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The social significance of recognizing the person who talks to us is obvious, but the neural mechanisms that mediate talker identification are unclear. Regions along the bilateral superior temporal sulcus (STS) and the inferior frontal cortex (IFC) of the human brain are selective for voices, and they are sensitive to rapid voice changes. Although it has been proposed that voice recognition is supported by prototype-centered voice representations, the involvement of these category-selective cortical regions in the neural coding of such "mean voices" has not previously been demonstrated. Using fMRI in combination with a voice identity learning paradigm, we show that voice-selective regions are involved in the mean-based coding of voice identities. Voice typicality is encoded on a supra-individual level in the right STS along a stimulus-dependent, identity-independent (i.e., voice-acoustic) dimension, and on an intra-individual level in the right IFC along a stimulus-independent, identity-dependent (i.e., voice identity) dimension. Voice recognition therefore entails at least two anatomically separable stages, each characterized by neural mechanisms that reference the central tendencies of voice categories., (Copyright © 2013 Elsevier Inc. All rights reserved.)

In a recent fMRI study we showed that left posterior middle temporal gyrus (LpMTG) subserves the retrieval of a word's lexical-syntactic properties from the mental lexicon (long-term memory), while left posterior inferior frontal gyrus (LpIFG) is involved in unifying (on-line integration of) this information into a sentence structure (Snijders et al., 2009). In addition, the right IFG, right MTG, and the right striatum were involved in the unification process. Here we report results from a psychophysical interactions (PPI) analysis in which we investigated the effective connectivity between LpIFG and LpMTG during unification, and how the right hemisphere areas and the striatum are functionally connected to the unification network. LpIFG and LpMTG both showed enhanced connectivity during the unification process with a region slightly superior to our previously reported LpMTG. Right IFG better predicted right temporal activity when unification processes were more strongly engaged, just as LpIFG better predicted left temporal activity. Furthermore, the striatum showed enhanced coupling to LpIFG and LpMTG during unification. We conclude that bilateral inferior frontal and posterior temporal regions are functionally connected during sentence-level unification. Cortico-subcortical connectivity patterns suggest cooperation between inferior frontal and striatal regions in performing unification operations on lexical-syntactic representations retrieved from LpMTG., (Copyright 2010 Elsevier Inc. All rights reserved.)

We investigated neural mechanisms that support voice recognition in a training paradigm with fMRI. The same listeners were trained on different weeks to categorize the mid-regions of voice-morph continua as an individual's voice. Stimuli implicitly defined a voice-acoustics space, and training explicitly defined a voice-identity space. The pre-defined centre of the voice category was shifted from the acoustic centre each week in opposite directions, so the same stimuli had different training histories on different tests. Cortical sensitivity to voice similarity appeared over different time-scales and at different representational stages. First, there were short-term adaptation effects: increasing acoustic similarity to the directly preceding stimulus led to haemodynamic response reduction in the middle/posterior STS and in right ventrolateral prefrontal regions. Second, there were longer-term effects: response reduction was found in the orbital/insular cortex for stimuli that were most versus least similar to the acoustic mean of all preceding stimuli, and, in the anterior temporal pole, the deep posterior STS and the amygdala, for stimuli that were most versus least similar to the trained voice-identity category mean. These findings are interpreted as effects of neural sharpening of long-term stored typical acoustic and category-internal values. The analyses also reveal anatomically separable voice representations: one in a voice-acoustics space and one in a voice-identity space. Voice-identity representations flexibly followed the trained identity shift, and listeners with a greater identity effect were more accurate at recognizing familiar voices. Voice recognition is thus supported by neural voice spaces that are organized around flexible 'mean voice' representations., (Copyright 2010 Elsevier Inc. All rights reserved.)

