Société de Biomécanique Young Investigator Award 2021: Numerical investigation of the time-dependent stress-strain mechanical behaviour of skeletal muscle tissue in the context of pressure ulcer prevention.

BACKGROUND: Pressure-induced tissue strain is one major pathway for Pressure Ulcer development and, especially, Deep Tissue Injury. Biomechanical investigation of the time-dependent stress-strain mechanical behaviour of skeletal muscle tissue is therefore essential. In the literature, a viscoelastic formulation is generally assumed for the experimental characterization of skeletal muscles, with the limitation that the underlying physical mechanisms that give rise to the time dependent stress-strain behaviour are not known. The objective of this study is to explore the capability of poroelasticity to reproduce the apparent viscoelastic behaviour of passive muscle tissue under confined compression. METHODS: Experimental stress-relaxation response of 31 cylindrical porcine samples tested under fast and slow confined compression by Vaidya and collaborators were used. An axisymmetric Finite Element model was developed in ABAQUS and, for each sample a one-to-one inverse analysis was performed to calibrate the specimen-specific constitutive parameters, namely, the drained Young's modulus, the void ratio, hydraulic permeability, the Poisson's ratio, the solid grain's and fluid's bulk moduli. FINDINGS: The peak stress and consolidation were recovered for most of the samples (N=25) by the poroelastic model (normalised root-mean-square error ≤0.03 for fast and slow confined compression conditions). INTERPRETATION: The strength of the proposed model is its fewer number of variables (N=6 for the proposed poroelastic model versus N=18 for the viscohyperelastic model proposed by Vaidya and collaborators). The incorporation of poroelasticity to clinical models of Pessure Ulcer formation could lead to more precise and mechanistic explorations of soft tissue injury risk factors.

The thalamus in trigeminal neuralgia: structural and metabolic abnormalities, and influence on surgical response.

BACKGROUND: Medically-refractory trigeminal neuralgia (TN) can be treated successfully with operative intervention, but a significant proportion of patients are non-responders despite undergoing technically successful surgery. The thalamus is a key component of the trigeminal sensory pathway involved in transmitting facial pain, but the role of the thalamus in TN, and its influence on durability of pain relief after TN surgery, are relatively understudied. We aimed to test the hypothesis that variations in thalamic structure and metabolism are related to surgical non-response in TN. METHODS: We performed a longitudinal, peri-operative neuroimaging study of the thalamus in medically-refractory TN patients undergoing microvascular decompression or percutaneous balloon compression rhizotomy. Patients underwent structural MRI and MR spectroscopy scans pre-operatively and at 1-week following surgery, and were classified as responders or non-responders based on 1-year post-operative pain outcome. Thalamus volume, shape, and metabolite concentration (choline/creatine [Cho/Cr] and N-acetylaspartate/creatine [NAA/Cr]) were evaluated at baseline and 1-week, and compared between responders, non-responders, and healthy controls. RESULTS: Twenty healthy controls and 23 patients with medically-refractory TN treated surgically (17 responders, 6 non-responders) were included. Pre-operatively, TN patients as a group showed significantly larger thalamus volume contralateral to the side of facial pain. However, vertex-wise shape analysis showed significant contralateral thalamus volume reduction in non-responders compared to responders in an axially-oriented band spanning the outer thalamic circumference (peak p = 0.019). Further, while pre-operative thalamic metabolite concentrations did not differ between responders and non-responders, as early as 1-week after surgery, long-term non-responders showed a distinct decrease in contralateral thalamic Cho/Cr and NAA/Cr, irrespective of surgery type, which was not observed in responders. CONCLUSIONS: Atrophy of the contralateral thalamus is a consistent feature across patients with medically-refractory TN. Regional alterations in preoperative thalamic structure, and very early post-operative metabolic changes in the thalamus, both appear to influence the durability of pain relief after TN surgery.

MRI Texture Analysis Reveals Brain Abnormalities in Medically Refractory Trigeminal Neuralgia.

