The Role of the Subgenual Anterior Cingulate Cortex and Amygdala in Environmental Sensitivity to Infant Crying.

Newborns and infants communicate their needs and physiological states through crying and emotional facial expressions. Little is known about individual differences in responding to infant crying. Several theories suggest that people vary in their environmental sensitivity with some responding generally more and some generally less to environmental stimuli. Such differences in environmental sensitivity have been associated with personality traits, including neuroticism. This study investigated whether neuroticism impacts neuronal, physiological, and emotional responses to infant crying by investigating blood-oxygenation-level dependent (BOLD) responses using functional magnetic resonance imaging (fMRI) in a large sample of healthy women (N = 102) with simultaneous skin conductance recordings. Participants were repeatedly exposed to a video clip that showed crying infants and emotional responses (valence, arousal, and irritation) were assessed after every video clip presentation. Increased BOLD signal during the perception of crying infants was found in brain regions that are associated with emotional responding, the amygdala and anterior insula. Significant BOLD signal decrements (i.e., habituation) were found in the fusiform gyrus, middle temporal gyrus, superior temporal gyrus, Broca's homologue on the right hemisphere, (laterobasal) amygdala, and hippocampus. Individuals with high neuroticism showed stronger activation in the amygdala and subgenual anterior cingulate cortex (sgACC) when exposed to infant crying compared to individuals with low neuroticism. In contrast to our prediction we found no evidence that neuroticism impacts fMRI-based measures of habituation. Individuals with high neuroticism showed elevated skin conductance responses, experienced more irritation, and perceived infant crying as more unpleasant. The results support the hypothesis that individuals high in neuroticism are more emotionally responsive, experience more negative emotions, and may show enhanced cognitive control during the exposure to infant distress, which may impact infant-directed behavior.

Who gets afraid in the MRI-scanner? Neurogenetics of state-anxiety changes during an fMRI experiment.

Experiments using functional magnetic resonance imaging (fMRI) play a fundamental role in affective neuroscience. When placed in an MR scanner, some volunteers feel safe and relaxed in this situation, while others experience uneasiness and fear. Little is known about the basis and consequences of such inter-individually different responses to the general experimental fMRI setting. In this study emotional stimuli were presented during fMRI and subjects' state-anxiety was assessed at the onset and end of the experiment while they were within the scanner. We show that Val/Val but neither Met/Met nor Val/Met carriers of the catechol-O-methyltransferase (COMT) Val(158)Met polymorphism-a prime candidate for anxiety vulnerability-became significantly more anxious during the fMRI experiment (N=97 females: 24 Val/Val, 51 Val/Met, and 22 Met/Met). Met carriers demonstrated brain responses with increased stability over time in the right parietal cortex and significantly better cognitive performances likely mediated by lower levels of anxiety. Val/Val, Val/Met and Met/Met did not significantly differ in state-anxiety at the beginning of the experiment. The exposure of a control group (N=56 females) to the same experiment outside the scanner did not cause a significant increase in state-anxiety, suggesting that the increase we observe in the fMRI experiment may be specific to the fMRI setting. Our findings reveal that genetics may play an important role in shaping inter-individual different emotional, cognitive and neuronal responses during fMRI experiments.

Structural basis of empathy and the domain general region in the anterior insular cortex.

Empathy is key for healthy social functioning and individual differences in empathy have strong implications for manifold domains of social behavior. Empathy comprises of emotional and cognitive components and may also be closely linked to sensorimotor processes, which go along with the motivation and behavior to respond compassionately to another person's feelings. There is growing evidence for local plastic change in the structure of the healthy adult human brain in response to environmental demands or intrinsic factors. Here we have investigated changes in brain structure resulting from or predisposing to empathy. Structural MRI data of 101 healthy adult females was analyzed. Empathy in fictitious as well as real-life situations was assessed using a validated self-evaluation measure. Furthermore, empathy-related structural effects were also put into the context of a functional map of the anterior insular cortex (AIC) determined by activation likelihood estimate (ALE) meta-analysis of previous functional imaging studies. We found that gray matter (GM) density in the left dorsal AIC correlates with empathy and that this area overlaps with the domain general region (DGR) of the anterior insula that is situated in-between functional systems involved in emotion-cognition, pain, and motor tasks as determined by our meta-analysis. Thus, we propose that this insular region where we find structural differences depending on individual empathy may play a crucial role in modulating the efficiency of neural integration underlying emotional, cognitive, and sensorimotor information which is essential for global empathy.

