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

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 human

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

Die Rolle der Amygdala und des insulären Kortex in emotionalen Funktionen: Untersuchungen mittels funktioneller Bildgebung kombiniert mit probabilistisch-anatomischen Karten

Activation of the human amygdala and the insular cortex has been reported in many neuroimaging studies that investigated emotions and its underlying brain network. The human amygdala is thought to play a pivotal role in the processing of emotionally sensory information and the insular cortex has been proposed as being involved in different functions including peripheral autonomic change and somatovisceral perception, which has been assumed to play an important role in emotion. There is anatomical evidence both for the amygdala and the insular cortex that they are not homogenous structures but are composed of multiple subregions. Very little is known, however, how these subregions behave functionally. (1) In this thesis functional MRI has been combined with cyto-architectonically defined probabilistic maps to analyze the response characteristics of the amygdala and its subregions (the laterobasal group = LB, the superficial group = SF, and the centromedial group = CM) in subjects during the processing of emotionally significant auditory stimuli. (2) Insular cortex subregions were investigated by conducting an activation likelihood estimate (ALE) meta-analysis mapping coordinates of activation foci obtained from different insula-neuroimaging studies. (3) In addition, based on a further coordinate-based meta-analysis of previous neuroimaging studies reporting amygdala-activation a co-activation likelihood estimation was carried out in order to delineate the brain areas consistently co-activated with the amygdala. (4) Finally, the impact of the degree to which the individual subjects experience the strength of their positive and negative emotions, a personally trait known as affect intensity, on brain activation patterns was studied using a correlation analysis. Based on previous studies it was expected that participants with high affect intensity scores activate more a network of brain areas that has been described to play a crucial role in emotion recognition, including the right somatosensory cortex, the supramarginal gyrus, and the right insular cortex. For interpretation of the results obtained, the usefulness of the functional map of the insular cortex that was established in this thesis was assessed. (1) In the fMRI experiment, differential, subregional amygdala response patterns could be demonstrated. Amygdala activity with positive auditory stimulation-related signal changes predominated in probabilistically defined LB, and negative responses predominated 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. (2) Subregional functional specialization in the anterior insular cortex was found based on the conducted ALE meta-analysis, showing different subregions consistently activated during motor tasks (located in the mid-insular cortex), language/auditory tasks (located in the rostral part of the anterior insula), and in respect to peripheral physiological changes (in the anteroventral insula), respectively. (3) The results of the amygdala meta-analysis revealed that probabilistically defined amygdala-activations co-activate with a restricted zone at the border of anterior insula and the frontal opercular cortex. (4) Correlation analysis with the affect intensity measure (AIM) revealed that subjects with high affect intensity demonstrated, as predicted, a stronger activity in the right somatosensory cortex, the supramarginal gyrus, and in the anteroventral insula region. The later brain region could be assigned, using the functional map of the insula established in part (3) of the thesis, to the part of the insula consistently showing peripheral autonomic change related activation, suggesting a stronger physiological response in the individuals scoring high in affect intensity as a possible cause for the AIM related differences in brain activation. The results of this thesis suggest that the combination of functional MRI and of meta-analyses of functional imaging studies with probabilistic anatomical maps may make an important contribution in improving functional localization and in investigating internal functional organization of emotion related brain areas.Funktionelle Aktivierung in der menschlichen Amygdala und im insulären Kortex wurde von einer Vielzahl bildgebender Studien berichtet, die die neurobiologischen Grundlagen von emotionalen Prozessen untersucht haben. Von der Amygdala wird angenommen, dass sie eine zentrale Rolle bei der Verarbeitung von emotional bedeutsamen sensorischen Reizen spielt. Der insuläre Kortex verfügt über vielfältige Funktionen, darunter die Wahrnehmung von peripher-physiologischen Veränderungen und die Verarbeitung von somato-visceralen Informationen, die auch als bedeutsam für emotionale Funktionen angesehen werden. Neuroanatomische Befunde deuten darauf hin, dass sowohl die Amygdala als auch der insuläre Kortex nicht homogene Strukturen darstellen, sondern dass in beiden Fällen von einer Untergliederung in Subareale auszugehen ist. Bisher ist jedoch wenig darüber bekannt, welche Funktionen diesen Subarealen beim Menschen zukommen. In der vorliegenden Arbeit wurde funktionelle Magnetresonanztomographie (fMRT) mit zytoarchitektonisch definierten, probabilistischen Karten kombiniert, um die Aktivierungseigenschaften der Amygdala und ihrer Subareale während der Darbietung auditiver Reize bei gesunden Versuchspersonen zu untersuchen. Des Weiteren wurden Subregionen des insulären Kortex durch eine 'activation likelihood estimate' (ALE) Meta-Analyse untersucht, bei der die Koordinaten von Aktivierungs-Foci aus publizierten funktionell-bildgebenden Studien zusammengefasst wurden. Basierend auf einer weiteren Meta-Analyse von Studien, die Amygdala-Aktivierung berichteten, wurde die Wahrscheinlichkeitsverteilung von gemeinsam mit Amygdala-Aktivierungen auftretenden Ko-Aktivierungen außerhalb der Amygdala bestimmt. Schließlich wurde der Einfluss von 'Affekt Intensität' auf neuronale Aktivierungsmuster während Darbietung von emotionalen Stimuli mittels einer Korrelationsanalyse ausgewertet. Als Ergebnis der fMRT Studie konnten differentielle, subregionale Aktivierungsmuster in der Amygdala gezeigt werden. Subregionale funktionelle Spezialisierung im anterioren insulären Kortex konnte basierend auf der durchgeführten Meta-Analyse gezeigt werden. Die Ergebnisse der Amygdala Meta-Analyse zeigen, dass Ko-Aktivierungen die konsistent zusammen mit probabilistisch definierten Amygdala-Aktivierugen auftreten, in der anterioren Insel lokalisiert sind. Die Ergebnisse legen nahe, dass die Kombination von fMRT und Meta-Analysen von bildgebenden Studien zusammen mit der Anwendung von probabilistisch-anatomischen Karten einen wichtigen Beitrag zur Verbesserung von funktionell-lokalisatorischer Studien leisten kann und eine Grundlage zur Untersuchung der internen Organisation von Gehirnstrukturen des emotionalen Systems beim Menschen darstellt

