A method to mitigate spatio-temporally varying task-correlated motion artifacts from overt-speech fMRI paradigms in aphasia.

Quantifying accurate functional magnetic resonance imaging (fMRI) activation maps can be dampened by spatio-temporally varying task-correlated motion (TCM) artifacts in certain task paradigms (e.g., overt speech). Such real-world tasks are relevant to characterize longitudinal brain reorganization poststroke, and removal of TCM artifacts is vital for improved clinical interpretation and translation. In this study, we developed a novel independent component analysis (ICA)-based approach to denoise spatio-temporally varying TCM artifacts in 14 persons with aphasia who participated in an overt language fMRI paradigm. We compared the new methodology with other existing approaches such as "standard" volume registration, nonselective motion correction ICA packages (i.e., AROMA), and combining the novel approach with AROMA. Results show that the proposed methodology outperforms other approaches in removing TCM-related false positive activity (i.e., improved detectability power) with high spatial specificity. The proposed method was also effective in maintaining a balance between removal of TCM-related trial-by-trial variability and signal retention. Finally, we show that the TCM artifact is related to clinical metrics, such as speech fluency and aphasia severity, and the implication of TCM denoising on such relationship is also discussed. Overall, our work suggests that routine bulkhead motion based denoising packages cannot effectively account for spatio-temporally varying TCM. Further, the proposed TCM denoising approach requires a one-time front-end effort to hand label and train the classifiers that can be cost-effectively utilized to denoise large clinical data sets.

A comprehensive data-driven analysis framework for detecting impairments in brain function networks with resting state fMRI in HIV-infected individuals on cART.

Central nervous system (CNS) sequelae continue to be common in HIV-infected individuals despite combination antiretroviral therapy (cART). These sequelae include HIV-associated neurocognitive disorder (HAND) and virologic persistence in the CNS. Resting state functional magnetic resonance imaging (rsfMRI) is a widely used tool to examine the integrity of brain function and pathology. In this study, we examined 16 HIV-positive (HIV+) subjects and 12 age, sex, and race matched HIV seronegative controls (HIV-) whole-brain high-resolution rsfMRI along with a battery of neurocognitive tests. A comprehensive data-driven analysis of rsfMRI revealed impaired functional connectivity, with very large effect sizes in executive function, language, and multisensory processing networks in HIV+ subjects. These results indicate the potential of high-resolution rsfMRI in combination with advanced data analysis techniques to yield biomarkers of neural impairment in HIV.

Task-residual functional connectivity of language and attention networks.

Functional connectivity using task-residual data capitalizes on remaining variance after mean task-related signal is removed from a time series. The degree of network specificity in language and attention domains featured by task-residual and resting-state data types were compared. Functional connectivity based on task-residual data evidenced stronger laterality of the language and attention connections and thus greater network specificity compared to resting-state functional connectivity of the same connections. Covariance between network nodes of task-residuals may thus reflect the degree to which two regions are coordinated in their specific activity, rather than a general shared co-activation. Task-residual functional connectivity provides complementary data to that of resting-state, emphasizing network relationships during task engagement.

Word-finding impairment in veterans of the 1991 Persian Gulf War.

Approximately one quarter of 1991 Persian Gulf War Veterans experience cognitive and physiological sequelae that continue to be unexplained by known medical or psychological conditions. Difficulty coming up with words and names, familiar before the war, is a hallmark of the illness. Three Gulf War Syndrome subtypes have been identified and linked to specific war-time chemical exposures. The most functionally impaired veterans belong to the Gulf War Syndrome 2 (Syndrome 2) group, for which subcortical damage due to toxic nerve gas exposure is the suspected cause. Subcortical damage is often associated with specific complex language impairments, and Syndrome 2 veterans have demonstrated poorer vocabulary relative to controls. 11 Syndrome 1, 16 Syndrome 2, 9 Syndrome 3, and 14 age-matched veteran controls from the Seabees Naval Construction Battalion were compared across three measures of complex language. Additionally, functional magnetic resonance imaging (fMRI) was collected during a covert category generation task, and whole-brain functional activity was compared between groups. Results demonstrated that Syndrome 2 veterans performed significantly worse on letter and category fluency relative to Syndrome 1 veterans and controls. They also exhibited reduced activity in the thalamus, putamen, and amygdala, and increased activity in the right hippocampus relative to controls. Syndrome 1 and Syndrome 3 groups tended to show similar, although smaller, differences than the Syndrome 2 group. Hence, these results further demonstrate specific impairments in complex language as well as subcortical and hippocampal involvement in Syndrome 2 veterans. Further research is required to determine the extent of language impairments in this population and the significance of altered neurologic activity in the aforementioned brain regions with the purpose of better characterizing the Gulf War Syndromes.

