Alana J. Muller

Visual Hallucinations in Parkinson's Disease: Theoretical Models

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 Parkinsons disease and significantly contribute to the burden of the disease. Because of the widespread pathological processes implicated in visual hallucinations in Parkinsons 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 hypothetical frameworks for visual hallucinations in Parkinsons 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.

Imagine that: elevated sensory strength of mental imagery in individuals with Parkinson's disease and visual hallucinations

Visual hallucinations occur when our conscious experience does not accurately reflect external reality. However, these dissociations also regularly occur when we imagine the world around us in the absence of visual stimulation. We used two novel behavioural paradigms to objectively measure visual hallucinations and voluntary mental imagery in 19 individuals with Parkinsons disease (ten with visual hallucinations; nine without) and ten healthy, age-matched controls. We then used this behavioural overlap to interrogate the connectivity both within and between the major attentional control networks using resting-state functional magnetic resonance imaging. Patients with visual hallucinations had elevated mental imagery strength compared with patients without hallucinations and controls. Specifically, the sensory strength of imagery predicted the frequency of visual hallucinations. Together, hallucinations and mental imagery predicted multiple abnormalities in functional connectivity both within and between the attentional control networks, as measured with resting-state functional magnetic resonance imaging. However, the two phenomena were also dissociable at the neural level, with both mental imagery and visual misperceptions associated with specific abnormalities in attentional network connectivity. Our results provide the first evidence of both the shared and unique neural correlates of these two similar, yet distinct phenomena.

Abnormal connectivity between the default mode and the visual system underlies the manifestation of visual hallucinations in Parkinson’s disease:A task-based fMRI study

Background:The neural substrates of visual hallucinations remain an enigma, due primarily to the difficulties associated with directly interrogating the brain during hallucinatory episodes.Aims:To delineate the functional patterns of brain network activity and connectivity underlying visual hallucinations in Parkinson’s disease.Methods:In this study, we combined functional magnetic resonance imaging (MRI) with a behavioral task capable of eliciting visual misperceptions, a confirmed surrogate for visual hallucinations, in 35 patients with idiopathic Parkinson’s disease. We then applied an independent component analysis to extract time series information for large-scale neuronal networks that have been previously implicated in the pathophysiology of visual hallucinations. These data were subjected to a task-based functional connectivity analysis, thus providing the first objective description of the neural activity and connectivity during visual hallucinations in patients with Parkinson’s disease.Results:Correct performance of the task was associated with increased activity in primary visual regions; however, during visual misperceptions, this same visual network became actively coupled with the default mode network (DMN). Further, the frequency of misperception errors on the task was positively correlated with the strength of connectivity between these two systems, as well as with decreased activity in the dorsal attention network (DAN), and with impaired connectivity between the DAN and the DMNs, and ventral attention networks. Finally, each of the network abnormalities identified in our analysis were significantly correlated with two independent clinical measures of hallucination severity.Conclusions:Together, these results provide evidence that visual hallucinations are due to increased engagement of the DMN with the primary visual system, and emphasize the role of dysfunctional engagement of attentional networks in the pathophysiology of hallucinations.

Dysfunction in attentional processing in patients with Parkinson’s disease and visual hallucinations

Mechanistic insights into visual hallucinations (VH) in Parkinson’s disease (PD) have suggested a role for impaired attentional processes. The current study tested 25 PD patients with and 28 PD patients without VH on the attentional network test. Hallucinators had significantly lower accuracy rates compared to non-hallucinators, but no differences were found in reaction times. This suggests that hallucinators show deficits in attentional processes and conflict monitoring. Our findings provide novel behavioural insights that dovetail with current neurobiological frameworks of VH.

Retrospective Neuropsychological Profile of Patients With Parkinson Disease Prior to Developing Visual Hallucinations

Visual hallucinations (VH) are a common feature of Parkinson disease (PD); however, the cognitive profile preceding the onset of VH has not yet been established. The present study investigated longitudinal neuropsychological performance of patients with PD who developed VH during follow-up compared to a group who did not develop VH. The patient groups were matched for demographic and disease severity variables at their baseline assessments. Patients who developed VH displayed impaired performance at baseline on measures of psychomotor speed, executive functioning, reaction time, and attention compared to patients who did not develop VH. These results demonstrate a profile of cognitive deficits specific to patients with PD at risk of developing VH and implicate attentional dysfunction in the early pathogenesis of VH.

