REVIEW
Visual Hallucinations in Parkinson’s Disease: Theoretical Models Alana J. Muller, BMedSc (Hons),1 James M. Shine, BSc (Adv), MBBS, PhD,1 Glenda M. Halliday, PhD,2 and Simon J.G. Lewis, MBBCh, BSc, MRCP, FRACP, MD1* 1
Brain & Mind Research Institute, University of Sydney, Sydney, New South Wales, Australia 2 Neuroscience Research Australia, University of NSW, Australia
ABSTRACT:
One of the most challenging tasks in neuroscience is to be able to meaningfully connect information across the different levels of investigation, from molecular or structural biology to the resulting behavior and cognition. Visual hallucinations are a frequent occurrence in Parkinson’s disease and significantly contribute to the burden of the disease. Because of the widespread pathological processes implicated in visual hallucinations in Parkinson’s disease, a final common mechanism that explains their manifestation will require an integrative approach, in which consideration is taken across all complementary levels of analysis. This review considers the leading
The development of hallucinations and psychosis in Parkinson’s disease (PD) commonly occurs in both demented and nondemented1-3 patients and places a high degree of burden on primary caregivers.4,5 Visual hallucinations (VH) are the most common modality and exist along a spectrum including non-menacing simple images as well as more complex images of people, animals, or scenery.6,7 Hallucinations can also include the feeling of an abnormal ‘presence’ (a vague and erroneous perception that another person or threat is present) or ‘passage’ hallucinations (transient undefined hallucinations that pass through the periphery of the visual field).7 Visual hallucinations usually appear recurrently and seemingly without provocation, in dimly lit environments while the patient is alert with open eyes.6 Insight, in which the hallucination is
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*Correspondence to: Dr. Simon J.G. Lewis, Brain & Mind Research Institute, University of Sydney, 94 Mallett Street, Camperdown, New South Wales, Australia, E-mail: [email protected] Funding agencies: This study was supported by
Relevant conflicts of interest/financial disclosures: Nothing to report. Author roles may be found in the online version of this article. Received: 29 April 2014; Revised: 29 July 2014; Accepted: 3 August 2014 Published online 22 August 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/mds.26004
hypothetical frameworks for visual hallucinations in Parkinson’s disease, summarizing the key aspects of each in an attempt to highlight the aspects of the condition that such a unifying hypothesis must explain. These competing hypotheses include implications of dream imagery intrusion, deficits in reality monitoring, and impairments in visual perception and attention. C V 2014 International Parkinson and Movement Disorder Society
K e y W o r d s : Parkinson’s disease; visual hallucinations; visual misperceptions
recognized as distinct from reality, is preserved in most cases6; however, they often become chronic and can progress to a loss of insight or delusions, frequently precipitating the need for nursing home placement.2,5,8 One of the most challenging tasks in neuroscience is to be able to meaningfully connect information across the different levels of investigation, from molecular or structural biology, to cellular neurophysiology, microcircuits, neural networks, and finally, the resulting behavior and cognition, often translating to clinical settings.9,10 Most early approaches in neuroscience have taken a reductionist approach, reducing complex processes into their constituent parts.11 However, these processes commonly lead to assumptions that misinterpret data across different levels of explanation and as such, an integrative approach, in which consideration is taken across all complementary levels of analysis, is being increasingly implemented.9 Because of the widespread pathological processes implicated in VH in PD, a final common mechanism that explains their manifestation will require this integrated approach. A number of hypotheses have been proposed to explain the neurobiological mechanisms underlying VH in PD. This review discusses the leading hypothetical frameworks for VH in PD,
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summarizing the key aspects of each in an attempt to highlight the aspects of the condition that such a unifying hypothesis must explain.
Dream Imagery Intrusion Model An early model of VH considers dysfunctional sleep or oneiric processes as the mechanism underlying these erroneous perceptual experiences. Endogenous imagery produced during dreaming is proposed to be the source of hallucinated or misperceived images, potentially associated with Rapid Eye Movement (REM) sleep intrusions during wakefulness.12,13 The risk of suffering from psychosis has been found to be nearly five times greater in those patients who experience comorbid disorders of sleep–wakefulness.14 Hallucinations also have been reported to have a close temporal relationship with the REM stage of sleep, with patients experiencing hallucinations concurrent with REM sleep intrusions during wakefulness as well as delusions post-REM sleep at night.13 Such observations have led to the proposal that VH in PD are due to the intrusion of dream imagery into the conscious wakeful state.15 Proponents of this model have suggested that psychosis in PD may reflect a narcolepsy-like REM sleep disorder; however, the results of a study examining Human Leukocyte Antigen blood markers of narcolepsy did not find any in PD patients with VH.13 Indeed, the prevalence of REM sleep behavior disorder cases without VH in this study suggested that these two conditions were clinically separable.13 Furthermore, not all hallucinatory events suffered by patients with PD are temporally related to REM or even nonREM sleep.12 As such, the Dream Imagery Intrusion Model cannot sufficiently explain hallucinations that commonly occur in a clinically and polysomnographically documented wakeful state.12 Indeed, reports of sleep fragmentation, altered dream phenomena, and vivid dreams or nightmares have been shown to be ineffective in predicting the eventual development of hallucinations in PD, again disputing this possible relationship.16 Disruption to the cholinergic systems and regions involved in sleep has been implicated as a potential pathophysiological mechanism for VH in PD, perhaps leading to intrusions of dream imagery into conscious perception. Indeed, cholinergic dysfunction, as measured by short latency afferent inhibition, a transcranial magnetic stimulation protocol that tests inhibitory cholinergic circuits in the motor cortex,17 has been demonstrated in PD patients with VH compared with PD patients without VH, as well as healthy controls.18 In addition, a similar significant reduction in short latency afferent inhibition has been shown in PD patients with REM sleep behavior disorder; however,
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20% of PD patients with hallucinations involved in the former study did not show abnormalities.17,18 Pathological and neuroimaging studies also have observed impaired function within cholinergic projection nuclei, such as the pedunculopontine nucleus and nucleus basalis of Meynert. The pedunculopontine nucleus has been implicated in both sleep and VH,17,19,20 and voxel-based morphometry analysis has shown a significantly reduced volume in this region in hallucinating PD patients compared with nonhallucinators.20 Anticholinesterase inhibitors, such as rivastigmine, have been demonstrated to improve hallucinatory symptoms in PD patients.21 However, alternative neurotransmitter systems also have been implicated in the pathogenesis of VH in PD, with preliminary clinical trials of treatments that have shown significant improvement in psychosis in PD, including pimavanserin, a highly selective 5-HT2A inverse agonist, and clozapine, an atypical anti-psychotic.22,23 In addition, the literature contains examples of PD patients who experience florid hallucinations and yet do not show significant pathology in these brainstem nuclei.24-26 Other brain regions involved in dreaming, rather than arousal or stages of sleep, have been implicated in the pathogenesis of VH in PD. Dreaming is proposed to be mediated by a forebrain, possibly dopaminergic, mechanism.27 Some of these structures, which are also implicated in VH in PD, include amygdala,28,29 orbitofrontal,20 anterior cingulate,25,30,31 and occipitotemporal cortical areas.27,32 Whereas these anatomical findings support a potential involvement of dream imagery in the pathogenesis of VH, some discrepancies between oneiric versus hallucinatory experiences should be considered. For example, recollection and insight are commonly retained in PD hallucinations,6 unlike most episodes of REM sleep behavior disorder.33,34 Indeed, dream imagery is usually distinctly different from that experienced during hallucinations in PD. Dreams often have intense emotional accompaniment, encompass the entire visual field, and the dreamer often plays a central role in events. This is in contrast to the often neutral, singleobject or person hallucinations described in PD.34-36