Background: Several neuroimaging studies report structural alterations of the trigeminal nerve in trigeminal neuralgia (TN). Less attention has been paid to structural brain changes occurring in TN, even though such changes can influence the development and response to treatment of other headache and chronic pain conditions. The purpose of this study was to apply a novel neuroimaging technique-texture analysis-to identify structural brain differences between classical TN patients and healthy subjects. Methods: We prospectively recruited 14 medically refractory classical TN patients and 20 healthy subjects. 3-Tesla T1-weighted brain MRI scans were acquired in all participants. Three texture features (autocorrelation, contrast, energy) were calculated within four a priori brain regions of interest (anterior cingulate, insula, thalamus, brainstem). Voxel-wise analysis was used to identify clusters of texture difference between TN patients and healthy subjects within regions of interest (p < 0.001, cluster size >20 voxels). Median raw texture values within clusters were also compared between groups, and further used to differentiate TN patients from healthy subjects (receiver-operator characteristic curve analysis). Median raw texture values were correlated with pain severity (visual analog scale, 1-100) and illness duration. Results: Several clusters of texture difference were observed between TN patients and healthy subjects: right-sided TN patients showed reduced autocorrelation in the left brainstem, increased contrast in the left brainstem and right anterior insula, and reduced energy in right and left anterior cingulate, right midbrain, and left brainstem. Within-cluster median raw texture values also differed between TN patients and healthy subjects: TN patients could be segregated from healthy subjects using brainstem autocorrelation (p = 0.0040, AUC = 0.84, sensitivity = 89%, specificity = 70%), anterior insula contrast (p = 0.0002, AUC = 0.92, sensitivity = 78%, specificity = 100%), and anterior cingulate energy (p = 0.0004, AUC = 0.92, sensitivity = 78%, specificity = 100%). Additionally, anterior insula contrast and duration of TN were inversely correlated (p = 0.030, Spearman r = -0.73). Conclusions: Texture analysis reveals distinct brain abnormalities in TN, which relate to clinical features such as duration of illness. These findings further implicate structural brain changes in the development and maintenance of TN.

Ten-year fracture risk predicted by proximal femur Hounsfield units.

Colon cancer screening occurs at younger ages than osteoporosis screening. Bone density measurements using virtual colonoscopy performed for colon cancer screening can provide an early warning sign of patients at potential risk for osteoporosis-related fractures. Earlier identification may improve treatment and potentially fracture prevention. INTRODUCTION: Opportunistic osteoporosis screening with computed tomography colonography (CTC) offers an opportunity to capitalize on earlier colorectal cancer screening to identify patients at risk of future fractures. The purpose of this study is to evaluate 10-year fracture and specifically hip fracture risk based on Hounsfield units (HU) obtained from CTC. METHODS: We identified all CTC scans between 2004 and 2007 of patients 40 years and older with 10 years minimum follow-up. Hounsfield units were measured within the proximal femur and fractures identified via worldwide military records. Patients were stratified into two cohorts based on the presence or lack of a fracture in the wrist, spine, hip, or proximal humerus. Hounsfield unit measurements were compared between groups using Student's t test and the HU threshold was calculated that best approximated an 80% sensitivity to optimally screen patients for fracture risk. The odds ratio, negative predictive value, 10-year incidence of fracture, and survival curves were calculated. RESULTS: We identified 3711 patients with 183 fractures over 10 years. The HU threshold that corresponded with an 80% sensitivity to identify fractures was 112 HU. The negative predictive value (NPV) for overall fractures and hip fractures was over 97%. The 10-year fracture incidence was higher in patients below 112 HU compared to those above for both overall fractures (6.3% vs 1.7%) and hip fractures (2.7% vs 0.07%). The 112 HU threshold corresponds with an odds ratio for overall fracture and hip fractures of 2.5 (95% confidence interval (CI), 1.7-3.6) and 24.5 (95% CI, 3.3-175.5), respectively. CONCLUSION: In the 10 years following CTC, patients who experienced a fracture had lower hip HU. Decreasing HU on CTC may be an early warning sign of fracture potential.

Hippocampal subfield measurement and ILAE hippocampal sclerosis subtype classification with in vivo 4.7 tesla MRI.