Cognitive Function in Parkinson’s Disease Patients with and without Anxiety

Research on the implications of anxiety in Parkinsons disease (PD) has been neglected despite its prevalence in nearly 50% of patients and its negative impact on quality of life. Previous reports have noted that neuropsychiatric symptoms impair cognitive performance in PD patients; however, to date, no study has directly compared PD patients with and without anxiety to examine the impact of anxiety on cognitive impairments in PD. This study compared cognitive performance across 50 PD participants with and without anxiety (17 PDA+; 33 PDA−), who underwent neurological and neuropsychological assessment. Group performance was compared across the following cognitive domains: simple attention/visuomotor processing speed, executive function (e.g., set-shifting), working memory, language, and memory/new verbal learning. Results showed that PDA+ performed significantly worse on the Digit Span forward and backward test and Part B of the Trail Making Task (TMT-B) compared to the PDA− group. There were no group differences in verbal fluency, logical memory, or TMT-A performance. In conclusion, anxiety in PD has a measurable impact on working memory and attentional set-shifting.

Cognitive training for freezing of gait in Parkinson’s disease: a randomized controlled trial

The pathophysiological mechanism of freezing of gait (FoG) has been linked to executive dysfunction. Cognitive training (CT) is a non-pharmacological intervention which has been shown to improve executive functioning in Parkinson’s disease (PD). This study aimed to explore whether targeted CT can reduce the severity of FoG in PD. Patients with PD who self-reported FoG and were free from dementia were randomly allocated to receive either a CT intervention or an active control. Both groups were clinician-facilitated and conducted twice-weekly for seven weeks. The primary outcome was percentage of time spent frozen during a Timed Up and Go task, assessed both on and off dopaminergic medications. Secondary outcomes included multiple neuropsychological and psychosocial measures. A full analysis was first conducted on all participants randomized, followed by a sample of interest including only those who had objective FoG at baseline, and completed the intervention. Sixty-five patients were randomized into the study. The sample of interest included 20 in the CT group and 18 in the active control group. The primary outcome of percentage time spent frozen during a gait task was significantly improved in the CT group compared to active controls in the on-state. There were no differences in the off-state. Patients who received CT also demonstrated improved processing speed and reduced daytime sleepiness compared to those in the active control. The findings suggest that CT can reduce the severity of FoG in the on-state, however replication in a larger sample is required.Freezing of gait: a non-pharmacological approachCognitive training can reduce the severity of gait freezing in Parkinson’s disease (PD) patients on dopaminergic medication. The inability to move forwards despite the intention to walk is one of the most debilitating symptoms in patients with PD and has been linked to cognitive dysfunction. Simon Lewis at the University of Sydney, Australia, and colleagues examined the effects of cognitive training in patients with self-reported freezing of gait and without dementia. Patients receiving cognitive therapy twice a week for seven weeks showed a significant reduction in gait freezing compared to the control group. Interestingly, the effect was observed when patients had maximum benefit from their PD medication (on-state) but not in the off-state. Cognitive training also improved patients’ processing speed and reduced their daytime sleepiness highlighting the usefulness of non-pharmacological interventions in the treatment of PD.

Clarifying the Role of Neural Networks in Complex Hallucinatory Phenomena

Visual hallucinations and related phenomena, such as deja vu, are reminders that conscious perception does not always accurately reflect external reality. We might be startled by a garden hose that at first glance looks like a snake, or feel an eerie sense of familiarity in new surroundings. For

Default mode and primary visual network coupling is associated with increased mind-wandering frequency in Parkinson\'s disease with visual hallucinations

