Refine
Has Fulltext
- yes (13)
Is part of the Bibliography
- yes (13)
Year of publication
Document Type
- Journal article (10)
- Doctoral Thesis (3)
Keywords
- amygdala (13) (remove)
Institute
- Klinik und Poliklinik für Psychiatrie, Psychosomatik und Psychotherapie (6)
- Institut für Psychologie (4)
- Graduate School of Life Sciences (2)
- Institut für Anatomie und Zellbiologie (2)
- Institut für Klinische Neurobiologie (1)
- Klinik und Poliklinik für Hals-, Nasen- und Ohrenkrankheiten, plastische und ästhetische Operationen (1)
- Lehrstuhl für Molekulare Psychiatrie (1)
- Neurologische Klinik und Poliklinik (1)
Humans form impressions of others by associating persons (faces) with negative or positive social outcomes. This learning process has been referred to as social conditioning. In everyday life, affective nonverbal gestures may constitute important social signals cueing threat or safety, which therefore may support aforementioned learning processes. In conventional aversive conditioning, studies using electroencephalography to investigate visuocortical processing of visual stimuli paired with danger cues such as aversive noise have demonstrated facilitated processing and enhanced sensory gain in visual cortex. The present study aimed at extending this line of research to the field of social conditioning by pairing neutral face stimuli with affective nonverbal gestures. To this end, electro-cortical processing of faces serving as different conditioned stimuli was investigated in a differential social conditioning paradigm. Behavioral ratings and visually evoked steady-state potentials (ssVEP) were recorded in twenty healthy human participants, who underwent a differential conditioning procedure in which three neutral faces were paired with pictures of negative (raised middle finger), neutral (pointing), or positive (thumbs-up) gestures. As expected, faces associated with the aversive hand gesture (raised middle finger) elicited larger ssVEP amplitudes during conditioning. Moreover, theses faces were rated as to be more arousing and unpleasant. These results suggest that cortical engagement in response to faces aversively conditioned with nonverbal gestures is facilitated in order to establish persistent vigilance for social threat-related cues. This form of social conditioning allows to establish a predictive relationship between social stimuli and motivationally relevant outcomes.
An important feature of addiction is the high drug craving that may promote the continuation of consumption. Environmental stimuli classically conditioned to drug-intake have a strong motivational power for addicts and can elicit craving. However, addicts differ in the attitudes towards their own consumption behavior: some are content with drug taking (consonant users) whereas others are discontent (dissonant users). Such differences may be important for clinical practice because the experience of dissonance might enhance the likelihood to consider treatment. This fMRI study investigated in smokers whether these different attitudes influence subjective and neural responses to smoking stimuli. Based on self-characterization, smokers were divided into consonant and dissonant smokers. These two groups were presented smoking stimuli and neutral stimuli. Former studies have suggested differences in the impact of smoking stimuli depending on the temporal stage of the smoking ritual they are associated with. Therefore, we used stimuli associated with the beginning (BEGIN-smoking-stimuli) and stimuli associated with the terminal stage (END-smoking-stimuli) of the smoking ritual as distinct stimulus categories. Stimulus ratings did not differ between both groups. Brain data showed that BEGIN-smoking-stimuli led to enhanced mesolimbic responses (amygdala, hippocampus, insula) in dissonant compared to consonant smokers. In response to END-smoking-stimuli, dissonant smokers showed reduced mesocortical responses (orbitofrontal cortex, subcallosal cortex) compared to consonant smokers. These results suggest that smoking stimuli with a high incentive value (BEGIN-smoking-stimuli) are more appetitive for dissonant than consonant smokers at least on the neural level. To the contrary, smoking stimuli with low incentive value (END-smoking-stimuli) seem to be less appetitive for dissonant smokers than consonant smokers. These differences might be one reason why dissonant smokers experience difficulties in translating their attitudes into an actual behavior change.
