Neural basis of sound-symbolic pseudoword-shape correspondences.

Non-arbitrary mapping between the sound of a word and its meaning, termed sound symbolism, is commonly studied through crossmodal correspondences between sounds and visual shapes, e.g., auditory pseudowords, like 'mohloh' and 'kehteh', are matched to rounded and pointed visual shapes, respectively. Here, we used functional magnetic resonance imaging (fMRI) during a crossmodal matching task to investigate the hypotheses that sound symbolism (1) involves language processing; (2) depends on multisensory integration; (3) reflects embodiment of speech in hand movements. These hypotheses lead to corresponding neuroanatomical predictions of crossmodal congruency effects in (1) the language network; (2) areas mediating multisensory processing, including visual and auditory cortex; (3) regions responsible for sensorimotor control of the hand and mouth. Right-handed participants (n = 22) encountered audiovisual stimuli comprising a simultaneously presented visual shape (rounded or pointed) and an auditory pseudoword ('mohloh' or 'kehteh') and indicated via a right-hand keypress whether the stimuli matched or not. Reaction times were faster for congruent than incongruent stimuli. Univariate analysis showed that activity was greater for the congruent compared to the incongruent condition in the left primary and association auditory cortex, and left anterior fusiform/parahippocampal gyri. Multivoxel pattern analysis revealed higher classification accuracy for the audiovisual stimuli when congruent than when incongruent, in the pars opercularis of the left inferior frontal (Broca's area), the left supramarginal, and the right mid-occipital gyri. These findings, considered in relation to the neuroanatomical predictions, support the first two hypotheses and suggest that sound symbolism involves both language processing and multisensory integration.

Neural Basis Of Sound-Symbolic Pseudoword-Shape Correspondences.

Non-arbitrary mapping between the sound of a word and its meaning, termed sound symbolism, is commonly studied through crossmodal correspondences between sounds and visual shapes, e.g., auditory pseudowords, like 'mohloh' and 'kehteh', are matched to rounded and pointed visual shapes, respectively. Here, we used functional magnetic resonance imaging (fMRI) during a crossmodal matching task to investigate the hypotheses that sound symbolism (1) involves language processing; (2) depends on multisensory integration; (3) reflects embodiment of speech in hand movements. These hypotheses lead to corresponding neuroanatomical predictions of crossmodal congruency effects in (1) the language network; (2) areas mediating multisensory processing, including visual and auditory cortex; (3) regions responsible for sensorimotor control of the hand and mouth. Right-handed participants ( n = 22) encountered audiovisual stimuli comprising a simultaneously presented visual shape (rounded or pointed) and an auditory pseudoword ('mohloh' or 'kehteh') and indicated via a right-hand keypress whether the stimuli matched or not. Reaction times were faster for congruent than incongruent stimuli. Univariate analysis showed that activity was greater for the congruent compared to the incongruent condition in the left primary and association auditory cortex, and left anterior fusiform/parahippocampal gyri. Multivoxel pattern analysis revealed higher classification accuracy for the audiovisual stimuli when congruent than when incongruent, in the pars opercularis of the left inferior frontal (Broca's area), the left supramarginal, and the right mid-occipital gyri. These findings, considered in relation to the neuroanatomical predictions, support the first two hypotheses and suggest that sound symbolism involves both language processing and multisensory integration. HIGHLIGHTS: fMRI investigation of sound-symbolic correspondences between auditory pseudowords and visual shapesFaster reaction times for congruent than incongruent audiovisual stimuliGreater activation in auditory and visual cortices for congruent stimuliHigher classification accuracy for congruent stimuli in language and visual areasSound symbolism involves language processing and multisensory integration.

Physical activity is associated with behavioral and neural changes across the lifespan.

Physical activity is known to positively impact brain structure and function, but its effects on resting-state functional connectivity (rsFC) and its relationship with complex tasks as a function of age remain unclear. Here, we address these issues in a large population-based sample (N = 540) from the Cambridge Centre for Ageing and Neuroscience (Cam-CAN) repository. We relate levels of physical activity to rsFC patterns in magnetoencephalographic (MEG) and functional magnetic resonance imaging (fMRI) data, and to measures of executive function and visuomotor adaptation, across the lifespan. We show that higher self-reported daily physical activity is associated with lower alpha-band (8-12 Hz) global coherence, indicating weaker synchrony of neural oscillations in this band. Physical activity affected between-network connectivity of resting-state functional networks, although its effects on individual networks did not survive correction for multiple comparisons. Furthermore, our results indicate that greater engagement in day-to-day physical activity is associated with better visuomotor adaptation, across the lifespan. Overall, our findings indicate that rsFC metrics indexed by MEG and fMRI are sensitive indicators of the brain's response to physical activity, and that a physically active lifestyle affects multiple aspects of neural function across the lifespan.