Background An imbalance between top-down expectations and incoming sensory information is implicated in the genesis of hallucinations across neuropsychiatric disorders. In Parkinson’s disease (PD) with visual hallucinations, over-activity in the default mode network (DMN) is a hypothesised source of excessive top-down influence that can dominate visual perception. Methods In 38 PD patients (18 with hallucinations; 20 without) and 20 age-matched controls, we administered a validated thought-sampling task to establish whether PD hallucinators experienced increased mind-wandering – a form of spontaneous thought strongly associated with DMN activity. Neural correlates of the behavioural differences in mind-wandering frequency were established via resting-state functional connectivity and voxel-based morphometry analyses. Results PD hallucinators (PD+VH) exhibited significantly higher mind-wandering frequencies compared to non-hallucinators (PD-VH), who showed reduced levels relative to controls. Inter-network connectivity and seed-to-voxel analyses confirmed increased mind-wandering in PD+VH was associated with greater coupling between the DMN and primary visual cortex (V1). In contrast, reduced mind-wandering was associated with grey matter loss in the left posterior parietal cortex in PD-VH. Conclusions Elevated mind-wandering associated with DMN-visual network coupling emerged as a distinguishing feature of PD hallucinators. We propose that increased mind-wandering reflects excessive spontaneous thought and mental imagery, which can furnish the content of visual hallucinations. DMN-V1 coupling may provide a neural substrate by which regions of the DMN exert disproportionate influence over ongoing visual perception. Our findings refine current models of visual hallucinations by identifying a specific cognitive feature and neural substrate consistent with the excessive top-down influences over perception that lead to hallucinations.Abstract A mismatch between top-down expectations and incoming sensory information is thought to be associated with hallucinations across a range of neuropsychiatric disorders. In Parkinson’s disease with visual hallucinations, abnormal activity within the default network, and its pattern of connectivity with early visual regions, has been identified as a potential pathological source of the internally generated expectations that override incoming sensory input. In the context of attention deficits and visual dysfunction, mental imagery and perceptual expectancies generated across the default network are suggested to exert excessive influence over earlier visual regions, leading to aberrant perceptual experiences. Whilst converging neuroimaging evidence has identified unconstrained default network activity in Parkinson’s disease with hallucinations, to date there has been a lack of behavioural evidence to confirm the consequences of an over-engaged default mode network – therefore the contributions it might make to hallucination phenomenology remain speculative. To address this, we administered a validated thought-sampling task to 38 Parkinson’s disease patients (18 with hallucinations; 20 without) and 40 controls, to test the hypothesis that individuals with hallucinations experience an increased frequency of mind-wandering – a form of spontaneous cognition strongly associated with mental imagery and default network activity. The neural correlates of mind-wandering frequency were examined in relation to resting-state functional connectivity. Our results showed that patients with hallucinations exhibited significantly higher mind-wandering frequencies compared to non-hallucinators, who in turn had reduced levels of mind-wandering relative to controls. Inter-network connectivity and seed-to-voxel analyses confirmed that increased mind-wandering in the hallucinating vs. non-hallucinating group was associated with greater coupling between the primary visual cortex and dorsal default network. Taken together, both elevated mind-wandering and increased default-visual network coupling emerged as a distinguishing feature of the hallucinatory phenotype. We propose that the finding of increased mind-wandering reflects unconstrained spontaneous thought and mental imagery, which in turn furnish the content of visual hallucinations. Our findings suggest that primary visual cortex to dorsal default network coupling may provide a neural substrate by which regions of the default network exert disproportionate influence over ongoing visual perception. These findings refine current models of visual hallucinations by identifying a specific cognitive phenomenon and neural substrate consistent with the top-down influences over perception that have been implicated in visual hallucinations.

Changes in structural network topology correlate with severity of hallucinatory behaviour in Parkinson's disease

An inefficient integration between bottom-up visual input and higher-order visual processing regions is implicated in the manifestation of visual hallucinations (VH) in Parkinson’s disease (PD). Using graph theory, the current study aimed to investigate white matter contributions to this perceptual imbalance hypothesis. Twenty-nine PD patients reported their hallucinatory behaviour on a questionnaire and performed a behavioural test that has been shown to elicit misperceptions. A composite score derived from these measures was used as a proxy for hallucinations severity and was correlated to connectivity strength of the network using the Network Based Statistic approach. The results showed that the severity of VH was associated with reduced connectivity within a large sub-network. This network included the majority of the diverse club and showed overall greater between- and within-module scores, compared to nodes not associated with hallucination severity. Furthermore, a reduction in between-module connectivity in the lateral occipital cortex, insula and pars orbitalis, as well as decreased within-module connectivity in the prefrontal, somatosensory and primary visual cortices were associated with VH severity. In contrast, the severity of VH was associated with an increase in between- and within-module connectivity in the orbitofrontal and temporal cortex, as well as regions comprising the dorsal attentional and DMN. These results suggest that the severity of VHs is associated with marked alterations in structural network topology, highlighted by a reduction in connectivity strength across a large sub-network, as well as changes in participation across top-down visual processing centres, visual and attentional networks. Therefore, impaired integration across the perceptual hierarchy may result in the inefficient transfer of information that gives rise to VHs in PD.