A fundamental and intensively discussed question is whether medial temporal lobe (MTL) processes that lead to non-associative item memories differ in their anatomical substrate from processes underlying associative memory formation. Using event-related functional magnetic resonance imaging, we implemented a novel design to dissociate brain activity related to item and associative memory formation not only by subsequent memory performance and anatomy but also in time, because the two constituents of each pair to be memorized were presented sequentially with an intra-pair delay of several seconds. Furthermore, the design enabled us to reduce potential differences in memory strength between item and associative memory by increasing task difficulty in the item recognition memory test. Confidence ratings for correct item recognition for both constituents did not differ between trials in which only item memory was correct and trials in which item and associative memory were correct. Specific subsequent memory analyses for item and associative memory formation revealed brain activity that appears selectively related to item memory formation in the posterior inferior temporal, posterior parahippocampal, and perirhinal cortices. In contrast, hippocampal and inferior prefrontal activity predicted successful retrieval of newly formed inter-item associations. Our findings therefore suggest that different MTL subregions indeed play distinct roles in the formation of item memory and inter-item associative memory as expected by several dual process models of the MTL memory system.

PET and fMRI experiments have previously shown that several brain regions in the frontal and parietal lobe are involved in working memory maintenance. MEG and EEG experiments have shown parametric increases with load for oscillatory activity in posterior alpha and frontal theta power. In the current study we investigated whether the areas found with fMRI can be associated with these alpha and theta effects by measuring simultaneous EEG and fMRI during a modified Sternberg task This allowed us to correlate EEG at the single trial level with the fMRI BOLD signal by forming a regressor based on single trial alpha and theta power estimates. We observed a right posterior, parametric alpha power increase, which was functionally related to decreases in BOLD in the primary visual cortex and in the posterior part of the right middle temporal gyrus. We relate this finding to the inhibition of neuronal activity that may interfere with WM maintenance. An observed parametric increase in frontal theta power was correlated to a decrease in BOLD in regions that together form the default mode network. We did not observe correlations between oscillatory EEG phenomena and BOLD in the traditional WM areas. In conclusion, the study shows that simultaneous EEG-fMRI recordings can be successfully used to identify the emergence of functional networks in the brain during the execution of a cognitive task.

Using event-related functional magnetic resonance imaging, we identified brain regions involved in storing associations of events discontinuous in time into long-term memory. Participants were scanned while memorizing item-triplets including simultaneous and discontinuous associations. Subsequent memory tests showed that participants remembered both types of associations equally well. First, by constructing the contrast between the subsequent memory effects for discontinuous associations and simultaneous associations, we identified the left posterior parahippocampal region, dorsolateral prefrontal cortex, the basal ganglia, posterior midline structures, and the middle temporal gyrus as being specifically involved in transforming discontinuous associations into episodic memory. Second, we replicated that the prefrontal cortex and the medial temporal lobe (MTL) especially the hippocampus are involved in associative memory formation in general. Our findings provide evidence for distinct neural operation(s) that supports the binding and storing discontinuous associations in memory. We suggest that top-down signals from the prefrontal cortex and MTL may trigger reactivation of internal representation in posterior midline structures of the first event, thus allowing it to be associated with the second event. The dorsolateral prefrontal cortex together with basal ganglia may support this encoding operation by executive and binding processes within working memory, and the posterior parahippocampal region may play a role in binding and memory formation.

In an event-related fMRI study, we examined the cortical networks involved in establishing reference during language comprehension. We compared BOLD responses to sentences containing referentially ambiguous pronouns (e.g., "Ronald told Frank that he..."), referentially failing pronouns (e.g., "Rose told Emily that he...") or coherent pronouns. Referential ambiguity selectively recruited medial prefrontal regions, suggesting that readers engaged in problem-solving to select a unique referent from the discourse model. Referential failure elicited activation increases in brain regions associated with morpho-syntactic processing, and, for those readers who took failing pronouns to refer to unmentioned entities, additional regions associated with elaborative inferencing were observed. The networks activated by these two referential problems did not overlap with the network activated by a standard semantic anomaly. Instead, we observed a double dissociation, in that the systems activated by semantic anomaly are deactivated by referential ambiguity, and vice versa. This inverse coupling may reflect the dynamic recruitment of semantic and episodic processing to resolve semantically or referentially problematic situations. More generally, our findings suggest that neurocognitive accounts of language comprehension need to address not just how we parse a sentence and combine individual word meanings, but also how we determine who's who and what's what during language comprehension.

