Resting-State Functional MRI for Determining Language Lateralization in Children with Drug-Resistant Epilepsy.

BACKGROUND AND PURPOSE: Task-based fMRI is a noninvasive method of determining language dominance; however, not all children can complete language tasks due to age, cognitive/intellectual, or language barriers. Task-free approaches such as resting-state fMRI offer an alternative method. This study evaluated resting-state fMRI for predicting language laterality in children with drug-resistant epilepsy. MATERIALS AND METHODS: A retrospective review of 43 children with drug-resistant epilepsy who had undergone resting-state fMRI and task-based fMRI during presurgical evaluation was conducted. Independent component analysis of resting-state fMRI was used to identify language networks by comparing the independent components with a language network template. Concordance rates in language laterality between resting-state fMRI and each of the 4 task-based fMRI language paradigms (auditory description decision, auditory category, verbal fluency, and silent word generation tasks) were calculated. RESULTS: Concordance ranged from 0.64 (95% CI, 0.48-0.65) to 0.73 (95% CI, 0.58-0.87), depending on the language paradigm, with the highest concordance found for the auditory description decision task. Most (78%-83%) patients identified as left-lateralized on task-based fMRI were correctly classified as left-lateralized on resting-state fMRI. No patients classified as right-lateralized or bilateral on task-based fMRI were correctly classified by resting-state fMRI. CONCLUSIONS: While resting-state fMRI correctly classified most patients who had typical (left) language dominance, its ability to correctly classify patients with atypical (right or bilateral) language dominance was poor. Further study is required before resting-state fMRI can be used clinically for language mapping in the context of epilepsy surgery evaluation in children with drug-resistant epilepsy.

Functional Connectivity Associated with Health-Related Quality of Life in Children with Focal Epilepsy.

BACKGROUND AND PURPOSE: Although functional connectivity has been linked to cognitive function in epilepsy, its relationship with physical, psychological, or social dysfunction is unknown. This study aimed to assess the relationship between network architecture from resting-state fMRI and health-related quality of life in children with medically intractable focal epilepsy. MATERIALS AND METHODS: Forty-seven children with nonlesional focal epilepsy were included; 22 had frontal lobe epilepsy and 15 had temporal lobe epilepsy. We computed graph metrics of functional connectivity, including network segregation (clustering coefficient and modularity) and integration (characteristic path length and participation coefficient). Health-related quality of life was measured using the Quality of Life in Childhood Epilepsy questionnaire. We examined the associations between graph metrics and the Quality of Life in Childhood Epilepsy total and domains scores, with age, sex, age at seizure onset, fMRI motion, and network density as covariates. RESULTS: There was a negative relationship between the clustering coefficient and total Quality of Life in Childhood Epilepsy score [t(40) = -2.0; P = .04] and social function [t(40) = -2.9; P = .005]. There was a positive association between the mean participation coefficient and total Quality of Life in Childhood Epilepsy score [t(40) = 2.2; P = .03] and cognition [t(40) = 3.8; P = .0004]. In temporal lobe epilepsy, there was a negative relationship between the clustering coefficient and total Quality of Life in Childhood Epilepsy score [t(8) = -2.8; P = .02] and social function [t(8) = -3.6; P = .0075] and between modularity and total Quality of Life in Childhood Epilepsy score [t(8) = -2.5; P = .04] and social function [t(8) = -4.4; P = .0021]. In frontal lobe epilepsy, there was no association between network segregation and integration and Quality of Life in Childhood Epilepsy total or domain scores. CONCLUSIONS: Our findings indicate that there are other higher order brain functions beyond cognition, which may be linked with functional connectivity of the brain.

MRI, Magnetoencephalography, and Surgical Outcome of Oligodendrocytosis versus Focal Cortical Dysplasia Type I.