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

Does laughing have a stress-buffering effect in daily life? An intensive longitudinal study.

Positive affect is associated with alleviating mental and physiological stress responses. As laughter is a common physiological operationalization of positive affect, we investigated whether the effects of experiencing a stressful event on stress symptoms is lessened by frequency and intensity of daily laughter. Using an intensive longitudinal design, we ambulatory assessed the self-reported experience of stressful events, stress symptoms and the frequency as well as the intensity of laughter in university students' daily lives. Our hierarchical ecological momentary assessment data were analyzed with multilevel models. The results support the stress-buffering model of positive affect: We found that the frequency of laughter attenuated the association between stressful events and subsequent stress symptoms. The level of intensity of laughter, however, was found to have no significant effect. Future studies should use additional psychophysiological indicators of stress and straighten out the differential contributions of frequency and intensity of daily laughter

Insular volume reductions in patients with major depressive disorder

Background: Major Depressive Disorder (MDD) is one of the most common mental disorders. Converging evidence suggests that the insula plays an important role in the pathophysiology of MDD. Little is known regarding in which insula subregion volume alterations occur in patients with MDD. Methods: We analyzed voxel-based morphometry in T1-weighted MRI scans of unmedicated DSM-IV MDD patients (n=26) and in age, education, and sex matched healthy controls (HC, n=26). Furthermore, we performed a quantitative meta-analysis across 14 structural MRI MDD studies by applying the anatomical likelihood estimation technique to identify concordant volume reductions in MDD in the insula cortex. Results: We found significantly reduced grey matter volumes (GMV) in patients with MDD compared to HCs in the left mid-insula and in the right and left caudate nucleus. The left mid-insular volume reduction in our sample was consistent with the coordinate-based meta-analysis results. Conclusions: The findings highlight the role of the mid-insula in the psychopathology of MDD. The mid-insula subregion might be associated with reduced interoceptive abilities in patients with MDD that is the ability to process information of “how the body feels”. In addition, the caudate nucleus has been described as being part of a network that mediates emotional and motivational processes which seems to be affected in MDD

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

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