Reality Monitoring Deficit Some researchers have proposed that VH in PD can be attributed to a deficit in reality monitoring.37 Evidence for this can be seen in the relative inability of PD patients with VH to judge the source of an item in a series of visual imagery- and memory-based tasks.37 Such tasks involve the presentation of stimuli as either words or pictures, and then after a delay some stimuli are re-presented exactly as before, or in an alternate form (eg, a word instead of a picture or vice versa).37
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TABLE 1. Compatibility of observed associations with theoretical models
Brief description
Disturbed function Perception30,48-52,57 Executive30,37,56,57 Sleep12-15,30 Pathology Brainstem18,20,44,46,47 Retina48-52 Subcortex25,28,29 Cortex25,27,30,32,39-43 Other relations Dopamine48-51 Other disorders68
Dream Imagery Intrusion
Reality Monitoring Deficit
Activation Input Modulation
Perception and Attention Deficit
Attentional Network Dysfunction
Intrusion of endogenous imagery produced during dreaming13
Inability to judge the source of a perception37
Dysregulated gating of external and internal imagery44
Impaired interactions between perception and attention36
Disrupted processing across attentional control networks59
– – 111
– 111 1
11 11 11
111 11 –
11 111 11
111 – – 1
– – – 111
111 1 – 1
11 1 1 111
1 1 11 11
– 1
– 1
1 11
– 1
1 111
Key: the number of “1” signifies the degree to which each model is associated with the factors in the first column. “–” symbols reflect an aspect of the hallucinatory phenotype not compatible with, or unaccounted for, in each model.
Subjects are then asked to recall which stimuli had been presented previously, and whether they had been presented in the same modality the second time. Hallucinating PD patients had most difficulty with identifying source when a stimulus was re-presented in its alternative form (ie, the cross-modal condition), and showed a tendency to report internally generated stimuli as external input stimuli.37 Correct recognition of items that had been presented previously, regardless of source identification, was not significantly impaired in PD with VH groups compared with non-hallucinators and healthy controls.37 However, hallucinators appeared to rely more heavily on a feeling of familiarity, with which they recognized an item as being presented before but could not specifically remember its previous presentation during the task.37 Barnes and colleagues suggest that accurate recollection of specific details from the encoding event is especially important in the accurate attribution of source to a piece of information. Namely, familiarity with a stimulus on its own is not a reliable method by which to determine the origin of information, and the less detailed the recollection of encoding events, the more susceptible memory is to misinterpretation, especially in regard to source.37 These results were taken to reflect a bias toward attributing an internally generated event to an external source, thereby misinterpreting mental imagery as veridical perception.37,38 Reality monitoring in healthy subjects has been localized to the frontal lobes,39 especially the prefrontal cortex.40,41 The frontal lobe has shown increased pathology in PD patients with VH compared with nonhallucinators, including significantly higher Lewy body burden30 and gray matter atrophy.25,42 The right superior, middle, and inferior frontal gyri also have shown a
diminished level of activation in PD with VH sufferers.43 As such, a failure in reality monitoring could give rise to visual hallucinations from endogenous imagery.37 However, that only one cognitive deficit underlies this complex symptom is unlikely. The progression of the VH to loss of insight or menacing content is not sufficiently explained by a reality monitoring deficit, and other processes must be affected to influence the content and character of the hallucinated images8 (Table 1).
Activation, Input, Modulation Model The Activation, Input, Modulation model of hallucinations considers the underlying cause of VH as a dysregulation of the gating and filtering of exogenous perception and endogenous image creation.44 Built on the framework of Hobson’s model of mental states,45 this model of VH in PD encompasses visual defects, cognition, and REM dysfunction within a single model (Table 1). It largely incorporates the hypotheses of dream imagery intrusion, reality monitoring deficit, and a cortical release phenomenon. The first dimension (activation) refers to the capacity to process information, which is postulated to be regulated by the reticulo-thalamocortical system.44 The second dimension (input) refers to the exchange of information with the external world or the generation of information internally. Importantly, the model suggests that the state of the gating system can rapidly change by means of a reciprocal relationship between REM-on, cholinergic cells located in the pedunculopontine nucleus; and REM-off aminergic cells located within the locus coeruleus and dorsal raphe nucleus.44,46,47 The final dimension (modulation) refers to the integration of activation and input over time. In
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an alert state, forebrain-mediated functions are enhanced by high aminergic activity arising from the locus coeruleus and dorsal raphe nucleus.47 In contrast, high cholinergic activity in brainstem regions such as the pedunculopontine nucleus, in association with aminergic demodulation, facilitates the production of endogenous visual imaging and hyper-associative cognition typically experienced during REM sleep.46,47 The activation, input, modulation model proposes that hallucinations are primarily a result of defects within the input dimension, whereby there is an imbalance between the gating of endogenous and exogenous inputs. This imbalance leads to a propensity for hallucinations as a result of a relative reduction in the strength of the external input with respect to the internal stimulus generation, which may then lead to the release of stored percepts—dream-like images and visual memory contents that may be a form of compensation to “fill in” for the lack of visual input. The resulting endogenous imagery is then incorporated into perception.44 Disruption of the dopaminergic cells of the retina has been described in PD and could contribute to a reduction in external input strength, consequently promoting VH. Poor color and contrast discrimination are two common visual deficits found in PD, and have been shown to be associated with VH, potentially acting as facilitating factors.48-52 However, more substantial primary visual deficits have not been found to predispose PD patients to VH.30 Imbalance between the gating of exogenous and endogenous inputs also could arise if the internal stimulus strength were greatly increased. This would result in a scenario in which perceptions were driven by a combination of poorly distinguished endogenous and exogenous imagery.45 The authors of this model suggested that REM intrusions into wakefulness could constitute increased internal input generation, where VH are associated with REM intrusions. Some evidence suggests that mental imagery is increased in PD patients with VH, and previous studies have shown that endogenous information is more likely to later be confused with perception if it is more easily generated.39 Although the activation, input, modulation model explains a large degree of disparate clinical information, it does not address the potential role of other brain regions crucial in attentional and perceptual processes. However, unlike the dream imagery intrusion model, this hypothesis does accommodate the possibility of experiencing strengthened internal imagery concurrently with external inputs, thus maintaining fundamental attributes of both perceptual systems. Within the activation, input, modulation model, VH reflect an abnormal state of consciousness exhibiting a combination of features from wakefulness and REM sleep. Although dream imagery may still underlie the hallucination, the patient could store the
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images in memory and even consider them with critical insight as the aminergically modulated wakeful state is maintained.44,45 In addition, a wide range of neurotransmitter systems are implicated in the pathogenesis of VH in PD, which is supported in the literature by the number of different neurotransmitters implicated by clinical trials in the literature.22,23,53,54