Characterization of visual processing in temporomandibular disorders using functional magnetic resonance imaging.

BACKGROUND AND PURPOSE: Many patients with chronic pain report hypersensitivity not only to noxious stimuli, but also to other modalities including innocuous touch, sound, and light, possibly due to differences in the processing of these stimuli. The goal of this study was to characterize functional connectivity (FC) differences between subjects with temporomandibular disorders (TMD) and pain-free controls during a visual functional magnetic resonance imaging (fMRI) task that included an unpleasant, strobing visual stimulus. We hypothesized the TMD cohort would exhibit maladaptations in brain networks consistent with multisensory hypersensitivities observed in TMD patients. METHODS: This pilot study included 16 subjects, 10 with TMD and 6 pain-free controls. Clinical pain was characterized using self-reported questionnaires. Visual task-based fMRI data were collected on a 3T MR scanner and used to determine differences in FC via group independent component analysis. RESULTS: Compared to controls, subjects with TMD exhibited abnormally increased FC between the default mode network and lateral prefrontal areas involved in attention and executive function, and impaired FC between the frontoparietal network and higher order visual processing areas. CONCLUSIONS: The results indicate maladaptation of brain functional networks, likely due to deficits in multisensory integration, default mode network function, and visual attention and engendered by chronic pain mechanisms.

Neural correlates of successful response inhibition in unmedicated patients with late-life depression.

OBJECTIVE: Accumulating evidence implicates a strong association between abnormal frontostriatal-limbic brain circuits, executive dysfunction, and late-life depression (LLD). The stop signal task (SST) was designed by Rubia et al. for use with functional magnetic resonance imaging (fMRI) to identify the neural correlates of motor response inhibition, a well-characterized executive function. In this study, we compared brain activation between a group of unmedicated participants with LLD and an unmedicated healthy cohort during SST performance. METHODS: Participants 55-85 years of age were screened, clinically evaluated, and entered into either the LLD (n = 15) or healthy comparison group (n = 13). Both groups underwent neuroimaging while performing the SST under similar conditions. The brain circuitry of successful motor inhibition was evaluated by contrasting the condition of correctly inhibiting responses with the condition of correctly responding to Go signals. Differential areas of brain activation between the LLD and comparison groups were determined with FMRIB Software Library. RESULTS: Despite comparable SST performance measures, LLD participants demonstrated greater blood oxygen level dependent activation relative to the comparison group in predominantly left-lateralized frontostriatal-limbic circuitry that included the bilateral superior frontal cortices and left-hemispheric orbitofrontal gyri, insular cortex, cingulate cortex, caudate, and putamen. Conversely, the healthy comparison group did not exhibit any areas of greater activation than the LLD group. CONCLUSION: Unmedicated participants with LLD activate additional areas within frontostriatal-limbic brain circuitry when performing the SST at a level comparable to a healthy cohort.

Reduced Interference and Serial Dependency Effects for Naming in Older but Not Younger Adults after 1 Hz rTMS of Right Pars Triangularis.

1 Hz repetitive transcranial magnetic stimulation (rTMS) was used to decrease excitability of right pars triangularis (R PTr) to determine whether increased R PTr activity during picture naming in older adults hampers word finding. We hypothesized that decreasing R PTr excitability would reduce interference with word finding, facilitating faster picture naming. 15 older and 16 younger adults received two rTMS sessions. In one, speech onset latencies for picture naming were measured after both sham and active R PTr stimulation. In the other session, sham and active stimulation of a control region, right pars opercularis (R POp), were administered before picture naming. Order of active vs. sham stimulation within session was counterbalanced. Younger adults showed no significant effects of stimulation. In older adults, a trend indicated that participants named pictures more quickly after active than sham R PTr stimulation. However, older adults also showed longer responses during R PTr than R POp sham stimulation. When order of active vs. sham stimulation was modeled, older adults receiving active stimulation first had significantly faster responding after active than sham R PTr stimulation and significantly faster responding after R PTr than R POp stimulation, consistent with experimental hypotheses. However, older adults receiving sham stimulation first showed no significant differences between conditions. Findings are best understood, based on previous studies, when the interaction between the excitatory effects of picture naming and the inhibitory effects of 1 Hz rTMS on R PTr is considered. Implications regarding right frontal activity in older adults and for design of future experiments are discussed.

