Journal of Clinical Psychopharmacology

From aberrant salience to jumping to conclusions: dopaminergic pathways todelusions in Parkinson's disease

--Manuscript Draft--

Manuscript Number: JCP-D-12-00219R2

Full Title: From aberrant salience to jumping to conclusions: dopaminergic pathways todelusions in Parkinson's disease

Article Type: Editorial

Keywords: Dopamine agonists; Parkinson's disease; Aberrant Salience; Jumping ToConclusions; Delusion; Psychosis.

Corresponding Author: Michele Poletti, Psy.DUniversity of PisaPisa, ITALY

Corresponding Author SecondaryInformation:

Corresponding Author's Institution: University of Pisa

Corresponding Author's SecondaryInstitution:

First Author: Michele Poletti, Psy.D

First Author Secondary Information:

Order of Authors: Michele Poletti, Psy.D

Ubaldo Bonuccelli

Order of Authors Secondary Information:

Manuscript Region of Origin: ITALY

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Guest Editorial

From aberrant salience to jumping to conclusions:

dopaminergic pathways to delusions in Parkinson’s disease

Michele Poletti, Psy.D

Ubaldo Bonuccelli, M.D.

Department of Neuroscience, University of Pisa, Pisa, Italy

Competing interest:

Authors declare no competing interests.

*Correspondence to: Prof.UbaldoBonuccelli, Department of Neuroscience, University of Pisa, Via

Roma 67, Pisa, 56126, Italy.

Tel.: +39 050993334

Fax: + 39 050550563

E-mail: u.bonuccelli@med.unipi.it

Title Page

Dear Editor

We added suggested citations in the text and in the references, underlying prefrontal deficits may be

a common diathesis of ICD and delusions in medicated PD patients. We also added more details for

reference 5, with DOI, that has been now published on MDS website as early view.

Best regards

Dr. Michele Poletti

Prof. Ubaldo Bonuccelli

Department of Neuroscience, UNIPI, Pisa, Italy

*Cover Letter

Guest Editorial

From aberrant salience to jumping to conclusions:

dopaminergic pathways to delusions in Parkinson’s disease

Psychotic symptoms are frequently reported in longitudinal studies on patients with Parkinson‟s

disease (PD).1

Hallucinations are the most common psychotic symptom in PD, especially in

advanced stages of disease, with an estimated cumulative lifetime prevalence of 40%-60%,2 and

disease-related factors play an important role in their pathophysiology in this clinical population.2

Although delusions are less common in PD patients and often represent a deterioration of

hallucinations,2 isolated delusions have been recently described in cognitively preserved PD

patients3

and recent empirical findings,4,5

here presented and integrated, permit to shed light on their

pathophysiology.

Conditions for delusion development

Studies on schizophrenic patients suggested that psychotic states are associated with an altered

striatal dopamine signaling system,6 reflecting in altered expected values and prediction error

abnormalities.7 Indeed Kapur

8 suggested that psychotic states may derive from an alteration of the

dopamine-based process of salience attribution. Dopamine mediates the conversion of the neural

representations of environmental stimuli from a neutral and cold bit of information into an attractive

or aversive entity: in particular the mesolimbic dopamine system is seen as a critical component of

the “attribution of salience”, a process whereby events and thoughts come to grab attention, drive

action and influence behaviour because of their association with reward or punishment.8 In this

account, delusions may arise from seemingly plausible top-down cognitive explanations that

individuals come up with to understand these experiences of aberrant salience of stimuli.8 The

*Manuscript

formulation of such cognitive explanations provides the patient with an “insight relief” or a

“psychotic relief” and becomes a guiding cognitive scheme for subsequent thoughts and actions.

Furthermore, in a reverberating loop, these explanations will make the patients look for further

confirmatory evidence for previous delusional accounts.2 Therefore two conditions could be, at

least, necessary for the development of delusions: 1) a state of aberrant salience attribution,

associated with a dysregulated striatal dopamine signaling system; 2) abnormal top-down cognitive

explanations attributed to subjective experiences of aberrant salience.

Aberrant salience attribution

Interestingly, a recent study of Nagy and colleagues4 suggested that the first condition is probably

present in medicated PD patients and that the non-physiological tonic dopaminergic stimulation

associated with the dopamine-agonist therapy may play a crucial role in the formation of delusions.

In this study, newly diagnosed drug-naïve PD patients and matched healthy controls were assessed

on a speeded reaction time task in which the probe stimulus was preceded by conditioned stimuli

that could signal monetary reward by color or shape. PD patients and controls were re-evaluated

after 12 weeks during which the patients received a dopamine agonist. Results indicated that

dopamine agonists increased both adaptive and aberrant salience in PD patients, that is, formation

of real and illusory associations between conditioned stimuli and reward, respectively. This effect

was present when associations were assessed by means of faster responding after conditioned

stimuli signaling reward (implicit salience) and overt rating of stimulus-reward links (explicit

salience). However, unusual feelings and experiences, which are subclinical manifestations of

psychotic-like symptoms, were specifically related to irrelevant and illusory stimulus-reward

associations (aberrant salience) in PD patients receiving dopamine agonists. The learning of

relevant and real stimulus-reward associations (adaptive salience) was not related to unusual

experiences. For authors these results suggested that dopamine agonists may rapidly increase

psychotic-like experiences in PD patients, possibly by facilitating dopaminergic transmission in the

ventral striatum, which results in aberrant associations between conditioned stimuli and reward.

