Elisabeth Roggenhofer

Activation of dopamine D1/D5 receptors facilitates the induction of presynaptic long-term potentiation at hippocampal output synapses

Encoding of novel information has been proposed to rely on the time‐locked release of dopamine in the hippocampal formation during novelty detection. However, the site of novelty detection in the hippocampus remains a matter of debate. According to current models, the CA1 and the subiculum act as detectors and distributors of novel sensory information. Although most CA1 pyramidal neurons exhibit regular‐spiking behavior, the majority of subicular pyramidal neurons fire high‐frequency bursts of action potentials. The present study investigates the efficacy of dopamine D1/D5 receptor activation to facilitate the induction of activity‐dependent long‐term potentiation (LTP) in rat CA1 regular‐spiking and subicular burst‐spiking pyramidal cells. Using a weak stimulation protocol, set at a level subthreshold for the induction of LTP, we show that activation of D1/D5 receptors for 5–10 min facilitates LTP in subicular burst‐spiking neurons but not in CA1 neurons. The results demonstrate that D1/D5 receptor‐facilitated LTP is NMDA receptor‐dependent, and requires the activation of protein kinase A. In addition, the D1/D5 receptor‐facilitated LTP is shown to be presynaptically expressed and relies on presynaptic Ca2+ signaling. The phenomenon of dopamine‐induced facilitation of presynaptic NMDA receptor‐dependent LTP in subicular burst‐spiking pyramidal cells is in accordance with observations of the time‐locked release of dopamine during novelty detection in this brain region, and reveals an intriguing mechanism for the encoding of hippocampal output information.

Early small vessel disease affects frontoparietal and cerebellar hubs in close correlation with clinical symptoms--a resting-state fMRI study.

Cerebral small vessel disease, mainly characterized by white matter lesions and lacunes, has a high clinical impact as it leads to vascular dementia. Recent studies have shown that this disease impairs frontoparietal networks. Here, we apply resting-state magnetic resonance imaging and data-driven whole-brain imaging analysis methods (eigenvector centrality) to investigate changes of the functional connectome in early small vessel disease. We show reduced connectivity in frontoparietal networks, whereas connectivity increases in the cerebellum. These functional changes are closely related to white matter lesions and typical neuropsychological deficits associated with small vessel disease.

Identifying the neural correlates of executive functions in early cerebral microangiopathy: a combined VBM and DTI study

Cerebral microangiopathy (CMA) has been associated with executive dysfunction and fronto-parietal neural network disruption. Advances in magnetic resonance imaging allow more detailed analyses of gray (e.g., voxel-based morphometry—VBM) and white matter (e.g., diffusion tensor imaging—DTI) than traditional visual rating scales. The current study investigated patients with early CMA and healthy control subjects with all three approaches. Neuropsychological assessment focused on executive functions, the cognitive domain most discussed in CMA. The DTI and age-related white matter changes rating scales revealed convergent results showing widespread white matter changes in early CMA. Correlations were found in frontal and parietal areas exclusively with speeded, but not with speed-corrected executive measures. The VBM analyses showed reduced gray matter in frontal areas. All three approaches confirmed the hypothesized fronto-parietal network disruption in early CMA. Innovative methods (DTI) converged with results from conventional methods (visual rating) while allowing greater spatial and tissue accuracy. They are thus valid additions to the analysis of neural correlates of cognitive dysfunction. We found a clear distinction between speeded and nonspeeded executive measures in relationship to imaging parameters. Cognitive slowing is related to disease severity in early CMA and therefore important for early diagnostics.

Menstrual cycle phase modulates emotional conflict processing in women with and without premenstrual syndrome (PMS) - A pilot study

