Prefrontal cortex, dopamine, and jealousy endophenotype

CNS Spectrums http://journals.cambridge.org/CNS Additional services for CNS Spectrums: Email alerts: Click here Subscriptions: Click here Commercial reprints: Click here Terms of use : Click here

Prefrontal cortex, dopamine, and jealousy endophenotype Donatella Marazziti, Michele Poletti, Liliana Dell'Osso, Stefano Baroni and Ubaldo Bonuccelli CNS Spectrums / FirstView Article / January 2013, pp 1 ­ 9 DOI: 10.1017/S1092852912000740, Published online: 30 November 2012

Link to this article: http://journals.cambridge.org/abstract_S1092852912000740 How to cite this article: Donatella Marazziti, Michele Poletti, Liliana Dell'Osso, Stefano Baroni and Ubaldo Bonuccelli Prefrontal cortex, dopamine,  and jealousy endophenotype. CNS Spectrums, Available on CJO 2012 doi:10.1017/S1092852912000740 Request Permissions : Click here

Downloaded from http://journals.cambridge.org/CNS, IP address: 195.62.185.251 on 07 Jan 2013

REVIEW

CNS Spectrums, page 1 of 9. & Cambridge University Press 2012 doi:10.1017/S1092852912000740

Prefrontal cortex, dopamine, and jealousy endophenotype Donatella Marazziti,1* Michele Poletti,2 Liliana Dell’Osso,1 Stefano Baroni,1 and Ubaldo Bonuccelli2 1 2

Department of Psychiatry, Neurobiology, Pharmacology, and Biotechnology, University of Pisa, Pisa, Italy Department of Neuroscience, University of Pisa, Pisa, Italy

Jealousy is a complex emotion characterized by the perception of a threat of loss of something that the person values, particularly in reference to a relationship with a loved one, which includes affective, cognitive, and behavioral components. Neural systems and cognitive processes underlying jealousy are relatively unclear, and only a few neuroimaging studies have investigated them. The current article discusses recent empirical findings on delusional jealousy, which is the most severe form of this feeling, in neurodegenerative diseases. After reviewing empirical findings on neurological and psychiatric disorders with delusional jealousy, and after considering its high prevalence in patients with Parkinson’s disease under dopamine agonist treatment, we propose a core neural network and core cognitive processes at the basis of (delusional) jealousy, characterizing this symptom as possible endophenotype. In any case, empirical investigation of the neural bases of jealousy is just beginning, and further studies are strongly needed to elucidate the biological roots of this complex emotion. Received 3 August 2012; Accepted 17 October 2012 Keywords: Default mode network, delusion, dopamine, endophenotype, jealousy, Research Domain Criteria, reward processing, theory of mind social bonds, ventromedial prefrontal cortex.

Introduction Jealousy is a complex emotion involving the perception of a threat of loss of something that the person values, which includes affective, cognitive, and behavioral components.1,2 Although different items, people, or conditions may be the object of jealousy, sexual jealousy is the most typical form, involving the perception of a threat of loss of a valued relationship to a real or imagined rival, and is the focus of the present article. Jealousy is rarely considered to be a primary emotion, since it requires certain types of social relationships, for instance some triadic conflicts, to be fully expressed.3 The primary feelings experienced when facing the potential loss of a social relationship, as triggered by the conviction of a spouse or loved one’s infidelity, range widely among different people, from anxiety or anger to sorrow.4 According to the affective neuroscience perspective of Panksepp,5 jealousy is bound to take on a larger variety of affective dynamics than is generated by any single one of the various emotional primes that can be aroused during jealousy.3 From the evolutionary perspective,6 the peculiar function of jealousy is to warn that the sexual partner is potentially desirable and attractive, can betray the *Address for correspondence: Donatella Marazziti, MD, Dipartimento di Psichiatria, Neurobiologia, Farmacologia e Biotecnologie, University of Pisa, Via Roma 67, 56100 Pisa, Italy. (Email: [email protected])

other, and strangers can jeopardize the stability of the couple, which is fundamental for the rearing of children, as they require specific care for a long time before they become mature and can survive on their own. According to this perspective, jealousy would be a primary emotion,7,8 as Sokoloff9 suggested in 1947, when he said, ‘‘Jealousy is not only inbred in human nature, but it is the most basic, all-pervasive emotion which touches man in all aspects of every human relationship.’’ Jealousy has long attracted the interest of both psychiatrists and psychologists, but only recently has it became the focus of neuroscientific investigation.3 In spite of its universality and the severity of some of its forms,10 jealousy is totally absent as a specific entity in the American classification system of psychiatric disorders (DSM-IV-TR); it is, however, hidden in other diagnostic categories, such as depression, obsessivecompulsive disorder, or paranoia.8 Therefore, while considering the recent emphasis on dimensional approaches of core psychiatric symptoms rather than on disorders (eg, the Research Domain Criteria (RDoC) project of the National Institute of Mental Health),11 it should be debated if jealousy itself could be considered a symptom endophenotype5,12 across distinct nosological categories, as recently proposed for the impulsivity/compulsivity dimension13 or for social cognitive deficits.14,15 The current article aims to provide a step forward in the understanding of the neural and cognitive bases of