Pain and emotion in the insular cortex: evidence for functional reorganization in major depression.

Major Depressive Disorder (MDD) is among the top causes of disability worldwide and many patients with depression experience pain symptoms. Little is known regarding what makes depressed persons feel like they are in pain. An increasing number of neuroimaging studies show that both physical pain and depression involve the insular cortex. The present study aimed to investigate whether emotional processing in MDD patients is topologically shifted towards the insular area(s) involved in pain processing in healthy individuals. To achieve this aim, we investigated the functional organization of the insula by conducting meta-analyses of previously published neuroimaging studies on: (1) emotion in patients with MDD, (2) emotion in healthy subjects, and (3) physical pain in healthy subjects. Our results show that the dorsal part of the insula is reproducibly activated during experimental pain in healthy individuals, with multiple separate pain-related areas aligned along its dorsal border. Regions with maximal pain-related activation likelihood estimate (ALE) were located in the posterior (left) and dorsal mid-anterior insula (left and right). Furthermore, emotion-related peaks in healthy subjects were found both in its ventral (as shown in a previous meta-analysis) and dorsal anterior part. Importantly, emotion-related peaks in depressed patients were shifted to the dorsal anterior insula, where regions related to physical pain in healthy subjects are located. This shift was reflected in the observation that median z-coordinates of emotion-related responses in the left hemisphere were significantly larger in depressed patients than in healthy controls. This shift of emotion-related responses to the dorsal insula, i.e., where pain-processing takes place in healthy subjects, may play a role in "emotional allodynia" - a notion that individuals with MDD experience pain in response to stimuli that are normally not painful.

Variability of fMRI-response patterns at different spatial observation scales.

Functional organization units of the cerebral cortex exist over a wide range of spatial scales, from local circuits to entire cortical areas. In the last decades, scale-space representations of neuroimaging data suited to probe the multi-scale nature of cortical functional organization have been introduced and methodologically elaborated. For this purpose, responses are statistically detected over a range of spatial scales using a family of Gaussian filters, with small filters being related to fine and large filters-to coarse spatial scales. The goal of the present study was to investigate the degree of variability of fMRI-response patterns over a broad range of observation scales. To this aim, the same fMRI data set obtained from 18 subjects during a visuomotor task was analyzed with a range of filters from 4- to 16-mm full width at half-maximum (FWHM). We found substantial observation-scale-related variability. For example, using filter widths of 6- to 8-mm FWHM, in the group-level results, significant responses in the right secondary visual but not in the primary visual cortex were detected. However, when larger filters were used, the responses in the right primary visual cortex reached significance. Often, responses in probabilistically defined areas were significant when both small and large filters, but not intermediate filter widths were applied. This suggests that brain responses can be organized in local clusters of multiple distinct activation foci. Our findings illustrate the potential of multi-scale fMRI analysis to reveal novel features in the spatial organization of human brain responses.

Time scales of auditory habituation in the amygdala and cerebral cortex.

Habituation is a fundamental form of learning manifested by a decrement of neuronal responses to repeated sensory stimulation. In addition, habituation is also known to occur on the behavioral level, manifested by reduced emotional reactions to repeatedly presented affective stimuli. It is, however, not clear which brain areas show a decline in activity during repeated sensory stimulation on the same time scale as reduced valence and arousal experience and whether these areas can be delineated from other brain areas with habituation effects on faster or slower time scales. These questions were addressed using functional magnetic resonance imaging acquired during repeated stimulation with piano melodies. The magnitude of functional responses in the laterobasal amygdala and in related cortical areas and that of valence and arousal ratings, given after each music presentation, declined in parallel over the experiment. In contrast to this long-term habituation (43 min), short-term decreases occurring within seconds were found in the primary auditory cortex. Sustained responses that remained throughout the whole investigated time period were detected in the ventrolateral prefrontal cortex extending to the dorsal part of the anterior insular cortex. These findings identify an amygdalocortical network that forms the potential basis of affective habituation in humans.

