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Advances in functional magnetic resonance imaging (fMRI) acquisition have improved signal to noise to the point where the physiology of the subject is the dominant noise source in resting state fMRI data (rsfMRI). Among these systemic, non-neuronal physiological signals, respiration and to some degree cardiac fluctuations can be removed through modeling, or in the case of newer, faster acquisitions such as simultaneous multislice acquisition, simple spectral filtering. However, significant low frequency physiological oscillation (∼0.01-0.15 Hz) remains in the signal. This is problematic, as it is the precise frequency band occupied by the neuronally modulated hemodynamic responses used to study brain connectivity, precluding its removal by spectral filtering. The source of this signal, and its method of production and propagation in the body, have not been conclusively determined. Here, we summarize the defining characteristics of the systemic low frequency noise signal, and review some current theories about the signal source and the evidence supporting them. The strength and distribution of the systemic LFO signal make characterizing and removing it essential for accurate quantification, especially for resting state connectivity, when no stimulation can be compared with the signal. Widespread correlated non-neuronal signals obscure and distort the more localized patterns of neuronal correlations between interacting brain regions; they may even cause apparent connectivity between regions with no neuronal interaction. Here, we discuss a simple method we have developed to parse the global, moving, blood-borne signal from the stationary, neuronal connectivity signals, substantially reducing the negative correlations that result from global signal regression. Finally, we will discuss some of the uses to which the moving systemic low frequency oscillation can be put if we consider it a \"signal\" carrying information, rather than simply \"noise\" complicating the interpretation of resting state connectivity. Properly utilizing this signal may offer insights into subtle hemodynamic alterations that can be used as early indicators of circulatory dysfunction in a number of neuropsychiatric conditions, such as prodromal stroke, moyamoya, and Alzheimer's disease.

Cognitive neuroimaging studies typically require fast whole brain image acquisition with maximal sensitivity to small BOLD signal changes. To increase the sensitivity, higher field strengths are often employed, since they provide an increased image signal-to-noise ratio (SNR). However, as image SNR increases, the relative contribution of physiological noise to the total time series noise will be greater compared to that from thermal noise. At 7T, we studied how the physiological noise contribution can be best reduced for EPI time series acquired at three different spatial resolutions (1.1mm×1.1mm×1.8mm, 2mm×2mm×2mm and 3mm×3mm×3mm). Applying optimal physiological noise correction methods improved temporal SNR (tSNR) and increased the numbers of significantly activated voxels in fMRI visual activation studies for all sets of acquisition parameters. The most dramatic results were achieved for the lowest spatial resolution, an acquisition parameter combination commonly used in cognitive neuroimaging which requires high functional sensitivity and temporal resolution (i.e. 3mm isotropic resolution and whole brain image repetition time of 2s). For this data, physiological noise models based on cardio-respiratory information improved tSNR by approximately 25% in the visual cortex and 35% sub-cortically. When the time series were additionally corrected for the residual effects of head motion after retrospective realignment, the tSNR was increased by around 58% in the visual cortex and 71% sub-cortically, exceeding tSNR ~140. In conclusion, optimal physiological noise correction at 7T increases tSNR significantly, resulting in the highest tSNR per unit time published so far. This tSNR improvement translates into a significant increase in BOLD sensitivity, facilitating the study of even subtle BOLD responses. ► Impact of physiological noise correction on tSNR versus SNR was characterized at 7T. ► tSNR was improved by 50 to 70% using physiological noise correction in task-free EPI. ► The reported results exceed values for tSNR per unit time published so far. ► tSNR improvements translated into more than 10% increase in BOLD activity in fMRI.

Blood oxygen-level-dependent functional magnetic resonance imaging (BOLD fMRI) has rapidly become a popular technique for the investigation of brain function in healthy individuals, patients as well as in animal studies. However, the BOLD signal arises from a complex mixture of neuronal, metabolic and vascular processes, being therefore an indirect measure of neuronal activity, which is further severely corrupted by multiple non-neuronal fluctuations of instrumental, physiological or subject-specific origin. This review aims to provide a comprehensive summary of existing methods for cleaning the BOLD fMRI signal. The description is given from a methodological point of view, focusing on the operation of the different techniques in addition to pointing out the advantages and limitations in their application. Since motion-related and physiological noise fluctuations are two of the main noise components of the signal, techniques targeting their removal are primarily addressed, including both data-driven approaches and using external recordings. Data-driven approaches, which are less specific in the assumed model and can simultaneously reduce multiple noise fluctuations, are mainly based on data decomposition techniques such as principal and independent component analysis. Importantly, the usefulness of strategies that benefit from the information available in the phase component of the signal, or in multiple signal echoes is also highlighted. The use of global signal regression for denoising is also addressed. Finally, practical recommendations regarding the optimization of the preprocessing pipeline for the purpose of denoising and future venues of research are indicated. Through the review, we summarize the importance of signal denoising as an essential step in the analysis pipeline of task-based and resting state fMRI studies. •Numerous techniques are available for denoising the BOLD fMRI signal.•Motion-related artifacts and physiological noise fluctuations are the main targets.•Phase-based and multi-echo fMRI can help to improve the performance of denoising.•There exist multiple equally-efficient alternatives to global signal regression.•There is no “best” method for preprocessing, but there are incorrect methods.

The global signal is widely used as a regressor or normalization factor for removing the effects of global variations in the analysis of functional magnetic resonance imaging (fMRI) studies. However, there is considerable controversy over its use because of the potential bias that can be introduced when it is applied to the analysis of both task-related and resting-state fMRI studies. In this paper we take a closer look at the global signal, examining in detail the various sources that can contribute to the signal. For the most part, the global signal has been treated as a nuisance term, but there is growing evidence that it may also contain valuable information. We also examine the various ways that the global signal has been used in the analysis of fMRI data, including global signal regression, global signal subtraction, and global signal normalization. Furthermore, we describe new ways for understanding the effects of global signal regression and its relation to the other approaches.