2

D. Marazziti et al.

this complex affective symptom, while presenting and discussing recent empirical findings on the most severe form of jealousy, delusional jealousy. Jealousy Jealousy is a heterogeneous and common condition ranging from normality to pathology, with different degrees of intensity, persistence, and degrees of insight. Several studies, carried out in different countries, have underlined that jealousy is present everywhere, and what differs from one society to another is the level of jealousy considered ‘‘normal.’’ A recent study in Italy reported that at least 10% of healthy subjects are excessively affected by jealous thoughts.10 If the recognition of pathological jealousy, at least in its most severe (eg, paranoid) forms, is relatively easy, setting boundaries for the so-called normal jealousy is an elusive, if not impossible, task.16,17 In psychological terms, the distinction between reactive jealousy and suspicious jealousy18 could be useful to better understand the development of delusional jealousy. Reactive jealousy is triggered by a real transgression, in particular a sexual affair impairing some critical aspect of the relationship, such as its exclusivity. Alternatively, suspicious jealousy occurs with no betrayal or other significant event, and it is triggered by minor or unspecific cues.18 Reactive and suspicious jealousy are mainly associated with distinct antecedents: reactive jealousy is more closely related to characteristics of the relationship with the partner, whereas suspicious jealousy is more closely related to characteristics of the individual who is experiencing the jealous feelings, such as insecurity or low self-esteem.4 Reactive jealousy is generally characterized by anger, fear, and sadness,18 while suspicious jealousy is characterized by high levels of anxiety, doubts, suspiciousness, and insecurity. In subjects presenting suspicious jealousy, the intensity of worries and anxiety about the partner’s behavior is excessive; in the absence of real clues, complex cognitive constructions are triggered by neutral clues and lead the subject to search for infidelity and constantly monitor the partner’s behavior. Suspicious jealousy often results in interpreting the partner’s behavior in a way that is biased toward perceiving ambiguous events as more threatening to the romantic relationship than objective information would indicate.18 Delusional jealousy In its delusional form, also defined as Othello’s syndrome, jealousy is characterized by a range of irrational thoughts, focused on the certainty of the partner’s sexual unfaithfulness based on unfounded evidence, which may lead to extremely aggressive

behaviors, such as stalking, suicide, and murder.19 Delusional jealousy is a clinical phenomenon at the interface between psychiatry and neurology,19 if we consider that it has been frequently described in psychiatric disorders,20 such as schizophrenia21 and alcoholism,22 and in neurological disorders, such as stroke and neurodegeneration.23,24 Interestingly, in a recent cross-sectional study,25 20 patients with Parkinson’s disease (PD) were reported to develop delusional jealousy that resulted independent of the presence of dementia and was significantly associated with dopamine agonist therapy. Furthermore, in a subgroup of 5 cognitively preserved PD patients, delusional jealousy appeared after a relatively short period of treatment with dopamine agonists (2.3 ± 1.2 years). The trigger of delusions by dopamine agonists may be due to their ability to induce states of aberrant salience attribution,26 a phenomenon that is hypothesized to be at the basis of delusion development in schizophrenia.27 The mesolimbic striatal dopamine signaling system is involved in the conversion of neural representations of environmental stimuli from a neutral and cold bit of information into an attractive or aversive entity; therefore it is a critical component of the ‘‘attribution of salience,’’27 a process whereby events and thoughts come to grab attention, drive action, and influence behavior because of their association with reward or punishment. When an altered dopaminergic system produces an aberrant attribution of salience to external stimuli, neutral and fortuitous events gain attention and importance, and become meaningful. Delusions may thus derive from seemingly plausible top-down cognitive explanations that some individuals attribute to these experiences of aberrant salience of stimuli in order to understand them. Once the patients complete such an explanation, an ‘‘insight or psychotic relief’’ occurs that serves as a guiding cognitive scheme for further thoughts and actions. Moreover, it may lead the subjects to search for further confirmatory evidence to support delusional explanations.27 This mechanism could suggest that the nonphysiological tonic dopaminergic stimulation associated with the dopamine-agonist therapy, which is able to induce an aberrant salience attribution,27 may play a crucial role in the development of delusions in medicated PD patients. In the clinical practice of a referral outpatients’ center for movement disorders, delusional jealousy appears as one of the most common types of delusions in medicated PD patients; not surprisingly, besides our cross-sectional study,25 delusional jealousy has been frequently reported in PD,24,28,29 while other types of delusions have been reported only seldom in this clinical population.30 While supposing that dopamine agonists increase the risk of developing delusions by

