Juraj Kukolja

Selective processing of social stimuli in the superficial amygdala

The human amygdala plays a pivotal role in the processing of socially significant information. Anatomical studies show that the human amygdala is not a single homogeneous structure but is composed of segregable subregions. These have recently been functionally delineated by using a combination of functional magnetic resonance imaging (fMRI) and cytoarchitectonically defined probabilistic maps. However, the response characteristics and individual contribution of these subregions to the processing of social‐emotional stimuli are little understood. Here, we used this novel technique to segregate intra‐amygdalar responses to facial expressions and nonsocial control stimuli. We localized facial expression‐evoked signal changes bilaterally in the superficial amygdala, which suggests that this subregion selectively extracts the social value of incoming sensory information. Hum Brain Mapp, 2009.

Modeling a negative response bias in the human amygdala by noradrenergic-glucocorticoid interactions.

An emerging theme in the neuroscience of emotion is the question of how acute stress shapes, and distorts, social-emotional behavior. The prevailing neurocircuitry models of social-emotional behavior emphasize the central role of the amygdala. Acute stress leads to increased central levels of norepinephrine (NE) and cortisol (CORT), and evidence suggests that these endogenous neuromodulators synergistically influence amygdala responses to social-emotional stimuli. We therefore hypothesized that amygdala responses to emotional facial expressions would be susceptible to pharmacologically induced increases in central NE and CORT levels. To specifically test this hypothesis, we measured amygdala activation to emotional faces using functional magnetic resonance imaging in 62 healthy subjects under four pharmacological conditions: (1) single oral dose of placebo, (2) 4 mg of the selective NE-reuptake inhibitor reboxetine (RBX), (3) 30 mg of hydrocortisone, or (4) both drugs in combination. We found that a decrease in amygdala activation to positive facial emotion was coupled with an increase in amygdala activation to negative facial emotion in the RBX-CORT combined challenge condition. In conclusion, a pharmacologically induced elevation of central NE and CORT levels in healthy subjects created a negative response bias in the amygdala that did not exist at baseline. Our results implicate a causative role of NE–CORT interactions in the emergence of a negative bias of cognitive and emotional functions which is germane in stress-related affective spectrum disorders.

Cholinergic stimulation enhances neural activity associated with encoding but reduces neural activity associated with retrieval in humans.

The cerebral cholinergic system is centrally involved in memory formation. Studies in rodents suggest that cholinergic stimulation may facilitate encoding of new information but may interfere with retrieval. We investigated the effect of cholinergic stimulation on encoding and retrieval of episodic memory in humans. We also tested whether the putative benefit of cholinergic stimulation on memory function depends on individual baseline performance. Since such effects were expected to be greatest in an older population resulting from an age-related degeneration of the cholinergic system, we recruited 22 healthy older subjects (51–68 years) for an event-related functional magnetic resonance imaging experiment. In two separate scanning sessions, subjects encoded and retrieved items and their spatial context under cholinergic stimulation or placebo with the acetylcholine-esterase inhibitor physostigmine or saline being administered intravenously in a double-blind cross-over design. Baseline performance was recorded at a separate occasion without scanning. Cholinergic stimulation enhanced neural activity for successful versus unsuccessful spatial context encoding in the right hippocampus but reduced activity for successful versus unsuccessful spatial context retrieval in the right amygdala. These data may bridge the gap between rodent and human studies by showing that also in man cholinergic stimulation enhances encoding but interferes with retrieval on a neural level. Furthermore, baseline performance negatively correlated with the effect of cholinergic stimulation. Thus, participants who were worse at baseline benefited more from cholinergic stimulation than those who had better baseline values, indicating that a cholinergic deficit contributes to the memory decline even in healthy older subjects.

