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Prior studies have shown that the left posterior superior temporal sulcus (pSTS) and left temporo-parietal junction (TPJ) both contribute to phonological short-term memory, speech perception and speech production. Here, by conducting a within-subjects multi-factorial fMRI study, we dissociate the response profiles of these regions and a third region - the anterior ascending terminal branch of the left superior temporal sulcus (atSTS), which lies dorsal to pSTS and ventral to TPJ. First, we show that each region was more activated by (i) 1-back matching on visually presented verbal stimuli (words or pseudowords) compared to 1-back matching on visually presented non-verbal stimuli (pictures of objects or non-objects), and (ii) overt speech production than 1-back matching, across 8 types of stimuli (visually presented words, pseudowords, objects and non-objects and aurally presented words, pseudowords, object sounds and meaningless hums). The response properties of the three regions dissociated within the auditory modality. In left TPJ, activation was higher for auditory stimuli that were non-verbal (sounds of objects or meaningless hums) compared to verbal (words and pseudowords), irrespective of task (speech production or 1-back matching). In left pSTS, activation was higher for non-semantic stimuli (pseudowords and hums) than semantic stimuli (words and object sounds) on the dorsal pSTS surface (dpSTS), irrespective of task. In left atSTS, activation was not sensitive to either semantic or verbal content. The contrasting response properties of left TPJ, dpSTS and atSTS was cross-validated in an independent sample of 59 participants, using region-by-condition interactions. We also show that each region participates in non-overlapping networks of frontal, parietal and cerebellar regions. Our results challenge previous claims about functional specialisation in the left posterior superior temporal lobe and motivate future studies to determine the timing and directionality of information flow in the brain networks involved in speech perception and production., (Copyright © 2021. Published by Elsevier Inc.)

Past attempts to identify the neural substrates of hand and finger imitation skills in the left hemisphere of the brain have yielded inconsistent results. Here, we analyse those associations in a large sample of 257 left hemisphere stroke patients. By introducing novel Bayesian methods, we characterise lesion symptom associations at three levels: the voxel-level, the single-region level (using anatomically defined regions), and the region-pair level. The results are inconsistent across those three levels and we argue that each level of analysis makes assumptions which constrain the results it can produce. Regardless of the inconsistencies across levels, and contrary to past studies which implicated differential neural substrates for hand and finger imitation, we find no consistent voxels or regions, where damage affects one imitation skill and not the other, at any of the three analysis levels. Our novel Bayesian approach indicates that any apparent differences appear to be driven by an increased sensitivity of hand imitation skills to lesions that also impair finger imitation. In our analyses, the results of the highest level of analysis (region-pairs) emphasise a role of the primary somatosensory and motor cortices, and the occipital lobe in imitation. We argue that this emphasis supports an account of both imitation tasks based on direct sensor-motor connections, which throws doubt on past accounts which imply the need for an intermediate (e.g. body-part-coding) system of representation., (Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.)

