Surgery of Motor Eloquent Glioblastoma Guided by TMS-Informed Tractography: Driving Resection Completeness Towards Prolonged Survival.

Background: Surgical treatment of patients with glioblastoma affecting motor eloquent brain regions remains critically discussed given the risk-benefit dilemma of prolonging survival at the cost of motor-functional damage. Tractography informed by navigated transcranial magnetic stimulation (nTMS-informed tractography, TIT) provides a rather robust estimate of the individual location of the corticospinal tract (CST), a highly vulnerable structure with poor functional reorganisation potential. We hypothesised that by a more comprehensive, individualised surgical decision-making using TIT, tumours in close relationship to the CST can be resected with at least equal probability of gross total resection (GTR) than less eloquently located tumours without causing significantly more gross motor function harm. Moreover, we explored whether the completeness of TIT-aided resection translates to longer survival. Methods: A total of 61 patients (median age 63 years, m = 34) with primary glioblastoma neighbouring or involving the CST were operated on between 2010 and 2015. TIT was performed to inform surgical planning in 35 of the patients (group T; vs. 26 control patients). To achieve largely unconfounded group comparisons for each co-primary outcome (i.e., gross-motor functional worsening, GTR, survival), (i) uni- and multivariate regression analyses were performed to identify features of optimal outcome prediction; (ii), optimal propensity score matching (PSM) was applied to balance those features pairwise across groups, followed by (iii) pairwise group comparison. Results: Patients in group T featured a significantly higher lesion-CST overlap compared to controls (8.7 ± 10.7% vs. 3.8 ± 5.7%; p = 0.022). The frequency of gross motor worsening was higher in group T, albeit non-significant (n = 5/35 vs. n = 0/26; p = 0.108). PSM-based paired-sample comparison, controlling for the confounders of preoperative tumour volume and vicinity to the delicate vasculature of the insula, showed higher GTR rates in group T (77% vs. 69%; p = 0.025), particularly in patients with a priori intended GTR (87% vs. 78%; p = 0.003). This translates into a prolonged PFS in the same PSM subgroup (8.9 vs. 5.8 months; p = 0.03), with GTR representing the strongest predictor of PFS (p = 0.001) and OS (p = 0.0003) overall. Conclusion: The benefit of TIT-aided GTR appears to overcome the drawbacks of potentially elevated motor functional risk in motor eloquent tumour localisation, leading to prolonged survival of patients with primary glioblastoma close to the CST.

A novel MRI-based quantitative water content atlas of the human brain.

The measurement of quantitative, tissue-specific MR properties, e.g., water content, longitudinal relaxation time (T1) and effective transverse relaxation time (T2⁎), using quantitative MRI at a clinical field strength (1.5 T to 3T) is a well-explored topic. However, none of the commonly used standard brain atlases, such as MNI or JHU, provide quantitative information. Within the framework of quantitative MRI of the brain, this work reports on the development of the first quantitative brain atlas for tissue water content at 3T. A methodology to create this quantitative atlas of in vivo brain water content based on healthy volunteers is presented, and preliminary, practical examples of its potential applications are also shown. Established methods for the fast and reliable measurement of the absolute water content were used to achieve high precision and accuracy. Water content and T2⁎ were mapped based on two different methods: an intermediate-TR, two-point method and a long-TR, single-scan method. Twenty healthy subjects (age 25.3 ± 2.5 years) were examined with these quantitative imaging protocols. The images were normalised to MNI stereotactic coordinates, and water content atlases of healthy volunteers were created for each method and compared. Regions-of-interest were generated with the help of a standard MNI template, and water content values averaged across the ROIs were compared to water content values from the literature. Finally, in order to demonstrate the strength of quantitative MRI, water content maps from patients with pathological changes in the brain due to stroke, tumour (glioblastoma) and multiple sclerosis were voxel-wise compared to the healthy brain. The water content atlases were largely independent of the method used to acquire the individual water maps. Global grey matter and white matter water content values between the methods agreed with each other to within 0.5 %. The feasibility of detecting abnormal water content in the brains of patients based on comparison to a healthy brain water content atlas was demonstrated. In summary, the first quantitative water content brain atlas in vivo has been developed, and a voxel-wise assessment of pathology-related changes in the brain water content has been performed. These results suggest that qMRI, in combination with a water content atlas, allows for a quantitative interpretation of changes due to disease and could be used for disease monitoring.

