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likely involved in the control of movement during sleep itself. Dysfunction
of dopamine is thought to underlie REM behavior disorder (RBD). RBD is
characterized by unusual gross motor activity during REMS, imagined as
people “acting out their dreams.” Normally during sleep, descending spinal
motor pathways are inhibited via descending glycinergic axons from the
ventromedial medullary reticular formation. 20 The locale of the effect of
dopamine on spinal motoneuron excitability is unknown and might occur
at the level of the pons, medulla, or the spinal cord itself. 21 Individuals with
RBD are more likely to develop PD, with about one-third converting to PD
within 5 years of initial presentation to a sleep clinic. 22 This too implies
either a progression of the disease or varying thresholds for different path-
ological phenotypes. It has been suggested that daytime sleepiness or
RBD may be useful as prodromal markers in PD, allowing for earlier treat-
ment when, perhaps, slowing the disease might prove more effective than
current treatments that begin after the onset of motor symptoms.
There are two separate loci of cholinergic neurons that appear to con-
tribute to the regulation of sleep and wake—basal forebrain and brain stem
pedunculopontine and laterodorsal tegmentum (PPT/LDT). Basal forebrain
cholinergic neurons mainly innervate the cortex, while those of the PPT/
LDT primarily innervate the thalamus. 23,24 These cholinergic neurons pro-
vide a major source of excitation to both cortical and thalamic neurons and
are mainly responsible for the control of cortical synchronization that varies
between wake, NREMS, and REM. 25 As described earlier, it is the return of
cholinergic tone during REMS that appears to drive thalamocortical neu-
rons from bursting to single-spike mode, resulting in a desynchronization
of cortical neurons. A dramatic loss of cholinergic neurons is the hallmark
of Alzheimer disease (AD). Not unexpectedly, there is often severe disrup-
tion of sleep in individuals with AD. 26 The common form of sleep disrup-
tion found in those with AD is a deterioration of the diurnal organization of
sleep and wake, so much so that in many cases, sleep and wake occur ran-
domly across the day and night. This type of sleep disturbance is so disruptive
that it often causes institutionalization of individuals with AD long before
memory disturbances become a bother to the primary caregiver. 27,28 It
has been surmised that this breakdown in sleep/wake organization is second-
ary to a reduction in the influence of the circadian clock (see below) due to
degeneration of this nucleus. 29 There have been no reported studies in
humans, however, that have demonstrated a reduced amplitude of the cir-
cadian clock in individuals with AD. Likewise, efforts to increase circadian
amplitude via administration of light during the daytime have had mixed
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