The N-Methyl-D-Aspartate Receptor Co-agonist D-Cycloserine Facilitates Declarative Learning and Hippocampal Activity in Humans

BACKGROUND The N-methyl-D-aspartate receptor (NMDAR) is critical for learning-related synaptic plasticity in amygdala and hippocampus. As a consequence, there is considerable interest in drugs targeting this receptor to help enhance amygdala- and hippocampus-dependent learning. A promising candidate in this respect is the NMDAR glycine-binding site partial agonist D-cycloserine (DCS). Accumulating clinical evidence indicates the efficacy of DCS in the facilitation of amygdala-dependent fear extinction learning in patients with phobic, social anxiety, panic, and obsessive-compulsive disorder. An important unresolved question though is whether the use of DCS can also facilitate hippocampus-dependent declarative learning in healthy people as opposed to being restricted to the fear memory domain. METHODS In the present study, we investigated whether or not DCS can facilitate hippocampus-dependent declarative learning. We have therefore combined functional magnetic resonance imaging with two different declarative learning tasks and cytoarchitectonic probabilistic mapping of the hippocampus and its major subdivisions in 40 healthy volunteers administered either a 250 mg single oral dose of DCS or a placebo. RESULTS We found that DCS facilitates declarative learning as well as blood-oxygen level dependent activity levels in the probabilistically defined cornu ammonis region of the hippocampus. The absence of activity changes in visual control areas underscores the specific action of DCS in the hippocampal cornu ammonis region. CONCLUSIONS Our findings highlight NMDAR glycine-binding site partial agonism as a promising pharmacological mechanism for facilitating declarative learning in healthy people.

Ageing-related changes of neural activity associated with spatial contextual memory.

Neuropsychological studies provide evidence for an ageing-related decline of memory for contextual information related to remembered items. Using event-related fMRI we investigated the neural correlates of ageing-related changes during encoding and retrieval of spatial contextual memory. Eighteen young and 17 older subjects were included in the analysis (mean age 24 and 60 years, respectively). Although young and older subjects recognised the same amount of items during retrieval, spatial context memory for remembered items was superior in younger subjects. In both groups, left parahippocampal activity during encoding predicted contextual memory performance during retrieval. During encoding, an interaction between age and success of spatial context encoding was found in the left fusiform gyrus. During retrieval, the left hippocampal formation showed higher activity for successful than for unsuccessful spatial context retrieval as well as an interaction between age and spatial context judgement. Both findings are likely to underlie the contextual memory deficit observed in older subjects.

Medial temporal lobe dysfunction during encoding and retrieval of episodic memory in non-demented APOE ε4 carriers

Presence of the apolipoprotein E (APOE) epsilon4 allele is linked to an increased risk to develop Alzheimers dementia (AD). However, there are controversial data concerning the impact of the APOE genotype on cognitive functioning and brain activity in healthy subjects. We used event-related functional magnetic resonance imaging (fMRI) to investigate the effects of APOE genotype on spatial contextual memory encoding and retrieval success in healthy older adults. Eighteen subjects (eight APOE4 heterozygotes (epsilon4+) and 10 non-carriers (epsilon4-), mean age 60.0+/-5.0 years) were included in the present analysis. Behaviorally, epsilon4+ subjects performed significantly worse than epsilon4- subjects in item memory and spatial context retrieval. fMRI data revealed that epsilon4+ subjects, compared to epsilon4-subjects, predominantly showed an increase of neural activity specific to encoding of items and their spatial context in prefrontal, temporal and parietal regions. In contrast, epsilon4+ subjects showed activity decreases in the right amygdala during successful item recognition and in the prefrontal cortex bilaterally during spatial context retrieval when compared to epsilon4- subjects. While the activity increases during encoding may reflect compensatory activity in the attempt to maintain normal performance, the decreases during retrieval indicate incipient neural decline in epsilon4+ subjects. These data highlight that preclinical ApoE-related changes in neural activity are not unidirectional but dissociate depending on the memory phase, i.e., encoding or retrieval.

