Neuroimaging and Sleep Medicine * 睡眠呼吸障碍综合征 Eric A

Sleep Medicine Reviews (2005) 9, 157–172

www.elsevier.com/locate/smrv

THEORETICAL REVIEW Neuroimaging and sleep medicine * 睡眠呼吸障碍综合征 Eric A. Nofzinger 周期性肢体运动障碍

Sleep Neuroimaging Research Program, Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, 3811 O’Hara Street, Pittsburgh, PA 15213, USA

KEYWORDS Summary In sleep medicine, patients with sleep disorders are evaluated and Sleep disorders treated. The primary assessment tool of the field has traditionally been medicine; polysomnography. While polysomnography has been helpful in the evaluation of Positron emission some sleep disorders, such as sleep apnea syndrome and periodic limb movement tomography; disorder, it has been less helpful in others, such as the insomnias, or sleep disorders Neuroimaging; secondary to mental disorders. These disorders are presumed to stem from some Brain function alteration in brain function that disrupts sleep. The development of functional neuroimaging methods provides a means to understand brain function in patients with sleep disorders in a manner not accessible to polysomnography. This paper summarizes functional neuroimaging findings during healthy sleep, then, reviews available studies in sleep disorders patients, and studies addressing the pharmacology of sleep and sleep disorders. Areas in which functional neuroimaging methods may be helpful in sleep medicine, and in which future development is advised, include: (1) clarification of pathophysiology; (2) aid in differential diagnosis; (3) assessment of treatment response; (4) guiding new drug development; and (5) monitoring treatment response. 未来研究五大方向： Q 2004 Elsevier Ltd. All rights reserved. 1.澄清病理生理学；2.鉴别诊断为目标； 3.评估治疗效果4.引导新药开发 5.检测治疗反应 Introduction example, the assessment of respiratory patterns in conjunction with some assessment of sleep is para- The field of sleep medicine has evolved around the mount to the diagnosis as well as assessment of 失眠症 diagnostic tools of the sleep lab, where a patient’s treatment response. In other disorders, such as sleep is defined in terms of a collection of electro- insomnia or sleep disorders secondary to psychiatric physiological measures that assess various aspects of disorders, the utility of electrophysiological assess- physiology. Over the early years of sleep medicine, ment of sleep is less clear in terms of assessment or there was a hope that the sleep lab assessment could management. Still, there remains a sense that some provide some objective and specific understanding of aspect of sleep is altered in a pathological manner in an alteration in sleep that relates to the clinical these disorders, perhaps in a way that is not captured disturbances in sleep experienced subjectively. This effectively in a standard sleep lab assessment. hope has been realized for some, but not all sleep In the past few decades, functional neuroimaging disorders. In obstructive sleep apnea (OSA), for has emerged as a new way to assess brain function 阻塞性睡眠呼吸暂停 in health and in pathology. These methods allow for * Tel.: C1-412-624-2246; fax: C1-412-624-2841. the quantification of a variety of aspects of E-mail address: [email protected]. brain function including metabolism, blood flow

1087-0792/$ - see front matter Q 2004 Elsevier Ltd. All rights reserved. 代谢，血流和受体结合情况 doi:10.1016/j.smrv.2004.07.003 158 E.A. Nofzinger and receptor binding. Given that sleep is regulated by the brain and may ultimately serve brain function, these tools may provide important information regarding abnormal brain function in sleep disorders patients in a manner not accessible to traditional polysomnographic assessment. If so, such assessments may serve an important function in the evaluation and management of sleep disorders patients and in the development of new pharmacologic agents to treat sleep disorder patients. This chapter will briefly review the functional neuroanatomy of healthy sleep, then turn its attention to the use of functional neuroimaging in the assessment and management of sleep disorders. Up to this point, most studies have addressed normative processes, while early efforts in sleep disorders have focused on pathological mechanisms. In reviewing this work, effort will be applied to potential applications in the evaluation and Figure 1 This figure shows brain structures where management of sleep disorders patients in a relative metabolism is less in NREM sleep than in waking manner to guide the field in future research in healthy subjects. The general pattern includes hetero- development in this area. modal association cortex and the thalamus (Reprinted from reference 45).

Healthy sleep neurophysiology and NREM sleep there are relative regional reductions in activity in heteromodal association Prior to conducting functional neuroimaging cortex in the frontal, parietal and temporal lobes as studies of sleep, it is important to ground the well as in the thalamus (Fig. 1). This suggests that development of hypotheses and the interpretation the thalamocortical circuits that play an important of results on the basic neuronal mechanisms role in NREM sleep function are those involving regulating the sleep/wake cycle. This is important regions that support waking, conscious, goal as the spatial and temporal resolution of current directed behavior. Preclinical work shows that imaging modalities provide limited information on REM sleep is associated with an electrophysiologi- function in small structures that are known to be cally active cortex, with selective activation of important in the regulation of sleep/wake cholinergic networks that originate in the brain- rhythms. The basic mechanisms of sleep/wake stem and basal forebrain and that densely innervate regulation in preclinical models have been limbic and paralimbic cortex. Consistent with this, 1–29 described elsewhere. in relation to waking and NREM sleep, REM sleep is associated with increased relative activity in the pontine reticular formation, as well as limbic (e.g. Functional neuroimaging studies amygdala and hypothalamus) and paralimbic cortex of healthy human sleep (e.g. ventral striatum, anterior cingulate and medial prefrontal cortex) (Fig. 2). This suggests Functional neuroimaging studies have revealed that REM sleep may play an important role in reliable broad changes in cerebral activity across emotional behavior, given the important involve- the sleep/wake cycle. Globally, brain activity ment of these structures in the regulation of affect decreases from waking to NREM sleep, then and in motivated behavior. increases to waking levels again during REM 脑桥网状结构，边缘和旁边缘系统 sleep.30–46 Preclinical studies support a deafferen- tation of the cortex at the level of the thalamus and Sleep deprivation and daytime alertness the occurrence of intrinsic thalamocortical elec- trical oscillations in NREM sleep. Studies across Sleep deprivation is a common consequence of a several laboratories and using various imaging variety of sleep disorders. In the insomnias, methods have demonstrated that between waking including those related to other mental and Neuroimaging and sleep medicine 159

