Prefrontal cortex and depression

Diego A Pizzagalli; Angela C Roberts

doi:10.1038/s41386-021-01101-7

. 2021 Aug 2;47(1):225–246. doi: 10.1038/s41386-021-01101-7

Prefrontal cortex and depression

Diego A Pizzagalli ^1,^✉,^#, Angela C Roberts ^2,^✉,^#

PMCID: PMC8617037 PMID: 34341498

Abstract

The prefrontal cortex (PFC) has emerged as one of the regions most consistently impaired in major depressive disorder (MDD). Although functional and structural PFC abnormalities have been reported in both individuals with current MDD as well as those at increased vulnerability to MDD, this information has not translated into better treatment and prevention strategies. Here, we argue that dissecting depressive phenotypes into biologically more tractable dimensions – negative processing biases, anhedonia, despair-like behavior (learned helplessness) – affords unique opportunities for integrating clinical findings with mechanistic evidence emerging from preclinical models relevant to depression, and thereby promises to improve our understanding of MDD. To this end, we review and integrate clinical and preclinical literature pertinent to these core phenotypes, while emphasizing a systems-level approach, treatment effects, and whether specific PFC abnormalities are causes or consequences of MDD. In addition, we discuss several key issues linked to cross-species translation, including functional brain homology across species, the importance of dissecting neural pathways underlying specific functional domains that can be fruitfully probed across species, and the experimental approaches that best ensure translatability. Future directions and clinical implications of this burgeoning literature are discussed.

Subject terms: Prefrontal cortex, Depression

Introduction

Major depressive disorder (MDD) has become the leading cause of disease burden globally [1, 2]. Clinically, MDD is characterized by feelings of sadness and helplessness, loss of pleasure (anhedonia) and lack of motivation, cognitive deficits, and vegetative symptoms. Despite its profound impact, the etiology and pathophysiology of MDD – and consequently its treatment and prevention – remain poorly understood. There are multiple possible reasons for this modest progress, including inattention to the vast heterogeneity of MDD, imprecise translational models, and lack of cross-species integration [3–6].

Here, we argue that dissecting depressive phenotypes into biologically more tractable dimensions allows the development of preclinical models relevant to depression to more strongly align across species, and provides unique opportunities for improving our understanding of MDD. Additionally, we propose that embracing a systems-level approach to the study of the neurobiological underpinnings of depressive phenotypes promises to provide novel insights into personalized treatments. Within this framework, we review clinical and preclinical animal literatures, highlighting the critical role of the prefrontal cortex (PFC) in depressive states. In particular, we focus on the functional heterogeneity of PFC contributions which we suggest is key to understanding the marked individual variation in the etiology, pathophysiology and treatment of MDD. In doing so, we prioritize three abnormalities most productively investigated in preclinical models [3, 6–10]: anhedonia, negative processing biases, and despair-like behavior (learned helplessness). Despite the focus on these domains, they could be a product, in part, of executive dysfunction. Thus, the contribution of PFC dysregulation to executive deficits in MDD will also be discussed. When reviewing treatment effects, a variety of interventions will be integrated; nevertheless, findings with the NMDA antagonist ketamine will be emphasized owing to its rapid antidepressant effects as well as robust parallel findings across species. Before reviewing the literature pertinent to these core phenotypes, we discuss several key issues linked to cross-species translation, including (1) functional brain homology or analogy across species, (2) the importance of parsing out neural pathways that underlie specific domains of functioning that can be investigated across species, and (3) the experimental approaches that best ensure translatability.

Issues of translatability

Prefrontal organization

A key consideration particularly pertinent to cross-species translatability is recognition of anatomical and functional boundaries within prefrontal and anterior cingulate cortices of humans and other animals. Prefrontal structural and functional organization of non-human primates (NHP) is far similar to humans than that of rodents [11–14], but the majority of preclinical studies relevant to MDD are performed in rodents. Since our current understanding of functional homology or analogy between the PFC of rodents and humans is still in its infancy, it is important not to overstate it, as it may inadvertently hinder translational opportunities. This highlights the importance of NHP research, where back translation to rodents and forward translation into the clinic can bridge the gap. As we shall see, evidence in humans implicates orbitofrontal (OFC), dorsolateral/ventrolateral (dl/vl), as well as medial PFC (mPFC)/anterior cingulate cortex (ACC) in MDD [15–17], dl/vlPFC, in particular, having no known homologous or analogous regions in rodents. Indeed, even for those regions where greater anatomical similarity exists (e.g., mPFC/ACC), the extent to which anatomical similarity reflects functional homology or analogy is unclear [9, 18]. Translational opportunities can also be hampered when comparing across human studies because of the use of different nomenclatures to describe distinct prefrontal regions e.g., cytoarchitectonic description e.g., areas 11, 47 and 46 (not always easily translated to MR images) vs. gross regional positioning e.g., ventromedial, subgenual, medial orbital. With this in mind, Fig. 1 clearly lays out the nomenclature used in this review for humans, NHPs and rats (see also Box 1).

Box 1 Cross-species prefrontal nomenclature.