BACKGROUND AND PURPOSE: Abnormalities of oligodendrocytes have been reported in surgical specimens of patients with medically intractable epilepsy. The aim of this study was to compare the MR imaging, magnetoencephalography, and surgical outcome of children with oligodendrocytosis relative to focal cortical dysplasia I. MATERIALS AND METHODS: Oligodendrocytosis included oligodendroglial hyperplasia, oligodendrogliosis, and oligodendroglial-like cells in the white matter, gray matter, or both from children with medically intractable epilepsy. Focal cortical dysplasia I included radial and tangential cortical dyslamination. The MR imaging, magnetoencephalography, type of operation, location, and seizure outcome of oligodendrocytosis, focal cortical dysplasia I, and oligodendrocytosis + focal cortical dysplasia I were compared. RESULTS: Eighteen subjects (39.1%) had oligodendrocytosis, 21 (45.7%) had focal cortical dysplasia I, and 7 (15.2%) had oligodendrocytosis + focal cortical dysplasia I. There were no significant differences in the type of seizures, focal or nonfocal epileptiform discharges, magnetoencephalography, and MR imaging features, including high T1 signal in the cortex, high T2/FLAIR signal in the cortex or subcortical white matter, increased cortical thickness, blurring of the gray-white junction, or abnormal sulcation and gyration among those with oligodendrocytosis, focal cortical dysplasia I, or oligodendrocytosis + focal cortical dysplasia I (P > .01). There were no significant differences in the extent of resection (unilobar versus multilobar versus hemispherectomy), location of the operation (temporal versus extratemporal versus both), or seizure-free outcome of oligodendrocytosis, focal cortical dysplasia I, and oligodendrocytosis + focal cortical dysplasia I (P > .05). CONCLUSIONS: Oligodendrocytosis shared MR imaging and magnetoencephalography features with focal cortical dysplasia I, and multilobar resection was frequently required to achieve seizure freedom. In 15% of cases, concurrent oligodendrocytosis and focal cortical dysplasia I were identified. The findings suggest that oligodendrocytosis may represent a mild spectrum of malformations of cortical development.

Thalamocortical Connections and Executive Function in Pediatric Temporal and Frontal Lobe Epilepsy.

BACKGROUND AND PURPOSE: Largely accepted in the literature is the role the interconnections between the thalamus and cortex play in generalized epilepsy. However, thalamocortical involvement is less understood in focal epilepsy in terms of the effect of seizures on thalamocortical circuitry in the developing brain and subsequent cognitive outcome. We investigated thalamocortical pathway microstructure in pediatric frontal lobe epilepsy and temporal lobe epilepsy and examined the associations between pathway microstructure and measures of executive function. MATERIALS AND METHODS: We examined thalamocortical connections in 24 children with frontal lobe epilepsy, 17 patients with temporal lobe epilepsy, and 25 healthy children using DTI. We investigated several executive function measures in patients and controls, which were distilled into latent executive function components to compare among groups, and the associations between measures of thalamocortical microstructure and executive function. RESULTS: We found no differences in thalamocortical pathway microstructure between the groups, but aspects of executive function (mental flexibility/inhibition/shifting) were impaired in the frontal lobe epilepsy group compared with controls. In patients with frontal lobe epilepsy, younger age at seizure onset and a greater number of antiepileptic drugs were associated with DTI indices indicative of damaged/less developed thalamocortical pathways. In patients with temporal lobe epilepsy, poorer performance on all measures of executive function was associated with DTI indices reflective of damaged/less developed pathways. CONCLUSIONS: Our results give insight into vulnerable neural networks in pediatric focal epilepsy and suggest thalamocortical pathway damage as a potential mechanism of executive function impairment in temporal lobe epilepsy but not frontal lobe epilepsy. Identifying structure-function relations can help inform how we measure functional and cognitive/behavioral outcomes in these populations.

Disrupted Global and Regional Structural Networks and Subnetworks in Children with Localization-Related Epilepsy.