Perception and Attention Deficit The perception and attention deficit model of hallucinations describes an interaction of impairments in both visual perception and attention36 (Table 1). These processes operate synergistically with relatively intact scene representations to produce the activation of contextually expected but incorrect proto-objects.36 Proto-objects are envisioned as abstracted object representations in mutual competition to reach awareness, primarily through directing attention toward themselves, and act as candidate objects for further processing. Hallucinations arise when the wrong proto-object is drawn into the attentional focus of a scene, and the degree of the disparity between the correct and selected incorrect proto-objects determines the severity of the hallucinatory experience.36 The emergence of the incorrect proto-object is believed to relate to an interaction between attentional binding impairments and the limited sensory activation of the correct proto-object. Numerous studies have associated the presence of attentional deficits and reduced perception with VH in PD.43,55-57 The perception and attention deficit model proposes that these attentional and perceptional impairments are localized to the lateral frontal cortex and ventral visual stream, respectively, which may show cholinergic pathology, disrupting communication between these regions.36 This impairment would in turn disrupt the working memory and semantic associations believed to underlie the retrieval of images, as well as image and scene perception.58 This model has received support from studies implicating cholinergic dysfunction,18 as well as from neuroimaging studies, including one functional magnetic resonance imaging study that revealed hypoactivation within the right prefrontal network of hallucinators.43 However, work using fluorodeoxyglucose positron emission tomography to look at metabolic activity has provided evidence that both of these two major visual processing routes (dorsal and ventral visual stream) may be affected in PD patients with VH.32
Dysfunction of the Attentional Control Networks A recent hypothesis has suggested that visual misperceptions and hallucinations may arise from
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disrupted processing across attentional networks.59 This hypothesis posits that hallucinations may arise from dysfunction across the dorsal attention network (DAN), the ventral attention network (VAN), and default mode network (DMN) (Table 159). Specifically, this model proposes that VH are due to a relative inability to recruit activation in the DAN, which underlies the capacity to focus attention on externally driven percepts in the presence of an ambiguous percept, leading to an “overreliance” on the VAN, which normally assists in the rapid reorienting of attention toward salient stimuli,60 and the DMN, which consists of regions normally involved in the retrieval and manipulation of episodic memories and semantic knowledge, in the interpreting of visual perception.58,61 Impairments at multiple levels of this neuronal architecture could ultimately manifest as hallucinatory behavior. For example, impaired visual input via a dopaminergically dysfunctional retina may cause impairments in visual processing, which, in the context of impaired attentional capabilities,57,62 may lead to incorrect perceptual recognition of objects.60 Alternatively, the neural regions responsible for exogenous attention, such as those constituting the DAN, may be pathologically impaired. The DAN is composed of widespread neural regions within the frontal eye fields, the dorsolateral prefrontal cortex, and the superior posterior parietal cortices, all of which send efferents to the head of the caudate nucleus,63 and some of these regions have been implicated in structural neuroimaging studies.64,65 In addition, PD patients who performed poorly on a novel paradigm designed to measure VH and elicit misperceptions during functional neuroimaging demonstrated reduced activation of regions implicated in this network.66 The VAN works closely with the DAN, because it presents “bottom-up” visuoperceptive information that usually requires further “top-down” processing by the DAN, particularly in the event of an ambiguous percept.60 The VAN is involved in engaging attention to salient stimuli, as well as mediating the activation of the DAN and DMN, acting as a quick override for directing attentional resources.59,66 The VAN is believed to be located primarily in the temporoparietal junction, ventral striatum, the basolateral amygdala, and the lateral and inferior prefrontal cortex.31,66 Anatomical and pathological studies of PD patients have reported results associating a number of these regions with the presence of VH: for example, the occipitotemporoparietal region has shown a decreased regional cerebral metabolic rate for glucose consumption in hallucinators.32 The amygdala also has been implicated by numerous studies in the pathogenesis of VH in PD, demonstrating significant atrophy,25 as well as a significantly higher density of Lewy body distribution.28,29
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Alternatively, dysfunction within the VAN could result in difficulties in orienting attention to relevant stimuli by switching between the DAN and DMN. Indeed, pathological studies of PD patients have reported results associating a number of VAN regions, including the basolateral amygdala, with the presence of VH.25,29 This pathology would then lead to a relative inability to “shut down” resting activity within the DMN, which is typically associated with the retrieval and manipulation of semantic and episodic memories.67 This would lead to the surfacing of previously stored percepts from within the DMN, either by a failure to recall appropriate information or by the selection of inappropriate stored information, potentially resulting in VH.59 Although this hypothesis can adequately incorporate known sleep impairments that are associated with VH, such as REM sleep behavior disorder, the model does not specifically implicate particular neurotransmitter impairments, making pharmacotherapeutic translation difficult.68
Conclusion Several competing theories exist regarding the development and progression of VH in PD. Inherent difficulties arise in comparing models of neural network activity, because models designed to account for a symptom with such widespread implications are fundamentally abstract. This very quality allows a model to be amenable to the variety of experiences of VH in PD.69 Unfortunately, this causes some difficulty in disambiguating explicit predictions of each of the models (Table 2). Whereas broad similarities can be seen across the models, generally implicating attentional and perceptual impairments,31 they also display important differences (Table 1). Successfully disambiguating specific aspects of the models through neuropsychological testing may prove difficult; for example, executive dysfunction is broadly implicated in several of the hypotheses.36,37,59 However, tests assessing vision, such as acuity or contrast sensitivity, provide objective evidence that would address some of the predictions in the perception and attention deficit, and activation, input, modulation models.36,44 Furthermore, differentiation of the models could be tested effectively in future studies, using a combination of alternative investigative techniques (Table 2). For example, a high priority for future research lies with the role of neurotransmitters. Dopaminergic medications have been long implicated in the pathogenesis of VH in PD, and often the first line of management of hallucinatory symptoms is to reduce dopaminergic medications.70 However, evidence in the literature suggests that the role medication plays in the pathogenesis of VH in PD may be less significant than previously believed. Before
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TABLE 2. Brief description and testable predictions of theoretical models Dream Imagery Intrusion
Reality Monitoring Deficit
Activation Input Modulation
Perception and Attention Deficit
Cholinergic dysfunction in projection nuclei to frontotemporal cortices PET, SAI
Functional disorder of attention and perception
Hallucinators should demonstrate a specific pattern of brainstem cholinergic change as demonstrated by specific PET ligands
Hallucinators should display a relative underactivation of the DAN and over-activation of the DMN and VAN
Core feature
Impaired REM ‘switching’ mechanism
Specific reality monitoring deficit in all patients with VH
Impaired gating of input and endogenous imagery
Investigational approach
Ambulatory high-density EEG
Neuropsychological testing; fMRI
Prediction
EEG pattern during hallucinatory episodes should be similar to the pattern observed during REM sleep
Reality monitoring impairments should be exclusive to hallucinators and correlated with eventrelated fMRI signals during reality monitoring
Mental imagery and visual acuity testing; PET Impairments in imagery production or vision should be exclusive to hallucinators and correlated with a specific pattern of brainstem NT changes
Attentional Network Dysfunction
fMRI
PET, positron emission tomography; EEG, electroencephalography; fMRI, functional magnetic resonance imaging; REM, rapid eye movement sleep; DAN, dorsal attention network; DMN, default mode network; VAN, ventral attention network; NT, neurotransmitter; SAI, short-latency afferent inhibition.
