R E VI E W

Emotional Dysfunctions in Neurodegenerative Diseases Leonie A.K. L€offler,1* Sina Radke,1,2 Carmen Morawetz,3 and Birgit Derntl1,2,4 1

Department of Psychiatry, Psychotherapy and Psychosomatics, Medical Faculty, RWTH Aachen, 52074 Aachen, Germany JARA—Translational Brain Medicine, 52074, Aachen, Germany 3 Department of Education and Psychology, Freie Universit€at Berlin, 14195 Berlin, Germany 4 Institute for Neuroscience and Medicine (INM-1), Research Center J€ulich, 52425 J€ulich, Germany 2

ABSTRACT Neurodegenerative diseases are characterized primarily by motor signs but are also accompanied by emotional disturbances. Because of the limited knowledge about these dysfunctions, this Review provides an overview of emotional competencies in Huntington’s disease (HD), Parkinson’s disease (PD), and multiple sclerosis (MS), with a focus on emotion recognition, emotion regulation, and depression. Most studies indicate facial emotion recognition deficits in HD and PD, whereas data for MS are inconsistent. On a neural level, dysfunctions of amygdala and striatum, among others, have been

linked to these impairments. These dysfunctions also tap brain regions that are part of the emotion regulation network, suggesting problems in this competency, too. Research points to dysfunctional emotion regulation in MS, whereas findings for PD and HD are missing. The high prevalence of depression in all three disorders emphasizes the need for effective therapies. Research on emotional disturbances might improve treatment, thereby increasing patients’ and caregivers’ well-being. J. Comp. Neurol. 524:1727–1743, 2016. C 2015 Wiley Periodicals, Inc. V

INDEXING TERMS: Huntington’s disease; Parkinson’s disease; multiple sclerosis; emotion recognition; emotion regulation; depression

Neurodegenerative disorders are very debilitating diseases and can progress until death (Estrada-Sanchez and Rebec, 2013). They are characterized primarily by motor signs but can also entail emotional disturbances such as anxiety, irritability, or depression (Rickards, 2005; Novak and Tabrizi, 2010; Rosti-Otaj€arvi and H€am€al€ainen, 2013). For example, although Parkinson’s disease (PD) is most well known for bradykinesia, rigidity, tremor, and/or postural instability (Jankovic, 2008), many of these patients also suffer from affective disturbances, and up to 35% are affected by clinically significant depression (Reijnders et al., 2008). Notably, our knowledge about emotional dysfunction in these patients is quite limited. Although regulating (distressing) emotions is crucial for mental health (Gross and Mu~ noz, 1995; Gross, 1998; John and Gross, 2004; Eftekhari et al., 2009), only a few studies have addressed that issue in neurodegenerative diseases, and the findings point to dysfunctional emotion regulation processes (Harel et al., 2007, for multiple sclerosis; MS). Although little is known about the regulation of emotions in these patients, several studies indicate impairC 2015 Wiley Periodicals, Inc. V

ments in (facial) emotion recognition, a competency needed for emotion regulation and successful social interaction (Gray and Tickle-Degnen, 2010; Henley et al., 2012; Cecchetto et al., 2014). Because of the disabling nature of emotional dysfunctions in neurodegenerative diseases, it seems mandatory to investigate and characterize them further. The current Review seeks to provide a topical overview of emotional dysfunctions in three neurodegenerative disorders, Huntington’s disease (HD), PD, and MS. In all of these disorders, emotional disturbances have been frequently reported. HD is an autosomal dominant neurodegenerative disease caused by an extended repetition of the CAG

Grant sponsor: RWTH Aachen PhD scholarship (to L.A.K.L.); Grant sponsor: JARA-BRAIN (to S.R., B.D.). *CORRESPONDENCE TO: Leonie A.K. L€ offler, Department of Psychiatry, Psychotherapy and Psychosomatics, Medical Faculty, RWTH Aachen, Pauwelsstr. 30, 52074 Aachen, Germany. E-mail: [email protected] Received January 30, 2015; Revised May 6, 2015; Accepted May 18, 2015. DOI 10.1002/cne.23816 Published online June 5, 2015 in Wiley (wileyonlinelibrary.com)

Online

The Journal of Comparative Neurology | Research in Systems Neuroscience 524:1727–1743 (2016)

Library

1727

L.A.K. L€offler et al.

triplet in the huntingtin gene on chromosome 4 (Walker, 2007), resulting in striatal degeneration and atrophy in extended brain areas (Walker, 2007; Dogan et al., 2013). In Western countries, approximately six individuals per 100,000 are affected by HD (Pringsheim et al., 2012). Once the first motor signs arise and the disease becomes manifest, the disease progresses over 15–20 years until death (Estrada-Sanchez and Rebec, 2013). Core symptoms of HD are motor, cognitive, metabolic, and emotional symptoms (e.g., depression, irritability, apathy, obsessive-compulsive symptoms; Novak and Tabrizi, 2010). Parkinson’s disease (PD) is, after Alzheimer’s disease, the second most common neurodegenerative disorder and affects approximately 0.3% of the population in industrialized countries (De Lau and Breteler, 2006). The hallmark of PD is a selective loss of dopaminegenerating neurons in the pars compacta region of the substantia nigra, resulting in denervation of the striatum (Tessitore et al., 2002). Apart from motor signs, patients with PD suffer from autonomic dysfunctions, cognitive impairments, and emotional symptoms (e.g., apathy, depression, anxiety; Jankovic, 2008). Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease marked by multiple regions of axonal demyelination in the brain as well as the spinal cord (Compston and Coles, 2008). Approximately 2–2.5 million people worldwide suffer from MS, with an uneven distribution depending on the country (Milo and Kahana, 2010). In addition to common motor signs such as muscle stiffness, patients with MS often report cognitive and emotional impairments (e.g., depression, apathy, euphoria, aggression; Rosti-Otaj€arvi and H€am€al€ainen, 2013). The following sections summarize the current literature on emotional dysfunctions in HD, PD, and MS. Given that emotional dysfunctions cover a wide range of impairments, this Review is confined to emotion recognition, emotion regulation, depressive symptoms, and treatment of these (see Fig. 1). Studies included in the Review were identified by the first author (L.A.K.L.) through searches in PubMed, PsycINFO, and Google Scholar in December, 2014. The key words Huntington, Parkinson, and multiple sclerosis were entered in combination with emotion recognition, emotion/affect/mood regulation, fMRI, or imaging. Only full-text and Englishlanguage articles focusing on human adults were included. Imaging studies were restricted to (functional, diffusion-weighted) magnetic resonance imaging (MRI), positron emission tomography (PET), and transcranial sonography. We included articles published between 1980 and 2014, with a focus on the most recent publications. Because of the wide range of topics covered, a topical rather than a systematic Review was written.

1728

Figure 1. Neurodegenerative diseases, such as Huntington’s disease (HD), Parkinson’s disease (PD), and multiple sclerosis (MS), are associated not only with motor signs but also with emotional dysfunctions. These dysfunctions might comprise emotion recognition deficits, dysfunctional emotion regulation, and depression.

EMOTION RECOGNITION For details on all disorders see Tables 1, 2

Huntington’s disease Recognition of emotional expressions is typically investigated by using pictures or videos of emotional faces. In patients with HD, deficits in emotion recognition (for review see Henley et al., 2012) are already present in the premanifest stage, i.e., prior to the onset of motor signs. Whereas some studies point toward a specific deficit in recognizing facial disgust (Gray et al., 1997; Hennenlotter et al., 2004), others reveal a general impairment in recognizing negative emotions (Johnson et al., 2007; Labuschagne et al., 2013; Rees et al., 2014). However, intact emotion recognition competencies in premanifest HD have also been reported (Novak et al., 2012; Van Asselen et al., 2012), which might be due to variability in disease severity or gene dosage. As the disease progresses to a manifest stage (i.e., when motor signs become apparent), emotion recognition deficits become more pronounced and extend to other negative emotions (e.g., disgust, fear, and anger; Henley et al., 2012; Van Asselen et al., 2012; Trinkler et al., 2013; Croft et al., 2014) and to other modalities such as prosody (Calder et al., 2010; Robotham et al., 2011). With regard to the recognition of happy faces, findings remain inconsistent, with some studies reporting deficient happiness recognition in manifest HD (Calder et al., 2010; Labuschagne et al., 2013) and others showing no impairments (Van Asselen et al., 2012; Croft et al., 2014).