Figure 2 This ﬁgure shows brain structures where relative metabolism is greater in REM sleep than in waking in healthy subjects. The general pattern includes limbic and paralimbic structures, hippocampus, amygdala, ventral striatum, basal ganglia, supplementary motor area (SMA), anterior cingulate and medial prefrontal cortex (Nofzinger EA, unpublished data).

physical disorders, inefficient sleep results in ally, these declines were most notable in fronto- sleep deprivation. Sleep deprivation is also a parietal cortex and in the thalamus. This is consequence of sleep apnea syndrome and peri- consistent with studies showing that the effects odic limb movement disorder (PLMD). Across these of sleep deprivation on slow wave sleep are disorders, sleep is not providing a restorative function. The impact of sleep deprivation on brain function during waking may be common across multiple sleep disorders. It is important, therefore, to understand the effects of experimentally produced sleep deprivation on waking brain function. Wu et al.47 assessed regional cerebral metabolism using the [18F] fluorodeoxyglucose ([18F]FDG) method in healthy subjects before 睡眠剥夺 and after 32 h of sleep deprivation. They noted 降低了 prominent decreases in metabolism in the thala- 丘脑，基底节mus, basal ganglia, temporal lobes, and cerebel- 颞叶和小脑 lum with increases in visual cortex. Whole brain 代谢 absolute metabolic rate was not different. Tho- 视觉提高了 mas et al.48,49 described the effects of 24, 48 and 72 h of sleep deprivation on waking regional Figure 3 This figure shows brain structures (Brodmann areas) where relative metabolism is less after 24 h of sleep cerebral metabolism assessed via [18F]FDG posi- deprivation in waking in healthy subjects. Note the tron emission tomography (PET), as well as similarities between these regions and those where alertness and cognitive performance (Fig. 3). metabolism is less in NREM sleep than in waking (hetero- Sleep deprivation was associated with global modal association cortex and thalamus) (Reprinted from declines in absolute cerebral metabolism. Region- reference 48). 额顶网络和丘脑的代谢降低，而脑电节律能力提高对于一些疾病，其结果在睡眠 160 对于另一些疾病，其起因在睡眠E.A. Nofzinger 发作性睡病失眠症 the presumed causes of sleep disorders, such as narcolepsy or insomnia, are thought to reside in the central nervous system. In other sleep disorders, such as sleep apnea syndrome, many of the effects of the disorder, such as sleep disruption lending to sleep deprivation, occur in the central nervous system. The pathophysiology and effects, therefore, of sleep disorders may be clarified by an Figure 4 This figure shows brain structures where delta increased understanding of the brain mechanisms power during sleep is greatest both before and after sleep of the disorders. Functional neuroimaging studies deprivation (left and middle) and where the increases may aid in this pursuit. To date, most functional from pre- to post-sleep deprivation are greatest (right) in neuroimaging studies in sleep disorder patients healthy subjects (Reprinted from reference 82). have served this overall goal. In general, very limited information is available for most sleep greatest in frontal EEG leads (Fig. 4). Alertness disorders. This represents a major area for future and cognitive performance on a sleep-deprivation research in sleep disorders medicine.54 sensitive serial addition/subtraction test declined in association with the sleep-deprivation associated regional deactivations. Paus et al.37,50–52 have demonstrated that blood flow in the thala- Obstructive sleep apnea syndrome mus and ponto-mesencephalic tegmentum as 15 assessed by [ O]H2O PET positively correlates OSA syndrome is characterized by repetitive cessa- with arousal associated with sleep,37 with per- tions or reductions in air movement during sleep. formance on vigilance tasks50 and with loss of OSA has received increased recognition in the past consciousness associated with anesthesia.52 In decade owing to its high prevalence and to its some instances, this arousal network also included recognized adverse health outcomes.55–62 Early the basal forebrain and anterior cingulate cor- concerns regarding the impact of OSA on health tex.50 Anesthesia produces declines in alertness to were related to its impact on cardiovascular and the point of unconsciousness. Alkire et al.53 cerebrovascular health. There is increasing recog- assessed functional brain activity in 11 healthy nition, however, that its impact on brain function subjects undergoing general anesthesia. They accounts for considerable mortality and morbidity, found specific suppression of regional thalamic including motor vehicle accidents, psychosocial and midbrain reticular formation activity across dysfunction, and lost productivity.63–69 two different commonly used volatile agents. In Despite this increased awareness, comparatively light of other findings in sleep, they suggest that little effort has been devoted to understanding the the essential common neurophysiologic mechan- effects of OSA on brain function or its potential ism underlying anesthetic-induced unconscious- reversibility with therapy. OSA leads to sleep ness is, as with sleep-induced unconsciousness, a fragmentation and episodic systemic arterial oxy- hyperpolarization block of thalamocortical neur- hemoglobin desaturations. Recent integrative ons. These findings support the role for sleep in models suggest that these disturbances preferen- restoration of brain function in thalamocortical tially lead to dysfunction in the prefrontal cortex, a networks associated with higher order cognition. region of the brain that controls various executive In terms of sleep disorders, the severity of a sleep functions.70 This may account for problems disorder on waking brain function may be with behavioral inhibition,71 set-shifting,63,71,72 measured by the degree to which there is a self-regulation of affect and arousal,73 working reduction in activity in the thalamus and fronto- memory,71,72,74 analysis/synthesis,63,71,74 and con- parietal cortex. Treatment response in sleep textual memory.75 These OSA-induced executive disorders may be measured by the ability of an function deficits cannot be accounted for by intervention to reverse these alterations in thala- sleepiness itself,63 do not all reverse following mocortical function. treatment,71,76–78 and may represent neuronal damage. The neurobehavioral consequences of OSA may Sleep disorders: pathophysiology be related to a disruption in the usual NREM sleep- related restoration of prefrontal cortex function. A core principle in medicine is the identification of Sleep in general, and slow wave sleep, in particular, the causes of illness. In sleep medicine, many of have been hypothesized to play a role in brain Neuroimaging and sleep medicine 161 restoration.79,80 Several observations suggest that muscarinic cholinergic receptors in narcoleptic the NREM sleep-related brain restoration preferen- subjects using [11C]N-methyl-4-piperidylbenzilate tially involves the prefrontal cortex. Topographic ([11C]NMPB) both before and after pharmacother- EEG sleep studies show that slow wave sleep is apy. No differences were observed between greatest in frontal EEG leads.81,82 Sleep deprivation patients and healthy subjects at baseline and results in an increase in slow wave sleep that is minimal treatment effects were observed. This greatest in frontal EEG leads.79,82–86 Cognitive complex of findings using a variety of different deficits resulting from sleep deprivation are nuclear medicine techniques do not yet provide any in domains thought to involve the prefrontal consistent model of alterations in regional cerebral cortex.75,87,88 Studies of the metabolic and cogni- function in this sleep disorder. Additional studies tive consequences of sleep deprivation support a are needed. role for sleep in restoration of function in the prefrontal cortex.48,49 OSA is associated with a loss of slow wave sleep in addition to the behavioral Recurrent hypersomnia deficits reflecting altered prefrontal cortex function. Nose et al.96 report the results of SPECT scans Given this context, functional neuroimaging obtained on a single patient with recurrent studies of sleep apnea lag far behind other studies hypersomnia both during a period of hypersomnia of the pathophysiology of this disorder. Ficker and during insomnia which followed. They report et al.89 assessed cerebral blood flow in OSA patients that the hypersomnolent period was associated using HMPAO single photon emission computerised with decreased blood flow in the thalamus. They tomography (SPET). They reported frontal hyper- propose that this alteration in thalamic function perfusion by visual inspection. Statistically, they may be pathophysiologically linked with hyper- showed parietal hypoperfusion. Both these changes somnia. This single case report requires replica- reversed following effective nasal continous posi- tion in larger sample sizes and with a control tive airway pressure (nCPAP) therapy. These find- comparison. ings require replication and extension using larger sample sizes and more advanced methods. Primary insomnia

