Methylphenidate, an amphetamine derivative, is commonly used for treating narcolepsy. One SPECT study used ¹³³Xe inhalation to examine rCBF in narcoleptic individuals before and after treatment with methylphenidate for about 2 weeks. Administration of the drug increased rCBF during the awake state in the brainstem and cerebellar region (Meyer et al. 1980). The specificity of this finding to narcolepsy cannot be assessed, because controls were omitted in this study.

Modafinil is another psychostimulant drug used to promote wakefulness in patients with sleep disorders. In one experiment, ^99mTc-ECD SPECT was performed when narcoleptic patients were in the awake state, both before and after a 4-week treatment with either modafinil or placebo (Joo et al. 2008). Modafinil caused a significant reduction in subjective daytime sleepiness, while the placebo did not, and patients in the on-modafinil condition showed an increase in rCBF in the bilateral prefrontal cortices (Joo et al. 2008). Thirty-two narcolepsy patients took part in this experiment, but in the absence of controls, the findings cannot be specifically applied to narcolepsy. Another experiment employed ¹⁸F-FDG PET to measure CMRglu in narcoleptic patients (Dauvilliers et al. 2010). Some of the patients were given modafinil and/or antidepressants (for treating cataplexy). Narcoleptics who received the treatment had a higher CMRglu in the cerebellum and the primary sensorimotor cortex compared to untreated patients, which contrasts with the SPECT study by Joo et al. (2008), in which modafinil was associated with a decrease in rCBF in the cerebellum. Researchers conducted another study using ¹⁸F-FDG PET to assess changes in CMRglu after the administration of modafinil (Kim et al. 2007). Seven narcoleptics patients completed the experiment. After 2 weeks of treatment with modafinil, the left hippocampus of narcoleptics exhibited an increase in CMRglu compared to pretreatment scans. Given that similar neuroimaging pattern was found with modafinil treatment in healthy volunteers (Joo et al. 2008), the specificity of this finding to narcolepsy might be questioned.

There are few functional neuroimaging studies of RLS. A PET study by Trenkwalder et al. (1999) involving six RLS patients and six age-matched controls measured CMRglu with ¹⁸F-FDG and found no significant differences. It is noteworthy that the patients were scanned outside of the symptomatic period.

Most PET and SPECT studies of RLS have looked for neurotransmission abnormalities using radioligands for DA and opioids. It has been shown that DA antagonists exacerbate RLS symptoms, whereas DA agonists and opioids are the major form of therapy for RLS (Stiasny-Kolster et al. 2005; Trenkwalder et al. 2008).

DA studies focused mainly on the striatum, examining both presynaptic DA transporter (DAT) and postsynaptic D2-receptor binding. Striatal DAT can be taken as an indicator of DA neuron density in the substantia nigra (SN). Some PET studies showed decreased presynaptic DA function in the striatum of RLS patients versus controls, using either ¹⁸F-dopa (Ruottinen et al. 2000; Turjanski et al. 1999) or ¹¹C-methylphenidate (Earley et al. 2011). However, an early PET study using ¹⁸F-dopa found no such difference, albeit with a limited sample of patients (Trenkwalder et al. 1999). Furthermore, a number of SPECT studies found no difference in DAT in RLS versus controls, using ¹²³I-2beta-carbomethoxy-3beta-(4-iodophenyl) tropane (¹²³I-β-CIT) (Michaud et al. 2002; Mrowka et al. 2005) or ¹²³I-IPT(Eisensehr et al. 2001; Linke et al. 2004). The discrepancy in these findings may be attributable to particular pharmacokinetic properties of radioligands used in PET and SPECT. Earley and colleagues (2011), in the aforementioned study, scanned their patients in the morning (n = 20) and evening (n = 16) and found no difference in DA according to time of day. Hence, time of day does not seem to modulate DAT binding. There was also no significant correlation between severity of RLS symptoms and DAT. Kim et al. (2012) employed SPECT with ¹²³I-β-CIT and ¹²³I-IBZM and, in contrast with all previous presynaptic DA studies, found an increase in DAT density in the striatum, as well as the caudate and posterior putamen.

