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Movement disorders
Research paper
Neuroanatomical substrates of visual hallucinations in patients with non-demented Parkinson's disease
  1. Soojeong Shin1,
  2. Ji Eun Lee1,
  3. Jin Yong Hong1,
  4. Mun-Kyung Sunwoo1,
  5. Young Ho Sohn1,
  6. Phil Hyu Lee1,2
  1. 1Department of Neurology and Brain Research Institute, Yonsei University College of Medicine, Seoul, Korea
  2. 2Severance Biomedical Science Institute, Seoul, Korea
  1. Correspondence to Phil Hyu Lee, Department of Neurology, Yonsei University Medical College, 250 Seongsanno, Seodaemun-gu, Seoul, 120-752, South Korea; phisland{at}chol.net

Abstract

Background Visual hallucinations (VH), which are common in patients with Parkinson's disease (PD), lead to increased disability and are a significant predictor of the development of dementia. However, the neuroanatomical basis for VH in non-demented PD patients remains controversial.

Methods A total of 110 patients with PD were classified into PD with VH (n=46) and PD without VH (n=64) groups, depending on the presence of VH assessed by the caregiver-based structured interview of the Neuropsychiatric Inventory. We performed voxel-based morphometry (VBM) for grey matter (GM) volume and a region-of-interest-based volumetric analysis of the substantia innominata (SI) between two groups.

Results The comprehensive neuropsychological assessment showed that PD patients with VH showed more severe cognitive deficits in delayed visual memory and frontal executive functions compared with those without VH. A VBM analysis revealed that PD patients with VH had significantly lower GM volume in the right orbitofrontal, left temporal and left thalamic areas compared with those without VH. The normalised SI volume was significantly reduced in PD patients with VH compared with those without VH (1.28±0.22 vs 1.41±0.25, p=0.005).

Conclusions The present study demonstrates that non-demented PD patients with VH exhibited a smaller volume in the frontal, temporal and thalamic areas as well as the SI, suggesting that PD hallucinators may have distinctive neuroanatomical bases relative to PD non-hallucinators.

  • Parkinson's disease
  • visual hallucination
  • neural substrates
  • Alzheimer's disease
  • movement disorders

https://doi.org/10.1136/jnnp-2012-303391

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    Introduction

    Visual hallucinations (VH), which are common in patients with Parkinson's disease (PD), lead to increased disability and placement in nursing homes. Risk factors for VH in patients with PD include older age, long disease duration, greater disease severity, autonomic dysfunction and sleep alterations.1 ,2 Of those, several studies have demonstrated that VH in PD are associated with greater impairment of neuropsychological performance in frontal or visuoconstructional domains3–5 and act as a significant predictor of the development of dementia.6

    The pathogenic mechanisms underlying VH in PD are not completely understood, although functional and structural abnormalities have been suggested. Functional imaging studies have demonstrated that VH are associated with dysfunctions in posterior cortical areas of the visual association and temporal cortices and frontal area in non-demented patients with PD.7–9 These results suggest that the neuropathological substrates responsible for VH may already be present in patients with PD during non-demented stage of PD patients. This concept is supported by a recent longitudinal study demonstrating that non-demented PD patients with VH present progressive and extensive grey matter (GM) atrophy involving limbic, paralimbic and neocortical areas compared with those without VH.10 However, the neuroanatomical basis for VH in non-demented patients with PD is still controversial due to the limited number of studies and different designs; Ramirez-Ruiz et al 11 reported VH is associated with loss of GM volume in the parietal and occipital areas, whereas Meppelink et al 12 did not find a significant difference in GM volume between non-demented PD patients with and without VH. Additionally, neurochemical alterations in the dopaminergic, cholinergic or serotonergic systems may play a role in the development of VH.13 ,14 Of those, the cholinergic system from the nucleus basalis of Meynert, located in the substantia innominata (SI), has been suggested to be important in the development of VH in patients with PD.15 In the present study, we explored the cognitive profiles and neuroanatomical characteristics of VH in non-demented patients with PD using voxel-based morphometry (VBM) and region-of-interest-based volumetric analysis of the SI to further elucidate neuroanatomical substrates and the role of cholinergic structures.