The irrelevant speech effect illustrates that sounds that are irrelevant to a visually presented short-term memory task still interfere with neuronal function. In the present study we explore the functional and effective connectivity of such interference. The functional connectivity analysis suggested an interaction between the level of irrelevant speech and the correlation between in particular the left superior temporal region, associated with verbal working memory, and the left medial temporal lobe. Based on this psycho-physiological interaction, and to broaden the understanding of this result, we performed a network analysis, using a simple network model for verbal working memory, to analyze its interaction with the medial temporal lobe memory system. The results showed dissociations in terms of network interactions between frontal as well as parietal and temporal areas in relation to the medial temporal lobe. The results of the present study suggest that a transition from phonological loop processing towards an engagement of episodic processing might take place during the processing of interfering irrelevant sounds. We speculate that, in response to the irrelevant sounds, this reflects a dynamic shift in processing as suggested by a closer interaction between a verbal working memory system and the medial temporal lobe memory system.

Doubts have been cast on the strict dissociation between short- and long-term memory systems. Specifically, several neuroimaging studies have shown that the medial temporal lobe, a region almost invariably associated with long-term memory, is involved in active short-term memory maintenance. Furthermore, a recent study in hippocampally lesioned patients has shown that the hippocampus is critically involved in associating objects and their locations, even when the delay period lasts only 8 s. However, the critical feature that causes the medial temporal lobe, and in particular the hippocampus, to participate in active maintenance is still unknown. This study was designed in order to explore hippocampal involvement in active maintenance of spatial and non-spatial associations. Eighteen participants performed a delayed-match-to-sample task in which they had to maintain either object-location associations, color-number association, single colors, or single locations. Whole-brain activity was measured using event-related functional magnetic resonance imaging and analyzed using a random effects model. Right lateralized hippocampal activity was evident when participants had to maintain object-location associations, but not when they had to maintain object-color associations or single items. The present results suggest a hippocampal involvement in active maintenance when feature combinations that include spatial information have to be maintained online.

Knowing what is going to happen next, that is, the capacity to predict upcoming events, modulates the extent to which aversive stimuli induce stress and anxiety. We explored this issue by manipulating the temporal predictability of aversive events by means of a visual cue, which was either correlated or uncorrelated with pain stimuli (electric shocks). Subjects reported lower levels of anxiety, negative valence and pain intensity when shocks were predictable. In addition to attenuate focus on danger, predictability allows for correct temporal estimation of, and selective attention to, the sensory input. With functional magnetic resonance imaging, we found that predictability was related to enhanced activity in relevant sensory-discriminative processing areas, such as the primary and secondary sensory cortex and posterior insula. In contrast, the unpredictable more aversive context was correlated to brain activity in the anterior insula and the orbitofrontal cortex, areas associated with affective pain processing. This context also prompted increased activity in the posterior parietal cortex and lateral prefrontal cortex that we attribute to enhanced alertness and sustained attention during unpredictability.

The human brain supports acquisition mechanisms that extract structural regularities implicitly from experience without the induction of an explicit model. It has been argued that the capacity to generalize to new input is based on the acquisition of abstract representations, which reflect underlying structural regularities in the input ensemble. In this study, we explored the outcome of this acquisition mechanism, and to this end, we investigated the neural correlates of artificial syntactic classification using event-related functional magnetic resonance imaging. The participants engaged once a day during an 8-day period in a short-term memory acquisition task in which consonant-strings generated from an artificial grammar were presented in a sequential fashion without performance feedback. They performed reliably above chance on the grammaticality classification tasks on days 1 and 8 which correlated with a corticostriatal processing network, including frontal, cingulate, inferior parietal, and middle occipital/occipitotemporal regions as well as the caudate nucleus. Part of the left inferior frontal region (BA 45) was specifically related to syntactic violations and showed no sensitivity to local substring familiarity. In addition, the head of the caudate nucleus correlated positively with syntactic correctness on day 8 but not day 1, suggesting that this region contributes to an increase in cognitive processing fluency.

The posterior medial parietal cortex and left prefrontal cortex (PFC) have both been implicated in the recollection of past episodes. In a previous study, we found the posterior precuneus and left lateral inferior frontal cortex to be activated during episodic source memory retrieval. This study further examines the role of posterior precuneal and left prefrontal activation during episodic source memory retrieval using a similar source memory paradigm but with longer latency between encoding and retrieval. Our results suggest that both the precuneus and the left inferior PFC are important for regeneration of rich episodic contextual associations and that the precuneus activates in tandem with the left inferior PFC during correct source retrieval. Further, results suggest that the left ventro-lateral frontal region/frontal operculum is involved in searching for task-relevant information (BA 47) and subsequent monitoring or scrutiny (BA 44/45) while regions in the dorsal inferior frontal cortex are important for information selection (BA 45/46).