Postsynaptic D2-receptor binding studies are also rather equivocal. A few SPECT studies used ¹²³I-IBZM. Most found no difference (Eisensehr et al. 2001; Tribl et al. 2002, 2004), while one found a slight decrease in striatal D2-receptor binding in RLS patients versus controls (Michaud et al. 2002). Two PET studies using ¹¹C-raclopride found divergent results: Turjanski et al. (1999) found a decrease and Cervenka et al. (2006) an increase in striatal D2-receptor binding. This discrepancy may be explained by the inclusion of a sample of RLS patients previously exposed to DA drugs in the study by Turjanski and colleagues (1999), whereas patients in the other study were drug naïve (Cervenka et al. 2006). It has in fact been shown that D2 receptors can be downregulated by chronic drug treatment, hence decreasing ligand binding (Stanwood et al. 2000). Cervenka and colleagues (2006) measured D2-receptor binding in extrastriatal structures by scanning 16 RLS patients with ¹¹C-FLB457 and found increased binding potential in the striatum as well as in the insula, thalamus, and anterior cingulate cortex. The areas showing increased D2-receptor binding are part of the medial nociceptive system, which regulates the affective component of pain. If this system were to undergo endogenous DA depletion, one could expect upregulation of D2 receptors, just as the study showed. The authors also took measurements in the morning and the evening and found no diurnal changes in D2 binding potential. Furthermore, no significant correlation was found between RLS symptom rating and D2 binding potential. Hence, diurnal changes in RLS symptom severity cannot be accounted for by presynaptic DA transmission (Earley et al. 2011) or postsynaptic D2 binding (Cervenka et al. 2006). In a later PET study using ¹¹C-raclopride, Earley et al. (2013) found that RLS patients had lower D2-receptor binding potential in the putamen, as well as the caudate but not ventral striatum. Interestingly, in light of the divergent results of previous PET and SPECT studies, the authors of the study deemed D2-receptor binding potential of questionable value to RLS research.

Since RLS seems to be a disorder of the nociceptive system, it follows that the opioid system, which modulates pain, may play a role in RLS. Indeed, opioid receptor agonists have been shown to improve RLS symptoms (Walters 2002). This effect may however be mediated by DA and may not necessarily reflect a deficiency in endogenous opioids (Barriere et al. 2005). In support of this, one PET study has examined opioids in RLS, using ¹¹C-diprenorphine (a nonselective opioid receptor ligand), and found no differences between patients and controls, although the authors did find some correlations between RLS severity or pain scores and opioid binding in several brain areas (von Spiczak et al. 2005).

In addition to nigrostriatal abnormalities in DA neurotransmission, descending dopaminergic projections to the lower brainstem and spinal cord, as well as opioid receptors in the spinal cord, are also thought to play an important role in RLS pathophysiology. In addition, spinal cord lesions and peripheral neuropathies are associated with RLS (Trenkwalder and Paulus 2010). However, limitations in the resolution of PET and SPECT in these areas preclude further investigation using these imaging techniques.

Dopaminergic transmission has been studied in relation to PLM. At the presynaptic level, Happe and colleagues (2003) measured DA transmission in 11 patients with Parkinson’s disease (PD) using SPECT with ¹²³I-β-CIT. Patients with PD showed a stark reduction in striatal binding compared to controls, as expected. By also measuring PLMS by polysomnography, the authors detected a negative correlation between the number of PLMS and striatal DA binding values. This suggests a possible role of presynaptic DA deficiency in PD-induced PLMS. Staedt and colleagues examined postsynaptic D2-receptor binding in the striatum of PLMS patients in a few studies using SPECT and ¹²³I-IBZM (Staedt et al. 1993, 1995a, b) and found decreased D2-receptor occupancy (Staedt et al. 1993, 1995a). DA replacement therapy can reverse this pattern and restore sleep quality (Staedt et al. 1995b).

PET and SPECT studies on RLS and PLM seem to indicate a hypoactivity of DA neurotransmission underlying these disorders, both at the presynaptic and postsynaptic levels. DA deficiency, in concert with CNS iron depletion, may unbalance the sensorimotor control of pain. Further research into RLS and PLM brain activation during sleep is needed to confirm these findings and shed further light on these little explored disorders.

One common type of NREM parasomnia is sleepwalking, formally known as somnambulism. It “consists of a series of complex behaviors that are usually initiated during arousals and slow wave sleep (SWS) and culminate in walking around with an altered state of consciousness and impaired judgment” (AASM 2005). To date, there is only a single case studying sleepwalking with neuroimaging. Bassetti et al. (2000) hypothesized that sleepwalking is a dissociated state, consisting of both mental and motor arousal. Using SPECT, recordings were taken from a 16-year-old man in two conditions: one recording during SWS, the other 24 s after the occurrence of a sleepwalking episode arising from SWS. In both conditions, the patient was injected with ^99mTc-ECD. Compared to undisturbed SWS, there was an increase in rCBF post-sleepwalking, particularly in the posterior cingulate cortex and the anterior cerebellum (Bassetti et al. 2000). Interestingly, these areas showed a decrease in activity in healthy volunteers during SWS compared to wakefulness (Maquet et al. 2000). Furthermore, Bassetti et al. compared their data to those of control subjects and observed that the patient demonstrated a decrease in perfusion in the frontoparietal associative cortices during the sleepwalking episode compared to wakefulness in controls. This hypoperfusion was interpreted as reflecting a lack of self-related awareness and the inability to recall the events of the sleepwalking episode. In contrast, the hyperperfusion of the posterior cingulate and cerebellum was thought to reflect persistent arousal patterns, which is in line with the hypothesis of a dissociated state. Further studies should confirm these findings using a larger sample size.