Stroke survivors with acquired language deficits are commonly thought to reach a 'plateau' within a year of stroke onset, after which their residual language skills will remain stable. Nevertheless, there have been reports of patients who appear to recover over years. Here, we analysed longitudinal change in 28 left-hemisphere stroke patients, each more than a year post-stroke when first assessed-testing each patient's spoken object naming skills and acquiring structural brain scans twice. Some of the patients appeared to improve over time while others declined; both directions of change were associated with, and predictable given, structural adaptation in the intact right hemisphere of the brain. Contrary to the prevailing view that these patients' language skills are stable, these results imply that real change continues over years. The strongest brain-behaviour associations (the 'peak clusters') were in the anterior temporal lobe and the precentral gyrus. Using functional magnetic resonance imaging, we confirmed that both regions are actively involved when neurologically normal control subjects name visually presented objects, but neither appeared to be involved when the same participants used a finger press to make semantic association decisions on the same stimuli. This suggests that these regions serve word-retrieval or articulatory functions in the undamaged brain. We teased these interpretations apart by reference to change in other tasks. Consistent with the claim that the real change is occurring here, change in spoken object naming was correlated with change in two other similar tasks, spoken action naming and written object naming, each of which was independently associated with structural adaptation in similar (overlapping) right hemisphere regions. Change in written object naming, which requires word-retrieval but not articulation, was also significantly more correlated with both (i) change in spoken object naming; and (ii) structural adaptation in the two peak clusters, than was change in another task-auditory word repetition-which requires articulation but not word retrieval. This suggests that the changes in spoken object naming reflected variation at the level of word-retrieval processes. Surprisingly, given their qualitatively similar activation profiles, hypertrophy in the anterior temporal region was associated with improving behaviour, while hypertrophy in the precentral gyrus was associated with declining behaviour. We predict that either or both of these regions might be fruitful targets for neural stimulation studies (suppressing the precentral region and/or enhancing the anterior temporal region), aiming to encourage recovery or arrest decline even years after stroke occurs., (© The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Motor speech disorders, including apraxia of speech (AOS), account for over 50% of the communication disorders following stroke. Given its prevalence and impact, and the need to understand its neural mechanisms, we used resting state functional MRI to examine functional connectivity within a network of regions previously hypothesized as being associated with AOS (bilateral anterior insula (aINS), inferior frontal gyrus (IFG), and ventral premotor cortex (PM)) in a group of 32 left hemisphere stroke patients and 18 healthy, age-matched controls. Two expert clinicians rated severity of AOS, dysarthria and nonverbal oral apraxia of the patients. Fifteen individuals were categorized as AOS and 17 were AOS-absent. Comparison of connectivity in patients with and without AOS demonstrated that AOS patients had reduced connectivity between bilateral PM, and this reduction correlated with the severity of AOS impairment. In addition, AOS patients had negative connectivity between the left PM and right aINS and this effect decreased with increasing severity of non-verbal oral apraxia. These results highlight left PM involvement in AOS, begin to differentiate its neural mechanisms from those of other motor impairments following stroke, and help inform us of the neural mechanisms driving differences in speech motor planning and programming impairment following stroke.

Functional neuroimaging and lesion studies have frequently reported thalamic and putamen activation during reading and speech production. However, it is currently unknown how activity in these structures interacts with that in other reading and speech production areas. This study investigates how reading aloud modulates the neuronal interactions between visual recognition and articulatory areas, when both the putamen and thalamus are explicitly included. Using dynamic causal modeling in skilled readers who were reading regularly spelled English words, we compared 27 possible pathways that might connect the ventral anterior occipito-temporal sulcus (aOT) to articulatory areas in the precentral cortex (PrC). We focused on whether the neuronal interactions within these pathways were increased by reading relative to picture naming and other visual and articulatory control conditions. The results provide strong evidence that reading boosts the aOT-PrC pathway via the putamen but not the thalamus. However, the putamen pathway was not exclusive because there was also evidence for another reading pathway that did not involve either the putamen or the thalamus. We conclude that the putamen plays a special role in reading but this is likely to vary with individual reading preferences and strategies.

An important and unresolved question is how the human brain processes speech for meaning after initial analyses in early auditory cortical regions. A variety of left-hemispheric areas have been identified that clearly support semantic processing, although a systematic analysis of directed interactions among these areas is lacking. We applied dynamic causal modeling of functional magnetic resonance imaging responses and Bayesian model selection to investigate, for the first time, experimentally induced changes in coupling among three key multimodal regions that were activated by intelligible speech: the posterior and anterior superior temporal sulcus (pSTS and aSTS, respectively) and pars orbitalis (POrb) of the inferior frontal gyrus. We tested 216 different dynamic causal models and found that the best model was a "forward" system that was driven by auditory inputs into the pSTS, with forward connections from the pSTS to both the aSTS and the POrb that increased considerably in strength (by 76 and 150%, respectively) when subjects listened to intelligible speech. Task-related, directional effects can now be incorporated into models of speech comprehension.

