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Background Neuroimaging studies of patients with major depression have revealed abnormal intrinsic functional connectivity measured during the resting state in multiple distributed networks. However, it is unclear whether these findings reflect the state of major depression or reflect trait neurobiological underpinnings of risk for major depression. Methods We compared resting-state functional connectivity, measured with functional magnetic resonance imaging, between unaffected children of parents who had documented histories of major depression (at-risk, n = 27; 8–14 years of age) and age-matched children of parents with no lifetime history of depression (control subjects, n = 16). Results At-risk children exhibited hyperconnectivity between the default mode network and subgenual anterior cingulate cortex/orbital frontal cortex, and the magnitude of connectivity positively correlated with individual symptom scores. At-risk children also exhibited 1) hypoconnectivity within the cognitive control network, which also lacked the typical anticorrelation with the default mode network; 2) hypoconnectivity between left dorsolateral prefrontal cortex and subgenual anterior cingulate cortex; and 3) hyperconnectivity between the right amygdala and right inferior frontal gyrus, a key region for top-down modulation of emotion. Classification between at-risk children and control subjects based on resting-state connectivity yielded high accuracy with high sensitivity and specificity that was superior to clinical rating scales. Conclusions Children at familial risk for depression exhibited atypical functional connectivity in the default mode, cognitive control, and affective networks. Such task-independent functional brain measures of risk for depression in children could be used to promote early intervention to reduce the likelihood of developing depression.

We asked whether brain connectomics can predict response to treatment for a neuropsychiatric disorder better than conventional clinical measures. Pre-treatment resting-state brain functional connectivity and diffusion-weighted structural connectivity were measured in 38 patients with social anxiety disorder (SAD) to predict subsequent treatment response to cognitive behavioral therapy (CBT). We used a priori bilateral anatomical amygdala seed-driven resting connectivity and probabilistic tractography of the right inferior longitudinal fasciculus together with a data-driven multivoxel pattern analysis of whole-brain resting-state connectivity before treatment to predict improvement in social anxiety after CBT. Each connectomic measure improved the prediction of individuals' treatment outcomes significantly better than a clinical measure of initial severity, and combining the multimodal connectomics yielded a fivefold improvement in predicting treatment response. Generalization of the findings was supported by leave-one-out cross-validation. After dividing patients into better or worse responders, logistic regression of connectomic predictors and initial severity combined with leave-one-out cross-validation yielded a categorical prediction of clinical improvement with 81% accuracy, 84% sensitivity and 78% specificity. Connectomics of the human brain, measured by widely available imaging methods, may provide brain-based biomarkers (neuromarkers) supporting precision medicine that better guide patients with neuropsychiatric diseases to optimal available treatments, and thus translate basic neuroimaging into medical practice.

Depression is among the most common neuropsychiatric disorders. It remains unclear whether brain abnormalities associated with depression reflect the pathological state of the disease or neurobiological traits predisposing individuals to depression. Parental history of depression is a risk factor that more than triples the risk of depression. We compared white matter (WM) microstructure cross-sectionally in 40 children ages 8-14 with versus without parental history of depression (At-Risk vs. Control). There were significant differences in age-related changes of fractional anisotropy (FA) between the groups, localized in the anterior fronto-limbic WM pathways, including the anterior cingulum and the genu of the corpus callosum. Control children exhibited typical increasing FA with age, whereas At-Risk children exhibited atypical decreasing FA with age in these fronto-limbic regions. Furthermore, dorsal cingulate FA significantly correlated with depressive symptoms for At-Risk children. The results suggest maturational WM microstructure differences in mood-regulatory neurocircuitry that may contribute to neurodevelopmental risk for depression. The study provides new insights into neurodevelopmental susceptibility to depression and related disabilities that may promote early preventive intervention approaches.

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.

Despite growing evidence for atypical amygdala function and structure in major depression, it remains uncertain as to whether these brain differences reflect the clinical state of depression or neurobiological traits that predispose individuals to major depression. We examined function and structure of the amygdala and associated areas in a group of unaffected children of depressed parents (at-risk group) and a group of children of parents without a history of major depression (control group). Compared to the control group, the at-risk group showed increased activation to fearful relative to neutral facial expressions in the amygdala and multiple cortical regions, and decreased activation to happy relative to neutral facial expressions in the anterior cingulate cortex and supramarginal gyrus. At-risk children also exhibited reduced amygdala volume. The extensive hyperactivation to negative facial expressions and hypoactivation to positive facial expressions in at-risk children are consistent with behavioral evidence that risk for major depression involves a bias to attend to negative information. These functional and structural brain differences between at-risk children and controls suggest that there are trait neurobiological underpinnings of risk for major depression., Highlights • We studied brain correlates of familial risk for major depression. • At-risk children exhibited hyperactivation to fearful faces compared to controls. • At-risk children exhibited hypoactivation to happy faces compared to controls. • At-risk children exhibited reduced amygdala volume compared to controls. • These results identify trait neurobiological underpinnings of risk for depression.

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.

Faces and bodies are arguably the visual stimuli most relevant for human social interactions. Only recently, however, has research begun to reveal the interaction between face and body perception. Here we report on a recent study by Ghuman and colleagues and other behavioral and neuroimaging investigations that, taken together, provide compelling evidence for a tight coupling of face and body perception.