Spatial memory deficits are core features of aging-related changes in cognitive abilities. The neural correlates of these deficits are largely unknown. In the present study, we investigated the neural underpinnings of age-related differences in spatial memory by functional MRI using a navigational memory task with route encoding and route recognition conditions. We investigated 20 healthy young (18-29 years old) and 20 healthy old adults (53-78 years old) in a random effects analysis. Old subjects showed slightly poorer performance than young subjects. Compared to the control condition, route encoding and route recognition showed activation of the dorsal and ventral visual processing streams and the frontal eye fields in both groups of subjects. Compared to old adults, young subjects showed during route encoding stronger activations in the dorsal and the ventral visual processing stream (supramarginal gyrus and posterior fusiform/parahippocampal areas). In addition, young subjects showed weaker anterior parahippocampal activity during route recognition compared to the old group. In contrast, old compared to young subjects showed less suppressed activity in the left perisylvian region and the anterior cingulate cortex during route encoding. Our findings suggest that age-related navigational memory deficits might be caused by less effective route encoding based on reduced posterior fusiform/parahippocampal and parietal functionality combined with diminished inhibition of perisylvian and anterior cingulate cortices correlated with less effective suppression of task-irrelevant information. In contrast, age differences in neural correlates of route recognition seem to be rather subtle. Old subjects might show a diminished familiarity signal during route recognition in the anterior parahippocampal region.

Irrelevant speech impairs the immediate serial recall of visually presented material. Previously, we have shown that the irrelevant speech effect (ISE) was associated with a relative decrease of regional blood flow in cortical regions subserving the verbal working memory, in particular the superior temporal cortex. In this extension of the previous study, the working memory load was increased and an increased activity as a response to irrelevant speech was noted in the dorsolateral prefrontal cortex. We suggest that the two studies together provide some basic insights as to the nature of the irrelevant speech effect. Firstly, no area in the brain can be ascribed as the single locus of the irrelevant speech effect. Instead, the functional neuroanatomical substrate to the effect can be characterized in terms of changes in networks of functionally interrelated areas. Secondly, the areas that are sensitive to the irrelevant speech effect are also generically activated by the verbal working memory task itself. Finally, the impact of irrelevant speech and related brain activity depends on working memory load as indicated by the differences between the present and the previous study. From a brain perspective, the irrelevant speech effect may represent a complex phenomenon that is a composite of several underlying mechanisms, which depending on the working memory load, include top-down inhibition as well as recruitment of compensatory support and control processes. We suggest that, in the low-load condition, a selection process by an inhibitory top-down modulation is sufficient, whereas in the high-load condition, at or above working memory span, auxiliary adaptive cognitive resources are recruited as compensation., (Copyright 2004 Elsevier Inc.)

The autonomic responses to acute pain exposure usually habituate rapidly while the subjective ratings of pain remain high for more extended periods of time. Thus, systems involved in the autonomic response to painful stimulation, for example the hypothalamus and the brainstem, would be expected to attenuate the response to pain during prolonged stimulation. This suggestion is in line with the hypothesis that the brainstem is specifically involved in the initial response to pain. To probe this hypothesis, we performed a positron emission tomography (PET) study where we scanned subjects during the first and second minute of a prolonged tonic painful cold stimulation (cold pressor test) and nonpainful cold stimulation. Galvanic skin response (GSR) was recorded during the PET scanning as an index of autonomic sympathetic response. In the main effect of pain, we observed increased activity in the thalamus bilaterally, in the contralateral insula and in the contralateral anterior cingulate cortex but no significant increases in activity in the primary or secondary somatosensory cortex. The autonomic response (GSR) decreased with stimulus duration. Concomitant with the autonomic response, increased activity was observed in brainstem and hypothalamus areas during the initial vs. the late stimulation. This effect was significantly stronger for the painful than for the cold stimulation. Activity in the brainstem showed pain-specific covariation with areas involved in pain processing, indicating an interaction between the brainstem and cortical pain networks. The findings indicate that areas in the brainstem are involved in the initial response to noxious stimulation, which is also characterized by an increased sympathetic response.

