FUNCTIONAL CONNECTIVITY MRI IN PATIENTS WITH BRAIN TUMORS XIX Symposium Neuroradiologicum The World Congress of Neuroradiology Bologna, Italy, 4-9 October 2010 REORGANIZATION OF FUNCTIONAL CONNECTIVITY MRI IN PATIENTS WITH BRAIN TUMORS Thank you mister chairman Good evening everybody Briganti C, Pravatà E*, Mantini D, Sestieri C, Tartaro A, Caulo M Department of Neuroscience and Imaging. University “G. d’Annunzio” Chieti-Pescara - Italy * Department of Radiology, Catholic University - Rome - Italy

Introduction_1 Pre-surgical cortical brain mapping using functional MRI (fMRI) is a widely diffuse procedure permitting a non-invasive neurosurgical planning in patients with brain tumors Due to the high social relevance of speech, the accurate mapping of the language functions in the brain and the identification of the dominant hemisphere are crucial for minimizing postoperative neurological deficits Pre-surgical cortical brain mapping using functional MRI (fMRI) is a widely diffuse procedure permitting a non-invasive neurosurgical planning in patients with brain tumors Due to the high social relevance of speech, The accurate mapping of the language functions in the brain and the identification of the dominant hemisphere are crucial for minimizing postoperative neurological deficits in patient with brain tumors. The annual incidence of primary and secondary intracranial tumors ranges from 10 to 17 per 100,000 people. � Since preventive care is not possible, the only valid procedure to influence the prognosis is a correct timely diagnosis and, in most cases, a surgery. The target of an effective surgical treatment is to radically remove the tumor while preserving the integrity of functionally eloquent cortical regions to prevent undesirable post-operative functional deficits. � Pre-surgical cortical brain mapping using Blood Oxygenated Level Dependent contrast (BOLD) Functional Magnetic Resonance Imaging (fMRI) is a widely diffuse procedure, permitting a non-invasive neurosurgical planning�Due to the high social relevance of speech, the accurate mapping of the language functions in the brain and the identification of the dominant hemisphere for language are the most frequent requests of neurosurgeons, especially in cases of right-handed patients with tumors of the left hemisphere (Duffau H, 2005).

Introduction_2 Language is left lateralized in 92.5% of right-handed individuals (Knecht et al., 2000) Language is left lateralized in 92.5% of right-handed individuals Right-handed patients with left hemisphere brain tumors show an increased recruitment of homologue regions of the classical language areas in the right hemisphere. This phenomenon is called Plasticity Right-handed patients with left hemisphere brain tumors show an increased recruitment of homologue regions of the classical language areas in the right hemisphere (Plasticity) (Thiel et al., 2001; Desmurget et al, 2007)

Introduction_3 The leading roles of language production and comprehension are classically attributed to Broca’s and Wernicke’s cortical areas (Naeser et al, 1989) More recently, a distributed dynamic model of language organization focuses on the importance of functional correlations between brain regions belonging to the language network (Vigneau et al, 2006) Language production and comprehension are classically attributed to Broca’s and Wernicke’s cortical areas although, recently, a distributed dynamic model of language organization focuses on the importance of functional correlations between the regions of the language network. As for language, all the complex brain processes are computed via a �network� of communicating brain areas. The presence of communicating networks broadening trough the white matter fibers of the brain can be virtually demonstrated and it is defined as functional connectivity. � The FC underlying to different sensory modalities, language, default network and attention.�FC has also been used as a useful marker of brain disease in Alzheimer痴 disease , schizofrenia (Whitfield-Gabrieli S et al, 2009), epilepsy (Waites AB et al, 2006) �.Modifications of FC in patients with brain tumors were demonstrated only using Magnetoencephalography (MEG); patients with brain tumors, especially left hemisphere tumors, showed a significant loss of FC compared to healthy controls. (Bartolomei F et al, Ann Neurol 2006; Bartolomei F et al, Clin Neurophysiol 2006; Guggisberg AG et al, 2008; Douw L et al, 2008).