    Patients and methods

    Subjects

    Of 277 non-demented PD patients who were recruited retrospectively from May 2008 to March 2012 at a university hospital, a total of 110 patients who completed both MR and comprehensive neuropsychological studies were enrolled in the present study. PD was diagnosed according to the clinical diagnostic criteria of the UK PD Society Brain Bank.16 The patients were classified into PD with VH (n=46) and PD without VH (n=64) groups, depending on the presence of VH. VH was defined as ‘repetitive involuntary images of people, animals, or objects that were experienced as real during the waking state, but for which there was no objective reality’17 using the caregiver-based structured interview of the Neuropsychiatric Inventory (NPI),18 which was administered by a trained neuropsychologist.

    We used the Seoul Neuropsychological Screening Battery (SNSB) to determine the cognitive performance of both groups.19 ,20 The SNSB includes cognitive subsets of attention (forward and backward digit span and letter-cancellation tests), language and related functions (reading, writing, comprehension, repetition, confrontational naming using the Korean version of the Boston Naming Test),21 visuospatial function (drawing an interlocking pentagon and the Rey Complex Figure Test (RCFT)), verbal memory (the Seoul Verbal Learning Test), visual memory (the RCFT; immediate recall, 20 min delayed recall and recognition) and frontal executive function (contrasting programme, go-no-go test, Luria loop, phonemic and semantic Controlled Oral Word Association Test, and stroop test). The Pentagon scoring system used in this study was a 6-point hierarchical scale, where 6 represented a perfect attempt and 1 was the worst.22 Age-, sex- and education-specific norms for each test based on 447 normal subjects are available. All patients with PD had scores of the Korean version of the Mini-Mental State Examination (K-MMSE) above the 16th percentile for the age- and education-appropriate norm, and no evidence of abnormal activities of daily living, judged clinically and by activities of daily living scale.23 Parkinsonian motor symptoms were assessed using the Unified PD Rating Scale Part III. Total medication dosages were calculated in levodopa equivalents. Patients having a history of offending drugs causing Parkinsonism (antipsychotics, gastrointestinal kinetics, antiepileptic drugs or L-type calcium channel blockers) were excluded. Odour identification was assessed with a cross-cultural smell identification test,24 which encompassed 12 pads that released odours when scratched; a high score indicated good olfactory performance.

    Exclusion criteria included evidence of dementia compatible with the clinical diagnostic criteria for probable PD dementia,25 presence of focal brain lesions on MRI or the presence of other neurodegenerative diseases that might account for Parkinsonism. Possible medical comorbidities were excluded by laboratory tests, including the thyroid function test, vitamin B12 and folic acid levels, and Venereal Disease Research Laboratory test. Healthy age- and gender-matched volunteers were used as controls for imaging analysis (n=25, age = 70.3±4.1 years). Controls were recruited by advertisements about the project, or were healthy relatives of patients with movement disorders or dementia. Control subjects had no active neurological disorders, no cognitive complaints and a minimum score of 28 on the K-MMSE. This study was approved by the Yonsei University Severance Hospital ethical standards committee on human experimentation for experiments using human subjects. Written informed consent was obtained from all subjects participating in this study.

    MRI acquisition

    All scans were acquired using a Philips 3.0-T scanner (Philips Intera; Philips Medical System, Best, The Netherlands) with a SENSE head coil (SENSE factor=2). A high-resolution T1-weighted MRI volume data set was obtained from all subjects using a 3D T1-TFE sequence configured with the following acquisition parameters: axial acquisition with a 224×256 matrix; 256×256 reconstructed matrix with 182 slices; 220 mm field of view; 0.98×0.98×1.2 mm3 voxels; TE, 4.6 ms; TR, 9.6 ms; flip angle, 8°; and slice gap, 0 mm.

    VBM of GM

    VBM was conducted using DARTEL26 in the SPM8 software (Institute of Neurology, University College London, UK). A group of GM templates was generated from controls and patients with PD to which all individual GM was spatially normalised. Spatially normalised GM maps were modulated by the Jacobian determinant of the deformation field to adjust volume changes during non-linear transformation. GM maps were smoothed using a 6-mm full-width at half-maximum isotropic Gaussian kernel. To obtain the intracerebral volume, segmentation of the normalised whole brain MR image into three compartments (GM, white matter and cerebrospinal fluid) was performed, and the intracerebral volume was represented by the sum of the GM, white matter and cerebrospinal fluid volumes. Regional volume differences were determined using a one-way analysis of variance at every voxel in the GM from PD patients and controls, where age, sex, intracerebral volume and K-MMSE score were included as covariates in the analysis of covariance. Age, sex, PD duration, intracerebral volume and K-MMSE score were also included as covariates in the analysis of covariance when analysing GM volume between PD patients with and without VH. Statistical significance was set at p<0.05, family-wise error-corrected, and at a more liberal threshold of uncorrected p<0.001 at the voxel level with a minimum cluster size of 100 voxels.

