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In the later stages of addiction, automatized processes play a prominent role in guiding drug-seeking and drug-taking behavior. However, little is known about the neural correlates of automatized drug-taking skills and drug-related action knowledge in humans. We employed functional magnetic resonance imaging (fMRI) while smokers and non-smokers performed an orientation affordance task, where compatibility between the hand used for a behavioral response and the spatial orientation of a priming stimulus leads to shorter reaction times resulting from activation of the corresponding motor representations. While non-smokers exhibited this behavioral effect only for control objects, smokers showed the affordance effect for both control and smoking-related objects. Furthermore, smokers exhibited reduced fMRI activation for smoking-related as compared to control objects for compatible stimulus-response pairings in a sensorimotor brain network consisting of the right primary motor cortex, supplementary motor area, middle occipital gyrus, left fusiform gyrus and bilateral cingulate gyrus. In the incompatible condition, we found higher fMRI activation in smokers for smoking-related as compared to control objects in the right primary motor cortex, cingulate gyrus, and left fusiform gyrus. This suggests that the activation and performance of deeply embedded, automatized drug-taking schemata employ less brain resources. This might reduce the threshold for relapsing in individuals trying to abstain from smoking. In contrast, the interruption or modification of already triggered automatized action representations require increased neural resources., Highlights • We measured smokers and non-smokers with fMRI and a behavioral affordance task. • Smoking paraphernalia and control objects were employed as stimuli. • Automatized smoking schemata employ less brain resources in sensorimotor regions. • This might reduce the motor threshold in smokers trying to abstain from smoking. • Interruption of triggered action representations requires more neural resources.

Human neuroimaging studies suggest that neural cue reactivity is strongly associated with indices of drug use, including addiction severity and treatment success. However, little is known about factors that modulate cue reactivity. The goal of this review, in which we survey published fMRI and PET studies on drug cue reactivity in cocaine, alcohol, and tobacco cigarette users, is to highlight major factors that modulate brain reactivity to drug cues. First, we describe cue reactivity paradigms used in neuroimaging research and outline the brain circuits that underlie cue reactivity. We then discuss major factors that have been shown to modulate cue reactivity and review specific evidence as well as outstanding questions related to each factor. Building on previous model-building reviews on the topic, we then outline a simplified model that includes the key modulatory factors and a tentative ranking of their relative impact. We conclude with a discussion of outstanding challenges and future research directions, which can inform future neuroimaging studies as well as the design of treatment and prevention programs.

Behavioral experiments have demonstrated that the sensory modality of presentation modulates drug cue reactivity. The present study on nicotine addiction tested whether neural responses to smoking cues are modulated by the sensory modality of stimulus presentation. We measured brain activation using functional magnetic resonance imaging (fMRI) in 15 smokers and 15 nonsmokers while they viewed images of smoking paraphernalia and control objects and while they touched the same objects without seeing them. Haptically presented, smoking-related stimuli induced more pronounced neural cue reactivity than visual cues in the left dorsal striatum in smokers compared to nonsmokers. The severity of nicotine dependence correlated positively with the preference for haptically explored smoking cues in the left inferior parietal lobule/somatosensory cortex, right fusiform gyrus/inferior temporal cortex/cerebellum, hippocampus/parahippocampal gyrus, posterior cingulate cortex, and supplementary motor area. These observations are in line with the hypothesized role of the dorsal striatum for the expression of drug habits and the well-established concept of drug-related automatized schemata, since haptic perception is more closely linked to the corresponding object-specific action pattern than visual perception. Moreover, our findings demonstrate that with the growing severity of nicotine dependence, brain regions involved in object perception, memory, self-processing, and motor control exhibit an increasing preference for haptic over visual smoking cues. This difference was not found for control stimuli. Considering the sensory modality of the presented cues could serve to develop more reliable fMRI-specific biomarkers, more ecologically valid experimental designs, and more effective cue-exposure therapies of addiction.