Introduction_4 The functional correlation can be evaluated by functional connectivity MRI (fcMRI), a technique that measures the spontaneous and synchronous low-frequency (<0.1 Hz) fluctuations of the BOLD signal between distant brain regions (Biswal, 1995; Fox, 2005; Greicius, 2003) The functional correlation can be evaluated by functional connectivity MRI, a technique that measures the spontaneous and synchronous low-frequency fluctuations of the BOLD signal between distant brain regions. These brain regions can be considered as a “network” with increased functional synchrony. These brain regions can be considered as a “network” with increased functional synchrony (default network, attention, motor system, language, ….)

Purposes To evaluate language lateralization in patients with a left hemisphere brain tumor using BOLD fMRI during a block-designed verb-generation task To investigate potential differences in fcMRI within the language network between patients and controls To explore variability of fcMRI correlated with the position, the histopathology and the volume of the tumors This study aims To evaluate the language lateralization in patients with left hemisphere brain tumor during a blocked-designed verb-generation task To investigate modifications of functional connectivity MRI within the language network in patients and controls To explore variability of fcMRI correlated with the position, the histopathology and the volume of the tumors

Degree of lesion overlap across all patients Subjects and Methods 39 patients (21 male and 18 female; mean age 51 ±14 years) with a pathologically confirmed brain glioma of the left hemisphere 13 healthy controls Degree of lesion overlap across all patients Patients and controls were strongly right-handed as determined by the Edinburgh Handedness Inventory test with a Laterality Index (L.I.) > 80 (Oldfield, 1971) We retrospectively evaluated thirty-nine consecutively patients with a brain glioma of the left hemisphere and a control group of thirteen healthy volunteers. Patients and controls were right-handed

Tumors classification LOCATION HISTOLOGY Anterior Posterior “In” “Out” High Grade Low Grade n=22 n=17 n=9 n=30 “anterior” or “posterior” considering their position with respect to the anterior commissure "in" or "out" depending on their distance from the left Broca and Wernicke areas “low grade” or “high grade” on the basis of the latest WHO classification Tumors were classified as: Tumors were classified as anterior or posterior considering their position with respect to the anterior commissure, "in" or "out" depending on their distance from the left Broca and Wernicke areas and as low or high grade on the basis of the latest WHO classification The volume of the tumors was calculated using a manual segmentation The volume of the tumors was calculated in mm3 after a manual segmentation

fMRI 1.5 T SIEMENS and PHILIPS scanners Verb Generation Task pen 1.5 T SIEMENS and PHILIPS scanners BOLD fMRI: block-designed verb-generation task fMRI statistical activation maps were generated with a combined Independent Component Analysis – General Linear Model (ICA-GLM) method Patients and controls underwent BOLD fMRI to lateralize language with a block designed verb generation task fMRI statistical activation maps were generated with a combined Independent Component Analysis – General Linear Model (ICA-GLM) method The Lateralization Index was calculated for each subject using the number of active voxels of each hemisphere The Lateralization Index (L.I.) was calculated for each subject using a formula for the correction of the tumor volume

fcMRI_1 The fcMRI was calculated using a seed-based method The time-course of the BOLD activity was extracted from each seed region of interest (ROI) after the regression of several nuisance variables, including task-evoked activity (Fox et al, 2005; Fair et al, 2006) For each subject, an initial seed ROI was identified as the region with the strongest task-evoked activity within the pars opercolaris of the left inferior frontal gyrus (left Broca) The fcMRI was calculated using a seed-based method After the regression of several nuisance variables including task-evoked activity, the fcMRI was calculated using a seed- based method, for each subject, an initial seed ROI was identified in the individual BOLD activation within the left Broca region Before FC analysis, the BOLD time series were pre-processed by means of MATLAB (The Mathworks Inc., Natick, MA, U.S.A.) according to the procedure described in Fox et al. (Fox MD et al, 2005). The pre-processing steps included: 1) band-pass filtering between 0.009 and 0.08 Hz; 2) regression of global, white matter and ventricle signals, and their first derivatives; 3) regression of three-dimensional motion parameters, and their first derivatives; 4) removing of the deterministic component of the signal induced by the task. Resting state epochs for functional connectivity analysis were obtained from interleaved blocks extracted from the same word-generation task, as recently described in a comparative study by Fair et al. (Fair DA et al, 2007). For each ROI, a representative BOLD time-course was obtained by averaging the signals of the voxels within a sphere of 6 mm radius.