Anatomical specificity of functional amygdala imaging of responses to stimuli with positive and negative emotional valence.

Non-invasive neuroimaging is increasingly used for investigating the human amygdala. Accurate functional localization in the amygdala region is, however, challenging and quantitative data on the anatomical specificity of functional amygdala imaging is lacking. We have therefore retrospectively investigated 114 recently published human functional imaging studies concerned with the amygdala. We determined the anatomical assignment probabilities of a total of 339 reported activation sites to the amygdala defined using a cytoarchitectonically verified probabilistic atlas system. We find that approximately 50% of reported responses were located in the region with high probability (> or =80%) of belonging to the amygdala. This group included responses related both to stimuli of positive and negative emotional valence. Approximately 10% of reported response sites were assigned to the hippocampus, with up to 100% assignment probability. The remaining peaks were either located in the border regions of the amygdala and/or hippocampus or outside of both of these structures. Within the amygdala, the majority of peaks (96.3%) were found in the laterobasal (LB) and superficial (SF) subregions. Only 3.7% of peaks were found in the centromedial group (CM), possibly because anatomically delineating the CM region of the amygdala is particularly difficult and hence its extent might have been underestimated. Moreover, these results show that a core region of the amygdala is responsive to stimuli both of positive and negative emotional valence. The current findings highlight the usefulness of probabilistic amygdala maps and also point to a need for the development of accurate in vivo delineation and parcellation of the amygdala.

Functional organization of the human anterior insular cortex.

The human insular cortex is involved in a wide range of functions including motor control, language, and homeostatic regulation. Little is known, however, how these functions are topographically organized in the insular cortex and how they are functionally related to the amygdala, which is anatomically connected to the insular cortex. We have investigated these questions by conducting an activation likelihood estimate (ALE) meta-analysis of previously published neuroimaging studies reporting insula effects. We find auditory and language tasks to preferentially activate an area in the dorsal part of the anterior insular cortex (AIC). Motor tasks involving both the upper and lower extremity reproducibly activated a posterior AIC region, adjacent to the sulcus centralis insulae (SCI). Significant co-activation with the probabilistically defined amygdala was located in the ventral AIC where also responses related to peripheral physiological changes were repeatedly reported. These findings show that the human AIC is a functionally differentiated brain region. The dorsal region of the AIC may be involved in auditory-motor integration, while the ventral part of the AIC may interface the amygdala with insular regions involved in the regulation of physiological changes related to emotional states. Thus, the present findings provide insights into the organization of human AIC and a methodological approach that may be further used to refine the emerging functional map of the insular cortex.

Signal quality of simultaneously recorded invasive and non-invasive EEG.

Both invasive and non-invasive electroencephalographic (EEG) recordings from the human brain have an increasingly important role in neuroscience research and are candidate modalities for medical brain-machine interfacing. It is often assumed that the major artifacts that compromise non-invasive EEG, such as caused by blinks and eye movement, are absent in invasive EEG recordings. Quantitative investigations on the signal quality of simultaneously recorded invasive and non-invasive EEG in terms of artifact contamination are, however, lacking. Here we compared blink related artifacts in non-invasive and invasive EEG, simultaneously recorded from prefrontal and motor cortical regions using an approach suitable for detection of small artifact contamination. As expected, we find blinks to cause pronounced artifacts in non-invasive EEG both above prefrontal and motor cortical regions. Unexpectedly, significant blink related artifacts were also found in the invasive recordings, in particular in the prefrontal region. Computing a ratio of artifact amplitude to the amplitude of ongoing brain activity, we find that the signal quality of invasive EEG is 20 to above 100 times better than that of simultaneously obtained non-invasive EEG. Thus, while our findings indicate that ocular artifacts do exist in invasive recordings, they also highlight the much better signal quality of invasive compared to non-invasive EEG data. Our findings suggest that blinks should be taken into account in the experimental design of ECoG studies, particularly when event related potentials in fronto-anterior brain regions are analyzed. Moreover, our results encourage the application of techniques for reducing ocular artifacts to further optimize the signal quality of invasive EEG.

