Basal forebrain activity predicts functional degeneration in the entorhinal cortex in Alzheimer's disease.

Recent models of Alzheimer's disease suggest the nucleus basalis of Meynert (NbM) as an early origin of structural degeneration followed by the entorhinal cortex (EC). However, the functional properties of NbM and EC regarding amyloid-ß and hyperphosphorylated tau remain unclear. We analysed resting-state functional fMRI data with CSF assays from the Alzheimer's Disease Neuroimaging Initiative (n = 71) at baseline and 2 years later. At baseline, local activity, as quantified by fractional amplitude of low-frequency fluctuations, differentiated between normal and abnormal CSF groups in the NbM but not EC. Further, NbM activity linearly decreased as a function of CSF ratio, resembling the disease status. Finally, NbM activity predicted the annual percentage signal change in EC, but not the reverse, independent from CSF ratio. Our findings give novel insights into the pathogenesis of Alzheimer's disease by showing that local activity in NbM is affected by proteinopathology and predicts functional degeneration within the EC.

Differential effects of expectancy on memory formation in young and older adults.

Novelty can promote subsequent long-term memory via the mesolimbic system, including the medial temporal lobe and midbrain structures. Importantly, these and other brain regions typically degenerate during healthy aging, which suggests a reduced impact of novelty on learning. However, evidence in favor of such a hypothesis is scarce. Thus, we used functional MRI in combination with an established paradigm in healthy young (19-32 years, n = 30) and older (51-81 years, n = 32) humans. During encoding, colored cues predicted the subsequent presentation of either a novel or previously familiarized image (75% cue validity), and approximately 24 h later, recognition memory for novel images was tested. Behaviorally, expected novel images, as compared to unexpected novel images, were better recognized in young and, to a lesser degree, older subjects. At the neural level, familiar cues activated memory related areas, especially the medial temporal lobe, whereas novelty cues activated the angular gyrus and inferior parietal lobe, which may reflect enhanced attentional processing. During outcome processing, expected novel images activated the medial temporal lobe, angular gyrus and inferior parietal lobe. Importantly, a similar activation pattern was observed for subsequently recognized novel items, which helps to explain the behavioral effect of novelty on long-term memory. Finally, age-effects were pronounced for successfully recognized novel images with relatively stronger activations in attention-related brain regions in older adults; younger adults, on the other hand, showed stronger hippocampal activation. Together, expectancy promotes memory formation for novel items via neural activity in medial temporal lobe structures and this effect appears to be reduced with age.

Basal forebrain activity predicts functional degeneration in the entorhinal cortex and decreases with Alzheimer's Disease progression.

BACKGROUND AND OBJECTIVES: Recent models of Alzheimer's Disease (AD) suggest the nucleus basalis of Meynert (NbM) as the origin of structural degeneration followed by the entorhinal cortex (EC). However, the functional properties of NbM and EC regarding amyloid-ß and hyperphosphorylated tau remain unclear. METHODS: We analyzed resting-state (rs)fMRI data with CSF assays from the Alzheimer's Disease Neuroimaging Initiative (ADNI, n=71) at baseline and two years later. RESULTS: At baseline, local activity, as quantified by fractional amplitude of low-frequency fluctuations (fALFF), differentiated between normal and abnormal CSF groups in the NbM but not EC. Further, NbM activity linearly decreased as a function of CSF ratio, resembling the disease status. Finally, NbM activity predicted the annual percentage signal change in EC, but not the reverse, independent from CSF ratio. DISCUSSION: Our findings give novel insights into the pathogenesis of AD by showing that local activity in NbM is affected by proteinopathology and predicts functional degeneration within the EC.

Anticipating social feedback involves basal forebrain and mesolimbic functional connectivity.

