An fMRI Investigation of Cortical Contributions to Spatial and Nonspatial Visual Working Memory

The experiments presented in this report were designed to test the hypothesis that visual working memory for spatial stimuli and for object stimuli recruits separate neuronal networks in prefrontal cortex. We acquired BOLD fMRI data from subjects while they compared each serially presented stimulus to the one that had appeared two or three stimuli previously. Three experiments failed to reject the null hypothesis that prefrontal cortical activity associated with spatial working memory performance cannot be dissociated from prefrontal cortical activity associated with nonspatial working memory performance. Polymodal regions of parietal cortex (inferior and superior parietal lobules), as well as cortex surrounding the superior frontal sulcus (and encompassing the frontal eye fields), also demonstrated equivalent levels of activation in the spatial and object conditions. Posterior cortical regions associated with the ventral visual processing stream (portions of lingual, fusiform, and inferior temporal gyri), however, demonstrated greater object than spatial working memory-related activity, particularly when stimuli varied only along spatial or featural dimensions. These experiments, representing fMRI studies of spatial and object working memory in which the testing procedure and the stimuli were identical in the two conditions, suggest that domain-specific visual working memory processing may be mediated by posterior regions associated with domain-specific sensory processing.     

Spatiotemporal signatures of an abnormal auditory system in stuttering

People who stutter (PWS) can reduce their stuttering rates under masking noise and altered auditory feedback; such a response can be attributed to altered auditory input, which suggests that abnormal speech processing in PWS results from abnormal processing of auditory input. However, the details of this abnormal processing of basic auditory information remain unclear. In order to characterize such abnormalities, we examined the functional and structural changes in the auditory cortices of PWS by using a 306-channel magnetoencephalography system to assess auditory sensory gating (P50m suppression) and tonotopic organization. Additionally, we employed voxel-based morphometry to compare cortical gray matter (GM) volumes on structural MR images. PWS exhibited impaired left auditory sensory gating. The tonotopic organization in the right hemisphere of PWS is expanded compared with that of the controls. Furthermore, PWS showed a significant increase in the GM volume of the right superior temporal gyrus, consistent with the right tonotopic expansion. Accordingly, we suggest that PWS have impaired left auditory sensory gating during basic auditory input processing and that some error signals in the auditory cortex could result in abnormal speech processing. Functional and structural reorganization of the right auditory cortex appears to be a compensatory mechanism for impaired left auditory cortex function in PWS.     

Generators of the intracranial P50 response in auditory sensory gating

Clarification of the cortical mechanisms underlying auditory sensory gating may advance our understanding of brain dysfunctions associated with schizophrenia. To this end, data from nine epilepsy patients who participated in an auditory paired-click paradigm during pre-surgical evaluation and had grids of electrodes covering temporal and frontal lobe were analyzed. A distributed source localization approach was applied to the intracranial P50 response and the Gating Difference Wave obtained by subtracting the response to the second stimuli from the response to the first stimuli. Source reconstruction of the P50 showed that the main generators of the response were localized in the temporal lobes. The analysis also suggested that the maximum neuronal activity contributing to the amplitude reduction in the P50 time range (phenomenon of auditory sensory gating) is localized at the frontal lobe. Present findings suggest that while the temporal lobe is the main generator of the P50 component, the frontal lobe seems to be a substantial contributor to the process of sensory gating as observed from scalp recordings.     

The neural basis of temporal auditory discrimination

When two identical stimuli, such as a pair of clicks, are presented with a sufficiently long time-interval between them they are readily perceived as two separate events. However, as they are presented progressively closer together, there comes a point when the two separate stimuli are perceived as one. This phenomenon applies not only to hearing but also to other sensory modalities. Damage to the basal ganglia disturbs this type of temporal discrimination irrespective of sensory modality, suggesting a multimodal process is involved. Our aim was to study the neural substrate of auditory temporal discrimination in healthy subjects and to compare it with structures previously associated with analogous tactile temporal discrimination. During fMRI scanning, paired-clicks separated by variable inter-stimulus intervals (1-50 ms) were delivered binaurally, with different intensities delivered to each ear, yielding a lateralised auditory percept. Subjects were required (a) to report whether they heard one or two stimuli (TD: temporal discrimination); or (b) to report whether the stimuli were located on the right or left side of the head mid-line (SD: spatial discrimination); or (c) simply to detect the presence of an auditory stimulus (control task). Our results showed that both types of auditory discrimination (TD and SD) compared to simple detection activated a network of brain areas including regions of prefrontal cortex and basal ganglia. Critically, two clusters in pre-SMA and the anterior cingulate cortex were specifically activated by TD. Furthermore, these clusters overlap with regions activated for similar judgments in the tactile modality suggesting that they fulfill a multimodal function in the temporal processing of sensory events.     