The Journal of Comparative Neurology | Research in Systems Neuroscience

Premanifest HD 115 (63 F) 41.25 years Manifest HD 113 (61 F) 49.2 years Premanifest HD 16 (12 F) 43.8 years

Labuschagne et al. (2013)

Novak et al. (2012)

Premanifest HD 464 (292 F) 41.43 years

Premanifest HD 17 (—) 38.53 years Premanifest HD 9 (4 F) 37.4 years Manifest HD 18 (8 F) 51.9 years

Manifest HD 11 (3 F) 56.82 years Manifest HD 14 (6 F) 43.9 years

Manifest HD 21 (9 F) 50.38 years

Johnson et al. (2007)

Ille et al. (2011)

Hennenlotter et al. (2004)

Gray et al. (1997)

Dogan et al. (2014)5

Croft et al. (2014)

Huntington’s disease Calder et al. (2010)

Study

Population No. of patients Age (mean)

Anger Disgust Happiness

Six basic emotions

Identify emotion

Identify emotion

Six basic emotions

Identify emotion

Six basic emotions

Six basic emotions

Rate emotion6

Identify emotion

Six basic emotions

Identify emotion

Identify emotion

Identify emotion

Anger Disgust Happiness Anger Disgust Fear Sadness Happiness Six basic emotions

Six basic emotions (Vocalizations)

Identify emotion

Identify emotion

Six basic emotions

Included emotions2

Identify emotion4

Task

TABLE 1. Overview of Included Studies Investigating Emotion Recognition1

None

Anger Disgust Fear7 Sadness Anger Disgust Fear Sadness Anger Fear Surprise All

Disgust

Disgust

Anger Disgust Fear Sadness

Anger Disgust Fear Anger Disgust

All

Impaired emotions3

Emotions in neurodegenerative diseases

The Journal of Comparative Neurology | Research in Systems Neuroscience

1729

1730

The Journal of Comparative Neurology | Research in Systems Neuroscience

Premanifest 16 (14 F) 36.2 years Manifest 9 (0 F) 48.8 years

Van Asselen et al. (2012)

Hipp et al. (2014)

Herrera et al. (2011)

Buxton et al. (2013)

Parkinson’s disease Baggio et al. (2012)

Idiopathic PD 30 (10 F) 66.97 years PD 40 (14 F) 69.62 years Idiopathic PD 28 (15 F) 62.49 years

PD 39 (12 F) 64.5 years

Manifest 13 (6 F) 54.1 years Mixed HD 239 (109 F) 44.65 years

Trinkler et al. (2013)

Scahill et al. (2013)

Manifest 14 (6 F) 51.29 years

Robotham et al. (2011)

Study Rees et al. (2014)

Population No. of patients Age (mean) Manifest HD 15 (12 F) 52.29 years Six basic emotions (Vocalizations) Achievement Amusement Pleasure Anger Disgust Fear Sadness (Vocalizations) Six basic emotions

Identify emotion

Identify emotion

Identify emotion

Categorize emotion (not specified)

Identify emotion

Six basic emotions

Six basic emotions

Six basic emotions

Six basic emotions

Six basic emotions

Identify emotion

Identify emotion

Anger Disgust Fear Sadness Six basic emotions

Not specified

Identify emotion

Identify emotion

Included emotions2 Six basic emotions

Task Identify emotion

TABLE 1. Continued

Sadness

Deficit (not specified)

Anger Disgust Fear Sadness All

Anger Disgust Fear Sadness

None

Disgust Fear Sadness Deficit (not specified)

Impaired emotions3 Anger Disgust Fear8 Disgust Fear Achievement Pleasure Anger Fear

L.A.K. L€offler et al.

Krause et al. (2009)5

Jehna et al. (2011)5

Jehna et al. (2010)

Henry et al. (2009)

Cecchetto et al. (2014)

Multiple sclerosis Beatty et al. (1989)

MS 27 (18 F) 47.0 years CIS and mixed MS 20 (13 F) 36.4 years RMMS 15 (10 F) 29.5 years Mixed MS 22 (18 F) 39.5 years

CPMS 21 (—) 52.0 years RMMS 30 (21 F) 34.2 years

PD 24 (12 F) 63.83 years Idiopathic PD 18 (5 F) 62.9 years

Saenz et al. (2013)

Wieser et al. (2012)

PD 23 (9 F) 62.8 years

Narme et al. (2013)

Study Ibarretxe-Bilbao et al. (2009)

Population No. of patients Age (mean) PD 24 (8 F) 56.13 years

Six basic emotions

Identify emotion Discriminate emotion10

Match emotion11

Anger Disgust Fear Anger Fear Sadness

Anger Fear Sadness Happiness (Bodily expressions) Six basic emotions

Identify emotion

Identify emotion

Six basic emotions

Six basic emotions

Fear Sadness Anger Disgust Happiness Fear Sadness Happiness Six basic emotions

Included emotions2 Six basic emotions

Identify emotion

Identify emotion

Identify emotion

Identify emotion

Identify emotion

Task Identify emotion

TABLE 1. Continued

Anger Fear Sadness

None

None

Anger Fear

All9

All

All

None

Fear Sadness

Impaired emotions3 Anger Disgust Fear Sadness Surprise Fear Sadness

Emotions in neurodegenerative diseases

The Journal of Comparative Neurology | Research in Systems Neuroscience

1731

1732

RMMS 12 (7 F) 29.3 years Mixed MS 32 (28 F) 44.0 years Mixed MS 56 (32 F) 38.95 years Mixed MS 35 (23 F) 48.2 years Identify emotion

Identify emotion

Identify emotion

Match emotion

Task

Six basic emotions

Six basic emotions

Included emotions2 Happiness Anger Fear Sadness Six basic emotions

Fear Sadness Anger Surprise

None

Deficit (not specified)

None

Impaired emotions3

For simplicity, reviews are not included in the table. The indicated age of the patients might deviate slightly in the original sample. CIS, clinically isolated syndrome suggestive of MS; CPMS, chronic progressive MS; F, female; fMRI, functional magnetic resonance imaging; HD, Huntington’s disease; MS, multiple sclerosis; PD, Parkinson’s disease; RMMS, relapsing-remitting MS. 2 Facial emotions if not otherwise stated. 3 Patients compared with healthy controls. 4 Identify emotion: Individuals had to choose the right label for the emotion presented. 5 Emotion recognition task performed during fMRI. 6 Rate emotion: Individuals had to indicate how intensively the depicted person experienced the six basic emotions. 7 Patients and controls differed in intensity ratings but not classification accuracy of this emotion. 8 Patients were impaired only for pictures not for video clips of this emotion. 9 Only in patients with a high disability score. 10 Discriminate emotion: Individuals had to decide whether two presented faces showed the same emotion. 11 Match emotion: Individuals had to match a simultaneously presented target emotion to one of several other emotions.

1

Prochnow et al. (2011)

Pinto et al. (2012)

Phillips et al. (2011)

Passamonti et al. (2009)5

Study

Population No. of patients Age (mean)

TABLE 1. Continued

L.A.K. L€offler et al.

The Journal of Comparative Neurology | Research in Systems Neuroscience

Ibarretxe-Bilbao et al. (2009)

Baggio et al. (2012)

Parkinson’s disease Anders et al. (2012)

Scahill et al. (2013)

Novak et al. (2012)

Ille et al. (2011)

Hobbs et al. (2011)

Hennenlotter et al. (2004)

Huntington’s disease Dogan et al. (2014)

Study

PD 24 (8 F) 56.13 years

Asymptomatic Parkin mutation carriers 8 (4 F) 44.5 years PD 39 (12 F) 63.5 years

Mixed 239 (109 F) 44.65 years

Premanifest 9 (4 F) 37.4 years Mixed 60 (27 F) 43.6 years Manifest 18 (8 F) 51.9 years Premanifest 16 (12 F) 43.8 years

Manifest 14 (6 F) 43.9 years

Population No. of patients Age (mean)

T1-weighted MRI

T1-weighted MRI

Functional MRI

T1-weighted MRI

Functional MRI

T1-weighted MRI

T1-weighted MRI

Functional MRI

Functional MRI

Method

Observe or express

Smile Kiss (Neutral)

Anger Disgust Happiness (Neutral)

Disgust Surprise (Neutral)

Indicate5 gender

Indicate gender5

Anger Disgust Fear Sadness Happiness (Neutral)

Facial emotions

Identify3 emotion

Task





Correlation EmoRec deficits with volume

Correlation EmoRec deficits with volume

Functional6

Correlation EmoRec deficits with volume

Functional6

5



Correlation EmoRec deficits with volume

Correlation EmoRec deficits with volume

Functional4

Functional4

# Right OFC, right amygdala, right postcentral gyrus, right occipital fusiform gyrus, ventral striatum, subgenual cortex, dorsal ACC # Right IFOF FA levels # OFC

# Left lateral OFC " Right ventrolateral premotor cortex (associated with better ER)

# Hippocampus, insula, OFC, left amygdala, left DLPFC Altered activation in prefrontal, parietal, insular, and cingulate cortices (only after adjusting for gene dosage) # Right cuneus, precuneus

