Nuisance Signal Regression¶
A key step in preparing fMRI data for statistical analysis is the removal of nusiance signals and noise. C-PAC provides a number of options for removing nuisance signals. These methods can be combined as desired by you, and are described below.
Mean White Matter / CSF¶
The mean WM and CSF time series are calculated by averaging signal over all voxels within a WM or CSF mask for each time point. Mean WM and CSF time series are then used as temporal covariates and removed from the raw data through linear regression.
Note: The Lateral Ventricles Mask in standard space is provided for isolating signal changes in the CSF. This mask is based off of the HarvardOxford atlas that is in standard MNI space. If you wish to use your own standard and lateral ventricles mask, and wish to run CSF nuisance regression, you must specify it in your pipeline configuration.
The term “noise region-of-interest” (noise ROI) refers to areas such as white matter (WM) and cerebral spinal fluid (CSF) in which temporal fluctuations are unlikely to be modulated by neural activity, and thus primarily reflect physiological noise (Behzadi et al., 2007). Based on the assumption that signal from a noise ROI can be used to accurately model physiological fluctuations in gray matter regions, a novel component based noise reduction method (CompCor) was proposed to correct for physiological noise by regressing out principal components from noise ROIs (Behzadi et al., 2007). Compared to the average signal from WM and CSF regions (i.e. WM/CSF regression methods), signals captured by principal components derived from these noise ROIs can better account for voxel-specific phase differences in physiological noise due to the potential of principle component analysis to identify temporal pattern of physiological noise (Tomas et al., 2002). Thus, preprocessing with CompCor can significantly reduce physiological noise as well as noise from other sources (Behzadi et al., 2007; Chai et al., 2012).
The first step of CompCor is to determine noise ROIs. This can be done either by using anatomical data to identify voxels that consist primarily of either WM or CSF, or by defining noise ROIs as voxels with high temporal standard deviation. A principal component analysis (PCA) is then applied to characterize the time series data from the noise ROIs. Significant principal components are then introduced as covariates in a general linear model (GLM) as an estimate of the physiological noise signal space (Behzadi et al., 2007).
Also, C-PAC allows users configure nuisance correction to perform cosine/linear filtering on the time series data prior to CompCor calculation.
As showed by Lund and Hanson (2001), voxel time courses with a relatively high temporal standard deviation were dominated by physiological noise. Behzadi et al. (2007) proposed an unsupervised method to assess the temporal standard deviation and then used princial components analysis to reduce the data dimensionality.
Global Signal Regression¶
Global signal, the average signal across all voxels in the brain, is assumed to reflect a combination of resting-state fluctuations, physiological noise (e.g. respiratory and cardiac noise), and other noise signals with non-neural origin. Global signal regression (GSR) is a preprocessing technique for removing the spontaneous BOLD fluctuations common to the whole brain using a general linear model (GLM). Although GSR can potentially change functional connectivity distributions and result in increased negative correlations (Murphy et al., 2009; Saad et al., 2012; Weissenbacher et al., 2009), this technique has been shown to facilitate the detection of localized neuronal signals and improve the specificity of functional connectivity analysis (Fox et al., 2005; Fox et al., 2009). Thus, GSR remains a common and useful processing technique in some situations.
A global mean (defined as the average signal over all voxels for each time point) is used as a temporal covariate and regressed out using linear regression.
Principle Components Removal¶
Performs a Principal Components Analysis and regresses out the chosen principal component. The first component is assumed to be the global mean signal.
Removes linear or quadratic trends in the timeseries. The linear trend is likely due to the scanner heating up as the scan progresses, while the quadratic trend is possibly due to slow movement-related effects.