levodopa (L-dopa) medication, hallucinations were reportedly still experienced in PD,70 and a high-dose intravenous L-dopa infusion did not precipitate VH in five nondemented PD patients who regularly experienced the symptom, indicating a lack of a simple relationship between VH and high levels of dopamine.71 Employing positron emission tomography and magnetic resonance spectroscopy in studies may become useful noninvasive methods of investigating these neurotransmitters.72 Furthermore, a greater understanding of the connectional abnormalities involved in VH could advance our understanding of the communication both within and between different neural networks. Intrinsic difficulties are seen in studying distributed networks such as those implicated in the pathogenesis of VH; however, the use of complementary neuroimaging techniques such as diffusion tensor imaging to assess structural connectivity, and functional magnetic resonance imaging and electroencephalography, to assess functional connectivity, in combination with magnetic resonance spectroscopy and positron emission tomography, will vastly improve this area of research. The neural correlates of VH remain unclear, and future studies should use advances in neuroimaging to clarify the neuronal architecture underlying abnormal perceptual experience. For example, the role of brainstem nuclei remains controversial, being strongly implicated in both the dream imagery intrusion and activation, input, modulation models, with a less central role in the other models discussed, and requires investigation in future studies, as illustrated in Table 2. In association with neuroimaging and neurophysiological measures, an analytical approach using graph theory is increasingly being implemented in the investi-
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gation of complex neural networks and their role in neuropathological disorders.73,74 The human brain can be modeled as a complex network, and it is purported to have a small-world structure of connectivity at both the anatomical and functional levels. This is believed to reflect an optimal configuration for segregation (local specialization for particular tasks) and integration (the consolidation of all information) requirements of the brain.73,74 Neurological disorders can disrupt this optimal pattern, potentially leading to more random networks that may result in cognitive dysfunction.73 Network and graph theory modeling provide a unique unifying approach for information collected across different investigative techniques such as functional magnetic resonance imaging, magnetoencephalography, and electroencephalography.74 An approach based in graph theory may lead to a better understanding of neurological disease at the network level. Continued research using an integrative approach such as this, across multiple levels of investigation, will lead to improved theoretical models of VH in PD, which ultimately will provide an empirical framework to guide therapeutic intervention in this complex, disabling symptom.
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Goetz CG, Leurgans S, Pappert EJ, Raman R, Stemer AB. Prospective longitudinal assessment of hallucinations in Parkinson’s disease. Neurology 2001;57:2078-2082.
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Nardone R, Bergmann J, Brigo F, et al. Functional evaluation of central cholinergic circuits in patients with Parkinson’s disease and REM sleep behavior disorder: a TMS study. J Neural Transm 2013;120:413-422.
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Manganelli F, Vitale C, Santangelo G, et al. Functional involvement of central cholinergic circuits and visual hallucinations in Parkinson’s disease. Brain 2009;132:2350-2355.
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Janzen J, ‘t Ent D, Lemstra AW, Berendse HW, Barkhof F, Foncke EMJ. The pedunculopontine nucleus is related to visual hallucinations in Parkinson’s disease: preliminary results of a voxel-based morphometry study. J Neurol 2012;259:147-154.
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Shin S, Lee JE, Hong JY, Sunwoo M-K, Sohn YH, Lee PH. Neuroanatomical substrates of visual hallucinations in patients with nondemented Parkinson’s disease. J Neurol Neurosurg Psychiatry 2012;83:1155-1161.
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Zahodne LB, Fernandez HH. Pathophysiology and treatment of psychosis in Parkinson’s disease. Drugs Aging 2008;25:665-682.
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Meltzer HY, Mills R, Revell S, et al. Pimavanserin, a serotonin2A receptor inverse agonist, for the treatment of Parkinson’s disease psychosis. Neuropsychopharmacology 2010;35:881-892.
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Miyasaki J, Shannon K, Voon V, et al. Practice parameter: evaluation and treatment of depression, psychosis, and dementia in Parkinson disease (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2006;66:996-1002. Goetz CG, Vaughan CL, Goldman JG, Stebbins GT. I finally see what you see: Parkinson’s disease visual hallucinations captured with functional neuroimaging. Mov Disord 2014;29:115-117. Ibarretxe-Bilbao N, Ramirez-Ruiz B, Junque C, et al. Differential progression of brain atrophy in Parkinson’s disease with and without visual hallucinations. J Neurol Neurosurg Psychiatry 2010;81: 650-657.
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Ramırez-Ruiz B, Martı MJ, Tolosa E, et al. Cerebral atrophy in Parkinson’s disease patients with visual hallucinations. Eur J Neurol 2007;14:750-756.
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Solms M. Dreaming and REM sleep are controlled by different brain mechanisms. Behav Brain Sci 2000;23:843-850.
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Asplund CL, Todd JJ, Snyder AP, Marois R. A central role for the lateral prefrontal cortex in goal-directed and stimulus-driven attention. Nat Neurosci 2010;13:507-512.