Multisensory and lexical information in speech perception.

Both multisensory and lexical information are known to influence the perception of speech. However, an open question remains: is either source more fundamental to perceiving speech? In this perspective, we review the literature and argue that multisensory information plays a more fundamental role in speech perception than lexical information. Three sets of findings support this conclusion: first, reaction times and electroencephalographic signal latencies indicate that the effects of multisensory information on speech processing seem to occur earlier than the effects of lexical information. Second, non-auditory sensory input influences the perception of features that differentiate phonetic categories; thus, multisensory information determines what lexical information is ultimately processed. Finally, there is evidence that multisensory information helps form some lexical information as part of a phenomenon known as sound symbolism. These findings support a framework of speech perception that, while acknowledging the influential roles of both multisensory and lexical information, holds that multisensory information is more fundamental to the process.

Cross-Modal Interactions of the Tactile System.

The sensory systems responsible for perceptions of touch, vision, hearing, etc. have traditionally been regarded as mostly separate, only converging at late stages of processing. Contrary to this dogma, recent work has shown that interactions between the senses are robust and abundant. Touch and vision are both commonly used to obtain information about a number of object properties, and share perceptual and neural representations in many domains. Additionally, visuotactile interactions are implicated in the sense of body ownership, as revealed by powerful illusions that can be evoked by manipulating these interactions. Touch and hearing both rely in part on temporal frequency information, leading to a number of audiotactile interactions reflecting a good deal of perceptual and neural overlap. The focus in sensory neuroscience and psychophysics is now on characterizing the multisensory interactions that lead to our panoply of perceptual experiences.

Perceptual Dissimilarity Analysis Distinguishes Grapheme-Color Synesthetes from Nonsynesthetes.

Synesthetes can be distinguished from nonsynesthetes on a variety of experimental tasks because their concurrent synesthetic experiences can affect task performance if these experiences match or conflict with some aspect of the stimulus. Here, we tested grapheme-color synesthetes and nonsynesthetic control participants using a novel perceptual similarity task to assess whether synesthetes' concurrent color experiences influence perceived grapheme similarity. Participants iteratively arranged graphemes and, separately, their associated synesthetic colors in a display, such that similar items were placed close together and dissimilar items further apart. The resulting relative inter-item distances were used to calculate the pair-wise (dis)similarity between items in the set, and thence to create separate perceptual representational dissimilarity matrices (RDMs) for graphemes and colors, on an individual basis. On the assumption that synesthetes' similarity judgments for graphemes would be influenced by their concurrent color experiences, we predicted that grapheme and color RDMs would be more strongly correlated for synesthetes than nonsynesthetes. We found that the mean grapheme-color RDM correlation was indeed significantly higher in synesthetes than nonsynesthetes; in addition, synesthetes' grapheme-color RDM correlations were more likely to be individually statistically significant, even after correction for multiple tests, than those of nonsynesthetes. Importantly, synesthetes' grapheme-color RDM correlations were scaled with the consistency of their grapheme-color associations as measured by their Synesthesia Battery (SB) scores. By contrast, the relationship between SB scores and grapheme-color RDM correlations for nonsynesthetes was not significant. Thus, dissimilarity analysis quantitatively distinguished synesthetes from nonsynesthetes, in a way that meaningfully reflects a key aspect of synesthetic experience.

Toward rational use of cognitive training in those with mild cognitive impairment.

The term cognitive training includes a range of techniques that hold potential for treating cognitive impairment caused by neurologic injury and disease. Our central premise is that these techniques differ in their mechanisms of action and therefore engage distinct brain regions (or neural networks). We support this premise using data from a single-blind randomized-controlled trial in which patients with mild cognitive impairment were randomized to either mnemonic strategy training (MST) or spaced retrieval training (SRT) as they learned ecologically relevant object-location associations. Both training approaches were highly effective in the short term, but MST demonstrated a clear advantage after days to weeks. MST also increased activation in and functional connectivity between frontal, temporal, and parietal regions as well as the hippocampus. In contrast, patterns of reduced activation and functional connectivity were evident following SRT. These findings support the rational development of cognitive training techniques.

Neural Basis of the Sound-Symbolic Crossmodal Correspondence Between Auditory Pseudowords and Visual Shapes.