This paper investigates how neuronal activation for naming photographs of objects is influenced by the addition of appropriate colour or sound. Behaviourally, both colour and sound are known to facilitate object recognition from visual form. However, previous functional imaging studies have shown inconsistent effects. For example, the addition of appropriate colour has been shown to reduce antero-medial temporal activation whereas the addition of sound has been shown to increase posterior superior temporal activation. Here we compared the effect of adding colour or sound cues in the same experiment. We found that the addition of either the appropriate colour or sound increased activation for naming photographs of objects in bilateral occipital regions and the right anterior fusiform. Moreover, the addition of colour reduced left antero-medial temporal activation but this effect was not observed for the addition of object sound. We propose that activation in bilateral occipital and right fusiform areas precedes the integration of visual form with either its colour or associated sound. In contrast, left antero-medial temporal activation is reduced because object recognition is facilitated after colour and form have been integrated.

Previous behavioral and electrophysiological studies have shown dissociation between consonants and vowels. We used functional magnetic resonance imaging to investigate whether vowel and consonant processing differences are expressed in the neuronal activation pattern and whether they are modulated by task. The experimental design involved reading aloud and lexical decision on visually presented pseudowords created by transposing or replacing consonants or vowels in words. During reading aloud, changing vowels relative to consonants increased activation in a right middle temporal area previously associated with prosodic processing of speech input. In contrast, during lexical decision, changing consonants relative to vowels increased activation in a right middle frontal area associated with inhibiting go-responses. The task-sensitive nature of these effects demonstrates that consonants and vowels differ at a processing, rather than stimulus, level. We argue that prosodic processing of vowel changes arise during self-monitoring of speech output, whereas greater inhibition of go-responses to consonant changes follows insufficient lexico-semantic processing when nonwords looking particularly like words must be rejected. Our results are consistent with claims that vowels and consonants place differential demands on prosodic and lexico-semantic processing, respectively. They also highlight the different types of information that can be drawn from functional imaging and neuropsychological studies.

Human adults can assess the number of objects in a set (numerosity) by approximate estimation or by exact counting. There is evidence suggesting that numerosity estimation depends on a dedicated mechanism that is a-modal and non-verbal. By contrast, counting requires the coordination between the pre-existing numerosity estimation abilities with language and one-to-one correspondence principles. In this paper we investigate with fMRI the neural correlates of numerosity estimation and counting in human adults, using both visual and auditory stimuli. Results show that attending to approximate numerosity correlates with increased activity of a right lateralized fronto-parietal cortical network, and that this activity is independent of the stimuli presentation's modality. Counting activates additional left prefrontal, parietal, and bilateral premotor areas, again independently from stimulus modality. These results dissociate two neuronal systems that underlie different numerosity judgements.

In this functional magnetic resonance imaging study, we investigated human brain mechanisms that are involved in the analysis of voices as sound sources and in the pre-semantic analysis of voice information. The source of the voice was altered by changing the speaker, and the salience of the voice was altered by changing the amount of spectrotemporal detail. We identified a mechanism for detecting a change in the source of the voice in the posterior superior temporal lobe and anatomically distinct mechanisms for the detailed analysis of voice information in a bilateral network extending from the posterior to the anterior superior temporal lobe surrounding the superior temporal sulcus. The findings are consistent with a processing hierarchy in which general source attributes are analyzed in the posterior superior temporal lobe, abstraction of voice identity features occurs in posterior superior temporal sulcus, and further analysis of voice information occurs in anterior superior temporal sulcus and higher order cortices in the middle and anterior temporal lobe.

We used functional Magnetic Resonance Imaging to explore the neural correlates of semantic relevance in 12 healthy participants performing a picture-naming task. In addition, we tested the hypothesis that category effects typically found in functional imaging can be partly explained in terms of different semantic relevance for animals and artefacts. We report that semantic relevance modulates neuronal responses in the medial fusiform gyrus bilaterally. As predicted, category effects in this region are strongly modulated by the semantic relevance of the items. Specifically, the effect of artefacts > animals is greatly reduced when the two categories are matched for semantic relevance. Thus, the present study demonstrates that neuronal responses during concept retrieval are modulated by the semantic relevance of the features. It also suggests that increased activation in the medial fusiform gyrus typically found for artefacts > animals can be explained by different semantic relevance for animal and artefact items.