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Goetz CG, Fan W, Leurgans S. Antipsychotic medication treatment for mild hallucinations in Parkinson’s disease: positive impact on long-term worsening. Mov Disord 2008;23:1541-1545.
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Tagai K, Nagata T, Shinagawa S, Tsuno N, Ozone M, Nakayama K. Mirtazapine improves visual hallucinations in Parkinson’s disease: a case report. Psychogeriatrics 2013;13:103-107.
Goldman JG, Stebbins GT, Dinh V, Bernard B, Merkitch D, Goetz CG. Visuoperceptive region atrophy independent of cognitive status in patients with Parkinson’s disease with hallucinations. Brain 2014:awt360.
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Pizzi SD, Franciotti R, Tartaro A, et al. Structural alteration of the dorsal visual network in DLB patients with visual hallucinations: a cortical thickness MRI study. PloS One 2014;9:e86624.
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Bronnick K, Emre M, Tekin S, Haugen SB, Aarsland D. Cognitive correlates of visual hallucinations in dementia associated with Parkinson’s disease. Mov Disord 2011;26:824-829.
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Imamura K, Wada-Isoe K, Kitayama M, Nakashima K. Executive dysfunction in non-demented Parkinson’s disease patients with hallucinations. Acta Neurol Scand 2008;117:255-259.
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Greicius MD, Krasnow B, Reiss AL, Menon V. Functional connectivity in the resting brain: a network analysis of the default mode hypothesis. Proc Natl Acad Sci 2003;100:253-258.
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Koerts J, Borg MA, Meppelink AM, Leenders KL, van Beilen M, van Laar T. Attentional and perceptual impairments in Parkinson’s disease with visual hallucinations. Parkinsonism Relat Disord 2010;16:270-274.
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Shine JM, O’Callaghan C, Halliday GM, Lewis SJG. Tricks of the mind: visual hallucinations as disorders of attention. Prog Neurobiol 2014;116:58-65.
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Spreng RN, Grady CL. Patterns of brain activity supporting autobiographical memory, prospection, and theory of mind, and their relationship to the default mode network. J Cogn Neurosci 2010; 22:1112-1123.
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Fenelon G, Goetz CG, Karenberg A. Hallucinations in Parkinson disease in the prelevodopa era. Neurology 2006;66:93-98.
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Shine JM, Halliday GM, Naismith SL, Lewis SJG. Visual misperceptions and hallucinations in Parkinson’s disease: dysfunction of attentional control networks? Mov Disord 2011;26:2154-2159.
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Visual Hallucinations in Parkinson’s Disease: Theoretical Models Alana J. Muller, BMedSc (Hons),1 James M. Shine, BSc (Adv), MBBS, PhD,1 Glenda M. Halliday, PhD,2 and Simon J.G. Lewis, MBBCh, BSc, MRCP, FRACP, MD1* 1
Brain & Mind Research Institute, University of Sydney, Sydney, New South Wales, Australia 2 Neuroscience Research Australia, University of NSW, Australia
ABSTRACT:
One of the most challenging tasks in neuroscience is to be able to meaningfully connect information across the different levels of investigation, from molecular or structural biology to the resulting behavior and cognition. Visual hallucinations are a frequent occurrence in Parkinson’s disease and significantly contribute to the burden of the disease. Because of the widespread pathological processes implicated in visual hallucinations in Parkinson’s disease, a final common mechanism that explains their manifestation will require an integrative approach, in which consideration is taken across all complementary levels of analysis. This review considers the leading
The development of hallucinations and psychosis in Parkinson’s disease (PD) commonly occurs in both demented and nondemented1-3 patients and places a high degree of burden on primary caregivers.4,5 Visual hallucinations (VH) are the most common modality and exist along a spectrum including non-menacing simple images as well as more complex images of people, animals, or scenery.6,7 Hallucinations can also include the feeling of an abnormal ‘presence’ (a vague and erroneous perception that another person or threat is present) or ‘passage’ hallucinations (transient undefined hallucinations that pass through the periphery of the visual field).7 Visual hallucinations usually appear recurrently and seemingly without provocation, in dimly lit environments while the patient is alert with open eyes.6 Insight, in which the hallucination is
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*Correspondence to: Dr. Simon J.G. Lewis, Brain & Mind Research Institute, University of Sydney, 94 Mallett Street, Camperdown, New South Wales, Australia, E-mail: [email protected] Funding agencies: This study was supported by
Relevant conflicts of interest/financial disclosures: Nothing to report. Author roles may be found in the online version of this article. Received: 29 April 2014; Revised: 29 July 2014; Accepted: 3 August 2014 Published online 22 August 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/mds.26004
hypothetical frameworks for visual hallucinations in Parkinson’s disease, summarizing the key aspects of each in an attempt to highlight the aspects of the condition that such a unifying hypothesis must explain. These competing hypotheses include implications of dream imagery intrusion, deficits in reality monitoring, and impairments in visual perception and attention. C V 2014 International Parkinson and Movement Disorder Society
K e y W o r d s : Parkinson’s disease; visual hallucinations; visual misperceptions
recognized as distinct from reality, is preserved in most cases6; however, they often become chronic and can progress to a loss of insight or delusions, frequently precipitating the need for nursing home placement.2,5,8 One of the most challenging tasks in neuroscience is to be able to meaningfully connect information across the different levels of investigation, from molecular or structural biology, to cellular neurophysiology, microcircuits, neural networks, and finally, the resulting behavior and cognition, often translating to clinical settings.9,10 Most early approaches in neuroscience have taken a reductionist approach, reducing complex processes into their constituent parts.11 However, these processes commonly lead to assumptions that misinterpret data across different levels of explanation and as such, an integrative approach, in which consideration is taken across all complementary levels of analysis, is being increasingly implemented.9 Because of the widespread pathological processes implicated in VH in PD, a final common mechanism that explains their manifestation will require this integrated approach. A number of hypotheses have been proposed to explain the neurobiological mechanisms underlying VH in PD. This review discusses the leading hypothetical frameworks for VH in PD,
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summarizing the key aspects of each in an attempt to highlight the aspects of the condition that such a unifying hypothesis must explain.