# Amygdala, hippocampus, striatum, left insula, cingulate, thalamus, prefrontal cortices (e.g., MPFC, OFC) " Amygdala, hippocampus, right parahippocampal gyrus # Left dorsal anterior insula (in response to disgust) # Whole cingulate, PCC

Brain alterations









EmoRec performance2

TABLE 2. Overview of Included Neuroimaging Studies Investigating Emotion Recognition1

Emotions in neurodegenerative diseases

The Journal of Comparative Neurology | Research in Systems Neuroscience

1733

1734

RMMS 12 (7 F) 29.3 years

RMMS 15 (10 F) 29.5 years Mixed MS 22 (18 F) 39.5 years

Population No. of patients Age (mean) Idiopathic PD 36 (—) 58.6 years

Functional MRI

Functional MRI

Functional MRI

PET

Method

Match emotion

Match emotion7

Indicate gender5

Task Identify emotion

Anger Fear Disgust (Neutral) Happiness Sadness Fear Anger (Neutral) Sadness Fear Anger (Geometric shapes)

Facial emotions Six basic emotions (Neutral)

# Insula, left OFC (impaired vs. unimpaired patients) " Left temporal white matter " VLPFC, left precuneus, left superior parietal cortex activation # Connectivity between VLPFC/MPFC and left amygdala

Functional6 Correlation EmoRec deficits with lesions Functional3



5

Brain alterations # Right precuneus, left inferior occipital gyrus " PCC, superior frontal gyri " PCC and precuneus

Correlation6 EmoRec deficits with metabolism Functional6

5

EmoRec performance2

For simplicity, reviews are not included in the table. The indicated age of the patients might slightly deviate in the original sample. ACC, anterior cingulate cortex; DLPFC, dorsolateral PFC; EmoRec, emotion recognition; F, females; FA, fractional anisotropy; HD, Huntington’s disease; IFOF, inferior fronto-occipital fasciculus; MPFC, medial PFC; MRI, magnetic resonance imaging; MS, multiple sclerosis; OFC, orbitofrontal cortex; PCC, posterior cingulate cortex; PD, Parkinson’s disease; PET, positron emission tomography; PFC, prefrontal cortex; RMMS, relapsing-remitting MS; y, years; 5, same emotion recognition performance in patients and controls; —, worse emotion recognition performance in patients than controls. 2 For more information about the recognition task see Table 1. 3 Identify emotion: Individuals had to choose the appropriate label for the presented emotion. 4 Patients compared with healthy controls. 5 An additional behavioral emotion recognition task has been conducted to assess EmoRec performance (see Table 1). 6 No healthy control group included. 7 Match emotion: Individuals had to match a target emotion to one of several other presented emotions.

1

Passamonti et al. (2009)

Krause et al. (2009)

Multiple sclerosis Jehna et al. (2011)

Study Robert et al. (2014)

TABLE 2. Continued

L.A.K. L€offler et al.

The Journal of Comparative Neurology | Research in Systems Neuroscience

Emotions in neurodegenerative diseases

Neuroimaging studies on the neural correlates of facial emotion processing have also distinguished between premanifest and manifest HD. During passive viewing of emotional faces, premanifest patients, compared with controls, showed altered activity in a widespread network including prefrontal, cingulate, parietal, and insular cortices only after adjusting for gene dosage (Novak et al., 2012). Moreover, altered insula activation was specifically linked to the processing of disgust in premanifest HD (Hennenlotter et al., 2004; Novak et al., 2012). In both premanifest and manifest HD patients, behavioral recognition impairments correlate with volume reductions in the (pre-)cuneus (Scahill et al., 2013) and cingulate cortex (Hobbs et al., 2011). In manifest HD patients, deficient recognition of negative emotions is accompanied by reduced activity in distributed regions including the amygdala, hippocampus, striatum, and cingulate and prefrontal cortices (Dogan et al., 2014). Atrophies in the insula, orbitofrontal cortex (OFC), dorsolateral prefrontal cortex (DLPFC), amygdala, and hippocampus have further been associated with recognition deficits in manifest HD (Ille et al., 2011).

Parkinson’s disease As in HD, individuals with PD show significant impairments in facial emotion recognition, with more pronounced deficits for negative emotions than for positive emotions (see meta-analysis by Gray and TickleDegnen, 2010; Narme et al., 2013). These deficits are present even at an early disease stage (Hipp et al., 2014) and in cognitively preserved PD patients (Herrera et al., 2011). Recognition impairments further extend to emotional prosody (Buxton et al., 2013) and music (Saenz et al., 2013). Impaired emotion recognition in PD has been linked to both reduced and increased brain metabolism, with reductions in the precuneus and increases in the posterior cingulate cortex (PCC) and superior frontal gyri (Robert et al., 2014). Asymptomatic Parkin mutation carriers, who are predisposed to develop PD (Davie, 2008; Lesage and Brice, 2009), display reduced activation in the lateral OFC while watching videos of facial gestures (Anders et al., 2012). Correlation studies reveal an association between poor emotion recognition performance and atrophy in the ventral striatum, amygdala, anterior cingulate cortex (ACC; Baggio et al., 2012), and OFC in PD patients (Ibarretxe-Bilbao et al., 2009; Baggio et al., 2012).

Multiple sclerosis Emotion recognition in MS has been only sparsely studied, especially compared with the amount of studies on HD and PD. Furthermore, the findings are rather

heterogeneous. Whereas some studies indicate a general facial emotion recognition deficit in MS patients (Beatty et al., 1989; Phillips et al., 2011; Cecchetto et al., 2014), others reveal selective impairments for negative facial emotions (Henry et al., 2009; Prochnow et al., 2011) or even no deficits at all (Jehna et al., 2010; Pinto et al., 2012). As impairments in emotion recognition also affect bodily gestures in highly disabled MS patients (Cecchetto et al., 2014), some authors propose emotion recognition impairments in MS to be a general feature of the disease, which increases with progressing degeneration (Cecchetto et al., 2014). MS patients with emotion recognition deficits, compared with unimpaired patients, show reduced activation in the insula and left OFC while matching emotional faces (Krause et al., 2009). Behavioral and neural alterations in MS, however, do not always converge, as demonstrated by increased activation in the precuneus and PCC, despite intact behavioral emotion recognition (Jehna et al., 2011). Similarly, precuneus and VLPFC activation were increased during matching of negative facial emotions in behaviorally unimpaired MS patients (Passamonti et al., 2009). These patients further display a reduced connectivity between prefrontal areas and the amygdala (Passamonti et al., 2009).

Conclusions and future directions Impairments in the recognition of facial emotions have been demonstrated in HD and PD, particularly for negative emotions. A limited number of studies further points to emotion recognition deficits in MS, although results remain inconsistent. Diverging findings in MS patients might be attributed to different samples (e.g., chronic progressive MS, relapsing-remitting MS) or varying tasks. Common emotion recognition tasks include either 1) labeling a presented emotion or 2) matching a target emotion with one of several other emotional expressions. Passive viewing tasks, however, provide only limited information on emotion recognition abilities. Almost all of the studies described include various negative emotions, such as sadness, anger, fear, and disgust, but only happiness as a purely positive emotion. Intact happiness recognition in HD and PD is likely to reflect a ceiling effect (Ibarretxe-Bilbao et al., 2009; Henley et al., 2012; Trinkler et al., 2013). Ceiling effects could be reduced by presenting emotional expressions at different intensity levels or morphing facial emotions. This would also provide more realistic expressions of facial emotions, because in everyday life we hardly ever are confronted with 100% anger or joy. An interesting avenue in this regard might also be to collect facial expressions by patients in order to analyze differences and difficulties in expression or variability of

The Journal of Comparative Neurology | Research in Systems Neuroscience

1735

L.A.K. L€offler et al.

