Comparison between inferior frontal gyrus intrinsic connectivity network and verb-generation task fMRI network for presurgical language mapping in healthy controls and in glioma patients.

Task-based functional MRI (tb-fMRI) represents an extremely valuable approach for the identification of language eloquent regions for presurgical mapping in patients with brain tumors. However, its routinely application is limited by patient-related factors, such as cognitive disability and difficulty in coping with long-time acquisitions, and by technical factors, such as lack of equipment availability for stimuli delivery. Resting-state fMRI (rs-fMRI) instead, allows the identification of distinct language networks in a 10-min acquisition without the need of performing active tasks and using specific equipment. Therefore, to test the feasibility of rs-fMRI as a preoperative mapping tool, we reconstructed a lexico-semantic intrinsic connectivity network (ICN) in healthy controls (HC) and in a case series of patients with gliomas and compared the organization of this language network with the one derived from tb-fMRI in the patient's group. We studied three patients with extra-frontal gliomas who underwent functional mapping with auditory verb-generation (AVG) task and rs-fMRI with a seed in the left inferior frontal gyrus (IFG). First, we identified the functional connected areas to the IFG in HC. We qualitatively compared these areas with those that showed functional activation in AVG task derived from Neurosynth meta-analysis. Last, in each patient we performed single-subject analyses both for rs- and tb-fMRI, and we evaluated the spatial overlap between the two approaches. In HC, the IFG-ICN network showed a predominant left fronto-temporal functional connectivity in regions overlapping with the AVG network derived from a meta-analysis. In two patients, rs- and tb-fMRI showed comparable patterns of activation in left fronto-temporal regions, with different levels of contralateral activations. The third patient could not accomplish the AVG task and thus it was not possible to make any comparison with the ICN. However, in this patient, task-free approach disclosed a consistent network of fronto-temporal regions as in HC, and additional parietal regions. Our preliminary findings support the value of rs-fMRI approach for presurgical mapping, particularly for identifying left fronto-temporal core language-related areas in glioma patients. In a preoperative setting, rs-fMRI approach could represent a powerful tool for the identification of eloquent language areas, especially in patients with language or cognitive impairments.

Diagnostic efficacy and safety of gadoteridol compared to gadobutrol and gadoteric acid in a large sample of CNS MRI studies at 1.5T.

PURPOSE: To evaluate safety and diagnostic accuracy of gadoteridol vs. other macrocyclic gadolinium-based contrast agents (GBCAs) in a large cohort of consecutive and non-selected patients referred for CE-MRI of the CNS. MATERIAL AND METHODS: Between November 2017 and March 2018, we prospectively enrolled a consecutive cohort of patients referred for neuroradiological CE-MRI (1.5T MRI). Image quality and adverse events were assessed. Diagnostic performance was determined for a subgroup of patients with truth standard findings available. Comparison was made between patients receiving gadoteridol and patients receiving other macrocyclic GBCAs. Inter-reader agreement (kappa) between two expert neuroradiologists was calculated for the diagnosis of malignancy. RESULTS: Overall, 460 patients (220M/240F; mean age 54±16 years) were enrolled of which 230 received gadoteridol (Group 1) and 230 either gadoteric acid or gadobutrol [n=83 (36.1%) and n=147 (63.9%), respectively; Group 2]. Image quality was rated as good or excellent in both groups. The sensitivity, specificity and diagnostic accuracy for determination of malignancy was 88.2%, 96.5% and 95.4%, respectively, for Group 1 and 93.7%, 97.4% and 96.9%, respectively, for Group 2, with no significant differences between groups (P>0.75) for any determination. Inter-reader agreement for the identification of malignancy was excellent [K=0.877 (95%CI: 0.758-0.995) and K=0.818 (95%CI: 0.663-0.972) for groups 1 and 2, respectively; P=0.0913]. Adverse events occurred in 5 of 460 (1.09%) patients overall, with no significant difference (P=0.972) between groups. CONCLUSION: Gadoteridol was safe and guaranteed good image quality without significant differences when compared to gadobutrol and gadoteric acid in a wide range of CNS pathologies.

Along-tract statistics of neurite orientation dispersion and density imaging diffusion metrics to enhance MR tractography quantitative analysis in healthy controls and in patients with brain tumors.