Brain and jealousy inducing an aberrant salience attribution process,26,27 why are jealousy delusions over-represented in PD patients, comparison with other types of delusions? Furthermore, while considering that jealous thoughts are less common in delusions of psychiatric patients,31 why is delusional jealousy over-represented in comparison with other types of content-specific delusions in patients with neurodegenerative diseases?23,24 The answer to these questions is important for two reasons. From a theoretical point of view, it could suggest further clues on the neuroanatomical and neurochemical basis of jealousy, and from the clinical point of view, it could help to prevent or to better manage jealousy and its pathological forms, such as delusional jealousy. Neural bases of jealousy, love, and sexual desire A starting point is perhaps to look at the neural bases of jealousy. Unfortunately, the neurochemical and neuroanatomical bases of jealousy have been poorly investigated by neuroscience.3 One study reported that obsessive jealousy is associated with a specific abnormality of the platelet serotonin transporter,32 while suggesting a role of the serotonergic system at least in obsessional jealousy. A functional magnetic resonance imaging (fMRI) study33 with a behavioral task involving jealousy-arousing scenarios reported that men and women recruit different brain networks in the experience of jealousy. In men, jealousy mostly involves activation of the visual cortex, limbic systems, and related structures (amygdala, hippocampal regions, and hypothalamus) and of somatic and visceral areas (eg, insula). In women, the activation is recorded in the so-called mentalizing network (posterior temporal sulcus and angular gyrus) and in the visual cortex, in the middle frontal gyrus, thalamus, and cerebellum. Overall, these fMRI findings highlighted that jealousy is associated with the recruitment of brain areas mediating mentalizing, basic emotions, and somatic and visceral experience. An electroencephalography (EEG) study34 with a behavioral game task evoking jealousy reported a greater left prefrontal activation while subjects experienced that feeling. Taken as a whole, these findings suggest that jealousy recruits a pattern of cortical and subcortical structures and is modulated by monoaminergic systems. These findings are corroborated by those emerging from a lesion study35 reporting that the mentalizing network, including the ventromedial prefrontal cortex (vmPFC), plays a fundamental role in mediating the understanding of complex social emotions such as envy and gloating. Jealousy, like envy and gloating, involves a process of social comparison with potential competitors: Jealousy is characterized by the fear of losing a loved

3

one to another person; envy is characterized by the wish to possess what another person has or his/her or success, and/or the wish that the other person did not possess the desired characteristic or object; gloating is characterized by the pleasure associated with undesirable events happening to another person. Furthermore, while considering the strong relationship between love and jealousy, the investigation of neural bases of the experience of being in love could also help us to better understand the neural bases of jealousy. An increasing number of neuroimaging studies have explored the brain activations of individuals experiencing love.36–40 These studies, which have been recently reviewed,41,42 highlight the role of the reward-related striatal dopamine signaling system for motivating individuals in pair bonding, and that the experience of love also involves the activation of higher cognitive processes, such as social cognition and bodily self-representation.41 Although these studies provide intriguing results, they also present significant limitations, such as the choice of loveevoking tasks and selection bias based on gender, duration of love affair, and cultural differences.42 It is interesting to underline that the dopaminergic system also plays a major role in sexual arousal and sexual performance.43 Not surprisingly, neuroimaging studies have shown that sex drive and love are regulated by many overlapping regions.44 Authors of a recent review of fMRI studies on sexual desire and love suggest that one may consider sexual desire and love on a spectrum that evolves from integrative representations of affective visceral sensations (mainly associated with insula activation) to an ultimate representation of feelings incorporating mechanisms of reward expectancy and habit learning (mainly associated with the frontostriatal dopaminergic system).45 Parkinson’s disease, frontostriatal circuits, and delusional jealousy The analysis of dysfunctional neural networks in PD patients and the effects of dopaminergic drugs on them, in relation to neural networks associated with feeling jealousy, could permit us to better understand the phenomenon of delusional jealousy in this clinical population. In the early clinical stages of PD, the functioning of the ‘‘dorsolateral’’ frontostriatal circuit (linking the dorsal striatum and the dorsolateral portions of the prefrontal cortex), which mediates executive control functions, is impaired by striatal dopamine depletion and, therefore, is restored by dopaminergic drugs, such as levodopa and dopamine agonists.46,47 At the same time, the functioning of the ‘‘orbital’’ frontostriatal circuit (linking the ventral striatum with medial