Human neuroplasticity of multisensory integration has been studied mainly in the context of natural or artificial training situations in healthy subjects. However, regular smokers also offer the opportunity to assess the impact of intensive daily multisensory interactions with smoking-related objects on the neural correlates of crossmodal object processing. The present functional magnetic resonance imaging study revealed that smokers show a comparable visuo-haptic integration pattern for both smoking paraphernalia and control objects in the left lateral occipital complex, a region playing a crucial role in crossmodal object recognition. Moreover, the degree of nicotine dependence correlated positively with the magnitude of visuo-haptic integration in the left lateral occipital complex (LOC) for smoking-associated but not for control objects. In contrast, in the left LOC non-smokers displayed a visuo-haptic integration pattern for control objects, but not for smoking paraphernalia. This suggests that prolonged smoking-related multisensory experiences in smokers facilitate the merging of visual and haptic inputs in the lateral occipital complex for the respective stimuli. Studying clinical populations who engage in compulsive activities may represent an ecologically valid approach to investigating the neuroplasticity of multisensory integration.

The processing of visual and haptic inputs, occurring either separately or jointly, is crucial for everyday-life object recognition, and has been a focus of recent neuroimaging research. Previously, visuohaptic convergence has been mostly investigated with matching-task paradigms. However, much less is known about visuohaptic convergence in the absence of additional task demands. We conducted two functional magnetic resonance imaging experiments in which subjects actively touched and/or viewed unfamiliar object stimuli without any additional task demands. In addition, we performed two control experiments with audiovisual and audiohaptic stimulation to examine the specificity of the observed visuohaptic convergence effects. We found robust visuohaptic convergence in bilateral lateral occipital cortex and anterior cerebellum. In contrast, neither the anterior cerebellum nor the lateral occipital cortex showed any involvement in audiovisual or audiohaptic convergence, indicating that multisensory convergence in these regions is specifically geared to visual and haptic inputs. These data suggest that in humans the lateral occipital cortex and the anterior cerebellum play an important role in visuohaptic processing even in the absence of additional task demands.

Several regions in human temporal and frontal cortex are known to integrate visual and auditory object features. The processing of audio–visual (AV) associations in these regions has been found to be modulated by object familiarity. The aim of the present study was to explore training-induced plasticity in human cortical AV integration. We used functional magnetic resonance imaging to analyze the neural correlates of AV integration for unfamiliar artificial object sounds and images in naïve subjects (PRE training) and after a behavioral training session in which subjects acquired associations between some of these sounds and images (POST-training). In the PRE-training session, unfamiliar artificial object sounds and images were mainly integrated in right inferior frontal cortex (IFC). The POST-training results showed extended integration-related IFC activations bilaterally, and a recruitment of additional regions in bilateral superior temporal gyrus/sulcus and intraparietal sulcus. Furthermore, training-induced differential response patterns to mismatching compared with matching (i.e., associated) artificial AV stimuli were most pronounced in left IFC. These effects were accompanied by complementary training-induced congruency effects in right posterior middle temporal gyrus and fusiform gyrus. Together, these findings demonstrate that short-term cross-modal association learning was sufficient to induce plastic changes of both AV integration of object stimuli and mechanisms of AV congruency processing.

The cortical integration of auditory and visual features is crucial for efficient object recognition. Previous studies have shown that audiovisual (AV) integration is affected by where and when auditory and visual features occur. However, because relatively little is known about the impact of what is integrated, we here investigated the impact of semantic congruency and object familiarity on the neural correlates of AV integration. We used functional magnetic resonance imaging to identify regions involved in the integration of both (congruent and incongruent) familiar animal sounds and images and of arbitrary combinations of unfamiliar artificial sounds and object images. Unfamiliar object images and sounds were integrated in the inferior frontal cortex (IFC), possibly reflecting learning of novel AV associations. Integration of familiar, but semantically incongruent combinations also correlated with IFC activation and additionally involved the posterior superior temporal sulcus (pSTS). For highly familiar semantically congruent AV pairings, we again found AV integration effects in pSTS and additionally in superior temporal gyrus. These findings demonstrate that the neural correlates of object-related AV integration reflect both semantic congruency and familiarity of the integrated sounds and images.