The cognitive and neural mechanisms mediating category-selective responses in the human brain remain controversial. Using functional magnetic resonance imaging and effective connectivity analyses (Dynamic Causal Modelling), we investigated animal- and tool-selective responses by manipulating stimulus modality (pictures versus words) and task (implicit versus explicit semantic). We dissociated two distinct mechanisms that engender category selectivity: in the ventral occipito-temporal cortex, tool-selective responses were observed irrespective of task, greater for pictures and mediated by bottom-up effects. In a left temporo-parietal action system, tool-selective responses were observed irrespective of modality, greater for explicit semantic tasks and mediated by top-down modulation from the left prefrontal cortex. These distinct activation and connectivity patterns suggest that the two systems support different cognitive operations, with the ventral occipito-temporal regions engaged in structural processing and the dorsal visuo-motor system in strategic semantic processing. Consistent with current semantic theories, explicit semantic processing of tools might thus rely on reactivating their associated action representations via top-down modulation. In terms of neuronal mechanisms, the category selectivity may be mediated by distinct top-down (task-dependent) and bottom-up (stimulus-dependent) mechanisms.

The morphology of the human cortex varies remarkably across individuals, regardless of overall brain size. It is currently unclear whether related cortical regions covary in gray matter density, as a result of mutually trophic influences or common experience-related plasticity. We acquired a structural magnetic resonance imaging scan from 172 subjects and extracted the regional gray matter densities from 12 readily identifiable regions of interest involved in sensorimotor or higher-order cognitive functions. We then used these values to predict regional densities in the remaining areas of the cortex, using voxel-based morphometry. This revealed patterns of positive and negative covariance that provide insight into the topographical organization of multiple cortical regions. We report that the gray matter density of a region is a good predictor of the density of the homotopic region in the contralateral hemisphere, with the striking exception of primary visual cortex. Whereas some regions express patterns of regional covariance that are mirror symmetrical relative to the interhemispheric fissure, other regions express asymmetric patterns of regional covariance. Finally, patterns of covariance are remarkably consistent between males and females, with the exception of the left amygdala, which is positively associated with the left and right anterior inferior temporal cortex in males and with the right angular gyrus in females. Our study establishes that the density of different cortical regions is coordinated within an individual. The coordinated variations we report are likely to be determined by both genetic and environmental factors and may be the basis for differences in individual behavior.

In this study we demonstrate that, even in blocked design fMRI, an event-related analysis may provide a more accurate model of the hemodynamic responses than an epoch-related analysis. This is because the temporal shape of the predicted response differs between the event-related and the epoch model, with the former reaching its peak sooner and returning to baseline later than the latter. We present data from a blocked design fMRI study of single word reading alternated with rest. Conventionally, such a design would be analyzed using an epoch analysis with boxcar regressors. However, here we used a combined model in which trials were modeled as both single events and epochs. This allowed us to estimate the variance in the BOLD signal that was explained by either the event-related or the epoch regressors having discounted the effect of the other. We found that, in a number of language regions, the event-related model explained changes in activity that were not accounted for by the epoch model. In addition, we show that the advantage of the event-related over epoch model was engendered by its early onset rather than its late offset, relative to the epoch model.

This technical note deals with a priori estimation of efficiency of functional magnetic resonance imaging (fMRI) designs. The efficiency of an estimator is a measure of how reliable it is and depends on error variance (the variance not modeled by explanatory variables in the design matrix) and the design variance (a function of the explanatory variables and the contrast tested). Changes in the experimental design can induce changes in the variance of estimated responses. This translates into changes in the standard error of the response estimate or equivalently into changes in efficiency. One consequence is that statistics, testing for the same activation in different contexts (i.e., experimental designs), can change substantially even if the activation and error variance are exactly the same. We demonstrate this effect using an event-related fMRI study of single word reading during blocked and randomized trial presentations. Furthermore, we show that the error variance can change with the experimental design. This highlights a problem with a priori comparison of efficiency for two or more experimental designs, which usually assumes identical error variance.