4

D. Marazziti et al.

portions of the prefrontal cortex), which mediates reward processing, is preserved and therefore overdosed by dopaminergic drugs.46,47 Dopaminergic drugs interfere with reward processing by facilitating dopaminergic bursts and hampering dopaminergic dips, and this interference should be stronger for tonicacting dopamine agonists in comparison to phasic-acting levodopa.48 While considering the role of the dopaminergic system in love and sexual desire,45 the increased dopaminergic stimulation of the orbital frontostriatal circuit facilitates the evaluation of stimuli as positive rewards, but may also produce an aberrant salience given to the relationship with the loved one, and consequently also an increased fear of losing this relationship. Furthermore, basal ganglia and their connections with the prefrontal cortex (PFC) play a major role in habit formation,49 and preliminary empirical evidence suggests that the nonphysiological stimulation of dopaminergic drugs may interfere with habit formation in PD patients50; thus we must investigate whether dopaminergic drugs may facilitate a progressive transformation of jealousy into a ‘‘habit’’ associated with a shift of neural control from ventromedial striatum-PFC circuits to dorsolateral striatum-PFC circuits.49 In addition to drug-related risk factors, PD patients present other risk factors for suspicious jealousy, because they can experience altered affective status,51 low perceived quality of life,52 and sexual dysfunctions.53 To summarize, the development of delusional jealousy in PD is probably due to the complex interaction of different risk factors, such as premorbid idiosyncratic personality factors (low or high levels of jealousy), affective factors (depression, anxiety, low perceived quality of life), disease-related physical effects (ie, sexual dysfunction), and dopamine agonist side effects (delusion proneness and aberrant salience of social bonds, especially for the relationship with the partner). Discussion The study of PD patients has highlighted the possible major role of the orbital frontostriatal circuit in the clinical phenomenon of delusional jealousy. While the ventral striatum is mainly involved in reward processing,46,47 the ventromedial prefrontal cortex (vmPFC) is involved in many other high-order cognitive and affective functions, as recently proposed in a new conceptual framework by Roy et al.54 At least three of the proposed high-order functions of vmPFC-based neural networks could be involved in the experience of jealousy, and therefore in its delusional expression (Figures 1–3). A framework for vmPFC functions The first network includes the vmPFC, ventral striatum and pallidum, amygdala, ventral tegmental

First Network: Reward Processing

VMPFC

ventral striatum

insula

- Joy - Affective value of social bonds - Rewarding salience of the partner Figure 1. Neural network of reward processing, involved in the processing of the affective value of the social bond and of the rewarding salience of the partner. VMPFC5ventromedial prefrontal cortex.

area, periaqueductal gray (PAG), and parts of the insula and lateral PFC. This neural network is involved in reward processing, emotion processing, and autonomic/endocrine responses, globally providing the generation of affective value (Figure 1).54 The second and the third vmPFC-based neural networks both include neural structures of the default mode network (DMN)55 (ie, a set of brain regions that becomes engaged when individuals are resting, compared with when they are engaged in a goal-directed task). The DMN core includes the cortical midline and is connected to two distinct DMN subsystems—one mainly including the medial temporal lobe (MTL) and involved in the act of simulating the future by using mnemonic imagery-based processes, and the other mainly encompassing the temporo-parietal junction, lateral temporal cortex, and temporal pole, which is preferentially activated when participants reflect on their present mental states or infer others’ mental states (ie, ToM tasks). The second neural network includes the anterior and dorsal portion of the vmPFC, the posterior cingulate cortex (PCC), and the MTL subsystem of the DMN, and is involved in constructing internal models of the world based on mnemonic information, and in using them to prospect future scenarios (Figure 2).54 The third neural network is based on the second DMN subsystem and on cortical and subcortical structures that are also part of the first neural network (ie, ventral striatum and pallidum, amygdala, ventral tegmental area, PAG, and

Brain and jealousy Second Network: Memories allow Imagining the Future

VMPFC

5

information—from sensory systems, interoceptive cues and long-term memory, into a gestalt representation of how an organism is situated in the environment, which then drives predictions about future events: authors conclude their theoretical review suggesting that a straightforward term for such process is affective meaning (p 153).54 Neural and cognitive bases of (delusional) jealousy

medial temporal lobe network - Imagining future partner scenarios - Bonding or loss Figure 2. Neural network of future imagination, which is involved in the construction of future partner scenarios of bonding or loss.

Third Network: Self Reflection and Empathy

VMPFC

mentalizing subsystem

ventral striatum

- Evaluating one’s own behaviors, thoughts and feelings - Evaluating partner’s behaviors, thoughts and feelings Figure 3. Neural network of self-reflection, empathy, and mentalizing, which is involved in the processing of mentalizing one’s own and the partner’s behaviors, thoughts, and feelings.

parts of the insula and lateral PFC): This neural network is engaged when subjects must refer to their own mental states (self-reflection) or of others (theory of mind and empathy) (Figure 3).54 The interaction of these neural networks and related functions allows vmPFC to link situational appraisals to specific patterns of behavioral and autonomic response elicited by the particular context. Therefore, Roy et al concluded that: the main function of vmPFC probably regards the infusion of conceptual information into the generation of affective responses: this critical process is one of combining elemental units of