The successful integration of visual and auditory stimuli requires information about whether visual and auditory signals originate from corresponding places in the external world. Here we report crossmodal effects of spatially congruent and incongruent audio-visual (AV) stimulation. Visual and auditory stimuli were presented from one of four horizontal locations in external space. Seven healthy human subjects had to assess the spatial fit of a visual stimulus (i.e. a gray-scaled picture of a cartoon dog) and a simultaneously presented auditory stimulus (i.e. a barking sound). Functional magnetic resonance imaging (fMRI) revealed two distinct networks of cortical regions that processed preferentially either spatially congruent or spatially incongruent AV stimuli. Whereas earlier visual areas responded preferentially to incongruent AV stimulation, higher visual areas of the temporal and parietal cortex (left inferior temporal gyrus [ITG], right posterior superior temporal gyrus/sulcus [pSTG/STS], left intra-parietal sulcus [IPS]) and frontal regions (left pre-central gyrus [PreCG], left dorsolateral pre-frontal cortex [DLPFC]) responded preferentially to congruent AV stimulation. A position-resolved analysis revealed three robust cortical representations for each of the four visual stimulus locations in retinotopic visual regions corresponding to the representation of the horizontal meridian in area V1 and at the dorsal and ventral borders between areas V2 and V3. While these regions of interest (ROIs) did not show any significant effect of spatial congruency, we found subregions within ROIs in the right hemisphere that showed an incongruency effect (i.e. an increased fMRI signal during spatially incongruent compared to congruent AV stimulation). We interpret this finding as a correlate of spatially distributed recurrent feedback during mismatch processing: whenever a spatial mismatch is detected in multisensory regions (such as the IPS), processing resources are re-directed to low-level visual areas.

Visuo-haptic integration contributes essentially to object shape recognition. Although there has been a considerable advance in elucidating the neural underpinnings of multisensory perception, it is still unclear whether seeing an object and exploring it with the dominant hand elicits the same brain response as compared to the non-dominant hand. Using fMRI to measure brain activation in right-handed participants, we found that for both left- and right-hand stimulation the left lateral occipital complex (LOC) and anterior cerebellum (aCER) were involved in visuo-haptic integration of familiar objects. These two brain regions were then further investigated in another study, where unfamiliar, novel objects were presented to a different group of right-handers. Here the left LOC and aCER were more strongly activated by bimodal than unimodal stimuli only when the left but not the right hand was used. A direct comparison indicated that the multisensory gain of the fMRI activation was significantly higher for the left than the right hand. These findings are in line with the principle of "inverse effectiveness", implying that processing of bimodally presented stimuli is particularly enhanced when the unimodal stimuli are weak. This applies also when right-handed subjects see and simultaneously touch unfamiliar objects with their non-dominant left hand. Thus, the fMRI signal in the left LOC and aCER induced by visuo-haptic stimulation is dependent on which hand was employed for haptic exploration.

Dual-coding theory (Paivio, 1986) postulates that the human mind represents objects not just with an analogous, or semantic code, but with a perceptual representation as well. Previous studies (eg, Fiebach & Friederici, 2004) indicated that the modality of this representation is not necessarily the one that triggers the representation. The human visual cortex contains several regions, such as the Lateral Occipital Complex (LOC), that respond specifically to object stimuli. To investigate whether these principally visual representations regions are also recruited for auditory stimuli, we presented subjects with spoken words with specific, concrete meanings (‘car’) as well as words with abstract meanings (‘hope’). Their brain activity was measured with functional magnetic resonance imaging. Whole-brain contrasts showed overlap between regions differentially activated by words for concrete objects compared to words for abstract concepts with visual regions activated by a contrast of object versus non-object visual stimuli. We functionally localized LOC for individual subjects and a preliminary analysis showed a trend for a concreteness effect in this region-of-interest on the group level. Appropriate further analysis might include connectivity and classification measures. These results can shed light on the role of crossmodal representations in cognition.

Primate multisensory object perception involves distributed brain regions. To investigate the network character of these regions of the human brain, we applied data-driven group spatial independent component analysis (ICA) to a functional magnetic resonance imaging (fMRI) data set acquired during a passive audio-visual (AV) experiment with common object stimuli. We labeled three group-level independent component (IC) maps as auditory (A), visual (V), and AV, based on their spatial layouts and activation time courses. The overlap between these IC maps served as definition of a distributed network of multisensory candidate regions including superior temporal, ventral occipito-temporal, posterior parietal and prefrontal regions. During an independent second fMRI experiment, we explicitly tested their involvement in AV integration. Activations in nine out of these twelve regions met the max-criterion (A V) for multisensory integration. Comparison of this approach with a general linear model-based region-of-interest definition revealed its complementary value for multisensory neuroimaging. In conclusion, we estimated functional networks of uni- and multisensory functional connectivity from one dataset and validated their functional roles in an independent dataset. These findings demonstrate the particular value of ICA for multisensory neuroimaging research and using independent datasets to test hypotheses generated from a data-driven analysis. Electronic supplementary material The online version of this article (doi:10.1007/s00221-011-2669-0) contains supplementary material, which is available to authorized users.