Narcolepsy Three neuroimaging studies have been reported that help to clarify the functional neuroanatomy of Recent advances have linked narcolepsy with insomnia. Smith et al.97 assessed cerebral blood altered function in the hypocretin system, a flow during NREM sleep using Tc-99m-HMPAO SPECT peptide produced in the posterior lateral hypo- in five insomniacs and four healthy controls. The thalamus that has activating properties and is primary finding of their study was that insomniacs functionally related to all known arousal systems had lower overall blood flow in NREM sleep in in the central nervous system.90–92 The role of relation to healthy controls. Regionally, this was functional neuroimaging studies in human narco- noted to be greater in the basal ganglia. leptic patients is in further clarifying the mechan- Nofzinger et al.98 used [18F]-FDG PET to define isms of the extra-hypothalamic manifestations of regional cerebral correlates of arousal in NREM the illness, such as cataplexy, sleep attacks, and sleep in nine healthy and 12 depressed patients. hypnogogic hallucinations. Few studies have They assessed EEG power in the beta high frequency been conducted to date. Hublin et al.93 performed spectrum as a measure of cortical arousal. They 123I-iodobenzamide SPECT studies in narcoleptic then correlated beta power with metabolism in patients and Parkinsonian controls. They found no NREM sleep. They found that beta power negatively differences in striatal/frontal D2 occupancy ratios correlated with sleep quality. Further, beta power between these two groups. Asenbaum et al.94 positively correlated with ventromedial prefrontal assessed blood flow during waking and sleep onset cortex metabolism in both a group of depressed and REM periods in six narcoleptic patients using the healthy groups. They concluded that elevated HMPAO SPECT method. They found evidence for function in the ventromedial prefrontal cortex, an right hemispheric increased flow and thalamic area associated with obsessive behavior and anato- decreased flow in REM sleep. Given the small mically linked with brainstem and hypothalamic sample sizes, they suggested that a replication of arousal centers, may contribute to dysfunctional the findings was needed. Sudo et al.95 assessed arousal. 162 E.A. Nofzinger

