- Email: [email protected]
Cortical thinning network in Alzheimer disease
S432
Poster Presentations P2
model that may be successfully applied to investigate pharmacological treatments for AD.
P2-392
CHARACTERISATION OF [18F]-THK523, A NOVEL IN VIVO TAU IMAGING LIGAND
Michelle T. Fodero-Tavoletti1, Nobuyuki Okamura2, Rachel Mulligan3, Shozo Furumoto2, Andrea R. Connor1, Yukitsuka Kudo2, Diana X. Cao4, Angela Rigopoulos4, Graeme O’Keefe4, Sylvia Gong4, Paul A. Adlard5, Colin L. Masters5, Roberto Cappai1, Kazuhiko Yanai2, Victor L. Villemagne3, 1University of Melbourne, Melbourne, Australia; 2 Tohoku University, Sendai, Japan; 3Austin Health, Melbourne, Australia; 4 Ludwig Institute, Melbourne, Australia; 5The Mental Health Reserarch Institute, Melbourne, Australia. Contact e-mail: [email protected] Background: Neurodegenerative diseases such as Alzheimer’s disease (AD) and frontotemporal lobe degeneration (FTLD) are characterized by the pathological accumulation of tau. Tau accumulation is recognized histologically as intraneuronal neurofibrillary tangles (NFTs), neuropil threads and in the case of AD, as dystrophic neurites surrounding amyloid-b (Ab) plaques. Unlike Ab imaging, no tau imaging agent is available for clinical studies. In vivo imaging of tau pathology by positron emission tomography (PET) will allow new insights into tau deposition in the human brain, facilitating research into causes, diagnosis and treatment monitoring of AD and FTLD. In this study we characterized [18F]-THK523, developed at Tohoku University, Japan, as a novel tau imaging agent. Methods: In vitro [18F]-THK523 saturation studies were conducted using K18D280-tau fibrils; with non-specific binding established with THK523 (1mM). Human AD hippocampal serial sections were analysed by immunohistochemistry and fluorescence microscopy and [18F]-THK523 microPET studies were undertaken in tau transgenic (rTg4510) mice (n ¼ 8) and wildtype littermates (n ¼ 8). Results: In vitro binding assays indicated that there are two [18F]-THK523 high affinity binding sites on K18D280-tau fibrils (KD1’KD2 ¼ 1.67, 21.74nM; Bmax1, Bmax2 ¼ 2.20, 4.46pmol [18F]THK523/nmol fibrils). Furthermore, THK523 bound to NFTs, with negligible binding to Ab plaques in AD brain sections. MicroPET studies demonstrated that brain radioactivity peaked at 5 min post injection (2.4% injected dose) and the binding appeared to be reversible with slower washout from rTg4510 mice than from wildtype mice. At 30 min after injection, significantly higher brain retention of [18F]-THK523 (48%; p < 0.007) was observed in rTg4510 mice compared to wildtype littermates, while there were no significant differences on the other organs examined. Conclusions: This study has demonstrated that [18F]-THK523 satisfies a number of criteria making it a viable tau neuroimaging agent for human PET studies. P2-393
Using high-dimensional warping, the PD-weighted volumes were normalized to a postmortem template. The same deformations were applied to T2 volumes. Following imaging, hemispheres were histologically examined for AD pathology, using NIA-Reagan criteria for low (n ¼ 34), intermediate (n ¼ 25), and high (n ¼ 21) likelihood for AD. Voxelwise multiple linear regression was performed to test if changes in T2 are associated with the NIA-Reagan score. Covariates included the subject’s age at death and the time interval between death and postmortem imaging. Results for a given voxel were considered to be statistically significant when p < 0.01 and the voxel was part of a cluster with volume larger than 0.25 cm3. Results: Around the horns of the lateral ventricle and in subcortical white matter in the frontal and parietal lobes, T2 times were elevated 5-15 ms in the high likelihood of AD group compared to the low likelihood group (orange in figure). In the globus pallidus, T2 times were depressed 5-10 ms in the high group (blue). Smaller T2 differences were observed between the high and intermediate groups, and between the intermediate and low groups. Conclusions: Substantial differences in T2 times were observed in hemisphere high compared to low likelihood of AD, assessed by NIA-Reagan criteria. Because the NIA-Reagan score is a summary measure of AD neuropathology, further work will be needed to determine whether specific types of AD pathology are associated with the observed alterations in T2 times.
