Hallucinations in Parkinsons Disease who is vulnerable and can neuropsychology improve prediction

1
Hallucinations in Parkinsons Disease who is
vulnerable and can neuropsychology improve
prediction ?

• D.L.Whitehead1, A.D.M. Davies2,4, C.J.
  Turnbull2,5, J.R. Playfer3
• MRC Centre for Neurodegeneration, Institute of
  Psychiatry, London1,
• Departments of Psychology2, and Geriatric
  Medicine3, University of Liverpool
• Mersey Care NHS Trust, Merseyside4,
• Department of Medicine for the Elderly, Arrowe
  Park Hospital, Wirral5

2
Parkinsons Disease not just a movement
disorder

• Loss of 80 of dopaminergic
• cells in basal ganglia
• Classic triad of motor symptoms
• Tremor
• Bradykinesia
• Rigidity
• Medication-related changes
• Fluctuations in effectiveness
• Off-period freezing
• On-period dyskinesias

Cognitive-perceptual- neuropsychiatric disorder
Movement Disorder

• Deficits in
• Executive function
• Visual and perceptual function
• Memory, attention
• Disorders of sleep and arousal
• due to brainstem dysfunction
• Neuropsychiatric
• Hallucinations and delusions
• Affective disorders
• Compulsive behaviours

3
Unusual perceptual experiences in Parkinsons
Disease

• Hallucination A sensory experience without
  apparent external stimulant (Berrios, 1984)
• Hallucinations typical of PD (Fenelon et al,
  2000)

Passage hallucinations - seeing something
passing-by oneself for a fleeting
moment Presence hallucinations - the feeling
that someone else is present in the
room Illusions - mistaking an object for an
animal or person Complex hallucinations -
seeing, hearing, feeling or smelling
something that is not really there
4
Examples of passage and presence illusions

• KM I kept seeing these ants on the carpet ...
  crawling about...When I was reading in the
  evening they were there, but I couldnt find
  them..... I put down powder, but they were still
  there of course!
• JM In the mornings I feel as though theres two
  of us. I cant phrase it very well ... as though
  were side by side, going up the stairs... Very
  peculiar it is !

5
Examples of visual illusions the role of real
stimuli

• Faces or figures seen in patterned upholstery
• A hanging basket as a mans head
• A vase of flowers as a poodle
• A parasol as an angel in a pointed hat
• A torch as a chap in a French policemans hat
• An umbrella as a ladies leg in high heels
• A cordless phone with a red light became a woman
  smoking a cigarette
• RH Oh ... shes the worst, Fag-Ash Lil ! ...
  Shes always lighting up at night. I tell her to
  put it (the cigarette) out, but she never listens
  ... I never did approve of women who smoke !

6
First generation studies

• Hallucinations in PD rarely reported before
  L-dopa (1960s)
• Early levodopa trials describe hallucinations,
  confusion, agitation and delirium (Celesia
  Barr, 1970)
• The kindling hypothesis
  hypersensitivity of dopamine receptors over time
• Model of a gradual decline into psychosis
• (Moskowitz et al, 1978)

Hallucinations with preserved insight
Sleep fragmentation Vivid dreams
Delirium and confusion
Psychosis
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Second generation studies findings

• Greater motor severity more disability, motor
  fluctuations, more rapid decline
• (Klein et al, 1997 Kraft et al, 1999, Fenelon et
  al, 2000)
• Cognitive decline in particular executive
  deficits, and MRI scan anomalies
• (Ramirez-Ruiz et al, 2004 Okada et al, 1998)
• Visual disturbance in particular poor contrast
  sensitivity, and colour perception
• (Buttner et al, 1996 Diederich et al, 1999)
• More sleep disruption in particular daytime
  sleepiness
• (Sanchez-Ramos et al, 1996 Fenelon et al,
  2000, Arnulf et al, 2000)

8
Psychosis - signal detection tests and
false positives - i.e. low threshold
for accepting signal as external
(Slade Rankin, 1985)
Hallucinations in the wider literature useful
models
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Psychosis - signal detection tests and
false positives - i.e. low threshold
for accepting signal as external
(Slade Rankin, 1985)Schizophrenia - negative
symptoms i.e. apathy, withdrawal and errors of
omission
Hallucinations in the wider literature useful
models
- positive symptoms i.e.
hallucinations, delusions and errors of
commission (Bentall, 1990 Frith, 1992
Brebion et al, 1997 1998 1999)
Errors of COMMISSION
Errors of OMISSION
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Psychosis - signal detection tests and
false positives - i.e. low threshold
for accepting signal as external
(Slade Rankin, 1985)Schizophrenia - negative
symptoms i.e. apathy, withdrawal and errors of
omission
Hallucinations in the wider literature useful
models
- positive symptoms i.e.
hallucinations, delusions and errors of
commission (Bentall, 1990 Frith, 1992
Brebion et al, 1997 1998 1999)
Dementia - visual hallucinations and visual
deficits - poor visual acuity, problems
with object recognition, clock drawing etc
(Chapman et al, 1999 Mori et al, 2000
Murgatroyd Prettyman, 2001)
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Hallucinations Third generation studies
Hallucinations Third generation studies

