Noradrenergic neuromodulation in ageing and disease.

The locus coeruleus (LC) is a small brainstem structure located in the lower pons and is the main source of noradrenaline (NA) in the brain. Via its phasic and tonic firing, it modulates cognition and autonomic functions and is involved in the brain's immune response. The extent of degeneration to the LC in healthy ageing remains unclear, however, noradrenergic dysfunction may contribute to the pathogenesis of Alzheimer's (AD) and Parkinson's disease (PD). Despite their differences in progression at later disease stages, the early involvement of the LC may lead to comparable behavioural symptoms such as preclinical sleep problems and neuropsychiatric symptoms as a result of AD and PD pathology. In this review, we draw attention to the mechanisms that underlie LC degeneration in ageing, AD and PD. We aim to motivate future research to investigate how early degeneration of the noradrenergic system may play a pivotal role in the pathogenesis of AD and PD which may also be relevant to other neurodegenerative diseases.

Selective alteration of human value decisions with medial frontal tDCS is predicted by changes in attractor dynamics.

During value-based decision making, ventromedial prefrontal cortex (vmPFC) is thought to support choices by tracking the expected gain from different outcomes via a competition-based process. Using a computational neurostimulation approach we asked how perturbing this region might alter this competition and resulting value decisions. We simulated a perturbation of neural dynamics in a biophysically informed model of decision-making through in silico depolarization at the level of neuronal ensembles. Simulated depolarization increased baseline firing rates of pyramidal neurons, which altered their susceptibility to background noise, and thereby increased choice stochasticity. These behavioural predictions were compared to choice behaviour in healthy participants performing similar value decisions during transcranial direct current stimulation (tDCS), a non-invasive brain stimulation technique. We placed the soma depolarizing electrode over medial frontal PFC. In line with model predictions, this intervention resulted in more random choices. By contrast, no such effect was observed when placing the depolarizing electrode over lateral PFC. Using a causal manipulation of ventromedial and lateral prefrontal function, these results provide support for competition-based choice dynamics in human vmPFC, and introduce computational neurostimulation as a mechanistic assay for neurostimulation studies of cognition.

Domain-specific suppression of auditory mismatch negativity with transcranial direct current stimulation.

OBJECTIVE: To evaluate the influence of frontal transcranial direct current stimulation (tDCS) on auditory mismatch negativity (MMN). METHODS: MMN is an event related potential calculated by subtracting the amplitude of the evoked potentials in response to a "standard" stimulus from the evoked potentials produced by a rare "oddball" stimulus. Here we assessed the influence of anodal tDCS, cathodal tDCS or sham stimulation delivered over the right inferior frontal cortex on MMN in response to duration and frequency auditory deviants in 10 healthy subjects. RESULTS: MMN to frequency deviants was significantly reduced after anodal tDCS compared with sham or cathodal stimulation which did not change MMN to frequency deviants. Neither anodal nor cathodal tDCS had any effect on MMN to duration deviants. CONCLUSIONS: Non-invasive brain stimulation with tDCS can influence MMN. The differing networks known to be activated by duration and frequency deviants could account for the differential effect of tDCS on duration and frequency MMN. SIGNIFICANCE: Non-invasive brain stimulation could be a useful method to manipulate MMN for experimental purposes.