TABLE 3. Overview of Included Studies Investigating Emotion Regulation1 Population No. of patients Age (mean)

Study Huntington’s disease Croft et al. (2014)

Parkinson’s disease — Multiple sclerosis Harel et al. (2007)

Phillips et al. (2009)

Phillips et al. (2014)

Assessment instruments

Main findings

Manifest HD 11 (3 F) 56.82 years

ERQ

No difference between HD and HC in reappraisal and suppression

Definite MS 651 (474 F) 43.6 years Mixed MS 86 (63 F) 44.8 years

Psychiatric interview

Dysregulated affect in 6.5% of the patients (N 5 42)

ERQ WHOQoL-BREF

Mixed MS 31 (23 F) 43.97 years

DERS WHOQoL-BREF HADS

More reappraisal use predicted better psychological and environmental QoL, independent of disease severity More difficulties in emotion regulation in MS compared with HC Emotion regulation difficulties were negatively correlated with social QoL in MS but not HC

1 For simplicity, no reviews are included in the table. CFQ, Cognitive Failures Questionnaire; DERS, Difficulties in Emotion Regulation Scales; ERQ, Emotion Regulation Questionnaire; F, female; HADS, Hospital Anxiety and Depression Scale; HC, healthy controls; HD, Huntington’s disease; MS, multiple sclerosis; PD, Parkinson’s disease; QoL, Quality of Life; WHOQoL-BREF, World Health Organization Quality of Life questionnaire abbreviated.

facial expression across the course of the disease. Moreover, little is known about the recognition of social or more complex emotions, such as pride or interest (as positive examples) or shame, guilt, and schadenfreude, in these patient groups. Various disease-specific degenerations in subcortical and cortical brain areas related to emotion recognition contribute to the reported deficits. For example, the basal ganglia, which are affected in HD and PD, play an important role in emotion recognition and connect to other brain regions implicated in emotional processing (e.g., amygdala, OFC; Adolphs, 2002; Le Jeune et al., 2008). Furthermore, degenerations in prefrontal cortices (e.g., OFC) and the insula are frequently associated with emotion recognition deficits in patients. Increased activations (e.g., in the VLPFC in MS patients), in turn, might represent a compensation mechanism for less efficient brain networks. Although behavioral emotion recognition has been relatively well investigated, hardly any studies have addressed neural correlates of this competency, e.g., on explicit emotion recognition in premanifest HD. Furthermore, only facial emotions have been used as stimuli in neuroimaging until now. Investigating emotion recognition from other modalities, such as prosody or olfaction, could be a promising research avenue in determining the specificity of impairments as well as

1736

preserved competencies in neurodegenerative diseases. Necessarily, current medications and other therapeutic methods (e.g., deep brain stimulation) ought to be considered because differential effects of neuroleptic and selective serotonin reuptake inhibitor (SSRI) intake on emotion recognition performance have been demonstrated at least for HD (Labuschagne et al., 2013).

EMOTION REGULATION For details on all disorders see Table 3. Emotions emerge when individuals attend to situations and interpret these situations as relevant for them (Gross and Jazaieri, 2014). The emerging emotions are not fixed but can be changed either automatically or voluntarily. Individuals can “influence which emotions they have, when they have them, and how they experience and express these emotions” (Gross, 1998, p.275). In contrast to coping, emotion regulation is not restricted to taxing situations (such as having HD, PD, or MS) and emphasizes the regulation of both negative and positive emotions (e.g., also increasing positive emotions; Lazarus and Folkman, 1984; Gross, 1998).

Huntington’s disease Only one article on emotion regulation in HD could be identified (Croft et al., 2014), in which no difference

The Journal of Comparative Neurology | Research in Systems Neuroscience

Emotions in neurodegenerative diseases

emerged in self-reported usage of the emotion regulation strategies “cognitive reappraisal” and “suppression” between manifest HD patients and healthy controls.

Parkinson’s disease To our knowledge, studies explicitly addressing emotion regulation abilities in PD patients are not available.

Multiple sclerosis Affective dysregulation has been identified in MS as inappropriate or exaggerated affect (Harel et al., 2007), which can become apparent in behavioral symptoms such as exaggerated aggression or unusual feelings of euphoria (Rosti-Otaj€arvi and H€am€al€ainen, 2013). Phillips et al. (2014) further show that MS patients have significantly more difficulty in regulating emotions than healthy controls. Disrupted emotion regulation is not explained solely by disease severity or executive functioning of the patients (Harel et al., 2007; Phillips et al., 2014). The relationship between a more frequent use of adaptive emotion regulation strategies such as cognitive reappraisal and improved quality of life in MS (Phillips et al., 2009, 2014) emphasizes the need to investigate emotion regulation in MS further.

emotional tasks) and structural changes in HD, PD, and MS patients compared with healthy controls are also part of the emotion regulation network. Thus, it seems likely that emotion regulation is impaired in neurodegenerative disorders, potentially mediated via depressive symptoms, which should be tested directly in future studies. To advance our understanding of the role of emotion regulation in neurodegenerative diseases, an important first step could be a systematic assessment of emotion regulation strategies in daily life. In addition to selfreport questionnaires (e.g., the emotion regulation questionnaire; Gross and John, 2003), objective ratings by therapists and caregivers might shed more light on the actual use of emotion regulation because neurodegenerative patients show a reduced insight in emotional competencies and deficits (Seltzer et al., 2001; Ho et al., 2006). HD patients, for instance, under- and overestimate their emotional control relative to ratings of a close person (Hoth et al., 2007). Furthermore, experimental tasks can be used to examine how much patients can benefit from applying emotion regulation strategies (for more information see Gross, 1998; Ochsner et al., 2012), which could have treatment implications.

Conclusions and future directions In contrast to emotion recognition, studies on emotion regulation in patients with neurodegenerative disorders are almost completely lacking. Based on limited information, it seems that MS patients have difficulties with emotion regulation, although no conclusions can be drawn on emotion regulation capabilities in PD and HD. However, these patients often suffer from psychiatric symptoms such as depression, which are linked to emotional dysregulation (Aldao et al., 2010), so emotion regulation difficulties could be assumed. Over the last decade, several models of emotion regulation in healthy individuals have evolved, establishing a well-described network of regions implicated in emotion regulation (Ochsner and Gross, 2005; Phillips et al., 2008; Kalisch, 2009; Diekhof et al., 2011; Ochsner et al., 2012; Buhle et al., 2013; Frank et al., 2014; Kohn et al., 2014). The emotion regulation network involves frontal (DLPFC, VLPFC), temporal (temporal pole, superior and middle temporal gyrus, temporoparietal junction), medial (dorsomedial and ventromedial PFC, medial OFC, ACC, PCC), parietal (inferior and superior parietal lobe), and subcortical regions (ventral striatum, amygdala) and the insula. Impairments in emotional processing in HD, PD, and MS might extend to emotion regulation because efficient emotional processing lies at the very basis of successful emotion regulation. Most regions demonstrating functional (during

DEPRESSION AND TREATMENT Huntington’s disease For details for all disorders see Table 4. Patients with HD frequently suffer from depressive symptoms. Approximately 33–69% of these patients are affected, with 29% meeting the criteria for major depression (Van Duijn et al., 2007). Depressive symptoms emerge already in premanifest HD and seem to be unrelated to disease progression (Craufurd et al., 2001). The patients’ perceptions of the illness and the availability of coping strategies significantly influence the severity of depressive symptoms in HD (Arran et al., 2014). On a neural level, lower metabolism in the orbital inferior PFC distinguishes depressed from nondepressed HD patients and healthy controls (Mayberg et al., 1992). Moreover, volume reductions in the rostral ACC are positively associated with depressive symptoms in HD (Hobbs et al., 2011). In a transcranial sonography (TCS) study, HD patients with a history of depression further show a disturbed echogenicity of the serotonergic brainstem raphe (Krogias et al., 2011). Treatment in HD focuses primarily on motor signs, whereas only few controlled trials have targeted affective disturbances such as depression (Venuto et al., 2012). Pharmacological studies report beneficial effects of serotonergic/noradrenergic antidepressants and

The Journal of Comparative Neurology | Research in Systems Neuroscience

1737

L.A.K. L€offler et al.

TABLE 4. Overview of Included Studies Investigating Depressive Symptoms1 Population No. of patients Age (mean)

Study Huntington’s disease Craufurd et al. (2001)

Arran et al. (2014)

Mayberg et al. (1992)

Hobbs et al. (2011)

Krogias et al. (2011)

Pickett et al. (2007)

Parkinson’s disease Cardoso et al. (2009)

Hurt et al. (2012)

Rod et al. (2013)

Wen et al. (2013)

Multiple sclerosis Feinstein (2002)

Feinstein et al. (2010)

1738

Method

Assessment instruments

Main findings

Mixed HD 134 (71 F) 50.0 years Manifest HD 87 (49 F) —

Behavioral

PBA-HD

Behavioral

IPQ-R Brief COPE HADS

Manifest HD 9 (—) 41.0 years Mixed HD 60 (27 F) 43.6 years Manifest HD 39 (23 F) 47.9 years

PET

HRSD Modified PSE

T1-weighted MRI

BDI-II

Transcranial sonography

Pathological echogenicity of the brainstem raphe in HD patients with current/past depression

Manifest HD 62 (36) 51.62 years

Behavioral

Psychiatric interview HRSD BDI BSI

Idiopathic PD 36 (0 F) 63.8 years

Functional MRI Task: Gender identification of sad faces

Psychiatric interview MMSE HRSD

Idiopathic PD 347 (123 F) 65.8 years Idiopathic PD2 221 (94 F) 69.0 years

Behavioral

CISS HADS PDQ-8 Psychiatric interview GDS, short form SOC scale Psychiatric interview HRSD