POSTMORTEM MRI REVEALS DIFFERENCES IN T2 RELAXATION TIMES AMONG BRAINS WITH VARYING LEVELS OF ALZHEIMER’S PATHOLOGY
Konstantinos Arfanakis1, Julie A. Schneider2, David A. Bennett2, Chunhui Yang2, Robert J. Dawe1, 1Illinois Institute of Technology, Chicago, IL, USA; 2Rush University Medical Center, Chicago, IL, USA. Contact e-mail: [email protected] Background: Postmortem MRI may provide a unique opportunity for evaluating the ability of MRI to detect tissue changes due to Alzheimer’s disease (AD) and other neurodegenerative diseases. The purpose of this work was to investigate differences in T2 relaxation times among postmortem brain specimens with low, intermediate, and high likelihood of AD, assessed neuropathologically, according to the National Institute on Aging (NIA)Reagan Institute criteria. Methods: After rapid autopsy, one cerebral hemisphere from each of 80 elderly subjects was immersed in 4% formaldehyde and refrigerated. After approximately two months of fixation, hemispheres were scanned at using a 3.0-T MR imager. A 2D fast spin echo sequence was used to acquire proton density (PD)-weighted and T2weighted sagittal slices, with true resolution of 0.625x0.625x1.5 mm3.
P2-394
CORTICAL THINNING NETWORK IN ALZHEIMER DISEASE
˚ sa Peterse´n1, John H. Dougherty2, 1Translational Yongxia Zhou1, A Neuroendocrine Research Unit, Department of Experimental Medical Science, Lund University, Lund, Sweden; 2Department of Medicine and Cole
Poster Presentations P2 Neuroscience Center, University of Tennessee, Knoxville, TN, USA. Contact e-mail: [email protected] Background: The objective of this study was to combine two methods for cortical thickness measurements and then to confirm the cortical thickness measure with fMRI and DTI connectivity analysis. Methods: In this initial study, 13 normal controls (NC), 10 individuals with mild cognitive impairment (MCI) and 10 with early Alzheimer disease (AD) were enrolled. The MRI scans were conducted using the 1.5T scanner. The anatomical data were processed using Freesurfer and UNC (http://www.ia.unc.edu/dev/) with manually drawn ROI. Each subject’s cortical thickness map from the UNC software was normalized to the optimal subject population template with FSL and SPM for voxel-wise across-group comparison of thickness measure. FMRI and DTI datasets were normalized to the MNI template using SPM. Functional connectivity map was derived by seeding from the gray matter cortical thinning network (CTN) identified with the voxel-wise method. Structural connectivity was derived from the white matter CTN with the group normalized DTI datasets. Results: The receiver operator characteristics (ROC) analysis with addition of average curvature and folding index did not show improvement of detection accuracy as determined by the average of sensitivity and specificity, in comparison to the average thickness alone. Freesurfer software identified average cortical thinning ROI of right fusiform region, left parsorbitalis, left medial occipito-temporal and lingual sulci, right middle occipital gyrus and right lateral occipito-temporal fusiform gyrus in individuals with both MCI and AD compared to NC. The UNC method identified extra subcortical regional gray and white matter thinning in the dorsal caudate, putamen, ventral striatum, thalamus, amygdala; as well as in the posterior cingulate. Voxel-wise group cortical thickness comparison confirmed gray matter thinning in the fusiform, thalamus, amygdala and hippocampus. The fMRI group comparison seeding from the CTN showed reduced positive functional connectivity in the left amygdala, and reduced power in the low frequency band (0.01 to 0.03 HZ). The DTI results showed reduced fractional anisotropy, increased axial diffusivity and reduced distributed cortical connections from CTN. Conclusions: Our initial results showed that there were less neuronal activations and axonal degeneration in the cortical thinning areas in both MCI and early AD, possibly due to accumulation of amyloid.