Attentional and linguistic interactions in speech perception

The role of attention in speech comprehension is not well understood. We used fMRI to study the neural correlates of auditory word, pseudoword, and nonspeech (spectrally rotated speech) perception during a bimodal (auditory, visual) selective attention task. In three conditions, Attend Auditory (ignore visual), Ignore Auditory (attend visual), and Visual (no auditory stimulation), 28 subjects performed a one-back matching task in the assigned attended modality. The visual task, attending to rapidly presented Japanese characters, was designed to be highly demanding in order to prevent attention to the simultaneously presented auditory stimuli. Regardless of stimulus type, attention to the auditory channel enhanced activation by the auditory stimuli (Attend Auditory>Ignore Auditory) in bilateral posterior superior temporal regions and left inferior frontal cortex. Across attentional conditions, there were main effects of speech processing (word+pseudoword>rotated speech) in left orbitofrontal cortex and several posterior right hemisphere regions, though these areas also showed strong interactions with attention (larger speech effects in the Attend Auditory than in the Ignore Auditory condition) and no significant speech effects in the Ignore Auditory condition. Several other regions, including the postcentral gyri, left supramarginal gyrus, and temporal lobes bilaterally, showed similar interactions due to the presence of speech effects only in the Attend Auditory condition. Main effects of lexicality (word>pseudoword) were isolated to a small region of the left lateral prefrontal cortex. Examination of this region showed significant word>pseudoword activation only in the Attend Auditory condition. Several other brain regions, including left ventromedial frontal lobe, left dorsal prefrontal cortex, and left middle temporal gyrus, showed Attention x Lexicality interactions due to the presence of lexical activation only in the Attend Auditory condition. These results support a model in which neutral speech presented in an unattended sensory channel undergoes relatively little processing beyond the early perceptual level. Specifically, processing of phonetic and lexical-semantic information appears to be very limited in such circumstances, consistent with prior behavioral studies.     

Evidence for a frontal cortex role in both auditory and somatosensory habituation: a MEG study

Auditory and somatosensory responses to paired stimuli were investigated for commonality of frontal activation that may be associated with gating using magnetoencephalography (MEG). A paired stimulus paradigm for each sensory evoked study tested right and left hemispheres independently in ten normal controls. MR-FOCUSS, a current density technique, imaged simultaneously active cortical sources. Each subject showed source localization, in the primary auditory or somatosensory cortex, for the respective stimuli following both the first (S1) and second (S2) impulses. Gating ratios for the auditory M50 response, equivalent to the P50 in EEG, were 0.54+/-0.24 and 0.63+/-0.52 for the right and left hemispheres. Somatosensory gating ratios were evaluated for early and late latencies as the pulse duration elicits extended response. Early gating ratios for right and left hemispheres were 0.69+/-0.21 and 0.69+/-0.41 while late ratios were 0.81+/-0.41 and 0.80+/-0.48. Regions of activation in the frontal cortex, beyond the primary auditory or somatosensory cortex, were mapped within 25 ms of peak S1 latencies in 9/10 subjects during auditory stimulus and in 10/10 subjects for somatosensory stimulus. Similar frontal activations were mapped within 25 ms of peak S2 latencies for 75% of auditory responses and for 100% of somatosensory responses. Comparison between modalities showed similar frontal region activations for 17/20 S1 responses and for 13/20 S2 responses. MEG offers a technique for evaluating cross modality gating. The results suggest similar frontal sources are simultaneously active during auditory and somatosensory habituation.     