OBJECTIVE: Neuropathological studies indicate that hippocampal sclerosis (HS) consists of three subtypes (ILAE types 1-3 HS). However, HS subtypes currently can only be diagnosed by pathological analysis of hippocampal tissue resected during epilepsy surgery or at autopsy. In vivo diagnosis of HS subtypes holds potential to improve our understanding of these variants in the ipsilateral as well as contralateral hippocampus. In this study, we aimed to: i) evaluate the reliability of our histology-derived segmentation protocol when applied to in vivo MRI; and ii) characterize variability of HS subtypes along the hippocampal long axis in patients with epilepsy. METHODS: Eleven subjects with unilateral HS were compared with ten healthy controls. We used 4.7 T MRI to acquire high resolution MR Images of the hippocampus in each subject. In vivo MRI-based diagnoses of HS subtypes were then determined in each patient by two methods: i) hippocampal subfield volumetry of the entire hippocampal body; and ii) subfield area analysis at multiple thin slices throughout the hippocampal body. RESULTS: Hippocampal body subfield segmentation demonstrated excellent reliability and volumetry of the symptomatic hippocampus revealed abnormalities in all eleven patients. Six subjects demonstrated findings consistent with type 1 HS while five subjects had volumetry-defined atypical HS (two with type 2 HS & three with type 3 HS) in the symptomatic hippocampus, while five subjects were found to have type 3 HS in the contralateral hippocampus. Subfield area analyses demonstrated remarkable variability of HS subtypes along the hippocampal long axis, both ipsilateral and contralateral to the seizure focus. SIGNIFICANCE: Our results provide preliminary evidence that determining HS Subtype using in vivo MRI may allow preoperative diagnosis of ILAE HS subtypes. Further studies are essential to determine the pathological correlates of these neuroimaging findings. The heterogeneity of abnormalities observed along the long axis of the hippocampus is consistent with previous autopsy studies and highlights the necessity of studying the entire hippocampus both ipsilateral and contralateral to the seizure focus in these future studies.

Regional hippocampal diffusion abnormalities associated with subfield-specific pathology in temporal lobe epilepsy.

OBJECTIVE: Hippocampal sclerosis (HS) is the most common pathology and best predictor of surgical outcome for medically refractory patients with temporal lobe epilepsy (TLE). Current clinical MRI methods can detect HS, but subfield pathology is poorly characterized, limiting accurate prediction of seizure-free outcomes after surgery. Diffusion tensor imaging (DTI) can probe regional microstructural changes associated with focal hippocampal pathology, but is typically limited by low-resolution whole-brain acquisitions. METHODS: High-resolution (1 × 1 × 1 mm3) DTI, T1, and quantitative T2 of the hippocampus was acquired in 18 preoperative TLE patients and 19 healthy controls. Diffusion images were qualitatively assessed for loss of internal architecture, and whole-hippocampus diffusion, volume, and quantitative T2 were compared across groups. Regional hippocampal diffusion abnormalities were examined in all subjects and compared to histology in four subjects who underwent anterior temporal lobectomy. RESULTS: High-resolution mean diffusion-weighted images enabled visualization of internal hippocampal architecture, used to visually identify HS with 86% specificity and 93% sensitivity. Mean diffusivity (MD) elevations were regionally heterogenous within the hippocampus and varied across TLE patients. The spatial location of diffusion abnormalities corresponded with the location of focal subfield neuron loss, gliosis, and reduced myelin staining abnormalities identified with postsurgical histology in four subjects who underwent anterior temporal lobectomy. Whole-hippocampus MD and T2 relaxation times were higher, and fractional anisotropy (FA) and volumes were lower in TLE patients relative to controls. Left hippocampus MD correlated with verbal memory in the TLE group. SIGNIFICANCE: Visualization of internal architecture and focal diffusion abnormalities on high-resolution diffusion imaging suggests potential clinical utility of diffusion imaging in TLE and may have significant implications for surgical planning and prediction of seizure-free outcomes in individual patients.

Intraoperative acquisition of DTI in cranial neurosurgery: readout-segmented DTI versus standard single-shot DTI.

