score was significant lower compared with healthy controls. They scored specifically lower on the receptive language index and language content index (both p = 0.002). A trend towards decreased expressive language index was observed (p = 0.054). Language structure and language working memory were in the normal range.
CONCLUSION: Language was found to be impaired in children with typical Rolandic epilepsy. Especially semantic language processing including receptive language and language content was significantly impaired. The common denominator of these functions is semantic language processing.},
	language = {eng},
	number = {4},
	journal = {European journal of paediatric neurology: EJPN: official journal of the European Paediatric Neurology Society},
	author = {Overvliet, Geke M. and Besseling, René M. H. and van der Kruijs, Sylvie J. M. and Vles, Johan S. H. and Backes, Walter H. and Hendriksen, Jos G. and Ebus, Saskia C. M. and Jansen, Jacobus F. A. and Hofman, Paul A. M. and Aldenkamp, Albert P.},
	month = jul,
	year = {2013},
	pmid = {23422906},
	keywords = {Female, Humans, Male, Adolescent, Case-Control Studies, Child, Epilepsy, Rolandic, Language Tests, Sensitivity and Specificity, Developmental Disabilities, Language Disorders},
	pages = {390--396}
}

@article{braakman_frontal_2013,
	title = {Frontal lobe connectivity and cognitive impairment in pediatric frontal lobe epilepsy},
	volume = {54},
	copyright = {CC0 1.0 Universal Public Domain Dedication},
	issn = {1528-1167},
	doi = {10.1111/epi.12044},
	abstract = {PURPOSE: Cognitive impairment is frequent in children with frontal lobe epilepsy (FLE), but its etiology is unknown. With functional magnetic resonance imaging (fMRI), we have explored the relationship between brain activation, functional connectivity, and cognitive functioning in a cohort of pediatric patients with FLE and healthy controls.
METHODS: Thirty-two children aged 8-13 years with FLE of unknown cause and 41 healthy age-matched controls underwent neuropsychological assessment and structural and functional brain MRI. We investigated to which extent brain regions activated in response to a working memory task and assessed functional connectivity between distant brain regions. Data of patients were compared to controls, and patients were grouped as cognitively impaired or unimpaired.
KEY FINDINGS: Children with FLE showed a global decrease in functional brain connectivity compared to healthy controls, whereas brain activation patterns in children with FLE remained relatively intact. Children with FLE complicated by cognitive impairment typically showed a decrease in frontal lobe connectivity. This decreased frontal lobe connectivity comprised both connections within the frontal lobe as well as connections from the frontal lobe to the parietal lobe, temporal lobe, cerebellum, and basal ganglia.
SIGNIFICANCE: Decreased functional frontal lobe connectivity is associated with cognitive impairment in pediatric FLE. The importance of impairment of functional integrity within the frontal lobe network, as well as its connections to distant areas, provides new insights in the etiology of the broad-range cognitive impairments in children with FLE.},
	language = {eng},
	number = {3},
	journal = {Epilepsia},
	author = {Braakman, Hilde M. H. and Vaessen, Maarten J. and Jansen, Jacobus F. A. and Debeij-van Hall, Mariette H. J. A. and de Louw, Anton and Hofman, Paul A. M. and Vles, Johan S. H. and Aldenkamp, Albert P. and Backes, Walter H.},
	month = mar,
	year = {2013},
	pmid = {23253092},
	keywords = {Female, Humans, Male, Adolescent, Child, Cognition Disorders, Nerve Net, Epilepsy, Frontal Lobe, Psychomotor Performance, Cohort Studies, Frontal Lobe, Neural Pathways, Photic Stimulation, Registries},
	pages = {446--454}
}