P2-395
DEFAULT MODE NETWORK IN PATIENTS WITH DEGENERATIVE BRAIN DISEASES: AN FMRI STUDY
Irena Rektorova, Lenka Krajcovicova, Michal Mikl, Radek Marecek, Ivan Rektor, Masaryk University and St Anne’s Hospital, Brno, Czech Republic. Contact e-mail: [email protected] Background: The ‘‘default mode’’ system (DMS) is an organized network of brain structures (i.e. medial prefrontal cortex, anterior cingulate cortex, precuneus/posterior cingulate cortex (P/PCC), lateral parietal and medial temporal cortices) involved in brain activity during the resting state; it is characterized by a deactivation of these cortical areas during the performance of a cognitive task. Methods: DMS investigated in 18 patients with Alzheimer’s disease (AD), 18 non-demented patients with Parkinson’s disease (PD) on medication, and 18 healthy controls (HC). Imaging performed using a 1.5 T Siemens Symphony. Group differences assessed for ICA of resting state data, simple deactivations during a visual memory task, and functional connectivity (FC) analysis with seed located in P/PCC. Correlation analyses used to evaluate the effect of age and levodopa equivalent dose (LED) in PD. Results: Results in the visual memory task (recognition; relative achievement in %): 38% 6 23.3% for AD, 74% 6 9.7% for PD, and 91% 6 9.0% for HC. There was a significantly reduced FC within the selected resting state network, specifically in the precuneus in AD compared to HC (p ¼ 0.026 FWE, cluster level inference). No significant differences in DMS between PD and HC. A significant positive correlation observed between the strength of the seed FC in P/PCC and LED,
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i.e. the higher the LED, the higher the strength of correlation between the seed located in P/PCC and PCC. A significant negative correlation identified between the strength of the seed FC in the substantia nigra (SN) and LED, i.e. the higher the LED, the lower the strength of anti-correlation between the seed located in P/PCC and SN. A negative correlation found between subject age and deactivation in PCC. Conclusions: We found a significantly reduced FC within the selected resting state network, specifically in the precuneus of AD patients as compared to HC. No significant differences in DMS integrity were identified between cognitively normal PD patients on medication and HC. We demonstrated (i) a significant impact of LED on the strength of the correlation between P/PCC and PCC and (ii) a significant impact of LED on the strength of the anti-correlation between P/PCC and the SN.
P2-396
CHANGES IN BRAIN CONNECTIVITY IN AGING AND MILD COGNITIVE IMPAIRMENT, INVESTIGATED WITH DIFFUSION TENSOR IMAGING AND RESTING STATE MRI
Pawel Skudlarski1,2, Beata A. Skudlarska3, Michael Stevens1,2, Godfrey Pearlson1,2, 1Hartford Hospital/IOL, Hartford, CT, USA; 2 Yale School of Medicine, New Haven, CT, USA; 3Bridgeport Hospital, Bridgeport, CT, USA. Contact e-mail: [email protected] Background: The analysis of Resting State correlation in time course of functional MRI (intrinsic connectivity) and structural analysis of white matter with Diffusion Tensor Imaging have been previously applied to study of Alzheimer disease and Mild Cognitive Impairment showing decline in connectivity in MCI. A novel technique[1] of combining both methods allows to measure both aspects of connectivity at once. This can detect not only differences is strength of connectivity but also more subtle of complex changes in its organization. Methods: 8 MCI patients and 12 healthy subjects were scanned using CTI and resting state functional MRI. Each subject underwent 2 identical scanning sessions two years apart. Fractional Anisothropy (FA) analysis revealed significant between groups differences in white matter integrity (Figure 1). The gray matter area surrounding the affected white matter was used to define Regions of Interest (Figure 2) that were used to simultaneous mapping of strength of structural and functional connectivity. Results: As expected gray matter regions surrounding white matter tracts that were compromised in MCI showed both structural and functional connectivity to be lower in MCI patients than in healthy control. The measures of spatial agreement of structural and functional connectivity maps shows that in MCI subjects, the agreement between both measures of connectivity is higher than in healthy control. This agreement is increasing with age even when the strength of both connectivity measures goes down. In contrast to MCI subjects healthy subjects show decrease of coherence (possible decoupling) between structural and functional connectivity with age. Conclusions: The gray matter regions surrounding cingulum, show different behavior in MCI patients and healthy subjects. The decoupling between structural and functional connectivity that increase in age in healthy subjects suggest compensatory mechanisms that in healthy subjects follow the decline in white matter connectivity and is disturbed in MCI patients. Skudlarski, P. et al. (2008), ‘Measuring brain connectivity: Diffusion tensor imaging validates resting state temporal correlations.’, Neuroimage, vol. 2008, no. 43, pp. 554-561.