Figure 5 This ﬁgure shows brain structures where the decline in relative metabolism from waking to NREM sleep is less in insomnia patients than in healthy subjects. The general pattern includes structures involved in promoting arousal (Reprinted from reference 99).

Nofzinger et al.99 investigated the neurobiolo- decreased activity in prefrontal cortex that results gical basis of poor sleep and daytime fatigue in from inefficient sleep. These findings suggest insomnia (Fig. 5). Insomnia patients and healthy interacting neural networks in the neurobiology subjects completed regional cerebral glucose of insomnia. These include a general arousal metabolic assessments during both waking and system (ascending reticular formation and hypo- 18 NREM sleep using [ F]fluoro-2-deoxy-D-glucose thalamus), an emotion regulating system (hippo- positron emission tomography (PET). Healthy sub- campus, amygdala and anterior cingulate cortex), jects reported better sleep quality than did and a cognitive system (prefrontal cortex). Future insomnia subjects. Insomnia subjects scored worse studies are needed to determine how these neural on measures of daytime concentration and fatigue. systems can be differentially affected by the The two groups did not differ on any measure of diverse causes of insomnia. Future work is also visually scored or automated measure of sleep. needed to determine the impact of interventions Insomnia patients showed increased global cerebral on altering function in these networks in order to glucose metabolism during sleep and wakefulness. (1) alleviate the sleep complaints of insomnia A group!state interaction analysis confirmed that sufferers; (2) alter the clinical course of insomnia; insomnia subjects showed a smaller decrease than and (3) potentially reduce future adverse did healthy subjects in relative metabolism from consequences of insomnia. waking to NREM sleep in the ascending reticular activating system, hypothalamus, thalamus, insular cortex, amygdala and hippocampus and in the anterior cingulate and medial prefrontal cortices. While awake, in relation to healthy subjects, insomnia subjects showed relative hypometabolism in a broad region of the frontal cortex bilaterally, left hemispheric superior temporal, parietal and occipital cortices, the thalamus, hypothalamus and brainstem reticular formation (Fig. 6). This study demonstrated that subjectively disturbed sleep in insomnia patients is associated Figure 6 This figure shows brain structures where with increased brain metabolism. Their inability to relative metabolism during waking is less in insomnia fall asleep may be related to a failure of arousal patients than in healthy subjects. The general pattern mechanisms to decline in activity from waking to includes bilateral prefrontal cortex (Reprinted from sleep. Further, their daytime fatigue may reflect reference 99). Neuroimaging and sleep medicine 163

Fatal familial insomnia including sensorimotor cortex, inferior temporal cortex, uncal gyrus-amygdala, and subicular com- Perani et al.100 assessed cerebral metabolism in plex. Many of these structures are primary brain- four patients with fatal familial insomnia, a prion stem and limbic regions that are important in disease with a mutation at codon 178 of the prion modulating emotional arousal. This pattern of protein gene. Thalamic hypometabolism was found wake–REM increases suggested that the increases in all cases and more widespread non-specific in REM sleep in depressed patients may signal an cortical hypometabolism was noted in others. increase in affective responsivity in depressed They suggest that the thalamic dysfunction is patients. In this preliminary report, in contrast to consistent with the neuropathologic findings in the hypotheses, depressed patients did not show disorder and is a hallmark of the disease. Kloppel increases in relative metabolism in anterior para- et al.101 report the results of a [123I] beta-CIT SPECT limbic structures during REM sleep compared to study in two cases of fatal familial insomnia. They waking. Subsequent analyses, however,103 showed a 57 and 73% reduced availability of suggested that the lack of increase from waking to serotonin transporters in a thalamus/hypothalamus REM sleep in depressed patients may have been region in the two patients in relation to age- related to a ceiling effect, i.e. hypermetabolism in expected control values. While the interpretation these structures during waking that could not be is not entirely clear, they suggest that this may further increased in REM sleep. reflect altered serotonergic function in regions of Nofzinger et al.104 completed a larger con- the brain thought to be important in sleep/wake firmatory analysis that included 24 depressed regulation in this patient group. patients and 14 healthy subjects (Fig. 7). They received EEG sleep studies and regional cerebral glucose metabolism (rCMRglu) assessments during Depression both waking and REM sleep using [18F]-FDG. Depressed patients showed greater REM sleep The majority of patients with mood disorders percent. Consistent with the hypothesis that describe difficulty in falling asleep, difficulty in depressed patients would show increased acti- staying asleep, and difficulty in returning to sleep vation in limbic and anterior limbic structures after early morning awakenings. Clinically, they from waking to REM, depressed patients showed report a paradoxical state of physical daytime greater increases in relative metabolism from fatigue, yet with persistent mental activity that waking to REM sleep than healthy subjects in the makes it difficult for them to fall asleep at night. midbrain reticular formation including the pre- EEG sleep changes include increases in sleep tectal area and in a larger region of anterior latency and decreases in sleep continuity. paralimbic cortex. Additionally, depressed Depressed patients often show reduced stages 3 patients showed greater increases in relative and 4 NREM sleep. They also show an increase in the metabolism from waking to REM sleep than amount of REM sleep, a shortening of the time to healthy subjects in a broadly distributed region onset of the first REM period of the night, a of predominantly left hemispheric dorsolateral shortened REM latency, and an increase in the prefrontal, parietal and temporal cortex. This frequency of eye movements within a rapid eye area included the dorsolateral prefrontal cortex, movement period. and the frontal and parietal eye fields (FEF, PEF).