Analysis of vmPFC-based high-order functions,54 fMRI findings on normal jealousy,33 and frontostriatal circuitry in PD46,47 suggests a core of neural and cognitive/affective correlates of jealousy, particularly of its delusional expression, which will be examined herein (Figures 4–7). Frontostriatal circuits, vmPFC, and insula would be mainly involved in the evaluation of the rewarding nature of the social bonds and in the representation of associated emotions and somatic sensations, globally providing an affective meaning to the relationship with the partner. The mentalizing network would play a role in representing behaviors, thoughts, and feelings of the loved one, and in selfrelated processes related to his/her possible loss. The construction of internal models of the relationship with the partner and imagination of future scenarios followed by its potential loss would be modulated by a MTL subsystem of the DMN. As it is involved in all these neural networks, the vmPFC therefore probably plays a key role in the integration of these affective and conceptual responses that are activated during the jealousy experience; moreover, further investigation must be done regarding whether frontostriatal circuits play a role in the progressive consolidation of jealousy as a ‘‘habit,’’49 and how alterations of dopaminergic connections may interfere with this process. The identification of a core of neural and cognitive/ affective bases of jealousy suggests how this feeling may become delusional thoughts: alterations of the dopamine signaling system could cause an aberrant salience given to social bonds, especially to the relationship with the partner (Figure 4). Alterations of the MTL subsystem of the DMN could cause an aberrant construction scenario related to the potential loss of the partner (Figure 5). Finally, alterations of the mentalizing network could cause aberrant representations of behaviors, thoughts, and feelings of the loved one, and aberrant constructions of self-related process related to his/her possible loss (Figure 6). Delusional jealousy probably arises when at least three conditions are present simultaneously: (1) an aberrant salience given to the relationship with the loved one; (2) aberrant representations of the partner’s behaviors, thoughts, and feelings; and (3) aberrant scenarios related to the potential loss of the relationship (Figure 7).

6

D. Marazziti et al. Development of Othello’s Syndrome Part 1:

Development of Othello’s Syndrome Part 3:

First Network: Reward Processing with Abnormal Partner Salience

Third Network: Misinterpretation of Partner and Catastrophizing

VMPFC ventral striatum DA

VMPFC partner & relationship overly reinforcing/ addicting

control seek reassurance restrict mentalizing subsystem

ventral striatum DA

insula - Aberrant scenario related to partner loss Figure 4. First process involved in the development of delusional jealousy, with an attribution of aberrant salience to the partner. DA5dopamine.

Figure 6. Third process involved in the development of delusional jealousy, with misinterpretations of partner’s behaviors, thoughts, and feelings and consequent catastrophizing tendency.

Development of Othello’s Syndrome Part 2: Second Network: Aberrant Interpretations of Partner VMPFC

he/she loves me

he/she does not love me

medial temporal lobe network - Partner behavior, thoughts and feelings imagined as loss

Figure 5. Second process involved in the development of delusional jealousy, with an aberrant construction of future scenarios of loss of partner.

The universality of jealousy, which is present at different degrees in each subject,10 may explain why this feeling is a symptom described in psychotic, mood, anxiety, and personality disorders.8,20 Moreover, the proposed neural and cognitive correlates may also provide an explanation of the evidence that its delusional form is common in different psychiatric disorders, such as schizophrenia21 and alcoholism,22 and in different neurological disorders, such neurodegenerative diseases (Alzheimer’s disease, behavioral variant of frontotemporal dementia, PD, and Lewybody dementia).24 All these disorders share, at different degrees of impairment, neural alterations of at least the dopamine striatal signaling system56–60 and the vmPFC,61–65 and cognitive alterations of at least reward processing66–68 and mentalizing.69–71 In summary,

these shared alterations should confirm that, although jealousy is a common feeling, delusional jealousy may arise only with the combination of aberrant salience given to the relationship with the loved one and aberrant representations of the partner’s behaviors, thoughts, and feelings. Jealousy as symptom endophenotype or RDoC construct Recent dimensional approaches to psychiatry disorders11 attempt to characterize them as clusters of core symptoms (or symptom endophenotype), which are more easily linked to brain and genetic processes. Within this clinical and empirical perspective, therefore, there is a decreased concern that some endophenotypes may be found in several distinct nosological categories by reducing the need for abused concepts, such as that of comorbidity.12 For example, impulsivity and compulsivity have been proposed as symptom endophenotypes, presenting comorbidities and commonalities across a range of disorders (attention deficit/hyperactivity disorder, substance dependence, obsessive-compulsive, and eating disorder), and are associated with dysfunctions of frontostriatal loops.13 The RDoC project11 proposed a two-dimensional matrix with ‘‘constructs’’ (dimensions of observable behavior and neurobiological measures, regarding brain organization and functioning) that can be described at different levels of analysis (genes, molecules, cells, circuits, physiology, behavior, self-reports, and paradigms). The proposed description of core neural and cognitive bases of jealousy and of its delusional