Dream Imagery Intrusion Model An early model of VH considers dysfunctional sleep or oneiric processes as the mechanism underlying these erroneous perceptual experiences. Endogenous imagery produced during dreaming is proposed to be the source of hallucinated or misperceived images, potentially associated with Rapid Eye Movement (REM) sleep intrusions during wakefulness.12,13 The risk of suffering from psychosis has been found to be nearly five times greater in those patients who experience comorbid disorders of sleep–wakefulness.14 Hallucinations also have been reported to have a close temporal relationship with the REM stage of sleep, with patients experiencing hallucinations concurrent with REM sleep intrusions during wakefulness as well as delusions post-REM sleep at night.13 Such observations have led to the proposal that VH in PD are due to the intrusion of dream imagery into the conscious wakeful state.15 Proponents of this model have suggested that psychosis in PD may reflect a narcolepsy-like REM sleep disorder; however, the results of a study examining Human Leukocyte Antigen blood markers of narcolepsy did not find any in PD patients with VH.13 Indeed, the prevalence of REM sleep behavior disorder cases without VH in this study suggested that these two conditions were clinically separable.13 Furthermore, not all hallucinatory events suffered by patients with PD are temporally related to REM or even nonREM sleep.12 As such, the Dream Imagery Intrusion Model cannot sufficiently explain hallucinations that commonly occur in a clinically and polysomnographically documented wakeful state.12 Indeed, reports of sleep fragmentation, altered dream phenomena, and vivid dreams or nightmares have been shown to be ineffective in predicting the eventual development of hallucinations in PD, again disputing this possible relationship.16 Disruption to the cholinergic systems and regions involved in sleep has been implicated as a potential pathophysiological mechanism for VH in PD, perhaps leading to intrusions of dream imagery into conscious perception. Indeed, cholinergic dysfunction, as measured by short latency afferent inhibition, a transcranial magnetic stimulation protocol that tests inhibitory cholinergic circuits in the motor cortex,17 has been demonstrated in PD patients with VH compared with PD patients without VH, as well as healthy controls.18 In addition, a similar significant reduction in short latency afferent inhibition has been shown in PD patients with REM sleep behavior disorder; however,
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20% of PD patients with hallucinations involved in the former study did not show abnormalities.17,18 Pathological and neuroimaging studies also have observed impaired function within cholinergic projection nuclei, such as the pedunculopontine nucleus and nucleus basalis of Meynert. The pedunculopontine nucleus has been implicated in both sleep and VH,17,19,20 and voxel-based morphometry analysis has shown a significantly reduced volume in this region in hallucinating PD patients compared with nonhallucinators.20 Anticholinesterase inhibitors, such as rivastigmine, have been demonstrated to improve hallucinatory symptoms in PD patients.21 However, alternative neurotransmitter systems also have been implicated in the pathogenesis of VH in PD, with preliminary clinical trials of treatments that have shown significant improvement in psychosis in PD, including pimavanserin, a highly selective 5-HT2A inverse agonist, and clozapine, an atypical anti-psychotic.22,23 In addition, the literature contains examples of PD patients who experience florid hallucinations and yet do not show significant pathology in these brainstem nuclei.24-26 Other brain regions involved in dreaming, rather than arousal or stages of sleep, have been implicated in the pathogenesis of VH in PD. Dreaming is proposed to be mediated by a forebrain, possibly dopaminergic, mechanism.27 Some of these structures, which are also implicated in VH in PD, include amygdala,28,29 orbitofrontal,20 anterior cingulate,25,30,31 and occipitotemporal cortical areas.27,32 Whereas these anatomical findings support a potential involvement of dream imagery in the pathogenesis of VH, some discrepancies between oneiric versus hallucinatory experiences should be considered. For example, recollection and insight are commonly retained in PD hallucinations,6 unlike most episodes of REM sleep behavior disorder.33,34 Indeed, dream imagery is usually distinctly different from that experienced during hallucinations in PD. Dreams often have intense emotional accompaniment, encompass the entire visual field, and the dreamer often plays a central role in events. This is in contrast to the often neutral, singleobject or person hallucinations described in PD.34-36
Reality Monitoring Deficit Some researchers have proposed that VH in PD can be attributed to a deficit in reality monitoring.37 Evidence for this can be seen in the relative inability of PD patients with VH to judge the source of an item in a series of visual imagery- and memory-based tasks.37 Such tasks involve the presentation of stimuli as either words or pictures, and then after a delay some stimuli are re-presented exactly as before, or in an alternate form (eg, a word instead of a picture or vice versa).37
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H A L L U C U N A T I O N S
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TABLE 1. Compatibility of observed associations with theoretical models
Brief description
Disturbed function Perception30,48-52,57 Executive30,37,56,57 Sleep12-15,30 Pathology Brainstem18,20,44,46,47 Retina48-52 Subcortex25,28,29 Cortex25,27,30,32,39-43 Other relations Dopamine48-51 Other disorders68
Dream Imagery Intrusion
Reality Monitoring Deficit
Activation Input Modulation
Perception and Attention Deficit
Attentional Network Dysfunction
Intrusion of endogenous imagery produced during dreaming13
Inability to judge the source of a perception37
Dysregulated gating of external and internal imagery44
Impaired interactions between perception and attention36
Disrupted processing across attentional control networks59
– – 111
– 111 1
11 11 11
111 11 –
11 111 11
111 – – 1
– – – 111
111 1 – 1
11 1 1 111
1 1 11 11
– 1
– 1
1 11
– 1
1 111
Key: the number of “1” signifies the degree to which each model is associated with the factors in the first column. “–” symbols reflect an aspect of the hallucinatory phenotype not compatible with, or unaccounted for, in each model.
Subjects are then asked to recall which stimuli had been presented previously, and whether they had been presented in the same modality the second time. Hallucinating PD patients had most difficulty with identifying source when a stimulus was re-presented in its alternative form (ie, the cross-modal condition), and showed a tendency to report internally generated stimuli as external input stimuli.37 Correct recognition of items that had been presented previously, regardless of source identification, was not significantly impaired in PD with VH groups compared with non-hallucinators and healthy controls.37 However, hallucinators appeared to rely more heavily on a feeling of familiarity, with which they recognized an item as being presented before but could not specifically remember its previous presentation during the task.37 Barnes and colleagues suggest that accurate recollection of specific details from the encoding event is especially important in the accurate attribution of source to a piece of information. Namely, familiarity with a stimulus on its own is not a reliable method by which to determine the origin of information, and the less detailed the recollection of encoding events, the more susceptible memory is to misinterpretation, especially in regard to source.37 These results were taken to reflect a bias toward attributing an internally generated event to an external source, thereby misinterpreting mental imagery as veridical perception.37,38 Reality monitoring in healthy subjects has been localized to the frontal lobes,39 especially the prefrontal cortex.40,41 The frontal lobe has shown increased pathology in PD patients with VH compared with nonhallucinators, including significantly higher Lewy body burden30 and gray matter atrophy.25,42 The right superior, middle, and inferior frontal gyri also have shown a
diminished level of activation in PD with VH sufferers.43 As such, a failure in reality monitoring could give rise to visual hallucinations from endogenous imagery.37 However, that only one cognitive deficit underlies this complex symptom is unlikely. The progression of the VH to loss of insight or menacing content is not sufficiently explained by a reality monitoring deficit, and other processes must be affected to influence the content and character of the hallucinated images8 (Table 1).
