Diego Pizzagalli

• Harvard Medical School

Anhedonia and rumination, a form of repetitive negative thinking (RNT), are key features of depression associated with poor treatment outcomes, chronic disease progression, and an increased risk of suicidality. Despite their hypothesized interaction in sustaining depression, the mechanisms connecting these symptoms remain unclear. This within-subje...

Tracking emotion fluctuations in adolescents’ daily lives is essential for understanding mood dynamics and identifying early markers of affective disorders. This study examines the potential of text-based approaches for emotion prediction by comparing nomothetic (group-level) and idiographic (individualized) models in predicting adolescents’ daily...

Past research on option generation, the mental process of creating possible courses of action for goal‐directed behaviors, focused extensively on the outcomes of the process, specifically, the quantity and quality of options generated. Accordingly, various effects were introduced to describe and categorize observed trends in option properties, yet...

Ketamine, a dissociative anesthetic with well-documented abuse liability, can also provide rapid-onset and persistent antidepressant effects and is currently used for the management of treatment-resistant depression. Although the precise neurobiological mechanisms underlying its antidepressant actions are not fully determined, a critical feature of...

Importance Although several predictive models for response to antidepressant treatment have emerged on the basis of individual clinical trials, it is unclear whether such models generalize to different clinical and geographical contexts. Objective To assess whether neuroimaging and clinical features predict response to sertraline and escitalopram...

Background: Identifying robust neural signatures of posttraumatic stress disorder (PTSD) symptoms is important to facilitate precision psychiatry and help in understanding and treatment of the disorder. Emergent research suggests structural covariance of early visual regions is associated with later PTSD development. However, large-scale analyses a...

These are exciting times for psychiatry and clinical neuroscience. Our knowledge of basic brain function continues to increase at an accelerating pace as the experimental tools available to basic and clinical scientists become ever more powerful and penetrating. After decades of frustration and relatively slow progress, this explosion of knowledge...

Background: Psychiatric disorders are notoriously heterogenous, often rendering diagnostic efforts challenging, and leading to poor therapeutic outcomes. The growing emphasis on 'transdiagnostic' approaches in psychiatry aligns well with the National Institute of Health- devised Research Domain Criteria (RDoc) framework that seeks to enable precisi...

Depression rates surge during adolescence. Early identification of youth at increased risk for depression is crucial for timely intervention and, ideally, prevention. This study aims to improve the prediction of future depressive symptoms in adolescents by using a multimodal approach that integrates relevant clinical, demographic, behavioral, and n...

Background: Abnormalities in emotion dynamics and processes, such as emotional inflexibility and dominance of negative emotions, are characteristic of depression. The extent to which these abnormalities persist following depressive episodes, and represent a vulnerability factor for recurrent depressive episodes, remains unknown. The current study i...

Abnormalities in the functional connectivity of large-scale brain networks, including the default mode network (DMN), salience network (SN), fronto-parietal network (FPN), and limbic network, have been implicated in repetitive negative thinking (RNT) – a construct characterized by repetitive and intrusive thoughts. However, the potential of large-s...

Background Childhood sexual abuse (CSA) and emotional maltreatment are salient risk factors for the development of major depressive disorder (MDD) in women. However, the type- and timing-specific effects of emotional maltreatment experienced during adolescence on future depressive symptomatology in women with CSA have not been explored. The goal of...

As a neurobiological process, addiction involves pathological patterns of engagement with substances and a range of behaviors with a chronic and relapsing course. Neuroimaging technologies assess brain activity, structure, physiology, and metabolism at scales ranging from neurotransmitter receptors to large-scale brain networks, providing unique wi...

Background Deficits in cognitive control are implicated in numerous neuropsychiatric disorders. However, relevant pharmacological treatments are limited, likely due to weak translational validity of applicable preclinical models used. Neural indices derived from electroencephalography may prove useful in comparing and translating the effects of cog...

Perceived control is strongly related to mental health and well-being. Specifically, lack of perceived control has been associated with learned helplessness and stress-related disorders, such as depression and anxiety. However, it is unknown whether brain activation to control and its protective effect against stress can predict changes in quality...

Background A dysregulated stress response, including exaggerated affective reactivity and abnormal hypothalamic-pituitary-adrenal axis responsivity, has been implicated in the etiology, maintenance, and relapse of major depressive disorder (MDD). Among adolescents, discordant affective and physiological stress response profiles have been linked to...