REM sleep in depression

Given that REM sleep activates limbic and anterior paralimbic cortex in healthy subjects, the increased REM sleep in depressed patients may reﬂect a greater re-activation of these structures in REM sleep. Three reports to date have addressed this Figure 7 This ﬁgure shows brain structures where the question. A preliminary analysis of [18F]FDG PET 102 increase in relative metabolism from waking to REM sleep studies in six depressed patients showed that is greater in depressed patients than in healthy subjects. depressed subjects showed greater increases from Note that this includes a region of the brainstem waking to REM sleep in relative metabolism in the implicated in the generation of REM sleep (Reprinted tectal area and a series of left hemispheric areas from reference 104). 164 E.A. Nofzinger

The first primary finding in this study was the the depressed subjects. Regionally, these increases increased activation of the brainstem reticular were most noticeable in the posterior cingulate, formation from waking to REM sleep in depressed the amygdala, hippocampus, occipital and tem- patients. This is consistent with the model of an poral cortex and the pons. Relative hypofrontality altered balance in brainstem monoaminergic was noted in the patients as well as reduced relative (norepinephrine and serotonin) systems and metabolism in the anterior cingulate, caudate, and brainstem acetylcholine neuronal systems in medial thalamus in relation to the controls. On the depressed patients as proposed by McCarley.105 basis of the increased overall brain metabolism, A second primary finding in this study was the they interpreted these findings to suggest that increased activation of limbic and anterior para- depressed patients have ‘hyperarousal’ during limbic (hippocampus, basal forebrain/ventral pal- NREM sleep. lidum, anterior cingulate and medial prefrontal) Several lines of evidence suggest that the cortex from waking to REM sleep in the depressed restorative aspect of sleep is related to slow wave patients. The highest density of cholinergic axons NREM sleep and that this aspect of sleep has some is in core limbic structures such as the hippo- regional preference for more frontal regions of campus and amygdala. Limbic and anterior para- cortex. NREM sleep is associated with decreases in limbic cortices also have high densities of frontal, parietal, and temporal cortex metabolic inhibitory 5-HT1A post-synaptic receptors in activity compared to wakefulness. Depressed relation to other areas of cortex. Behaviorally, patients demonstrate ‘lighter’ NREM sleep and increased activation of limbic and paralimbic waking hypofrontality. Therefore, Germain cortex in depressed patients may reflect a et al.107 tested the hypothesis that depressed susceptibility of depressed patients to experience patients would show less of a decrease in frontal stimuli in a more affectively intense, negative metabolism between waking and NREM sleep. They context, given the increased activation of these assessed 12 medication-free depressed patients and structures in response to negatively valenced 18 13 healthy subjects using [ F]-fluoro-2-deoxy-D- stimuli or increased affective states. A third 18 glucose ([ F]-FDG) positron emission tomography primary finding in this study is the relatively (PET) scans during presleep wakefulness and during greater activation of executive cortex from NREM sleep. Compared to healthy subjects, waking to REM sleep in depressed patients. This depressed patients showed less of a decrease in may reflect a change in modulation of cortical relative metabolism from presleep wakefulness to function from monoaminergic during waking to NREM bilaterally in the laterodorsal frontal gyri, cholinergic in REM sleep, coupled with a mono- right medial prefrontal cortex, right superior and aminergic/cholinergic imbalance in depressed middle temporal gyri and insula, as well as right patients. Behaviorally, this may also reflect a posterior cingulate cortex, lingual gyrus, striate greater involvement of executive function during cortex, cerebellar vermis, and left thalamus. These REM sleep in depressed patients, perhaps in findings suggest that abnormal thalamocortical response to the increased affective state produced by the abnormal re-activation of limbic network function may underlie non-restorative and paralimbic cortex during REM sleep in sleep in depressed patients. depressed patients.