Along-tract statistics analysis enables the extraction of quantitative diffusion metrics along specific white matter fiber tracts. Besides quantitative metrics derived from classical diffusion tensor imaging (DTI), such as fractional anisotropy and diffusivities, new parameters reflecting the relative contribution of different diffusion compartments in the tissue can be estimated through advanced diffusion MRI methods as neurite orientation dispersion and density imaging (NODDI), leading to a more specific microstructural characterization. In this study, we extracted both DTI- and NODDI-derived quantitative microstructural diffusion metrics along the most eloquent fiber tracts in 15 healthy subjects and in 22 patients with brain tumors. We obtained a robust intraprotocol reference database of normative along-tract microstructural metrics, and their corresponding plots, from healthy fiber tracts. Each diffusion metric of individual patient's fiber tract was then plotted and statistically compared to the normative profile of the corresponding metric from the healthy fiber tracts. NODDI-derived metrics appeared to account for the pathological microstructural changes of the peritumoral tissue more accurately than DTI-derived ones. This approach may be useful for future studies that may compare healthy subjects to patients diagnosed with other pathological conditions.

fMRI-Targeted High-Angular Resolution Diffusion MR Tractography to Identify Functional Language Tracts in Healthy Controls and Glioma Patients.

BACKGROUND: MR Tractography enables non-invasive preoperative depiction of language subcortical tracts, which is crucial for the presurgical work-up of brain tumors; however, it cannot evaluate the exact function of the fibers. PURPOSE: A systematic pipeline was developed to combine tractography reconstruction of language fiber bundles, based on anatomical landmarks (Anatomical-T), with language fMRI cortical activations. A fMRI-targeted Tractography (fMRI-T) was thus obtained, depicting the subsets of the anatomical tracts whose endpoints are located inside a fMRI activation. We hypothesized that fMRI-T could provide additional functional information regarding the subcortical structures, better reflecting the eloquent white matter structures identified intraoperatively. METHODS: Both Anatomical-T and fMRI-T of language fiber tracts were performed on 16 controls and preoperatively on 16 patients with left-hemisphere brain tumors, using a q-ball residual bootstrap algorithm based on High Angular Resolution Diffusion Imaging (HARDI) datasets (b = 3000 s/mm2; 60 directions); fMRI ROIs were obtained using picture naming, verbal fluency, and auditory verb generation tasks. In healthy controls, normalized MNI atlases of fMRI-T and Anatomical-T were obtained. In patients, the surgical resection of the tumor was pursued by identifying eloquent structures with intraoperative direct electrical stimulation mapping and extending surgery to the functional boundaries. Post-surgical MRI allowed to identify Anatomical-T and fMRI-T non-eloquent portions removed during the procedure. RESULTS: MNI Atlases showed that fMRI-T is a subset of Anatomical-T, and that different task-specific fMRI-T involve both shared subsets and task-specific subsets - e.g., verbal fluency fMRI-T strongly involves dorsal frontal tracts, consistently with the phonogical-articulatory features of this task. A quantitative analysis in patients revealed that Anatomical-T removed portions of AF-SLF and IFOF were significantly greater than verbal fluency fMRI-T ones, suggesting that fMRI-T is a more specific approach. In addition, qualitative analyses showed that fMRI-T AF-SLF and IFOF predict the exact functional limits of resection with increased specificity when compared to Anatomical-T counterparts, especially the superior frontal portion of IFOF, in a subcohort of patients. CONCLUSION: These results suggest that performing fMRI-T in addition to the 'classic' Anatomical-T may be useful in a preoperative setting to identify the 'high-risk subsets' that should be spared during the surgical procedure.

Integration of Diffusion Magnetic Resonance Tractography into tomotherapy radiation treatment planning for high-grade gliomas.

INTRODUCTION: Fractionated radiotherapy in brain tumors is commonly associated with several detrimental effects, largely related to the higher radiosensitivity of the white matter (WM) with respect to gray matter. However, no dose constraints are applied to preserve WM structures at present. Magnetic Resonance (MR) Tractography is the only technique that allows to visualize in vivo the course of WM eloquent tracts in the brain. In this study, the feasibility of integrating MR Tractography in tomotherapy treatment planning has been investigated, with the aim to spare eloquent WM regions from the dose delivered during treatment. METHODS: Nineteen high grade glioma patients treated with fractionated radiotherapy were enrolled. All the patients underwent pre-treatment MR imaging protocol including Diffusion Tensor Imaging (DTI) acquisitions for MR Tractography analysis. Bilateral tracts involved in several motor, language, cognitive functions were reconstructed and these fiber bundles were integrated into the Tomotherapy Treatment planning system. The original plans without tracts were compared with the optimized plans incorporating the fibers, to evaluate doses to WM structures in the two differently optimized plans. RESULTS: No significant differences were found between plans in terms of planning target volume (PTV) coverage between the original plans and the optimized plans incorporating fiber tracts. Comparing the mean as well as the maximal dose (Dmean and Dmax), a significant dose reduction was found for most of the tracts. The dose sparing was more relevant for contralateral tracts (P < 0.0001). CONCLUSION: The integration of MR Tractography into radiotherapy planning is feasible and beneficial to preserve important WM structures without reducing the clinical goal of radiation treatment.