Within REM parasomnias, RBD is accompanied by a loss of skeletal muscle atonia usually present during REM sleep and involves complex motor activity occurring specifically in association with dream mentation. The disorder is characterized by unpleasant dreams and dream enactment, which could be disturbing to the patient or the bed partner (AASM 2005). RBD can exist with or without a medical condition, respectively known as secondary RBD or idiopathic RBD. Parkinson’s disease, dementia with Lewy bodies (DLB), and multiple system atrophy tend to develop in patients with RBD several years later (Postuma et al. 2009). SPECT and PET have played a significant role in highlighting the brain regions involved in RBD pathophysiology and clinical evolution (Fig. 34.2).

A study performed by Shirakawa et al. (2002) compared 20 male idiopathic RBD patients to 7 healthy male subjects using N-isopropyl-p-¹²³I-iodoamphetamine (¹²³I-IMP) SPECT. Compared to the control group, a statistically significant decrease of rCBF was found in the right and left upper portion of the frontal lobe and in the pons. The scans were performed at night, although it was not clear which state of vigilance they were experiencing.

Mazza et al. (2006) conducted a study using ^99mTc-ECD SPECT, which included eight idiopathic RBD patients and nine healthy control subjects. In contrast to Shirakawa et al. (2002), significant hyperperfusions were found in the pons, as well as in the putamen and the right hippocampus. Interestingly, increased rCBF is also present in the latter two regions during the early stages of Parkinson’s disease (Imon et al. 1999). In addition, decreased perfusion was found in the frontal lobe, particularly in the motor cortices and in the temporo-parietal cortices. A larger study of 20 idiopathic RBD patients and 20 control subjects exhibited similar results (Vendette et al. 2011). Once again using ^99mTc-ECD SPECT, hyperperfusion was displayed in pons, putamen, and bilaterally in the hippocampus and hypoperfusion in frontal and medial parietal areas.

Hanyu et al. (2011) monitored rCBF using ¹²³I-IMP SPECT in 24 patients with IRBD. In contrast with previous studies, they did not find significant differences between patients and controls in the brainstem and frontal areas. Results did however display hypoperfusion in RBD patients, in the precuneus, cerebellum, and uncus, regions also identified by Vendette and colleagues (2011).

Two studies led by Caselli et al. (2006) and Fujishiro et al. (2010) assessed CMRglu with ¹⁸F-FDG PET in subjects with dream-enactment behavior. These subjects displayed decreased CMRglu in multiple cortical areas, such as occipital, frontal, parietal, temporal, and cingulate. No polysomnographic recording was performed to confirm a diagnosis of RBD; rather, patients were selected based on questionnaires and interviews only, hence diminishing the validity of the study.

SPECT with ^99mTc-ECD was recently used to predict the onset of PD and DLB in 20 idiopathic RBD patients (Dang-Vu et al. 2012). The average follow-up of 3 years revealed that PD or DLB emerged in ten of the patients; interestingly, these ten patients showed an increase in hippocampal rCBF at baseline. It can thus be proposed that the progression of idiopathic RBD into PD or DLB can be predicted via abnormal perfusion in the hippocampus.

While the studies above described functional neuroimaging acquired in RBD patients mainly during wakefulness, only one study reported brain activations associated with RBD behavioral manifestations. This study was conducted on a single patient, with multiple system atrophy and RBD, and compared to two healthy control subjects (Dauvilliers et al. 2011). After injecting ^99mTc-ECD during a RBD episode, compared to wakefulness, the patient showed increased perfusion in the supplementary motor area, suggesting this area’s involvement in the onset of dream-enactment behaviors. The effect was not present in controls when contrasting REM sleep versus wakefulness. No SPECT data was obtained during REM sleep outside the behavioral episode in RBD patients.