The mesolimbic system and basal forebrain (BF) are implicated in processing rewards and punishment, but their interplay and functional properties of subregions with respect to future social outcomes remain unclear. Therefore, this study investigated regional responses and interregional functional connectivity of the lateral (l), medial (m), and ventral (v) Substantia Nigra (SN), Nucleus Accumbens (NAcc), Nucleus basalis of Meynert (NBM), and Medial Septum/Diagonal Band (MS/DB) during reward and punishment anticipation in a social incentive delay task with neutral, positive, and negative feedback using high-resolution fMRI (1.5mm3). Neuroimaging data (n = 36 healthy humans) of the anticipation phase was analyzed using mass-univariate, functional connectivity, and multivariate-pattern analysis. As expected, participants responded faster when anticipating positive and negative compared to neutral social feedback. At the neural level, anticipating social information engaged valence-related and valence-unrelated functional connectivity patterns involving the BF and mesolimbic areas. Precisely, valence-related connectivity between the lSN and NBM was associated with anticipating neutral social feedback, while connectivity between the vSN and NBM was associated with anticipating positive social feedback. A more complex pattern was observed for anticipating negative social feedback, including connectivity between the lSN and MS/DB, lSN and NAcc, as well as mSN and NAcc. To conclude,  functional connectivity patterns of the BF and mesolimbic areas signal the anticipation of social feedback depending on their emotional valence. As such, our findings give novel insights into the underlying neural processes of social information processing.

Functional coupling between CA3 and laterobasal amygdala supports schema dependent memory formation.

The medial temporal lobe drives semantic congruence dependent memory formation. However, the exact roles of hippocampal subfields and surrounding brain regions remain unclear. Here, we used an established paradigm and high-resolution functional magnetic resonance imaging of the medial temporal lobe together with cytoarchitectonic probability estimates in healthy humans. Behaviorally, robust congruence effects emerged in young and older adults, indicating that schema dependent learning is unimpaired during healthy aging. Within the medial temporal lobe, semantic congruence was associated with hemodynamic activity in the subiculum, CA1, CA3 and dentate gyrus, as well as the entorhinal cortex and laterobasal amygdala. Importantly, a subsequent memory analysis showed increased activity for later remembered vs. later forgotten congruent items specifically within CA3, and this subfield showed enhanced functional connectivity to the laterobasal amygdala. As such, our findings extend current models on schema dependent learning by pinpointing the functional properties of subregions within the medial temporal lobe.

Electrophysiology of goal-directed versus habitual control during outcome devaluation.

Dual-system accounts posit that instrumental behavior is controlled by both a goal-directed and a habitual system. In this study, we aimed to identify the electrophysiological components associated with goal-directed versus habitual performance using an outcome devaluation procedure. Datasets from 35 healthy participants were analyzed. Behaviorally, in line with previous research, participants displayed sensitivity to outcome devaluation, a hallmark of goal-directed control. Electrophysiologically, decreased N2 and increased error-related negativity (ERN) amplitudes were associated with slips of action in conditions that could potentially engage both the goal-directed and habitual systems. These amplitude differences were more pronounced in participants that displayed more sensitivity to devaluation. Furthermore, we show how specific neurophysiological learning signals, namely ERN and feedback-locked P3, could predict subsequent sensitivity to devaluation. Our findings indicate that the N2 and ERN components can be used as indices of goal-directed versus habitual control, and emphasize the importance of the ERN as an electrophysiological trait in the context of goal-directed behavior.

Neural processing of food and monetary rewards is modulated by metabolic state.

In humans, food is considered a powerful primary reinforcer, whereas money is a secondary reinforcer, as it gains a value through learning experience. Here, we aimed to identify the neural regions supporting the processing of food-related reinforcers, relate it to the neural underpinnings of monetary reinforcers, and explore their modulation by metabolic state (hunger vs satiety). Twenty healthy male participants were tested in two experimental sessions, once hungry and once satiated, using functional magnetic resonance imaging. Participants performed an associative learning task, receiving food or monetary rewards (in the form of images) on separate blocks. Irrespective of incentive type, both food and monetary rewards engaged ventral striatum, medial orbitofrontal cortex and amygdala, regions that have been previously associated with reward processing. Food incentives additionally engaged the opercular part of the inferior frontal gyrus and the insula, collectively known as a primary gustatory cortex. Moreover, in response to negative feedback (here, reward omission), robust activation was observed in anterior insula, supplementary motor area and lateral parts of the prefrontal cortex, including middle and inferior frontal gyrus. Furthermore, the interaction between metabolic state and incentive type resulted in supramarginal gyrus (SMG) activity, among other motor and sensory-related regions. Finally, functional connectivity analysis showed correlation in the hungry state between the SMG and mesolimbic regions, including the hippocampus, midbrain and cingulate areas. Also, the interaction between metabolic state and incentive type revealed coupling between SMG and ventral striatum. Whereas general purpose reward-related regions process incentives of different kinds, the current results suggest that the SMG might play a key role in integrating the information related to current metabolic state and available incentive type.