Increased cortisol levels in cognitively challenging situations are beneficial in young but not older subjects

RationaleAdaptation to stressful situations changes with increasing age. This is also reflected in age-related differences in effects of acute stress on, e.g., episodic memory. Less is known about age-related differences of the cognitive effects of individual stress responses to challenging situations.ObjectiveTo investigate the influence of the individual cortisol response (as a marker for the individual stress level) on behavioral and neural measures during a challenging memory paradigm.Materials and methodsTwenty young and 12 older subjects were scanned using functional magnetic resonance imaging during encoding and retrieval of spatial contextual information. Salivary cortisol levels were measured before and after scanning.ResultsA multiple regression analysis of behavioral data showed an interaction effect of age and cortisol response on memory for the items and their spatial context during retrieval due to increased accuracy with increasing cortisol responses in young compared to old subjects. During encoding, this was reflected in a positive effect of the cortisol response on prefrontal activity in young but not in older subjects. During retrieval, there was a negative effect of the cortisol response on brain activity in the hippocampus and prefrontal regions in older but not in young subjects.ConclusionsThe data suggest an increased efficiency to encode items and their context with increasing cortisol responses in young subjects, and a decreased efficiency to retrieve information with increasing cortisol responses in older subjects. We conclude that neuroendocrine responses are differentially associated with behavioral and neural measures in cognitively challenging situations in young and older volunteers.

Impact of tau and amyloid burden on glucose metabolism in Alzheimer's disease.

In a multimodal PET imaging approach, we determined the differential contribution of neurofibrillary tangles (measured with [18F]AV‐1451) and beta‐amyloid burden (measured with [11C]PiB) on degree of neurodegeneration (i.e., glucose metabolism measured with [18F]FDG‐PET) in patients with Alzheimers disease. Across brain regions, we observed an interactive effect of beta‐amyloid burden and tau deposition on glucose metabolism which was most pronounced in the parietal lobe. Elevated beta‐amyloid burden was associated with a stronger influence of tau accumulation on glucose metabolism. Our data provide the first in vivo insights into the differential contribution of Aβ and tau to neurodegeneration in Alzheimers disease.

In vivo Patterns of Tau Pathology, Amyloid-β Burden, and Neuronal Dysfunction in Clinical Variants of Alzheimer’s Disease

The clinical heterogeneity of Alzheimers disease is not reflected in the rather diffuse cortical deposition of amyloid-β. We assessed the relationship between clinical symptoms, in vivo tau pathology, amyloid distribution, and hypometabolism in variants of Alzheimers disease using novel multimodal PET imaging techniques. Tau pathology was primarily observed in brain regions related to clinical symptoms and overlapped with areas of hypometabolism. In contrast, amyloid-β deposition was diffusely distributed over the entire cortex. Tau PET imaging may thus serve as a valuable biomarker for the localization of neuronal injury in vivo and may help to validate atypical subtypes of Alzheimers disease.

Cognitive training with and without additional physical activity in healthy older adults: cognitive effects, neurobiological mechanisms, and prediction of training success

Data is inconsistent concerning the question whether cognitive-physical training (CPT) yields stronger cognitive gains than cognitive training (CT). Effects of additional counseling, neurobiological mechanisms, and predictors have scarcely been studied. Healthy older adults were trained with CT (n = 20), CPT (n = 25), or CPT with counseling (CPT+C; n = 23). Cognition, physical fitness, BDNF, IGF-1, and VEGF were assessed at pre- and post-test. No interaction effects were found except for one effect showing that CPT+C led to stronger gains in verbal fluency than CPT (p = 0.03). However, this superiority could not be assigned to additional physical training gains. Low baseline cognitive performance and BDNF, not carrying apoE4, gains in physical fitness and the moderation of gains in physical fitness × gains in BDNF predicted training success. Although all types of interventions seem successful to enhance cognition, our data do not support the hypotheses that CPT shows superior CT gains compared to CT or that CPT+C adds merit to CPT. However, as CPT leads to additional gains in physical fitness which in turn is known to have positive impact on cognition in the long-term, CPT seems more beneficial. Training success can partly be predicted by neuropsychological, neurobiological, and genetic parameters. Unique Identifier: WHO ICTRP (http://www.who.int/ictrp); ID: DRKS00005194.