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There is a strong correlation between signature EEG frequency patterns and the relative levels of distinct neuromodulators. These associations become particularly evident during the sleep-wake cycle. The monoamine-acetylcholine balance hypothesis is a theory of neurophysiological markers of the EEG and a detailed description of the findings that support this proposal are presented in this paper. According to this model alpha rhythm reflects the relative predominance of cholinergic muscarinic signals and delta rhythm that of monoaminergic receptor effects. Both high voltage synchronized rhythms are likely mediated by inhibitory Gαi/o-mediated transduction of inhibitory interneurons. Cognitively, alpha and delta EEG measures are proposed to indicate automatic and flexible strategies, respectively. Sleep is associated with marked changes in relative neuromodulator levels corresponding to EEG markers of distinct stages. Sleep studies on memory consolidation present some of the strongest evidence yet for the respective roles of monoaminergic and cholinergic projections in declarative and non-declarative memory processes, a key theoretical premise for understanding the data. Affective dysregulation is reflected in altered EEG patterns during sleep.

The pathognomonic feature of Alzheimer's disease is a loss of declarative memory. This has generally been attributed to early involvement of medial temporal lobe structures with neurofibrillary tangles and loss of neurons in the entorhinal cortex. However, there has been a re-emerging emphasis on the causal role of brainstem monoaminergic nuclei as involvement of the cholinergic basal forebrain loses prominence. The rejection of this latter theory of cognitive decline is related to inconsistencies in time course and modest effects of treatment using cholinergic agents. The amyloid hypothesis of cortical dysfunction is also losing favor as current trials of plaque dissolution are proving again disappointing. Recent pre-clinical studies on APP/PS1 (familial Alzheimer's disease) transgenic mouse models using serotonergic receptor modulating agents, demonstrate clear neuroprotective effects. The involvement of midbrain raphe in the earliest stages of dementia requires a reassessment of relevant pathophysiology beyond behavioral and affective dimensions. Indeed, a theory of serotonergic modulation of explicit memory formation by direct enhancement of synaptic strength could change the view of the role of these nuclei in AD and lead to more effective treatments.

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