Activation, Input, Modulation Model The Activation, Input, Modulation model of hallucinations considers the underlying cause of VH as a dysregulation of the gating and filtering of exogenous perception and endogenous image creation.44 Built on the framework of Hobson’s model of mental states,45 this model of VH in PD encompasses visual defects, cognition, and REM dysfunction within a single model (Table 1). It largely incorporates the hypotheses of dream imagery intrusion, reality monitoring deficit, and a cortical release phenomenon. The first dimension (activation) refers to the capacity to process information, which is postulated to be regulated by the reticulo-thalamocortical system.44 The second dimension (input) refers to the exchange of information with the external world or the generation of information internally. Importantly, the model suggests that the state of the gating system can rapidly change by means of a reciprocal relationship between REM-on, cholinergic cells located in the pedunculopontine nucleus; and REM-off aminergic cells located within the locus coeruleus and dorsal raphe nucleus.44,46,47 The final dimension (modulation) refers to the integration of activation and input over time. In
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an alert state, forebrain-mediated functions are enhanced by high aminergic activity arising from the locus coeruleus and dorsal raphe nucleus.47 In contrast, high cholinergic activity in brainstem regions such as the pedunculopontine nucleus, in association with aminergic demodulation, facilitates the production of endogenous visual imaging and hyper-associative cognition typically experienced during REM sleep.46,47 The activation, input, modulation model proposes that hallucinations are primarily a result of defects within the input dimension, whereby there is an imbalance between the gating of endogenous and exogenous inputs. This imbalance leads to a propensity for hallucinations as a result of a relative reduction in the strength of the external input with respect to the internal stimulus generation, which may then lead to the release of stored percepts—dream-like images and visual memory contents that may be a form of compensation to “fill in” for the lack of visual input. The resulting endogenous imagery is then incorporated into perception.44 Disruption of the dopaminergic cells of the retina has been described in PD and could contribute to a reduction in external input strength, consequently promoting VH. Poor color and contrast discrimination are two common visual deficits found in PD, and have been shown to be associated with VH, potentially acting as facilitating factors.48-52 However, more substantial primary visual deficits have not been found to predispose PD patients to VH.30 Imbalance between the gating of exogenous and endogenous inputs also could arise if the internal stimulus strength were greatly increased. This would result in a scenario in which perceptions were driven by a combination of poorly distinguished endogenous and exogenous imagery.45 The authors of this model suggested that REM intrusions into wakefulness could constitute increased internal input generation, where VH are associated with REM intrusions. Some evidence suggests that mental imagery is increased in PD patients with VH, and previous studies have shown that endogenous information is more likely to later be confused with perception if it is more easily generated.39 Although the activation, input, modulation model explains a large degree of disparate clinical information, it does not address the potential role of other brain regions crucial in attentional and perceptual processes. However, unlike the dream imagery intrusion model, this hypothesis does accommodate the possibility of experiencing strengthened internal imagery concurrently with external inputs, thus maintaining fundamental attributes of both perceptual systems. Within the activation, input, modulation model, VH reflect an abnormal state of consciousness exhibiting a combination of features from wakefulness and REM sleep. Although dream imagery may still underlie the hallucination, the patient could store the
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images in memory and even consider them with critical insight as the aminergically modulated wakeful state is maintained.44,45 In addition, a wide range of neurotransmitter systems are implicated in the pathogenesis of VH in PD, which is supported in the literature by the number of different neurotransmitters implicated by clinical trials in the literature.22,23,53,54
Perception and Attention Deficit The perception and attention deficit model of hallucinations describes an interaction of impairments in both visual perception and attention36 (Table 1). These processes operate synergistically with relatively intact scene representations to produce the activation of contextually expected but incorrect proto-objects.36 Proto-objects are envisioned as abstracted object representations in mutual competition to reach awareness, primarily through directing attention toward themselves, and act as candidate objects for further processing. Hallucinations arise when the wrong proto-object is drawn into the attentional focus of a scene, and the degree of the disparity between the correct and selected incorrect proto-objects determines the severity of the hallucinatory experience.36 The emergence of the incorrect proto-object is believed to relate to an interaction between attentional binding impairments and the limited sensory activation of the correct proto-object. Numerous studies have associated the presence of attentional deficits and reduced perception with VH in PD.43,55-57 The perception and attention deficit model proposes that these attentional and perceptional impairments are localized to the lateral frontal cortex and ventral visual stream, respectively, which may show cholinergic pathology, disrupting communication between these regions.36 This impairment would in turn disrupt the working memory and semantic associations believed to underlie the retrieval of images, as well as image and scene perception.58 This model has received support from studies implicating cholinergic dysfunction,18 as well as from neuroimaging studies, including one functional magnetic resonance imaging study that revealed hypoactivation within the right prefrontal network of hallucinators.43 However, work using fluorodeoxyglucose positron emission tomography to look at metabolic activity has provided evidence that both of these two major visual processing routes (dorsal and ventral visual stream) may be affected in PD patients with VH.32
Dysfunction of the Attentional Control Networks A recent hypothesis has suggested that visual misperceptions and hallucinations may arise from
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disrupted processing across attentional networks.59 This hypothesis posits that hallucinations may arise from dysfunction across the dorsal attention network (DAN), the ventral attention network (VAN), and default mode network (DMN) (Table 159). Specifically, this model proposes that VH are due to a relative inability to recruit activation in the DAN, which underlies the capacity to focus attention on externally driven percepts in the presence of an ambiguous percept, leading to an “overreliance” on the VAN, which normally assists in the rapid reorienting of attention toward salient stimuli,60 and the DMN, which consists of regions normally involved in the retrieval and manipulation of episodic memories and semantic knowledge, in the interpreting of visual perception.58,61 Impairments at multiple levels of this neuronal architecture could ultimately manifest as hallucinatory behavior. For example, impaired visual input via a dopaminergically dysfunctional retina may cause impairments in visual processing, which, in the context of impaired attentional capabilities,57,62 may lead to incorrect perceptual recognition of objects.60 Alternatively, the neural regions responsible for exogenous attention, such as those constituting the DAN, may be pathologically impaired. The DAN is composed of widespread neural regions within the frontal eye fields, the dorsolateral prefrontal cortex, and the superior posterior parietal cortices, all of which send efferents to the head of the caudate nucleus,63 and some of these regions have been implicated in structural neuroimaging studies.64,65 In addition, PD patients who performed poorly on a novel paradigm designed to measure VH and elicit misperceptions during functional neuroimaging demonstrated reduced activation of regions implicated in this network.66 The VAN works closely with the DAN, because it presents “bottom-up” visuoperceptive information that usually requires further “top-down” processing by the DAN, particularly in the event of an ambiguous percept.60 The VAN is involved in engaging attention to salient stimuli, as well as mediating the activation of the DAN and DMN, acting as a quick override for directing attentional resources.59,66 The VAN is believed to be located primarily in the temporoparietal junction, ventral striatum, the basolateral amygdala, and the lateral and inferior prefrontal cortex.31,66 Anatomical and pathological studies of PD patients have reported results associating a number of these regions with the presence of VH: for example, the occipitotemporoparietal region has shown a decreased regional cerebral metabolic rate for glucose consumption in hallucinators.32 The amygdala also has been implicated by numerous studies in the pathogenesis of VH in PD, demonstrating significant atrophy,25 as well as a significantly higher density of Lewy body distribution.28,29
