By Alan Z. Segal, MD

Associate Professor of Clinical Neurology, Weill Cornell Medical College

Dr. Segal reports no financial relationships relevant to this field of study.

Synopsis: REM behavior disorder may precede α-synucleinopathies by decades and may be a biomarker of future disease.

Source: Mayer G, et al. Ictal SPECT in patients with rapid eye movement sleep behaviour disorder. Brain 2015;138:1263-1270.

Rapid eye movement (REM) sleep is a fascinating combination of an active dreaming brain along with typically complete muscle paralysis. When REM sleep occurs without appropriate muscle atonia (RSWA), the physical enactment of dreams (known as REM behavior disorder or RBD) becomes possible.

RBD is a known precursor of neurodegenerative disease, in particular the α-synucleinopathies — Parkinson’s disease (PD), dementia with Lewy Bodies, or multiple system atrophy (MSA). The occurrence of such disorders may occur in up to 90% of RBD patients, often delayed by decades after the initial RBD symptoms. During polysomnography, patients with no clinical history of RBD may show muscle activity during REM (RSWA), but it is unknown whether this isolated laboratory finding is clinically relevant. RSWA is likely a necessary but not sufficient component of RBD-associated neurodegeneration.

The neuroanatomical basis of RBD is not completely understood but is thought to relate to a failure of the sublaterodorsal (SLD) and pedunculopontine (PPN) nuclei in the tegmentum of the pons. In normal REM sleep, the SLD-PPN nuclei have excitatory glutaminergic input on inhibitory interneurons that project to and downregulate anterior horn cells in the spinal cord. In normal REM sleep, which closely resembles the wake-state on EEG, there is activation of alerting neurons in periaqueductal gray matter (PAG-adrenergic) and locus ceruleus (LC-serotonergic). REM atonia is produced because the PAG-LC upregulates the SLD-PPN. This pathway fails in RBD. Animal models of RBD confirm this anatomy, as bilateral lesions of the LC facilitate muscle activity in REM.

Narcolepsy is well-known as a disorder of daytime sleepiness, but nocturnal sleep disturbances in narcolepsy are many. Although seemingly unrelated to the basal ganglia, movement disorders in narcoleptic sleep, ranging from excessive periodic limb movements (PLMs) to full-blown RBD, are present in at least 50% of patients. Furthermore, it is possible that narcolepsy may not be merely a deficiency of hypothalamic hypocretin neurons, but rather a more widespread neurodegenerative process. Narcolepsy studies using diffusion tensor imaging (DTI) have shown microstructural changes extending through the mesencephalon (particularly in the substantia nigra), pons, and medulla. Parallels between narcolepsy and PD have been drawn clinically, as both may be accompanied by impaired smell (hyposmia) and depression. Of note, PLMs and RBD are also more common among patients with depression, particularly those treated with SSRIs. These medications suppress REM, but are known contributors to PLMs and RBD. It is also increasingly apparent that it may not be the SSRIs, but rather the depression itself that results in these movement disorders.

Parkinson’s is a disorder that has been typically referred to as “state dependent,” particularly due to the common observation that the findings of PD (tremor in particular) disappear during sleep. Interestingly, when PD patients exhibit movements in their dreams, they do not have the typical jerky quality of their daytime activity. Instead, patients with daytime hypophonia may scream loudly, and those with profound bradykinesia may kick or punch violently. This phenomenon is not thought to be related to dopamine, since even non-dopamine responsive patients, such as those with MSA, in which the fundamental problem is degenerative and not chemical, exhibit this phenomenon.

In the present study, the authors studied only four patients — all with known RBD. Two had concomitant narcolepsy, one had PD, and the last had isolated RBD only. Although the numbers are small, impressively, these investigators were able to carry out a protocol in which they diagnosed RBD in the sleep lab and then rapidly imaged the patients to capture ictal abnormalities. It was required that each subject demonstrate 5 minutes of REM sleep, with 5 minutes of complex REM behaviors. Technetium (Tc-99) was injected within 15 minutes (with persistence of violent movements in all cases) and imaging was performed within 30 minutes. Each patient showed precisely the same SPECT activation pattern. This included activation of the bilateral premotor areas, the interhemispheric cleft, the periaqueductal area, the dorsal and ventral pons, and the anterior lobe of the cerebellum.

This pattern, which “bypassed the basal ganglia,” was found to be in stark contrast to typical SPECT patterns seen in normal, awake subjects, which show bilateral basal ganglia activation. This bypass pattern was perhaps more similar to that seen in awake PD patients, which consistently show decreased basal ganglia activation. Technetium SPECT scan data are limited in PD patients, who have been most actively studied using 18-fluorodopa PET or [123I]-FP-CIT SPECT (DAT scans), which can be diagnostic for the disease even in its earliest stages.


This work provides unique insight into a large spectrum of disorders, from asymptomatic RSWA to RBD, narcolepsy, PD, and a wider variety of α-synuclein-related neurodegenerative disorders. It is unique in its documentation of otherwise unknown ictal patterns of RBD, but raises many more questions than it answers. What would the test subjects show if studied following similar movements in the awake state? What might PD or healthy controls who lack RBD demonstrate if studied in REM using the same paradigm? Why does RBD predict PD as well as other degenerative disorders such as MSA, with markedly different neuroanatomy? As with any predictor of a neurodegenerative process, most prominently MCI in Alzheimer’s disease, any technique that can predict disease onset will be even more important when neuroprotective treatments to prevent disease or slow deterioration are successfully developed.