Selective blockade of rat brain T-type calcium channels provides insights on neurophysiological basis of arousal dependent resting state functional magnetic resonance imaging signals.

A number of studies point to slow (0.1-2 Hz) brain rhythms as the basis for the resting-state functional magnetic resonance imaging (rsfMRI) signal. Slow waves exist in the absence of stimulation, propagate across the cortex, and are strongly modulated by vigilance similar to large portions of the rsfMRI signal. However, it is not clear if slow rhythms serve as the basis of all neural activity reflected in rsfMRI signals, or just the vigilance-dependent components. The rsfMRI data exhibit quasi-periodic patterns (QPPs) that appear to increase in strength with decreasing vigilance and propagate across the brain similar to slow rhythms. These QPPs can complicate the estimation of functional connectivity (FC) via rsfMRI, either by existing as unmodeled signal or by inducing additional wide-spread correlation between voxel-time courses of functionally connected brain regions. In this study, we examined the relationship between cortical slow rhythms and the rsfMRI signal, using a well-established pharmacological model of slow wave suppression. Suppression of cortical slow rhythms led to significant reduction in the amplitude of QPPs but increased rsfMRI measures of intrinsic FC in rats. The results suggest that cortical slow rhythms serve as the basis of only the vigilance-dependent components (e.g., QPPs) of rsfMRI signals. Further attenuation of these non-specific signals enhances delineation of brain functional networks.

Striatal functional connectivity networks are modulated by fMRI resting state conditions.

Resting state fluctuations in blood oxygenation level dependent functional connectivity magnetic resonance imaging (BOLD fcMRI) time-series have been increasingly employed to study functional connectivity networks in healthy and diseased brain. FcMRI studies have been conducted under a number of different conditions, including resting eyes open, visual fixation and finger tapping. BOLD fcMRI networks are believed to reflect both anatomically constrained spontaneous fluctuations and state-dependent activity. In this study, state-dependence of functional connectivity to dorsal and ventral striatum was assessed with fcMRI during an eyes open resting state condition (REST) and during continuous 3 Hz transcutaneous electrical nerve stimulation (TENS), with the a priori hypotheses: (1) dorsal striatum connectivity with sensorimotor/attention networks will be stronger during TENS compared to REST, (2) ventral striatum connectivity with limbic system emotion-processing network will be weaker during TENS compared to REST and (3) ventral striatum connectivity with sensorimotor/attention networks will be stronger during TENS compared to REST. These hypotheses were confirmed by the results obtained, indicating that resting state BOLD fMRI networks reflect, in substantial measure, state-dependent activity.

Single-camera motion measurement and monitoring for magnetic resonance applications.

An optically based rigid-body six-degrees of freedom (DOF) measurement system optimized for prospective (real-time) motion correction in magnetic resonance imaging (MRI) applications is described. By optimizing system capabilities to the specific applications requirements, the six-DOF measurement is accomplished using a single camera and simple three-disc fiducial at rates of 50 Hz. The algorithm utilizes successive approximation to solve the three point pose problem for angles close to the origin. Convergence to submicroradian levels occurs within 20 iterations for angles in an approximate half-radian (29°) arc centered on the origin. The overall absolute accuracy of the instrument is 10-100 µm for translational and <100 µrad (0.005°) for rotational motions. Results for head nodding and speech tasks are presented for subjects in the MR scanner, and the instrument results are compared to standard prospective acquisition correction.

Examining fMRI time-series entropy as a marker for brain E/I balance with pharmacological neuromodulation in a non-human primate translational model.

Recently, there has been a lot of interest in the neuroimaging community in exploring fMRI time-series measures of local neuronal activity and excitation/inhibition (E/I) balance in the brain. In this preliminary study we probed the sensitivity of widely used sample entropy (SE) measure at multiple scales to controlled alteration of the brain's E/I balance in non-human primates (NHPs) with a well-characterized sub-anesthetic ketamine infusion fMRI model. We found that SE failed to detect the expected changes in E/I balance induced by ketamine. Subsequently, noticing that the complexity in the time series contributing SE could be dominated by non-neuronal noise in this experimental setting, we developed a new time-series measure called restricted sample entropy (RSE) by restricting SE estimations to regular portions of the fMRI time-series. RSE was able to adequately reflect the increased excitatory activity engendered by disinhibition of glutamergic neurons, through sub-anesthetic ketamine infusion. These results show that RSE is potentially a powerful tool for examining local neural activity, E/I balance, and alterations in brain state.

