Circuit Mechanisms of Reward, Anhedonia, and Depression
Open accessAbstract
Pleasure and motivation are important factors for goal-directed behavior and well-being in both animals and humans. Intact hedonic capacity requires an undisturbed interplay between a number of different brain regions and transmitter systems. Concordantly, dysfunction of networks encoding for reward have been shown in depression and other psychiatric disorders. The development of technological possibilities to investigate connectivity on a functional level in humans and to directly influence networks in animals using optogenetics among other techniques has provided new important insights in this field of research.In this review, we aim to provide an overview on the neurobiological substrates of anhedonia on a network level. For this purpose, definition of anhedonia and the involved reward components are described first, then current data on reward networks in healthy individuals and in depressed patients are summarized, and the roles of different neurotransmitter systems involved in reward processing are specified. Based on this information, the impact of different therapeutic approaches on reward processing is described with a particular focus on deep brain stimulation (DBS) as a possibility for a direct modulation of human brain structures in vivo.Overall, results of current studies emphasize the importance of anhedonia in psychiatric disorders and the relevance of targeting this phenotype for a successful psychiatric treatment. However, more data incorporating these results for the refinement of methodological approaches are needed to be able to develop individually tailored therapeutic concepts based on both clinical and neurobiological profiles of patients.
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TL;DR
This review summarizes neurobiological substrates of anhedonia in depression at the network level, covering reward components, reward circuits, neurotransmitter systems, and treatment effects. It concludes that anhedonia is a clinically important phenotype for precision treatment, but more data are needed to develop individually tailored therapeutic concepts.
Key findings
- Anhedonia is a core, transdiagnostic symptom and a negative prognostic factor: the “interest-activity dimension” predicted poor antidepressant outcome in 811 MDD patients and was replicated in 3737 MDD patients from STAR*D; approximately 40% of patients remitting after 8 weeks of fluoxetine still had residual diminished pleasure or interest, and bupropion-treated patients had a lower anhedonia rate (33%) than the overall rate (46%).
- Reward processing depends on the mesocorticolimbic dopamine circuit (VTA–NAc–mPFC), with VTA comprising about 60% dopaminergic, 25% GABAergic, and 15% glutamatergic neurons; other systems and regions include serotonergic, glutamatergic, and opioid systems, plus LHb, MFB, and OFC, and opioid microinjection in NAc shell/ventral pallidum increased hedonic experience 2–3 times.
- MDD is associated with altered reward-network function: a meta-analysis of 22 fMRI studies (341 patients, 367 controls) found decreased activation mainly in subcortical/limbic areas (caudate, thalamus, ACC, putamen, insula) and increased cortical activation; individual studies report reduced NAc/caudate responses, disrupted ventral striatal prediction-error/anhedonia relationships, and altered NAc connectivity.
- Treatment studies show mixed effects: SSRIs may insufficiently treat reward-related symptoms; ketamine significantly reduced anhedonia for up to 2 weeks with increased ventral striatal metabolism; DBS of NAc, VTA, or MFB modulates reward circuits; and one machine-learning study found anhedonia in 96.7% of patients and 89.6% predictive accuracy for rTMS response using biotype plus connectivity features.
Methods
- Selective narrative review, not a systematic overview; it included studies explicitly focusing on reward processing in depression at baseline and during treatment, but not all resting-state functional connectivity studies in depression.
- Synthesized human fMRI/functional connectivity, PET/SPECT, animal optogenetic/lesion/DBS work, and pharmacological/nonpharmacological treatment studies; Tables 1 and 2 summarize MDD-vs-HC and treatment-effect findings.
- Main analysis was qualitative synthesis of reward subdomains, reward networks, neurotransmitter involvement, and therapeutic modulation, with particular focus on deep brain stimulation.
Limitations
- The paper states it is a selective review intended as a basis for further research rather than a systematic overview, and that inclusion was restricted to studies explicitly focusing on reward processing in depression at baseline and during treatment.
- The paper notes that results are too heterogeneous to make a definite statement about MDD-associated alterations in reward processing, and that differences in reward tasks, analysis approaches, and presentation hamper comparability.
