Biochemical, electrophysiological, and pharmacological evidence supporting a role for cholinergic dysfunction in age-related memory disturbances is critically reviewed. An attempt has been made to identify pseudoissues, resolve certain controversies, and clarify misconceptions that have occurred in the literature. Significant cholinergic dysfunctions occur in the aged and demented central nervous system, relationships between these changes and loss of memory exist, similar memory deficits can be artificially induced by blocking cholinergic mechanisms in young subjects, and under certain tightly controlled conditions reliable memory improvements in aged subjects can be achieved after cholinergic stimulation. Conventional attempts to reduce memory impairments in clinical trials hav not been therapeutically successful, however. Possible explanations for these disappointments are given and directions for future laboratory and clinical studies are suggested.

https://science.sciencemag.org/content/sci/217/4558/408.full.pdf

The Cholinergic Hypothesis of Geriatric Memory Dysfunction

The neural networks that putatively modulate aspects of normal emotional behavior have been implicated in the pathophysiology of mood disorders by converging evidence from neuroimaging, neuropathological and lesion analysis studies. These networks involve the medial prefrontal cortex (MPFC) and closely related areas in the medial and caudolateral orbital cortex (medial prefrontal network), amygdala, hippocampus, and ventromedial parts of the basal ganglia, where alterations in grey matter volume and neurophysiological activity are found in cases with recurrent depressive episodes. Such findings hold major implications for models of the neurocircuits that underlie depression. In particular evidence from lesion analysis studies suggests that the MPFC and related limbic and striato-pallido-thalamic structures organize emotional expression. The MPFC is part of a larger “default system” of cortical areas that include the dorsal PFC, mid- and posterior cingulate cortex, anterior temporal cortex, and entorhinal and parahippocampal cortex, which has been implicated in self-referential functions. Dysfunction within and between structures in this circuit may induce disturbances in emotional behavior and other cognitive aspects of depressive syndromes in humans. Further, because the MPFC and related limbic structures provide forebrain modulation over visceral control structures in the hypothalamus and brainstem, their dysfunction can account for the disturbances in autonomic regulation and neuroendocrine responses that are associated with mood disorders. This paper discusses these systems together with the neurochemical systems that impinge on them and form the basis for most pharmacological therapies.

/pdf/brain-structural-and-functional-abnormalities-in-mood-4313buqwur.pdf

Brain structural and functional abnormalities in mood disorders: implications for neurocircuitry models of depression

Patient satisfaction in primary health care: a literature review and analysis.

A monograph communicating the current realities and future possibilities of unifying basic studies on anatomy and cellular physiology with investigations of the behavioral and physiological events of waking and sleep. Steriade established the Laboratory of Neurophysiology at Laval U., Quebec; McCarl

Brainstem control of wakefulness and sleep

This review summarizes the brain mechanisms controlling sleep and wakefulness. Wakefulness promoting systems cause low-voltage, fast activity in the electroencephalogram (EEG). Multiple interacting neurotransmitter systems in the brain stem, hypothalamus, and basal forebrain converge onto common effector systems in the thalamus and cortex. Sleep results from the inhibition of wake-promoting systems by homeostatic sleep factors such as adenosine and nitric oxide and GABAergic neurons in the preoptic area of the hypothalamus, resulting in large-amplitude, slow EEG oscillations. Local, activity-dependent factors modulate the amplitude and frequency of cortical slow oscillations. Non-rapid-eye-movement (NREM) sleep results in conservation of brain energy and facilitates memory consolidation through the modulation of synaptic weights. Rapid-eye-movement (REM) sleep results from the interaction of brain stem cholinergic, aminergic, and GABAergic neurons which control the activity of glutamatergic reticular formation neurons leading to REM sleep phenomena such as muscle atonia, REMs, dreaming, and cortical activation. Strong activation of limbic regions during REM sleep suggests a role in regulation of emotion. Genetic studies suggest that brain mechanisms controlling waking and NREM sleep are strongly conserved throughout evolution, underscoring their enormous importance for brain function. Sleep disruption interferes with the normal restorative functions of NREM and REM sleep, resulting in disruptions of breathing and cardiovascular function, changes in emotional reactivity, and cognitive impairments in attention, memory, and decision making.