• Uses models of positive
• symptoms in psychosis
• Bias to attribute internal
• events to being external
• (Barnes et al, 2003)

Reality monitoring
The role of sleep

• Reduced bottom-up
• visual abilities (colour vision
• and contrast sensitivity)
• Disinhibits top-down
• processes
• effort after meaning
• (Diederich et al, 1999)

• Parallels with narcoleptic hallucinations
• Intrusion of REM activity into wake states
  measured by PSG
• (Arnulf et al, 2001 Manni et al, 2002)

Visual deficits
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Cognitive deficits in PD
MEMORY
ATTENTION
Recall
Vigilance
Recognition
Working memory
EXECUTIVE
Fluency
Set shifting
Planning
Perception
LANGUAGE
VISUOSPATIAL
Sentence comprehension
Construction
Word finding
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Dysexecutive syndrome ?
MEMORY
ATTENTION
Recall
Vigilance
Recognition
Working memory
EXECUTIVE
Fluency
Set shifting
Planning
Perception
LANGUAGE
VISUOSPATIAL
Sentence comprehension
Construction
Word finding
14
Executive deficits
MEMORY
ATTENTION
EXECUTIVE
Recall
Vigilance
Recognition
Working memory
Perception
LANGUAGE
VISUOSPATIAL
Sentence comprehension
Construction
Word finding
15
Mnemonic deficits
MEMORY
ATTENTION
Vigilance
Working memory
EXECUTIVE
Fluency
Set shifting
Planning
Perception
LANGUAGE
VISUOSPATIAL
Sentence comprehension
Construction
Word finding
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Attentional deficits
ATTENTION
MEMORY
3-6-9 3-1-7-4 1-8-5-2-4 2-4-7-3-9-1 REVERSE ?
Recall
Recognition
EXECUTIVE
Working memory
Fluency
Set shifting
Planning
Perception
LANGUAGE
VISUOSPATIAL
Sentence comprehension
Construction
Word finding
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Visuospatial deficits
MEMORY
ATTENTION
Recall
Vigilance
Recognition
Working memory
EXECUTIVE
Fluency
Set shifting
VISUOSPATIAL
Planning
LANGUAGE
Sentence comprehension
Word finding
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Language deficits
MEMORY
ATTENTION
Recall
Vigilance
Recognition
Working memory
EXECUTIVE
LANGUAGE
Fluency
Set shifting
Planning
The cook that is short pulls the box
TOTP
Perception
VISUOSPATIAL
Sentence comprehension
Word finding
Construction
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MEMORY
ATTENTION
Recall
Vigilance
Recognition
Working memory
EXECUTIVE
Fluency
Set shifting
Planning
Perception
LANGUAGE
VISUOSPATIAL
Sentence comprehension
Construction
Word finding
20
Neuropsychiatric symptoms
Compulsive behaviours
Delusions
MEMORY
ATTENTION
Recall
Vigilance
Recognition
Working memory
EXECUTIVE
Misidentification syndromes
Fluency
Set shifting
Apathy
Planning
Perception
LANGUAGE
VISUOSPATIAL
Sentence comprehension
Hallucinations
Construction
Word finding
Hypersexuality
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Study aims

• Seek correlates for hallucinations, independent
  of covariates
• Clinical
• Disease severity and global cognition
• Neuropsychological and perceptual profile
• Visual object perception and recognition
• Executive and attentional function
• Qualitative cognitive performance
• Cognitive errors intrusions and visual errors
• Compare the strength of the medical model and
  an integrated cognitive model

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How to quantify hallucinations ?

• Most studies use single item questions
• But Does not take severity into account
• Pilot study on 113 PD patients
• Range of sleep and hallucinatory symptoms by
  frequency
• Allowed examination of factor structure
• Factor analysis

- 3 sleep factors emerged - Daytime
sleepiness - Altered dream events - Sleep
activity - 4 UPE factors emerged
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Participants and Measures

• 77 patients diagnosed with idiopathic PD from
  across the North West were tested at home.