Predictability of threat is one of the key modulators of neural activity in fear and anxiety-related threat processes and there is a considerable number of studies focusing on the exact contribution of centromedial amygdala and Bed nucleus of stria terminalis (BNST) in animals as well as in humans. In this research field, some studies already investigated the differential involvement of both areas during temporally predictable and unpredictable threat processes in humans. However, these studies showed several limitations e.g. small sample size, no predictable threat conditions, no separation of anticipation and confrontation processes, which should be addressed in future studies. Furthermore, evidence for group-based inter-individual differences of amygdala and BNST activity during predictable and unpredictable threat processes have not been studied extensively.
Several studies suggest a relevant role of the amygdala and BNST activity in phobic processes in patients with specific phobia, but no study so far has investigated the exact contribution of centromedial amygdala (CM) and BNST during temporally predictable and unpredictable threat processes in specific phobia.
This thesis consisted of three studies and aimed to evaluate the exact contribution of CM and BNST during temporally predictable and unpredictable threat anticipation and confrontation with the use of an optimized functional magnetic resonance imaging (fMRI) paradigm, which aimed to solve methodological limitations of recent studies. Study 1 used a large sample of healthy participants who were grouped based on NPSR1 genotype, and study 2 and study 3 used a sample of patients with spider phobia. In sum, the results of all three studies indicated, that BNST is more relevant for anticipation processes as compared to the CM. Contrary, during the confrontation phase the CM displays a greater relevance for threat confrontation processes.
In recent years, various studies have investigated the extent to which treatment success can be predicted in patients with anxiety disorders based on pre-treatment fMRI activity. Therefore, this was investigated for the first time in study 3 in patients with spider phobia during temporally predictable and unpredictable threat processes. Results indicated that independent of temporal predictability lower anterior cingulate cortex (ACC) activity during threat anticipation and engaged BNST during threat confrontation might be benefitting factors for successful therapy response in spider phobia.
Borderline personality disorder (BPD) patients’ hypersensitivity for emotionally relevant stimuli has been suggested be due to abnormal activity and connectivity in (para-)limbic and prefrontal brain regions during stimulus processing. The neuropeptide oxytocin has been shown to modulate activity and functional connectivity in these brain regions, thereby optimizing the processing of emotional and neutral stimuli. To investigate whether oxytocin would be capable of attenuating BPD patients’ hypersensitivity for such stimuli, we recorded brain activity and gaze behavior during the processing of complex scenes in 51 females with and 48 without BPD after intranasal application of either oxytocin or placebo. We found divergent effects of oxytocin on BPD and healthy control (HC) participants’ (para-)limbic reactivity to emotional and neutral scenes: Oxytocin decreased amygdala and insula reactivity in BPD participants but increased it in HC participants, indicating an oxytocin-induced normalization of amygdala and insula activity during scene processing. In addition, oxytocin normalized the abnormal coupling between amygdala activity and gaze behavior across all scenes in BPD participants. Overall, these findings suggest that oxytocin may be capable of attenuating BPD patients’ hypersensitivity for complex scenes, irrespective of their valence.
Der Mandelkernkomplex (Amygdala) ist ein Kerngebiet im medialen Temporallappen, das zum limbischen System gehört und dem eine wichtige Rolle in der Regulation von Gefühlen, sozialem Verhalten, Affekten, Gedächtnis und Sexualität zugeschrieben wird. Die mit Hilfe der 3D-Software Amira erstellten dreidimensionalen Rekonstruktionen des Mandelkernkomplexes von Kontrollfällen und Personen mit M. Alzheimer, Chorea Huntington, M. Little und Megalenzephalie basierten auf den mikroskopisch ausgewerteten zytoarchitektonischen Abgrenzungen der amygdaloiden Kerngebiete der nach Nissl gefärbten Hirnschnittpräparate. Die quantitativen Ergebnisse wurden mit bewährten stereologischen Methoden verglichen und den mit Post-mortem- und In-vivo-Verfahren generierten Ergebnissen anderer Studien gegenüber gestellt. Dabei wurden die Nomenklatur und die Abgrenzung der einzelnen Kerne diskutiert und auf exogene und biologische Volumen und Zelldichte beeinflussende Faktoren eingegangen, die die exakte und reproduzierbare Volumenbestimmung des menschlichen ZNS und seiner Komponenten erschweren. Unter Berücksichtigung von Schrumpfungsfaktoren und mehr oder minder großen Differenzen in der Abgrenzung des Mandelkernkomplexes sind die eigenen Daten mit bisher veröffentlichten Untersuchungen gut vergleichbar. Die in dieser Arbeit beschriebene Methode der dreidimensionalen Rekonstruktion von Hirnstrukturen eröffnet neue Möglichkeiten der Darstellung und Animation, die entscheidende wissenschaftliche Kenntnisse und wichtige Hinweise zur Auswertung MRT-basierter Morphometrie liefern und damit zur Diagnostik neuropsychiatrischer Erkrankungen beitragen kann.