Sound symbolism refers to the association between the sounds of words and their meanings, often studied using the crossmodal correspondence between auditory pseudowords, e.g., 'takete' or 'maluma', and pointed or rounded visual shapes, respectively. In a functional magnetic resonance imaging study, participants were presented with pseudoword-shape pairs that were sound-symbolically congruent or incongruent. We found no significant congruency effects in the blood oxygenation level-dependent (BOLD) signal when participants were attending to visual shapes. During attention to auditory pseudowords, however, we observed greater BOLD activity for incongruent compared to congruent audiovisual pairs bilaterally in the intraparietal sulcus and supramarginal gyrus, and in the left middle frontal gyrus. We compared this activity to independent functional contrasts designed to test competing explanations of sound symbolism, but found no evidence for mediation via language, and only limited evidence for accounts based on multisensory integration and a general magnitude system. Instead, we suggest that the observed incongruency effects are likely to reflect phonological processing and/or multisensory attention. These findings advance our understanding of sound-to-meaning mapping in the brain.

Consistency and strength of grapheme-color associations are separable aspects of synesthetic experience.

Consistency of synesthetic associations over time is a widely used test of synesthesia. Since many studies suggest that consistency is not a completely reliable feature, we compared the consistency and strength of synesthetes' grapheme-color associations. Consistency was measured by scores on the Synesthesia Battery and by the Euclidean distance in color space for the specific graphemes tested for each participant. Strength was measured by congruency magnitudes on the Implicit Association Test. The strength of associations was substantially greater for synesthetes than non-synesthetes, suggesting that this is a novel, objective marker of synesthesia. Although, intuitively, strong associations should also be consistent, consistency and strength were uncorrelated, indicating that they are likely independent, at least for grapheme-color synesthesia. These findings have implications for our understanding of synesthesia and for estimates of its prevalence since synesthetes who experience strong, but inconsistent, associations may not be identified by tests that focus solely on consistency.

Stimulus Parameters Underlying Sound-Symbolic Mapping of Auditory Pseudowords to Visual Shapes.

Sound symbolism refers to non-arbitrary mappings between the sounds of words and their meanings and is often studied by pairing auditory pseudowords such as "maluma" and "takete" with rounded and pointed visual shapes, respectively. However, it is unclear what auditory properties of pseudowords contribute to their perception as rounded or pointed. Here, we compared perceptual ratings of the roundedness/pointedness of large sets of pseudowords and shapes to their acoustic and visual properties using a novel application of representational similarity analysis (RSA). Representational dissimilarity matrices (RDMs) of the auditory and visual ratings of roundedness/pointedness were significantly correlated crossmodally. The auditory perceptual RDM correlated significantly with RDMs of spectral tilt, the temporal fast Fourier transform (FFT), and the speech envelope. Conventional correlational analyses showed that ratings of pseudowords transitioned from rounded to pointed as vocal roughness (as measured by the harmonics-to-noise ratio, pulse number, fraction of unvoiced frames, mean autocorrelation, shimmer, and jitter) increased. The visual perceptual RDM correlated significantly with RDMs of global indices of visual shape (the simple matching coefficient, image silhouette, image outlines, and Jaccard distance). Crossmodally, the RDMs of the auditory spectral parameters correlated weakly but significantly with those of the global indices of visual shape. Our work establishes the utility of RSA for analysis of large stimulus sets and offers novel insights into the stimulus parameters underlying sound symbolism, showing that sound-to-shape mapping is driven by acoustic properties of pseudowords and suggesting audiovisual cross-modal correspondence as a basis for language users' sensitivity to this type of sound symbolism.

Primary motor cortical activity during unimanual movements with increasing demand on precision.