# DMPFC/middle cingulate gyrus, mediodorsal thalamus activation, and " mediosorsal nuclei volume in depressed vs. nondepressed PD Coping strategies correlated with depressive symptoms and health-related QoL Coping capacities and social support seemed to modify the risk of developing depression after major life events

Behavioral

Idiopathic PD 33 (18 F) 62.6 years

Resting state

Mixed MS 140 (104 F) 43.9 years

Behavioral

Mixed MS 62 (51 F) 40.7 years

Diffusion-weighted MRI

Psychiatric interview HADS BSS BDI-II

The Journal of Comparative Neurology | Research in Systems Neuroscience

No correlation between depressive symptoms and disease duration Illness perceptions of identity, perceiving the cause of disease to be related to chance, and coping strategies predicted depressive symptoms Positive reframing correlated negatively with depressive symptoms # Orbital frontal-inferior PFC metabolism in depressed HD vs. nondepressed HD and HC RACC volume correlated positively with depressive symptoms

Caregivers’ depressive symptoms correlated positively with patients’ depressive symptoms

# DLPFC, VMPFC, rACC, superior frontal cortex, and middle temporal gyrus ALFF in depressed vs. nondepressed PD Positive correlation between ALFF in DLPFC and depressive symptoms Severity of major depression predicted suicidal intent

# Superior frontal region NAWM volume, anterior temporal lobe NAWM FA, and " medial inferior frontal region hypointense lesion volume, anterior temporal lobe NAGM mean diffusivity, inferior frontal lesion mean diffusivity in depressed vs. nondepressed MS

Emotions in neurodegenerative diseases

TABLE 4. Continued

Study Gold et al. (2010)

Gold et al. (2014)

Phillips et al. (2014)

Population No. of patients Age (mean) RRMS 29 (25 F) 37.5 years MS 109 (109 F) 42.9 years Mixed MS 31 (23 F) 43.97 years

Method T2-weighted MRI

Assessment instruments BDI-II

T1-weighted MRI

CES-D scale

Behavioral

DERS WHOQoL-BREF HADS

Main findings # CA23DG volume in depressed vs. nondepressed MS # CA23 and posterior subiculum volume in high depressed vs. low depressed MS Emotion regulation difficulties correlated positively with depressive symptoms in MS but not HC Depressive symptoms mediated MS effects on emotion regulation difficulties; emotion regulation difficulties mediated effects of MS on depression

1 For simplicity, reviews are not included in the table. ALFF, amplitude of low-frequency fluctuations; BDI, Beck Depression Inventory; BSI, Brief Symptoms Inventory; BSS, Beck Suicide Scale; CA23, cornu ammonis 2–3 (hippocampus); CAS, Caregiver Appraisal Scale; CES-D, Center for Epidemiologic Studies—Depression; DERS, Difficulties in Emotion Regulation Scale; CISS, Coping Inventory for Stressful Situations; DG, dentate gyrus; DLPFC, dorsolateral PFC; DMPFC, dorsomedial PFC; DSM-IV, Diagnostic and Statistical Manual of Mental Disorders, fourth edition; FA, fractional anisotropy; F, female; GDS, Geriatric Depression Scale; HADS, Hospital Anxiety and Depression Scale; HC, healthy controls; HD, Huntington’s disease; HRSD, Hamilton Rating Scale of Depression; IPQ-R, Illness Perceptions Questionnaire-Revised; MMSE, Mini-Mental State Examination; MRI, magnetic resonance imaging; MS, multiple sclerosis; NAGM, normal-appearing gray matter; NAWM, normal-appearing white matter; PBA-HD, Problem Behaviors Assessment for Huntington Disease; PD, Parkinson’s disease; PDQ-8, Parkinson’s Disease Questionnaire; PET, positron emission tomography; PFC, prefrontal cortex; PSE, Present State Examination; QoL, quality of life; rACC, rostral anterior cingulate cortex; RMMS, relapsingremitting MS; SCID, Structured Clinical Interview for the DSM-IV-TR; SOC, Sense of Coherence; VMPFC, ventromedial PFC; WHOQoL-BREF, World Health Organization Quality of Life, abbreviated; the indicated age of the patients might slightly deviate in the original sample. 2 Probable/possible idiopathic PD.

antipsychotic treatments. However, no controlled trial shows significant reductions in depressive symptoms, and most of these studies have serious methodological limitations (e.g., no control group, no clinical comparison group such as depressed patients, missing statistical data; cf. Moulton et al., 2014). None of the identified studies has investigated psychotherapy as a treatment for HD-related depression. In addition, depression is highly distressing not only for patients. According to Pickett et al. (2007), depression in HD patients is also associated with depression in the patients’ caregivers, which is why the authors recommend extending the depression treatment to caregivers.

Parkinson’s disease Depression is assumed to be the most distressing psychological burden in PD (Hermanns et al., 2012). Clinically significant depression reaches 35%, with 17% of the patients suffering from major depression (Reijnders et al., 2008). Depressive symptoms are found to be prevalent already at early stages of the disease (Hermanns et al., 2012) and seem to be modified by the availability of coping strategies (Hurt et al., 2012; Rod et al., 2013). MRI, PET, and TCS studies show a link between PDassociated depression and abnormalities in the limbic system and frontal lobes, including the OFC, ACC,

medial PFC, striatum, caudate, and thalamus (for review see Blonder and Slevin, 2011). For instance, depressed compared with nondepressed PD patients show decreased activity in the DLPFC and mediodorsal thalamic nucleus in response to sad faces (Cardoso et al., 2009). In resting-state data sets, PD-related depression is further associated with increased normalized amplitudes of low-frequency fluctuations (ALFF; Skidmore et al., 2013) as well as decreased ALFF in the DLPFC, ventromedial PFC, and rostral ACC (Wen et al., 2013). Currently, pharmacotherapy is the first-line therapy for treatment of depression in PD. Still, more controlled trials are needed to uphold this strategy. Tricyclic antidepressants (TCAs) show significant reductions in depression and are proposed to be more effective than SSRIs, which have moderate but nonsignificant effect sizes (see meta-analysis by Troeung et al., 2013). Though less well investigated, cognitive behavioral therapy (CBT) shows promising results with even larger effect sizes than TCAs (Troeung et al., 2013).

Multiple sclerosis Similar to HD and PD patients, MS patients frequently suffer from depression. The lifetime prevalence of major depressive disorder reaches 50%, with an annual prevalence of approximately 20% (Siegert and Abernethy, 2005). An adequate management of

The Journal of Comparative Neurology | Research in Systems Neuroscience

1739

L.A.K. L€offler et al.

depression in MS is essential because it is associated with an increased suicidal risk (Feinstein, 2002). How patients appraise stressors such as uncertainty or feelings of helplessness (Dennison et al., 2009; Feinstein et al., 2014) is strongly associated with depression in MS. Changing these appraisals by thinking more positive about the situation is related to better adjustment (Dennison et al., 2009). Maladaptive strategies, such as wishful thinking or avoidance, increases depression in MS patients (Dennison et al., 2009; Feinstein et al., 2014). Not only does emotion regulation mediate the effects of MS on depression, but depression itself mediates the effects of MS on emotion regulation problems (Phillips et al., 2014). In a diffusion-weighted MRI study, depressed MS patients showed not only an increased lesion volume in medial inferior frontal regions and atrophy in superior frontal regions but also higher mean diffusivity in the anterior temporal gray matter and lower fractional anisotropy in anterior temporal white matter differentiating depressed from nondepressed patients (Feinstein et al., 2010). In addition, reduced hippocampal volume seems to play a role in MS-associated depression (Gold et al., 2010, 2014). Even though effective therapies exist, MS-associated depression is often undertreated (Mohr et al., 2006). Pharmacotherapy and CBT have both been evaluated as effective, with CBT having beneficial long-term effects (for review see Feinstein et al., 2014). With the help of CBT techniques, MS patients might modify their stress and threat appraisal and generate more helpful thoughts (Dennison et al., 2009). The effectiveness of other psychotherapeutic approaches such as mindfulness is also supported by previous studies (for review see Feinstein et al., 2014).