The Behavioral Inhibition System (BIS) as defined within the Reinforcement Sensitivity Theory (RST) modulates reactions to stimuli indicating aversive events. Gray's trait Anxiety determines the extent to which stimuli activate the BIS. While studies have identified the amygdala-septo-hippocampal circuit as the key-neural substrate of this system in recent years and measures of resting-state dynamics such as randomness and local synchronization of spontaneous BOLD fluctuations have recently been linked to personality traits, the relation between resting-state dynamics and the BIS remains unexplored. In the present study, we thus examined the local synchronization of spontaneous fMRI BOLD fluctuations as measured by Regional Homogeneity (ReHo) in the hippocampus and the amygdala in twenty-seven healthy subjects. Correlation analyses showed that Gray's trait Anxiety was significantly associated with mean ReHo in both the amygdala and the hippocampus. Specifically, Gray's trait Anxiety explained 23% and 17% of resting-state ReHo variance in the left amygdala and the left hippocampus, respectively. In summary, we found individual differences in Gray's trait Anxiety to be associated with ReHo in areas previously associated with BIS functioning. Specifically, higher ReHo in resting-state neural dynamics corresponded to lower sensitivity to punishment scores both in the amygdala and the hippocampus. These findings corroborate and extend recent findings relating resting-state dynamics and personality while providing first evidence linking properties of resting-state fluctuations to Gray's BIS.
Juvenile neuronal ceroid lipofuscinosis (JNCL or Batten disease) caused by mutations in the CLN3 gene is the most prevalent inherited neurodegenerative disease in childhood resulting in widespread central nervous system dysfunction and premature death. The consequences of CLN3 mutation on the progression of the disease, on neuronal transmission, and on central nervous network dysfunction are poorly understood. We used Cln3 knockout (Cln3\(^{Δex1-6}\)) mice and found increased anxiety-related behavior and impaired aversive learning as well as markedly affected motor function including disordered coordination. Patch-clamp and loose-patch recordings revealed severely affected inhibitory and excitatory synaptic transmission in the amygdala, hippocampus, and cerebellar networks. Changes in presynaptic release properties may result from dysfunction of CLN3 protein. Furthermore, loss of calbindin, neuropeptide Y, parvalbumin, and GAD65-positive interneurons in central networks collectively support the hypothesis that degeneration of GABAergic interneurons may be the cause of supraspinal GABAergic disinhibition.
Several studies have investigated the neural responses triggered by emotional pictures, but the specificity of the involved structures such as the amygdala or the ventral striatum is still under debate. Furthermore, only few studies examined the association of stimuli’s valence and arousal and the underlying brain responses. Therefore, we investigated brain responses with functional magnetic resonance imaging of 17 healthy participants to pleasant and unpleasant affective pictures and afterwards assessed ratings of valence and arousal. As expected, unpleasant pictures strongly activated the right and left amygdala, the right hippocampus, and the medial occipital lobe, whereas pleasant pictures elicited significant activations in left occipital regions, and in parts of the medial temporal lobe. The direct comparison of unpleasant and pleasant pictures, which were comparable in arousal clearly indicated stronger amygdala activation in response to the unpleasant pictures. Most important, correlational analyses revealed on the one hand that the arousal of unpleasant pictures was significantly associated with activations in the right amygdala and the left caudate body. On the other hand, valence of pleasant pictures was significantly correlated with activations in the right caudate head, extending to the nucleus accumbens (NAcc) and the left dorsolateral prefrontal cortex. These findings support the notion that the amygdala is primarily involved in processing of unpleasant stimuli, particularly to more arousing unpleasant stimuli. Reward-related structures like the caudate and NAcc primarily respond to pleasant stimuli, the stronger the more positive the valence of these stimuli is.