The detailed architectural-based parcellations [273–275] summarized in Fig. 1 are often replaced by another nomenclature which is based on the overall spatial location of regions, e.g., ventromedial (vm)PFC, dorsolateral (dl)PFC, perigenual (pg)ACC, medial OFC, which are variably used across both human and animal studies. This can lead to confusion in the literature both between human imaging studies and across human and animals studies, not only because the precise spatial location of these descriptors can vary between studies e.g., medial OFC in monkeys is commonly used to indicate area 14 [115] but recently used to describe areas 11 and 13 instead [151] but also, because in some cases the spatially defined area is very extensive and includes multiple, functionally heterogenous regions, e.g., vmPFC variably includes areas 14, 10, 32, 25, 24, and rarely do activations in imaging studies or interventions in animals include the entire region. Consequently, we have divided what is often traditionally referred to as vmPFC into three subregions, subgenual cingulate cortex (sgACC), caudal vmPFC and rostral vmPFC and OFC into lateral, central and medial regions and these, along with the other descriptors e.g., dlPFC, pgACC, are illustrated in color on the medial, lateral and orbital views of the human brain.

Symptom complexity

The complexity of depression-associated symptoms makes them difficult to assess with simple questionnaires in the clinic or single behavioral tests in animals. Recognition of the importance of parsing out distinct neural pathways underlying specific cognitive processes led to the Research Domain Criterion (RDoC) initiative [19]. Key to this initiative is a fundamental understanding of the neurocognitive processes regulating adaptive behavior to understand maladaptive behavior. For example, studies of the neurobiology of reward processing have highlighted the variety of distinct pathways involved in its different aspects resulting in the recognition of separate subtypes of anhedonia, including consummatory, anticipatory, motivational and decisional [20, 21]. Whilst traditionally the focus in depression-relevant rodent studies has been on consumption (e.g., sucrose preference test [22–24]), this has been re-assessed due to evidence indicating preserved consummatory reward in functionally analogous tests (e.g., sweet taste test) in MDD [25, 26]. Thus, there is growing interest in developing functionally analogous tasks that probe subdomains of reward processing, including reward learning [27–29] and effort-based decision making [30].

Negative processing biases are prevalent in MDD [31] and implicated in its etiology and treatment [31–33]. They exist across domains, including perception, attention, memory and decision making. Among the most widely used perceptual paradigms to probe negative biases in MDD are backward masking tasks, which allow experimenters to assess non-conscious responses to emotional stimuli (e.g., facial expressions) or tasks requiring implicit (e.g., judging the sex of a facial expression) vs. explicit (e.g., judging a facial expression) processing. These paradigms have been complemented by tasks involving self-referential processing (e.g., does a negative attribute apply to the self?). Whilst the latter is clearly specific to humans, the former have received little attention in animal studies of depression. Recently though, tests to measure other aspects of negative bias linked to decision making have been developed that are suitable for both humans and other animals, including probabilistic discrimination, approach-avoidance and ambiguous cue tasks. Probabilistic discrimination tasks are related to reward learning paradigms but focus particularly on the responsivity to misleading negative feedback [34–37]. In approach-avoidance decision making tasks responding for reward in the presence of punishment introduces conflict [38–42]. In ambiguous cue tests reward and punishment [43, 44] or different amounts of reward [45, 46] are associated with two different sensory cues lying along a continuum, e.g., low or high frequency tones. Subsequent presentation of an ambiguous cue (e.g., a tone equidistant in frequency between the high and low frequency tones), assesses the tendency to predict the more positive or negative of the two potential outcomes.

Behavioral despair is often associated with symptoms of helplessness and hopelessness in MDD in which a perceived lack of cognitive control is a core feature [47]. It has been a major focus in preclinical animal studies but has received relatively little attention in humans and when it has, there has been little cross-species overlap in responses measured. Despair is purported measured in rodents using the forced swim (FST) and tail suspension (TST) tests [48–50]. The quicker animals stop swimming or stop struggling, respectively, is proposed to reflect behavioral despair [51, 52]. Alternative accounts suggest instead that these tests measure adaptive learned responses to acute stress and reflect a natural shift from active to passive coping strategies [53, 54] as distinct from behavioral despair. Thus, they may be more relevant to studying brain mechanisms underlying acute stress rather than a chronic state, like depression. Moreover, increases in escape behavior, hypothesized to reflect an antidepressant effect, may reflect instead an increase in anxiety [55]. Accordingly, caution is required when equating enhanced or reduced immobility on these tests, respectively, with depressant and antidepressant behavior.

Behavioral despair may be more readily associated with concepts of learned helplessness whereby animals, having experienced uncontrollable negative events, subsequently display impaired instrumental learning in otherwise, controllable, contexts involving similar or different negative and positive reinforcers to that used in the uncontrollable context [56–59]. The finding that animals that had control over those same negative events do not subsequently show impaired instrumental actions demonstrates the critical factor of controllability. While superficially, the FST and TST appear to link to concepts of learned helplessness in that animals learn that their actions are ineffective, they do not capture the central tenet of learned helplessness [60], which is, that having experienced the ineffectiveness of actions when in an uncontrollable context, animals subsequently fail to learn actions even in a situation that is controllable. Aspects of controllability, per se, have been studied in the context of depression in humans although, as shall be seen, such studies are limited.

Experimental approaches

Neuroimaging studies have provided important insight into the neural correlates of MDD by identifying alterations in functional activity, resting state and structural integrity. Although findings from other imaging modalities will be mentioned, we focus primarily on fMRI because they allow (1) direct evaluation of brain responses related to environmental stimuli and behavioral performance and (2) a network-level analysis. Critically, imaging findings not only reveal changes associated with MDD but also determine markers that may act as predictors of disease onset as well as predictors of efficacious treatment. For example, with respect to risk, a growing number of studies have compared unaffected (never-depressed and symptom-free) first-degree relatives (e.g., children, monozygotic twins) of individuals with lifetime MDD (“high-risk” group) to “low-risk” groups (e.g., children without parental depression). Similarly, some studies have evaluated fully remitted individuals with past MDD to identify putative trait-like markers of MDD vulnerability.