Conclusions and future directions Depression is highly prevalent in HD, PD, and MS. Effective treatment is needed, but clinical trials are rare. Especially psychotherapeutic approaches are understudied and should be investigated further. Future research should also examine the relationship between depressive symptoms and emotion regulation competencies in neurodegenerative diseases. Phillips et al. (2009) have revealed reciprocal influences of depression and emotion dysregulation in MS patients. Whether such a relationship exists in HD and PD is still unknown. Furthermore, comparing depressed patients with and without a neurodegenerative disorder might reveal whether differences in depressive symptoms and their neural correlates exist between the two patient groups. When investigating depression in neurodegenerative diseases, depressive symptoms have to be considered with

1740

caution. Several somatic symptoms (e.g., weight loss) might be attributable to the primal disease (Roos, 2010). To reduce the risk of false diagnoses, depression scales for medically ill patients should be applied. The Hospital Anxiety and Depression Scale (Zigmond and Snaith, 1983), for instance, has been validated for patients with HD, PD, and MS (Mondolo et al., 2006; Honarmand and Feinstein, 2009; De Souza et al., 2010). This might also be a suitable tool for examining treatment effects.

CONCLUSIONS The current Review provides an overview of emotional dysfunctions in patients suffering from HD, PD, or MS. The focus is on emotion recognition, emotion regulation, and depression in these patients, even though affective dysfunctions are not limited to these aspects. Because of the wide range of topics covered, no systematic review was conducted. Furthermore, potential influences of clinical (e.g., cognitive functioning, gene dosage in HD) and demographic (e.g., age) characteristics on emotional functioning have not been taken into account. Another important aspect regarding emotional competences is gender. Differences between males and females have been frequently shown among healthy participants for emotion recognition and regulation (Nolen-Hoeksema, 2012; Stevens and Hamann, 2012). Likewise, the prevalence of depression differs between neurologically healthy females and males (American Psychiatric Association, 2000). With regard to neurodegenerative patients, information on gender differences is sparse, requiring further investigation. Instead of giving an extensive summary of the literature, this Review should draw attention to frequently neglected impairments in patients suffering from neurodegenerative diseases. Imaging studies are needed to reveal underlying neural mechanisms of affective dysfunctions and to evaluate therapeutic strategies. In particular, research on emotion regulation is sparse. Future studies should explore reciprocal influences of depression and emotional dysregulation in neurodegenerative diseases. Preliminary results show that emotion regulation can be linked to quality of life as well as depression in MS patients. For this reason, research in this field could significantly contribute to the well-being of the patients and their relatives.

CONFLICT OF INTEREST STATEMENT The authors have no conflicts of interest.

ROLE OF AUTHORS All authors had full access to all full-text articles included in this Review and take responsibility for the

The Journal of Comparative Neurology | Research in Systems Neuroscience

Emotions in neurodegenerative diseases

integrity of the article. LAKL conducted the literature search. The first draft of the manuscript was written by LAKL and CM. All authors critically revised the manuscript. Funding played no further role in the publication of this review.

LITERATURE CITED Adolphs R. 2002. Neural systems for recognizing emotion. Curr Opin Neurobiol 12:169–177. Aldao A, Nolen-Hoeksema S, Schweizer S. 2010. Emotion-regulation strategies across psychopathology: a metaanalytic review. Clin Psychol Rev 30:217–237. American Psychiatric Association. 2000. Diagnostic and statistical manual of mental disorders, 4th ed, text revision. Washington, DC: American Psychiatric Association. Anders S, Sack B, Pohl A, M€unte T, Pramstaller P, Klein C, Binkofski F. 2012. Compensatory premotor activity during affective face processing in subclinical carriers of a single mutant Parkin allele. Brain 135:1128–1140. Arran N, Craufurd D, Simpson J. 2014. Illness perceptions, coping styles and psychological distress in adults with Huntington’s disease. Psychol Health Med 19:169–179. Baggio HC, Segura B, Ibarretxe-Bilbao N, Valldeoriola F, Marti MJ, Compta Y, Tolosa E, Junque C. 2012. Structural correlates of facial emotion recognition deficits in Parkinson’s disease patients. Neuropsychologia 50:2121–2128. Beatty WW, Weffi WS, Staton RD, Monson N, Beatty PA. 1989. Affective judgments by patients with Parkinson’ s disease or chronic progressive multiple sclerosis. Bull Psychon Soc 27:1–3. Blonder LX, Slevin JT. 2011. Emotional dysfunction in Parkinson’s disease. Behav Neurol 24:201–217. Buhle JT, Silvers JA, Wager TD, Lopez R, Onyemekwu C, Kober H, Weber J, Ochsner KN. 2013. Cognitive reappraisal of emotion: a meta-analysis of human neuroimaging studies. Cereb Cortex 24:1–10. Buxton SL, MacDonald L, Tippett LJ. 2013. Impaired recognition of prosody and subtle emotional facial expressions in Parkinson’s disease. Behav Neurosci 127:193–203. Calder AJ, Keane J, Young AW, Lawrence AD, Mason S, Barker RA. 2010. The relation between anger and different forms of disgust: implications for emotion recognition impairments in Huntington’s disease. Neuropsychologia 48:2719–2729. Cardoso EF, Maia FM, Fregni F, Myczkowski ML, Melo LM, Sato JR, Marcolin MA, Rigonatti SP, Cruz AC, Barbosa ER, Amaro E. 2009. Depression in Parkinson’s disease: convergence from voxel-based morphometry and functional magnetic resonance imaging in the limbic thalamus. Neuroimage 47:467–472. Cecchetto C, Aiello M, D’Amico D, Cutuli D, Cargnelutti D, Eleopra R, Rumiati RI. 2014. Facial and bodily emotion recognition in multiple sclerosis: the role of alexithymia and other characteristics of the disease. J Int Neuropsychol Soc 20:1004–1014. Compston A, Coles A. 2008. Multiple sclerosis. Lancet 372: 1502–1517. Craufurd D, Thompson JC, Snowden JS. 2001. Behavioral changes in Huntington disease. Cogn Behav Neurol 14: 219–226. Croft RJ, McKernan F, Gray M, Churchyard A, GeorgiouKaristianis N. 2014. Emotion perception and electrophysiological correlates in Huntington’s disease. Clin Neurophysiol 125:1618–1625. Davie C. 2008. A review of Parkinson’s disease. Br Med Bull 86:109–127.

De Lau LML, Breteler MMB. 2006. Epidemiology of Parkinson’s disease. Lancet Neurol 5:525–535. De Souza J, Jones L, Rickards H. 2010. Validation of selfreport depression rating scales in Huntington’s disease. Mov Disord 25:91–96. Dennison L, Moss-Morris R, Chalder T. 2009. A review of psychological correlates of adjustment in patients with multiple sclerosis. Clin Psychol Rev 29:141–153. Diekhof EK, Geier K, Falkai P, Gruber O. 2011. Fear is only as deep as the mind allows: a coordinate-based meta-analysis of neuroimaging studies on the regulation of negative affect. Neuroimage 58:275–285. Dogan I, Eickhoff SB, Schulz JB, Shah NJ, Laird AR, Fox PT, Reetz K. 2013. Consistent neurodegeneration and its association with clinical progression in Huntington’s disease: a coordinate-based meta-analysis. Neurodegener Dis 12:23–35. Dogan I, Saß C, Mirzazade S, Kleiman A, Werner CJ, Pohl A, Schiefer J, Binkofski F, Schulz JB, Shah NJ, Reetz K. 2014. Neural correlates of impaired emotion processing in manifest Huntington’s disease. Soc Cogn Affect Neurosci 9:671–680. Eftekhari A, Zoellner LA, Vigil SA. 2009. Patterns of emotion regulation and psychopathology. Anxiety Stress Coping 22:571–586. Estrada-Sanchez AM, Rebec G V. 2013. Role of cerebral cortex in the neuropathology of Huntington’s disease. Front Neural Circuits 7:1–9. Feinstein A. 2002. An examination of suicidal intent in patients with multiple sclerosis. Neurology 59:674–678. Feinstein A, O’Connor P, Akbar N, Moradzadeh L, Scott CJM, Lobaugh NJ. 2010. Diffusion tensor imaging abnormalities in depressed multiple sclerosis patients. Mult Scler 16:189–196. Feinstein A, Magalhaes S, Richard J-F, Audet B, Moore C. 2014. The link between multiple sclerosis and depression. Nat Rev Neurol 10:507–517. Frank DW, Dewitt M, Hudgens-Haney M, Schaeffer DJ, Ball BH, Schwarz NF, Hussein AA, Smart LM, Sabatinelli D. 2014. Emotion regulation: quantitative meta-analysis of functional activation and deactivation. Neurosci Biobehav Rev 45:202–211. Gold SM, Kern KC, O’Connor MF, Montag MJ, Kim A, Yoo YS, Giesser BS, Sicotte NL. 2010. Smaller cornu ammonis 23/dentate gyrus volumes and elevated cortisol in multiple sclerosis patients with depressive symptoms. Biol Psychiatry 68:553–559. Gold SM, O’Connor MF, Gill R, Kern KC, Shi Y, Henry RG, Pelletier D, Mohr DC, Sicotte NL. 2014. Detection of altered hippocampal morphology in multiple sclerosisassociated depression using automated surface mesh modeling. Hum Brain Mapp 35:30–37. Gray HM, Tickle-Degnen L. 2010. A meta-analysis of performance on emotion recognition tasks in Parkinson’s disease. Neuropsychology 24:176–191. Gray JM, Young AW, Barker WA, Curtis A, Gibson D, Gray J. 1997. Impaired recognition of disgust in Huntington’s disease gene carriers. Brain 120:2029–2038. Gross JJ. 1998. The emerging field of emotion regulation: an integrative review. Rev Gen Psychol 2:271–299. Gross JJ, Jazaieri H. 2014. Emotion, emotion regulation, and psychopathology: an affective science perspective. Clin Psychol Sci 2:387–401. Gross JJ, John OP. 2003. Individual differences in two emotion regulation processes: Implications for affect, relationships, and well-being. J Pers Soc Psychol 85:348–362. Gross JJ, Mu~noz RF. 1995. Emotion regulation and mental health. Clin Psychol Sci Pract 2:151–164.