BACKGROUND AND PURPOSE: Structural connectivity has been thought to be a less sensitive measure of network changes relative to functional connectivity in children with localization-related epilepsy. The aims of this study were to investigate the structural networks in children with localization-related epilepsy and to assess the relation among structural connectivity, intelligence quotient, and clinical parameters. MATERIALS AND METHODS: Forty-five children with nonlesional localization-related epilepsy and 28 healthy controls underwent DTI. Global network (network strength, clustering coefficient, characteristic path length, global efficiency, and small-world parameters), regional network (nodal efficiency), and the network-based statistic were compared between patients and controls and correlated with intelligence quotient and clinical parameters. RESULTS: Patients showed disrupted global network connectivity relative to controls, including reduced network strength, increased characteristic path length and reduced global efficiency, and reduced nodal efficiency in the frontal, temporal, and occipital lobes. Connectivity in multiple subnetworks was reduced in patients, including the frontal-temporal, insula-temporal, temporal-temporal, frontal-occipital, and temporal-occipital lobes. The frontal lobe epilepsy subgroup demonstrated more areas with reduced nodal efficiency and more impaired subnetworks than the temporal lobe epilepsy subgroup. Network parameters were not significantly associated with intelligence quotient, age at seizure onset, or duration of epilepsy. CONCLUSIONS: We found disruption in global and regional networks and subnetworks in children with localization-related epilepsy. Regional efficiency and subnetworks were more impaired in frontal lobe epilepsy than in temporal lobe epilepsy. Future studies are needed to evaluate the implications of disrupted networks for surgical resection and outcomes for specific epileptogenic zones and the relation of disrupted networks to more complex cognitive function.

Epilepsy surgery: recent advances in brain mapping, neuroimaging and surgical procedures.

The general principle of epilepsy surgery is to achieve seizure freedom without causing any neurological deficit that would outweigh the clinical benefit. To achieve this, the epileptogenic zone, which is the part of the brain responsible for seizure generation, as well as the anatomic location of the eloquent cortex must be precisely identified in order to spare those functions during excision of the epileptogenic tissue. Major technical advances over the last decade have continuously contributed to increase our ability to map the brain and identify these critical areas. These technologies and innovations that can be routinely used today include non-invasive studies such as magnetoencephalography (MEG), functional MRI (fMRI), simultaneous EEG-fMRI, and nuclear medicine based methods like PET and SPECT as well as invasive studies through chronically implanted electrodes. Electrodes can be either placed subdurally via burr holes and craniotomies or within the brain parenchima via frame-based and frameless stereotactic methods. Apart from a continuous change in these insertion techniques, the most valuable advances here include recordings on high frequency bandwidth (100-600 Hz EEG) that are capable to delineate high-frequency oscillations (HFOs). These HFOs have been recognized as a biomarker for epileptogenic tissue. All of these technical advances have made epilepsy surgery a truly multidisciplinary field and surgeons have to be able to understand and interpret all of the gathered data. Moreover, this development has influenced surgical approaches and techniques and epilepsy surgery today includes a wide variety of procedures. These can be subdivided into resective, disconnective and neuromodulation procedures and vary from a small, targeted lesionectomy to disconnection/resection of one entire hemisphere. This review will give an overview of the available surgical techniques today and will focus on how the technical advances enable us to map the brain and delineate the critical areas.

Abnormal functional network connectivity among resting-state networks in children with frontal lobe epilepsy.

BACKGROUND AND PURPOSE: Epilepsy is considered a disorder of neural networks. The aims of this study were to assess functional connectivity within resting-state networks and functional network connectivity across resting-state networks by use of resting-state fMRI in children with frontal lobe epilepsy and to relate changes in resting-state networks with neuropsychological function. MATERIALS AND METHODS: Fifteen patients with frontal lobe epilepsy and normal MR imaging and 14 healthy control subjects were recruited. Spatial independent component analysis was used to identify the resting-state networks, including frontal, attention, default mode network, sensorimotor, visual, and auditory networks. The Z-maps of resting-state networks were compared between patients and control subjects. The relation between abnormal connectivity and neuropsychological function was assessed. Correlations from all pair-wise combinations of independent components were performed for each group and compared between groups. RESULTS: The frontal network was the only network that showed reduced connectivity in patients relative to control subjects. The remaining 5 networks demonstrated both reduced and increased functional connectivity within resting-state networks in patients. There was a weak association between connectivity in frontal network and executive function (P = .029) and a significant association between sensorimotor network and fine motor function (P = .004). Control subjects had 79 pair-wise independent components that showed significant temporal coherence across all resting-state networks except for default mode network-auditory network. Patients had 66 pairs of independent components that showed significant temporal coherence across all resting-state networks. Group comparison showed reduced functional network connectivity between default mode network-attention, frontal-sensorimotor, and frontal-visual networks and increased functional network connectivity between frontal-attention, default mode network-sensorimotor, and frontal-visual networks in patients relative to control subjects. CONCLUSIONS: We found abnormal functional connectivity within and across resting-state networks in children with frontal lobe epilepsy. Impairment in functional connectivity was associated with impaired neuropsychological function.