OBJECTIVE: Diffusion tensor imaging (DTI) tractography is commonly used in neurosurgical practice but is largely limited to the preoperative setting. This is due primarily to image degradation caused by susceptibility artifact when conventional single-shot (SS) echo-planar imaging (EPI) DTI (SS-DTI) is acquired for open cranial, surgical position intraoperative DTI (iDTI). Readout-segmented (RS) EPI DTI (RS-DTI) has been reported to reduce such artifact but has not yet been evaluated in the intraoperative MRI (iMRI) environment. The authors evaluated the performance of RS versus SS EPI for DTI of the human brain in the iMRI setting. METHODS: Pre- and intraoperative 3-T 3D T1-weighted and 2D multislice RS-iDTI (called RESOLVE [readout segmentation of long variable echo-trains] on the Siemens platform) and SS-iDTI images were acquired in 22 adult patients undergoing intraaxial iMRI resections for suspected low-grade glioma (14; 64%), high-grade glioma (7; 32%), or focal cortical dysplasia. Regional susceptibility artifact, anatomical deviation relative to T1-weighted imaging, and tractographic output for surgically relevant tracts were compared between iDTI sequences as well as the intraoperative tract shifts from preoperative DTI. RESULTS: RS-iDTI resulted in qualitatively less regional susceptibility artifact (resection cavity, orbitofrontal and anterior temporal cortices) and mean anatomical deviation in regions most prone to susceptibility artifact (RS-iDTI 2.7 ± 0.2 vs SS-iDTI 7.5 ± 0.4 mm) compared to SS-iDTI. Although tract reconstruction success did not significantly differ by DTI method, susceptibility artifact-related tractography failure (of at least 1 surgically relevant tract) occurred for SS-iDTI in 8/22 (36%) patients, and in 5 of these 8 patients RS-iDTI permitted successful reconstruction. Among cases with successful tractography for both sequences, maximal intersequence differences were substantial (mean 9.5 ± 5.7 mm, range -27.1 to 18.7 mm). CONCLUSIONS: RS EPI enables higher quality and more accurate DTI for surgically relevant tractography of major white matter tracts in intraoperative, open cranium neurosurgical applications at 3 T.

Absent in melanoma 2 regulates tumor cell proliferation in glioblastoma multiforme.

INTRODUCTION: Inflammation is a key aspect of glioblastoma multiforme (GBM) although it remains unclear how it contributes to GBM pathogenesis. Inflammasomes are intracellular multi-protein complexes that are involved in innate immunity and are activated by cellular stress, principally in macrophages. This study examined the expression of inflammasome-associated genes in GBM, particularly absent in melanoma 2 (AIM2). METHODS: Tissue samples from surgically-resected GBM tumors (n = 10) were compared to resected brain specimens from patients with epilepsy (age- and sex-matched Other Disease Controls (ODC, n=5)) by qRT-PCR, western blotting and immunofluorescence. Gene expression studies in human astrocytoma U251 cells were performed and the effects of deleting the absent in melanoma 2 (AIM2) gene using the CRISPR-Cas9 system were analyzed. RESULTS: GBM tissues showed significantly elevated expression of multiple immune (CD3E, CD163, CD68, MX1, ARG1) and inflammasome (AIM2, NLRP1, IL18, CASP1, and IL-33) genes compared to ODC tissues, without induction of IL1B, IFNG or TNFA. An insert-containing AIM2 variant transcript was highly expressed in GBM tissues and in U251 cells. AIM2 immunoreactivity was concentrated in the tumor core in the absence of PCNA immunodetection and showed a predominant 52 kDa immunoreactive band on western blot. Deletion of AIM2 resulted in significantly enhanced proliferation of U251 cells, which also displayed increased resistance to temozolomide treatment. CONCLUSIONS: GBM tumors express a distinct profile of inflammasome-associated genes in a tumor-specific manner. AIM2 expression in tumor cells suppressed cell proliferation while also conferring increased susceptibility to contemporary GBM therapy.

Seizure outcome in pediatric medically refractory temporal lobe epilepsy surgery: selective amygdalohippocampectomy versus anterior temporal lobectomy.