Neuropsychological variables Memory Logical
memory (WMS) Executive Verbal fluency
Trailmaking test Visual Visual Object battery
(VOSP) Overlapping figures Construction Block
Design (WAIS III R) Attention Computerised
divided / undivided attention test
Clinical Age, sex MMSE, Mill Hill Vocab,
NART Depression (GDS), anxiety (STAI) Disease
variables Disease and medication
duration Disease severity (UPDRS-III) Sleep
variables Sleep duration, maintenance,
Circadian rhythm (actigraphy) Daytime sleepiness
(ESS) Sleep activity Altered dream events
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VOSP subtests
Silhouettes task
Object decision task
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Overlapping figures
e.g. Poppelreuter
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Verbal tests
Logical memory test Story 1 Anna Thompson of
South London, employed as a cook at a school
canteen, reported at the police station that she
had been held up at the High Street the night
before and robbed of fifty-six pounds. She had
four small children, the rent was due and they
had not eaten for two days. The police, touched
by the womans story made up a collection for
her. Errors Recall inaccuracies Novel
intrusions Cross-trial intrusions
Verbal fluency test One minute per trial Single
letter - P Single category - Girls
names Alternating - D letter
M Alternating - Animals category
Furniture Alternating letter - Vegetables and
category B Errors Repetitions Perseverations
Intrusions
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Examples of cognitive errors

• Logical memory
• Recall inaccuracy
• Anna Simpson
• Novel intrusion
• She was shot on the High St
• The mugger was locked up
• They crossed over to the other side of the
  river
• Verbal fluency - intrusions
• P words
• ..penny, pool, paper, pencil,
• pen, eraser, ruler..
• Vegetables
• ..carrot, cabbage, potato,
• pepper, pomegranate,
• mango..

car seat
giraffe
tap
man with a gun
birdcage
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Results
Correlates of hallucinations included - Global
cognition (MMSE), NS trend for disease
severity - Daytime sleep, sleep activity and
altered dream events - Object recognition tests
(VOSP and overlapping figures) - Verbal
intrusions, visual misidentification Linear
regression model to predict hallucinations factor
score
29
Results
Correlates of hallucinations included - Global
cognition (MMSE), NS trend for disease
severity - Daytime sleep, sleep activity and
altered dream events - Object recognition tests
(VOSP and overlapping figures) - Verbal
intrusions, visual misidentification Linear
regression model to predict hallucinations factor
score
30
Results
Correlates of hallucinations included - Global
cognition (MMSE), NS trend for disease
severity - Daytime sleep, sleep activity and
altered dream events - Object recognition tests
(VOSP and overlapping figures) - Verbal
intrusions, visual misidentification Linear
regression model to predict hallucinations factor
score
31
Summary and Implications

• What kind of cognitive model do the data suggest
  ?
• Deficits in visual object recognition
• - Disinhibition of top-down visual deficits
• - Problems retrieving correct perceptual
  hypothesis
• Task-irrelevant intrusions
• - Saliency given to internally generated
  associations
• Excessive daytime sleepiness
• - Intrusion of dream narrative in waking
  state

• Neuropsychological tests valuable adjuncts in
  differentiating subtypes of PD
• Neuropsychological model (apathy, hallns,
  gambling)
• extension to other neuropsychiatric symptoms

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Practical management

• Improve lighting level or use nightlight
• Correct double vision using prism lenses
• But other visual problems remain
• Remove stimuli that feed hallucinations
• Antimacassars
• Highly patterned upholstery
• Cluttered objects

• Caregiver role
• Do not dispute the reality of the experience
• Provide emotional reassurance
• Provide distraction

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Thanks to

• Dr Christopher Turnbull
• Dr Jeremy Playfer
• Sue Woods
• Alison Monaghan
• Beverly Webster-Walsh

• Dr Ann Davies
• Dr Jon Cole
• Dr John Downes
• PDS branches Wirral, South and Central Liverpool

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Pathogenesis of PD motor and other symptoms I

• Loss of dopamine in striatum has upstream
  effects on ascending corticostriatal dopaminergic
  pathways
• Executive dysfunction results from loss of
  cortical dopaminergic input

35
Pathological basis of hallucinations?

• Source monitoring
• - external vs internal
• Prefrontal cortex
• - binding sensory contextual data
• - decision making about reality
• DLPFC implicated in source monitoring (Johnson et
  al, 2004, fMRI study)
• Response inhibition associated OFC (Gambling
  tasks and fMRI)

36
Pathogenesis of PD motor and other symptoms II

• Pathological hallmark of PD is LB in striatal
  pathway - PD as an a-synucleinopathy

37
Pathological basis of hallucinations?

• Problems integrating bottom-up and top-down
  visual processes
• Harding et al (2002) LB containing neurons in
  basolateral nucleus in hallucinators
• Halliday (2006) LB apoptosis
• increased activity

• Hypometabolism primary visual cortex
• Hypermetabolism amygdala, parahippocampus
• Amygdala integrates visual ventral stream and
  unconscious extrageniculostriate pathway

38
Flemingers three stage model of perception
(Fleminger, 1994)
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An integrated model hallucinations as false
perceptual hypotheses

• Problems selecting an appropriate perceptual
  hypothesis
• - Dream narrative, intrusion of default schemata
• Problems matching poor sensory data to hypothesis
• - Visual problems leading to reliance on
  top-down processes
• Problems with judging the validity of the
  hypothesis
• - Problems with internal/external attribution,
  and with executive decision making processes