To provide insight into the role of the PFC in the etiology and treatment of MDD in preclinical animal studies, a range of experimental approaches have been adopted from basic science to more clinically relevant animal models. Specific to the former (Fig. 2) are studies determining the depression-related behavioral effects of central interventions within specific prefrontal subregions and circuits shown to be dysregulated in depression. In some cases, the ability of known antidepressants to ameliorate these intervention-induced effects have also been assessed [61, 62]. This approach allows independent study of specific depression-related alterations in prefrontal activity to determine not only their causal role in symptoms of depression but also their potential differential sensitivity to treatments. A second, related approach has identified prefrontal interventions that induce so-called ‘antidepressant’ effects in otherwise healthy animals or alternatively identified prefrontal interventions that block the behavioral effects of known systemically administered ‘antidepressants’, again, in the otherwise healthy animal [63]. Alternatively, as summarized in Fig. 3, a persistent depressive-like phenotype has been induced by exposing experimental animals to uncontrollable, chronic physical and/or psychological stress [64, 65], a known risk factor for depression [66]. Associated changes in prefrontal physiology and function are then determined, alongside the ability of targeted prefrontal manipulations to reverse/ameliorate these effects. Persistent depressive-like phenotypes are also produced with genetic modifications or other direct physiological-inducers, such as corticosterone or immune activation [67], but of these, chronic stress models have provided the majority of insight into PFC contributions and are discussed here.

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There are advantages and disadvantages with all of these approaches with respect to translatability. The insight gained into the potential contribution to depressive symptoms of a particular brain region by studying the effects of a selective intervention within that region may be limited, especially if those interventions are acute, since any such changes in depression do not occur in isolation and are not acute. In contrast, although depressive phenotypes induced by e.g., uncontrollable stressors appear more clinically relevant, the state they produce may, nevertheless, be as variable in their etiology and treatment as human depression, limiting the level of insight gained. Finally, caution should be employed when interpreting findings from a study describing antidepressant effects in a context in which there is no explicit ‘depressant’ effect to ameliorate. In sum, advances in our understanding of the role of the PFC in depression will best be achieved by the synthesis of results from these varied approaches, especially when the results are convergent, as highlighted below.

MDD and chronic stress models in rodents

Resting state (task-free) functional connectivity findings in MDD

The literature probing resting state functional connectivity (rsFC) in MDD is vast, and generally points to abnormalities (1) between discrete PFC regions, (2) within networks anchored on different PFC regions (e.g., central executive network, default mode network), and (3) between PFC and other networks (for reviews, see [68–70]). Due to space limitation, the following sections present a selected summary of recent findings that are particularly relevant.

A recent voxel-wise meta-analysis compared MDD (N = 1399) and healthy controls (N = 1332) in their amplitude of low frequency fluctuations (ALFF), which represents an indirect measure of spontaneous brain activity [70]. Compared to controls, individuals with MDD showed increased ALFF in a region spanning the medial orbitofrontal cortex (OFC) and perigenual ACC (pgACC). In a coordinate-based meta-analysis [69], increased rsFC in the pgACC predicted response to a variety of treatments (e.g., repetitive transcranial magnetic stimulation (rTMS), pharmacotherapy, cognitive behavior therapy, electroconvulsive therapy (ECT)) (see also [16]). In a sample of 421 individuals with MDD and 488 healthy controls, reduced rsFC emerged in MDD between the central OFC (BA13) and memory-related regions (e.g., parahippocampal gyrus), with increasingly weaker rsFC correlating with higher depression severity [71]. In light of prior data [72], the authors speculated that reduced central OFC-memory regions rsFC might weaken reward-related information to be consolidated in memory.

These findings were extended by a recent study, which compared individuals with current MDD, unaffected first-degree relatives, and healthy controls in their rsFC between OFC and mPFC sub-regions and the rest of the brain [73]. Current MDD and increased risk for MDD shared several abnormalities, including dysregulated coupling involving the pgACC, dmPFC and dorsal ACC (dACC) to other cortical regions (Fig. 4a). However, current MDD was uniquely characterized by abnormal rsFC between various orbital and mPFC sub-regions (pgACC, dACC, lateral and central OFC) and PFC (dlPFC), subcortical (e.g., dorsal striatum), as well as cortical (e.g., precuneus, inferior temporal lobes) regions. Based on these findings, the authors speculated that dmPFC plays a pivotal role in MDD vulnerability, with additional OFC and mPFC abnormalities emerging with the onset of MDD.

Fig. 4 — a Individuals with current MDD and at-risk individuals (unaffected first-degree relatives) showed abnormal coupling involving the pgACC (see “p32”; decreased coupling with posterior cingulate), dmPFC (see “BA9”; decreased coupling with ventral intraparietal sulcus), and dACC (see “d32”; increased coupling with the occipital cortex) [73]. b pgACC region showing a positive correlation between cortical thickness change and improvement in depression symptoms with repetitive transcranial magnetic stimulation of the left dlPFC [90]. c pgACC region in which pre- to post-treatment changes in gray matter volume correlated with antidepressant response to transcranial magnetic stimulation of the left dlPFC [91]. d pgACC region showing higher activation to masked sad faces in MDD than healthy controls [169]. e Greater activation in the pgACC (and other mPFC regions) in response to a sad mood manipulation predicted relapse among fully remitted individuals 18 months later [155]. f Increased functional connectivity between the sgACC/pgACC and the amygdala during an implicit emotional processing task in individuals with increased MDD vulnerability [189]. g Increased pgACC activation 80 ms after committing a mistake in a speeded reaction time task in MDD vs. healthy controls [242]; and h Decreased left dlPFC activation 472 ms after committing a mistake in MDD vs. healthy controls [242]. Adapted with permission from publishers.