Correcting Task fMRI Signals for Variability in Baseline CBF Improves BOLD-Behavior Relationships: A Feasibility Study in an Aging Model.

Blood Oxygen Level Dependent (BOLD) functional MRI is a complex neurovascular signal whose magnitude depends on baseline physiological factors such as cerebral blood flow (CBF). Because baseline CBF varies across the brain and is altered with aging, the interpretation of stand-alone aging-related BOLD changes can be misleading. The primary objective of this study was to develop a methodology that combines task fMRI and arterial spin labeling (ASL) techniques to sensitize task-induced BOLD activity by covarying out the baseline physiology (i.e., CBF) in an aging model. We recruited 11 younger and 13 older healthy participants who underwent ASL and an overt language fMRI task (semantic category member generation). We measured in-scanner language performance to investigate the effect of BOLD sensitization on BOLD-behavior relationships. The results demonstrate that our correction approach is effective at enhancing the specificity and sensitivity of the BOLD signal in both groups. In addition, the correction strengthens the statistical association between task BOLD activity and behavioral performance. Although CBF has inherent age dependence, our results show that retaining the age factor within CBF aides in greater sensitization of task fMRI signals. From a cognitive standpoint, compared to young adults, the older participants showed a delayed domain-general language-related task activity possibly due to compromised vessel compliance. Further, assessment of functional evolution of corrected BOLD activity revealed biphasic BOLD dynamics in both groups where BOLD deactivation may reflect greater semantic demand or increased premium on domain general executive functioning in response to task difficulty. Although it was promising to note that the predictability of behavior using the proposed methodology outperforms other methodologies (i.e., no correction and normalization by division), and provides moderate stability and adequate power, further work with a larger cohort and other task designs is necessary to improve the stability of predicting associated behavior. In summary, we recommend correction of task fMRI signals by covarying out baseline CBF especially when comparing groups with different neurovascular properties. Given that ASL and BOLD fMRI are well established and widely employed techniques, our proposed multi-modal methodology can be readily implemented into data processing pipelines to obtain more accurate BOLD activation maps.

Selective detrending method for reducing task-correlated motion artifact during speech in event-related FMRI.

Task-correlated motion artifacts that occur during functional magnetic resonance imaging can be mistaken for brain activity. In this work, a new selective detrending method for reduction of artifacts associated with task-correlated motion (TCM) during speech in event-related functional magnetic resonance imaging is introduced and demonstrated in an overt word generation paradigm. The performance of this new method is compared with that of three existing methods for reducing artifacts because of TCM: (1) motion parameter regression, (2) ignoring images during speech, and (3) detrending time course datasets of signal components related to TCM (deduced from artifact corrupted voxels). The selective detrending method outperforms the other three methods in reducing TCM artifacts and in retaining blood oxygenation level dependent signal.

Neural substrates of object identification: Functional magnetic resonance imaging evidence that category and visual attribute contribute to semantic knowledge.

Recent findings suggest that neural representations of semantic knowledge contain information about category, modality, and attributes. Although an object's category is defined according to shared attributes that uniquely distinguish it from other category members, a clear dissociation between visual attribute and category representation has not yet been reported. We investigated the contribution of category (living and nonliving) and visual attribute (global form and local details) to semantic representation in the fusiform gyrus. During functional magnetic resonance imaging (fMRI), 40 adults named pictures of animals, tools, and vehicles. In a preliminary study, identification of objects in these categories was differentially dependent on global versus local visual feature processing. fMRI findings indicate that activation in the lateral and medial regions of the fusiform gyrus distinguished stimuli according to category, that is, living versus nonliving, respectively. In contrast, visual attributes of global form (animals) were associated with higher activity in the right fusiform gyrus, while local details (tools) were associated with higher activity in the left fusiform gyrus. When both global and local attributes were relevant to processing (vehicles), cortex in both left and right medial fusiform gyri was more active than for other categories. Taken together, results support distinctions in the role of visual attributes and category in semantic representation.

Effects of ketamine treatment on cocaine-induced reinstatement and disruption of functional connectivity in unanesthetized rhesus monkeys.