Anticipation of potentially threatening social situations is a key process in social anxiety disorder (SAD). In other anxiety disorders, recent research of neural correlates of anticipation of temporally unpredictable threat suggests a temporally dissociable involvement of amygdala and bed nucleus of the stria terminalis (BNST) with phasic amygdala responses and sustained BNST activation. However, the temporal profile of amygdala and BNST responses during temporal unpredictability of threat has not been investigated in patients suffering from SAD. We used functional magnetic resonance imaging (fMRI) to investigate neural activation in the central nucleus of the amygdala (CeA) and the BNST during anticipation of temporally unpredictable aversive (video camera observation) relative to neutral (no camera observation) events in SAD patients compared to healthy controls (HC). For the analysis of fMRI data, we applied two regressors (phasic/sustained) within the same model to detect temporally dissociable brain responses. The aversive condition induced increased anxiety in patients compared to HC. SAD patients compared to HC showed increased phasic activation in the CeA and the BNST for anticipation of aversive relative to neutral events. SAD patients as well as HC showed sustained activity alterations in the BNST for aversive relative to neutral anticipation. No differential activity during sustained threat anticipation in SAD patients compared to HC was found. Taken together, our study reveals both CeA and BNST involvement during threat anticipation in SAD patients. The present results point towards potentially SAD-specific threat processing marked by elevated phasic but not sustained CeA and BNST responses when compared to HC.
Despite fine tuning voluntary movement as the most prominently studied function of the cerebellum, early human studies suggested cerebellar involvement emotion regulation. Since, the cerebellum has been associated with various mood and anxiety-related conditions. Research in animals provided evidence for cerebellar contributions to fear memory formation and extinction. Fear and anxiety can broadly be referred to as defensive states triggered by threat and characterized by multimodal adaptations such as behavioral and cardiac responses integrated into an intricately orchestrated defense reaction. This is mediated by an evolutionary conserved, highly interconnected network of defense-related structures with functional connections to the cerebellum. Projections from the deep cerebellar nucleus interpositus to the central amygdala interfere with retention of fear memory. Several studies uncovered tight functional connections between cerebellar deep nuclei and pyramis and the midbrain periaqueductal grey. Specifically, the fastigial nucleus sends direct projections to the ventrolateral PAG to mediate fear-evoked innate and learned freezing behavior. The cerebellum also regulates cardiovascular responses such as blood pressure and heart rate-effects dependent on connections with medullary cardiac regulatory structures. Because of the integrated, multimodal nature of defensive states, their adaptive regulation has to be highly dynamic to enable responding to a moving threatening stimulus. In this, predicting threat occurrence are crucial functions of calculating adequate responses. Based on its role in prediction error generation, its connectivity to limbic regions, and previous results on a role in fear learning, this review presents the cerebellum as a regulator of integrated cardio-behavioral defensive states.
