Cortical reconstruction and volumetric segmentation was performed with the Freesurfer image analysis suite, which is documented and freely available for download online ( The technical details of these procedures are described in prior publications (Dale et al., 1999; Dale and Sereno, 1993; Fischl and Dale, 2000; Fischl et al., 2001; Fischl et al., 2002; Fischl et al., 2004a; Fischl et al., 1999a; Fischl et al., 1999b; Fischl et al., 2004b; Han et al., 2006; Jovicich et al., 2006; Segonne et al., 2004, Reuter et al. 2010, Reuter et al. 2012). Briefly, this processing includes motion correction and averaging (Reuter et al. 2010) of multiple volumetric T1 weighted images (when more than one is available), removal of non-brain tissue using a hybrid watershed/surface deformation procedure (Segonne et al., 2004), automated Talairach transformation, segmentation of the subcortical white matter and deep gray matter volumetric structures (including hippocampus, amygdala, caudate, putamen, ventricles) (Fischl et al., 2002; Fischl et al., 2004a) intensity normalization (Sled et al., 1998), tessellation of the gray matter white matter boundary, automated topology correction (Fischl et al., 2001; Segonne et al., 2007), and surface deformation following intensity gradients to optimally place the gray/white and gray/cerebrospinal fluid borders at the location where the greatest shift in intensity defines the transition to the other tissue class (Dale et al., 1999; Dale and Sereno, 1993; Fischl and Dale, 2000). Once the cortical models are complete, a number of deformable procedures can be performed for in further data processing and analysis including surface inflation (Fischl et al., 1999a), registration to a spherical atlas which utilized individual cortical folding patterns to match cortical geometry across subjects (Fischl et al., 1999b), parcellation of the cerebral cortex into units based on gyral and sulcal structure (Desikan et al., 2006; Fischl et al., 2004b), and creation of a variety of surface based data including maps of curvature and sulcal depth. This method uses both intensity and continuity information from the entire three dimensional MR volume in segmentation and deformation procedures to produce representations of cortical thickness, calculated as the closest distance from the gray/white boundary to the gray/CSF boundary at each vertex on the tessellated surface (Fischl and Dale, 2000). The maps are created using spatial intensity gradients across tissue classes and are therefore not simply reliant on absolute signal intensity. The maps produced are not restricted to the voxel resolution of the original data thus are capable of detecting submillimeter differences between groups. Procedures for the measurement of cortical thickness have been validated against histological analysis (Rosas et al., 2002) and manual measurements (Kuperberg et al., 2003; Salat et al., 2004). Freesurfer morphometric procedures have been demonstrated to show good test-retest reliability across scanner manufacturers and across field strengths (Han et al., 2006; Reuter et al., 2012).

Longitudinal Processing
To extract reliable volume and thickness estimates, images where automatically processed with the longitudinal stream (Reuter et al., 2012) in FreeSurfer. Specifically an unbiased within-subject template space and image is created using robust, inverse consistent registration (Reuter et al., 2010). Several processing steps, such as skull stripping, Talairach transforms, atlas registration as well as spherical surface maps and parcellations are then initialized with common information from the within-subject template, significantly increasing reliability and statistical power (Reuter et al., 2012).
Please cite at least (Reuter et al., 2012) if the longitudinal stream was used!


Dale, A.M., Fischl, B., Sereno, M.I., 1999. Cortical surface-based analysis. I. Segmentation and surface reconstruction. Neuroimage 9, 179-194.

Dale, A.M., Sereno, M.I., 1993. Improved localization of cortical activity by combining EEG and MEG with MRI cortical surface reconstruction: a linear approach. J Cogn Neurosci 5, 162-176.

Desikan, R.S., Segonne, F., Fischl, B., Quinn, B.T., Dickerson, B.C., Blacker, D., Buckner, R.L., Dale, A.M., Maguire, R.P., Hyman, B.T., Albert, M.S., Killiany, R.J., 2006. An automated labeling system for subdividing the human cerebral cortex on MRI scans into gyral based regions of interest. Neuroimage 31, 968-980.

Fischl, B., Dale, A.M., 2000. Measuring the thickness of the human cerebral cortex from magnetic resonance images. Proc Natl Acad Sci U S A 97, 11050-11055.

Fischl, B., Liu, A., Dale, A.M., 2001. Automated manifold surgery: constructing geometrically accurate and topologically correct models of the human cerebral cortex. IEEE Trans Med Imaging 20, 70-80.