The posterior medial parietal cortex and the left prefrontal cortex have both been implicated in the recollection of past episodes. In order to clarify their functional significance, we performed this functional magnetic resonance imaging study, which employed event-related source memory and item recognition retrieval of words paired with corresponding imagined or viewed pictures. Our results suggest that episodic source memory is related to a functional network including the posterior precuneus and the left lateral prefrontal cortex. This network is activated during explicit retrieval of imagined pictures and results from the retrieval of item-context associations. This suggests that previously imagined pictures provide a context with which encoded words can be more strongly associated.

In a within-subject design we investigated the levels-of-processing (LOP) effect using visual material in a behavioral and a corresponding PET study. In the behavioral study we characterize a generalized LOP effect, using pleasantness and graphical quality judgments in the encoding situation, with two types of visual material, figurative and nonfigurative line drawings. In the PET study we investigate the related pattern of brain activations along these two dimensions. The behavioral results indicate that instruction and material contribute independently to the level of recognition performance. Therefore the LOP effect appears to stem both from the relative relevance of the stimuli (encoding opportunity) and an altered processing of stimuli brought about by the explicit instruction (encoding mode). In the PET study, encoding of visual material under the pleasantness (deep) instruction yielded left lateralized frontoparietal and anterior temporal activations while surface-based perceptually oriented processing (shallow instruction) yielded right lateralized frontoparietal, posterior temporal, and occipitotemporal activations. The result that deep encoding was related to the left prefrontal cortex while shallow encoding was related to the right prefrontal cortex, holding the material constant, is not consistent with the HERA model. In addition, we suggest that the anterior medial superior frontal region is related to aspects of self-referential semantic processing and that the inferior parts of the anterior cingulate as well as the medial orbitofrontal cortex is related to affective processing, in this case pleasantness evaluation of the stimuli regardless of explicit semantic content. Finally, the left medial temporal lobe appears more actively engaged by elaborate meaning-based processing and the complex response pattern observed in different subregions of the MTL lends support to the suggestion that this region is functionally segregated.

Several functional imaging studies of pain, using a number of different experimental paradigms and a variety of reference states, have failed to detect activations in the somatosensory cortices, while other imaging studies of pain have reported significant activations in these regions. The role of the somatosensory areas in pain processing has therefore been debated. In the present study the left hand was immersed in painfully cold water (standard cold pressor test) and in nonpainfully cold water during 2 min, and PET-scans were obtained either during the first or the second minute of stimulation. We observed no significant increase of activity in the somatosensory regions when the painful conditions were directly compared with the control conditions. In order to better understand the role of the primary somatosensory cortex (S1) in pain processing we used a regression analysis to study the relation between a ROI (region of interest) in the somatotopic S1-area for the stimulated hand and other regions known to be involved in pain processing. We hypothesized that although no increased activity was observed in the S1 during pain, this region would change its covariation pattern during noxious input as compared to the control stimulation if it is involved in or affected by the processing of pain. In the nonpainful cold conditions widespread regions of the ipsilateral and contralateral somatosensory cortex showed a positive covariation with the activity in the S1-ROI. However, during the first and second minute of pain this regression was significantly attenuated. During the second minute of painful stimulation there was a significant positive covariation between the activity in the S1-ROI and the other regions that are known to be involved in pain processing. Importantly, this relation was significantly stronger for the insula and the orbitofrontal cortex bilaterally when compared to the nonpainful state. The results indicate that the S1-cortex may be engaged in or affected by the processing of pain although no differential activity is observed when pain is compared with the reference condition.

The effects of spatial filtering in functional magnetic resonance imaging were investigated by reevaluating the data of a previous study of episodic memory encoding at 2 x 2 x 4-mm(3) resolution with use of a SPM99 analysis involving a Gaussian kernel of 8-mm full width at half maximum. In addition, a multisubject analysis of activated regions was performed by normalizing the functional images to an approximate Talairach brain atlas. In individual subjects, spatial filtering merged activations in anatomically separated brain regions. Moreover, small foci of activated pixels which originated from veins became blurred and hence indistinguishable from parenchymal responses. The multisubject analysis resulted in activation of the hippocampus proper, a finding which could not be confirmed by the activation maps obtained at high resolution. It is concluded that the validity of multisubject fMRI analyses can be considerably improved by first analyzing individual data sets at optimum resolution to assess the effects of spatial filtering and minimize the risk of signal contamination by macroscopically visible vessels.