Background Premenstrual syndrome (PMS) is characterized by a cluster of psychological and somatic symptoms during the late luteal phase of the menstrual cycle that disappear after the onset of menses. Behavioral differences in emotional and cognitive processing have been reported in women with PMS, and it is of particular interest whether PMS affects the parallel execution of emotional and cognitive processing. Related to this is the question of how the performance of women with PMS relates to stress levels compared to women without PMS. Cortisol has been shown to affect emotional processing in general and it has also been shown that women with severe PMS have a particular cortisol profile. Methods We measured performance in an emotional conflict task and stress levels in women with PMS (n = 15) and women without PMS (n = 15) throughout their menstrual cycle. Results We found a significant increase (p = 0.001) in the mean reaction time for resolving emotional conflict from the follicular to the luteal cycle phase in all subjects. Only women with PMS demonstrated an increase in physiological and subjective stress measures during the luteal menstrual cycle phase. Conclusions Our findings suggest that the menstrual cycle modulates the integration of emotional and cognitive processing in all women. Preliminary data are supportive of the secondary hypothesis that stress levels are mediated by the menstrual cycle phase only in women with PMS. The presented evidence for menstrual cycle-specific differences in integrating emotional and cognitive information highlights the importance of controlling for menstrual cycle phase in studies that aim to elucidate the interplay of emotion and cognition.

Regional reproducibility of calibrated BOLD functional MRI: Implications for the study of cognition and plasticity

Calibrated BOLD fMRI is a promising alternative to the classic BOLD contrast due to its reduced venous sensitivity and greater physiological specificity. The delayed adoption of this technique for cognitive studies may stem partly from a lack of information on the reproducibility of these measures in the context of cognitive tasks. In this study we have explored the applicability and reproducibility of a state-of-the-art calibrated BOLD technique using a complex functional task at 7 tesla. Reproducibility measures of BOLD, CBF, CMRO2 flow-metabolism coupling n and the calibration parameter M were compared and interpreted for three ROIs. We found an averaged intra-subject variation of CMRO2 of 8% across runs and 33% across days. BOLD (46% across runs, 36% across days), CBF (33% across runs, 46% across days) and M (41% across days) showed significantly higher intra-subject variability. Inter-subject variability was found to be high for all quantities, though CMRO2 was the most consistent across brain regions. The results of this study provide evidence that calibrated BOLD may be a viable alternative for longitudinal and cognitive MRI studies.

Using carbogen for calibrated fMRI at 7 Tesla: Comparison of direct and modelled estimation of the M parameter

Task-evoked changes in cerebral oxygen metabolism can be measured using calibrated functional Magnetic Resonance Imaging (fMRI). This technique requires the use of breathing manipulations such as hypercapnia, hyperoxia or a combination of both to determine a calibration factor M. The M-value is usually obtained by extrapolating the BOLD signal measured during the gas manipulation to its upper theoretical physiological limit using a biophysical model. However, a recently introduced technique uses a combination of increased inspired concentrations of O2 and CO2 to saturate the BOLD signal completely. In this study, we used this BOLD saturation technique to measure M directly at 7Tesla (T). Simultaneous carbogen-7 (7% CO2 in 93% O2) inhalation and visuo-motor task performance were used to elevate venous oxygen saturation in visual and motor areas close to their maximum, and the BOLD signal measured during this manipulation was used as an estimate of M. As accurate estimation of M is crucial for estimation of valid oxidative metabolism values, these directly estimated M-values were assessed and compared with M-values obtained via extrapolation modelling using the generalized calibration model (GCM) on the same dataset. Average M-values measured using both methods were 10.4±3.9% (modelled) and 7.5±2.2% (direct) for a visual-related ROI, and 11.3±5.2% (modelled) and 8.1±2.6% (direct) for a motor-related ROI. Results from this study suggest that, for the CO2 concentration used here, modelling is necessary for the accurate estimation of the M parameter. Neither gas inhalation alone, nor gas inhalation combined with a visuo-motor task, was sufficient to completely saturate venous blood in most subjects. Calibrated fMRI studies should therefore rely on existing models for gas inhalation-based calibration of the BOLD signal.

Neural synchrony indexes impaired motor slowing after errors and novelty following white matter damage.

In humans, action errors and perceptual novelty elicit activity in a shared frontostriatal brain network, allowing them to adapt their ongoing behavior to such unexpected action outcomes. Healthy and pathologic aging reduces the integrity of white matter pathways that connect individual hubs of such networks and can impair the associated cognitive functions. Here, we investigated whether structural disconnection within this network because of small-vessel disease impairs the neural processes that subserve motor slowing after errors and novelty (post-error slowing, PES; post-novel slowing, PNS). Participants with intact frontostriatal circuitry showed increased right-lateralized beta-band (12-24 Hz) synchrony between frontocentral and frontolateral electrode sites in the electroencephalogram after errors and novelty, indexing increased neural communication. Importantly, this synchrony correlated with PES and PNS across participants. Furthermore, such synchrony was reduced in participants with frontostriatal white matter damage, in line with reduced PES and PNS. The results demonstrate that behavioral change after errors and novelty result from coordinated neural activity across a frontostriatal brain network and that such cognitive control is impaired by reduced white matter integrity.