Poster Presentations P2
model that may be successfully applied to investigate pharmacological treatments for AD.
P2-392
CHARACTERISATION OF [18F]-THK523, A NOVEL IN VIVO TAU IMAGING LIGAND
Michelle T. Fodero-Tavoletti1, Nobuyuki Okamura2, Rachel Mulligan3, Shozo Furumoto2, Andrea R. Connor1, Yukitsuka Kudo2, Diana X. Cao4, Angela Rigopoulos4, Graeme O’Keefe4, Sylvia Gong4, Paul A. Adlard5, Colin L. Masters5, Roberto Cappai1, Kazuhiko Yanai2, Victor L. Villemagne3, 1University of Melbourne, Melbourne, Australia; 2 Tohoku University, Sendai, Japan; 3Austin Health, Melbourne, Australia; 4 Ludwig Institute, Melbourne, Australia; 5The Mental Health Reserarch Institute, Melbourne, Australia. Contact e-mail: [email protected] Background: Neurodegenerative diseases such as Alzheimer’s disease (AD) and frontotemporal lobe degeneration (FTLD) are characterized by the pathological accumulation of tau. Tau accumulation is recognized histologically as intraneuronal neurofibrillary tangles (NFTs), neuropil threads and in the case of AD, as dystrophic neurites surrounding amyloid-b (Ab) plaques. Unlike Ab imaging, no tau imaging agent is available for clinical studies. In vivo imaging of tau pathology by positron emission tomography (PET) will allow new insights into tau deposition in the human brain, facilitating research into causes, diagnosis and treatment monitoring of AD and FTLD. In this study we characterized [18F]-THK523, developed at Tohoku University, Japan, as a novel tau imaging agent. Methods: In vitro [18F]-THK523 saturation studies were conducted using K18D280-tau fibrils; with non-specific binding established with THK523 (1mM). Human AD hippocampal serial sections were analysed by immunohistochemistry and fluorescence microscopy and [18F]-THK523 microPET studies were undertaken in tau transgenic (rTg4510) mice (n ¼ 8) and wildtype littermates (n ¼ 8). Results: In vitro binding assays indicated that there are two [18F]-THK523 high affinity binding sites on K18D280-tau fibrils (KD1’KD2 ¼ 1.67, 21.74nM; Bmax1, Bmax2 ¼ 2.20, 4.46pmol [18F]THK523/nmol fibrils). Furthermore, THK523 bound to NFTs, with negligible binding to Ab plaques in AD brain sections. MicroPET studies demonstrated that brain radioactivity peaked at 5 min post injection (2.4% injected dose) and the binding appeared to be reversible with slower washout from rTg4510 mice than from wildtype mice. At 30 min after injection, significantly higher brain retention of [18F]-THK523 (48%; p < 0.007) was observed in rTg4510 mice compared to wildtype littermates, while there were no significant differences on the other organs examined. Conclusions: This study has demonstrated that [18F]-THK523 satisfies a number of criteria making it a viable tau neuroimaging agent for human PET studies. P2-393
Using high-dimensional warping, the PD-weighted volumes were normalized to a postmortem template. The same deformations were applied to T2 volumes. Following imaging, hemispheres were histologically examined for AD pathology, using NIA-Reagan criteria for low (n ¼ 34), intermediate (n ¼ 25), and high (n ¼ 21) likelihood for AD. Voxelwise multiple linear regression was performed to test if changes in T2 are associated with the NIA-Reagan score. Covariates included the subject’s age at death and the time interval between death and postmortem imaging. Results for a given voxel were considered to be statistically significant when p < 0.01 and the voxel was part of a cluster with volume larger than 0.25 cm3. Results: Around the horns of the lateral ventricle and in subcortical white matter in the frontal and parietal lobes, T2 times were elevated 5-15 ms in the high likelihood of AD group compared to the low likelihood group (orange in figure). In the globus pallidus, T2 times were depressed 5-10 ms in the high group (blue). Smaller T2 differences were observed between the high and intermediate groups, and between the intermediate and low groups. Conclusions: Substantial differences in T2 times were observed in hemisphere high compared to low likelihood of AD, assessed by NIA-Reagan criteria. Because the NIA-Reagan score is a summary measure of AD neuropathology, further work will be needed to determine whether specific types of AD pathology are associated with the observed alterations in T2 times.