In functional magnetic resonance imaging (fMRI) studies, performance of unilateral hand movements is associated with primary motor cortex activity ipsilateral to the moving hand (M1ipsi), in addition to contralateral activity (M1contra). The magnitude of M1ipsi activity increases with the demand on precision of the task. However, it is unclear how demand-dependent increases in M1ipsi recruitment relate to the control of hand movements. To address this question, we used fMRI to measure blood oxygenation level-dependent (BOLD) activity during performance of a task that varied in demand on precision. Participants (n = 23) manipulated an MRI-compatible joystick with their right or left hand to move a cursor into targets of different sizes (small, medium, large, extra large). Performance accuracy, movement time, and number of velocity peaks scaled with target size, whereas reaction time, maximum velocity, and initial direction error did not. In the univariate analysis, BOLD activation in M1contra and M1ipsi was higher for movements to smaller targets. Representational similarity analysis, corrected for mean activity differences, revealed multivoxel BOLD activity patterns during movements to small targets were most similar to those for medium targets and least similar to those for extra-large targets. Only models that varied with demand (target size, performance accuracy, and number of velocity peaks) correlated with the BOLD dissimilarity patterns, though differently for right and left hands. Across individuals, M1contra and M1ipsi similarity patterns correlated with each other. Together, these results suggest that increasing demand on precision in a unimanual motor task increases M1 activity and modulates M1 activity patterns.NEW & NOTEWORTHY Contralateral primary motor cortex (M1) predominantly controls unilateral hand movements, but the role of ipsilateral M1 is unclear. We used functional magnetic resonance imaging (fMRI) to investigate how M1 activity is modulated by unimanual movements at different levels of demand on precision. Our results show that task characteristics related to demand on precision influence bilateral M1 activity, suggesting that in addition to contralateral M1, ipsilateral M1 plays a key role in controlling hand movements to meet performance precision requirements.

Olfactory Costimulation Influences Intranasal Somatosensory Perception.

Olfactory sensitivity is influenced by intranasal trigeminal sensation. For instance, sniffing is central to how humans and animals perceive odorants. Here, we investigated the influence of olfactory costimulation on the perception of intranasal somatosensory stimulation. In this study, 22 healthy human subjects, with normal olfactory function, performed a localization task for stimulation using weak air puffs, a pure odorant, phenyl ethyl alcohol (PEA; rose odor), or their combination. Visual cues were used to inform participants to briefly hold their breath while weak, poorly localizable, air puffs and/or PEA were delivered to either nostril. Although PEA alone could not be localized to the correct nostril, when it accompanied a weak air puff in the ipsilateral nostril, localization accuracy significantly improved, relative to presentation of the air puff without the odorant. The enhancement of localization was absent when the air puff and PEA were presented to opposite nostrils. Since ipsilateral but not contralateral costimulation with PEA increased the accuracy of weak air puff localization, the results argue against a non-specific alerting effect of PEA. These findings suggest an interaction between olfactory and intranasal somatosensory stimuli leading to their integration.

Crossmodal Visuospatial Effects on Auditory Perception of Musical Contour.

The crossmodal correspondence between auditory pitch and visuospatial elevation (in which high- and low-pitched tones are associated with high and low spatial elevation respectively) has been proposed as the basis for Western musical notation. One implication of this is that music perception engages visuospatial processes and may not be exclusively auditory. Here, we investigated how music perception is influenced by concurrent visual stimuli. Participants listened to unfamiliar five-note musical phrases with four kinds of pitch contour (rising, falling, rising-falling, or falling-rising), accompanied by incidental visual contours that were either congruent (e.g., auditory rising/visual rising) or incongruent (e.g., auditory rising/visual falling) and judged whether the final note of the musical phrase was higher or lower in pitch than the first. Response times for the auditory judgment were significantly slower for incongruent compared to congruent trials, i.e., there was a congruency effect, even though the visual contours were incidental to the auditory task. These results suggest that music perception, although generally regarded as an auditory experience, may actually be multisensory in nature.

Mnemonic strategy training increases neocortical activation in healthy older adults and patients with mild cognitive impairment.

Learning and memory deficits characterize the diagnosis of amnestic mild cognitive impairment (aMCI), which is widely viewed as a clinical precursor to Alzheimer's type dementia. There is a growing interest in non-pharmacologic interventions, such as mnemonic strategies, for improving learning and memory in patients with aMCI as well as for maintaining functioning in healthy older adults. Using an ecologically relevant object-location association paradigm, we conducted a randomized, controlled, single-blind study in which healthy older adults and patients with aMCI were randomized to either mnemonic strategy training or a control group that was matched for stimulus exposure. We previously reported that mnemonic strategy training resulted in significantly greater learning and memory improvements compared to the matched exposure condition, in both aMCI patients and healthy controls. The current study examined changes in neocortical activation during encoding in a subset of participants who underwent functional magnetic resonance imaging (fMRI) scanning both before and after training. To minimize potential confounds in between-group comparisons, we employed non-linear cortex based alignment and included only correctly encoded stimuli in our analyses. When re-encoding stimuli learned during training (i.e., trained stimuli), we found a general enhancement of activation in right prefrontal and parietal regions, possibly reflecting practice-related improvement in coordinate spatial processing in all but the aMCI exposure group. Left hemisphere activation was typically only evident in the mnemonic strategy trained participants, regardless of diagnostic status, with the ventrolateral prefrontal cortex appearing especially important for strategy use. While encoding relatively novel stimuli, both mnemonic strategy groups (aMCI patients and healthy controls) demonstrated increased activation in a subset of regions showing change for the trained stimuli, indicating a mnemonic strategy-induced change in the processing of new information. These findings could not be explained by repeated exposure since there was little to no activation overlap in the respective exposure control groups. The current results reinforce the potential benefits of cognitive interventions in these growing populations and indicate that neuroplastic change in key rostral and lateral prefrontal regions mediate this behavioral change.