OBJECTIVE The aim of this study was to investigate long-term seizure outcome, rate of reoperation, and postoperative neuropsychological performance following selective amygdalohippocampectomy (SelAH) or anterior temporal lobectomy (ATL) in pediatric patients with medically refractory temporal lobe epilepsy (TLE). METHODS The authors performed a retrospective review of cases of medically refractory pediatric TLE treated initially with either SelAH or ATL. Standardized pre- and postoperative evaluation included seizure charting, surface and long-term video-electroencephalography, 1.5-T MRI, and neuropsychological testing. RESULTS A total of 79 patients treated initially with SelAH (n = 18) or ATL (n = 61) were included in this study, with a mean follow-up of 5.3 ± 4 years (range 1-16 years). The patients' average age at initial surgery was 10.6 ± 5 years, with an average surgical delay of 5.7 ± 4 years between seizure onset and surgery. Seizure freedom (Engel I) following the initial operation was significantly more likely following ATL (47/61, 77%) than SelAH (8/18, 44%; p = 0.017, Fisher's exact test). There was no statistically significant difference in the proportion of patients with postoperative neuropsychological deficits following SelAH (8/18, 44%) or ATL (21/61, 34%). However, reoperation was significantly more likely following SelAH (8/18, 44%) than after ATL (7/61, 11%; p = 0.004) and was more likely to result in Engel I outcome for ATL after failed SelAH (7/8, 88%) than for posterior extension after failed ATL (1/7, 14%; p = 0.01). Reoperation was well tolerated without significant neuropsychological deterioration. Ultimately, including 15 reoperations, 58 of 79 (73%) patients were free from disabling seizures at the most recent follow-up. CONCLUSIONS SelAH among pediatric patients with medically refractory unilateral TLE yields significantly worse rates of seizure control compared with ATL. Reoperation is significantly more likely following SelAH, is not associated with incremental neuropsychological deterioration, and frequently results in freedom from disabling seizures. These results are significant in that they argue against using SelAH for pediatric TLE surgery.

Longitudinal hippocampal and extra-hippocampal microstructural and macrostructural changes following temporal lobe epilepsy surgery.

OBJECTIVES: 1) Characterize the evolution of microstructural changes in the contralateral, non-operated hippocampus-using longitudinal diffusion tensor imaging (DTI)-following surgery for temporal lobe epilepsy (TLE). 2) Characterize the downstream extra-hippocampal volumetric changes of the fornix and mammillary bodies after TLE surgery. 3) Examine the relationship between these measures and seizure/cognitive outcome. METHODS: Serial structural and DTI brain MRI scans were collected in 25 TLE patients pre- and post-surgery (anterior temporal lobectomy, ATL - 13; selective amygdalohippocampectomy, SelAH - 12) and in 12 healthy controls. Contralateral hippocampal fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD) were computed with manual hippocampal tracings as volumes of interest following co-registration to anatomical images. Fornix and mammillary body volumetry was performed by manual segmentation. RESULTS: After surgery, the non-resected hippocampus showed significant postoperative decline in FA (p = 0.0001), with increase of MD (p = 0.01) and RD (p = 0.0001). In contrast to the timing of our previously reported volume changes where atrophy is observed in the first week, diffusion changes occurred late, taking 1-3 years to develop and are not significant at one week after surgery. Diffusion changes are accompanied by delayed limbic circuit volume loss in the mammillary bodies (35%; p < 0.0001) and fornix (24%; p < 0.0001) compared to baseline. There was no correlation between postoperative diffusion or structural changes and memory score nor did the degree of postoperative change in hippocampal DTI parameters, mammillary body volume or fornix volume vary significantly based on seizure outcome. SIGNIFICANCE: Differences observed in the timing of postoperative volume (first week) and FA/MD (one year) changes would suggest that early contralateral hippocampal atrophy is not secondary to fluid shifts (dehydration) while the late DTI changes suggest ongoing microstructural changes extending beyond the early postoperative period. Postoperative hippocampal diffusion changes are accompanied by delayed mammillary body and fornix volume loss which did not differ when stratified by seizure outcome nor was correlated with degree of hippocampal diffusion change. Finally, we did not identify any significant correlation between postoperative diffusion parameter change and memory performance.

Progressive contralateral hippocampal atrophy following surgery for medically refractory temporal lobe epilepsy.