Flexible Adaptive Paradigms for fMRI Using a Novel Software Package ‘Brain Analysis in Real-Time’ (BART)

In this work we present a new open source software package offering a unified framework for the real-time adaptation of fMRI stimulation procedures. The software provides a straightforward setup and highly flexible approach to adapt fMRI paradigms while the experiment is running. The general framework comprises the inclusion of parameters from subject’s compliance, such as directing gaze to visually presented stimuli and physiological fluctuations, like blood pressure or pulse. Additionally, this approach yields possibilities to investigate complex scientific questions, for example the influence of EEG rhythms or fMRI signals results themselves. To prove the concept of this approach, we used our software in a usability example for an fMRI experiment where the presentation of emotional pictures was dependent on the subject’s gaze position. This can have a significant impact on the results. So far, if this is taken into account during fMRI data analysis, it is commonly done by the post-hoc removal of erroneous trials. Here, we propose an a priori adaptation of the paradigm during the experiment’s runtime. Our fMRI findings clearly show the benefits of an adapted paradigm in terms of statistical power and higher effect sizes in emotion-related brain regions. This can be of special interest for all experiments with low statistical power due to a limited number of subjects, a limited amount of time, costs or available data to analyze, as is the case with real-time fMRI.

Reduced threshold for induction of LTP by activation of dopamine D1/D5 receptors at hippocampal CA1-subiculum synapses.

The phasic release of dopamine in the hippocampal formation has been shown to facilitate the encoding of novel information. There is evidence that the subiculum operates as a detector and distributor of sensory information, which incorporates the novelty and relevance of signals received from CA1. The subiculum acts as the final hippocampal relay station for outgoing information. Subicular pyramidal cells have been classified as regular- and burst-spiking neurons. The goal of the present study was to study the effect of dopamine D1/D5 receptor activation on synaptic transmission and plasticity in the subicular regular-spiking neurons of 4–6 week old Wistar rats. We demonstrate that prior activation of D1/D5 receptors reduces the threshold for the induction of long-term potentiation (LTP) in subicular regular-spiking neurons. Our results indicate that D1/D5 receptor activation facilitates a postsynaptic form of LTP in subicular regular-spiking cells that is NMDA receptor-dependent, relies on postsynaptic Ca2+ signaling, and requires the activation of protein kinase A. The enhanced propensity of subicular regular-spiking cells to express postsynaptic LTP after activation of D1/D5 receptors provides an intriguing mechanism for the encoding of hippocampal output information.

Intermittent compared to continuous real-time fMRI neurofeedback boosts control over amygdala activation

&NA; Real‐time fMRI neurofeedback is a feasible tool to learn the volitional regulation of brain activity. So far, most studies provide continuous feedback information that is presented upon every volume acquisition. Although this maximizes the temporal resolution of feedback information, it may be accompanied by some disadvantages. Participants can be distracted from the regulation task due to (1) the intrinsic delay of the hemodynamic response and associated feedback and (2) limited cognitive resources available to simultaneously evaluate feedback information and stay engaged with the task. Here, we systematically investigate differences between groups presented with different variants of feedback (continuous vs. intermittent) and a control group receiving no feedback on their ability to regulate amygdala activity using positive memories and feelings. In contrast to the feedback groups, no learning effect was observed in the group without any feedback presentation. The group receiving intermittent feedback exhibited better amygdala regulation performance when compared with the group receiving continuous feedback. Behavioural measurements show that these effects were reflected in differences in task engagement. Overall, we not only demonstrate that the presentation of feedback is a prerequisite to learn volitional control of amygdala activity but also that intermittent feedback is superior to continuous feedback presentation. HighlightsComparison of continuous vs. intermittent real‐time fMRI neurofeedback in amygdala.Feedback is necessary to learn volitional regulation of amygdala activity.Intermittent feedback presentation outperforms continuous feedback during training runs.Behavioral data show analogous differences in task engagement between conditions.Results are promising for connectivity‐based rt‐fMRI neurofeedback approaches.