POSTMORTEM MRI REVEALS DIFFERENCES IN T2 RELAXATION TIMES AMONG BRAINS WITH VARYING LEVELS OF ALZHEIMER’S PATHOLOGY
Konstantinos Arfanakis1, Julie A. Schneider2, David A. Bennett2, Chunhui Yang2, Robert J. Dawe1, 1Illinois Institute of Technology, Chicago, IL, USA; 2Rush University Medical Center, Chicago, IL, USA. Contact e-mail: [email protected] Background: Postmortem MRI may provide a unique opportunity for evaluating the ability of MRI to detect tissue changes due to Alzheimer’s disease (AD) and other neurodegenerative diseases. The purpose of this work was to investigate differences in T2 relaxation times among postmortem brain specimens with low, intermediate, and high likelihood of AD, assessed neuropathologically, according to the National Institute on Aging (NIA)Reagan Institute criteria. Methods: After rapid autopsy, one cerebral hemisphere from each of 80 elderly subjects was immersed in 4% formaldehyde and refrigerated. After approximately two months of fixation, hemispheres were scanned at using a 3.0-T MR imager. A 2D fast spin echo sequence was used to acquire proton density (PD)-weighted and T2weighted sagittal slices, with true resolution of 0.625x0.625x1.5 mm3.
P2-394
CORTICAL THINNING NETWORK IN ALZHEIMER DISEASE
˚ sa Peterse´n1, John H. Dougherty2, 1Translational Yongxia Zhou1, A Neuroendocrine Research Unit, Department of Experimental Medical Science, Lund University, Lund, Sweden; 2Department of Medicine and Cole
Poster Presentations P2 Neuroscience Center, University of Tennessee, Knoxville, TN, USA. Contact e-mail: [email protected] Background: The objective of this study was to combine two methods for cortical thickness measurements and then to confirm the cortical thickness measure with fMRI and DTI connectivity analysis. Methods: In this initial study, 13 normal controls (NC), 10 individuals with mild cognitive impairment (MCI) and 10 with early Alzheimer disease (AD) were enrolled. The MRI scans were conducted using the 1.5T scanner. The anatomical data were processed using Freesurfer and UNC (http://www.ia.unc.edu/dev/) with manually drawn ROI. Each subject’s cortical thickness map from the UNC software was normalized to the optimal subject population template with FSL and SPM for voxel-wise across-group comparison of thickness measure. FMRI and DTI datasets were normalized to the MNI template using SPM. Functional connectivity map was derived by seeding from the gray matter cortical thinning network (CTN) identified with the voxel-wise method. Structural connectivity was derived from the white matter CTN with the group normalized DTI datasets. Results: The receiver operator characteristics (ROC) analysis with addition of average curvature and folding index did not show improvement of detection accuracy as determined by the average of sensitivity and specificity, in comparison to the average thickness alone. Freesurfer software identified average cortical thinning ROI of right fusiform region, left parsorbitalis, left medial occipito-temporal and lingual sulci, right middle occipital gyrus and right lateral occipito-temporal fusiform gyrus in individuals with both MCI and AD compared to NC. The UNC method identified extra subcortical regional gray and white matter thinning in the dorsal caudate, putamen, ventral striatum, thalamus, amygdala; as well as in the posterior cingulate. Voxel-wise group cortical thickness comparison confirmed gray matter thinning in the fusiform, thalamus, amygdala and hippocampus. The fMRI group comparison seeding from the CTN showed reduced positive functional connectivity in the left amygdala, and reduced power in the low frequency band (0.01 to 0.03 HZ). The DTI results showed reduced fractional anisotropy, increased axial diffusivity and reduced distributed cortical connections from CTN. Conclusions: Our initial results showed that there were less neuronal activations and axonal degeneration in the cortical thinning areas in both MCI and early AD, possibly due to accumulation of amyloid.