The ability to discriminate signal from noise plays a key role in the analysis and interpretation of functional magnetic resonance imaging (fMRI) measures of brain activity. Over the past two decades, a number of major sources of noise have been identified, including system-related instabilities, subject motion, and physiological fluctuations. This article reviews the characteristics of the various noise sources as well as the mechanisms through which they affect the fMRI signal. Approaches for distinguishing signal from noise and the associated challenges are also reviewed. These challenges reflect the fact that some noise sources, such as respiratory activity, are generated by the same underlying brain networks that give rise to functional signals that are of interest.

The goal of resting-state functional magnetic resonance imaging (fMRI) is to investigate the brain's functional connections by using the temporal similarity between blood oxygenation level dependent (BOLD) signals in different regions of the brain “at rest” as an indicator of synchronous neural activity. Since this measure relies on the temporal correlation of fMRI signal changes between different parts of the brain, any non-neural activity-related process that affects the signals will influence the measure of functional connectivity, yielding spurious results. To understand the sources of these resting-state fMRI confounds, this article describes the origins of the BOLD signal in terms of MR physics and cerebral physiology. Potential confounds arising from motion, cardiac and respiratory cycles, arterial CO2 concentration, blood pressure/cerebral autoregulation, and vasomotion are discussed. Two classes of techniques to remove confounds from resting-state BOLD time series are reviewed: 1) those utilising external recordings of physiology and 2) data-based cleanup methods that only use the resting-state fMRI data itself. Further methods that remove noise from functional connectivity measures at a group level are also discussed. For successful interpretation of resting-state fMRI comparisons and results, noise cleanup is an often over-looked but essential step in the analysis pipeline. •Resting-state fMRI measures temporal similarity between BOLD signals.•Confounds can arise that affect the BOLD signals leading to spurious results.•Motion, cardiac/respiration, arterial CO2 concentration & blood pressure are sources.•Techniques to remove resting-state fMRI confounds are reviewed.•Noise correction is an essential step for resting-state fMRI analyses.

For the robust estimation of evoked brain activity from functional Near-Infrared Spectroscopy (fNIRS) signals, it is crucial to reduce nuisance signals from systemic physiology and motion. The current best practice incorporates short-separation (SS) fNIRS measurements as regressors in a General Linear Model (GLM). However, several challenging signal characteristics such as non-instantaneous and non-constant coupling are not yet addressed by this approach and additional auxiliary signals are not optimally exploited. We have recently introduced a new methodological framework for the unsupervised multivariate analysis of fNIRS signals using Blind Source Separation (BSS) methods. Building onto the framework, in this manuscript we show how to incorporate the advantages of regularized temporally embedded Canonical Correlation Analysis (tCCA) into the supervised GLM. This approach allows flexible integration of any number of auxiliary modalities and signals. We provide guidance for the selection of optimal parameters and auxiliary signals for the proposed GLM extension. Its performance in the recovery of evoked HRFs is then evaluated using both simulated ground truth data and real experimental data and compared with the GLM with short-separation regression. Our results show that the GLM with tCCA significantly improves upon the current best practice, yielding significantly better results across all applied metrics: Correlation (HbO max. +45%), Root Mean Squared Error (HbO max. −55%), F-Score (HbO up to 3.25-fold) and p-value as well as power spectral density of the noise floor. The proposed method can be incorporated into the GLM in an easily applicable way that flexibly combines any available auxiliary signals into optimal nuisance regressors. This work has potential significance both for conventional neuroscientific fNIRS experiments as well as for emerging applications of fNIRS in everyday environments, medicine and BCI, where high Contrast to Noise Ratio is of importance for single trial analysis. •Reducing nuisance signals in fNIRS leads to more robust estimation of evoked brain activity.•GLM with tCCA flexibly combines any available auxiliary signals into optimal nuisance regressors.•The proposed method significantly improves upon conventional GLM with short separation regression.•Improved HRF recovery particularly for low Contrast to Noise Ratios and low number of stimuli/trials.

Anticorrelated relationships in spontaneous signal fluctuation have been previously observed in resting-state functional magnetic resonance imaging (fMRI). In particular, it was proposed that there exists two systems in the brain that are intrinsically organized into anticorrelated networks, the default mode network, which usually exhibits task-related deactivations, and the task-positive network, which usually exhibits task-related activations during tasks that demands external attention. However, it is currently under debate whether the anticorrelations observed in resting state fMRI were valid or were instead artificially introduced by global signal regression, a common preprocessing technique to remove physiological and other noise in resting-state fMRI signal. We examined positive and negative correlations in resting-state connectivity using two different preprocessing methods: a component base noise reduction method (CompCor, Behzadi et al., 2007), in which principal components from noise regions-of-interest were removed, and the global signal regression method. Robust anticorrelations between a default mode network seed region in the medial prefrontal cortex and regions of the task-positive network were observed under both methods. Specificity of the anticorrelations was similar between the two methods. Specificity and sensitivity for positive correlations were higher under CompCor compared to the global regression method. Our results suggest that anticorrelations observed in resting-state connectivity are not an artifact introduced by global signal regression and might have biological origins, and that the CompCor method can be used to examine valid anticorrelations during rest. ►Resting-state connectivity analysis without global signal regression. ►Principal components from noise regions-of-interest were regressed out (CompCor). ►Robust anticorrelations were observed under CompCor. ►Specificity was equal or higher under CompCor compared to global signal regression.