@article{van_der_kruijs_neurophysiological_2014,
	title = {Neurophysiological correlates of dissociative symptoms},
	volume = {85},
	copyright = {CC0 1.0 Universal Public Domain Dedication},
	issn = {1468-330X},
	doi = {10.1136/jnnp-2012-302905},
	abstract = {OBJECTIVE: Dissociation is a mental process with psychological and somatoform manifestations, which is closely related to hypnotic suggestibility and essentially shows the ability to obtain distance from reality. An increased tendency to dissociate is a frequently reported characteristic of patients with functional neurological symptoms and syndromes (FNSS), which account for a substantial part of all neurological admissions. This review aims to investigate what heart rate variability (HRV), EEG and neuroimaging data (MRI) reveal about the nature of dissociation and related conditions.
METHODS: Studies reporting HRV, EEG and neuroimaging data related to hypnosis, dissociation and FNSS were identified by searching the electronic databases Pubmed and ScienceDirect.
RESULTS: The majority of the identified studies concerned the physiological characteristics of hypnosis; relatively few investigations on dissociation related FNSS were identified. General findings were increased parasympathetic functioning during hypnosis (as measured by HRV), and lower HRV in patients with FNSS. The large variety of EEG and functional MRI investigations with diverse results challenges definite conclusions, but evidence suggests that subcortical as well as (pre)frontal regions serve emotion regulation in dissociative conditions. Functional connectivity analyses suggest the presence of altered brain networks in patients with FNSS, in which limbic areas have an increased influence on motor preparatory regions.
CONCLUSIONS: HRV, EEG and (functional) MRI are sensitive methods to detect physiological changes related to dissociation and dissociative disorders such as FNSS, and can possibly provide more information about their aetiology. The use of such measures could eventually provide biomarkers for earlier identification of patients at risk and appropriate treatment of dissociative conditions.},
	language = {eng},
	number = {2},
	journal = {Journal of Neurology, Neurosurgery, and Psychiatry},
	author = {van der Kruijs, Sylvie J. M. and Bodde, Nynke M. G. and Carrette, Evelien and Lazeron, Richard H. C. and Vonck, Kristl E. J. and Boon, Paul A. J. M. and Langereis, Geert R. and Cluitmans, Pierre J. M. and Feijs, Loe M. G. and Hofman, Paul A. M. and Backes, Walter H. and Jansen, Jacobus F. A. and Aldenkamp, A. P.},
	month = feb,
	year = {2014},
	pmid = {23175855},
	keywords = {Humans, Brain, Heart Rate, Dissociative Disorders, Brain Waves, Eeg, Functional Imaging, Functional Neuroimaging, Hypnosis, Nervous System Diseases, Neurophysiology, Somatisation Disorder},
	pages = {174--179}
}

@article{braakman_microstructural_2012,
	title = {Microstructural and functional {MRI} studies of cognitive impairment in epilepsy},
	volume = {53},
	copyright = {CC0 1.0 Universal Public Domain Dedication},
	issn = {1528-1167},
	doi = {10.1111/j.1528-1167.2012.03624.x},
	abstract = {Cognitive impairment is the most common comorbidity in children with epilepsy, but its pathophysiology and predisposing conditions remain unknown. Clinical epilepsy characteristics are not conclusive in determining cognitive outcome. Because many children with epilepsy do not have macrostructural magnetic resonance imaging (MRI) abnormalities, the underlying substrate for cognitive impairment may be found at the microstructural or functional level. In the last two decades, new MRI techniques have been developed that have the potential to visualize microstructural or functional abnormalities associated with cognitive impairment. These include volumetric MRI, voxel-based morphometry (VBM), diffusion tensor imaging (DTI), MR spectroscopy (MRS), and functional MRI (fMRI). All of these techniques have shed new light on various aspects associated with, or underlying, cognitive impairment, although their use in epilepsy has been limited and focused mostly on adults. Therefore, in this review, the use of all these different MRI techniques to unravel cognitive impairment in epilepsy is discussed both in adults and children with epilepsy. Volumetric MRI and VBM have revealed significant volume losses in the area of the seizure focus as well as in distant areas. DTI adds evidence of loss of integrity of connections from the seizure focus to distant areas as well as between distant areas. MRS and fMRI have shown impaired function both in the area of the