The Journal of Comparative Neurology | Research in Systems Neuroscience

1741

L.A.K. L€offler et al.

Harel Y, Barak Y, Achiron A. 2007. Dysregulation of affect in multiple sclerosis: new phenomenological approach. Psychiatry Clin Neurosci 61:94–98. Henley SMD, Novak MJU, Frost C, King J, Tabrizi SJ, Warren JD. 2012. Emotion recognition in Huntington’s disease: a systematic review. Neurosci Biobehav Rev 36:237–253. Hennenlotter A, Schroeder U, Erhard P, Haslinger B, Stahl R, Weindl A, Von Einsiedel HG, Lange KW, CeballosBaumann AO. 2004. Neural correlates associated with impaired disgust processing in pre-symptomatic Huntington’s disease. Brain 127:1446–1453. Henry JD, Phillips LH, Beatty WW, McDonald S, Longley WA, Joscelyne A, Rendell PG. 2009. Evidence for deficits in facial affect recognition and theory of mind in multiple sclerosis. J Int Neuropsychol Soc 15:277–285. Hermanns M, Deal B, Haas B. 2012. Biopsychosocial and spiritual aspects of Parkinson disease: an integrative review. J Neurosci Nurs 44:194–205. Herrera E, Cuetos F, Rodrıguez-Ferreiro J. 2011. Emotion recognition impairment in Parkinson’s disease patients without dementia. J Neurol Sci 310:237–240. Hipp G, Diederich NJ, Pieria V, Vaillant M. 2014. Primary vision and facial emotion recognition in early Parkinson’s disease. J Neurol Sci 338:178–182. Ho AK, Robbins OG, Barker R. 2006. Huntington’s disease patients have selective problems with insight. Mov Disord 21:385–389. Hobbs NZ, Pedrick AV, Say MJ, Frost C, Dar Santos R, Coleman A, Sturrock A, Craufurd D, Stout JC, Leavitt BR, Barnes J, Tabrizi SJ, Scahill RI. 2011. The structural involvement of the cingulate cortex in premanifest and early Huntington’s disease. Mov Disord 26:1684–1690. Honarmand K, Feinstein A. 2009. Validation of the Hospital Anxiety and Depression Scale for use with multiple sclerosis patients. Mult Scler 15:1518–1524. Hoth KF, Paulsen JS, Moser DJ, Tranel D, Clark LA, Bechara A. 2007. Patients with Huntington’s disease have impaired awareness of cognitive, emotional, and functional abilities. J Clin Exp Neuropsychol 29:365–376. Hurt CS, Landau S, Burn DJ, Hindle JV, Samuel M, Wilson K, Brown RG. 2012. Cognition, coping, and outcome in Parkinson’s disease. Int Psychogeriatr 24:1656–1663. Ibarretxe-Bilbao N, Junque C, Tolosa E, Marti M-J, Valldeoriola F, Bargallo N, Zarei M. 2009. Neuroanatomical correlates of impaired decision-making and facial emotion recognition in early Parkinson’s disease. Eur J Neurosci 30: 1162–1171. Ille R, Sch€afer A, Scharm€uller W, Enzinger C, Sch€oggl H, Kapfhammer H-P, Schienle A. 2011. Emotion recognition and experience in Huntington disease: a voxel-based morphometry study. J Psychiatry Neurosci 36:383–390. Jankovic J. 2008. Parkinson’s disease: clinical features and diagnosis. J Neurol Neurosurg Psychiatry 79:368–376. Jehna M, Neuper C, Petrovic K, Wallner-Blazek M, Schmidt R, Fuchs S, Fazekas F, Enzinger C. 2010. An exploratory study on emotion recognition in patients with a clinically isolated syndrome and multiple sclerosis. Clin Neurol Neurosurg 112:482–484. Jehna M, Langkammer C, Wallner-Blazek M, Neuper C, Loitfelder M, Ropele S, Fuchs S, Khalil M, Pluta-Fuerst A, Fazekas F, Enzinger C. 2011. Cognitively preserved MS patients demonstrate functional differences in processing neutral and emotional faces. Brain Imaging Behav 5:241–251. John OP, Gross JJ. 2004. Healthy and unhealthy emotion regulation: personality processes, individual differences, and life span development. J Pers 72:1301–1333. Johnson SA, Stout JC, Solomon AC, Langbehn DR, Aylward EH, Cruce CB, Ross CA, Nance M, Kayson E, Julian-Baros

1742

E, Hayden MR, Kieburtz K, Guttman M, Oakes D, Shoulson I, Beglinger L, Duff K, Penziner E, Paulsen JS. 2007. Beyond disgust: impaired recognition of negative emotions prior to diagnosis in Huntington’s disease. Brain 130:1732–1744. Kalisch R. 2009. The functional neuroanatomy of reappraisal: time matters. Neurosci Biobehav Rev 33:1215–1226. Kohn N, Eickhoff SB, Scheller M, Laird AR, Fox PT, Habel U. 2014. Neural network of cognitive emotion regulation—an ALE meta-analysis and MACM analysis. Neuroimage 87: 345–355. Krause M, Wendt J, Dressel A, Berneiser J, Kessler C, Hamm AO, Lotze M. 2009. Prefrontal function associated with impaired emotion recognition in patients with multiple sclerosis. Behav Brain Res 205:280–285. Krogias C, Strassburger K, Eyding J, Gold R, Norra C, Juckel G, Saft C, Ninphius D. 2011. Depression in patients with Huntington disease correlates with alterations of the brain stem raphe depicted by transcranial sonography. J Psychiatry Neurosci 36:187–194. Labuschagne I, Jones R, Callaghan J, Whitehead D, Dumas EM, Say MJ, Hart EP, Justo D, Coleman A, Dar Santos RC, Frost C, Craufurd D, Tabrizi SJ, Stout JC. 2013. Emotional face recognition deficits and medication effects in pre-manifest through stage-II Huntington’s disease. Psychiatry Res 207:118–126. Lazarus RS, Folkman S. 1984. Stress, appraisal and coping. New York: Springer. Le Jeune F, Peron J, Biseul I, Fournier S, Sauleau P, Drapier S, Haegelen C, Drapier D, Millet B, Garin E, Herry J-Y, Malbert C-H, Verin M. 2008. Subthalamic nucleus stimulation affects orbitofrontal cortex in facial emotion recognition: a PET study. Brain 131:1599–1608. Lesage S, Brice A. 2009. Parkinson’s disease: from monogenic forms to genetic susceptibility factors. Hum Mol Genet 18:48–59. Mayberg HS, Starkstein SE, Peyser CE, Brandt J, Dannals RF, Folstein SE. 1992. Paralimbic frontal lobe hypometabolism in depression associated with Huntington’s disease. Neurology 42:1791–1797. Milo R, Kahana E. 2010. Multiple sclerosis: geoepidemiology, genetics and the environment. Autoimmun Rev 9:A387– A394. Mohr D, Hart S, Fonareva I, Tasch E. 2006. Treatment of depression for patients with multiple sclerosis in neurology clinics. Mult Scler 12:204–208. Mondolo F, Jahanshahi M, Grana A, Biasutti E, Cacciatoria E, Di Benedetto P. 2006. The validity of the hospital anxiety and depression scale and the geriatric depression scale in Parkinson’s disease. Behav Neurol 17:109–115. Moulton CD, Hopkins CWP, Bevan-Jones WR. 2014. Systematic review of pharmacological treatments for depressive symptoms in Huntington’s disease. Mov Disord 29:1556– 1561. Narme P, Mouras H, Roussel M, Duru C, Krystkowiak P, Godefroy O. 2013. Emotional and cognitive social processes are impaired in Parkinson’s disease and are related to behavioral disorders. Neuropsychology 27: 182–192. Nolen-Hoeksema S. 2012. Emotion regulation and psychopathology: the role of gender. Annu Rev Clin Psychol 8: 161–187. Novak MJU, Tabrizi SJ. 2010. Huntington’s disease. BMJ 340: c3109. Novak MJU, Warren JD, Henley SMD, Draganski B, Frackowiak RS, Tabrizi SJ. 2012. Altered brain mechanisms of emotion processing in pre-manifest Huntington’s disease. Brain 135:1165–1179.