Due to the relationship between RBD and PD, multiple system atrophy, and other conditions associated with DA dysfunction (Gagnon et al. 2009), there have been numerous SPECT and PET ligand studies in the last decade analyzing the nigrostriatal DA system in RBD patients. A group performed two SPECT studies with ¹²³I-IPT demonstrating a decrease in DAT at the presynaptic site of the striatum in idiopathic RBD patients compared to age- and sex-matched controls (Eisensehr et al. 2000, 2003a). Additionally, these two studies also included an assessment of postsynaptic D2-receptor binding using ¹²³I-IBZM SPECT and found no significant change in RBD compared to controls and PD. This suggests that DA dysfunction in the striatum is restricted to the presynaptic level in RBD patients, in line with a loss of DA midbrain neurons, and similarly to findings in PD (Tatsch et al. 1997).

The same conclusion was reached in a PET study using ¹¹C-dihydrotetrabenazine (¹¹C-DTBZ) in a study comparing 6 idiopathic RBD patients to 19 controls (Albin et al. 2000). In agreement with the studies conducted by Eisensehr and colleagues (2000, 2003a), the density of striatal DA was measured, and a decrease in presynaptic binding was found, most prominently in the posterior putamen.

Similarly, another PET study was performed using ¹¹C-DTBZ to measure presynaptic striatal binding. The 13 patients who had RBD and probable multiple system atrophy showed a decrease in binding, which was negatively correlated with the severity of REM atonia (Gilman et al. 2003). These results suggest that a presynaptic DA deficit might contribute to the frequent occurrence of RBD in patients with multiple system atrophy.

Four studies examined DAT in RBD patients using SPECT with ¹²³I-2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl)-nortropane (¹²³I-FP-CIT). Two studies in particular concluded that an insignificant number of RBD patients demonstrated a decrease of striatal DAT (Stiasny-Kolster et al. 2005; Unger et al. 2008). Another report compared 14 idiopathic RBD patients, 14 early-stage Parkinson’s disease, and 12 controls (Kim et al. 2010). Further, confirming the studies performed by Eisensehr and colleagues (2000, 2003a), the RBD patients showed lower binding in the striatum compared to control subjects, more specifically in the putamen. This binding was however higher compared to Parkinson’s disease patients, suggesting a progressive DA impairment from RBD to Parkinson’s disease. In a more recent ¹²³I-FP-CIT SPECT study, 43 idiopathic RBD and 18 controls were examined longitudinally for striatal DAT (Iranzo et al. 2010). It was found that there was reduced binding in 40 % of the RBD patients. This study included a follow-up demonstrating that a neurodegenerative disorder developed in eight of the IRBD patients within 2.5 years after the imaging took place. Interestingly, 6 of these 8 patients had reduced DAT at baseline, highlighting the significance of lowered DAT in the prediction of disease evolution.

A case study involving a 73-year-old man used ¹¹C-CFT to assess changes of nigrostriatal presynaptic DA 1 and 3.5 years after the onset of RBD (Miyamoto et al. 2010). Compared to controls, the first year’s results displayed only a minor decrease in the posterior putamen, yet after 3.5 years there was a more pronounced decrease of 4–6 % per year. Similarly, a recent 3-year study used ¹²³I-FP-CIT SPECT on 20 IRBD patients (Iranzo et al. 2011). Complementary to the case report, there was a reduction in binding over time (compared to controls) in all striatal regions with the exception of the right caudate nucleus, further demonstrating a progressive nigrostriatal dopaminergic dysfunction.

Several SPECT and PET neuroimaging studies are available for RBD. However, to date, only one study has been devoted to sleepwalking. Sleepwalking demonstrates brain patterns reminiscent of both SWS and wakefulness states, therefore appearing as a dissociated state. Additional studies are needed to further qualify the role of SWS alterations in somnambulism.

In RBD patients, SPECT and PET have shown that there exists a presynaptic dysfunction of DA nigrostriatal pathways, further indicating that RBD represents the early stages of PD, DLB, and multiple system atrophy. Moreover, the risk of progression from RBD to other neurodegenerative disorders can be estimated using SPECT. Hypoperfusions found in the pons agree with human studies involving pontine lesions in RBD pathophysiology (Culebras and Moore 1989; Gomez-Choco et al. 2007; Kimura et al. 2000; Limousin et al. 2009; Plazzi and Montagna 2002; Provini et al. 2004; Schenck and Mahowald 2002; Tippmann-Peikert et al. 2006; Xi and Luning 2009; Zambelis et al. 2002). The role of structures such as the hippocampus and cognitive aspects of RBD should be further investigated. Finally, brain activity patterns during behavioral episodes and during sleep should be examined to shed further light on the pathophysiology of RBD.