Diagnostic evaluation in patients with intractable epilepsy and normal findings on MRI: a decision analysis and cost-effectiveness study.

BACKGROUND AND PURPOSE: Patients with focal intractable epilepsy and normal MR imaging findings frequently undergo further diagnostic tests to localize the epileptogenic zone. The aim of this study was to determine the cost-effective diagnostic strategy that will identify the epileptogenic zone in patients with suspected focal intractable epilepsy and normal MR imaging findings by using decision analysis. MATERIALS AND METHODS: A Markov decision model was constructed by using sensitivities and specificities of test strategies, seizure outcomes following surgical and medical treatment, cost, utilities, probabilities, and standardized mortality ratios. We compared 6 diagnostic test strategies: PET, ictal SPECT, and MEG individually; and combinations of PET+SPECT, PET+MEG, and SPECT+MEG. The outcomes measured were health care costs, QALY, and ICER. One-way and probabilistic sensitivity analyses were conducted to adjust for uncertainties in model parameters. RESULTS: The preferred strategies were PET+MEG and SPECT. The health care cost of the baseline strategy (PET+MEG) was $95,612 with 16.30 QALY gained. SPECT cost $97,479 with 16.45 QALY gained and an ICER of $12,934/QALY gained compared with those in PET+MEG. One-way sensitivity analyses showed that the decisions of the model were sensitive to variations in sensitivity and specificity of the test strategies. Probabilistic sensitivity analysis showed that when the willingness to pay was <$10,000, PET+MEG was the favored strategy, but the favored strategy changed to SPECT when the willingness to pay was >$10,000. CONCLUSIONS: PET+MEG and SPECT were the preferred strategies in the base case. The choice of test was dependent on the sensitivity and specificity of test strategies and willingness to pay. Further study with a larger sample size is needed to obtain better estimates of sensitivity and specificity of diagnostic tests.

Impaired default mode network on resting-state FMRI in children with medically refractory epilepsy.

BACKGROUND AND PURPOSE: Resting-state networks including the DMN have been shown to be abnormal in adults with temporal lobe epilepsy. However, little is known about the DMN in children with medically refractory epilepsy. The aim was to determine whether there was a difference in the DMN in children with medically refractory epilepsy relative to controls. MATERIALS AND METHODS: Eleven children with medically refractory epilepsy and 11 age-matched healthy controls underwent resting-state fMRI. IC analysis was used to identify the DMN. A random-effects analysis was performed on the Z-maps of the DMN within each group and between groups. We calculated the temporal correlation coefficients of pairs of ROIs: PCC/PCUN, mPFC, and left and right lateral parietal cortices. The relations between z scores of temporal correlation coefficients of pairs of ROIs and clinical seizure parameters and IQ were assessed. RESULTS: The patients demonstrated decreased DMN connectivity in the PCC/PCUN, bilateral lateral parietal cortex, and anterior and midcingulate relative to controls. There was reduced connectivity between the mPFC-right lateral parietal cortex, the PCC/PCUN-left lateral parietal cortex, and the PCC/PCUN-right lateral parietal cortex pairs of ROIs in patients compared with controls. There were no significant correlations between the z scores of temporal correlation coefficients of the 6 pairs of ROIs in patients and age of seizure onset, duration of epilepsy, number of medications, seizure frequency, and IQ. CONCLUSIONS: We have found reduced connectivity in the DMN in children with medically refractory epilepsy. Further studies are needed to determine whether different seizure types have different effects on the DMN and whether the impaired connectivity is related to cognitive functions subserved by the DMN.