Sleep deprivation in depression NREM sleep in depression The notion of hyperarousal in paralimbic structures As reviewed above, depressed patients tend to have in depressed patients has received further support increased sleep continuity disturbances and from an extensive literature describing the func- reductions in deeper, more restorative aspects of tional neuroanatomical correlates of the anti- NREM sleep. Several reports to date have assessed depressant response to sleep deprivation in regional brain function during NREM sleep in depressed patients. These studies identify the depressed patients to further clarify the neurobiol- anterior cingulate cortex as playing an important ogy of these changes in NREM sleep. Ho et al.106 role in the response to sleep deprivation. Across assessed cerebral metabolism using the [18F]-FDG studies, there is a general tendency for patients PET method in depressed and healthy men during who have elevated baseline metabolism in the the first NREM period and found increased anterior cingulate cortex to have more favorable whole brain metabolism during NREM sleep in responses to sleep deprivation, and normalization Neuroimaging and sleep medicine 165 of this increased function following sleep depri- Sleepwalking vation.97,108–113 Only one nuclear medicine study has studied regional brain function associated with sleepwalk- Schizophrenia ing. Bassetti et al.121 performed 99mTc ECD SPECT studies during stages 3 and 4 sleep one night before, Patients with schizophrenia are known to have and one night during a sleepwalking episode. They severely disturbed subjective sleep. EEG sleep reported increased blood flow in the cerebellar studies have largely supported alterations in NREM vermis and the posterior cingulate cortex during slow wave sleep in schizophrenic patients. Slow wave sleepwalking. In relation to healthy wakefulness, sleep is of particular interest to schizophrenia the sleepwalking episode was associated with because of the implication of the prefrontal cortex a decline in frontoparietal association cortices as in this disorder114 and in generation of slow wave would be typical of NREM sleep, albeit in the sleep (SWS).115 Only one functional neuroimaging absence of declines in thalamic blood flow. They study has explored the relationship between some interpret the results to reflect both unconscious- aspect of sleep and the pathophysiology of schizo- ness, as reflected by a loss of frontoparietal phrenia. Weiler et al.116 compared cerebral metab- function, and a persistence of motor generators, olism between 49 awake schizophrenic patients, 30 as reflected by preserved thalamocingulate awake controls and 12 controls in REM sleep. The aim circuits, in sleepwalking behavior. of the study was to determine if regional metabolism while awake in a psychotic disorder resembled healthy REM sleep, given some phenomenological REM sleep behavior disorder similarities between the cognitions reported in dreaming and those in psychosis. No similarities Shirakawa et al.122 reported the results of a [123I] IMP were observed discounting the notion that schizo- SPECT study of 20 patients with REM sleep behavior phrenia represents an intrusion of REM sleep cogni- disorder in comparison with seven healthy controls. tion into wakefulness. More functional neuroimaging They reported decreased blood flow in the upper studies of sleep in schizophrenia are needed. frontal lobe and pons. They suggest that these findings may be associated with the pathogenesis of RBD, especially the decreased blood flow in the pons Restless legs syndrome (RLS)/periodic as this has theoretically thought to play a role in RBD. 123 limb movement disorders (PLMD) of sleep Eisensehr et al. studied pre- and post-synaptic dopaminergic status using [123I]-IPT and [123I]-IBZM SPECT, respectively, in five patients with RBD, 7 age, RLS and PLMD are effectively treated with sex-matched controls, 14 Parkinson’s patients. They dopaminergic agents. This suggests a central found decreased DA transporter binding in RBD in dopaminergic dysfunction contributes to the patho- relation to controls, although not as severe as in physiology of these disorders. In a series 117–119 Parkinson’s patients, and no change in striatal D2- of studies, measured central dopamine 123 receptor binding in RBD. They suggest that this D2-receptor occupancy with [ I] labeled (S1)-2- supports a central striatal dopamine transporter hydroxy-3-iodo-6-methoxy-([1-ethyl-2-pyrrolidi- abnormality in the pathophysiology of RBD. Albin nyl]methyl) benzamide (IBZM) and single photon et al.124 assessed [11C]-dihydrotetrabenazine emission tomography in patients with PLMD. They 123 (DTBZ) PET in six patients with RBD and in 19 age, found lower striatal [ I]IBZM binding in patients sex-matched controls. They found decreased DTBZ with PLMD and higher binding following dopamin- 120 binding in RBD in relation to controls. This study ergic therapy. Michaud et al. report the results of supports a loss of dopaminergic midbrain neurons in pre- and post-synaptic dopaminergic status using 123 123 chronic RBD, however it remains unclear whether [ I]beta-CIT and [ I]IBZM SPECT, respectively, in this is primary or a secondary effect of the pontine 10 patients with both RLS and PLMD. They found no abnormality in RBD. differences in DA transporter binding, but lower striatal D2-receptor binding in patients (pZ0.006). They suggest that this indicates a decreased number of D2-receptors or a decreased affinity of Sleep disorders: differential diagnosis D2-receptors for IBZM. This supports a central striatal D2 receptor abnormality in the pathophy- Functional neuroimaging studies are showing great siology of RLS/PLMD. promise in helping to diagnose and manage a variety 166 E.A. Nofzinger of disorders that affect the central nervous models suggest that these compounds may have system including Alzheimer’s Disease125 movement novel mechanisms of action, however, the degree disorders,126 cerebrovascular disease,127 brain to which these mechanisms will translate into a tumors,128 and epilepsy.129 The above studies in clinical application are often unknown. Functional sleep disorders begin to support alterations in neuroimaging studies may identify the degree to functional neuroimaging studies in a variety of which these compounds have beneficial mechan- sleep disorders. At this point, they suggest that isms of action on brain structures that are known to these methods show promise in helping to clarify regulate behavioral states in humans. One way of the pathophysiology of distinct sleep disorders. achieving this goal is to administer the compound Considerably more research needs to be conducted to human subjects, then assess a functional in these areas. neuroanatomic response to the compound within Beyond pathophysiology, the next question is sleep in humans, such as a blood flow or metabolic whether functional neuroimaging studies can be response. Further, these studies may help to used in the clinical assessment or management of determine the optimum dose of the compound in sleep disorders patients. Even more work remains humans that maximizes beneficial effects of the to be done before any conclusions can be made in compound, yet does not lead to adverse effects. this area, although several sleep disorders appear The use of receptor ligands may clarify whether one worthwhile pursuing in this context. The insomnias compound has a unique mechanism of action on a would appear to be one area where functional specific receptor subtype that may not be shared by neuroimaging studies may aid in differential diag- other compounds in its class and may therefore hold nosis. At this point, models