Information integration across different sensory modalities contributes to object recognition, the generation of associations and long-term memory representations. Here, we used functional magnetic resonance imaging adaptation to investigate the presence of sensory integrative effects at cortical levels as early as nonprimary auditory and extrastriate visual cortices, which are implicated in intermediate stages of object processing. Stimulation consisted of an adapting audiovisual stimulus S1and a subsequent stimulus S2from the same basic-level category (e.g., cat). The stimuli were carefully balanced with respect to stimulus complexity and semantic congruency and presented in four experimental conditions: (1) the same image and vocalization for S1and S2, (2) the same image and a different vocalization, (3) different images and the same vocalization, or (4) different images and vocalizations. This two-by-two factorial design allowed us to assess the contributions of auditory and visual stimulus repetitions and changes in a statistically orthogonal manner. Responses in visual regions of right fusiform gyrus and right lateral occipital cortex were reduced for repeated visual stimuli (repetition suppression). Surprisingly, left lateral occipital cortex showed stronger responses to repeated auditory stimuli (repetition enhancement). Similarly, auditory regions of interest of the right middle superior temporal gyrus and sulcus exhibited repetition suppression to auditory repetitions and repetition enhancement to visual repetitions. Our findings of crossmodal repetition-related effects in cortices of the respective other sensory modality add to the emerging view that in human subjects sensory integrative mechanisms operate on earlier cortical processing levels than previously assumed.

Since its invention almost two decades ago functional magnetic resonance imaging (fMRI) has become the prime research methodology in human neuroscience. Its capabilities continue to evolve based on combined improvements of scanner hardware, experimental designs, and data analysis tools. Within the rapidly growing field of multisensory research the use of noninvasive neuroimaging techniques in general and fMRI in particular is also of increasing relevance. For several years, discussion in the multisensory fMRI community has mainly focused on principles of and statistical criteria for multisensory integration. The recent availability of more sophisticated experimental designs and increasingly sensitive (multivariate) analysis tools allows multisensory researchers to (noninvasively) differentiate between regional and neuronal convergence and to reveal the connectional basis of human multisensory integration.

In addition to reward- and craving-related processes, habitual mechanisms play an important role in addiction. While the dorsal striatum has been proposed to code for the motivational state of habitual drug-seeking actions, the neural underpinnings of the corresponding drug-taking skills and action knowledge remain poorly understood. We used functional magnetic resonance imaging (fMRI) and a behavioral orientation affordance paradigm to investigate the neural and behavioral correlates of automatized drug-taking actions in nicotine dependence. Smokers exhibited higher fMRI activations than nonsmokers when viewing smoking-related but not when viewing control images. These group differences in fMRI activations were located not only in brain regions associated with craving and habitual learning (left ventral and dorsal striatum, dorsolateral prefrontal cortex, insula, uncus, medial frontal gyrus, right subcallosal gyrus, and bilateral parahippocampal gyrus), but also in a network of brain regions which has been strongly implicated in the encoding of action knowledge and tool use skills (bilateral premotor cortex, left superior parietal lobule, and right lateral cerebellum). A behavioral affordance reaction-time task indicated that smokers, but not nonsmokers, showed an automatized responsiveness to smoking paraphernalia similar to everyday objects. Moreover, smokers showed strong intercorrelations between fMRI activations in tool use-related brain regions, behavioral responsiveness to smoking-related cues, and severity of nicotine dependence. Apparently smoking-related action representations in smokers are stored in brain regions typically representing tool use skills and action knowledge. Most importantly, cortical and behavioral correlates of the respective drug-taking skills vary with the individual degree of nicotine dependence.