Human auditory cortex is sensitive to the perceived clarity of speech

Feedback connections among auditory cortical regions may play an important functional role in processing naturalistic speech, which is typically considered a problem solved through serial feed-forward processing stages. Here, we used fMRI to investigate whether activity within primary auditory cortex (PAC) is sensitive to the perceived clarity of degraded sentences. A region-of-interest analysis using probabilistic cytoarchitectonic maps of PAC revealed a modulation of activity, in the most primary-like subregion (area Te1.0), related to the intelligibility of naturalistic speech stimuli that cannot be driven by stimulus differences. Importantly, this effect was unique to those conditions accompanied by a perceptual increase in clarity. Connectivity analyses suggested sources of input to PAC are higher-order temporal, frontal and motor regions. These findings are incompatible with feed-forward models of speech perception, and suggest that this problem belongs amongst modern perceptual frameworks in which the brain actively predicts sensory input, rather than just passively receiving it.     

Neural correlates of counting of sequential sensory and motor events in the human brain

Little is known about the ability to enumerate small numbers of successive stimuli and movements. It is possible that there exist neural substrates that are consistently recruited both to count sensory stimuli from different modalities and for counting movements executed by different effectors. Here, we identify a network of areas that was involved in enumerating small numbers of auditory, visual, and somatosensory stimuli, and in enumerating sequential movements of hands and feet, in the bilateral premotor cortex, presupplementary motor area, posterior temporal cortex, and thalamus. The most significant consistent activation across sensory and motor counting conditions was found in the lateral premotor cortex. Lateral premotor activation was not dependent on movement preparation, stimulus presentation timing, or number word verbalization. Movement counting, but not sensory counting, activated the anterior parietal cortex. This anterior parietal area may correspond to an area recruited for movement counting identified by recent single-neuron studies in monkeys. These results suggest that overlapping but not identical networks of areas are involved in counting sequences of sensory stimuli and sequences of movements in the human brain.     

Auditory cortex activation is modulated by emotion: a functional near-infrared spectroscopy (fNIRS) study

Visual emotional stimuli evoke enhanced activation in early visual cortex areas which may help organisms to quickly detect biologically salient cues and initiate appropriate approach or avoidance behavior. Functional neuroimaging evidence for the modulation of other sensory modalities by emotion is scarce. Therefore, the aim of the present study was to test whether sensory facilitation by emotional cues can also be found in the auditory domain. We recorded auditory brain activation with functional near-infrared-spectroscopy (fNIRS), a non-invasive and silent neuroimaging technique, while participants were listening to standardized pleasant, unpleasant, and neutral sounds selected from the International Affective Digitized Sound System (IADS). Pleasant and unpleasant sounds led to increased auditory cortex activation as compared to neutral sounds. This is the first study to suggest that the enhanced activation of sensory areas in response to complex emotional stimuli is apparently not restricted to the visual domain but is also evident in the auditory domain.     

Modality effects in verbal working memory: differential prefrontal and parietal responses to auditory and visual stimuli

The neural bases of verbal (nonspatial) working memory (VWM) have been primarily examined using visual stimuli. Few studies have investigated the neural bases of VWM using auditory stimuli, and fewer have explored modality differences in VWM. In this study, we used functional magnetic resonance imaging (fMRI) to examine similarities and differences between visual VWM (vis-VWM) and auditory VWM (aud-VWM) utilizing identical stimuli and a within-subjects design. Performance levels were similar in the two modalities and there was extensive overlap of activation bilaterally in the dorsolateral and ventrolateral prefrontal cortex (DLPFC and VLPFC), intraparietal sulcus, supramarginal gyrus and the basal ganglia. However, a direct statistical comparison revealed significant modality differences: the left posterior parietal cortex, primarily along the intraparietal sulcus, showed greater responses during vis-VWM whereas the left dorsolateral prefrontal cortex showed greater responses during aud-VWM. No such differences were observed in the right hemisphere. Other modality differences in VWM were also observed, but they were associated with relative decreases in activation. In particular, we detected bilateral suppression of the superior and middle temporal (auditory) cortex during vis-VWM, and of the occipital (visual) cortex during aud-VWM, thus suggesting that cross-modal inhibitory processes may help to provide preferential access to high-order heteromodal association areas. Taken together, our findings suggest that although similar prefrontal and parietal regions are involved in aud-VWM and vis-VWM, there are important modality differences in the way neural signals are generated, processed and routed during VWM.     