Several functional neuroimaging studies have compared words and pseudowords to test different cognitive models of reading. There are difficulties with this approach, however, because cognitive models do not make clear-cut predictions at the neural level. Therefore, results can only be interpreted on the basis of prior knowledge of cognitive anatomy. Furthermore, studies comparing words and pseudowords have produced inconsistent results. The inconsistencies could reflect false-positive results due to the low statistical thresholds applied or confounds from nonlexical aspects of the stimuli. Alternatively, they may reflect true effects that are inconsistent across subjects; dependent on experimental parameters such as stimulus rate or duration; or not replicated across studies because of insufficient statistical power. In this fMRI study, we investigate consistent and inconsistent differences between word and pseudoword reading in 20 subjects, and distinguish between effects associated with increases and decreases in activity relative to fixation. In addition, the interaction of word type with stimulus duration is explored. We find that words and pseudowords activate the same set of regions relative to fixation, and within this system, there is greater activation for pseudowords than words in the left frontal operculum, left posterior inferior temporal gyrus, and the right cerebellum. The only effects of words relative to pseudowords consistent over subjects are due to decreases in activity for pseudowords relative to fixation; and there are no significant interactions between word type and stimulus duration. Finally, we observe inconsistent but highly significant effects of word type at the individual subject level. These results (i) illustrate that pseudowords place increased demands on areas that have previously been linked to lexical retrieval, and (ii) highlight the importance of including one or more baselines to qualify word type effects. Furthermore, (iii) they suggest that inconsistencies observed in the previous literature may result from effects arising from a small number of subjects only.

In this study we demonstrate the importance of distributed sampling of peristimulus time in blocked design fMRI studies. Distributed sampling ensures all the components of an event-related hemodynamic response are sampled and avoids the bias incurred when stimulus presentation is time-locked to data acquisition. We found that differences in the temporal offset between stimulus presentation and data acquisition had a significant effect on some language-related activations. These effects, induced by simply shifting stimulus presentation by a fraction of the interscan interval, suggest that fixed sampling does indeed bias estimated responses, even in blocked designs.

This article is about intersubject variability in the functional integration of activity in different brain regions. Previous studies of functional and effective connectivity have dealt with intersubject variability by analyzing data from different subjects separately or pretending the data came from the same subject. These approaches do not allow one to test for differences among subjects. The aim of this work was to illustrate how differences in connectivity among subjects can be addressed explicitly using structural equation modeling. This is enabled by constructing a multisubject network that comprises m regions of interest for each of the n subjects studied, resulting in a total of m x n nodes. Constructing a network of regions from different subjects may seem counterintuitive but embodies two key advantages. First, it allows one to test directly for differences among subjects by comparing models that do and do not allow a particular connectivity parameter to vary over subjects. Second, a multisubject network provides additional degrees of freedom to estimate the model's free parameters. Any neurobiological hypothesis normally addressed by single-subject or group analyses can still be tested, but with greater sensitivity. The common influence of experimental variables is modeled by connecting a virtual node, whose time course reflects stimulus onsets, to the sensory or "input" region in all subjects. Further experimental changes in task or cognitive set enter through modulation of the connections. This approach allows one to model both endogenous (or intrinsic) variance and exogenous effects induced by experimental design. We present a functional magnetic resonance imaging study that uses a multisubject network to investigate intersubject variability in functional integration in the context of single word and pseudoword reading. We tested whether the effect of word type on the reading-related coupling differed significantly among subjects. Our results showed that a number of forward and backward connections were stronger for reading pseudowords than words, and, in one case, connectivity showed significant intersubject variability. The discussion focuses on the implications of our findings and on further applications of the multisubject network analysis.