Importantly, rsFC abnormalities have emerged also in youth with increased MDD vulnerability but can be ameliorated by treatment. Thus, relative to healthy children (8–17 years old), children at increased vulnerability due to parental MDD history (as well as children with current MDD) had lower rsFC between the right dlPFC (BA6/8/9) and the amygdala [74] – a pathway previously linked to inhibition of emotional responses in adult MDD [75]. Treatment-resistant depression (TRD) was characterized by decreased global connectivity within the right dlPFC and bilateral dmPFC (including the dACC) [76]. Notably, ketamine infusion increased global connectivity in all three regions. In a similar study [77], TRD was characterized by higher pre-treatment resting state activity in a region between the pgACC and sgACC, and a course of ECT treatment normalized activity in this region and its connectivity with the vmPFC; moreover, higher pre-treatment sgACC activity predicted better response to ECT. Together, these findings indicate downregulation of sgACC activity and connectivity is key for ECT response.

Structural findings in MDD

An early meta-analysis (64 structural MRI studies) reported that frontal regions showed the largest volumetric reductions in MDD [78], particularly in the ACC and bilateral OFC, although distinct subregions were not investigated (see also [79]). A link between MDD and gray matter volume (GMV) reduction in the ACC (at the juncture between the pgACC and dACC) was confirmed in a later meta-analysis [80]. In the largest ever conducted structural MRI study, relative to controls (N = 7658), adults with MDD (N = 1902) showed thinner cortical gray matter in the ACC (with reduction spanning subgenual, perigenual and dorsal regions) and OFC/vmPFC [81]. In a 3-year prospective study, MDD patients with larger volumes in similar ACC regions (sgACC, pgACC and dACC) had better outcomes (fewer hospitalizations) than those with smaller volumes [82]. Similarly, in a 5-year naturalistic prospective study, GMV in the right dACC and right inferior frontal gyrus contributed to disease trajectory predictions; specifically, larger volume in these areas predicted better clinical outcome and lower depressive symptoms over 5 years [83]. Altogether, these findings point to structural reductions in mPFC regions, particularly various ACC subdivisions. Additional important insight has emerged from this literature.

First, recent meta-analyses have yielded surprisingly few structural abnormalities linked to MDD [79]. We believe one reason is the large heterogeneity of “MDD”; accordingly, studies linking structural abnormalities to biologically more homogenous phenotypes of depression might provide key insights. Fitting this, in the UK Biobank sample, polygenic risk for anhedonia was linked to smaller OFC volumes [84].

Second, some of these abnormalities appear early in the course of the disorder and might, in fact, represent risk markers. Thus, relative to healthy children, children (7–12 years) with a history of preschool-onset depression (age of onset: 3–6 years) had thinner right sgACC cortical thickness [85]. Importantly, decreased right sgACC cortical thickness at age 7–12 was predicted by depression severity at age 3–6 (and age 7–12). Thus, structural abnormalities spanning the sgACC and OFC emerge early in MDD and affect regions playing a key role in the regulation of negative emotion, value representation, and self-referential processing [17]. The laterality effect was intriguing in light of rodent data that the right vmPFC/ACC (the putative homolog to the human sgACC) is critically implicated in the regulation of HPA axis [86], which points to a possible risk mechanism. Similarly, adolescents with MDD (N = 213) had lower cortical thickness in the medial OFC/vmPFC and superior frontal gyrus than adolescents without MDD history (N = 294) [81]. Notably, similar regions emerged from a 5-year prospective study assessing never-depressed daughters (10–15 years old) with a mother with depression. Specifically, lower cortical thickness in the right medial OFC/vmPFC (but larger pgACC cortical thickness) emerged as two of the top three neural features predicting the first episode of MDD [87].

Third, some of these PFC abnormalities predicted clinical response and were ameliorated by treatment. Accordingly, before starting TMS stimulation over the left dlPFC, eventual non-remitting TRD patients had lower structural integrity within the central executive network (anchored on the dlPFC) relative to both eventual remitters and healthy controls. Moreover, higher structural integrity within the central executive network predicted greater symptom reduction [88]. Similarly, ECT treatment was associated with increased cortical thickness across PFC (dlPFC) and dACC [89]. Changes in the dACC emerged only in treatment responders, and early increases in dACC cortical thickness 48 h after the second ECT administration predicted eventual clinical response. Finally, reduction in depressive symptoms after left dlPFC rTMS treatment was associated with increases in pgACC thickness (Fig. 4b) [90]. These findings replicated prior results showing that left dlPFC rTMS treatment increased GMV in the pgACC (Fig. 4c) and such volumetric increases correlated with symptom reduction [91].