Abnormal white matter on diffusion tensor imaging in children with new-onset seizures.

The aim of this study was to use whole brain quantitative analysis to identify impaired white matter (WM) integrity using diffusion tensor imaging (DTI) in children with new-onset seizures. Thirty-five children with new-onset seizures and normal MRI were recruited. Twelve patients had generalized seizures, and 23 had partial seizures. Thirty-one healthy controls were also recruited. Whole brain fractional anisotropy (FA), apparent diffusion coefficient (ADC), radial diffusivity (RD) and axial diffusivity (AD) maps of patients were compared to controls, corrected for multiple comparisons. There was significantly reduced FA in left postcentral, elevated RD in left posterior cingulum and right external capsule, elevated AD in left middle temporal WM and left thalamus, and reduced AD in left anterior cingulum, left temporal, and right supramarginal WM in patients relative to controls. Patients with partial epilepsy showed elevated RD in bilateral posterior cingulum, increased AD in left middle frontal, reduced AD in left temporal, right parietal and right supramarginal WM. Patients with generalized epilepsy showed increased AD in right cerebellum, and reduced AD in left anterior cingulum and left middle temporal WM. The findings indicate that impaired WM integrity with abnormal myelin and axons is present in children with new-onset seizures.

Reduced cortical thickness in children with new-onset seizures.

BACKGROUND AND PURPOSE: Children with new-onset seizures may have antecedent neurobiologic alterations that predispose them to developing seizures. Our aim was to evaluate hippocampal and thalamic volumes and lobar cortical thickness of children with new-onset seizures. MATERIALS AND METHODS: Twenty-nine children with new-onset seizures and normal MR imaging findings were recruited. Ten patients had generalized seizures, 19 had partial seizures, and 15 were on antiepileptic medications. Twenty-three age-matched healthy controls were also recruited. Hippocampal and thalamic volumes and lobar cortical thickness, including frontal, medial temporal, lateral temporal, parietal, cingulate, and occipital cortical thickness, were assessed by using volumetric T1-weighted imaging and were compared between patients and controls. RESULTS: There were no significant differences in hippocampal and thalamic volumes of patients with new-onset seizures, including the subgroups with generalized and partial seizures and those on and off antiepileptic medications, compared with controls (P > .01). There was significant reduction in cortical thickness in right cingulate (P = .004), right medial temporal (P = .006), and left frontal (P = .007) cortices in patients with new-onset seizures. Patients with generalized seizures did not demonstrate a significant reduction in cortical thickness (P > .01). Patients with partial seizures demonstrated a significant reduction in cortical thickness in the right frontal (P = .008), right parietal (P = .003), and left frontal (P = .007) cortices. There were no significant differences in cortical thickness among patients on or off antiepileptic medications (P > .01). CONCLUSIONS: We found reduced cortical thickness in children with new-onset seizures. Further studies are necessary to elucidate the neurobiologic relevance of these structural changes.

Diffusion tensor imaging assessment of the epileptogenic zone in children with localization-related epilepsy.