In complex natural environments, auditory and visual information often have to be processed simultaneously. Previous functional magnetic resonance imaging (fMRI) studies focused on the spatial localization of brain areas involved in audiovisual (AV) information processing, but the temporal characteristics of AV information flow in these regions remained unclear. In this study, we used fMRI and a novel information–theoretic approach to study the flow of AV sensory information. Subjects passively perceived sounds and images of objects presented either alone or simultaneously. Applying the measure of mutual information, we computed for each voxel the latency in which the blood oxygenation level-dependent signal had the highest information content about the preceding stimulus. The results indicate that, after AV stimulation, the earliest informative activity occurs in right Heschl's gyrus, left primary visual cortex, and the posterior portion of the superior temporal gyrus, which is known as a region involved in object-related AV integration. Informative activity in the anterior portion of superior temporal gyrus, middle temporal gyrus, right occipital cortex, and inferior frontal cortex was found at a later latency. Moreover, AV presentation resulted in shorter latencies in multiple cortical areas compared with isolated auditory or visual presentation. The results provide evidence for bottom-up processing from primary sensory areas into higher association areas during AV integration in humans and suggest that AV presentation shortens processing time in early sensory cortices.

Earlier studies reported evidence suggesting distinct category-related auditory representations for environmental sounds such as animal vocalizations and tool sounds in superior and middle temporal regions of the temporal lobe. However, the degree of selectivity of these representations remains to be determined. The present study combined functional magnetic resonance imaging (fMRI) adaptation with a silent acquisition protocol to further investigate category-related auditory processing of environmental sounds. To this end, we consecutively presented pairs of sounds taken from the categories 'tool sounds' or 'animal vocalizations' with either the same or different identity/category. We examined the degree of selectivity as evidenced by adaptation effects to both or only one sound category in the course of whole-brain as well as functionally and anatomically constrained region of interest analyses. While most regions predominately in the temporal cortex showed an adaptation to both sound categories, particularly the left superior temporal gyrus (STG) and the left posterior middle temporal gyrus (pMTG) selectively adapted to animal vocalizations and tool sounds, respectively. However, the activation profiles of these regions differed with respect to the general responsiveness to sounds. While tool sounds still produced fMRI signals significantly different from fixation baseline in the STG, this was not the case for animal vocalizations in pMTG. Consistent with the interpretation of STG as an intermediate auditory processing stage, this region might differentiate auditory stimuli into categories based on variations of physical stimulus properties. However, processing in left pMTG seems to be even more restricted to action-related sounds of man-made objects.

To date, noninvasive neuroimaging research on multisensory perception has focused on cortical activations. In a series of elegant functional magnetic resonance imaging experiments, Beauchamp and Ro recently investigated altered cortical activations associated with acquired sound–touch synesthesia resulting from a thalamic lesion. Their findings highlight the important role of intact thalamocortical projections for preventing illusory crossmodal perception and for underlying reliable multisensory integration.

The processing of audiovisual information is an important aspect of object recognition since many objects are characterized by visual and auditory features. The images and sounds of everyday life objects are often associated with positive or negative emotions. There is evidence that emotional valence modulates the neural processing of object images and sounds presented in isolation. However, the impact of emotional valence on the neural processing of audiovisual objects is unknown. The aim of the present study was to investigate the influence of evaluative conditioning on cortical plasticity in human audiovisual object processing. We used functional magnetic resonance imaging (fMRI) to analyze changes in cortical audiovisual processing of unfamiliar artificial objects and sounds in naive subjects (Pre fMRI) and after a behavioral evaluative conditioning session in which subjects acquired positive and negative emotional associations with the artificial stimuli (Post fMRI). Results from the Post fMRI showed that additional brain regions were recruited for the processing of positively and negatively conditioned stimuli compared to the Pre fMRI data. The processing of positive stimuli additionally involved the left caudate nucleus and the right medial prefrontal cortex whereas the processing of negative stimuli additionally recruited the left insula. Furthermore, a congruence effect for matching emotional stimulus pairs was found in the right transversal temporal gyrus. These results indicate that emotional valence modulates object-related audiovisual processing. Moreover, we were able to show that emotional valence can be induced by a behavioral evaluative conditioning procedure leading to plastic changes in the processing of audiovisual stimuli.