Structural changes in chronic stress models in rodents

Chronic stress (e.g., social defeat, restraint stress, unpredictable mild stress) over a period of days to weeks induces a variety of depression-related symptoms (Fig. 3, top right-hand panel), including behavioral despair, blunted reward-related behaviors, negative biases and cognitive dysfunction [67, 92]. Specifically, animals display decreased swimming in the FST or struggling in the TST, reductions in sucrose preference or consumption and social interactions, changes in the HPA axis and cardiovascular function, negative judgment biases in ambiguous cue tests [43, 44] and impaired cognitive control [93, 94]. The latter includes response and attentional inflexibility [95], spatial working memory (WM) deficits [96] and insensitivity of goal-directed actions to action-outcome contingency and outcome value [93], although these may vary depending on the nature of the stressor. For example, chronic cold stress induces cognitive inflexibility specific to reversal learning, while chronic mild unpredictable stress or restraint stress disrupts higher-order attentional set-shifting more consistently than lower-order associative reversal learning [94, 97].

Accompanying these behavioral changes are marked physiological and structural alterations, not only in the amygdala and hippocampus but, importantly, the PFC [98, 99], that are similar to those seen in MDD. In rodents, the most abundant and consistent changes are in the mPFC (anterior cingulate, prelimbic and infralimbic) with somewhat more variable, mixed direction effects in the OFC (Fig. 3, top left-hand panel). The contrasting patterns between mPFC and OFC in dendritic spine density are particularly intriguing given similar contrasting effects pertaining to hyper- or hypo-activity in MDD, although differences in measures and precise regions involved render comparison challenging. Outstanding questions include (1) whether there are comparable increases in activity within sgACC (putative ILc in rodents) as seen in MDD; (2) whether there are structural/functional changes in dACC in rodents as reported in MDD; (3) what factors may determine whether increases or decreases in dendritic spine density are seen in the OFC in rats and whether there are differences between medial and lateral OFC regions, which we shall see below show contrasting effects in functional activity in MDD.

Anhedonia

Major depressive disorder

Recent reviews and meta-analyses have elucidated the neural correlates of reward processing dysfunctions in MDD [3, 100–104]. In general, these syntheses have highlighted that MDD-related deficits in different sub-domains of reward processing – including incentive motivation (reward anticipation), valuation (reward consumption), and reward learning – are associated with frontostriatal abnormalities. In the following sections, we summarize the main patterns, highlight recent findings (particularly those from large and prospective studies), and provide a synthesis of reward-related frontostriatal abnormalities linked to MDD.

Consummatory anhedonia

In tasks probing consummatory anhedonia (e.g., receipt of secondary rewards such as money), MDD has been associated with reduced activation in ventral (nucleus accumbens) and dorsal (caudate, putamen) striatum, ACC (rostral, dorsal), and OFC but hyperactivation in the mPFC, vmPFC (including sgACC) and dlPFC [100, 102, 104]. In some studies, blunted ventral striatal activation to rewards correlated with anhedonic symptoms [102]. In an instrumental reinforcement learning task, unmedicated MDD subjects showed lower reward value encoding in the pgACC but higher sgACC activation during the decision phase than healthy controls [105]. Among unmedicated individuals with MDD, FC between the caudal vmPFC and various reward hubs (nucleus accumbens, ventral tegmental area (VTA), OFC) in response to pleasant music correlated negatively with anhedonia [106]. Finally, although some abnormalities persist after remission (e.g., OFC hypo-responses to rewards [107], inability to sustain ventral striatal responses to positive cues [108]), acute striatal responses to rewards appear to normalize in individuals with past MDD [109].

Evidence of disrupted frontostriatal activation during reward consumption has been reported also in children with MDD, suggesting that such dysfunctions emerge early. In general, blunted striatal activation coupled with over-recruitment of PFC regions – including the dlPFC during reward outcome – has emerged [104]. In a subclinical sample, adolescents with elevated depressive symptoms showed blunted pgACC and rostral vmPFC activation during reward consumption, with the former correlating with higher anhedonia [110]. Across studies, over-recruitment of PFC regions (mPFC, dlPFC) during reward processing has been interpreted as suggesting over-compensation for reduced striatal responses to rewards [104, 111, 112].

Anticipatory anhedonia

In tasks probing reward anticipation, MDD has been linked to decreased activation in ventral and dorsal striatum as well as middle frontal gyrus (BA8), but hyperactivation in the dlPFC and mPFC including pgACC and caudal vmPFC [3, 102, 113]. In the IMAGEN study (N = 1877 at age 14, N = 1140 at age 19), during reward anticipation, individuals with higher depression severity had reduced sensitivity to differing reward values in the central regions of OFC (areas 11 and 13) but higher lateral OFC (area 12) activation to non-rewards (no-win outcome) at both age 14 and 19 (Fig. 5) [114] (This paper refers to areas 11 and 13 as medial OFC but this nomenclature can be confusing as medial OFC is often used to refer to area 14 which lies on the gyrus rectus, and spans both the medial OFC and vmPFC surfaces. Thus, here, we refer to area 11 and 13 as central OFC and area 14 as medial OFC [115]). Moreover, at age 19, blunted reward-related central OFC activation correlated with more anhedonic symptoms, whereas potentiated non-reward lateral OFC activation correlated with sadness. Critically, depressive symptoms at ages 16 and 19 could be predicted by potentiated lateral OFC activation to non-rewards, but not central OFC activation to rewards, at age 14. Based on these findings, the authors suggested that “hypersensitivity to non-reward of the lateral OFC is an indicator for both current and future depression and that hyposensitivity to reward of the [central] OFC is an indicator for the current, but not future, status of depression” (p. 266). In this context, two recent findings are particularly interesting. First, among patients with TRD, a single ketamine infusion rapidly reduced anhedonic symptoms, and reduction in anhedonia correlated with decreased metabolism in the right lateral OFC (as well as increased glucose metabolism in dACC) [116]. Second, if MDD is characterized by excessive activation within a “non-reward pathway” centered on the right lateral OFC, inhibition of such a system might be beneficial. A case study indeed showed that disruption of such a system (through inhibitory 1 Hz rTMS over the right OFC) reduced both anhedonic symptoms and FC between the right lateral OFC and the ventral striatum [117]. Building on this evidence, the same group recently showed that inhibitory (1 Hz) TMS over the right OFC in TRD was associated with a 30% response rate [118].

