Dicyanovinylnaphthalenes for neuroimaging of amyloids and relationships of electronic structures and geometries to binding affinities.

The positron-emission tomography (PET) probe 2-(1-[6-[(2-fluoroethyl)(methyl)amino]-2-naphthyl]ethylidene) (FDDNP) is used for the noninvasive brain imaging of amyloid-ß (Aß) and other amyloid aggregates present in Alzheimer's disease and other neurodegenerative diseases. A series of FDDNP analogs has been synthesized and characterized using spectroscopic and computational methods. The binding affinities of these molecules have been measured experimentally and explained through the use of a computational model. The analogs were created by systematically modifying the donor and the acceptor sides of FDDNP to learn the structural requirements for optimal binding to Aß aggregates. FDDNP and its analogs are neutral, environmentally sensitive, fluorescent molecules with high dipole moments, as evidenced by their spectroscopic properties and dipole moment calculations. The preferred solution-state conformation of these compounds is directly related to the binding affinities. The extreme cases were a nonplanar analog t-butyl-FDDNP, which shows low binding affinity for Aß aggregates (520 nM K(i)) in vitro and a nearly planar tricyclic analog cDDNP, which displayed the highest binding affinity (10 pM K(i)). Using a previously published X-ray crystallographic model of 1,1-dicyano-2-[6-(dimethylamino)naphthalen-2-yl]propene (DDNP) bound to an amyloidogenic Aß peptide model, we show that the binding affinity is inversely related to the distortion energy necessary to avoid steric clashes along the internal surface of the binding channel.

How Reliably Do Eye Parameters Indicate Internal Versus External Attentional Focus?

Eye behavior is increasingly used as an indicator of internal versus external focus of attention both in research and application. However, available findings are partly inconsistent, which might be attributed to the different nature of the employed types of internal and external cognition tasks. The present study, therefore, investigated how consistently different eye parameters respond to internal versus external attentional focus across three task modalities: numerical, verbal, and visuo-spatial. Three eye parameters robustly differentiated between internal and external attentional focus across all tasks. Blinks, pupil diameter variance, and fixation disparity variance were consistently increased during internally directed attention. We also observed substantial attentional focus effects on other parameters (pupil diameter, fixation disparity, saccades, and microsaccades), but they were moderated by task type. Single-trial analysis of our data using machine learning techniques further confirmed our results: Classifying the focus of attention by means of eye tracking works well across participants, but generalizing across tasks proves to be challenging. Based on the effects of task type on eye parameters, we discuss what eye parameters are best suited as indicators of internal versus external attentional focus in different settings.

Neurophysiological indicators of internal attention: An fMRI-eye-tracking coregistration study.

Many goal-directed, as well as spontaneous everyday activities (e.g., planning, mind-wandering), rely on an internal focus of attention. This fMRI-eye-tracking coregistration study investigated brain mechanisms and eye behavior related to internally versus externally directed cognition. Building on an established paradigm, we manipulated internal attention demands within tasks utilizing conditional stimulus masking. Internally directed cognition involved bilateral activation of the lingual gyrus and inferior parietal lobe areas as well as wide-spread deactivation of visual networks. Moreover, internally directed cognition was related to greater pupil diameter, pupil diameter variance, blink duration, fixation disparity variance, and smaller amounts of microsaccades. FMRI-eye-tracking covariation analyses further revealed that larger pupil diameter was related to increased activation of basal ganglia and lingual gyrus. It can be concluded that internally and externally directed cognition are characterized by distinct neurophysiological signatures. The observed neurophysiological differences indicate that internally directed cognition is associated with reduced processing of task-irrelevant information and increased mental load. These findings shed further light on the interplay between neural and perceptual mechanisms contributing to an internal focus of attention.

Neurophysiological indicators of internal attention: An electroencephalography-eye-tracking coregistration study.

INTRODUCTION: Many goal-directed and spontaneous everyday activities (e.g., planning, mind wandering) rely on an internal focus of attention. Internally directed cognition (IDC) was shown to differ from externally directed cognition in a range of neurophysiological indicators such as electroencephalogram (EEG) alpha activity and eye behavior. METHODS: In this EEG-eye-tracking coregistration study, we investigated effects of attention direction on EEG alpha activity and various relevant eye parameters. We used an established paradigm to manipulate internal attention demands in the visual domain within tasks by means of conditional stimulus masking. RESULTS: Consistent with previous research, IDC involved relatively higher EEG alpha activity (lower alpha desynchronization) at posterior cortical sites. Moreover, IDC was characterized by greater pupil diameter (PD), fewer microsaccades, fixations, and saccades. These findings show that internal versus external cognition is associated with robust differences in several indicators at the neural and perceptual level. In a second line of analysis, we explored the intrinsic temporal covariation between EEG alpha activity and eye parameters during rest. This analysis revealed a positive correlation of EEG alpha power with PD especially in bilateral parieto-occipital regions. CONCLUSION: Together, these findings suggest that EEG alpha activity and PD represent time-sensitive indicators of internal attention demands, which may be involved in a neurophysiological gating mechanism serving to shield internal cognition from irrelevant sensory information.