OBJECTIVE: Determine the extent and time course of volumetric changes in the contralateral hippocampus following surgery for medically refractory temporal lobe epilepsy (TLE). METHODS: Serial T1-weighted MRI brain scans were obtained in 26 TLE patients pre- and post-temporal lobe epilepsy surgery as well as in 12 control subjects of similar age. Patients underwent either anterior temporal lobectomy (ATL) or selective amygdalohippocampectomy (SAH). Blinded, manual hippocampal volumetry (head, body, and tail) was performed in two groups: 1) two scan group [ATL (n=6); SAH (n=10)], imaged pre-surgery and on average at 5.4 years post-surgery; and 2) longitudinal group [ATL (n=8); SAH (n=2)] imaged pre-surgery and on post-operative day 1, 2, 3, 6, 60, 120 and a delayed time point (average 2.4 years). RESULTS: In the two scan group, there was atrophy by 12% of the unresected contralateral hippocampus (p<0.001), with atrophy being most pronounced (27%) in the hippocampal body (p<0.001) with no significant differences seen for the hippocampal head or tail. In the longitudinal group, significant atrophy was also observed for the whole hippocampus and the body with atrophy seen as early as post-operative day #1 which progressed significantly over the first post-operative week (1.3%/day and 3.0%./day, respectively) before stabilizing over the long-term to a 13% reduction in total volume. There was no significant difference in atrophy compared by surgical approach (ATL vs. SAH; p=0.94) or side (p=0.31); however, atrophy was significantly more pronounced in patients with ongoing post-operative seizures (hippocampal body, p=0.019; whole hippocampus, p=0.048). There were no detectable post-operative neuropsychological deficits attributable to contralateral hippocampal atrophy. SIGNIFICANCE: Significant contralateral hippocampal atrophy occurs following TLE surgery, which begins immediately and progresses over the first post-operative week. The observation that seizure free patients had significantly less atrophy of the contralateral hippocampus after surgery suggests the possibility of an early post-operative imaging marker to predict surgical outcome.

Inflammasome induction in Rasmussen's encephalitis: cortical and associated white matter pathogenesis.

BACKGROUND: Rasmussen's encephalitis (RE) is an inflammatory encephalopathy of unknown cause defined by seizures with progressive neurological disabilities. Herein, the pathogenesis of RE was investigated focusing on inflammasome activation in the brain. METHODS: Patients with RE at the University of Alberta, Edmonton, AB, Canada, were identified and analyzed by neuroimaging, neuropsychological, molecular, and pathological tools. Primary human microglia, astrocytes, and neurons were examined using RT-PCR, enzyme-linked immunosorbent assay (ELISA), and western blotting. RESULTS: Four patients with RE were identified at the University of Alberta. Magnetic resonance imaging (MRI) disclosed increased signal intensities in cerebral white matter adjacent to cortical lesions of RE patients, accompanied by a decline in neurocognitive processing speed (P <0.05). CD3ϵ, HLA-DRA, and TNFα together with several inflammasome-associated genes (IL-1ß, IL-18, NLRP1, NLRP3, and CASP1) showed increased transcript levels in RE brains compared to non-RE controls (n = 6; P <0.05). Cultured human microglia displayed expression of inflammasome-associated genes and responded to inflammasome activators by releasing IL-1ß, which was inhibited by the caspase inhibitor, zVAD-fmk. Major histocompatibility complex (MHC) class II, IL-1ß, caspase-1, and alanine/serine/cysteine (ASC) immunoreactivity were increased in RE brain tissues, especially in white matter myeloid cells, in conjunction with mononuclear cell infiltration and gliosis. Neuroinflammation in RE brains was present in both white matter and adjacent cortex with associated induction of inflammasome components, which was correlated with neuroimaging and neuropsychological deficits. CONCLUSION: Inflammasome activation likely contributes to the disease process underlying RE and offers a mechanistic target for future therapeutic interventions.

The acute phase of Wallerian degeneration: longitudinal diffusion tensor imaging of the fornix following temporal lobe surgery.

Numerous animal studies have shown the applicability of diffusion tensor imaging (DTI) to track Wallerian degeneration that occurs after injury to the neural fiber. Non-invasive biomarkers that may differentiate the early axonal breakdown and later myelin degradation have been attributed to either reduced parallel and elevated perpendicular diffusivity, respectively. While several human DTI studies have shown this potential at subacute and chronic time points, the diffusion changes that occur within the first week are unknown. Anterior temporal lobectomy (i.e. resection of hippocampus) is the standard surgical treatment of medically refractory temporal lobe epilepsy. The concomitant transection of the fimbria-fornix serves as a unique opportunity to examine the process of Wallerian degeneration since the timing is known. Six temporal lobe epilepsy patients underwent brain DTI before the surgery, three to four times within the first week post-operatively, and at one to four months following surgery. Both parallel and perpendicular diffusivities decreased markedly by a similar amount in the ipsilateral fornix within the first two days post-surgery. Approaching the end of the first week, perpendicular (but not parallel) diffusivity pseudo-recovered towards its pre-surgical value, but then increased dramatically months later. Fractional anisotropy, as a result of the combined action of the parallel and perpendicular diffusivities, stayed relatively stable within the first week and only reduced drastically at the chronic stage. DTI demonstrated acute water diffusion changes within days of transection that are not just limited to parallel diffusivity. While the chronic diffusion changes in the fornix are compatible with myelin degradation, the acute changes may reflect beading and swelling of axolemma, granular disintegration of the axonal neurofilaments, ischemia induced cytotoxic edema, and/or changes in the extra-axonal space including inflammatory changes and gliosis.

