Anhedonia across borders: Transdiagnostic relevance of reward dysfunction for noninvasive brain stimulation endophenotypes

Abstract Introduction Anhedonia is a transdiagnostic psychopathological dimension, consisting in the impaired ability to experience pleasure. In order to further our understanding of its neural correlates and to explore its potential relevance as a predictor of treatment response, in this article we systematically reviewed studies involving anhedonia and neuromodulation interventions, across different disorders. Methods We included seven studies fulfilling inclusion/exclusion criteria and involving different measures of anticipatory and consummatory anhedonia, as well as different noninvasive brain stimulation interventions (transcranial magnetic stimulation and transcranial direct current stimulation). Studies not exploring hedonic measures or not involving neuromodulation intervention were excluded. Results All the included studies entailed the use of rTMS protocols in one of the diverse prefrontal targets. The limited amount of studies and the heterogeneity of stimulation protocols did not allow to draw any conclusion with regard to the efficacy of rTMS in the treatment of transnosographic anhedonia. A potential for anhedonia in dissecting possible endophenotypes of different psychopathological conditions preliminarily emerged. Conclusions Anhedonia is an underexplored condition in neuromodulation trials. It may represent a valuable transdiagnostic dimension that requires further examination in order to discover new clinical predictors for treatment response.


| BACKG ROU N D
Transdiagnostic psychopathological dimensions have been increasingly recognized as relevant factors in the forecast of a more accurate classification and treatment of mental disorders. 1 The Research Domain Criteria (RDoC) strategic plan defines these markers as continuous dimensions increasingly present from general population to, in higher extent, the pathophysiology of mental conditions. 2 Moreover, transdiagnostic dimensions could be relevant in the clustering of mental disorders, in order to define different pathophysiologically based disease subtypes and possible predictors of treatment outcome. 3 Growing research is investigating possible biotypes of mental disorders, 4 with a predictive potential in terms of treatment response.
Anhedonia is a relevant, and often under-considered, transdiagnostic psychopathological dimension. 5 It is defined as the inability to experience pleasure or interest in almost all activities of daily life. 6 There are two faces of anhedonia that could be analyzed: the consummatory and anticipatory anhedonia. The consummatory pleasure consists in the immediate satisfaction and pleasurable feelings that are linked to the realization of a desire. On the other hand, the anticipatory pleasure is the association to the expectation of a pleasurable reward and therefore is connected to motivation. 7 Recently, neuromodulation interventions-also called noninvasive brain stimulation (NIBS) -have reached greater attention as tools for modulating local bran activity and as treatment options in several disorders. 8 Repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) are noninvasive and safe techniques that could inhibit or promote local neural activity in the underlying cortical areas. Also, following the neuronal projections of the targeted areas, it has been hypothesized that there could be a wider-range action, 9 while is not clear if in its mechanism of action, a modulation of the synaptic plasticity could be involved. 10 The application of NIBS in different conditions has been found to determine a clinical response in a portion, but not all, of the treated patients. 11 Nowadays, the efforts in medical research to improve and promote the neuromodulation interventions are focused on detecting different endophenotypes of mental diseases that could be more predictive of a better response to treatment.
Neuromodulation interventions have been tested in several conditions involving anhedonia by using different stimulation protocols and targeted areas, most leading to mixed results. [12][13][14] Interestingly, in pharmacological studies of MDD samples, the occurrence of anhedonia has been found to be predictive of poor treatment response, limited recovery and lower quality of life. 15 Considered the potential relevance of anhedonia in differentially affecting the clinical course of involved conditions, in this paper we aimed at exploring the concept of anhedonia as a putative transdiagnostic dimension characterizing different disorders' endophenotypes. In order to preliminarily test the hypothesis that reward dysfunctions could be proposed as a predictor of NIBS treatment response, we systematically reviewed original articles both involving the application of neuromodulation interventions (ie, rTMS and tDCS) and focusing on psychometric scales and cognitive tasks measuring anhedonia and reward dysfunctions.

| Transdiagnostic relevance of anhedonia in psychopathology
Anhedonia is a core symptom of major depressive disorder (MDD; especially in the definition of melancholic subtype). It is commonly found in the mental health history of patients who attempted suicide and have succeeded; anhedonic patients have greater social impairment, higher levels of hopelessness and are usually younger than nonanhedonic patients. 16,17 Interestingly, anhedonia has been found in bipolar disorder also during euthymic phases, 18 and it has been suggested as vulnerability factor involved in comorbid bipolar conditions. 19 Anhedonia is a relevant negative symptom in schizophrenia (SZ) 20 and social anhedonia, defined as the lack of pleasure or reward from social situations, is a key aspect of schizotypal personality disorder. 21 Moreover, anhedonia is a relevant symptom in patients with substance use disorders (SUDs), since it can represent a symptom of abstinence and therefore it may predict relapse, 22-24 posttraumatic stress disorder (PTSD), 25,26 anxiety disorder, 27 and obsessive-compulsive disorder. 7 Nonetheless, anhedonia is not only a symptom of various psychiatric disorders but is also often present in other conditions such as Parkinson's disease, 28,29 over-eating or risky behaviors. [30][31][32] According to a recent review, 33 anhedonia appears to be a heritable trait with both a biological and clinical basis and an anhedonic endophenotype could possibly be identified. Anhedonia is a trait linked to many mental diseases, and it represents a potential marker of vulnerability, especially for depression. The biological hypothesis could be that anhedonia is a symptom connected to a dysfunctional mechanism between life stressors and the brain re- Animal models of anhedonia are valuable tools allowing to explore the neurobiological underpinnings as well as to search for possible predictors of treatment outcome. Data from rodent models are starting to provide important insights into the pathophysiology of anhedonia, 38 especially through models impairing the responses to rewarding stimuli (eg, sucrose preference) or through the use of dopamine-related transgenic approaches. 39