Fischl, B., Salat, D.H., Busa, E., Albert, M., Dieterich, M., Haselgrove, C., van der Kouwe, A., Killiany, R., Kennedy, D., Klaveness, S., Montillo, A., Makris, N., Rosen, B., Dale, A.M., 2002. Whole brain segmentation: automated labeling of neuroanatomical structures in the human brain. Neuron 33, 341-355.

Fischl, B., Salat, D.H., van der Kouwe, A.J., Makris, N., Segonne, F., Quinn, B.T., Dale, A.M., 2004a. Sequence-independent segmentation of magnetic resonance images. Neuroimage 23 Suppl 1, S69-84.

Fischl, B., Sereno, M.I., Dale, A.M., 1999a. Cortical surface-based analysis. II: Inflation, flattening, and a surface-based coordinate system. Neuroimage 9, 195-207.

Fischl, B., Sereno, M.I., Tootell, R.B., Dale, A.M., 1999b. High-resolution intersubject averaging and a coordinate system for the cortical surface. Hum Brain Mapp 8, 272-284.

Fischl, B., van der Kouwe, A., Destrieux, C., Halgren, E., Segonne, F., Salat, D.H., Busa, E., Seidman, L.J., Goldstein, J., Kennedy, D., Caviness, V., Makris, N., Rosen, B., Dale, A.M., 2004b. Automatically parcellating the human cerebral cortex. Cereb Cortex 14, 11-22.

Han, X., Jovicich, J., Salat, D., van der Kouwe, A., Quinn, B., Czanner, S., Busa, E., Pacheco, J., Albert, M., Killiany, R., Maguire, P., Rosas, D., Makris, N., Dale, A., Dickerson, B., Fischl, B., 2006. Reliability of MRI-derived measurements of human cerebral cortical thickness: the effects of field strength, scanner upgrade and manufacturer. Neuroimage 32, 180-194.

Jovicich, J., Czanner, S., Greve, D., Haley, E., van der Kouwe, A., Gollub, R., Kennedy, D., Schmitt, F., Brown, G., Macfall, J., Fischl, B., Dale, A., 2006. Reliability in multi-site structural MRI studies: effects of gradient non-linearity correction on phantom and human data. Neuroimage 30, 436-443.

Kuperberg, G.R., Broome, M.R., McGuire, P.K., David, A.S., Eddy, M., Ozawa, F., Goff, D., West, W.C., Williams, S.C., van der Kouwe, A.J., Salat, D.H., Dale, A.M., Fischl, B., 2003. Regionally localized thinning of the cerebral cortex in schizophrenia. Arch Gen Psychiatry 60, 878-888.

Reuter, M., Schmansky, N.J., Rosas, H.D., Fischl, B. 2012. Within-Subject Template Estimation for Unbiased Longitudinal Image Analysis. Neuroimage 61 (4), 1402-1418.

Reuter, M., Fischl, B., 2011. Avoiding asymmetry-induced bias in longitudinal image processing. Neuroimage 57 (1), 19-21.

Reuter, M., Rosas, H.D., Fischl, B., 2010. Highly Accurate Inverse Consistent Registration: A Robust Approach. Neuroimage 53 (4), 1181–1196.

Rosas, H.D., Liu, A.K., Hersch, S., Glessner, M., Ferrante, R.J., Salat, D.H., van der Kouwe, A., Jenkins, B.G., Dale, A.M., Fischl, B., 2002. Regional and progressive thinning of the cortical ribbon in Huntington's disease. Neurology 58, 695-701.

Salat, D.H., Buckner, R.L., Snyder, A.Z., Greve, D.N., Desikan, R.S., Busa, E., Morris, J.C., Dale, A.M., Fischl, B., 2004. Thinning of the cerebral cortex in aging. Cereb Cortex 14, 721-730.

Segonne, F., Dale, A.M., Busa, E., Glessner, M., Salat, D., Hahn, H.K., Fischl, B., 2004. A hybrid approach to the skull stripping problem in MRI. Neuroimage 22, 1060-1075.

Segonne, F., Pacheco, J., Fischl, B., 2007. Geometrically accurate topology-correction of cortical surfaces using nonseparating loops. IEEE Trans Med Imaging 26, 518-529.

Sled, J.G., Zijdenbos, A.P., Evans, A.C., 1998. A nonparametric method for automatic correction of intensity nonuniformity in MRI data. IEEE Trans Med Imaging 17, 87-97.


This list of citations is available in the attached BibTeX file neuro.bib

FreeSurferMethodsCitation (last edited 2012-09-10 19:27:18 by MartinReuter)