Movement during scanning is one of of the largest factors influencing the quality of fMRI data. Movement of the head between the acquisition of each volume can cause brain images to become misaligned. Head motion during scanning can also cause spurious changes in signal intensity. If they are not corrected, these changes can influence the results of activation and connectivity analyses. Recent studies have shown that motion as small as 0.1 mm can systematically bias both within- and between- group effects during the analysis of fMRI data (Power et al., 2011; Satterhwaite et al., 2012; Van Dijk et al., 2012). Even the most cooperative participants often still show displacements of up to a millimeter, and head movements of several millimeters are not uncommon in studies of hyperkinetic subjects such as young children, older adults, or patient populations.
There are four main approaches to motion correction: volume realignment, using a general linear model to regress out motion-related artifacts (i.e. regression of motion parameters, as described as one of the regressors in nuisance regression above), de-spiking of motion confounded time points, and censoring of motion confounded time points (i.e. “scrubbing”).
Volume realignment aligns reconstructed volumes by calculating motion parameters based on a solid-body model of the head and brain (Friston 1996). Based on these parameters, each volume is registered to the volume preceding it.
C-PAC runs volume realignment on all functional images during functional preprocessing. You can select from two sets of motion parameters to use during this process:
6-Parameter Model - Three translation and three rotation parameters as described in Friston 1996.
Friston 24-Parameter Model - The 6 motion parameters of the current volume and the preceding volume, plus each of these values squared.
Regression of Motion Parameters¶
Another approach to motion correction is to regress out the effects of motion when running statistical analysis. This is done by calculating motion parameters and including them in your General Linear Model (Fox et al., 2005; Weissenbacher et al., 2009).
By default, C-PAC will calculate and output the motion parameters used during volume realignment. You can optionally enable the calculation of additional motion parameters, including Framewise Displacement (FD) and DVARS (as described below and in Power et al., 2011).
Note: You cannot run De-Spiking and Scrubbing at the same time.
One way to ensure that your results are have not been influenced by spurious, motion-related noise is to remove volumes during which significant movement occurred. This is known as volume censoring, or scrubbing. Power and colleagues (2011) proposed two measures to identify volumes contaminated by excessive motion; framewise displacement (FD) and DVARS:
FD is calculated from derivatives of the six rigid-body realignment parameters estimated during standard volume realignment, and is a compressed single index of the six realignment parameters.
DVARS is the root mean squared (RMS) change in BOLD signal from volume to volume (D referring to temporal derivative of time courses and VARS referring to RMS variance over voxels). DVARS is calculated by first differentiating the volumetric time series and then calculating the RMS signal change over the whole brain. This measure indexes the change rate of BOLD signal across the entire brain at each frame of data or, in other words, how much the intensity of a brain image changes relative to the previous time point.
Together, these two measures capture the head displacements and the brain-wide BOLD signal displacements from volume to volume over all voxels within the brain (Power et al., 2011).
After calculating FD and DVARS, thresholds can be applied to censor the data. Selecting thresholds for scrubbing is a trade-off. More stringent thresholds allow more complete removal of motion-contaminated data, and minimize motion-induced artifacts. Meanwhile, more stringent scrubbing will also remove more data, which may increase the variability and decrease the test-retest reliability of the data. Commonly used thresholds are FD > 0.2 to 0.5 mm and DVARS > 0.3 to 0.5% of BOLD.
IMPORTANT: Removing time points from a continuous time series (as is done during scrubbing) disrupts the temporal structure of the data and precludes frequency-based analyses such as ALFF/fAlff. However, scrubbing can effectively be used to minimize motion-related artifacts in seed-based correlation analyses (Power et al., 2011; 2012).
Note: You cannot run De-Spiking and Scrubbing at the same time.
The overall goal of temporal filtering is to increase the signal-to-noise ratio. Due to the relatively poor temporal resolution of fMRI, time series data contain little high-frequency noise. They do, however, often contain very slow frequency fluctuations that may be unrelated to the signal of interest. Slow changes in magnetic field strength may be responsible for part of the low-frequency signal observed in fMRI time series (Smith et al., 1999). Other factors contributing to noise in a time series are cardiac and respiratory effects, which will often show up as noise around ~0.15 and ~0.34 Hz, respectively (Wager et al., 2007). The temporal filtering method implemented by C-PAC is relatively simple. You specify a lower and upper bound for a band-pass filter, which then removes any information in frequencies outside the specified frequency band.
