Steady-state visual evoked potential temporal dynamics reveal correlates of cognitive decline.

OBJECTIVE: A central concern in aging is the preservation of cognitive skills. Tools to detect cognitive decline are sparse. The aim of this study was to ascertain whether cognitive decline is accompanied by alterations in the temporal dynamics of steady-state visual evoked potentials (SSVEPs). METHODS: We included 162 men from the Danish Metropolit birth cohort. Their cognitive trajectory was based on their intelligence test score at youth (age ~18), middle age (age ~56), and late middle age (age ~62). Subjects underwent cognitive tests and steady-state visual stimulation. Temporal dynamics of SSVEPs were assessed in terms of amplitude and phase coherence. RESULTS: The latency and magnitude of the amplitude modulation of the 36-Hz response correlated negatively with subjects' cognition indices. Furthermore, negative cognition index was associated with loss of SSVEPs at 36 Hz, and both 8 Hz and 36 Hz in severe cases. CONCLUSION: Latency and magnitude of gamma frequency SSVEPs increase with cognitive decline. This suggests that the facilitation of SSVEPs first becomes problematic at gamma frequencies, then at alpha frequencies. SIGNIFICANCE: Our data suggests that the temporal dynamics of SSVEPs can be used as an indicator of cognitive impairment. Furthermore, evoked gamma oscillations are especially vulnerable in cognitive decline.

EEG correlates of visual short-term memory in older age vary with adult lifespan cognitive development.

Visual short-term memory (vSTM) is a cognitive resource that declines with age. This study investigated whether electroencephalography (EEG) correlates of vSTM vary with cognitive development over individuals' lifespan. We measured vSTM performance and EEG in a lateralized whole-report task in a healthy birth cohort, whose cognitive function (intelligence quotient) was assessed in youth and late-middle age. Higher vSTM capacity (K; measured by Bundesen's theory of visual attention) was associated with higher amplitudes of the contralateral delay activity (CDA) and the central positivity (CP). In addition, rightward hemifield asymmetry of vSTM (Kλ) was associated with lower CDA amplitudes. Furthermore, more severe cognitive decline from young adulthood to late-middle age predicted higher CDA amplitudes, and the relationship between K and the CDA was less reliable in individuals who show higher levels of cognitive decline compared to individuals with preserved abilities. By contrast, there was no significant effect of lifespan cognitive changes on the CP or the relationship between behavioral measures of vSTM and the CP. Neither the CDA, nor the CP, nor the relationships between K or Kλ and the event-related potentials were predicted by individuals' current cognitive status. Together, our findings indicate complex age-related changes in processes underlying behavioral and EEG measures of vSTM and suggest that the K-CDA relationship might be a marker of cognitive lifespan trajectories.

Adapted wavelet transform improves time-frequency representations: a study of auditory elicited P300-like event-related potentials in rats.

OBJECTIVE: Active auditory oddball paradigms are simple tone discrimination tasks used to study the P300 deflection of event-related potentials (ERPs). These ERPs may be quantified by time-frequency analysis. As auditory stimuli cause early high frequency and late low frequency ERP oscillations, the continuous wavelet transform (CWT) is often chosen for decomposition due to its multi-resolution properties. However, as the conventional CWT traditionally applies only one mother wavelet to represent the entire spectrum, the time-frequency resolution is not optimal across all scales. To account for this, we developed and validated a novel method specifically refined to analyse P300-like ERPs in rats. APPROACH: An adapted CWT (aCWT) was implemented to preserve high time-frequency resolution across all scales by commissioning of multiple wavelets operating at different scales. First, decomposition of simulated ERPs was illustrated using the classical CWT and the aCWT. Next, the two methods were applied to EEG recordings obtained from prefrontal cortex in rats performing a two-tone auditory discrimination task. MAIN RESULTS: While only early ERP frequency changes between responses to target and non-target tones were detected by the CWT, both early and late changes were successfully described with strong accuracy by the aCWT in rat ERPs. Increased frontal gamma power and phase synchrony was observed particularly within theta and gamma frequency bands during deviant tones. SIGNIFICANCE: The study suggests superior performance of the aCWT over the CWT in terms of detailed quantification of time-frequency properties of ERPs. Our methodological investigation indicates that accurate and complete assessment of time-frequency components of short-time neural signals is feasible with the novel analysis approach which may be advantageous for characterisation of several types of evoked potentials in particularly rodents.