    Volumetric determination of SI

    The volumes of the SI were determined by manually delineating the boundaries of this structure with MRIcro software27 on the coronal T1-weighted MRI scans. The delineation of the SI on the MRI was based on the method reported previously.28 ,29 Briefly, with the first section at the level of the crossing of the anterior commissure, the ventral aspect of the globus pallidus demarcated the dorsal border of the SI, whereas the ventral border was the base of the brain containing the anterior perforated space. The medial border of the SI was operationally defined by a vertical line extending from the ventrolateral border of the stria terminalis to the base of the brain. The lateral border extended to the medial aspect of the putamen. In the second section traced, the anterior commissure might be uncrossed. The third section evaluated was at the level of the emergence of the anterior commissure from the temporal lobe. The anatomical landmarks used to define the borders of SI were applied to all three consecutive sections. The total SI volume calculated included both the right and left hemispheres. Normalised SI volume was defined by the following formula: total SI volume (mm3)/intracerebral volume (mm3) × 10 000. Tracings were performed blindly (by SS and LJE), and the intrarater and inter-rater reliability expressed as correlation coefficients were 0.87 and 0.81, respectively.

    Statistical analysis

    Data were expressed as the mean ± SD. The χ2 and independent t tests were used for categorical and continuous variables, respectively. Pearson's correlation analysis was used to evaluate the relationship between the SI volume and cognitive performance. Statistical analyses were performed using commercially available software (SPSS, V.18.0), and a two-tailed p<0.05 was considered significant.

    Results

    Demographic characteristics

    The demographic characteristics of the subjects are shown in table 1 and online supplementary table 1. No significant differences in age, sex, education level, cross-cultural smell identification scores, general cognitive deficits measured by the K-MMSE, the clinical dementia rating scale scores, disease duration, Unified PD Rating Scale Part motor scores, levodopa equivalent dosage, or use of dopamine agonist or anticholinergics were observed between PD patients with and without VH. The mean score of VH-item score in the NPI was higher in PD patients with VH than in those without VH. The detailed neuropsychological test results are shown in table 2 and online supplementary table 2. PD patients with VH showed more severe cognitive deficits in delayed visual memory (10.7 vs 7.7, p=0.012), go-no-go (16.4 vs 18.2, p=0.033) and the colour stroop (59.8 vs 71.9, p=0.026) tests compared with those without VH. The number of patients with abnormal score in letter cancellation test was slightly higher in PD patients with VH than in those without VH. Other subscores of the SNSB were not significantly different between PD patients with and without VH.

    View this table:
    Table 1

    Demographic characteristics between PD with and without VH

    View this table:
    Table 2

    Neuropsychological data between PD patients with and without VH

    GM analysis between PD patients with and without VH

    PD patients with VH had lower GM volume in the parahippocampal area and insular cortex compared with that in controls (p<0.05, FEW). Using a more liberal statistical threshold (uncorrected p<0.001), areas of lower GM volume in PD patients with VH relative to controls included the frontal, temporal, parietal, retrosplenial and cerebellar areas. However, area of lower GM volume in PD patients without VH relative to controls was restricted to the cerebellar areas (figure 1). The anatomical locations of the areas are listed in online supplementary table 3. In a direct comparison between PD patients with and without VH, PD patients with VH had significantly lower GM volume in right inferior frontal, the left temporal and thalamic areas compared with those without VH (figure 2). We found no area where PD patients without VH had more GM atrophy than those with VH. The anatomical locations of the areas are listed in table 3.

    Figure 1
    Figure 1

    Comparison of grey matter volume between Parkinson's disease (PD) patients and controls. Lower GM volume in PD patients without visual hallucination (VH) relative to controls was localised in the cerebellar areas, whereas the area of lower GM volume in PD patients with VH relative to controls was more extensive, involving the frontal, temporal, parietal, retrosplenial and cerebellar areas compared with that in controls. This figure is produced in colour in the online journal—please visit the website to view the colour figure.