Recent functional brain imaging studies have shown that sensory-specific brain regions that are activated during perception/encoding of sensory-specific information are reactivated during memory retrieval of the same information. Here we used PET to examine whether verbal retrieval of action phrases is associated with reactivation of motor brain regions if the actions were overtly or covertly performed during encoding. Compared to a verbal condition, encoding by means of overt as well as covert activity was associated with differential activity in regions in contralateral somatosensory and motor cortex. Several of these regions were reactivated during retrieval. Common to both the overt and covert conditions was reactivation of regions in left ventral motor cortex and left inferior parietal cortex. A direct comparison of the overt and covert activity conditions showed that activation and reactivation of left dorsal parietal cortex and right cerebellum was specific to the overt condition. These results support the reactivation hypothesis by showing that verbal-explicit memory of actions involves areas that are engaged during overt and covert motor activity., (Copyright 2001 Academic Press.)

Recent event-related FMRI studies indicate that the prefrontal (PFC) and the medial temporal lobe (MTL) regions are more active during effective encoding than during ineffective encoding. The within-subject design and the use of well-educated young college students in these studies makes it important to replicate these results in other study populations. In this PET study, we used an auditory word-pair association cued-recall paradigm and investigated a group of healthy upper middle-aged/older illiterate women. We observed a positive correlation between cued-recall success and the regional cerebral blood flow of the left inferior PFC (BA 47) and the MTLs. Specifically, we used the cued-recall success as a covariate in a general linear model and the results confirmed that the left inferior PFC and the MTL are more active during effective encoding than during ineffective encoding. These effects were observed during encoding of both semantically and phonologically related word pairs, indicating that these effects are robust in the studied population, that is, reproducible within group. These results generalize the results of Brewer et al. (1998, Science 281, 1185-1187) and Wagner et al. (1998, Science 281, 1188-1191) to an upper middle aged/older illiterate population. In addition, the present study indicates that effective relational encoding correlates positively with the activity of the anterior medial temporal lobe regions., (Copyright 1999 Academic Press.)

A key function of attention is to select an appropriate subset of available information by facilitation of attended processes and/or inhibition of irrelevant processing. Functional imaging studies, using positron emission tomography, have during different experimental tasks revealed decreased neuronal activity in areas that process input from unattended sensory modalities. It has been hypothesized that these decreases reflect a selective inhibitory modulation of nonrelevant cortical processing. In this study we addressed this question using a continuous arithmetical task with and without concomitant disturbing auditory input (task-irrelevant speech). During the arithmetical task, irrelevant speech did not affect task-performance but yielded decreased activity in the auditory and midcingulate cortices and increased activity in the left posterior parietal cortex. This pattern of modulation is consistent with a top down inhibitory modulation of a nonattended input to the auditory cortex and a coexisting, attention-based facilitation of task-relevant processing in higher order cortices. These findings suggest that task-related decreases in cortical activity may be of functional importance in the understanding of both attentional mechanisms and task-related information processing.

Understanding the role of the medial temporal lobe (MTL) in learning and memory is an important problem in cognitive neuroscience. Memory and learning processes that depend on the function of the MTL and related diencephalic structures (e.g., the anterior and mediodorsal thalamic nuclei) are defined as declarative. We have studied the MTL activity as indicated by regional cerebral blood flow with positron emission tomography and statistical parametric mapping during recall of abstract designs in a less practiced memory state as well as in a well-practiced (well-encoded) memory state. The results showed an increased activity of the MTL bilaterally (including parahippocampal gyrus extending into hippocampus proper, as well as anterior lingual and anterior fusiform gyri) during retrieval in the less practiced memory state compared to the well-practiced memory state, indicating a dynamic role of the MTL in retrieval during the learning processes. The results also showed that the activation of the MTL decreases as the subjects learn to draw abstract designs from memory, indicating a changing role of the MTL during recall in the earlier stages of acquisition compared to the well-encoded declarative memory state.