A Fast Protocol for Multiparametric Characterisation of Diffusion in the Brain and Brain Tumours.

Multi-parametric tissue characterisation is demonstrated using a 4-minute protocol based on diffusion trace acquisitions. Three diffusion regimes are covered simultaneously: pseudo-perfusion, Gaussian, and non-Gaussian diffusion. The clinical utility of this method for fast multi-parametric mapping for brain tumours is explored. A cohort of 17 brain tumour patients was measured on a 3T hybrid MR-PET scanner with a standard clinical MRI protocol, to which the proposed multi-parametric diffusion protocol was subsequently added. For comparison purposes, standard perfusion and a full diffusion kurtosis protocol were acquired. Simultaneous amino-acid (18F-FET) PET enabled the identification of active tumour tissue. The metrics derived from the proposed protocol included perfusion fraction, pseudo-diffusivity, apparent diffusivity, and apparent kurtosis. These metrics were compared to the corresponding metrics from the dedicated acquisitions: cerebral blood volume and flow, mean diffusivity and mean kurtosis. Simulations were carried out to assess the influence of fitting methods and noise levels on the estimation of the parameters. The diffusion and kurtosis metrics obtained from the proposed protocol show strong to very strong correlations with those derived from the conventional protocol. However, a bias towards lower values was observed. The pseudo-perfusion parameters showed very weak to weak correlations compared to their perfusion counterparts. In conclusion, we introduce a clinically applicable protocol for measuring multiple parameters and demonstrate its relevance to pathological tissue characterisation.

Invasive versus non-invasive mapping of the motor cortex.

Precise and comprehensive mapping of somatotopic representations in the motor cortex is clinically essential to achieve maximum resection of brain tumours whilst preserving motor function, especially since the current gold standard, that is, intraoperative direct cortical stimulation (DCS), holds limitations linked to the intraoperative setting such as time constraints or anatomical restrictions. Non-invasive techniques are increasingly relevant with regard to pre-operative risk-assessment. Here, we assessed the congruency of neuronavigated transcranial magnetic stimulation (nTMS) and functional magnetic resonance imaging (fMRI) with DCS. The motor representations of the hand, the foot and the tongue regions of 36 patients with intracranial tumours were mapped pre-operatively using nTMS and fMRI and by intraoperative DCS. Euclidean distances (ED) between hotspots/centres of gravity and (relative) overlaps of the maps were compared. We found significantly smaller EDs (11.4 ± 8.3 vs. 16.8 ± 7.0 mm) and better spatial overlaps (64 ± 38% vs. 37 ± 37%) between DCS and nTMS compared with DCS and fMRI. In contrast to DCS, fMRI and nTMS mappings were feasible for all regions and patients without complications. In summary, nTMS seems to be the more promising non-invasive motor cortex mapping technique to approximate the gold standard DCS results.

An MR technique for simultaneous quantitative imaging of water content, conductivity and susceptibility, with application to brain tumours using a 3T hybrid MR-PET scanner.

Approaches for the quantitative mapping of water content, electrical conductivity and susceptibility have been developed independently. The purpose of this study is to develop a method for simultaneously acquiring quantitative water content, electrical conductivity and susceptibility maps based on a 2D multi-echo gradient echo sequence. Another purpose is to investigate the changes in these properties caused by brain tumours. This was done using a 3T hybrid magnetic resonance imaging and positron emission tomography (MR-PET) scanner. Water content maps were derived after performing T2* and transmit-receive field bias corrections to magnitude images essentially reflecting only the H2O content contrast. Phase evolution during the multi-echo train was used to generate field maps and derive quantitative susceptibility, while the conductivity maps were retrieved from the phase value at zero echo time. Performance of the method is demonstrated on phantoms and two healthy volunteers. In addition, the method was applied to three patients with brain tumours and a comparison to maps obtained from PET using O-(2-[18 F]fluoroethyl)-L-tyrosine and clinical MR images is presented. The combined information of the water content, conductivity and susceptibility may provide additional information about the tissue viability. Future studies can benefit from the evaluation of these contrasts with shortened acquisition times.