    Figure 2
    Figure 2

    Comparison of grey matter volume between Parkinson's disease (PD) with and without visual hallucination (VH). PD patients with VH had significantly lower grey matter volume in right inferior frontal, left temporal and thalamic areas compared with those without VH. This figure is produced in colour in the online journal—please visit the website to view the colour figure.

    View this table:
    Table 3

    Anatomic location of areas showing significant difference in grey matter volume between PD patients with and without visual hallucination

    Comparison of SI volume between PD patients with and without VH

    No significant difference in total intracranial volume was found between PD patients with and without VH (table 1). The SI volume had a significant correlation with verbal memory functions of immediate (r=0.31, p=0.015) and delayed recall (r=0.29, p=0.018), semantic fluency (r=0.34, p=0.007) and go-no-go tests (r=0.30, p=0.016). When adjusting age and disease duration, the significant correlations remained unchanged. In a comparison of SI volume between two groups, PD patients with VH had a significantly smaller normalised SI volume than those without VH (1.28 ± 0.22 vs 1.41±0.25, p=0.005, figure 3).

    Figure 3
    Figure 3

    Comparison of substantia innominata (SI) volume between Parkinson's disease (PD) with and without visual hallucination (VH). The normalised SI volume was significantly decreased in PD patients with VH compared with those without VH.

    Discussion

    The pathogenesis of VH in PD seems to be complex in terms of anatomical, pathological and neurochemical substrates. The present study demonstrated that PD patients with VH had lower GM volume in the left temporal, right orbitofrontal and thalamic areas with a smaller volume of the SI than did those without VH. Additionally, PD patients with VH had lower cognitive performance scores in delayed visual memory and frontal executive functions compared with those without VH. These data suggest that non-demented PD patients with VH have distinctive neuroanatomical characteristics and neuropsychological profiles relative to those without VH.

    In terms of neuroanatomical substrates, both the posterior cortical area of parietal and lingual gyrus and the frontal areas play an important role in the development of VH in PD. In a VBM study, Ramirez-Ruiz et al 11 demonstrated that non-demented PD patients with VH showed lower GM volume in the left lingual gyrus and bilateral superior parietal lobe in comparison with those without VH, thus arguing the role of the posterior cortical areas involved visual information processing. In addition, Sanchez-Castaneda et al 5 reported that patients with VH in PD dementia or dementia with Lewy bodies (LB) showed significant GM volume loss in the inferior frontal or orbitofrontal area compared with those without VH. The pathogenic role of frontal and posterior cortical areas in VH is further supported by a functional MRI study, illustrating that PD patients with VH have greater activation in frontal and subcortical areas and less activation in posterior cortical areas in response to visual stimuli than do those without VH.7 ,8 In the present study, a direct comparative analysis of GM volume showed that PD patients with VH had more cortical atrophy involving the temporal areas extending into fusiform area and the frontal areas relative to those without VH. Together with previous studies, the present VBM result suggests that neuroanatomical basis of VH in non-demented PD seems to be more complex, encompassing both posterior cortical and frontal areas, where both alterations in the bottom-up visual processing of visual stimuli due to posterior cortical atrophy and impairments in the top-down visual processing due to the anterior cortical atrophy-associated attentional dysfunction may underlie the development of VH.

    LB pathology in the temporal or temporo-occipital area has been suggested as a pathological candidate for VH in LB diseases; Harding et al 30 demonstrated that well-formed VH are highly correlated with temporal lobe LB and Yamamoto et al 31 showed that LB pathology in the secondary visual pathway and the inferior temporal cortex may be the cause of visual stimulus-related cognition and visual misidentification. Additionally, a recent pathological study demonstrated that LB pathology and degeneration in the intralaminar thalamic nucleus is related to the presence of well-formed VH in LB diseases.32 Along with a dense projection to the striatum, the intralaminar nucleus projects to the anterior cingulate and prefrontal areas and, thus, involves cognitive performance related to attention, memory and awareness. Therefore, the present VBM results showing that PD patients with VH had lower GM volume in thalamic and temporal areas relative to those without VH are in accordance with the results of previous pathological studies.