Brain and jealousy

7

Pathological Jealousy: Putting it All Together

need to prevent loss

mentalizing subsystem

might lose partner

VMPFC

bad emotional output

insula

medial temporal lobe network

jealousy

partner overly valued

ventral striatum DA

DLPFC

habit addiction

dorsal striatum

Figure 7. The whole process hypothesized at the basis of (delusional) jealousy development. The shift form ventral to dorsal striatum and related prefrontal connections may be involved in the progressive transformation of a jealousy behavior into a habit. This model may explain the development of jealousy and also of delusional jealousy if core neural bases are altered and core cognitive/affective functions aberrant, as reported in many psychiatric (schizophrenia and alcoholism) and neurodegenerative diseases (Alzheimer’s disease, frontotemporal dementia, Parkinson’s disease, and Lewy body dementia). DLPFC5dorsolateral prefrontal cortex.

expression, present in distinct neuropsychiatric disorders, therefore, could characterize jealousy as a symptom endophenotype, or a ‘‘construct’’ in the RDoC matrix.

5.

6.

Conclusions In conclusion, a convergent amount of data from neuroimaging and from psychiatric and neurological disorders has confirmed the role of dopaminergic frontostriatal circuits, vmPFC and insula, and related functions of reward processing, mentalizing, and self-related processing in the feeling of jealousy and in its delusional form. However, the studies of neural bases of jealousy are just at their beginning, and further investigations are strongly needed to elucidate the biological roots of this emotion that still represents a great mystery of human nature.

7. 8.

9. 10.

11.

References 1. 2. 3.

4.

Van Sommers P. Jealousy. London: Penguin; 1988. Mullen PE. Jealousy: the pathology of passion. Br J Psychiatry. 1991; 158: 593–601. Panksepp J. The evolutionary sources of jealousy: crossspecies approaches to fundamental issues. In: Hart SL, Legerstee M, Eds. Handbook of Jealousy: Theory, Research and Multidisciplinary Approaches. West Suzzex, UK: Blackwell Publishing; 2010, pp 101–120. Parrott WG. The emotional experiences of envy and jealousy. In: Salovey P, ed. The Psychology of Jealousy and Envy. New York: Guilford; 1991: 3–30.

12.

13.

14.

Panksepp J. Neurologizing the psychology of affects: how appraisal-based constructivism and basic-emotion theory can coexist. Perspect Psychol Sci. 2007; 2(3): 281–296. Hart SL, Legerstee M, eds. Handbook of Jealousy: Theory, Research and Multidisciplinary Approaches. West Sussex, UK: Blackwell Publishing; 2010. Buss DM. The Dangerous Passion: Why Jealousy Is as Necessary as Love and Sex. New York: Free Press; 2000. Marazziti D. E Vissero Sempre Gelosi e Contenti: Come Trasformare un Sentimento Negativo nella Chiave della Felicita`. Milan, Italy: Rizzoli Editore; 2008. Sokoloff B. Jealousy: A Psychological Study. New York: Howell Soskin; 1947. Marazziti D, Sbrana A, Rucci P, et al. Heterogeneity of the jealousy phenomenon in the general population: an Italian study. CNS Spectr. 2010; 15(1): 19–24. Morris SE, Cuthbert BN. Research Domain Criteria: cognitive systems, neural circuits and dimensions of behaviour. Dialogues Clin Neurosci. 2012; 14(1): 29–37. Panksepp J. Emotional endophenotypes in evolutionary psychiatry. Prog Neuropsychopharmacol Biol Psychiatry. 2006; 30(5): 774–784. Robbins TW, Gillan CM, Smith DG, et al. Neurocognitive endophenotypes of impulsivity and compulsivity: towards dimensional psychiatry. Trends Cogn Sci. 2012; 16(1): 81–91. Zucker NL, Losh M, Bulik CM, et al. Anorexia nervosa and autism spectrum disorders: guided investigation of social cognitive endophenotypes. Psychol Bull. 2007; 133(6): 976–1006.

8

D. Marazziti et al.

15.