Recent work has revealed a portion of the low-frequency signal (0.01 to 0.1 Hz) to be the result of slow oscillations intrinsic to brain activity (Gee et al., 2011; Zuo et al., 2010; Schroeder and Lakatos, 2009). Utilizing measures such as Amplitude of Low Frequency Fluctuations (ALFF) and fractional ALFF, the power of these oscillations has been shown to differ both across subjects (Zang et al., 2007) and between conditions (Yan et al., 2009). Resting functional connectivity has been shown to be most prominent at these frequency bands (Cordes et al., 2001), and as such these fluctuations are commonly used to measure functional connectivity in the resting brain (Gee et al., 2010).
As these low-frequency oscillations are likely of interest to researchers, it is important to take this knowledge into account when deciding on what temporal filtering settings to use. As a general rule, it is safe to filter frequencies below 0.0083 Hz (Ashby, 2011).
Additionally, there is some evidence (Davey et al., 2012) that temporal filtering may induce correlation in resting fMRI data, breaking the assumption of temporal sample independence and potentially invalidating the results of connectivity analysis. This should be taken into account when running temporal filtering on data on which you will later run connectivity analysis.
Median Angle Correction¶
Median angle correction is another global signal correction approach. It is assumed that the global signal in resting-state fMRI can be viewed as the sum of two components: a component that reflects the intrinsic correlations of resting state fMRI signals between regions, and a nuisance component that reflects an additive global signal confound. Unlike the GSR method which removes both components, median angle correction can characterize the properties of the global signal and effectively minimize the effects of the additive global signal confound while preserving the desired components.
Principal component analysis (PCA) is used to decompose the resting-state data. Median angle is computed by taking the inverse cosine of each voxel’s time series vector’s projection onto the first principal component (i.e. the global mean signal) and then calculating the median over the angles from all the vectors. If an inverse relation is found between the median angle and the mean BOLD signal amplitude, then an additive signal confound is present. As resting-state data sets with high median angles and low mean BOLD magnitudes are likely to be the least contaminated by an additive global confound (He and Liu, 2011), the inverse relation between median angle and mean BOLD magnitude is used to correct for differences in the additive confound. Specifically, the angular distributions of datasets with small median angles can be shifted to attain a larger target median angle to effectively minimize the effects of the global signal confound. The calculation of target angle for median angle correction is described in He and Liu (2011).
You can provide your own custom regressor signals beyond those provided by C-PAC (e.g., task encodings or quasi-periodic pattern waveforms).
Each custom regressor must be either a CSV or NIFTI file that contains a single column of the same length as the functional signal with
1s indicating volumes to keep and
0s indicating volumes to censor.
The custom regressor specification also takes a boolean
convolve (default =
An example with one custom regressor is included in Configuration Without the GUI, below.
Configuring Nuisance Signal Regression Options¶
Run Nuisance Signal Correction - [Off, On, On/Off]: Covary out various sources of noise.
Lateral Ventricles Mask (Standard Space) - [path, None]: A binary mask of the lateral ventricles. If choosing None, no lateral ventricles mask will be applied.
Select Regressors: - [checkbox: compcor, wm, csf, global, pc1, motion, linear, quadratic]: Clicking on the + icon to the right of the box here will bring up a dialog where you can check off which nuisance variables you would like to include. You may generate multiple sets of nuisance regression strategies in this way. When you are done defining nuisance regression strategies, check the box next to each strategy you would like to run.
Configuring Temporal Filtering Options¶
Run Temporal Filtering - [Off, On, On/Off]: Apply a temporal band-pass filter to functional data.