The Journal of Comparative Neurology | Research in Systems Neuroscience

Emotions in neurodegenerative diseases

Ochsner KN, Gross JJ. 2005. The cognitive control of emotion. Trends Cogn Sci 9:242–249. Ochsner KN, Silvers J, Buhle JT. 2012. Functional imaging studies of emotion regulation: a synthetic review and evolving model of the cognitive control of emotion. Ann N Y Acad Sci 1251:E1–E24. Passamonti L, Cerasa A, Liguori M, Gioia MC, Valentino P, Nistico R, Quattrone A, Fera F. 2009. Neurobiological mechanisms underlying emotional processing in relapsing-remitting multiple sclerosis. Brain 132:3380– 3391. Phillips ML, Ladouceur CD, Drevets WC. 2008. A neural model of voluntary and automatic emotion regulation: implications for understanding the pathophysiology and neurodevelopment of bipolar disorder. Mol Psychiatry 13:829, 833–857. Phillips LH, Saldias A, McCarrey A, Henry JD, Scott C, Summers F, Whyte M. 2009. Attentional lapses, emotion regulation and quality of life in multiple sclerosis. Br J Clin Psychol 48:101–106. Phillips LH, Henry JD, Scott C, Summers F, Whyte M, Cook M. 2011. Specific impairments of emotion perception in multiple sclerosis. Neuropsychology 25:131–136. Phillips LH, Henry JD, Nouzova E, Cooper C, Radlak B, Summers F. 2014. Difficulties with emotion regulation in multiple sclerosis: links to executive function, mood, and quality of life. J Clin Exp Neuropsychol 36:831–842. Pickett T, Altmaier E, Paulsen JS. 2007. Caregiver burden in Huntington’s disease. Rehabil Psychol 52:311–318. Pinto C, Gomes F, Moreira I, Rosa B, Santos E, Silva AM, Cavaco S. 2012. Emotion recognition in multiple sclerosis. J Eye Track Vis Cogn Emot 2:76–81. Pringsheim T, Wiltshire K, Day L, Dykeman J, Steeves T, Jette N. 2012. The incidence and prevalence of Huntington’s disease: a systematic review and meta-analysis. Mov Disord 27:1083–1091. Prochnow D, Donell J, Sch€afer R, J€orgens S, Hartung HP, Franz M, Seitz RJ. 2011. Alexithymia and impaired facial affect recognition in multiple sclerosis. J Neurol 258: 1683–1688. Rees EM, Farmer R, Cole JH, Henley SMD, Sprengelmeyer R, Frost C, Scahill RI, Hobbs NZ, Tabrizi SJ. 2014. Inconsistent emotion recognition deficits across stimulus modalities in Huntington’s disease. Neuropsychologia 64:99– 104. Reijnders JSAM, Ehrt U, Weber WEJ, Aarsland D, Leentjens AFG. 2008. A systematic review of prevalence studies of depression in Parkinson’s disease. Mov Disord 23:183– 189; quiz 313. Rickards H. 2005. Depression in neurological disorders: Parkinson’s disease, multiple sclerosis, and stroke. J Neurol Neurosurg Psychiatry 76(Suppl 1):i48–i52. Robert G, Le Jeune F, Dondaine T, Drapier S, Peron J, Lozachmeur C, Sauleau P, Houvenaghel J-F, Travers D, Millet B, Verin M, Drapier D. 2014. Apathy and impaired emotional facial recognition networks overlap in Parkinson’s disease: a PET study with conjunction analyses. J Neurol Neurosurg Psychiatry 85:1153–1158. Robotham L, Sauter DA, Bachoud-Levi A-C, Trinkler I. 2011. The impairment of emotion recognition in Huntington’s disease extends to positive emotions. Cortex 47:880– 884. Rod NH, Bordelon Y, Thompson A, Marcotte E, Ritz B. 2013. Major life events and development of major depression in Parkinson’s disease patients. Eur J Neurol 20:663– 670.

Roos RAC. 2010. Huntington’s disease: a clinical review. Orphanet J Rare Dis 5:40. Rosti-Otaj€arvi E, H€am€al€ainen P. 2013. Behavioural symptoms and impairments in multiple sclerosis: a systematic review and meta-analysis. Mult Scler 19:31–45. Saenz A, Doe de Maindreville A, Henry A, De Labbey S, Bakchine S, Ehrle N. 2013. Recognition of facial and musical emotions in Parkinson’s disease. Eur J Neurol 20:571–577. Scahill RI, Hobbs NZ, Say MJ, Bechtel N, Henley SMD, Hyare H, Langbehn DR, Jones R, Leavitt BR, Roos R a C, Durr A, Johnson H, Lehericy S, Craufurd D, Kennard C, Hicks SL, Stout JC, Reilmann R, Tabrizi SJ. 2013. Clinical impairment in premanifest and early Huntington’s disease is associated with regionally specific atrophy. Hum Brain Mapp 34:519–529. Seltzer B, Vasterling JJ, Mathias CW, Brennan A. 2001. Clinical and neuropsychological correlates of impaired awareness of deficits in Alzheimer disease and Parkinson disease: a comparative study. Neuropsychiatry Neuropsychol Behav Neurol 14:122–129. Siegert RJ, Abernethy DA. 2005. Depression in multiple sclerosis: a review. J Neurol Neurosurg Psychiatry 76:469–475. Skidmore FM, Yang M, Baxter L, Von Deneen K, Collingwood J, He G, Tandon R, Korenkevych D, Savenkov A, Heilman KM, Gold M, Liu Y. 2013. Apathy, depression, and motor symptoms have distinct and separable resting activity patterns in idiopathic Parkinson disease. Neuroimage 81: 484–495. Stevens JS, Hamann S. 2012. Sex differences in brain activation to emotional stimuli: a meta-analysis of neuroimaging studies. Neuropsychologia 50:1578–1593. Tessitore A, Hariri AR, Fera F, Smith WG, Chase TN, Hyde TM, Weinberger DR, Mattay VS. 2002. Dopamine modulates the response of the human amygdala: a study in Parkinson’s disease. 22:9099–9103. Trinkler I, Cleret de Langavant L, Bachoud-Levi A-C. 2013. Joint recognition-expression impairment of facial emotions in Huntington’s disease despite intact understanding of feelings. Cortex 49:549–558. Troeung L, Egan SJ, Gasson N. 2013. A meta-analysis of randomised placebo-controlled treatment trials for depression and anxiety in Parkinson’s disease. PLoS One 8:e79510. Van Asselen M, Julio F, Januario C, Campos EB, Almeida I, Cavaco S, Castelo-Branco M. 2012. Scanning patterns of faces do not explain impaired emotion recognition in Huntington disease: evidence for a high level mechanism. Front Psychol 3:31. Van Duijn E, Kingma EM, van der Mast RC. 2007. Psychopathology in verified Huntington’s disease gene carriers. J Neuropsychiatry Clin Neurosci 19:441–448. Venuto CS, McGarry A, Ma Q, Kieburtz K. 2012. Pharmacologic approaches to the treatment of Huntington’s disease. Mov Disord 27:31–41. Walker FO. 2007. Huntington’s disease. Semin Neurol 27: 143–150. Wieser MJ, Klupp E, Weyers P, Pauli P, Weise D, Zeller D, Classen J, M€uhlberger A. 2012. Reduced early visual emotion discrimination as an index of diminished emotion processing in Parkinson’s disease? - Evidence from event-related brain potentials. Cortex 48:1207–1217. Wen X, Wu X, Liu J, Li K, Yao L. 2013. Abnormal baseline brain activity in nondepressed Parkinson’s disease and depressed Parkinson’s disease: a resting-state functional magnetic resonance imaging study. PLoS One 8:e63691. Zigmond AS, Snaith RP. 1983. The hospital anxiety and depression scale. Acta Psychiatr Scand 67:361–370.

The Journal of Comparative Neurology | Research in Systems Neuroscience

1743

Emotional dysfunctions in neurodegenerative diseases.

Neurodegenerative diseases are characterized primarily by motor signs but are also accompanied by emotional disturbances. Because of the limited knowl...
304KB Sizes 0 Downloads 18 Views