Movement related activity in the high gamma range of the human EEG.

Electrocorticographic (ECoG) recordings obtained using intracranially implanted electrodes in epilepsy patients indicate that high gamma band (HGB) activity of sensorimotor cortex is focally increased during voluntary movement. These movement related HGB modulations may play an important role in sensorimotor cortex function. It is however currently not clear to what extent this type of neural activity can be detected using non-invasive electroencephalography (EEG) and how similar HGB responses in healthy human subjects are to those observed in epilepsy patients. Using the same arm reaching task, we have investigated spectral power changes both in intracranial ECoG recordings in epilepsy patients and in non-invasive EEG recordings optimized for detecting HGB activity in healthy subjects. Our results show a common HGB response pattern both in ECoG and EEG recorded above the sensorimotor cortex contralateral to the side of arm movement. In both cases, HGB activity increased around movement onset in the 60-90 Hz range and became most pronounced at reaching movement end. Additionally, we found EEG HGB activity above the frontal midline possibly generated by the anterior supplementary motor area (SMA), a region that was however not covered by the intracranial electrodes used in the present study. In summary, our findings show that HGB activity from human sensorimotor cortex can be non-invasively detected in healthy subjects using EEG, opening a new perspective for investigating the role of high gamma range neuronal activity both in function and dysfunction of the human cortical sensorimotor network.

A rapid sound-action association effect in human insular cortex.

BACKGROUND: Learning to play a musical piece is a prime example of complex sensorimotor learning in humans. Recent studies using electroencephalography (EEG) and transcranial magnetic stimulation (TMS) indicate that passive listening to melodies previously rehearsed by subjects on a musical instrument evokes differential brain activation as compared with unrehearsed melodies. These changes were already evident after 20-30 minutes of training. The exact brain regions involved in these differential brain responses have not yet been delineated. METHODOLOGY/PRINCIPAL FINDING: Using functional mri (fmri), we investigated subjects who passively listened to simple piano melodies from two conditions: in the 'actively learned melodies' condition subjects learned to play a piece on the piano during a short training session of a maximum of 30 minutes before the fMRI experiment, and in the 'passively learned melodies' condition subjects listened passively to and were thus familiarized with the piece. We found increased fMRI responses to actively compared with passively learned melodies in the left anterior insula, extending to the left fronto-opercular cortex. The area of significant activation overlapped the insular sensorimotor hand area as determined by our meta-analysis of previous functional imaging studies. CONCLUSIONS/SIGNIFICANCE: Our results provide evidence for differential brain responses to action-related sounds after short periods of learning in the human insular cortex. As the hand sensorimotor area of the insular cortex appears to be involved in these responses, re-activation of movement representations stored in the insular sensorimotor cortex may have contributed to the observed effect. The insular cortex may therefore play a role in the initial learning phase of action-perception associations.

Response properties of human amygdala subregions: evidence based on functional MRI combined with probabilistic anatomical maps.

The human amygdala is thought to play a pivotal role in the processing of emotionally significant sensory information. The major subdivisions of the human amygdala-the laterobasal group (LB), the superficial group (SF), and the centromedial group (CM)-have been anatomically delineated, but the functional response properties of these amygdala subregions in humans are still unclear. We combined functional MRI with cyto-architectonically defined probabilistic maps to analyze the response characteristics of amygdala subregions in subjects presented with auditory stimuli. We found positive auditory stimulation-related signal changes predominantly in probabilistically defined LB, and negative responses predominantly in SF and CM. In the left amygdala, mean response magnitude in the core area of LB with 90-100% assignment probability was significantly larger than in the core areas of SF and CM. These differences were observed for pleasant and unpleasant stimuli. Our findings reveal that the probabilistically defined anatomical subregions of the human amygdala show distinctive fMRI response patterns. The stronger auditory responses in LB as compared with SF and CM may reflect a predominance of auditory inputs to human LB, similar to many animal species in which the majority of sensory, including auditory, afferents project to this subdivision of the amygdala. Our study indicates that the intrinsic functional differentiation of the human amygdala may be probed using fMRI combined with probabilistic anatomical maps.