Brain microbial populations in HIV/AIDS: α-proteobacteria predominate independent of host immune status.

The brain is assumed to be a sterile organ in the absence of disease although the impact of immune disruption is uncertain in terms of brain microbial diversity or quantity. To investigate microbial diversity and quantity in the brain, the profile of infectious agents was examined in pathologically normal and abnormal brains from persons with HIV/AIDS [HIV] (n = 12), other disease controls [ODC] (n = 14) and in cerebral surgical resections for epilepsy [SURG] (n = 6). Deep sequencing of cerebral white matter-derived RNA from the HIV (n = 4) and ODC (n = 4) patients and SURG (n = 2) groups revealed bacterially-encoded 16 s RNA sequences in all brain specimens with α-proteobacteria representing over 70% of bacterial sequences while the other 30% of bacterial classes varied widely. Bacterial rRNA was detected in white matter glial cells by in situ hybridization and peptidoglycan immunoreactivity was also localized principally in glia in human brains. Analyses of amplified bacterial 16 s rRNA sequences disclosed that Proteobacteria was the principal bacterial phylum in all human brain samples with similar bacterial rRNA quantities in HIV and ODC groups despite increased host neuroimmune responses in the HIV group. Exogenous viruses including bacteriophage and human herpes viruses-4, -5 and -6 were detected variably in autopsied brains from both clinical groups. Brains from SIV- and SHIV-infected macaques displayed a profile of bacterial phyla also dominated by Proteobacteria but bacterial sequences were not detected in experimentally FIV-infected cat or RAG1⁻/⁻ mouse brains. Intracerebral implantation of human brain homogenates into RAG1⁻/⁻ mice revealed a preponderance of α-proteobacteria 16 s RNA sequences in the brains of recipient mice at 7 weeks post-implantation, which was abrogated by prior heat-treatment of the brain homogenate. Thus, α-proteobacteria represented the major bacterial component of the primate brain's microbiome regardless of underlying immune status, which could be transferred into naïve hosts leading to microbial persistence in the brain.

Age- and disease-dependent HERV-W envelope allelic variation in brain: association with neuroimmune gene expression.

BACKGROUND: The glycoprotein, Syncytin-1, is encoded by a human endogenous retrovirus (HERV)-W env gene and is capable of inducing neuroinflammation. The specific allele(s) responsible for Syncytin-1 expression in the brain is uncertain. Herein, HERV-W env diversity together with Syncytin-1 abundance and host immune gene profiles were examined in the nervous system using a multiplatform approach. RESULTS: HERV-W env sequences were encoded by multiple chromosomal encoding loci in primary human neurons compared with less chromosomal diversity in astrocytes and microglia (p<0.05). HERV-W env RNA sequences cloned from brains of patients with systemic or neurologic diseases were principally derived from chromosomal locus 7q21.2. Within the same specimens, HERV-W env transcript levels were correlated with the expression of multiple proinflammatory genes (p<0.05). Deep sequencing of brain transcriptomes disclosed the env transcripts to be the most abundant HERV-W transcripts, showing greater expression in fetal compared with healthy adult brain specimens. Syncytin-1's expression in healthy brain specimens was derived from multiple encoding loci and linked to distinct immune and developmental gene profiles. CONCLUSIONS: Syncytin-1 expression in the brain during disease was associated with neuroinflammation and was principally encoded by a full length provirus. The present studies also highlighted the diversity in HERV gene expression within the brain and reinforce the potential contributions of HERV expression to neuroinflammatory diseases.

Cortical tubers, cognition, and epilepsy in tuberous sclerosis.