Reproducibility of dynamic contrast-enhanced MRI and dynamic susceptibility contrast MRI in the study of brain gliomas: a comparison of data obtained using different commercial software.

PURPOSE: Dynamic susceptibility contrast MRI (DSC) and dynamic contrast-enhanced MRI (DCE) are useful tools in the diagnosis and follow-up of brain gliomas; nevertheless, both techniques leave the open issue of data reproducibility. We evaluated the reproducibility of data obtained using two different commercial software for perfusion maps calculation and analysis, as one of the potential sources of variability can be the software itself. METHODS: DSC and DCE analyses from 20 patients with gliomas were tested for both the intrasoftware (as intraobserver and interobserver reproducibility) and the intersoftware reproducibility, as well as the impact of different postprocessing choices [vascular input function (VIF) selection and deconvolution algorithms] on the quantification of perfusion biomarkers plasma volume (Vp), volume transfer constant (K trans) and rCBV. Data reproducibility was evaluated with the intraclass correlation coefficient (ICC) and Bland-Altman analysis. RESULTS: For all the biomarkers, the intra- and interobserver reproducibility resulted in almost perfect agreement in each software, whereas for the intersoftware reproducibility the value ranged from 0.311 to 0.577, suggesting fair to moderate agreement; Bland-Altman analysis showed high dispersion of data, thus confirming these findings. Comparisons of different VIF estimation methods for DCE biomarkers resulted in ICC of 0.636 for K trans and 0.662 for Vp; comparison of two deconvolution algorithms in DSC resulted in an ICC of 0.999. CONCLUSIONS: The use of single software ensures very good intraobserver and interobservers reproducibility. Caution should be taken when comparing data obtained using different software or different postprocessing within the same software, as reproducibility is not guaranteed anymore.

Dynamic contrast-enhanced and dynamic susceptibility contrast perfusion MR imaging for glioma grading: Preliminary comparison of vessel compartment and permeability parameters using hotspot and histogram analysis.

INTRODUCTION: Dynamic susceptibility contrast (DSC)-MRI is a perfusion technique with high diagnostic accuracy for glioma grading, despite limitations due to inherent susceptibility effects. Dynamic contrast-enhanced (DCE)-MRI has been proposed as an alternative technique able to overcome the DSC-MRI shortcomings. This pilot study aimed at comparing the diagnostic accuracy of DSC and DCE-MRI for glioma grading by evaluating two estimates of blood volume, the DCE-derived plasma volume (Vp) and the DSC-derived relative cerebral blood volume (rCBV), and a measure of vessel permeability, the DCE-derived volume transfer constant K(trans). METHODS: Twenty-six newly diagnosed glioma patients underwent 3T-MR DCE and DSC imaging. Parametric maps of CBV, Vp and K(trans) were calculated and the region of highest value (hotspot) was measured on each map. Histograms of rCBV, Vp and K(trans) values were calculated for the tumor volume. Statistical differences according to WHO grade were assessed. The diagnostic accuracy for tumor grading of the two techniques was determined by ROC analysis. RESULTS: rCBV, Vp and K(trans) measures differed significantly between high and low-grade gliomas. Hotspot analysis showed the highest correlation with grading. K(trans) hotspots co-localized with Vp hotspots only in 56% of enhancing gliomas. For differentiating high from low-grade gliomas the AUC was 0.987 for rCBVmax, and 1.000 for Vpmax and K(trans)max. Combination of DCE-derived Vp and K(trans) parameters improved the diagnostic performance of the histogram method. CONCLUSION: This initial experience of DCE-derived Vp evaluation shows that this parameter is as accurate as the well-established DSC-derived rCBV for glioma grading. DCE-derived K(trans) is equally useful for grading, providing different informations with respect to Vp.

Evaluation of low-grade glioma structural changes after chemotherapy using DTI-based histogram analysis and functional diffusion maps.