Trigeminal activation using chemical, electrical, and mechanical stimuli

Tactile, proprioceptive, and nociceptive information, including also chemosensory functions are expressed in the trigeminal nerve sensory response. To study differences in the processing of different stimulus qualities, we performed a study based on functional magnetic resonance imaging. The first trigeminal branch (ophthalmic nerve) was activated by (a) intranasal chemical stimulation with gaseous CO2 which produces stinging and burning sensations, but is virtually odorless, (b) painful, but not nociceptive specific cutaneous electrical stimulation, and (c) cutaneous mechanical stimulation using air puffs. Eighteen healthy subjects participated (eight men, 10 women, mean age 31 years). Painful stimuli produced patterns of activation similar to what has been reported for other noxious stimuli, namely activation in the primary and secondary somatosensory cortices, anterior cingulate cortex, insular cortex, and thalamus. In addition, analyses indicated intensity-related activation in the prefrontal cortex which was specifically involved in the evaluation of stimulus intensity. Importantly, the results also indicated similarities between activation patterns after intranasal chemosensory trigeminal stimulation and patterns usually found following intranasal odorous stimulation, indicating the intimate connection between these two systems in the processing of sensory information.     

How the brain resolves high conflict situations: double conflict involvement of dorsolateral prefrontal cortex

Executive control is a human ability that allows to overcome automatic stimulus-response mappings and to act appropriate in the context of a task where the selection of relevant stimuli and the suppression of interfering information are crucial. In order to address the question which brain areas are involved in the detection and processing of two simultaneously operating sources of interference derived from a spatial incompatibility task, we used functional MRI to contrast neural activity related to a double conflict situation to single incompatibility conditions. Results show signal increase of left dorsolateral prefrontal cortex when monitoring simultaneously presented conflict. There was no additional activity in the medial prefrontal cortex or anterior cingulate cortex although these regions are expected to play an important role in all types of conflict monitoring. Further analyses of conflict resolution and post-error adaptation pointed to different underlying functional mechanisms. While the resolution of high conflict was associated with rostral ACC activation, the post-error adaptation reflecting activity during post-error trials suggests a specific medial and lateral prefrontal network which was functionally distinct from conflict-related activity. Our results also suggest a major role for the basal ganglia during error detection and resolution.     

Priming within and across modalities: exploring the nature of rCBF increases and decreases

Neuroimaging studies suggest that within-modality priming is associated with reduced regional cerebral blood flow (rCBF) in the extrastriate area, whereas cross-modality priming is associated with increased rCBF in prefrontal cortex. To characterize the nature of rCBF changes in within- and cross-modality priming, we conducted two neuroimaging experiments using positron emission tomography (PET). In experiment 1, rCBF changes in within-modality auditory priming on a word stem completion task were observed under same- and different-voice conditions. Both conditions were associated with decreased rCBF in extrastriate cortex. In the different-voice condition there were additional rCBF changes in the middle temporal gyrus and prefrontal cortex. Results suggest that the extrastriate involvement in within-modality priming is sensitive to a change in sensory modality of target stimuli between study and test, but not to a change in the feature of a stimulus within the same modality. In experiment 2, we studied cross-modality priming on a visual stem completion test after encoding under full- and divided-attention conditions. Increased rCBF in the anterior prefrontal cortex was observed in the full- but not in the divided-attention condition. Because explicit retrieval is compromised after encoding under the divided-attention condition, prefrontal involvement in cross-modality priming indicates recruitment of an aspect of explicit retrieval mechanism. The aspect of explicit retrieval that is most likely to be involved in cross-modality priming is the familiarity effect.     