RATIONALE: Substance use disorders are characterized by a loss of executive control over reward-based decision-making, and disruption of fronto-striatal connectivity has been implicated in this process. Sub-anesthetic ketamine has recently been shown to bolster fronto-striatal connectivity in drug-naïve subjects. OBJECTIVES: The influence of ketamine treatment was examined on the disruptive effects of cocaine on functional connectivity (FC) and on cocaine-seeking behavior in female rhesus monkeys. METHODS: Three female rhesus were trained for unanesthetized MRI scanning. Each received three drug-naïve/abstinent pharmacological MRI scans with acute injections of saline, cocaine (0.3 mg/kg i.v.), and cocaine (0.3 mg/kg i.v.) 48-h after a ketamine treatment (low dose = 0.345 mg/kg bolus + 0.256 mg/kg/h for 1 h; i.v.), and a fourth scan with saline injection following 2 months of daily cocaine self-administration. A separate cohort of five rhesus (4 female), all with extensive histories of cocaine exposure, underwent reinstatement testing 48 h after ketamine (or vehicle) treatment. Two sub-anesthetic doses were tested: low dose and high dose = 0.69 mg/kg + 0.512 mg/kg/h for 1 h. RESULTS: Ketamine treatment attenuated the effects of cocaine on both global and fronto-striatal FC in drug-naïve/abstinent subjects. Two months of daily cocaine self-administration led to prolonged disruption of both global and fronto-striatal FC. Cocaine-seeking behavior during reinstatement was reduced following ketamine treatment at the low dose, but not high dose. CONCLUSION: These findings illustrate the disruptive effects of cocaine on functional connectivity and provide evidence for the potential efficacy of ketamine as a treatment for stimulant use disorder.

Exploring brain mechanisms underlying Gulf War Illness with group ICA based analysis of fMRI resting state networks.

Around 200,000 veterans (up to 32% of those deployed) of the 1991 Gulf War (GW) suffer from GW illness (GWI), which is characterized by multiple deficits in cognitive, affective, sensory and nociception domains. In this study we employed resting state fMRI (rsfMRI) to map impairments in brain function in GWI with advanced network analysis. RsfMRI data was obtained from 60 GWI veterans and 30 age-matched military controls. Group independent component analysis (GICA) was conducted to probe the functional connectivity networks in all 90 subjects. GICA revealed impaired functional connectivity (FC) in GWI veterans between a number of brain function networks consistent with their self-reported symptoms. GWI veterans exhibited impaired FC between language networks, and sensory input networks of all modalities as well as motor output networks. GWI veterans also exhibited impaired FC between different sensory perception and motor networks, and between different networks in the sensorimotor domain. These FC impairments provide putative mechanism of central nervous system dysfunction in GWI.

Internally Guided Lower Limb Movement Recruits Compensatory Cerebellar Activity in People With Parkinson's Disease.

Background: Externally guided (EG) and internally guided (IG) movements are postulated to recruit two parallel neural circuits, in which motor cortical neurons interact with either the cerebellum or striatum via distinct thalamic nuclei. Research suggests EG movements rely more heavily on the cerebello-thalamo-cortical circuit, whereas IG movements rely more on the striato-pallido-thalamo-cortical circuit (1). Because Parkinson's (PD) involves striatal dysfunction, individuals with PD have difficulty generating IG movements (2). Objectives: Determine whether individuals with PD would employ a compensatory mechanism favoring the cerebellum over the striatum during IG lower limb movements. Methods: 22 older adults with mild-moderate PD, who had abstained at least 12 h from anti-PD medications, and 19 age-matched controls performed EG and IG rhythmic foot-tapping during functional magnetic resonance imaging. Participants with PD tapped with their right (more affected) foot. External guidance was paced by a researcher tapping participants' ipsilateral 3rd metacarpal in a pattern with 0.5 to 1 s intervals, while internal guidance was based on pre-scan training in the same pattern. BOLD activation was compared between tasks (EG vs. IG) and groups (PD vs. control). Results: Both groups recruited the putamen and cerebellar regions. The PD group demonstrated less activation in the striatum and motor cortex than controls. A task (EG vs. IG) by group (PD vs. control) interaction was observed in the cerebellum with increased activation for the IG condition in the PD group. Conclusions: These findings support the hypothesized compensatory shift in which the dysfunctional striatum is assisted by the less affected cerebellum to accomplish IG lower limb movement in individuals with mild-moderate PD. These findings are of relevance for temporal gait dysfunction and freezing of gait problems frequently noted in many people with PD and may have implications for future therapeutic application.