Fig. 5 — Central orbitofrontal cortex (see green) and lateral orbitofrontal cortex (see red) region in which individuals with elevated depression severity (see squares) had reduced sensitivity to differing reward values and potentiated activation to non-rewards (no-win outcome) during reward anticipation compared to the control group (see circles) [114]. Adapted with permission from publishers.

Imaging studies in children and adolescents with MDD have also highlighted blunted ventral striatal activation during reward anticipation, which was often accompanied by over-recruitment of PFC regions (e.g., pgACC/vmPFC) [104]. In a large youth sample (N = 1576; mean age: ~14 years), blunted reward-related ventral striatum correlated with anhedonia (but not low mood) and predicted transition to subthreshold or clinical depression 2 years later among previously healthy youths ([119]; see also [120]). Finally, among TRD patients, sgACC hyper-activation to positive feedback correlated with more anticipatory anhedonia (but not anxiety symptoms) [121]. Importantly, sgACC hyper-activation to positive (but not negative) incentives was normalized (decreased) by a single ketamine infusion. These findings fit recent evidence that a single-dose of ketamine reduced sgACC hyper-activity and improved an autonomic measure of anhedonia (anticipatory arousal to receipt of a primary reinforcer in marmosets (see below) [61]).

Reward learning

Studies probing reward learning have typically implemented computational modeling to estimate expected value and reward prediction errors (RPE) during Pavlovian, instrumental, and reversal learning tasks. These studies have generally linked MDD to blunted RPE in the ventral and dorsal striatum [122–124] (but see [125, 126] for important lack of replication), pgACC [127] and medial OFC [126], and greater RPE in the ventral striatum predicted reductions in anhedonia 6 months later [128]. In an instrumental reinforcement learning task, unmedicated individuals with MDD showed increasingly blunted medial OFC and ventral striatal RPE that correlated with anhedonia [126]. Moreover, in a community-based sample (N = 475) tested with a probabilistic reward learning task, increasing depressive symptoms were related to blunted (1) directional connectivity from the mPFC to the striatum, (2) RPE in the dACC, and (3) reward signal magnitude in the nucleus accumbens and caudal vmPFC [129]. Moreover, although fully remitted individuals showed normative ventral striatum RPE, they had greater RPE in the VTA [109], suggesting that some reward-related learning abnormalities do not normalize after recovery. Similarly, fully remitted MZ twins with a past history of mood disorders had blunted expected value signal in the frontal pole extending into middle frontal gyrus (BA10/46) as well as lower RPE signal in the left frontal pole and superior frontal gyrus (BA9/6) [130]. Interestingly, such dysfunctions did not emerge in their unaffected co-twins (high-risk group), suggesting that they might represent scars (as opposed to pre-existing vulnerabilities) of depression. Together, these data suggest that reduced valuation of expected rewards and blunted reward learning represent key vulnerabilities to future MDD.

Reward-related decision making

Several studies have used a variety of tasks to probe complex decision making in MDD, including gambling tasks that require weighting probabilities and amount of rewards and losses, and approach-avoidance decision making tasks. In general, these studies have highlighted abnormal task-related activation in various PFC regions.

In a reward-related decision making task parsing decision making (anticipation) and outcome, relative to healthy youths, youths with current MDD (9–17 years) showed potentiated responses in the left OFC (during anticipation), but decreased responses in the right OFC and dACC during both phases [131]. In a study using a card-guessing task, depressed adolescents had potentiated mPFC (BA10) activation (coupled with blunted ventral striatal activation) to rewards [111]. In studies using a “wheel-of-fortune” task, which involves making choices about varying amounts of monetary rewards with varying levels of risk, adults with MDD showed greater left OFC activation but reduced pgACC activation during the selection phase relative to controls; in addition, they showed greater activation to wins in the left inferior frontal gyrus (BA9/45) than controls [132]. In a sample tested with the same paradigm, adolescents with MDD had higher left OFC and dACC activation but lower right lateral OFC during high-risk trials (trials with only 25% chance of winning a higher amount) relative to controls [133]. In light of the functional role of these regions, the authors speculated that depressed adolescents might be characterized by reduced inhibitory control (right lateral OFC) but potentiated conflict monitoring (dACC) during risky decision making. Finally, initial evidence exists that abnormal reward-related decision making might index MDD vulnerability. Specifically, relative to healthy controls, unaffected individuals with a family history of MDD had significantly lower dlPFC (BA6) activation to risky choices in the Iowa Gambling task [134].

Recently, a study implemented a task modeled after a paradigm used in NHP [39] to probe neural correlates underlying approach-avoidance decision making in MDD [42]. In each trial, participants had to decide whether to approach a trial (which would be associated with the delivery of both a parametrically varying reward and punishment) or avoid a trial (which would be associated with no incentives). Relative to controls, unmedicated adults with MDD were less sensitive to reward. Moreover, they showed reduced approach-related activation in the dlPFC and, surprisingly, reduced avoidance-related pgACC activation. In MDD, reduced approach-related dlPFC activation correlated with increasing perceived stress.