Getting mixed messages: The impact of conflicting social signals on the brain's target emotional response

Amidst a barrage of sensory information in the environment, the impact that individual stimuli have on our behaviour is thought to depend on the outcome of competition that occurs within and between multiple brain regions. Although biased competition models of attention have been tested in visual cortices and to a lesser extent in auditory cortex, little is known about the nature of stimulus competition outside of sensory areas. Given the hypothesized role of multiple pathways (cortical and subcortical) and specialized brain regions for processing valence information, studies involving conflicting basic emotional stimuli provide a unique opportunity to examine whether the principles of biased competition apply outside of sensory cortex. We used fMRI to examine the neural representation and resolution of emotional conflict in a sample of healthy individuals. Participants made explicit judgments about the valence of happy or fearful target facial expressions in the context of emotionally congruent, neutral, or incongruent distracters. The results suggest that emotional conflict is reflected in a dissociable manner across distinct neural regions. Posterior areas of visual cortex showed enhanced responding to congruent relative to neutral or incongruent stimuli. Orbitofrontal cortex remained sensitive to positive affect in the context of conflicting emotional stimuli. In contrast, within the amygdala, activity associated with identifying positive target expressions declined with the introduction of neutral and incongruent expressions; however, activity associated with fearful target expressions was less susceptible to the influence of emotional context. Enhanced functional connectivity was observed between medial prefrontal cortex and the amygdala during incongruent trials; the degree of connectivity was correlated with reaction time costs incurred during incongruent trials. The results are interpreted with reference to current models of emotional attention and regulation.     

Hemodynamic correlates of stimulus repetition in the visual and auditory cortices: an fMRI study

We examined the effects of stimulus repetition upon the evoked hemodynamic response (HDR) in auditory and visual cortices measured by magnetic resonance imaging in two experiments. Experiment 1 focused on the effects of the interval duration between two identical stimuli on HDR. Pure auditory tones (1000 Hz) of 100-ms duration were presented singly or in pairs with intrapair intervals (IPIs: onset-to-onset) of 1, 4, and 6 s. In Experiment 2, using a within-subject design, we aimed to compare the HDR refractory period in both sensory cortices as well as the HDRs to auditory and visual stimuli. Identical auditory tone as described above and visual stimuli of 500-ms high-contrast checkerboard patterns were presented singly or in identical pairs with an IPI of 1 s. Images were acquired at 1.5 T using a gradient-echo echo-planar imaging sequence sensitive to blood oxygenation level-dependent (BOLD) contrast. Experiment 1 revealed that the HDR evoked by an auditory stimulus is followed by a refractory period of 4-6 s in the auditory cortex, as indicated by smaller HDR amplitudes to the second of each pair of stimuli. Furthermore, peak latency was dependent upon IPI, with longer latencies observed for shorter IPIs. Experiment 2 revealed that the HDR evoked in both sensory cortices by paired stimulus presentations is suppressed and delayed similarly by the refractory effects imposed by the preceding stimulus, suggesting similar refractory properties of the HDR at this specific IPI. We also provide evidence for additional neural resource allocation in response to repeated stimuli.     

Conditioning transcutaneous electrical nerve stimulation induces delayed gating effects on cortical response: a magnetoencephalographic study

The present study was undertaken to investigate after-effects of 7 Hz non-painful prolonged stimulation of the median nerve on somatosensory-evoked fields (SEFs). The working hypothesis that conditioning peripheral stimulations might produce delayed interfering ("gating") effects on the response of somatosensory cortex to test stimuli was evaluated. In the control condition, electrical thumb stimulation induced SEFs in ten subjects. In the experimental protocol, a conditioning median nerve stimulation at wrist preceded 6 electrical thumb stimulations. Equivalent current dipoles fitting SEFs modeled responses of contralateral primary area (SI) and bilateral secondary somatosensory areas (SII) following control and experimental conditions. Compared to the control condition, conditioning stimulation induced no amplitude modulation of SI response at the initial stimulus-related peak (20 ms). In contrast, later response from SI (35 ms) and response from SII were significantly weakened in amplitude. Gradual but fast recovery towards control amplitude levels was observed for the response from SI-P35, while a slightly slower cycle was featured from SII. These findings point to a delayed "gating" effect on the synchronization of somatosensory cortex after peripheral conditioning stimulations. This effect was found to be more lasting in SII area, as a possible reflection of its integrative role in sensory processing.     