Conceptual knowledge is thought to be represented in a large distributed network, indexing a range of different semantic features (e.g., visual, auditory, functional). We investigated the anatomical organization of these features, using PET, by contrasting brain activity elicited by heard words with (i) visual (e.g., blue), (ii) auditory (e.g., noise), or (iii) abstract (e.g., truth) meaning. The activation task was either repetition or semantic decision (e.g., does the meaning of the word relate to religion?). In the baseline conditions, the sound track of the words was reversed and subjects had to say "OK" (control for repetition) or make an acoustic decision (control for semantic decision). Irrespective of task, words relative to their corresponding controls activated the left posterior inferior temporal and inferior frontal cortices. In addition, semantic decisions on words with sensory (visual and auditory) meanings enhanced activation in a ventral region of the left anterior temporal pole. These results are consistent with neuropsychological studies showing that anterior temporal lobe damage can cause deficits for items that are mainly defined by their sensory features (i.e., concrete, particularly living items). Since modality-specific activation was observed only during the semantic decision task, we discuss whether it reflects retrieval of sensory semantics per se or the degree to which semantic associations are triggered during effortful retrieval., ((C)2002 Elsevier Science (USA).)

To investigate the neural correlates of semantic processing, previous functional imaging studies have used semantic decision and generation tasks. However, in addition to activating semantic associations these tasks also involve executive functions that are not specific to semantics. The study reported in this paper aims to dissociate brain activity due to stimulus-driven semantic associations and task-induced semantic and executive processing by using repetition and semantic decision on auditorily presented words in a cognitive conjunction design. The left posterior inferior temporal, inferior frontal (BA 44/45), and medial orbital gyri were activated by both tasks, suggesting a general role in stimulus-driven semantic and phonological processing. In addition, semantic decision increased activation in (i) left ventral inferior frontal cortex (BA 47), right cerebellum, and paracingulate, which have all previously been implicated in executive functions, and (ii) a ventral region in the left anterior temporal pole which is commonly affected in patients with semantic impairments. We attribute activation in this area to the effortful linkage of semantic features. Thus, our study replicated the functional dissociation between dorsal and ventral regions of the left inferior frontal cortex. Moreover, it also dissociated the semantic functions of the left posterior inferior temporal gyrus and anterior temporal pole: The posterior region subserves stimulus-driven activation of semantic associations and the left anterior region is involved in task-induced association of semantic information., ((C)2002 Elsevier Science (USA).)

Many cognitive theories of semantic organization stem from reports of patients with selective, category-specific deficits for particular classes of objects (e.g., fruit). The anatomical assumptions underlying the competing claims can be evaluated with functional neuroimaging but the findings to date have been inconsistent and insignificant when standard statistical criteria are adopted. We hypothesized that category differences in functional brain responses might be small and task dependent. To test this hypothesis, we entered data from seven PET studies into a single multifactorial design which crossed category (living vs man-made) with a range of tasks. Reliable category-specific effects were observed but only for word retrieval and semantic decision tasks. Living things activated medial aspects of the anterior temporal poles bilaterally while tools activated a left posterior middle temporal region. These category-by-task interactions provide robust evidence for an anatomical double dissociation according to category and place strong constraints on cognitive theories of the semantic system. Furthermore they reconcile some of the apparent inconsistencies between lesion studies and functional neuroimaging data., (©2002 Elsevier Science (USA).)

This paper will consider the consistencies and disparities between the classic 19(th) Century model of language and the results of functional neuro-imaging studies on auditory and visual word repetition. The functional imaging studies show that, as predicted by the 19(th) Century neurologists, auditory and visual word repetition engage perisylvian regions in the left posterior superior temporal and posterior inferior frontal cortices. More specifically, the roles that Wernicke and Broca assigned to these regions lie respectively in the upper banks of the left posterior superior temporal sulcus and the left anterior insula/frontal operculum. In addition, a region in the left posterior inferior temporal cortex is activated for word retrieval and provides a second route to reading, emphasised by 20(th) Century cognitive models of language. There is no firm evidence as yet to link the function of a visual word form area to a specific neural substrate. The angular gyrus, previously linked to the visual word form system, is shown to be part of a distributed semantic system that can be accessed by objects and faces as well as speech. Overall, functional neuroimaging demonstrates that the 19(th) Century neurological model of language is remarkably insightful.