P2-395
DEFAULT MODE NETWORK IN PATIENTS WITH DEGENERATIVE BRAIN DISEASES: AN FMRI STUDY
Irena Rektorova, Lenka Krajcovicova, Michal Mikl, Radek Marecek, Ivan Rektor, Masaryk University and St Anne’s Hospital, Brno, Czech Republic. Contact e-mail: [email protected] Background: The ‘‘default mode’’ system (DMS) is an organized network of brain structures (i.e. medial prefrontal cortex, anterior cingulate cortex, precuneus/posterior cingulate cortex (P/PCC), lateral parietal and medial temporal cortices) involved in brain activity during the resting state; it is characterized by a deactivation of these cortical areas during the performance of a cognitive task. Methods: DMS investigated in 18 patients with Alzheimer’s disease (AD), 18 non-demented patients with Parkinson’s disease (PD) on medication, and 18 healthy controls (HC). Imaging performed using a 1.5 T Siemens Symphony. Group differences assessed for ICA of resting state data, simple deactivations during a visual memory task, and functional connectivity (FC) analysis with seed located in P/PCC. Correlation analyses used to evaluate the effect of age and levodopa equivalent dose (LED) in PD. Results: Results in the visual memory task (recognition; relative achievement in %): 38% 6 23.3% for AD, 74% 6 9.7% for PD, and 91% 6 9.0% for HC. There was a significantly reduced FC within the selected resting state network, specifically in the precuneus in AD compared to HC (p ¼ 0.026 FWE, cluster level inference). No significant differences in DMS between PD and HC. A significant positive correlation observed between the strength of the seed FC in P/PCC and LED,
S433
i.e. the higher the LED, the higher the strength of correlation between the seed located in P/PCC and PCC. A significant negative correlation identified between the strength of the seed FC in the substantia nigra (SN) and LED, i.e. the higher the LED, the lower the strength of anti-correlation between the seed located in P/PCC and SN. A negative correlation found between subject age and deactivation in PCC. Conclusions: We found a significantly reduced FC within the selected resting state network, specifically in the precuneus of AD patients as compared to HC. No significant differences in DMS integrity were identified between cognitively normal PD patients on medication and HC. We demonstrated (i) a significant impact of LED on the strength of the correlation between P/PCC and PCC and (ii) a significant impact of LED on the strength of the anti-correlation between P/PCC and the SN.
P2-396
CHANGES IN BRAIN CONNECTIVITY IN AGING AND MILD COGNITIVE IMPAIRMENT, INVESTIGATED WITH DIFFUSION TENSOR IMAGING AND RESTING STATE MRI
Pawel Skudlarski1,2, Beata A. Skudlarska3, Michael Stevens1,2, Godfrey Pearlson1,2, 1Hartford Hospital/IOL, Hartford, CT, USA; 2 Yale School of Medicine, New Haven, CT, USA; 3Bridgeport Hospital, Bridgeport, CT, USA. Contact e-mail: [email protected] Background: The analysis of Resting State correlation in time course of functional MRI (intrinsic connectivity) and structural analysis of white matter with Diffusion Tensor Imaging have been previously applied to study of Alzheimer disease and Mild Cognitive Impairment showing decline in connectivity in MCI. A novel technique[1] of combining both methods allows to measure both aspects of connectivity at once. This can detect not only differences is strength of connectivity but also more subtle of complex changes in its organization. Methods: 8 MCI patients and 12 healthy subjects were scanned using CTI and resting state functional MRI. Each subject underwent 2 identical scanning sessions two years apart. Fractional Anisothropy (FA) analysis revealed significant between groups differences in white matter integrity (Figure 1). The gray matter area surrounding the affected white matter was used to define Regions of Interest (Figure 2) that were used to simultaneous mapping of strength of structural and functional connectivity. Results: As expected gray matter regions surrounding white matter tracts that were compromised in MCI showed both structural and functional connectivity to be lower in MCI patients than in healthy control. The measures of spatial agreement of structural and functional connectivity maps shows that in MCI subjects, the agreement between both measures of connectivity is higher than in healthy control. This agreement is increasing with age even when the strength of both connectivity measures goes down. In contrast to MCI subjects healthy subjects show decrease of coherence (possible decoupling) between structural and functional connectivity with age. Conclusions: The gray matter regions surrounding cingulum, show different behavior in MCI patients and healthy subjects. The decoupling between structural and functional connectivity that increase in age in healthy subjects suggest compensatory mechanisms that in healthy subjects follow the decline in white matter connectivity and is disturbed in MCI patients. Skudlarski, P. et al. (2008), ‘Measuring brain connectivity: Diffusion tensor imaging validates resting state temporal correlations.’, Neuroimage, vol. 2008, no. 43, pp. 554-561.