of insomnia rely heavily a therapeutic advantage over other agents. Finally, on behavioral theories of insomnia (e.g. Drummond once a compound has been identified and shown to et al.;130 Nofzinger131) with very unclear models of have effects in the central nervous system in the neurobiological basis of this sleep disorder. humans, functional neuroimaging studies can then Defining the pathophysiology of insomnia is cur- be used to determine the degree to which the rently troubled by the inclusion of a variety of compound reverses distinct alterations in neural pathologies that may result in insomnia as a final function in a clinical population. The review below common complaint. These include the primary reveals some of the early studies in these areas. insomnias, acute, transient and chronic insomnias, and insomnias secondary to various mental and physical disorders. The pathophysiology of the various mental and physical disorders, themselves, Receptor ligand studies can clearly be distinguished. The pathways leading from the pathology of the disorders to the pathol- Nuclear medicine has developed methods to label ogy of the sleep disruptions that occur as part of the central nervous system (CNS) active compounds, disorders are not known. Functional neuroimaging then define their presence in the brain via imaging studies may help to distinguish one type of insomnia the radiation emitted by the radiopharmaceutical vs. another based on the underlying causes of the via positron emission tomography or SPECT. Such insomnia complaints in affected individuals. studies can be used to determine if there are alterations in receptor distributions or densities of receptors in distinct sleep disorders. Such studies can also be used to determine the specific receptor Sleep disorders: pharmacotherapy types where pharmacologically active compounds are having their mechanism of action. Management of several sleep disorders is improved Cholinergic and dopamine receptor density and with pharmacologic interventions. Examples distributions have been studied in narcolepsy and include PLMDs, narcolepsy, and the insomnias. sleep-related movement disorders. Sudo et al.95 Functional neuroimaging studies may provide assessed muscarinic cholinergic receptors in important information regarding pharmacotherapy narcoleptic subjects using [11C]N-methyl-4-piper- in several realms: drug development, assessment of idylbenzilate ([11C]NMPB) both before and after mechanism of action of therapeutic compounds pharmacotherapy. No differences were observed and assessment of treatment response/non- between patients and healthy subjects at base- response to pharmacologic agents. line and minimal treatment effects were A variety of compounds have been discovered observed. While these findings are largely nega- with mechanisms of actions that may affect tive in this disorder, future studies could explore sleep/wake regulation. Testing in preclinical cholinergic function in other sleep disorders in Neuroimaging and sleep medicine 167 which alterations in REM sleep have been shown, zolpidem on NREM and REM sleep-related relative 15 such as depression. Several studies assessed cerebral blood flow [ O] H2O-PET in relation to a dopaminergic function in PLMD, RLS and REM placebo. They reported that across all sleep sleep behavior disorder, given the putative role periods, there was decreased flow in the basal of dopaminergic dysfunction in these disorders. ganglia and insula after treatment with zolpidem. These have been reviewed above in the sections Volkow et al.137 assessed the effects of the on sleep disorders. benzodiazepine, lorazepam, on regional cerebral Several studies have assessed changes in recep- glucose metabolism using [18F]FDG PET. They tor-binding following administration of pharmaco- found marked reductions in thalamic metabolism 132 logically active agents. Tashiro et al. report and these reductions correlated with sleepiness. the effects of antihistamine medications on hista- They suggested that the marked changes in the mine H1 receptor binding in the human brain using 11 thalamus may account for the sedative properties [ C]-doxepin PET. They report that fexofenadine, of this medication. an antihistamine with little sedation, manifested no Recently, Kajimura et al.138 assessed regional significant cerebral H1 receptor occupancy, while cerebral blood flow during NREM sleep in response cetirizine, a second generation antihistamine with to triazolam, a short acting benzodiazepine seda- moderate sedation, occupied 20–50% of cerebral H1 tive-hypnotic. They found that blood flow in the receptors. They propose that measurement of H1 basal forebrain and amygaloid complexes was lower receptor occupancy is a sensitive tool for assessing during NREM sleep following triazolam adminis- the potential CNS sedative side effects of anti- tration than following placebo. They suggest that histamine agents. Okamura et al.133 assessed regional changes in histamine H1 occupancy and the hypnotic effects of benzodiazepines may be blood flow associated with antihistamine associated mediated by deactivation of the basal forebrain and cognitive decline. They found blockade of H1R in amygdaloid arousal systems. frontal, temporal and anterior cingulate cortices Only one study has reported on the effects of following d-chlorpheniramine administration. They antidepressant medications on regional cerebral 98 suggest that attention systems of the brain may be function during sleep. Nofzinger et al. measured 18 altered by antihistamines. regional cerebral glucose metabolism using [ F]FDG PET during waking and REM sleep in nine depressed patients before and after treatment with bupropion SR. Based on prior research showing a blunted waking Regional cerebral responses to sleep- to REM sleep activation of anterior paralimbic cortex, related pharmacological probes they predicted that bupropion SR treatment would reverse this alteration given its effects on both Functional neuroimaging studies can assess changes noradrenergic and dopaminergic systems. They in blood flow and metabolism as correlates of found a significant reversal of some anterior para- overall cerebral function in response to a variety of limbic deficits following treatment. medications that affect the sleep/wake cycle. Reinsel et al.134 studied the effects of a sedating short acting benzodiazepine, midazolam, on 15 regional cerebral blood flow using [ O] H2O. They Practice points found dose-dependent reductions in left dorsolateral prefrontal cortex, bilateral orbital–frontal † Neuroimaging studies have defined reliable cortex, the left middle temporal gyrus and the changes in brain function across the states right hippocampus. They suggest that the prefron- of waking, NREM and REM sleep. tal reductions in blood flow may underlie some of † Neuroimaging studies can provide the anterograde amnesia effects of midazolam. information on regional brain activity and Two studies have assessed the effects of the receptor densities in relation to clinical sedative-hypnotic zolpidem on regional brain func- sleep disorders. tion. Gillin et al.135 assessed effects of zolpidem, an † While early studies demonstrate the promise imidazopyridine hypnotic, on cerebral glucose of these methods for clinical sleep metabolism in NREM sleep. They found that plasma medicine, significant work remains before concentration of zolpidem was associated with these techniques can be applied in the declines in metabolism in the medial frontal cortex, routine assessment and management of cingulate, putamen, thalamus and hippocampus. sleep disorders patients. Finelli et al.136 studied the effects of the hypnotic 168 E.A. Nofzinger