Tuberous sclerosis complex is an autosomal-dominant genetic disorder characterized by hamartomatous growth in various organs. Patients who have this disorder exhibit a high rate of epilepsy and cognitive problems. We investigated number of tubers, location, seizure types, and cognitive outcome, and we analyzed the relationships among them in our tuberous sclerosis patients in the Comprehensive Epilepsy Program at the University of Alberta. We also examined the seizure outcome after tuber resection. Our study cohort included 24 patients with tuberous sclerosis complex. We obtained seizure history, electroencephalogram, and neuropsychologic parameters. Magnetic resonance imaging was used to examine tuber numbers and locations. Ten patients underwent surgical removal of tubers responsible for intractable epilepsy. A negative correlation was found between the number of tubers and intelligent quotient score. Epilepsy surgery led to freedom from seizures in this patient group. We demonstrated that the total number and location of cortical tubers play a significant role in the extent of mental retardation in patients with tuberous sclerosis complex. In addition, patients with intractable seizures and well-defined epileptic focus had excellent surgical outcome.

Dopamine modulates synaptic plasticity in dendrites of rat and human dentate granule cells.

The mechanisms underlying memory formation in the hippocampal network remain a major unanswered aspect of neuroscience. Although high-frequency activity appears essential for plasticity, salience for memory formation is also provided by activity in ventral tegmental area (VTA) dopamine projections. Here, we report that activation of dopamine D1 receptors in dentate granule cells (DGCs) can preferentially increase dendritic excitability to both high-frequency afferent activity and high-frequency trains of backpropagating action potentials. Using whole-cell patch clamp recordings, calcium imaging, and neuropeptide Y to inhibit postsynaptic calcium influx, we found that activation of dendritic voltage-dependent calcium channels (VDCCs) is essential for dopamine-induced long-term potentiation (LTP), both in rat and human dentate gyrus (DG). Moreover, we demonstrate previously unreported spike-timing-dependent plasticity in the human hippocampus. These results suggest that when dopamine is released in the dentate gyrus with concurrent high-frequency activity there is an increased probability that synapses will be strengthened and reward-associated spatial memories will be formed.

In vivo diffusion tensor imaging and histopathology of the fimbria-fornix in temporal lobe epilepsy.

While diffusion tensor imaging (DTI) has been extensively used to infer micro-structural characteristics of cerebral white matter in human conditions, correlations between human in vivo DTI and histology have not been performed. Temporal lobe epilepsy (TLE) patients with mesial temporal sclerosis (MTS) have abnormal DTI parameters of the fimbria-fornix (relative to TLE patients without MTS) which are presumed to represent differences in axonal/myelin integrity. Medically intractable TLE patients who undergo temporal lobe resection including the fimbria-fornix provide a unique opportunity to study the anatomical correlates of water diffusion abnormalities in freshly excised tissue. Eleven patients with medically intractable TLE were recruited (six with and five without MTS) for presurgical DTI followed by surgical excision of a small specimen of the fimbria-fornix which was processed for electron microscopy. Blinded quantitative analysis of the microphotographs included axonal diameter, density and area, cumulative axon membrane circumference, and myelin thickness and area. As predicted by DTI the fimbria-fornix of TLE patients with MTS had increased extra-axonal fraction, and reduced cumulative axonal membrane circumference and myelin area. Consistent with the animal literature, water diffusion anisotropy over the crus of the fimbria-fornix was strongly correlated with axonal membranes (cumulative membrane circumference) within the surgical specimen (approximately 15% of what was analyzed with DTI). The demonstration of a correlation between histology and human in vivo DTI, in combination with the observation that in vivo DTI accurately predicted white matter abnormalities in a human disease condition, provides strong validation of the application of DTI as a noninvasive marker of white matter pathology.

Selective amygdalohippocampectomy: the trans-middle temporal gyrus approach.

The most common surgical procedure for the mesial temporal lobe is the standard anterior temporal resection or what is commonly called the anterior temporal lobectomy. There are, however, a number of other more selective procedures for removal of the mesial temporal lobe structures (amygdala, hippocampus, and parahippocampal gyrus) that spare much of the lateral temporal neocortex. Included in these procedures collectively referred to as selective amygdalohippocampectomy are the transsylvian, subtemporal, and transcortical (trans-middle temporal gyrus) selective amygdalohippocampectomy. In this manuscript the author reviews some of the surgical details of the trans-middle temporal gyrus approach to the mesial temporal structures.