    In the present study, we demonstrated for the first time that PD patients with VH have a significantly smaller SI volume compared with those without VH. The nucleus basalis of Meynert located in the SI of the basal forebrain is the major source of cholinergic input to the cerebral cortex, and degeneration of the basal forebrain may represent decline of cholinergic activity in the cerebral cortex.33 It has been noted that the VH in patients with LB disease is similar to those induced by muscarinic cholinergic receptor blockade,34 suggesting a cholinergic basis for the development of VH. A recent physiological study further supports the cholinergic role of VH, demonstrating that compared with non-demented PD patients without VH, those with VH had a significant reduction in short-latency afferent inhibition, a non-invasive technique that reflects cholinergic activity in the cerebral cortex.14 Furthermore, Janzen et al 35 reported reduced GM volume of the pedunculopontine region in PD patients with VH, suggesting that impaired cholinergic transmission to the thalamus may be involved in the development of VH. Generally, cholinergic inputs from the basal forebrain play a key role in attention, performance on frontal lobe-dependent tests and memory function through their connections with frontal or basolateral limbic areas.36 Of those, the cholinergic system has an important role in sustained attention through interaction with frontal lobe and thalamocortical processing, where acetylcholine regulates top-down control of attention in the parietal cortex by influencing orienting responses and in somatosensory areas by improving the signal to noise ratio and enhancing stimulus discrimination.37 Additionally, in vivo imaging studies indicate that the integrity of the cholinergic system is closely coupled with cognitive performance of patients with PD; Bohnen et al 38 demonstrated that cortical cholinergic activity has a significant correlation with attention and frontal executive function, and Choi et al 29 reported that hat SI volume is significantly correlated with attention, frontal executive function, memory, and visuoconstructional and object-naming performance. In this regard, our results indicate that attentional dysfunction and impaired cognitive performance secondary to cholinergic deficits may distort visual processing information in PD patients, thus leading to the development of VH. A further study using functional imaging with a cholinergic ligand is required to clarify the role of the cholinergic system in the development of VH.

    Neuropsychological studies have reported that non-demented PD patients with VH exhibit poorer performance in posterior cortex-associated cognitive functions, such as memory and visuospatial and visuoperceptive functions compared with those without VH.4 Additionally, frontal lobe-associated cognitive performance, such as verbal fluency, attention or executive functions, is also impaired in PD patients with VH.3–5 In longitudinal studies, PD patients with VH have shown a greater decline in both anterior and posterior cortical area-associated cognitive performance compared with those without VH, thus acting as a significant predictor of dementia in PD.6 ,39 In keeping with previous results, the present neuropsychological data indicate that non-demented PD patients with VH showed more severe cognitive deficits in visual memory and frontal executive functions compared with those without VH.

    The strengths and limitations of the present study need to be addressed. Compared with previous imaging studies, the present study included a relatively larger number of non-demented PD patients with VH, and analysed completely both imaging and neuropsychological data. Second, an uncorrected threshold used in the present study may not fully protect against results due to chance and thus the results may be prone to false positive. However, in previous VBM studies of patients with PD, the results rarely survived correction for multiple comparisons.40 Nevertheless, the significant clusters found in the present study may differ from previous results and need to be further validated. Third, the VH item of the NPI used in the present study is developed for demented patients and does not address the presence of minor hallucinations. Finally, the reduced SI volume in MR protocol measured in the present study does not reflect specifically and pathologically loss of cholinergic neuron in the nucleus basalis of Meynert. Therefore, the inference of a greater cholinergic deficit in PD patients with VH requires a close attention until functional neuroimaging can clarify the role of the cholinergic system in the development of VH.

    In summary, the present study showed that non-demented PD patients with VH exhibited a smaller volume in the frontal, temporal and thalamic areas as well as the SI with a lower cognitive performance in visual memory and frontal executive functions, suggesting that PD hallucinators might have distinctive neuroanatomical characteristics and neuropsychological profiles relative to PD non-hallucinators.

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    Supplementary materials

    • Supplementary Data

      This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

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    Footnotes

    • Funding This study was supported by Mid-career Researcher Program through NRF grant funded by the MEST (2010-0007749).

    • Competing interests None.

    • Patient consent Obtained.

    • Ethics approval This study was approved by the Yonsei University Severance Hospital ethical standards committee on human experimentation for experiments using human subjects.

    • Provenance and peer review Not commissioned; externally peer reviewed.