Neural substrates related to auditory working memory comparisons in dyslexia: an fMRI study.

Adult readers with developmental phonological dyslexia exhibit significant difficulty comparing pseudowords and pure tones in auditory working memory (AWM). This suggests deficient AWM skills for adults diagnosed with dyslexia. Despite behavioral differences, it is unknown whether neural substrates of AWM differ between adults diagnosed with dyslexia and normal readers. Prior neuroimaging of adults diagnosed with dyslexia and normal readers, and post-mortem findings of neural structural anomalies in adults diagnosed with dyslexia support the hypothesis of atypical neural activity in temporoparietal and inferior frontal regions during AWM tasks in adults diagnosed with dyslexia. We used fMRI during two binaural AWM tasks (pseudowords or pure tones comparisons) in adults diagnosed with dyslexia (n = 11) and normal readers (n = 11). For both AWM tasks, adults diagnosed with dyslexia exhibited greater activity in left posterior superior temporal (BA 22) and inferior parietal regions (BA 40) than normal readers. Comparing neural activity between groups and between stimuli contrasts (pseudowords vs. tones), adults diagnosed with dyslexia showed greater primary auditory cortex activity (BA 42; tones > pseudowords) than normal readers. Thus, greater activity in primary auditory, posterior superior temporal, and inferior parietal cortices during linguistic and non-linguistic AWM tasks for adults diagnosed with dyslexia compared to normal readers indicate differences in neural substrates of AWM comparison tasks.

Accounting for Non-Gaussian Sources of Spatial Correlation in Parametric Functional Magnetic Resonance Imaging Paradigms I: Revisiting Cluster-Based Inferences.

In a recent study, Eklund et al. employed resting-state functional magnetic resonance imaging data as a surrogate for null functional magnetic resonance imaging (fMRI) datasets and posited that cluster-wise family-wise error (FWE) rate-corrected inferences made by using parametric statistical methods in fMRI studies over the past two decades may have been invalid, particularly for cluster defining thresholds less stringent than p < 0.001; this was principally because the spatial autocorrelation functions (sACF) of fMRI data had been modeled incorrectly to follow a Gaussian form, whereas empirical data suggested otherwise. Here, we show that accounting for non-Gaussian signal components such as those arising from resting-state neural activity as well as physiological responses and motion artifacts in the null fMRI datasets yields first- and second-level general linear model analysis residuals with nearly uniform and Gaussian sACF. Further comparison with nonparametric permutation tests indicates that cluster-based FWE corrected inferences made with Gaussian spatial noise approximations are valid.

Accounting for Non-Gaussian Sources of Spatial Correlation in Parametric Functional Magnetic Resonance Imaging Paradigms II: A Method to Obtain First-Level Analysis Residuals with Uniform and Gaussian Spatial Autocorrelation Function and Independent and Identically Distributed Time-Series.

In a recent study Eklund et al. have shown that cluster-wise family-wise error (FWE) rate-corrected inferences made in parametric statistical method-based functional magnetic resonance imaging (fMRI) studies over the past couple of decades may have been invalid, particularly for cluster defining thresholds less stringent than p < 0.001; principally because the spatial autocorrelation functions (sACFs) of fMRI data had been modeled incorrectly to follow a Gaussian form, whereas empirical data suggest otherwise. Hence, the residuals from general linear model (GLM)-based fMRI activation estimates in these studies may not have possessed a homogenously Gaussian sACF. Here we propose a method based on the assumption that heterogeneity and non-Gaussianity of the sACF of the first-level GLM analysis residuals, as well as temporal autocorrelations in the first-level voxel residual time-series, are caused by unmodeled MRI signal from neuronal and physiological processes as well as motion and other artifacts, which can be approximated by appropriate decompositions of the first-level residuals with principal component analysis (PCA), and removed. We show that application of this method yields GLM residuals with significantly reduced spatial correlation, nearly Gaussian sACF and uniform spatial smoothness across the brain, thereby allowing valid cluster-based FWE-corrected inferences based on assumption of Gaussian spatial noise. We further show that application of this method renders the voxel time-series of first-level GLM residuals independent, and identically distributed across time (which is a necessary condition for appropriate voxel-level GLM inference), without having to fit ad hoc stochastic colored noise models. Furthermore, the detection power of individual subject brain activation analysis is enhanced. This method will be especially useful for case studies, which rely on first-level GLM analysis inferences.