A further confirmation of the psychotic risk associated with dopamine agonists came from a very

recent cross-sectional study5 in which we investigated delusional jealousy in 805 consecutive PD

patients. Delusional jealousy was identified in 20 patients (prevalence 2.48%) and in multivariate

logistic regression analyses dopamine agonists were significantly associated with delusional

jealousy, independently of the presence of dementia. Any other psychopharmacological treatment

was associated with delusional jealousy and 5 nondemented patients developed delusional jealousy

after a relatively short period of monotherapy with dopamine agonists (2.3 ± 1.4 years).

Overall, while showing that dopamine agonists may induce a state of aberrant salience attribution

and represent a risk factor for the development of delusions, these studies4,5

provided preliminary

empirical evidence that the first condition for the development of delusion (i.e. a state of aberrant

salience attribution associated with a dysregulated dopamine system) is probably satisfied in PD

patients ”on” dopamine agonist therapy.

Jumping to conclusions

Further studies are needed to investigate in PD patients other different factors that may contribute to

the second condition for the development of delusions, i.e. distorted top-down cognitive

explanations given to subjective experiences of aberrant salience. Although a recent study

suggested that the presence of cognitive difficulties and of depressive symptoms may represent a

risk factor for the development of psychotic features in PD patients,3 these factors cannot fully

explain the formation of delusions in cognitively preserved patients after few years of therapy.

Empirical findings of a very recent study of Djamshidian and colleagues10

for the first time

suggested that clinical characteristics associated with the second condition of delusion development,

i.e. abnormal cognitive explanations attributed to subjective experiences of aberrant salience, are

present in medicated PD patients. Indeed, studies in non-PD delusional patients reported that

delusions are associated with at least state-dependent atypical thinking characteristics or biases

related to probabilistic reasoning and data gathering (a tendency to early acceptance and, to a lesser

extent, the early rejection of hypotheses: i.e. “Jumping To Conclusions”, JTC) and impaired Theory

of Mind, i.e. the ability to represent others‟ mental states.9 These cognitive characteristics may play

a role in delusion development facilitating 1) an early acceptance of delusional interpretations of

experiences of aberrant salience and 2) a misinterpretation of others‟ intentions, as in paranoid

delusions. While altered mentalizing abilities have been already described in PD11

other cognitive

characteristics have not been investigated before the study of Djamshidian and colleagues.10

Authors adopted for the first time a measure of “JTC” (the Bead task) in PD patients with and

without impulse control disorders (ICD), matched with non-PD pathological gamblers, substance

abusers and healthy controls. In the Bead task participants are told that beads will be drawn from

one of two jars. The jars contain beads of two different colors, in complementary ratios, for

example, 85:15 red to green, versus 85:15 green to red. Participants are shown the beads supposedly

being drawn from the jar, the selection of which is actually predetermined, and are required to guess

from which jar they are being drawn. Delusional patients usually show a JTC tendency, as they

make a guess about the jar more quickly, or with greater certainty, than controls.9

In the discussed study,10

both PD subgroups (with and without ICD) showed a JTC bias, more

marked in the ICD subgroup, guessing more quickly about the jar in comparison to healthy controls.

JTC bias represents a “reflection impulsivity”, and although its relationship with behavioral

measures or self-report questionnaires on impulsivity deserves further studies,12

it could be

hypothesized that dopamine agonists, while enhancing cognitive impulsivity in PD,13

may play a

role also in JTC of PD patients. However, while considering the JTC was more marked in patients

with ICD, that were currently less treated with dopamine agonists (13 out of 26 patients) in

comparison to patients without ICD (21 out of 27 patients) it could be hypothesized that probably

also idiosyncratic premorbid characteristics (as elevated baseline impulsivity) and disease-related

factors,12

as executive dysfunction, play a role in JTC of PD patients. Indeed a recent lesion study14

reported that impaired JTC is associated with executive dysfunction, that is a common cognitive

hallmark of PD patients,15

in particular of those with ICD.12,16

Thus, although, further studies are needed to clarify how drug-related and disease-related factors interact

and play a role in the JTC bias of PD patients, this empirical finding demonstrated that cognitive

characteristics associated with the second condition for delusion development, are present in medicated PD

patients.

Supporting the possible role of JTC bias, present in PD patients and more marked in those with

ICD, also in delusion development, in our cross-sectional study on delusional jealousy in PD,4 we

found 7 patients that presented both ICD and delusions and a recent psychometric study17

found that

PD patients with ICD present also increased schizotipy (a condition clinically close to psychosis),

as assessed with the Oxford-Liverpool Inventory of Feeling and Experiences, in comparison to PD

patients without ICD and to healthy controls. Therefore both delusions and ICD could be

considered within the same spectrum of non-motor behavioral symptoms of cognitively preserved

PD patients, and caused by the interaction between individual factors, disease-related factors

(mainly prefrontal executive impairment) and the dopamine agonist therapy.

Conclusions

Medicated PD patients present clinical characteristics associated with both conditions of delusion

development: altered striatal dopaminergic system and cognitive bias (JTC). These characteristics

may play a pivotal role in delusion development inducing experiences of aberrant salience and

biasing data gathering through an early acceptance of their delusional interpretations. While drug-

related factors (mainly dopamine agonists) play a pivotal role in the aberrant salience attribution,

further studies are needed to clarify how drug-related and disease-related factors interplay in JTC

and therefore in the early acceptance of delusional interpretations of experiences of aberrant

salience.

References

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Psychiatry 2012;83;76-82.

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aberrant salience in Parkinson‟s disease. Neuropsychopharmacology 2012;37:950-958.

5. Poletti M, Perugi G, Logi C, et al. Dopamine agonists and delusion of jealousy in

Parkinson‟s disease: a cross-sectional prevalence study. Mov Disord. Epub ahead of Print 13

November; DOI: 10.1002/mds.25129

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