Interim summary

Findings emerging from studies probing different subdomains of reward processing converge in highlighting disrupted activation within and functional connectivity across nodes of the brain reward pathways. As summarized in Fig. 6a and Table 1, across reward subdomains, MDD has been generally linked to blunted activation to reward-related cues within ventral and dorsal striatal regions, perigenual and dorsal ACC regions, and central and medial OFC. In contrast, MDD has been associated with hyper-activation in the medial frontal pole (BA10), vmPFC (including sgACC) and dlPFC to reward-related cues, as well as hyper-activation in the lateral OFC to non-rewards. Of note, many of these markers correlated with anhedonia, predicted future anhedonia and depressive symptoms, and predated MDD. Moreover, several markers (e.g., blunted frontostriatal rsFC and reward-related striatal activation) emerged also in unaffected, never-depressed offspring with parental depression and/or predicted the new onset of depressive disorder years later, suggesting that they represent markers of MDD vulnerability (and thus possible targets for prevention). Of relevance, disrupted coupling within reward-related corticostriatal pathways has emerged also from resting state studies, with reports of increased rsFC between (1) vlPFC and dorsal striatum [135], and (2) dmPFC and various striatal regions [136]. Critically, in a community-based sample of 6–12 years children (N = 637), rsFC strength between the ventral striatum and other reward-related regions (vmPFC, dACC, VTA) predicted the new onset of depressive disorder 3 years later [112]. Highlighting specificity, this metric did not predict the emergence of ADHD, anxiety or substance abuse over the same time period. These findings are important because they highlight that disruptions within brain reward pathways are not only present in the acute phase of MDD but predates its emergence (for similar conclusions, see [137, 138]).

Fig. 6 — Regions highlighted in orange and blue show higher activation and lower activation, respectively, in MDD samples than healthy controls (HC). Orange and blue arrows denote higher and lower functional connectivity, respectively, in MDD samples than healthy controls. AMG amygdala, dACC dorsal anterior cingulate cortex, dlPFC dorsolateral prefrontal cortex, mPFC medial prefrontal cortex, pgACC perigenual anterior cingulate cortex, sgACC subgenual anterior cingulate cortex, Striat Striatum vmPFC ventromedial prefrontal cortex.

Table 1.

Summary of frontostriatal abnormalities in MDD in tasks probing different reward-related processes.

	Reward consumption	Reward anticipation	Reward learning
A. Hypo-activation
Ventral and Dorsal Striatum	↓ (greater ↓, higher anhedonia)	↓ (greater ↓, higher anhedonia & more transition to MDD)	↓ (greater ↓, higher anhedonia & higher anhedonia 6 months later)
pgACC	↓ (greater ↓, higher depressive symptoms)	↓	↓
dACC	↓
Medial OFC	↓	↓ (greater ↓, higher anhedonia)	↓ (greater ↓, higher anhedonia)
B. Hyper-activation
mPFC	↑	↑
vmPFC (subgenual PFC)	↑ (greater ↑, higher anhedonia & more future MDD)
dlPFC	↑	↑
Lateral OFC		↑ to non-rewards (greater ↑, more future MDD)

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Preclinical animal studies

By far the majority of depression-focused studies in rodents have investigated consummatory aspects of reward-elicited behaviors including sucrose preference and consumption and conspecific social interactions. Many of these studies have implicated the mPFC, although not distinguishing between PLc and ILc, in chronic-stress-induced anhedonia-like behaviors. They have shown that various interventions (as listed in detail in Fig. 3) can reverse the associated deficits, in some cases within PLc specifically. In the case of a fosB-CCK interaction underlying susceptibility to chronic social defeat stress, it was explicitly related to PLc and not ILc. In contrast, few studies have attempted to reverse the blunting of consummatory reward-related behaviors through interventions specifically within ILc or OFC. In one case of ILc, its inactivation selectively blocked the effects of chronic mild stress on reward-related dopamine activity [139].

Medial regions, in particular, have also been implicated in the consummatory aspects of reward-related behavior following interventions in healthy rodents although here, the majority have focused on ILc and the effects have been mixed. For example, increasing the excitability of ILc by blockade of the glutamate transporter (GLT1) had an anhedonia-like effect, including an increase in the latency to drink sucrose and an increased threshold for intracranial self-stimulation [140]. Consistent with the latter, NMDA infusions into ILc reduced spontaneous firing of DA neurons in the medial VTA [139]. Moreover, optogenetic stimulation of ILc reduced the BOLD response to optogenetic-induced dopamine stimulation and blocked DA-stimulation-induced place preference [62]. In contrast, prolonged ILc pyramidal stimulation for 60 min mirrored the putative antidepressant effects of ketamine on sucrose preference, while neuronal silencing of ILc (and not PLc), using the GABA-A agonist, muscimol, blocked the actions of ketamine, 24 h later [63]. The latter suggests that the delayed actions of ketamine are dependent upon an intact ILc at the time of the ketamine infusion and may be more consistent with the hypothesis that the long-term effects of ILc activation are antidepressant-like. Altered performance on sucrose preference tests has also been associated with abnormal activity within the OFC. Specifically, a reduction in sucrose preference followed weekly infusions of a 5-HT2a agonist into lateral OFC, mirroring the effects seen following chronic stress [141].