A Single-Scan, Rapid Whole-Brain Protocol for Quantitative Water Content Mapping With Neurobiological Implications.

Water concentration is tightly regulated in the healthy human brain and changes only slightly with age and gender in healthy subjects. Consequently, changes in water content are important for the characterization of disease. MRI can be used to measure changes in brain water content, but as these changes are usually in the low percentage range, highly accurate and precise methods are required for detection. The method proposed here is based on a long-TR (10 s) multiple-echo gradient-echo measurement with an acquisition time of 7:21 min. Using such a long TR ensures that there is no T1 weighting, meaning that the image intensity at zero echo time is only proportional to the water content, the transmit field, and to the receive field. The receive and transmit corrections, which are increasingly large at higher field strengths and for highly segmented coil arrays, are multiplicative and can be approached heuristically using a bias field correction. The method was tested on 21 healthy volunteers at 3T field strength. Calibration using cerebral-spinal fluid values (~100% water content) resulted in mean values and standard deviations of the water content distribution in white matter and gray matter of 69.1% (1.7%) and 83.7% (1.2%), respectively. Measured distributions were coil-independent, as seen by using either a 12-channel receiver coil or a 32-channel receiver coil. In a test-retest investigation using 12 scans on one volunteer, the variation in the mean value of water content for different tissue types was ~0.3% and the mean voxel variability was ~1%. Robustness against reduced SNR was assessed by comparing results for 5 additional volunteers at 1.5T and 3T. Furthermore, water content distribution in gray matter is investigated and regional contrast reported for the first time. Clinical applicability is illustrated with data from one stroke patient and one brain tumor patient. It is anticipated that this fast, stable, easy-to-use, high-quality mapping method will facilitate routine quantitative MR imaging of water content.

Correlation of Dynamic O-(2-[18F]Fluoroethyl)-L-Tyrosine Positron Emission Tomography, Conventional Magnetic Resonance Imaging, and Whole-Brain Histopathology in a Pretreated Glioblastoma: A Postmortem Study.

OBJECTIVE: Amino acid positron emission tomography (PET) using O-(2-[18F]fluoroethyl)-L-tyrosine (FET) provides important additional information on the extent of viable tumor tissue of glioblastoma compared with magnetic resonance imaging (MRI). Especially after radiochemotherapy, progression of contrast enhancement in MRI is equivocal and may represent either tumor progression or treatment-related changes. Here, the first case comparing postmortem whole-brain histology of a patient with pretreated glioblastoma with dynamic in vivo FET PET and MRI is presented. METHODS: A 61-year-old patient with glioblastoma initially underwent partial tumor resection and died 11 weeks after completion of chemoradiation with concurrent temozolomide. Three days before the patient died, a follow-up FET PET and MRI scan indicated tumor progression. Autopsy was performed 48 hours after death. After formalin fixation, a 7-cm bihemispherical segment of the brain containing the entire tumor mass was cut into 3500 consecutive 20µm coronal sections. Representative sections were stained with hematoxylin and eosin stain, cresyl violet, and glial fibrillary acidic protein immunohistochemistry. An experienced neuropathologist identified areas of dense and diffuse neoplastic infiltration, astrogliosis, and necrosis. In vivo FET PET, MRI datasets, and postmortem histology were co-registered and compared by 3 experienced physicians. RESULTS: Increased uptake of FET in the area of equivocal contrast enhancement on MRI correlated very well with dense infiltration by vital tumor cells and showed tracer kinetics typical for malignant gliomas. An area of predominantly reactive astrogliosis showed only moderate uptake of FET and tracer kinetics usually observed in benign lesions. CONCLUSIONS: This case report impressively documents the correct imaging of a progressive glioblastoma by FET PET.