Adrenergic pharmacology and cognition: focus on the prefrontal cortex

Norepinephrine (NE) has widespread projections throughout the brain, and thus, is ideally positioned to orchestrate neural functions based on arousal state. For example, NE can increase "signal/noise" ratio in the processing of sensory stimuli, and can enhance long-term memory consolidation in the amygdala and hippocampus through actions at alpha-1 and beta adrenoceptors. Over the last 20 years, NE has also been shown to play a powerful role in regulating the working memory and attention functions of the prefrontal cortex (PFC). Moderate levels of NE released under control conditions strengthen prefrontal cortical functions via actions at post-synaptic alpha-2A adrenoceptors with high affinity for NE, while high levels of NE release during stress impair PFC cortical functions via alpha-1 and possibly beta-1 receptors with lower affinity for NE. Thus, levels of NE determine whether prefrontal cortical or posterior cortical systems control our behavior and thought. Understanding these receptor mechanisms has led to new intelligent treatments for neuropsychiatric disorders associated with PFC dysfunction.     

fMRI during natural sleep as a method to study brain function during early childhood

Many techniques to study early functional brain development lack the whole-brain spatial resolution that is available with fMRI. We utilized a relatively novel method in which fMRI data were collected from children during natural sleep. Stimulus-evoked responses to auditory and visual stimuli as well as stimulus-independent functional networks were examined in typically developing 2-4-year-old children. Reliable fMRI data were collected from 13 children during presentation of auditory stimuli (tones, vocal sounds, and nonvocal sounds) in a block design. Twelve children were presented with visual flashing lights at 2.5 Hz. When analyses combined all three types of auditory stimulus conditions as compared to rest, activation included bilateral superior temporal gyri/sulci (STG/S) and right cerebellum. Direct comparisons between conditions revealed significantly greater responses to nonvocal sounds and tones than to vocal sounds in a number of brain regions including superior temporal gyrus/sulcus, medial frontal cortex and right lateral cerebellum. The response to visual stimuli was localized to occipital cortex. Furthermore, stimulus-independent functional connectivity MRI analyses (fcMRI) revealed functional connectivity between STG and other temporal regions (including contralateral STG) and medial and lateral prefrontal regions. Functional connectivity with an occipital seed was localized to occipital and parietal cortex. In sum, 2-4 year olds showed a differential fMRI response both between stimulus modalities and between stimuli in the auditory modality. Furthermore, superior temporal regions showed functional connectivity with numerous higher-order regions during sleep. We conclude that the use of sleep fMRI may be a valuable tool for examining functional brain organization in young children.     

Does training or deprivation modulate amygdala activation?

Amygdala involvement in visual emotional processing has been unequivocally established, but the amygdala's participation in auditory emotional processing is less clear. In a previous functional magnetic resonance imaging study (Klinge et al., 2010) we investigated the amygdala's role in auditory emotional processing in blind and sighted humans. We observed stronger amygdala responses to auditory emotional stimuli in the blind who were also better at discriminating emotional stimuli. Importantly, inter-individual differences in this skill correlated with amygdala activation. While these data suggested that the amygdala serves the dominant sensory modality for emotional perception, we could not rule out possible influences of use-dependent training effects. To disambiguate between plastic changes due to deprivation or training we now studied professional actors who have undergone extensive perceptual and expressive auditory emotional trainings but no sensory deprivation. Actors showed emotion discrimination skills comparable to those of blind individuals. However, in contrast to blind volunteers they lacked increased amygdala activations. Surprisingly, actors selectively rated angry stimuli as less intense than control participants, paralleled by a down-regulation of amygdala responses via the anterior cingulate cortex. Taken together, the data from our two studies suggest that enhanced amygdala responses in the blind are mainly due to deprivation-induced plasticity, as highly trained actors who possess the same excellent emotion discrimination skills as the blind did not show these responses. It is also conceivable that the actors' training requires a more professional and controlled dealing with the emotional stimuli, resulting in a down-regulation of affective experience and accompanying amygdala responses.     

Predictability modulates the affective and sensory-discriminative neural processing of pain

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.