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Alternatively, dysfunction within the VAN could result in difficulties in orienting attention to relevant stimuli by switching between the DAN and DMN. Indeed, pathological studies of PD patients have reported results associating a number of VAN regions, including the basolateral amygdala, with the presence of VH.25,29 This pathology would then lead to a relative inability to “shut down” resting activity within the DMN, which is typically associated with the retrieval and manipulation of semantic and episodic memories.67 This would lead to the surfacing of previously stored percepts from within the DMN, either by a failure to recall appropriate information or by the selection of inappropriate stored information, potentially resulting in VH.59 Although this hypothesis can adequately incorporate known sleep impairments that are associated with VH, such as REM sleep behavior disorder, the model does not specifically implicate particular neurotransmitter impairments, making pharmacotherapeutic translation difficult.68
Conclusion Several competing theories exist regarding the development and progression of VH in PD. Inherent difficulties arise in comparing models of neural network activity, because models designed to account for a symptom with such widespread implications are fundamentally abstract. This very quality allows a model to be amenable to the variety of experiences of VH in PD.69 Unfortunately, this causes some difficulty in disambiguating explicit predictions of each of the models (Table 2). Whereas broad similarities can be seen across the models, generally implicating attentional and perceptual impairments,31 they also display important differences (Table 1). Successfully disambiguating specific aspects of the models through neuropsychological testing may prove difficult; for example, executive dysfunction is broadly implicated in several of the hypotheses.36,37,59 However, tests assessing vision, such as acuity or contrast sensitivity, provide objective evidence that would address some of the predictions in the perception and attention deficit, and activation, input, modulation models.36,44 Furthermore, differentiation of the models could be tested effectively in future studies, using a combination of alternative investigative techniques (Table 2). For example, a high priority for future research lies with the role of neurotransmitters. Dopaminergic medications have been long implicated in the pathogenesis of VH in PD, and often the first line of management of hallucinatory symptoms is to reduce dopaminergic medications.70 However, evidence in the literature suggests that the role medication plays in the pathogenesis of VH in PD may be less significant than previously believed. Before
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TABLE 2. Brief description and testable predictions of theoretical models Dream Imagery Intrusion
Reality Monitoring Deficit
Activation Input Modulation
Perception and Attention Deficit
Cholinergic dysfunction in projection nuclei to frontotemporal cortices PET, SAI
Functional disorder of attention and perception
Hallucinators should demonstrate a specific pattern of brainstem cholinergic change as demonstrated by specific PET ligands
Hallucinators should display a relative underactivation of the DAN and over-activation of the DMN and VAN
Core feature
Impaired REM ‘switching’ mechanism
Specific reality monitoring deficit in all patients with VH
Impaired gating of input and endogenous imagery
Investigational approach
Ambulatory high-density EEG
Neuropsychological testing; fMRI
Prediction
EEG pattern during hallucinatory episodes should be similar to the pattern observed during REM sleep
Reality monitoring impairments should be exclusive to hallucinators and correlated with eventrelated fMRI signals during reality monitoring
Mental imagery and visual acuity testing; PET Impairments in imagery production or vision should be exclusive to hallucinators and correlated with a specific pattern of brainstem NT changes
Attentional Network Dysfunction
fMRI
PET, positron emission tomography; EEG, electroencephalography; fMRI, functional magnetic resonance imaging; REM, rapid eye movement sleep; DAN, dorsal attention network; DMN, default mode network; VAN, ventral attention network; NT, neurotransmitter; SAI, short-latency afferent inhibition.
levodopa (L-dopa) medication, hallucinations were reportedly still experienced in PD,70 and a high-dose intravenous L-dopa infusion did not precipitate VH in five nondemented PD patients who regularly experienced the symptom, indicating a lack of a simple relationship between VH and high levels of dopamine.71 Employing positron emission tomography and magnetic resonance spectroscopy in studies may become useful noninvasive methods of investigating these neurotransmitters.72 Furthermore, a greater understanding of the connectional abnormalities involved in VH could advance our understanding of the communication both within and between different neural networks. Intrinsic difficulties are seen in studying distributed networks such as those implicated in the pathogenesis of VH; however, the use of complementary neuroimaging techniques such as diffusion tensor imaging to assess structural connectivity, and functional magnetic resonance imaging and electroencephalography, to assess functional connectivity, in combination with magnetic resonance spectroscopy and positron emission tomography, will vastly improve this area of research. The neural correlates of VH remain unclear, and future studies should use advances in neuroimaging to clarify the neuronal architecture underlying abnormal perceptual experience. For example, the role of brainstem nuclei remains controversial, being strongly implicated in both the dream imagery intrusion and activation, input, modulation models, with a less central role in the other models discussed, and requires investigation in future studies, as illustrated in Table 2. In association with neuroimaging and neurophysiological measures, an analytical approach using graph theory is increasingly being implemented in the investi-
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gation of complex neural networks and their role in neuropathological disorders.73,74 The human brain can be modeled as a complex network, and it is purported to have a small-world structure of connectivity at both the anatomical and functional levels. This is believed to reflect an optimal configuration for segregation (local specialization for particular tasks) and integration (the consolidation of all information) requirements of the brain.73,74 Neurological disorders can disrupt this optimal pattern, potentially leading to more random networks that may result in cognitive dysfunction.73 Network and graph theory modeling provide a unique unifying approach for information collected across different investigative techniques such as functional magnetic resonance imaging, magnetoencephalography, and electroencephalography.74 An approach based in graph theory may lead to a better understanding of neurological disease at the network level. Continued research using an integrative approach such as this, across multiple levels of investigation, will lead to improved theoretical models of VH in PD, which ultimately will provide an empirical framework to guide therapeutic intervention in this complex, disabling symptom.
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