Cognitive control processes, specifically interference control and error monitoring, are often impaired across neuropsychiatric disorders and have been proposed as transdiagnostic markers of psychopathology and important treatment targets. Accurately probing them, however, requires understanding the psychometric properties of the measures used to a...

Background. Loneliness and social isolation have detrimental consequences on mental health and act as vulnerability factors for the development of depressive symptoms, such as anhedonia. The mitigation strategies used to contain the Coronavirus 2019 (COVID-19), such as social distancing and lockdowns, allowed us to investigate putative associations...

This article describes primary data and resources available from the Boston Adolescent Neuroimaging of Depression and Anxiety (BANDA) study, a novel arm of the Human Connectome Project (HCP). Data were collected from 215 adolescents (14–17 years old), 152 of whom had current diagnoses of anxiety and/or depressive disorders at study intake. Data inc...

Importance Research on resilience after trauma has often focused on individual-level factors (eg, ability to cope with adversity) and overlooked influential neighborhood-level factors that may help mitigate the development of posttraumatic stress disorder (PTSD). Objective To investigate whether an interaction between residential greenspace and se...

Poor inhibitory control contributes to deficits in emotion regulation, which are often targeted by treatments for major depressive disorder (MDD), including cognitive behavioral therapy (CBT). Brain regions that contribute to inhibitory control and emotion regulation overlap; thus, inhibitory control might relate to response to CBT. In this study,...

Background Exposure to adversity, including unpredictable environments, during early life is associated with neuropsychiatric illness in adulthood. One common factor in this sequela is anhedonia, the loss of responsivity to previously reinforcing stimuli. To accelerate the development of new treatment strategies for anhedonic disorders induced by e...

Approximately 40% of dementia cases could be prevented or delayed by modifiable risk factors related to lifestyle and environment. These risk factors, such as depression and vascular disease, do not affect all individuals in the same way, likely due to inter-individual differences in genetics. However, the precise nature of how genetic risk profile...

The Probabilistic Reward Task (PRT) is widely used to investigate the impact of Major Depressive Disorder (MDD) on reinforcement learning (RL), and recent studies have used it to provide insight into decision-making mechanisms affected by MDD. The current project used PRT data from unmedicated, treatment-seeking adults with MDD to extend these effo...

Objective: Preclinical work suggests that excess glucocorticoids and reduced cortical γ-aminobutyric acid (GABA) may affect sex-dependent differences in brain regions implicated in stress regulation and depressive phenotypes. The authors sought to address a critical gap in knowledge, namely, how stress circuitry is functionally affected by glucoco...

Adolescence is a critical developmental period marked by an elevated risk for Major Depressive Disorder (MDD). To identify individuals at risk, the current study investigated whether emotional rigidity is a prospective predictor of depressive symptoms in adolescence using both self-reported and clinician-rated depression assessments. Adolescents (n...

Introduction The neural underpinnings underlying individual differences in nicotine-enhanced reward sensitivity and smoking progression are poorly understood. Thus, we investigated whether brain resting-state functional connectivity (rsFC) during smoking abstinence predicts nicotine-enhanced reward sensitivity and smoking progression in young light...

Anhedonia, the loss of pleasure, is prevalent and impairing. Parsing its computational basis promises to explain its transdiagnostic character. We argue that one manifestation of anhedonia - reward insensitivity - may be linked to limited memory capacity. Further, the need to economize on limited capacity engenders a perseverative bias towards freq...

Preclinical research is an essential aspect of biomedical science that aids in clarifying the pathophysiology of underlying illness and devising new treatments. This special issues brings together original research and review papers that pertain to the development of novel models and behavioral assays of symptoms of neuropsychiatric disorders, whic...

Clinical assessments often fail to discriminate between unipolar and bipolar depression and identify individuals who will develop future (hypo)manic episodes. To address this challenge, we developed a brain-based graph-theoretical predictive model (GPM) to prospectively map symptoms of anhedonia, impulsivity, and (hypo)mania. Individuals seeking tr...

This study examines the association between brain dynamic functional network connectivity (dFNC) and current/future posttraumatic stress (PTS) symptom severity, and the impact of sex on this relationship. By analyzing 275 participants’ dFNC data obtained ~2 weeks after trauma exposure, we noted that brain dynamics of an inter-network brain state li...

Animal models of depression show that acute stress negatively impacts functioning in neural regions sensitive to reward and punishment, often manifesting as anhedonic behaviors. However, few human studies have probed stress-induced neural activation changes in relation to anhedonia, which is critical for clarifying risk for affective disorders. Par...