The 5-HT6 receptor antagonist idalopirdine potentiates the effects of donepezil on gamma oscillations in the frontal cortex of anesthetized and awake rats without affecting sleep-wake architecture.

The 5-HT6 receptor is a promising target for cognitive disorders, in particular for Alzheimer's disease (AD). The high affinity and selective 5-HT6 receptor antagonist idalopirdine (Lu AE58054) is currently in development for mild-moderate AD as adjunct therapy to acetylcholinesterase inhibitors (AChEIs). We studied the effects of idalopirdine alone and in combination with the AChEI donepezil on cortical function using two in vivo electrophysiological methods. Neuronal network oscillations in the frontal cortex were measured during electrical stimulation of the brainstem nucleus pontis oralis (nPO) in the anesthetized rat and by an electroencephalogram (EEG) in the awake, freely moving rat. In conjunction with the EEG study, we investigated the effects of idalopirdine and donepezil on sleep-wake architecture using telemetric polysomnography. Idalopirdine (2 mg/kg i.v.) increased gamma power in the medial prefrontal cortex (mPFC) during nPO stimulation. Donepezil (0.3 and 1 mg/kg i.v.) also increased cortical gamma power and pretreatment with idalopirdine (2 mg/kg i.v.) potentiated and prolonged the effects of donepezil. Similarly, donepezil (1 and 3 mg/kg s.c.) dose-dependently increased frontal cortical gamma power in the freely moving rat and pretreatment with idalopirdine (10 mg/kg p.o.) augmented the effect of donepezil 1 mg/kg. Analysis of the sleep-wake architecture showed that donepezil (1 and 3 mg/kg s.c.) dose-dependently delayed sleep onset and decreased the time spent in both REM and non REM sleep stages. In contrast, idalopirdine (10 mg/kg p.o.) did not affect sleep-wake architecture nor the effects of donepezil. In summary, we show that idalopirdine potentiates the effects of donepezil on frontal cortical gamma oscillations, a pharmacodynamic biomarker associated with cognition, without modifying the effects of donepezil on sleep. The increased cortical excitability may contribute to the procognitive effects of idalopirdine in donepezil-treated AD patients.

The 5-HT6 receptor antagonist idalopirdine potentiates the effects of acetylcholinesterase inhibition on neuronal network oscillations and extracellular acetylcholine levels in the rat dorsal hippocampus.

The 5-HT6 receptor has emerged as a promising target for cognitive disorders and combining a 5-HT6 receptor antagonist with an acetylcholinesterase inhibitor (AChEI) represents a novel approach for the symptomatic treatment of Alzheimer's disease (AD). A recent phase 2 trial showed that the selective 5-HT6 receptor antagonist idalopirdine (Lu AE58054) improved cognition in patients with moderate AD on stable treatment with the AChEI donepezil. Here we investigated the effects of idalopirdine in combination with donepezil on hippocampal function using in vivo electrophysiology and microdialysis. Network oscillations in the hippocampus were recorded during electrical stimulation of the brainstem nucleus pontis oralis (nPO) in the anesthetized rat and hippocampal acetylcholine (ACh) levels were measured in the freely-moving rat. In addition, potential pharmacokinetic interactions between idalopirdine and donepezil were assessed. Idalopirdine alone did not affect hippocampal network oscillations or ACh levels. Donepezil (0.3 and 1.0 mg/kg i.v.) dose-dependently increased hippocampal theta and gamma power during nPO stimulation. Idalopirdine (2 mg/kg i.v.), administered 1 h prior to donepezil, potentiated the theta and gamma response to 0.3 mg/kg donepezil and prolonged the gamma response to 1 mg/kg donepezil. Donepezil (1.3 mg/kg s.c.) increased extracellular ACh levels in the hippocampus and this was further augmented by administration of idalopirdine (10 mg/kg p.o.) 2 h prior to donepezil. These effects could not be attributed to a pharmacokinetic interaction between the compounds. This study demonstrates that idalopirdine potentiates the effects of donepezil on two pharmacodynamic biomarkers associated with cognition, i.e. neuronal oscillations and extracellular ACh levels in the hippocampus. Such potentiation could contribute to the procognitive effects of idalopirdine observed in donepezil-treated AD patients.