Derntl B, Habel U. Deficits in social cognition: a marker for psychiatric disorders? Eur Arch Psychiatry Clin Neurosci. 2011; 261(S2): S145–S149. Tarrier N, Beckett R, Harwood S, et al. Morbid jealousy: a review and cognitive behavioral formulation. Br J Psychiatry. 1990; 157: 319–326. Kingham M, Gordon H. Aspects of morbid jealousy. Advances in Psychiatric Treatment. 2004; 10: 207–215. Rydell RJ, Bringle RG. Differentiating reactive and suspicious jealousy. Soc Behav Pers. 2007; 35(8): 1099–1114. Camicioli R. Othello syndrome: at the interface of neurology and psychiatry. Nat Rev Neurol. 2011; 7(9): 477–478. Soyka M, Schmidt P. Prevalence of delusional jealousy in psychiatric disorders. J Forensic Sci. 2011; 56(2): 450–452. Soyka M. Prevalence of delusional jealousy in schizophrenia. Psychopathology. 1995; 28(2): 118–120. Michael A, Mirza S, Mirza KA, et al. Morbid jealousy in alcoholism. Br J Psychiatry. 1995; 167(5): 668–672. Ortigue S, Bianchi-Demicheli F. Intention, false beliefs, and delusional jealousy: insights into the right hemisphere from neurological patients and neuroimaging studies. Med Sci Monit. 2011; 17(1): RA1–11. Graff-Radford J, Whitwell JL, Geda YE, et al. Clinical and imaging features of Othello’s syndrome. Eur J Neurol. 2012; 19(1): 38–46. Poletti M, Perugi G, Logi G , et al. Dopamine agonists and delusion of jealousy in Parkinson’s disease: a crosssectional prevalence study. Mov Disord. DOI: 10.1002/ mds 250129. Nagy H, Levy-Gigi E, Somlaiu Z, et al. The effect of dopamine agonists on adaptive and aberrant salience in Parkinson’s disease. Neuropsychopharmacology. 2012; 37(4): 950–958. Kapur S. Psychosis as a state of aberrant salience: a framework linking biology, phenomenology and pharmacology in schizophrenia. Am J Psychiatry. 2003; 160(1): 13–23. Cannas A, Solla P, Floris G, et al. Othello syndrome in Parkinson’s disease patients without dementia. Neurologist. 2009; 15(1): 34–36. Graff-Radford J, Ahlskog JE, Bower JH, et al. Dopamine agonists and Othello’s syndrome. Parkinsonism Relat Disord. 2010; 16(10): 680–682. Stefanis N, Bozi M, Christodoulou C, et al. Isolated delusional syndrome in Parkinson’s disease. Parkinsonism Relat Disord. 2010; 16(8): 550–552. Appelbaum PS, Clark Robbins P, Roth LH, et al. Dimensional approach to delusions: comparison across types and diagnoses. Am J Psychiatry. 1999; 156(12): 1938–1943. Marazziti D, Akiskal HS, Rossi A, et al. Alteration of the platelet serotonin transporter in romantic love. Psychol Med. 1999; 29(3): 741–755. Takahashi H, Matsumara M, Yahata H, et al. Men and women show distinct brain activations during imagery of sexual and emotional infidelity. Neuroimage. 2006; 32(3): 1299–1307.

16.

17. 18.

19.

20.

21. 22. 23.

24.

25.

26.

27.

28.

29.

30.

31.

32.

33.

34.

35.

36. 37.

38.

39.

40.

41.

42.

43.

44.

45.

46.

47.

48.

49. 50.

51.

52.

Harmon-Jones E, Peterson CK, Harris CR. Jealousy: novel methods and neural correlates. Emotion. 2009; 9(1): 113–117. Shamay-Tsoory SG, Tibi-Elhanany Y, Aharon-Peretz J. The green-eyed monster and malicious joy: the neuroanatomical bases of envy and gloating (schadenfreude). Brain. 2007; 130(6): 1663–1678. Bartels A, Zeki S. The neural correlates of maternal and romantic love. Neuroimage. 2004; 21(3): 1155–1166. Aron A, Fisher H, Mashek DJ, et al. Reward, motivation and emotion systems associated with early stage intense romantic love. J Neurophysiol. 2005; 94(1): 327–337. Fisher H, Aron A, Brown LL. Romantic love: an fMRI study of a neural mechanism for mate choice. J Comp Neurol. 2005; 493(1): 58–62. Beauregard M, Courtemanche J, Paquette V, et al. The neural basis of unconditioned love. Psychiatry Res. 2009; 172(2): 93–98. Xu X, Aron A, Brown L, et al. Reward and motivation systems: a brain mapping study of early-stage intense romantic love in Chinese participants. Hum Brain Mapp. 2011; 32(2): 249–257. Ortigue S, Bianchi-Demicheli F, Patel N, et al. Neuroimaging of love: fMRI meta-analysis evidence toward new perspectives in sexual medicine. J Sex Med. 2010; 7(11): 3541–3552. De Boer A, van Buel EM, Ter Horst GJ. Love is more than just a kiss: a neurobiological perspective on love and affection. Neuroscience. 2012; 201: 114–124. Heaton JP. Central neuropharmacological agents and mechanisms in erectile dysfunction: the role of dopamine. Neurosci Biobehav Rev. 2000; 24(5): 561–569. Fisher HF, Aron A, Brown LL. Romantic love: a mammalian brain system for mate choice. Philos Trans R Soc Lond B Biol Sci. 2006; 361(1476): 2173–2186. Cacioppo S, Bianchi-Demicheli F, Fru C, et al. The common neural bases between sexual desire and love: a multilevel kernel density fMRI analysis. J Sex Med. 2012; 9(4): 1048–1054. Cools R. Dopaminergic modulation of cognitive function-implications for L-DOPA treatment in Parkinson’s disease. Neurosci Biobehav Rev. 2006; 30(1): 1–23. Poletti M, Bonuccelli U. Orbital and ventromedial prefrontal cortex functioning in Parkinson’s disease: neuropsychological evidence. Brain Cogn. 2012; 79(1): 23–33. Frank MJ, Seeberger LC, O’Reilly RC. By carrot or by stick: cognitive reinforcement learning in parkinsonism. Science. 2004; 306(5703): 1940–1943. Yin HH, Knowlton BJ. The role of the basal ganglia in habit formation. Nat Rev Neurosci. 2006; 7(6): 464–476. Marzinzik F, Wotka J, Wahl M, et al. Modulation of habit formation by levodopa in Parkinson’s disease. PloS One. 2011; 6(11): e27695. Aarsland D, Marsh L, Schrag A. Neuropsychiatric symptoms in Parkinson’s disease. Mov Disord. 2009; 24(15): 2175–2186. Knipe MD, Wickremaratchi MM, Wyatt-Haines E, et al. Quality of life in young- compared with late-onset Parkinson’s disease. Mov Disord. 2011; 26(11): 2011–2018.