The phenomenon of aesthetic chills—shivers and goosebumps associated with either rewarding or threatening stimuli—offers a unique window into the brain basis of conscious reward because of their universal nature and simultaneous subjective and physical counterparts. Elucidating the neural mechanisms underlying aesthetic chills can reveal fundamenta...

Background Exposure to acute stress is associated with reduced reward processing in laboratory studies in animals and humans. However, less clear is the association between reward processing and exposure to naturalistic stressful life events. The goal of the current study was to provide a novel investigation of the relation between past 6-month str...

Sex-specific neurobiological changes have been implicated in Major Depressive Disorder (MDD). Dysfunctions of the default mode network (DMN), salience network (SN) and frontoparietal network (FPN) are critical neural characteristics of MDD, however, the potential moderating role of sex on resting-state network dynamics in MDD has not been sufficien...

Introduction The ICD-11 and DSM-5 are the leading systems for the classification of mental disorders, and their relevance for clinical work and research, as well as their impact for policy making and legal questions, has increased considerably. In recent years, other frameworks have been proposed to supplement or even replace the ICD and the DSM, r...

Cannabis use has been linked to deficient reward processing; however, little is known about its relation to the specific construct of reward learning, in which behavior is modified through associating novel stimuli with a positive outcome. The probabilistic reward task was used to objectively evaluate reward learning in 38 individuals who use recre...

Background Stress exposure contributes to the onset, maintenance, and recurrence of major depressive disorder (MDD) in adolescents. However, the precise stress facets (e.g. chronicity, domain) most strongly linked to outcomes at different stages along the depression severity continuum remain unclear. Across two studies, chronic and episodic stresso...

Biomarkers predicting treatment outcome in major depressive disorder could enhance clinical improvement. Here this observational and prospective accuracy study investigates whether an age- and sex-normalized electroencephalography biomarker, based on the individual alpha frequency (iAF), can successfully stratify patients to different interventions...

Introduction Behavioral and pharmacological smoking cessation treatments are hypothesized to increase patients’ reward learning to reduce craving. Identifying changes in reward learning processes that support effective tobacco dependence interventions among smokers who experience depression may guide patients towards efficient treatment strategies....

Background: Trauma is a risk factor for developing maladaptive alcohol use. Preclinical research has shown that stress alters the processing of midbrain and striatal reward and incentive signals. However, little research has been conducted on alterations in reward-related neurocircuitry post-trauma in humans. Neuroimaging markers may be particularl...

The failure of preclinical research to advance successful candidate medications in psychiatry has created a paradigmatic crisis in psychiatry. The Research Domain Criteria (RDoC) initiative was designed to remedy this situation with a neuroscience-based approach that employs multimodal and cross-species in vivo methodology to increase the probabili...

The phenomenon of aesthetic chills—shivers and goosebumps associated with either rewarding or threatening stimuli—offers a unique window into the brain basis of conscious reward due to their universal nature and simultaneous subjective and physical counterparts. Elucidating the neural mechanisms underlying aesthetic chills can reveal fundamental in...

Objective: This study aimed to examine the potential of experiencing aesthetic chills to enhance reward learning in individuals with elevated depressive symptoms, specifically anhedonia, by investigating the effect of chills on participants’ ability to modulate behavior as a function of rewards. Methods: A total of 103 participants with elevated de...

Background: Anhedonia may contribute to individual differences in delay discounting (DD). In prior work, we found that higher anhedonia was associated with shallower DD in healthy controls (HC) but steeper DD in posttraumatic stress disorder (PTSD). In this study, we aimed to directly compare the relationship between anhedonia and DD across groups...

The probabilistic reward task (PRT) has identified reward learning impairments in those with major depressive disorder (MDD), as well as anhedonia-specific reward learning impairments. However, attempts to validate the anhedonia-specific impairments have produced inconsistent findings. Thus, we seek to determine whether the Reward Behavior Disengag...

Clinical assessments often fail to discriminate between unipolar and bipolar depression and identify individuals who will develop future (hypo)manic episodes. To address this challenge, we developed a brain-based graph-theoretical predictive model (GPM) to prospectively map symptoms of anhedonia, impulsivity, and (hypo)mania. Individuals seeking tr...

Leading professional health bodies have called for the wider adoption of Patient Reported Outcome Measures, such as quality of life, in research and clinical practice as a means for understanding why the global burden of depression continues to climb despite increased rates of treatment use. Here, we examined whether anhedonia—an often recalcitrant...