In summary, the rodent mPFC and OFC have been implicated in the control of consummatory aspects of reward-related behavior, although their precise contribution to such behaviors remain unclear (Figs. 2 and 3). The weight of evidence so far though does support the hypothesis that acute ILc activation blunts reward processing, potentially through its projections into the nucleus accumbens which would appear consistent with the heightened activation of sgACC in MDD reported above. Left unanswered from rodent studies are the role of these regions in the other aspects of reward-related behaviors shown to be disrupted in MDD, including reward anticipation, reward learning, and reward-related decision making. These have received far less attention in rodent studies although considerable insight has been gained from basic science studies, particularly of OFC function in both rodents and monkeys. Much of this is covered in another chapter in this Special Issue (e.g., Izquierdo and Rudebeck) so we will only touch upon this briefly here, focusing particularly on those issues highly pertinent to our understanding of MDD. Also, left unanswered, though, especially with respect to mPFC, is the functional analogy/homology between rodents and humans and NHPs in relation to this region’s control of reward-related processing.

Whilst the rodent mPFC is most commonly parcellated into ACC, ILc and PLc, an alternative parcellation that directly parallels that used for the caudal aspects of primate mPFC/ACC, is the one by Vogt and Paxinos [14] which described these regions in terms of areas 24, 25 and 32, respectively. With this in mind, we will now consider a series of studies that have investigated the roles of area 25 and 32 in primates, specifically marmosets, in the consummatory and anticipatory aspects of reward-related behaviors, specifically addressing the hypothesis that heightened activation in sgACC reported in MDD is associated with anhedonia symptomatology. Temporary infusions of the glutamate transporter blocker, dihydrokainic acid (DHK), which heightens the excitability of neurons, induced the blunting of both anticipatory and motivational arousal when infused into area 25. Specifically, area 25 overactivation reduced the cardiovascular and behavioral Pavlovian conditioned arousal in anticipation of marshmallow reward and also decreased the number of responses an animal was willing to perform for reward on a progressive ratio task [61]. In contrast, consummatory responses, including behavioral and cardiovascular arousal during reward consumption itself and performance on a sucrose preference test remained relatively unaffected. Of particular relevance to MDD treatments, systemic ketamine ameliorated area 25 overactivation-induced reductions in Pavlovian anticipatory positive arousal if administered systemically 24 h earlier. The selectivity of these findings was illustrated by the lack of such effects following activation or inactivation of area 32; interestingly, a similar blunting of anticipatory but not consummatory arousal was also seen following over-activation of neighboring area 14 within primate medial OFC/caudal vmPFC [142]. However, only inactivation of area 14 (and not area 25) induced marked increases (Fig. 7) in cardiovascular and behavioral arousal. Thus, whereas area 14 appears to play a fundamental role in regulating such appetitive arousal, area 25 seems to have its effects only when activated; artificially, in the case of the experimental study in marmosets and perhaps under conditions of stress under naturally-occurring conditions. Consistent with the latter is the finding that area 25 activity positively correlates with cortisol levels during anxiety-provoking contexts in macaques [143].

Fig. 7 — Relevant to anhedonia: Areas 47/12, 11/13, and 14 in macaques [115]; Areas 25 [61] and 14 [142] in marmosets; Negative bias in decision making: Area 32/24 border [39] and caudal OFC [202] in macaques; Areas 32 and 25 [41] and areas 47/12 and 11 [38] in marmosets; Action-outcome impairments: Areas 24 [206] and 32 [204] in marmosets; Attentional set-shifting: Area 47/12 in marmosets [207].

These blunted appetitive responses following area 25 over-activation appear comparable to reductions in reward responsivity associated with excitation of the putative homolog of area 25, namely ILc in rats, including increased threshold for intracranial stimulation [140] as well as reduced firing of DA neurons [139] and blocked DA-induced place preference [62]. The precise role of area 25 in reward processing, however, has yet to be fully determined. Its over-activation not only blunted appetitive processing but also enhanced responsivity to both uncertain threat and Pavlovian conditioned, certain threat [144], consistent with the high comorbidity of anxiety with MDD [145, 146]; but inconsistent with the role of ILc in inhibiting conditioned fear responses in rats [147]. (See [9] for a detailed discussion of the opposing effects in rats and marmosets on extinction of Pavlovian conditioned threat). It also reduced basal heart rate variability and increased sympathetic activity [144], consistent with sympathetically-driven alterations in cardiovascular activity in MDD [148, 149]. Thus, overall, this region in a primate may have a primary role in generating/maintaining negative affect which acts to dampen responsivity to reward.

In contrast to the relative paucity of information regarding mPFC and reward processing, the specializations for reward-guided learning and decision making within distinct regions of the OFC have been extensively studied and recently reviewed in [115, 150] and discussed in Rudebeck & Izquierdo (this volume). In summary, detailed parcellation studies in macaques have shown the importance of central regions of OFC in updating the valuations of expected outcomes on the basis of an animal’s current state (area 13) and translating that information into goals for action selection (area 11). Conversely, area 14 in the medial OFC/caudal vmPFC appears more important for comparing values of alternative options. It has been proposed that together these contribute to decisions based on desirability whilst the lateral OFC, extending onto the lateral surface of the vlPFC appears important for determining outcome availability. An alternative view for the lateral OFC, proposed by Rolls, stresses instead its importance for processing of non-reward [151]. The distinctions between lateral, central and medial OFC (summarized in Fig. 7) are particularly relevant to our understanding of depression since MDD appears primarily associated with reduced activity in central OFC but increased activity in lateral OFC and also in the caudal aspects of medial OFC, including area 14 (see above).