The main point made in this article is that the representational capacity and inherent function of any neuron, neuronal population or cortical area is dynamic and context-sensitive. This adaptive and contextual specialisation is mediated by functional integration or interactions among brain systems with a special emphasis on backwards or top-down connections. The critical notion is that neuronal responses, in any given cortical area, can represent different things at different times. Our argument is developed under the perspective of generative models of functional brain architectures, where higher-level systems provide a prediction of the inputs to lower-level regions. Conflict between the two is resolved by changes in the higher-level representations, driven by the resulting error in lower regions, until the mismatch is 'cancelled'. In this model the specialisation of any region is determined both by bottom-up driving inputs and by top-down predictions. Specialisation is therefore not an intrinsic property of any region but depends on both forward and backward connections with other areas. Because these other areas have access to the context in which the inputs are generated they are in a position to modulate the selectivity or specialisation of lower areas. The implications for 'classical' models (e.g., classical receptive fields in electrophysiology, classical specialisation in neuroimaging and connectionism in cognitive models) are severe and suggest these models provide incomplete accounts of real brain architectures. Generative models represent a far more plausible framework for understanding selective neurophysiological responses and how representations are constructed in the brain.

The effect of stimulus rate and its interaction with stimulus type on brain activity during reading was investigated using functional magnetic resonance imaging (fMRI). This (i) enabled the segregation of brain regions showing differential responses, (ii) identified the optimum experimental design parameters for maximizing sensitivity, and (iii) allowed us to evaluate further the sources of discrepancy between positron emission tomography (PET) and fMRI signals. The effect of visual word rate has already been investigated in a previous PET study. However, rate effects can be very different in PET and fMRI, as seen in previous studies of auditory word processing. In this work, we attempt to replicate rate-sensitive activations observed with PET using fMRI. Our objective was to characterize the discrepancies in regionally specific rate-sensitive effects between the two imaging modalities. Subjects were presented with words and pseudowords at varying rates while performing a silent reading task. The analysis specifically identified regions showing (i) an effect of stimulus rate on brain activity during reading; (ii) modulation of this effect by word type; and (iii) increased activity during reading relative to rest, but with no dependence on stimulus rate. The results identified similar effects of rate for words and pseudowords (no interactions between rate and word type reached significance). Irrespective of word type, strong positive linear effects of rate (i.e., activity increasing with rate) were detected in visual areas, right superior temporal gyrus, and bilateral precentral gyrus. These findings replicate the results of the previous PET study, confirming that activation in regions associated with visual processing and response generation increases with the number of stimuli. Likewise, we detected rate-independent effects reported in the previous PET study in bilateral anterior middle temporal, inferior frontal, and superior parietal regions. These results differentiate the functionally specific responses in rate-dependent and rate-independent areas. However, for negative effects of rate, fMRI did not replicate the effects seen in PET, suggesting some form of hemodynamic "rectification." The discussion focuses on differences between evoked rCBF and BOLD signals.

In this paper we present a critique of pure insertion. Pure insertion represents an implicit assumption behind many (but not all) studies that employ cognitive subtraction. The main contention is that pure insertion is not valid in relation to the neuronal instantiation of cognitive processes. Pure insertion asserts that there are no interactions among the cognitive components of a task. It is possible to evaluate and refute this assumption by testing explicitly for interactions using factorial experimental designs. It is proposed that factorial designs are more powerful than subtraction designs in characterizing cognitive neuroanatomy, precisely because they allow for interactions and eschew notions like pure insertion. In particular we suggest that the effect of a cognitive component (i.e., an effect that is independent of other components) is best captured by the main (activation) effect of that component and that the integration among components (i.e., the expression of one cognitive process in the context of another) can be assessed with the interaction terms. In this framework a complete characterization of cognitive neuroanatomy includes both regionally specific activations and regionally specific interactions. To illustrate our point we have used a factorial experimental design to show that inferotemporal activations, due to object recognition, are profoundly modulated by phonological retrieval of the object's name. This interaction implicates the inferotemporal regions in phonological retrieval, during object naming, despite the fact that phonological retrieval does not, by itself, activate this region.