OBJECTIVES: To explore the role of diffusion tensor imaging (DTI)-based histogram analysis and functional diffusion maps (fDMs) in evaluating structural changes of low-grade gliomas (LGGs) receiving temozolomide (TMZ) chemotherapy. METHODS: Twenty-one LGG patients underwent 3T-MR examinations before and after three and six cycles of dose-dense TMZ, including 3D-fluid-attenuated inversion recovery (FLAIR) sequences and DTI (b = 1000 s/mm(2), 32 directions). Mean diffusivity (MD), fractional anisotropy (FA), and tensor-decomposition DTI maps (p and q) were obtained. Histogram and fDM analyses were performed on co-registered baseline and post-chemotherapy maps. DTI changes were compared with modifications of tumour area and volume [according to Response Assessment in Neuro-Oncology (RANO) criteria], and seizure response. RESULTS: After three cycles of TMZ, 20/21 patients were stable according to RANO criteria, but DTI changes were observed in all patients (Wilcoxon test, P ≤ 0.03). After six cycles, DTI changes were more pronounced (P ≤ 0.005). Seventy-five percent of patients had early seizure response with significant improvement of DTI values, maintaining stability on FLAIR. Early changes of the 25th percentiles of p and MD predicted final volume change (R(2) = 0.614 and 0.561, P < 0.0005, respectively). TMZ-related changes were located mainly at tumour borders on p and MD fDMs. CONCLUSIONS: DTI-based histogram and fDM analyses are useful techniques to evaluate the early effects of TMZ chemotherapy in LGG patients. KEY POINTS: • DTI helps to assess the efficacy of chemotherapy in low-grade gliomas. • Histogram analysis of DTI metrics quantifies structural changes in tumour tissue. • Functional diffusion maps (fDMs) spatially localize the changes of DTI metrics. • Changes in DTI histograms and fDMs precede changes in conventional MRI. • Early changes in DTI histograms and fDMs correlate with seizure response.

The mirror neuron system and the strange case of Broca's area.

Mirror neurons, originally described in the monkey premotor area F5, are embedded in a frontoparietal network for action execution and observation. A similar Mirror Neuron System (MNS) exists in humans, including precentral gyrus, inferior parietal lobule, and superior temporal sulcus. Controversial is the inclusion of Broca's area, as homologous to F5, a relevant issue in light of the mirror hypothesis of language evolution, which postulates a key role of Broca's area in action/speech perception/production. We assess "mirror" properties of this area by combining neuroimaging and intraoperative neurophysiological techniques. Our results show that Broca's area is minimally involved in action observation and has no motor output on hand or phonoarticulatory muscles, challenging its inclusion in the MNS. The presence of these functions in premotor BA6 makes this area the likely homologue of F5 suggesting that the MNS may be involved in the representation of articulatory rather than semantic components of speech.

The auditory scene: an fMRI study on melody and accompaniment in professional pianists.

The auditory scene is a mental representation of individual sounds extracted from the summed sound waveform reaching the ears of the listeners. Musical contexts represent particularly complex cases of auditory scenes. In such a scenario, melody may be seen as the main object moving on a background represented by the accompaniment. Both melody and accompaniment vary in time according to harmonic rules, forming a typical texture with melody in the most prominent, salient voice. In the present sparse acquisition functional magnetic resonance imaging study, we investigated the interplay between melody and accompaniment in trained pianists, by observing the activation responses elicited by processing: (1) melody placed in the upper and lower texture voices, leading to, respectively, a higher and lower auditory salience; (2) harmonic violations occurring in either the melody, the accompaniment, or both. The results indicated that the neural activation elicited by the processing of polyphonic compositions in expert musicians depends upon the upper versus lower position of the melodic line in the texture, and showed an overall greater activation for the harmonic processing of melody over accompaniment. Both these two predominant effects were characterized by the involvement of the posterior cingulate cortex and precuneus, among other associative brain regions. We discuss the prominent role of the posterior medial cortex in the processing of melodic and harmonic information in the auditory stream, and propose to frame this processing in relation to the cognitive construction of complex multimodal sensory imagery scenes.

Role of diffusion tensor magnetic resonance tractography in predicting the extent of resection in glioma surgery.

Diffusion tensor imaging (DTI) tractography enables the in vivo visualization of the course of white matter tracts inside or around a tumor, and it provides the surgeon with important information in resection planning. This study is aimed at assessing the ability of preoperative DTI tractography in predicting the extent of the resection achievable in surgical removal of gliomas. Patients with low-grade gliomas (LGGs; 46) and high-grade gliomas (HGGs; 27) were studied using a 3T scanner according to a protocol including a morphological study (T2, fluid-attenuated inversion-recovery, T1 sequences) and DTI acquisitions (b = 1000 s/mm(2), 32 gradient directions). Preoperative tractography was performed off-line on the basis of a streamline algorithm, by reconstructing the inferior fronto-occipital (IFO), the superior longitudinal fascicle (SLF), and the corticospinal tract (CST). For each patient, the relationship between each bundle reconstructed and the lesion was analyzed. Initial and residual tumor volumes were measured on preoperative and postoperative 3D fluid-attenuated inversion-recovery images for LGGs and postcontrast T1-weighted scans for HGGs. The presence of intact fascicles was predictive of a better surgical outcome, because these cases showed a higher probability of total resection than did subtotal and partial resection. The presence of infiltrated or displaced CST or infiltrated IFO was predictive of a lower probability of total resection, especially for tumors with preoperative volume <100 cm(3). DTI tractography can thus be considered to be a promising tool for estimating preoperatively the degree of radicality to be reached by surgical resection. This information will aid clinicians in identifying patients who will mostly benefit from surgery.