Context: Current behavioral measures poorly predict treatment outcome in social anxiety disorder (SAD). To our knowledge, this is the first study to examine neuroimaging-based treatment prediction in SAD. Objective: To measure brain activation in patients with SAD as a biomarker to predict subsequent response to cognitive behavioral therapy (CBT). Design: Functional magnetic resonance imaging (fMRI) data were collected prior to CBT intervention. Changes in clinical status were regressed on brain responses and tested for selectivity for social stimuli. Setting: Patients were treated with protocol-based CBT at anxiety disorder programs at Boston University or Massachusetts General Hospital and underwent neuroimaging data collection at Massachusetts Institute of Technology. Patients: Thirty-nine medication-free patients meeting DSM-IV criteria for the generalized subtype of SAD. Interventions: Brain responses to angry vs neutral faces or emotional vs neutral scenes were examined with fMRI prior to initiation of CBT. Main Outcome Measures: Whole-brain regression analyses with differential fMRI responses for angry vs neutral faces and changes in Liebowitz Social Anxiety Scale score as the treatment outcome measure. Results: Pretreatment responses significantly predicted subsequent treatment outcome of patients selectively for social stimuli and particularly in regions of higher-order visual cortex. Combining the brain measures with information on clinical severity accounted for more than 40% of the variance in treatment response and substantially exceeded predictions based on clinical measures at baseline. Prediction success was unaffected by testing for potential confounding factors such as depression severity at baseline. Conclusions: The results suggest that brain imaging can provide biomarkers that substantially improve predictions for the success of cognitive behavioral interventions and more generally suggest that such biomarkers may offer evidence-based, personalized medicine approaches for optimally selecting among treatment options for a patient.

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.

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.

By using meaningful stimuli, multisensory research has recently started to investigate the impact of stimulus content on crossmodal integration. Variations in this respect have often been termed as "semantic". In this paper we will review work related to the question for which tasks the influence of semantic factors has been found and which cortical networks are most likely to mediate these effects. More specifically, the focus of this paper will be on processing of object stimuli presented in the auditory and visual sensory modalities. Furthermore, we will investigate which cortical regions are particularly responsive to experimental variations of content by comparing semantically matching ("congruent") and mismatching ("incongruent") experimental conditions. In this context, recent neuroimaging studies point toward a possible functional differentiation of temporal and frontal cortical regions, with the former being more responsive to semantically congruent and the latter to semantically incongruent audio-visual (AV) stimulation. To account for these differential effects, we will suggest in the final section of this paper a possible synthesis of these data on semantic modulation of AV integration with findings from neuroimaging studies and theoretical accounts of semantic memory.

We aimed at testing the cortical representation of complex natural sounds within auditory cortex using human functional magnetic resonance imaging (fMRI). To this end, we employed 2 different paradigms in the same subjects: a block-design experiment was to provide a localization of areas involved in the processing of animal vocalizations, whereas an event-related fMRI adaptation experiment was to characterize the representation of animal vocalizations in the auditory cortex. During the first experiment, we presented subjects with recognizable and degraded animal vocalizations. We observed significantly stronger fMRI responses for animal vocalizations compared with the degraded stimuli along the bilateral superior temporal gyrus (STG). In the second experiment, we employed an event-related fMRI adaptation paradigm in which pairs of auditory stimuli were presented in 4 different conditions: 1) 2 identical animal vocalizations, 2) 2 different animal vocalizations, 3) an animal vocalization and its degraded control, and 4) an animal vocalization and a degraded control of a different sound. We observed significant fMRI adaptation effects within the left STG. Our data thus suggest that complex sounds such as animal vocalizations are represented in putatively nonprimary auditory cortex in the left STG. Their representation is probably based on their spectrotemporal dynamics rather than simple spectral features.

Multisensory interactions occur early in time and in low-level cortical areas, including primary cortices. To test current models of early auditory-visual (AV) convergence in unisensory visual brain areas, we studied the effect of transcranial magnetic stimulation (TMS) of visual cortex on behavioral responses to unisensory (auditory or visual) or multisensory (simultaneous auditory-visual) stimulus presentation. Single-pulse TMS was applied over the occipital pole at short delays (30-150 ms) after external stimulus onset. Relative to TMS over a control site, reactions times (RTs) to unisensory visual stimuli were prolonged by TMS at 60-75 ms poststimulus onset (visual suppression effect), confirming stimulation of functional visual cortex. Conversely, RTs to unisensory auditory stimuli were significantly shortened when visual cortex was stimulated by TMS at the same delays (beneficial interaction effect of auditory stimulation and occipital TMS). No TMS-effect on RTs was observed for AV stimulation. The beneficial interaction effect of combined unisensory auditory and TMS-induced visual cortex stimulation matched and was correlated with the RT-facilitation after external multisensory AV stimulation without TMS, suggestive of multisensory interactions between the stimulus-evoked auditory and TMS-induced visual cortex activities. A follow-up experiment showed that auditory input enhances excitability within visual cortex itself (using phosphene-induction via TMS as a measure) over a similarly early time-window (75-120 ms). The collective data support a mechanism of early auditory-visual interactions that is mediated by auditory-driven sensitivity changes in visual neurons that coincide in time with the initial volleys of visual input.