Die Amygdala ist ein Kernkomplex, der dicht von serotonergen Afferenzen innerviert wird. Sowohl bei Tieren als auch beim Menschen spielen Interaktionen zwischen dem serotonergen System und der Amygdala bei der Verarbeitung von Reizen, die mit Angst oder Stress assoziiert sind, eine zentrale Rolle. Genetische Variationen im serotonergen System und/oder dauerhafter Stress können dazu führen, dass diese Verarbeitungsprozesse fehlerhaft ablaufen, wodurch Verhaltensanormalitäten bzw. die Entstehung psychiatrischer Erkrankungen begünstigt werden. Die Zielneurone der serotonergen Transmission in der Amygdala, die molekularen Mechanismen möglicher Interaktionen und strukturelle Konsequenzen der Störungen dieser Interaktionen sind jedoch bis zum heutigen Zeitpunkt noch nicht vollständig bekannt. Daher bestand ein Ziel der vorliegenden Arbeit darin, den Einfluss eines Ungleichgewichts im serotonergen System (5-Htt KO) sowie von wiederholtem, sozialem Stress auf die neuronale Morphologie der Amygdala zu analysieren und Zielneurone serotonerger Afferenzen zu identifizieren und zu charakterisieren, um die neuronalen Netzwerke der Emotionsverarbeitung besser verstehen zu können. Um vom 5-Htt–Genotyp abhängige und stressbedingte neuromorphologische Veränderungen zu untersuchen, wurden dreidimensionale Rekonstruktionen von Neuronen der laterobasalen Amygdala von männlichen, adulten Wildtyp (WT)- und 5-Htt KO-Mäusen angefertigt und bezüglich verschiedener morphologischer Parameter ausgewertet. An den Pyramidenzellen wurden nur geringfügige Veränderungen der dendritischen Komplexität, jedoch, im Vergleich zu WT-Mäusen, eine wesentliche Erhöhung der Dornendichte an spezifischen dendritischen Kompartimenten bei gestressten WT-Mäusen, sowie nicht gestressten und gestressten 5-Htt KO-Mäusen nachgewiesen. Im Vergleich zu nicht gestressten WT–Mäusen war die dendritische Dornendichte aller anderen Gruppen gleichermaßen erhöht. Die Sternzelle, zeigten bezüglich der untersuchten Parameter keine morphologischen Veränderungen auf. Eine besondere Subpopulation der Interneurone stellen die NeuropeptidY (NPY)–Neurone der laterobasalen Amygdala dar, da sie in diesen Nuclei anxiolytisch wirken. Es gibt nur wenige Anhaltspunkte darüber, durch welche Systeme NPY–Neurone moduliert werden. Da sowohl NPY–Neurone in der laterobasalen Amygdala als auch das serotonerge System an angstregulierenden Prozessen beteiligt sind, sollte im zweiten Teil der vorliegenden Arbeit untersucht werden, ob es sich bei diesen Neuronen um Zielstrukturen des serotonergen Systems handelt. Mittels licht- und elektronenmikroskopischer Analysen wurden synaptische Kontakte zwischen serotonergen Afferenzen und NPY-immunreaktiven Neuronen in der laterobasalen Amygdala von Ratten verifiziert. Da der funktionelle Einfluss der serotonergen Innervation auf diese Zielneurone von deren Serotoninrezeptor (5-HTR)-Ausstattung abhängt, wurden Koexpressionsanalysen von NPY mRNA mit den mRNAs verschiedener 5-HTR durchgeführt. Die Analysen ergaben, dass NPY mRNA–reaktive Neurone in der laterobasalen Amygdala 5-HT1A und 5-HT2C, jedoch nicht 5-HT3 mRNA koexprimieren. Die in der vorliegenden Arbeit erzielten Resultate liefern neue Erkenntnisse über den Einfluss des serotonergen Systems auf die laterobasale Amygdala von Mäusen und Ratten. Bei den Veränderungen der dendritischen Dornendichte nach sozialen Stresserfahrungen könnte es sich um neuroadaptive bzw. kompensatorische Mechanismen der Pyramidenzellen handeln, die WT-Mäusen eine Anpassung an sich ändernde, negative Umweltbedingungen ermöglicht. Die erhöhte Dornendichte könnte dabei die Ausbildung eines „emotionalen Gedächtnisses“ repräsentieren, das eine flexible Verhaltensantwort auf ein erneutes Auftauchen von Gefahr erlaubt. Eine solche Modulation der Erregbarkeit der laterobasalen Amygdala könnte beispielsweise über eine situationsentsprechende Hemmung des Outputs der Pyramidenzellen durch differentiell aktive inhibitorische Netzwerke erfolgen. Eine differentielle Aktivierung kann z. B. über unterschiedliche