Neuroanatomy of pain-deficiency and cross-modal activation in calcium channel subunit (CACN) α2δ3 knockout mice.

The phenotype of calcium channel subunit (CACN) α2δ3 knockout (KO) mice includes sensory cross-activation and deficient pain perception. Sensory cross-activation defines the activation of a sensory cortical region by input from another modality due to reorganization in the brain such as after sensory loss. To obtain mechanistic insight into both phenomena, we employed a comprehensive battery of neuroanatomical techniques. While CACNα2δ3 was ubiquitously expressed in wild-type mice, it was absent in α2δ3 KO animals. Immunostaining of α1A, α1B, and α1E revealed upregulation of N-type and R-type, but not P/Q-type Cav2 channels in cortical neurons of CACNα2δ3 KO mice. Compared to wild-type mice, axonal processes in somatosensory cortex were enhanced, and dendritic processes reduced, in CACNα2δ3 KO mice. Immunohistochemical and MRI analyses, investigating morphology, thalamocortical and intra-/intercortical trajectories, revealed a disparity between projection and commissural fibers with reduction of the number of spatial specificity of thalamocortical projections. L1cam staining revealed wide-ranging projections of thalamocortical fibers reaching both somatosensory/motor and visual cortical areas. Activation (c-fos+) of excitatory and inhibitory neurons suggested that deficient pain perception in α2δ3 KO mice is unlikely to result from cortical disinhibition. Collectively, our data demonstrate that knock out of CACN α2δ3 results in some structural abnormalities whose functional implications converge to dedifferentiation of sensory activation.

Functional MRI vs. navigated TMS to optimize M1 seed volume delineation for DTI tractography. A prospective study in patients with brain tumours adjacent to the corticospinal tract.

BACKGROUND: DTI-based tractography is an increasingly important tool for planning brain surgery in patients suffering from brain tumours. However, there is an ongoing debate which tracking approaches yield the most valid results. Especially the use of functional localizer data such as navigated transcranial magnetic stimulation (nTMS) or functional magnetic resonance imaging (fMRI) seem to improve fibre tracking data in conditions where anatomical landmarks are less informative due to tumour-induced distortions of the gyral anatomy. We here compared which of the two localizer techniques yields more plausible results with respect to mapping different functional portions of the corticospinal tract (CST) in brain tumour patients. METHODS: The CSTs of 18 patients with intracranial tumours in the vicinity of the primary motor area (M1) were investigated by means of deterministic DTI. The core zone of the tumour-adjacent hand, foot and/or tongue M1 representation served as cortical regions of interest (ROIs). M1 core zones were defined by both the nTMS hot-spots and the fMRI local activation maxima. In addition, for all patients, a subcortical ROI at the level of the inferior anterior pons was implemented into the tracking algorithm in order to improve the anatomical specificity of CST reconstructions. As intra-individual control, we additionally tracked the CST of the hand motor region of the unaffected, i.e., non-lesional hemisphere, again comparing fMRI and nTMS M1 seeds. The plausibility of the fMRI-ROI- vs. nTMS-ROI-based fibre trajectories was assessed by a-priori defined anatomical criteria. Moreover, the anatomical relationship of different fibre courses was compared regarding their distribution in the anterior-posterior direction as well as their location within the posterior limb of the internal capsule (PLIC). RESULTS: Overall, higher plausibility rates were observed for the use of nTMS- as compared to fMRI-defined cortical ROIs (p < 0.05) in tumour vicinity. On the non-lesional hemisphere, however, equally good plausibility rates (100%) were observed for both localizer techniques. fMRI-originated fibres generally followed a more posterior course relative to the nTMS-based tracts (p < 0.01) in both the lesional and non-lesional hemisphere. CONCLUSION: NTMS achieved better tracking results than fMRI in conditions when the cortical tract origin (M1) was located in close vicinity to a brain tumour, probably influencing neurovascular coupling. Hence, especially in situations with altered BOLD signal physiology, nTMS seems to be the method of choice in order to identify seed regions for CST mapping in patients.