Brain and jealousy 53.

54.

55.

56.

57.

58.

59.

60.

61.

62.

Bronner G. Sexual problems in Parkinson’s disease: the multidimensional nature of the problem and of the intervention. J Neurol Sci. 2011; 310(1–2): 139–143. Roy M, Shohamy D, Wager TD. Ventromedial prefrontal subcortical systems and the generation of affective meaning. Trends Cogn Sci. 2012; 16(3): 147–156. Andrews-Hanna JR, Reidler JS, Sepulcre J, et al. Functional-anatomic fractionation of the brain’s default network. Neuron. 2010; 65(4): 550–562. Howes OD, Kambeitz J, Kim E, et al. The nature of dopamine dysfunction in schizophrenia and what this means for treatment: meta-analysis of imaging studies. Arch Gen Psychiatry. 2012; 69(8): 776–786. Hendler RA, Ramachandani VA, Gilman J, et al. Stimulant and sedative effects of alcohol. Curr Top Behav Neurosci. 2013; 13: 489–509. Rinne JO, Laine M, Kaasinen V, et al. Striatal dopamine transporter and extrapyramidal symptoms in frontotemporal dementia. Neurology. 2002; 58(10): 1489–1493. Reeves S, Brown R, Howard R, et al. Increased striatal dopamine (D2/D3) receptor availability and delusions in Alzheimer’s disease. Neurology. 2009; 72(6): 528–534. Klein JC, Eggers C, Kalbe E, et al. Neurotransmitter changes in dementia with Lewy bodies and Parkinson disease dementia in vivo. Neurology. 2010; 74(11): 885–892. Pomarol-Clotet E, Canales-Rodriguez EJ, Salvador R, et al. Medial prefrontal cortex pathology in schizophrenia as revealed by convergent findings from multimodal imaging. Mol Psychiatry. 2010; 15(8): 823–830. Moselhy HF, Georgiou G, Kahn A. Frontal lobe changes in alcoholism: a review of the literature. Alcohol Alcohol. 2001; 36(5): 357–368.

63.

64.

65.

66.

67.

68.

69.

70.

71.

9

Hornberger M, Geng J, Hodges JR. Convergent grey and white matter evidence or orbitofrontal cortex changes related to disinhibition in behavioral variant frontotemporal dementia. Brain. 2011; 134(9): 2502–2512. Harvood DG, Sultzer DL, Feil D, et al. Frontal lobe hypometabolism and impaired insight in Alzheimer’s disease. Am J Geriatr Psychiatry. 2005; 13(11): 934–941. Perneczky R, Drzezga A, Boecker H, et al. Right prefrontal hypometabolism predicts delusions in dementia with Lewy bodies. Neurobiol Aging. 2009; 30(9): 1420–1429. Gradin VB, Kumar P, Waiter G, et al. Expected value and prediction error abnormalities in depression and schizophrenia. Brain. 2011; 134(6): 1751–1764. Beck A, Schlagenhauf F, Wustenberg T, et al. Ventral striatal activation during reward anticipation correlates with impulsivity in alcoholics. Biol Psychiatry. 2009; 66(8): 734–742. Gleichgerrcht E, Ibanez A, Roca M, et al. Decision making cognition in neurodegenerative diseases. Nat Rev Neurol. 2010; 6(11): 611–623. Shamay-Tsoory SG, Aharon-Peretz J, Levkovitz Y. The neuroanatomical basis of affective mentalizing in schizophrenia: comparison of patients with schizophrenia and patients with localized prefrontal lesions. Schizophr Res. 2007; 90(1–3): 274–283. Gizewski ER, Muller BW, Scherbaum N, et al. The impact of alcohol dependence on social brain function. Addict Biol. 2012; Epub ahead of print 17 Feb. DOI: 10.1111/J 1369-1600.2012 00932. Poletti M, Enrici I, Adenzato M. Cognitive and affective Theory of Mind in neurodegenerative diseases: neuropsychological, neuroanatomical and neurochemical levels. Neurosci Biobehav Rev. 2012; 36(9): 2147–2164.