fcMRI_2 Using the whole-brain fcMRI map generated from this ROI, 5 additional seed regions were obtained corresponding to: right Broca area and bilateral Superior Temporal Sulcus (STS) and Temporo-Parietal Junction (TPJ) Pearson’s correlation coefficients (r) between signal time-courses were calculated: Using the whole-brain fcMRI map generated from this ROI, 5 additional seed regions were obtained corresponding to right Broca area and bilateral STS and Temporo-Parietal Junctions Whole-Brain FC maps and Cross-correlation Matrices and Plots were calculated between each seed region and all the voxels of the brain (Whole-Brain FC maps) between pairs of seed regions (Cross-correlation Matrices and Plots)

Results Only patients with high grade tumors showed a significant reduction of language lateralization compared to controls (p< 0.05) fMRI Overall, patients presented a non-significant shift of language lateralization toward the non-dominant hemisphere compared to controls The size of the tumors was negatively correlated with lateralization index, so that patients with larger tumors were less left-lateralized Overall, patients and controls did not differ in term of language lateralization Althought, when we consider only patients with an high grade tumors, a significant reduction of language lateralization was observed the size of the tumors was negatively correlated with the lateralization index, so that patients with larger tumors were less left-lateralized

fcMRI Cross-correlation matrices and plots_1 In cross-correlation matrices and plots, both patients and controls showed significant functional correlations between all the 6 seed regions In cross-correlations matrices and plots both patients and controls showed significant functional correlations between all the 6 seeds regions However patients showed a significant reduction of the fcMRI among the language network compared to controls However, patients showed a significant reduction of the fcMRI among the language network (p < 0.01) compared to controls

fcMRI Cross-correlation matrices and plots_2 The contrast between the functional connectivity of patients and controls demonstrates that the left TPJ is the node showing the greatest reduction of fcMRI The contrast between the functional connectivity of patients and controls demonstrates that the left TPJ is the node showing the greatest reduction of fcMRI

fcMRI Considering the averaged values of fcMRI in the two hemispheres, patients show a significant reduction of connectivity (p < 0.01) in: Averaged Left intra-hemispheric fcMRI Averaged Inter-hemispheric fcMRI Global fcMRI Considering the averaged values of fcMRI in the two hemisphere, patients show a significant reduction of connectivity within the left hemisphere, between the two hemispheres and globally

fcMRI_subgroups Using a multivariated ANOVA, patients with a posterior tumor showed a significantly greater reduction of the left intra-hemispheric fcMRI compared to patients with an anterior tumor (p <0.05) Using a multivariated ANOVA, patients with a posterior tumor showed a significantly greater reduction of the left intra-hemispheric fcMRI compared to patients with an anterior tumor (p <0.05)

Conclusion_1 Tumor patients present a significant reorganization of the language towards the non-dominant hemisphere The presence of a brain tumor in the left hemisphere significantly reduces the fcMRI between language-related brain regions, especially when posterior To conclude: Tumor patients present a significant reorganization of the language towards the non-dominant hemisphere The presence of a brain tumor in the left hemisphere significantly reduces the functional connectivity between language-related brain regions, especially when posterior Modification of the FC is not restricted to the area surrounding the tumor; remote and controlateral areas are also influenced Modification of the fcMRI is not restricted to the area surrounding the tumor; remote and controlateral areas are also influenced

Conclusion_2 Tumors located near the TPJ determine the strongest reduction of the fcMRI, demonstrating the central role of the Wernicke area in the language network These findings reinforce the results of some theoretical lesional models (Alstott, 2009) demonstrating that lesion placed in proximity of hub nodes of high centrality, as the TPJ, determine greater changes of FC Tumors located near the TPJ determine the strongest reduction of the fcMRI, demonstrating the central role of the Wernicke area in the language network The presence of a brain tumor in the left hemisphere determines a cortical and networking reorganization of the language function

Conclusion_3 The presence of a brain tumor in the left hemisphere determines a cortical and networking reorganization of the language function The presence of a brain tumor in the left hemisphere determines a cortical and networking reorganization of the language function

Acknowledgments Massimo Caulo MD, PhD Emanuele Pravatà MD Carlo Sestieri PhD Dante Mantini PhD Armando Tartaro MD 20