BACKGROUND AND PURPOSE: Patients with MR imaging-negative epilepsy could have subtle FCD. Our aim was to determine if structural changes could be identified by using DTI in children with intractable epilepsy, from MR imaging-visible FCD and MR imaging-negative localization-related epilepsy, that were concordant with the epileptogenic zone as defined by using the MEG dipole cluster. MATERIALS AND METHODS: Eight children with MR imaging-visible FCD and 16 with MR imaging-negative epilepsy underwent DTI and MEG. Twenty-six age-matched healthy children underwent DTI. Analysis was performed on controls across individual patients. Agreement between the location of DTI abnormalities and FCD and MEG dipole clusters was assessed. RESULTS: In patients with MR imaging-visible FCD, abnormal FA, MD, λ(1), λ(2), and λ(3) were lobar concordant with the MEG dipole cluster in 4/8 (50.0%), 5/8 (62.5%), 3/8 (37.5%), 6/8 (75.0%), and 5/8 (62.5%), respectively. In patients with MR imaging-visible FCD, abnormal FA, MD, λ(1), λ(2), and λ(3) overlapped the x-, y-, and z-axes of the MEG dipole cluster in 1/8 (12.5%), 4/8 (50%), 4/8 (50%), 6/8 (75%), and 4/8 (50%), respectively, and with FCD in 1/8 (12.5%), 3/8 (37.5%), 0/8 (0%), 3/8 (37.5%), and 1/8 (12.5%), respectively. In patients with MR imaging-negative epilepsy, abnormal FA, MD, λ(1), λ(2), and λ(3) were lobar-concordant with the MEG dipole cluster in 11/16 (68.8%), 11/16 (68.8%), 8/16 (50.0%), 10/16 (62.5%), and 10/16 (62.5%), respectively, and overlapped the x-, y-, and z-axes of the MEG dipole cluster in 9/16 (56.3%), 10/16 (62.5%), 8/16 (50%), 8/16 (50%), and 8/16 (50%), respectively. There was no significant difference between abnormal DTI lobar concordance with the MEG dipole cluster in patients with MR imaging-visible FCD and MR imaging-negative epilepsy. CONCLUSIONS: White matter changes can be detected with DTI in children with MR imaging-visible FCD and MR imaging-negative epilepsy, which were concordant with the epileptogenic zone in more than half of the patients.

Abnormal axial diffusivity in the deep gray nuclei and dorsal brain stem in infantile spasm treated with vigabatrin.

We evaluated the DTI changes in the deep gray nuclei and dorsal brain stem, which demonstrated abnormal T2 and/or diffusion signal intensity, in 6 patients with infantile spasm treated with vigabatrin compared with 6 age-matched controls. Regions of interest were placed in the globi pallidi, thalami, and dorsal brain stem; FA, trace, D(‖), and D(⊥) were measured. Patients on vigabatrin had significantly lower FA in both globi pallidi (P = .01) and the dorsal brain stem (P < .01), significantly lower trace in both globi pallidi (P = .01) and the thalami (P = .02 and .01 for right and left, respectively), and significantly lower D(‖) in both globi pallidi (P ≤ .01), the thalami (P < .01), and the dorsal brain stem (P = .03). There were no significant differences in D(⊥) of the globi pallidi, thalami, or dorsal brain stem in patients compared with controls. The findings suggest that axonal changes play a greater role in the observed abnormal signal intensity, with lesser contribution from myelin changes.

Wavelets and fuzzy relational classifiers: a novel diffusion-weighted image analysis system for pediatric metabolic brain diseases.

The diffusion-weighted imaging (DWI) technique can be utilized to investigate a variety of diseases. We propose an automated pilot system, which assists in the diagnosis of metabolic brain diseases, utilizing the DWI. In this study, DWI images are preprocessed and exponential apparent diffusion coefficient (eADC) images are produced. The eADC images are later brain extracted and normalized to a standard brain template. Subsequently, we utilized wavelets to denoise the eADC images. The images are rectified, thresholded and now conspicuous abnormal regions are subsequently identified utilizing different brain atlases. Abnormal regions constitute the features that will be used by a fuzzy relational classifier in order to categorize the diseases. A sensitivity and specificity of 60% and 93.33%, respectively, in detecting metabolic brain diseases have been achieved.

Corroboration of normal and abnormal fetal cerebral lamination on postmortem MR imaging with postmortem examination.