Select regressors: - [dialogue: Low-frequency cutoff, High-frequency cutoff]: Clicking on the + icon to the right of the box here will bring up a dialog where you can define the upper and lower cutoffs for the bandpass filter. You may generate multiple sets of bandpass filter strategies in this way. When you are done defining bandpasses, check the box next to each bandpass you would like to run.
Configuration Without the GUI¶
The following nested key/value pairs will be set to these defaults if not defined in your pipeline configuration YAML.
2-nuisance_regression: # this is a fork point # run: [On, Off] - this will run both and fork the pipeline run: [On] # switch to Off if nuisance regression is off and you don't want to write out the regressors create_regressors: On # Select which nuisance signal corrections to apply Regressors: - Name: 'default' Motion: include_delayed: true include_squared: true include_delayed_squared: true aCompCor: summary: method: DetrendPC components: 5 tissues: - WhiteMatter - CerebrospinalFluid extraction_resolution: 2 CerebrospinalFluid: summary: Mean extraction_resolution: 2 erode_mask: true GlobalSignal: summary: Mean PolyOrt: degree: 2 Bandpass: bottom_frequency: 0.01 top_frequency: 0.1 method: default - Name: 'defaultNoGSR' Motion: include_delayed: true include_squared: true include_delayed_squared: true aCompCor: summary: method: DetrendPC components: 5 tissues: - WhiteMatter - CerebrospinalFluid extraction_resolution: 2 CerebrospinalFluid: summary: Mean extraction_resolution: 2 erode_mask: true PolyOrt: degree: 2 Bandpass: bottom_frequency: 0.01 top_frequency: 0.1 method: default # Standard Lateral Ventricles Binary Mask # used in CSF mask refinement for CSF signal-related regressions lateral_ventricles_mask: $FSLDIR/data/atlases/HarvardOxford/HarvardOxford-lateral-ventricles-thr25-2mm.nii.gz # Whether to run frequency filtering before or after nuisance regression. # Options: 'After' or 'Before' bandpass_filtering_order: 'After' # Process and refine masks used to produce regressors and time series for # regression. regressor_masks: erode_anatomical_brain_mask: # Erode binarized anatomical brain mask. If choosing True, please also set regressor_masks['erode_csf']['run']: True; anatomical_preproc['brain_extraction']['using']: niworkflows-ants. run: Off # Target volume ratio, if using erosion. # Default proportion is None for anatomical brain mask. # If using erosion, using both proportion and millimeters is not recommended. brain_mask_erosion_prop: # Erode brain mask in millimeters, default for brain mask is 30 mm # Brain erosion default is using millimeters. brain_mask_erosion_mm: 30 # Erode binarized brain mask in millimeter brain_erosion_mm: erode_csf: # Erode binarized csf tissue mask. run: Off # Target volume ratio, if using erosion. # Default proportion is None for cerebrospinal fluid mask. # If using erosion, using both proportion and millimeters is not recommended. csf_erosion_prop: # Erode cerebrospinal fluid mask in millimeters, default for cerebrospinal fluid is 30mm # Cerebrospinal fluid erosion default is using millimeters. csf_mask_erosion_mm: 30 # Erode binarized cerebrospinal fluid mask in millimeter csf_erosion_mm: erode_wm: # Erode WM binarized tissue mask. run: Off # Target volume ratio, if using erosion. # Default proportion is 0.6 for white matter mask. # If using erosion, using both proportion and millimeters is not recommended. # White matter erosion default is using proportion erosion method when use erosion for white matter. wm_erosion_prop: 0.6 # Erode white matter mask in millimeters, default for white matter is None wm_mask_erosion_mm: # Erode binarized white matter mask in millimeters wm_erosion_mm: erode_gm: # Erode gray matter binarized tissue mask. run: Off # Target volume ratio, if using erosion. # If using erosion, using both proportion and millimeters is not recommended. gm_erosion_prop: 0.6 # Erode gray matter mask in millimeters gm_mask_erosion_mm: # Erode binarized gray matter mask in millimeters gm_erosion_mm:
An example of a custom regressor with one file:
nuisance_corrections: 2-nuisance_regression: Regressors: - Name: 'first_custom_regressor' Custom: - file: custom_signal.1D convolve: true
An example of nuisance regressors¶
The following box contains an example of a TSV file generated by C-PAC with the regressors used on nuisance regression.