Rezeptorausstattungen, wie es in der Subpopulation der NPY–Neurone in der vorliegenden Arbeit nachgewiesen wurde, erfolgen. Das erhöhte angstähnliche Verhalten der 5-Htt KO-Mäuse nach wiederholtem Stress könnte mit der Unfähigkeit zusammenhängen, in entsprechenden Situationen durch Neubildung von Dornen zu reagieren, da die Dornendichte bei diesen Tieren schon unter stressarmen Umweltbedingungen ihr Maximum erreicht hat. Sowohl Fehlfunktionen der neuronalen Plastizität als auch mögliche Fehlfunktionen der differentiellen Inhibierung der Pyramidenzellen durch Interneurone, die durch genetische Variationen und/oder Stress bedingt sein können, könnten eine „offene Tür“ repräsentieren, die zu manifesten Auffälligkeiten im Verhalten bei Tieren führt bzw. auch zur Entstehung bestimmter psychiatrischer Erkrankungen beim Menschen beiträgt.
Pharmacobehavioral studies in experimental animals, and imaging studies in humans, indicate that serotonergic transmission in the amygdala plays a key role in emotional processing, especially for anxiety-related stimuli. The lateral and basolateral amygdaloid nuclei receive a dense serotonergic innervation in all species studied to date. We investigated interrelations between serotonergic afferents and neuropeptide Y (NPY)-producing neurons, which are a subpopulation of inhibitory interneurons in the rat lateral and basolateral nuclei with particularly strong anxiolytic properties. Dual light microscopic immunolabeling showed numerous appositions of serotonergic afferents on NPY-immunoreactive somata. Using electron microscopy, direct membrane appositions and synaptic contacts between serotonin-containing axon terminals and NPY-immunoreactive cellular profiles were unequivocally established. Double in situ hybridization documented that more than 50 %, and about 30–40 % of NPY mRNA-producing neurons, co-expressed inhibitory 5-HT1A and excitatory 5-HT2C mRNA receptor subtype mRNA, respectively, in both nuclei with no gender differences. Triple in situ hybridization showed that individual NPY mRNA-producing interneurons co-express both 5-HT1A and 5-HT2C mRNAs. Co-expression of NPY and 5-HT3 mRNA was not observed. The results demonstrate that serotonergic afferents provide substantial innervation of NPY-producing neurons in the rat lateral and basolateral amygdaloid nuclei. Studies of serotonin receptor subtype co-expression indicate a differential impact of the serotonergic innervation on this small, but important, population of anxiolytic interneurons, and provide the basis for future studies of the circuitry underlying serotonergic modulation of emotional stimulus processing in the amygdala.
We review the role of oscillations in the brain and in the auditory system showing that the ability of humans to distinguish changes in pitch can be explained as a precise analysis of temporal information in auditory signals by neural oscillations. The connections between auditory brain stem chopper neurons construct neural oscillators, which discharge spikes at various constant intervals that are integer multiples of 0.4 ms, contributing to the temporal processing of auditory cochlear output. This is subsequently spatially mapped in the inferior colliculus. Electrophysiological measurements of auditory chopper neurons in different species show oscillations with periods which are integer multiples of 0.4 ms. The constant intervals of 0.4 ms can be attributed to the smallest synaptic delay between interconnected simulated chopper neurons. We also note the patterns of similarities between microcircuits in the brain stem and other parts of the brain (e.g., the pallidum, reticular formation, locus coeruleus, oculomotor nuclei, limbic system, amygdala, hippocampus, basal ganglia and substantia nigra), dedicated to the processing of temporal information. Similarities in microcircuits across the brain reflect the importance of one of the key mechanisms in the information processing in the brain, namely the temporal coupling of different neural events via coincidence detection.