| Anhedonia and pharmacological treatments: outcome measure or predictor of response?
Since anhedonia is a difficult-to-treat target, several therapeutic approaches have been proposed, including psychosocial interventions, antipsychotics (for SZ conditions 40 ), antidepressants (in mood disorders 41 ), and neuromodulation interventions (in addictive use disorders 12,42 ).
The hypothesis that anhedonia is due to a dopaminergic hypofunction of the reward system leads to the implementation of pharmacological therapeutic approaches that are based on drugs that modulate that neurotransmitter as well as psychostimulants, dopamine agonists and norepinephrine or dopamine reuptake inhibitor such as Bupropion. 23,43,44 Since, as mentioned before, anhedonia is a well-known symptom in drugs' withdrawal, many efforts are made in finding a symptomatic treatment for patients with substance use disorder. A recent study proved the efficacy on the melancholic trait of acetyl-l-carnitine (ALC) on alcoholic patients with anhedonic features. 45 Recent evidence on this field highlighted the efficacy of second-generation antipsychotics on anhedonic traits, like quetiapine and aripiprazole. [46][47][48] Hence, such therapies could be also useful in dual diagnosis patients with anhedonia. 49 Only a few studies investigated the effect of antidepressants on anhedonia. A recent review 50 analyzed the possible effect of agomelatine. Its action appears to be mediated mainly through neurotrophins elevation, 51 but further studies are required to prove its efficacy in reducing anhedonic symptoms. 50 Preliminary studies on rats showed that while fluoxetine did not show any antianhedonic properties, imipramine did, but only on a subgroup. In this trial, the researchers have also studied the effect of other drugs, understanding that while clozapine and lithium showed an antianhedonic effect, haloperidol did not equivalently. Such findings confirm that dopaminergic dysfunction has a relevant role in anhedonia; drugs that interact with the dopaminergic system could be utilized to treat anhedonia and therefore the underlying mental illness. 52 Finally, a recent systematic review by Cao and colleagues 53 analyzed 17 studies on MDD patients with anhedonic features treated with 14 different antidepressants. This review suggested that antidepressants improve anhedonic symptoms, yet no significant difference was found among subjects.
Another valid therapeutic approach could be psychotherapy.
Behavioral activation (BA), which was initially developed as part of cognitive behavioral therapy (CBT), seems to be useful in cases with anticipatory anhedonia. Such results seem to be confirmed by fMRI studies. 54

| MATERIAL S AND ME THODS
A literature research of the databases PubMed/MEDLINE, ISI Web of Science, and Scopus was conducted in order to find appropriate published articles on the application of neuromodulation interventions (ie, TMS and tDCS) in any clinical and nonclinical sample in which anhedonic symptoms were assessed.

| RE SULTS
The qualitative synthesis included seven papers (Table 1)

| Depression
Downar and colleagues, 55 in an open-label study, recruited 47 patients (20 males and 27 females) with unipolar (n = 38) and bipolar (n = 9) TRD. These patients were treated with an add-on high-frequency rTMS over the dorsomedial prefrontal cortex (DMPFC), for a total of 20 daily sessions. Psychometric instruments showed a response rate in almost one-half of the sample (50% reduction in symptoms' severity). They reported that nonrespondent patients were more likely to be anhedonic at the baseline. Furthermore, nonresponders showed significant lower connectivity through the reward pathway on baseline functional magnetic resonance.

| Substance use disorders
Our research group, in an open-label pilot study, 12

| Healthy subjects
Duprat and colleagues 57 conducted a crossover study by using an in- Recently, in an open-label study, 59 20 healthy males were recruited to perform a fMRI food/nonfood discrimination task before and after TBS. In particular, 10 patients started with iTBS followed by continuous TBS (cTBS) and vice-versa. Both stimulation protocols targeted the right mid-VLPFC at a 70% of RMT intensity. The two neuromodulation interventions were able to increase fMRI neural responses for low-calorie food images. In addition, cTBS determined a significant decrease of the ventral tegmental area fMRI activation for high-calorie foods. The number of these studies is very limited, considering the constant spread of the NIBS worldwide and specifically in psychiatry.

| D ISCUSS I ON
Moreover, the protocols used in the clinical trials were found to be very heterogeneous in terms of number of applications, targeted area, and study design. Anhedonia, as transnosographic symptom, has a good potential in dissecting the population involved in neuromodulation trials, in particular it could be used as an outcome predic-  65,66 In fact, the occurrence of anhedonic symptoms would detect possible response predictors to neuromodulation treatment. 51 As discussed, anhedonia has a relevant impact on patients' quality of life. It worsens the rate of suicidal ideation in different samples [67][68][69][70][71] and determines poor social functioning 72 and higher and prolonged hospitalization. 73 Lastly, anhedonia could be considered a pivotal psychopathological symptom, also noted in the DSM-5 as a core symptom of MDD.
Since it also correlates to more severe clinical frames and worse outcomes, 74 it could be an important target for treatment. Treating anhedonia with specific tools could also improve the clinical course of these patients.
In conclusion, current literature does not support a specific role of neuromodulation interventions for the treatment of anhedonia.
Nevertheless, it could be promising to dissect the involved endophenotypes to predict neuromodulation treatment response, but this proposal needs more research and verification in experimental conditions. Further studies are necessary to clarify the role of these approaches to reverse anhedonia and its disabling consequences.

ACK N OWLED G M ENTS
This work was supported by the "Departments of Excellence