/pdf/control-of-sleep-and-wakefulness-51vkuya5ho.pdf

Control of Sleep and Wakefulness

MAMMALIAN sleep is characterised by the cyclical occurrence of rapid eye movement (REM) and non-REM sleep. In humans, REM sleep (consisting of a desyncronised electroencephalogram (EEG), rapid eye movements, atonic electromyogram (EMG), and usually accompanied by dreaming), occurs every 90–110 min1 and is presumed to be under the control of an underlying ultradian oscillatory mechanism2. The biological basis of the above ultradian rhythm is unknown. Although in humans the amount of REM sleep itself can be experimentally increased3–6 or decreased7–9 by pharmacological and physiological means, none of these manipulations has been shown to alter the frequency of its presumed oscillator. We demonstrate here that a normal 104-min REM sleep ultradian rhythm can be experimentally shortened to a 56-min rhythm by repeated infusions of arecholine, a cholinergic muscarinic agonist10. Conversely, scopolamine, a cholinergic muscarinic antagonist11, prolonged the interval between successive REM periods. We speculate that acetylcholine may have a specific role in the timing of the ultradian oscillatory mechanism controlling REM sleep.

Experimental acceleration and slowing of REM sleep ultradian rhythm by cholinergic agonist and antagonist.

The sleep changes induced in normal volunteers following the administration of scopolamine on 3 consecutive mornings resemble many of the abnormalities observed in the sleep of patients with primary depression: increased sleep latency and reduced rapid eye movement (REM) latency, total sleep time, and sleep efficiency. Furthermore, in a multivariate discriminant analysis—previously shown to distinguish the sleep records of depressed patients from those of normal controls and insomniac patients—the records from baseline nights were selected as normal and those after scopolamine as predominately depressed. Those observations suggest to us that muscarinic supersensitivity in normals may function as a pharmacological model for the sleep disturbances of depression.

Muscarinic supersensitivity: a possible model for the sleep disturbance of primary depression?

Attempts to understand the physiology of sleep and wakefulness have been gov­ erned, on the one hand, by the specific phenomena that the investigator has chosen to explain, and, on the other, by the concepts 1Uld techniques available for studying the central nervous system. Prior to the discovery of rapid eye movement (REM) sleep in 1953, and its association with dreaming, investigators had only to explain sleep and wakefulness and the oscillation between the two states. Thus, investigators of "wet" physiology looked for "hypnotoxins" which accumulated during wakeful­ ness and which were presumably dissipated during sleep (1). Similarly, investigators of "dry" physiology explained sleep as a passive state resulting from inactivity of the reticular activating system (2). The discovery that consciousness consists of three major states (REM, wakeful­ ness, and nonREM) complicated but not not obviate these older approaches. It became necessary, however, to account not only for the physiology of each state, but also for their orderly sequence (that is, sleep normally begins with the nonREM phase and consists of the well-known nonREM-REM cycle). Thus, more recent biochemical models, such as that of Jouvet (2), postulates that the mechanism re!iponsible for nonREM sleep "primes" and "triggers" REM sleep. Similarly', the neurophysiological model of Hobson & McCarley (3) suggests that nonREM and REM sleep result from the reciprocal interaction of two anatomically distinct neuronal groups. Physiological models that account for this normal, orderly se­ quence (wakefulness � nonREM � REM) must be flexible enough, however, to account ultimately for the expected deviation (wakefulness � REM � nonREM) which is seen in certain pathological conditions (narcolepsy, psychotic depression), following REM sleep deprivation, and in "phase shift" studies.

The Neuropharmacology of Sleep and Wakefulness

Arecholine, a cholinergic muscarinic agonist, was administered intravenously 35 min after sleep onset in eight normal volunteers who had been pretreated with either methscopolamine or scopolamine, muscarinic receptor blockers that do not and do cross the blood--brain barrier, respectively. Following pretreatment with methscopolamine, arecholine shortened the REM latency and increased the number of REM periods without altering the duration of individual REM periods or altering the REM--REM intervals. Pretreatment with scopolamine blocked the effects of arecholine. The results support the hypothesis that cholinergic muscarinic mechanisms are involved in the timing but not the duration of REM sleep.

/pdf/induction-and-resetting-of-rem-sleep-rhythm-in-normal-man-by-1fxorth8rq.pdf

N. Sitaram

Papers

Experimental acceleration and slowing of REM sleep ultradian rhythm by cholinergic agonist and antagonist.

Muscarinic supersensitivity: a possible model for the sleep disturbance of primary depression?

The Neuropharmacology of Sleep and Wakefulness

Induction and resetting of REM sleep rhythm in normal man by arecholine: blockade by scopolamine.

Choline: Selective enhancement of serial learning and encoding of low imagery words in man.