BACKGROUND AND PURPOSE: The presence of normal fetal cerebral lamination of the germinal matrix, intermediate zone, subplate layer, and cortex can be used as a marker of normal fetal cerebral development. Our aim was to compare postmortem MR imaging assessment of normal and abnormal fetal cerebral lamination on T1- and T2-weighted images with histopathology. MATERIALS AND METHODS: Fifty-five formalin-fixed brains from postmortem fetuses, ranging from 16 to 30 weeks' gestational age, mean of 23 weeks, underwent T1- and T2- weighted MR imaging and subsequent sectioning and histologic examination. The cerebral lamination was graded as normal or abnormal on T1- and T2-weighted imaging and compared with postmortem findings. The sensitivity, specificity, and positive and negative predictive values of T1 and T2 assessment of cerebral lamination were calculated. RESULTS: Twenty-six fetuses had abnormal and 29 had normal cerebral lamination on histology. On T1, the overall sensitivity, specificity, and positive and negative predictive values of evaluating cerebral lamination were 96.15%(CI, 78.42%-99.80%), 89.66%(CI, 71.50%-97.29%), 89.29%(CI, 70.63%-97.19%), and 96.29%(CI, 79.11%-99.80%), respectively. On T2, the overall sensitivity, specificity, and positive and negative predictive values of evaluating cerebral lamination were 73.08%(CI, 51.95%-87.65%), 96.55%(CI, 80.37%-99.82%), 95.00%(CI, 73.06%-99.74%), and 80.00%(CI, 62.54%-90.94%), respectively. CONCLUSIONS: Postmortem MR imaging has high sensitivity, specificity, and positive and negative predictive values in assessing fetal cerebral lamination compared with histology. T1-weighted imaging has a higher sensitivity and negative predictive value, while T2-weighted imaging has a higher specificity and positive predictive value.

Influence of polymer content on stabilizing milled amorphous salbutamol sulphate.

The study investigates the influence of polyvinyl pyrrolidone (PVP) concentration on stabilizing the amorphous form of salbutamol sulphate (SS) before and after storage under ambient and elevated humidity conditions. Different mass ratios of SS and PVP (0-90wt%) were co-milled using a planetary ball mill. X-ray powder diffraction (XRPD), high sensitivity differential scanning calorimetry (HSDSC), dynamic vapor sorption (DVS), infrared spectroscopy (FT-IR), scanning electron microscopy (SEM) and Raman microscopy (RM) were used to analyze the stability of the co-milled mixtures against heat and humidity treatments as well as storage at different humidity conditions. Prior storage, DSC and DVS analyses revealed that re-crystallization of amorphous SS was suppressed above PVP content of 33 wt%. Probable hydrogen bond interaction between SS and PVP was found in FT-IR analysis. XRPD diffractograms and SEM analysis showed stability against re-crystallization was achieved in the co-milled mixtures with a minimum PVP content of 80 wt% after storage. Homogeneous distribution of SS and PVP from RM analysis showed fine clustering of SS and PVP, suggesting the formation of an amorphous dispersion at molecular level. The results provide insights on the application of thermal and humidity treatments, accelerated stability testing and investigations on drug-excipient interactions to predict the minimum ratio of an excipient for stabilizing the amorphous state of a milled API.

Alteration of human fetal subplate layer and intermediate zone during normal development on MR and diffusion tensor imaging.

BACKGROUND AND PURPOSE: The subplate layer and intermediate zone are the precursors for neonatal white matter. The aims of this study were to evaluate 1) T1 and T2 signal intensity, and 2) FA of subplate and intermediate zone in postmortem fetuses and correlate with histology, and 3) T2 signal intensity of subplate and intermediate zone on antenatal MR imaging. MATERIALS AND METHODS: Fourteen immersion-fixed normal brains from 18 to 25 gestational weeks underwent 1.5T MR imaging, including DTI and histologic examination. The subplate and intermediate zone were graded on a scale of 1-5 on T1 and T2, and FAs were evaluated and then correlated with age. Seventeen antenatal MR images from 20 to 26 gestational weeks with normal brain were evaluated by using the same grading. RESULTS: On T1 postmortem MR imaging, subplate has lower signal intensity compared with intermediate zone; subplate signal intensity correlated positively (r = 0.66, P = .012) with age, and intermediate zone signal intensity correlated negatively (r = -0.78, P = .001) with age. On T2 postmortem MR imaging, subplate has higher signal intensity compared with intermediate zone and remained persistently high in signal intensity; intermediate zone signal intensity showed moderate correlation (r = 0.48, P = .086) with age. FA of subplate correlated positively (r = 0.55, P < .001) with age; FA of intermediate zone correlated negatively (r = -0.64, P < .0001) with age. On histology, extracellular matrix decreased and cellularity increased in subplate layer, tangentially organized cellularity decreased, and projecting fibers became thicker in intermediate zone with increasing gestation. The findings on T2-weighted antenatal MR imaging were similar to T2-weighted postmortem MR imaging. CONCLUSIONS: The changes in signal intensity and FA of subplate and intermediate zone in the second trimester reflect microstructural changes on histology.