Improved nTMS- and DTI-derived CST tractography through anatomical ROI seeding on anterior pontine level compared to internal capsule.

Imaging of the course of the corticospinal tract (CST) by diffusion tensor imaging (DTI) is useful for function-preserving tumour surgery. The integration of functional localizer data into tracking algorithms offers to establish a direct structure-function relationship in DTI data. However, alterations of MRI signals in and adjacent to brain tumours often lead to spurious tracking results. We here compared the impact of subcortical seed regions placed at different positions and the influences of the somatotopic location of the cortical seed and clinical co-factors on fibre tracking plausibility in brain tumour patients. The CST of 32 patients with intracranial tumours was investigated by means of deterministic DTI and neuronavigated transcranial magnetic stimulation (nTMS). The cortical seeds were defined by the nTMS hot spots of the primary motor area (M1) of the hand, the foot and the tongue representation. The CST originating from the contralesional M1 hand area was mapped as intra-individual reference. As subcortical region of interests (ROI), we used the posterior limb of the internal capsule (PLIC) and/or the anterior inferior pontine region (aiP). The plausibility of the fibre trajectories was assessed by a-priori defined anatomical criteria. The following potential co-factors were analysed: Karnofsky Performance Scale (KPS), resting motor threshold (RMT), T1-CE tumour volume, T2 oedema volume, presence of oedema within the PLIC, the fractional anisotropy threshold (FAT) to elicit a minimum amount of fibres and the minimal fibre length. The results showed a higher proportion of plausible fibre tracts for the aiP-ROI compared to the PLIC-ROI. Low FAT values and the presence of peritumoural oedema within the PLIC led to less plausible fibre tracking results. Most plausible results were obtained when the FAT ranged above a cut-off of 0.105. In addition, there was a strong effect of somatotopic location of the seed ROI; best plausibility was obtained for the contralateral hand CST (100%), followed by the ipsilesional hand CST (>95%), the ipsilesional foot (>85%) and tongue (>75%) CST. In summary, we found that the aiP-ROI yielded better tracking results compared to the IC-ROI when using deterministic CST tractography in brain tumour patients, especially when the M1 hand area was tracked. In case of FAT values lower than 0.10, the result of the respective CST tractography should be interpreted with caution with respect to spurious tracking results. Moreover, the presence of oedema within the internal capsule should be considered a negative predictor for plausible CST tracking.

Advances in multimodal neuroimaging: hybrid MR-PET and MR-PET-EEG at 3 T and 9.4 T.

Multi-modal MR-PET-EEG data acquisition in simultaneous mode confers a number of advantages at 3 T and 9.4 T. The three modalities complement each other well; structural-functional imaging being the domain of MRI, molecular imaging with specific tracers is the strength of PET, and EEG provides a temporal dimension where the other two modalities are weak. The utility of hybrid MR-PET at 3 T in a clinical setting is presented and critically discussed. The potential problems and the putative gains to be accrued from hybrid imaging at 9.4 T, with examples from the human brain, are outlined. Steps on the road to 9.4 T multi-modal MR-PET-EEG are also illustrated. From an MR perspective, the potential for ultra-high resolution structural imaging is discussed and example images of the cerebellum with an isotropic resolution of 320 µm are presented, setting the stage for hybrid imaging at ultra-high field. Further, metabolic imaging is discussed and high-resolution images of the sodium distribution are presented. Examples of tumour imaging on a 3 T MR-PET system are presented and discussed. Finally, the perspectives for multi-modal imaging are discussed based on two on-going studies, the first comparing MR and PET methods for the measurement of perfusion and the second which looks at tumour delineation based on MRI contrasts but the knowledge of tumour extent is based on simultaneously acquired PET data.