Ocular adnexal lymphoma: diffusion-weighted mr imaging for differential diagnosis and therapeutic monitoring.

PURPOSE: To describe the magnetic resonance (MR) imaging and diffusion-weighted (DW) imaging features of ocular adnexal lymphomas (OALs), to determine the diagnostic accuracy of apparent diffusion coefficient (ADC) for discriminating OALs from other orbital mass lesions, and to assess whether variations in ADC constitute a reliable biomarker of OAL response to therapy. MATERIALS AND METHODS: Institutional ethical committee approval and informed consent were obtained. In this prospective study, 114 white subjects (65 females and 49 males) were enrolled. Thirty-eight patients with histopathologically proved OAL underwent serial MR and DW imaging examination of the orbits. ADCs of OALs were compared with those of normal orbital structures, obtained in 18 healthy volunteers, and other orbital mass lesions, prospectively acquired in 58 patients (20 primary non-OAL neoplasms, 15 vascular benign lesions, 12 inflammatory lesions, 11 metastases). Interval change in ADC of OALs before and after treatment was analyzed in 29 patients. Analysis of covariance and a paired t test were used for statistical analysis. RESULTS: Baseline ADCs in OALs were lower than those in normal structures and other orbital diseases (P < .001). An ADC threshold of 775 x 10(-6) mm(2)/sec resulted in 96% sensitivity, 93% specificity, 88% positive predictive value, 98.2% negative predictive value, and 94.4% accuracy in OAL diagnosis. Following appropriate treatment, 10 (34%) of 29 patients showed OAL volumetric reduction, accompanied (n = 7) or preceded (n = 3) by an increase in ADC (P = .005). Conversely, a further reduction of ADC was observed in the seven patients who experienced disease progression (P < .05). CONCLUSION: ADC permits accurate diagnosis of OALs. Interval change in ADC after therapy represents a helpful tool for predicting therapeutic response.

Brain activation changes before and after PAP treatment in obstructive sleep apnea.

STUDY OBJECTIVES: Obstructive sleep apnea syndrome (OSAS) is associated with cognitive and functional deficits, most of which are corrected after positive airway pressure (PAP) treatment. Previous studies investigating the neural underpinnings of OSAS failed to provide consistent results both on the cerebral substrates underlying cognitive deficits and on the effect of treatment on these anomalies. The aims of the study were a) to investigate whether never-treated OSA patients demonstrated differences in brain activation compared to healthy controls during a cognitive task; and b) to investigate whether any improvements in cognitive functioning found in OSA patients after treatment reflected a change in the underlying cerebral activity. DESIGN: OSA patients and healthy controls underwent functional magnetic resonance imaging (fMRI) scanning. They were compared on performance and brain activation during a 2-back working-memory task. Patients were also re-evaluated after 3 months treatment with PAP. Cognitive functions were evaluated using neurocognitive tests. Sleepiness (ESS), mood (Beck Depression Inventory) and, quality-of-life (SF-36) were also assessed. SETTING: The Sleep Disorders Center and CERMAC at the Vita-Salute San Raffaele University. PATIENTS OR PARTICIPANTS: 17 OSA patients and 15 age- and education-matched healthy controls. INTERVENTIONS: PAP treatment for 3 months. MEASUREMENTS AND RESULTS: Compared to controls, never-treated OSA patients showed increased activations in the left frontal cortex, medial precuneus, and hippocampus, and decreased activations in the caudal pons. OSA patients showed decreases in activation with treatment in the left inferior frontal gyrus and anterior cingulate cortex, and bilaterally in the hippocampus. Most neurocognitive domains, impaired at baseline, showed significant improvement after treatment. CONCLUSIONS: OSA patients showed an overrecruitment of brain regions compared to controls, in the presence of the same level of performance on a working-memory task. Decreases of activation in prefrontal and hippocampal structures were observed after treatment in comparison to baseline. These findings may reflect a neural compensation mechanism in never-treated patients, which is reduced by effective treatment.