# CPAC 1.4.1 # Nuisance regressors: # RotY RotYBack RotYSq RotYBackSq RotX RotXBack RotXSq RotXBackSq RotZ RotZBack RotZSq RotZBackSq Y YBack YSq YBackSq X XBack XSq XBackSq Z ZBack ZSq ZBackSq aCompCorDetrendPC0 aCompCorDetrendPC1 aCompCorDetrendPC2 aCompCorDetrendPC3 aCompCorDetrendPC4 CerebrospinalFluidMean -0.0276 0 0.0007 0 0.1954 0 0.0381 0 0.0488 0 0.0023 0 -0.3694 0 0.1364 0 -0.0061 0 0.0000 0 -0.3843 0 0.1476 0 -0.0458 0.0335 -0.0736 0.0579 -0.0114 10392.7714 -0.0192 -0.0276 0.0003 0.0007 0.2613 0.1954 0.0682 0.0381 0.0774 0.0488 0.0059 0.0023 -0.4328 -0.3694 0.1873 0.1364 0.0202 -0.0061 0.0004 0.0000 -0.3547 -0.3843 0.1258 0.1476 -0.1048 0.0727 -0.2194 0.1391 0.0235 10432.6865 -0.0394 -0.0192 0.0015 0.0003 0.1324 0.2613 0.0175 0.0682 0.0132 0.0774 0.0001 0.0059 -0.3399 -0.4328 0.1155 0.1873 -0.0262 0.0202 0.0006 0.0004 -0.3366 -0.3547 0.1132 0.1258 -0.1030 0.0668 -0.1124 0.0937 0.0553 10460.6806 -0.0394 -0.0394 0.0015 0.0015 0.1597 0.1324 0.0255 0.0175 0.0389 0.0132 0.0015 0.0001 -0.3419 -0.3399 0.1168 0.1155 0.0004 -0.0262 0.0000 0.0006 -0.3387 -0.3366 0.1147 0.1132 -0.0984 0.0633 -0.1343 0.1038 0.0736 10421.9697 -0.0232 -0.0394 0.0005 0.0015 0.1393 0.1597 0.0194 0.0255 0.0316 0.0389 0.0009 0.0015 -0.3486 -0.3419 0.1215 0.1168 -0.0081 0.0004 0.0000 0.0000 -0.3391 -0.3387 0.1149 0.1147 -0.0924 0.0698 -0.0869 0.1085 0.0369 10433.9453 -0.0225 -0.0232 0.0005 0.0005 0.1565 0.1393 0.0244 0.0194 0.0339 0.0316 0.0011 0.0009 -0.3828 -0.3486 0.1465 0.1215 -0.0033 -0.0081 0.0000 0.0000 -0.3498 -0.3391 0.1223 0.1149 -0.1071 0.0753 -0.0597 0.1258 -0.0705 10426.4130 -0.0233 -0.0225 0.0005 0.0005 0.1494 0.1565 0.0223 0.0244 0.0288 0.0339 0.0008 0.0011 -0.3405 -0.3828 0.1159 0.1465 -0.0062 -0.0033 0.0000 0.0000 -0.3458 -0.3498 0.1195 0.1223 -0.1158 0.0549 -0.1046 0.0821 -0.0871 10445.0371
Configuring Median Angle Correction Options¶
median angle correction functionality was removed in C-PAC v1.8.0.
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