photon detectors placed around the head. More Research agenda recent approaches have used a gamma camera that can be rapidly moved around the head to collect Research needs to be conducted in order to photons from many different angles, thus permit- determine if neuroimaging methods can be ting a more accurate three-dimensional image. The helpful in sleep disorders medicine in the spatial resolution of SPECT is inferior to PET following areas: especially in deeper brain structures, although it is much less expensive than PET and is more widely † clarification of pathophysiology; available. † aid in differential diagnosis; † assessment of treatment response; † guiding new drug development; and Magnetic resonance imaging † monitoring treatment response. BOLD-fMRI Blood-Oxygen-Level-Dependent fMRI (BOLD-fMRI) is Appendix A the most commonly used fMRI technique. BOLD-fMRI measures regional differences in oxygenated blood, Fundamentals of functional which is thought to relate to variations in neuronal neuroimaging activity across brain regions. This method is good for measuring relatively rapid changes in brain activity in which there is a stable background of blood flow Understanding the potential application of neuroi- across the study. It is sensitive to movement artifacts maging assessments to the field of sleep disorders and there are some regions of the brain that are more medicine requires a general understanding of the difficult to study due to artifacts from surrounding various functional neuroimaging methods available. tissues. This method only provides information on They differ in terms of the physiological process relative changes in blood flow between conditions. measured and in the practicalities of obtaining the Blood-oxygen-level-dependent fMRI potentially measurements. While complete descriptions of offers imaging with a temporal resolution on the these methods are beyond the scope of this review, order of 100 ms and a spatial resolution of 1–2 mm. brief descriptions of measures currently available Most fMRI techniques are non-invasive and allow for are provided below. multiple repeated measures within a subject. Positron emission tomography (PET) Perfusion fMRI PET is the non-invasive dynamic measurement of Perfusion fMRI measures absolute regional cerebral the distribution in the body of compounds labeled blood flow. Arterial spin-labeling is a T1-weighted with positron-emitting isotopes. Detectors in the non-invasive technique where intrinsic hydrogen PET cameras reveal the regions in the brain where atoms in arterial water outside of the slice of the positrons were emitted and thereby define the interest are magnetically tagged (‘flipped’) as they area of the labeled compound. Common physiologi- course through the blood. Then they are imaged as cal processes measured with PET include glucose they enter the slice of interest. This method is utilization ([18F]fluorodeoxyglucose), perfusion limited in that it takes several minutes to acquired 15 15 information on slices of brain such that within ([ O]H2O), and blood volume ([ O]CO). PET can also be used to determine the distribution of subject analyses are difficult. neurotransmitters across the brain by labeling transmitters with unstable positron-emitting Diffusion-weighted fMRI isotopes. Diffusion-weighted fMRI measures random movement of water molecules. In the while matter of the Single-photon emission computerized brain, water diffusion is highly directional along the tomography (SPECT) long axis of fibre tracts. Application of large magnetic field gradients during MR imaging, allows SPECT produces images based on the detection of the determination of the diffusion of water, hence single gamma photons derived from the decay of the direction of flow of information in these tracts radioactive isotope that has been injected into a throughout the brain. The importance of this subject. The rate of clearance of the probes was method is to help define functional connectivity initially detected using an array of sodium iodide between different regions of the brain. Neuroimaging and sleep medicine 169

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