Background: Growing evidence indicates that anhedonia is a multifaceted construct. This study examined the possibility of identifying subgroups of people with anhedonia using multiple reward-related measures to provide greater understanding the Research Domain Criteria's Positive Valence Systems Domain and pathways for developing treatments. Meth...

Pleasure is a fundamental driver of human behaviour, yet its neural basis remains largely unknown. Rodent studies highlight opioidergic neural circuits connecting the nucleus accumbens, ventral pallidum, insula and orbitofrontal cortex as critical for the initiation and regulation of pleasure, and human neuroimaging studies exhibit some translation...

Resilience is a dynamic process of recovery after trauma, but in most studies it is conceptualized as the absence of specific psychopathology following trauma. Using the large emergency department AURORA study (n=1,865, 63% women), we took a longitudinal, dynamic and transdiagnostic approach to define a static resilience (r) factor, that could expl...

Background: Several hypotheses may explain the association between substance use, posttraumatic stress disorder (PTSD), and depression. However, few studies have utilized a large multisite dataset to understand this complex relationship. Our study assessed the relationship between alcohol and cannabis use trajectories and PTSD and depression sympt...

Animal models of depression show that acute stress negatively impacts functioning in neural regions sensitive to reward and punishment, often manifesting as anhedonic behaviors. However, few human studies have probed stress-induced neural activation changes in relation to anhedonia, which is critical for clarifying risk for affective disorders. Par...

Background: Cognitive distancing is an emotion regulation strategy commonly used in psychological treatment of various mental health disorders, but its therapeutic mechanisms are unknown. Methods: 935 participants completed an online reinforcement learning task involving choices between pairs of symbols with differing reward contingencies. Half...

Background Anhedonia is hypothesized to be associated with blunted mesocorticolimbic dopamine (DA) functioning in samples with major depressive disorder. The purpose of this study was to examine linkages between striatal DA, reward circuitry functioning, anhedonia, and, in an exploratory fashion, self-reported stress, in a transdiagnostic anhedonic...

Objective Studies in estrogen deficiency states such as primary ovarian insufficiency and Turner syndrome suggest that estrogen status may be an important modulator of mood and emotions. In this study we compared depressive and anxiety symptoms between adolescent and young adult female oligo-amenorrheic athletes (AA) and eumenorrheic females (EM),...

Background: Distinguishing between trait- and state-like neural alternations in major depressive disorder (MDD) may advance our understanding of this recurring disorder. We aimed to investigate dynamic functional connectivity alternations in unmedicated individuals with current or past MDD using co-activation pattern analyses. Methods: Resting-s...

Increase in stress-related disorders in women begins post-puberty and persists throughout the lifespan. To characterize sex differences in stress response in early adulthood, we used functional magnetic resonance imaging while participants underwent a stress task in conjunction with serum cortisol levels and questionnaires assessing anxiety and moo...

Childhood trauma is a known risk factor for trauma and stress-related disorders in adulthood. However, limited research has investigated the impact of childhood trauma on brain structure linked to later posttraumatic dysfunction. We investigated the effect of childhood trauma on white matter microstructure after recent trauma and its relationship w...

During the past 60 years, perceptions about the origins of mental illness have shifted toward a biomedical model, depicting depression as a biological disorder caused by genetic abnormalities and/or chemical imbalances. Despite benevolent intentions to reduce stigma, biogenetic messages promote prognostic pessimism, reduce feelings of agency, and a...

Background: Suicidal ideation is highly prevalent in Major Depressive Disorder (MDD). However, the factors determining who will transition from ideation to attempt are not established. Emerging research points to suicide capability (SC), which reflects fearlessness of death and increased pain tolerance, as a construct mediating this transition. Th...

Considerable racial/ethnic disparities persist in exposure to life stressors and socioeconomic resources that can directly affect threat neurocircuitry, particularly the amygdala, that partially mediates susceptibility to adverse posttraumatic outcomes. Limited work to date, however, has investigated potential racial/ethnic variability in amygdala...

Deficits in motivational functioning including impairments in reward learning or reward sensitivity are common in psychiatric disorders characterized by anhedonia. Recently, anhedonic symptoms have been exacerbated by the pandemic caused by the Coronavirus disease 2019 (COVID-19) in the general population. The present study examined the putative as...

Objective: A general psychopathology ('p') factor captures shared variation across mental disorders. Structural neural alterations have been associated with p concurrently, but less is known about whether these alterations relate to within-person change in p over time, especially during preadolescence, a period of neurodevelopmental changes. Meth...