Effects of gradient encoding and number of signal averages on fractional anisotropy and fiber density index in vivo at 1.5 tesla.

BACKGROUND: Tensor estimation can be improved by increasing the number of gradient directions (NGD) or increasing the number of signal averages (NSA), but at a cost of increased scan time. PURPOSE: To evaluate the effects of NGD and NSA on fractional anisotropy (FA) and fiber density index (FDI) in vivo. MATERIAL AND METHODS: Ten healthy adults were scanned on a 1.5T system using nine different diffusion tensor sequences. Combinations of 7 NGD, 15 NGD, and 25 NGD with 1 NSA, 2 NSA, and 3 NSA were used, with scan times varying from 2 to 18 min. Regions of interest (ROIs) were placed in the internal capsules, middle cerebellar peduncles, and splenium of the corpus callosum, and FA and FDI were calculated. Analysis of variance was used to assess whether there was a difference in FA and FDI of different combinations of NGD and NSA. RESULTS: There was no significant difference in FA of different combinations of NGD and NSA of the ROIs (P>0.005). There was a significant difference in FDI between 7 NGD/1 NSA and 25 NGD/3 NSA in all three ROIs (P<0.005). There were no significant differences in FDI between 15 NGD/3 NSA, 25 NGD/1 NSA, and 25 NGD/2 NSA and 25 NGD/3 NSA in all ROIs (P>0.005). CONCLUSION: We have not found any significant difference in FA with varying NGD and NSA in vivo in areas with relatively high anisotropy. However, lower NGD resulted in reduced FDI in vivo. With larger NGD, NSA has less influence on FDI. The optimal sequence among the nine sequences tested with the shortest scan time was 25 NGD/1 NSA.

White matter abnormalities in children with idiopathic developmental delay.

BACKGROUND: The underlying cause of developmental delay (DD) often remains unclear despite extensive clinical examination and investigations. Interference in normal development of the brain may result in DD. PURPOSE: To identify the prevalence of abnormalities on magnetic resonance (MR) imaging in idiopathic developmental delay. MATERIAL AND METHODS: Of the 124 children referred for MR imaging with DD, 34 were excluded due to known history of progressive neurodevelopmental disorders, birth asphyxia, congenital CNS infections, metabolic disorder, chromosomal anomalies, and severe epileptic syndromes. The following structures were systematically reviewed: ventricles, corpus callosum, gray and white matter, limbic system, basal ganglia, brainstem, and cerebellum. RESULTS: Ten out of 90 (11%) were referred with DD only, whilst 80/90 (89%) were referred with DD and additional clinical findings, such as seizures, neurological deficit, and abnormal head size. Of the 90 patients, 14 (16%) had normal MR and 76 (84%) had abnormal MR findings. Abnormal ventricles were seen in 43/90 (48%); abnormal corpus callosum was identified in 40/90 (44%). Other MR findings included abnormalities in the white matter (23/90, 26%), hippocampi (5/90, 6%), cerebellum (5/90, 6%), and brainstem (4/90, 4%). CONCLUSION: Abnormalities of the ventricles and corpus callosum were identified in a large proportion of patients with idiopathic DD, indicative of changes in the white matter. Further studies using quantitative methods and diffusion tensor imaging are required to evaluate the white matter in these children.

PCA-SGA implementation in classification and disease specific feature extraction of the brain MRS signals.

The medical diagnostic systems often suffer from the high dimensional data. In this study, Principle Component Analysis (PCA) has been used for dimensionality reduction of the brain Magnetic Resonance Spectroscopy (MRS) signals. Afterwards, the Simple Genetic Algorithms (SGA) is utilized in order to classify different brain diseases. SGA is later used to extract MRS signal features in case of metabolic brain diseases (MD). The PCA-SGA implementation received the specificity of 89.91%. The SGA was able to achieve the sensitivity of 84.84% and positive predictivity of 88.46% in extracting disease specific MRS signal features.