Model-based assessment and neural correlates of spatial memory deficits in mild cognitive impairment.

Mild cognitive impairment (MCI) is characterized by subjective and objective memory impairments within the context of generally intact everyday functioning. Such memory deficits are typically thought to arise from medial temporal lobe dysfunction; however, differences in memory task performance can arise from a variety of altered processes (e.g., strategy adjustments) rather than, or in addition to, "pure" memory deficits. To address this problem, we applied the linear ballistic accumulator (LBA: Brown and Heathcote, 2008) model to data from individuals with MCI (n = 18) and healthy older adults (HOA; n = 16) who performed an object-location association memory retrieval task during functional magnetic resonance imaging (fMRI). The primary goals were to 1) assess between-group differences in model parameters indexing processes of interest (memory sensitivity, accumulation speed, caution and time spent on peripheral perceptual and motor processes) and 2) determine whether differences in model-based metrics were consistent with fMRI data. The LBA provided evidence that, relative to the HOA group, those with MCI displayed lower sensitivity (i.e., difficulty discriminating targets from lures), suggestive of memory impairment, and displayed higher evidence accumulation speed and greater caution, suggestive of increased arousal and strategic changes in this group, although these changes had little impact on MCI-related accuracy differences. Consistent with these findings, fMRI revealed reduced activation in brain regions previously linked to evidence accumulation and to the implementation of caution reductions in the MCI group. Findings suggest that multiple cognitive mechanisms differ during memory retrieval in MCI, and that these mechanisms may explain neuroimaging alterations outside of the medial temporal lobes.

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.

Diminished neural network dynamics in amnestic mild cognitive impairment.

Mild cognitive impairment (MCI) is widely regarded as an intermediate stage between typical aging and dementia, with nearly 50% of patients with amnestic MCI (aMCI) converting to Alzheimer's dementia (AD) within 30 months of follow-up (Fischer et al., 2007). The growing literature using resting-state functional magnetic resonance imaging reveals both increased and decreased connectivity in individuals with MCI and connectivity loss between the anterior and posterior components of the default mode network (DMN) throughout the course of the disease progression (Hillary et al., 2015; Sheline & Raichle, 2013; Tijms et al., 2013). In this paper, we use dynamic connectivity modeling and graph theory to identify unique brain "states," or temporal patterns of connectivity across distributed networks, to distinguish individuals with aMCI from healthy older adults (HOAs). We enrolled 44 individuals diagnosed with aMCI and 33 HOAs of comparable age and education. Our results indicated that individuals with aMCI spent significantly more time in one state in particular, whereas neural network analysis in the HOA sample revealed approximately equivalent representation across four distinct states. Among individuals with aMCI, spending a higher proportion of time in the dominant state relative to a state where participants exhibited high cost (a measure combining connectivity and distance), predicted better language performance and less perseveration. This is the first report to examine neural network dynamics in individuals with aMCI.

Neural basis of the crossmodal correspondence between auditory pitch and visuospatial elevation.

Crossmodal correspondences refer to associations between otherwise unrelated stimulus features in different sensory modalities. For example, high and low auditory pitches are associated with high and low visuospatial elevation, respectively. The neural mechanisms underlying crossmodal correspondences are currently unknown. Here, we used functional magnetic resonance imaging (fMRI) to investigate the neural basis of the pitch-elevation correspondence. Pitch-elevation congruency effects were observed bilaterally in the inferior frontal and insular cortex, the right frontal eye field and right inferior parietal cortex. Independent functional localizers failed to provide strong evidence for any of three proposed mechanisms for crossmodal correspondences: semantic mediation, magnitude estimation, and multisensory integration. Instead, pitch-elevation congruency effects overlapped with areas selective for visually presented non-word strings relative to sentences, and with regions sensitive to audiovisual asynchrony. Taken together with the prior literature, the observed congruency effects are most consistent with mediation by multisensory attention.

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.