- The text makes evident that functional connectivity is an indirect measure that cannot establish anatomical tracts or rule out third-region modulation, and that animal data are based nearly exclusively on male animals, limiting translation, particularly to females.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
0 of 111 cited sources checked · 0 supported · 0 flagged
- Interpretationcitation
Undisturbed interaction between striatum and mPFC via dopaminergic system is essential for reward-related behavior.
“Thus, the results of this study implicate that the undisturbed interaction between the striatum and mPFC via the dopaminergic transmitter system is essential for the functioning of reward-related behavior.”
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Optogenetic stimulation of midbrain dopaminergic neurons leads to ipsilateral BOLD increases in dorsal and ventral striatum.
“The optogenetic stimulation of dopaminergic neurons in the midbrain led to ipsilateral increases of the blood oxygenation level dependent (BOLD) signal in the dorsal and VS.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Ferenczi et al., 2016 source
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- Interpretationreasoning
Disruption of striatum-mPFC circuit via increased mPFC excitability might be a correlate for dysfunctional reward processing and anhedonia.
“Disruption of this circuit as demonstrated by increased mPFC excitability might be a correlate for dysfunctional reward processing and anhedonia.”
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Blue light inducing dopaminergic stimulation is self-administered by rodents, indicating rewarding effect.
“On a behavioral level, blue light, inducing dopaminergic stimulation, was self-administered by the rodents as an expression of its rewarding effect.”
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- Premisecitation
Activation of VTA leads to dopamine release in NAc.
“This evidence was recently further investigated in an animal study using optogenetics, which showed that activation of the VTA leads to dopamine release in the NAc (Tsai et al., 2009; for a review, see Lenz and Lobo, 2013).”
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- cites Lenz and Lobo, 2013
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Anhedonia is a negative prognostic factor for treatment outcome in adolescents and adults.
“Furthermore, it was shown that anhedonia is a negative prognostic factor for treatment outcome both in adolescents (McMakin et al., 2012) and adults (Spijker et al., 2001; Vrieze et al., 2014).”
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The most consistently described reward network is the dopaminergic mesolimbic pathway from VTA to NAc, BNST, amygdala, and hippocampus.
“The most consistently described reward network is the dopaminergic mesolimbic pathways originating in the ventral tegmental area (VTA) and spreading onto the NAc located in the ventral striatum (VS), bed nucleus of the stria terminalis, amygdala, and hippocampus (Dunlop and Nemeroff, 2007).”
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- Premisecitation
In remitted bipolar patients, only some aspects of hedonic capacity (interests and social interactions) are impaired.
“In remitted bipolar patients, for example, who display increased levels of anhedonia compared to healthy volunteers, only some aspects of hedonic capacity, namely interests and social interactions, seem to be impaired (Di Nicola et al., 2013).”
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- Premisecitation
Reduction of the interest-activity dimension predicts poor outcome in depressed patients undergoing antidepressant treatment, found in 811 MDD patients and replicated in 3737 MDD patients from STAR*D.
“This result was found in a large cohort of 811 patients with major depressive disorder (MDD) and consecutively replicated in a regression analysis in a larger population of 3737 MDD patients derived from the STAR*D trial within the same publication (Uher et al., 2012).”
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Improvement of anhedonia is a strong predictor for improvement in psychosocial functioning.
“and improvement of anhedonia is a strong predictor for improvement in psychosocial functioning (Vinckier et al., 2017).”
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vmPFC and OFC are highly interconnected, overlapping regions with limited possibilities to distinguish them in lesioning studies.
“Importantly, it has to be highlighted that the ventromedial PFC (vmPFC) and the OFC, although they differ in terms of function, are two highly interconnected, overlapping regions with limited possibilities to clearly distinguish these two areas in lesioning and other studies depending on the methodology (Pujara and Koenigs, 2014).”
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Improvement of anhedonia significantly correlates with improvement of overall functioning in depressed patients.
“Conversely, improvement of anhedonia was shown to significantly correlate with improvement of overall functioning in depressed patients (Llorca and Gourion, 2015)”
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NAc is an integral hub for corticolimbic circuitry.
“The complex relationship and interconnections of the involved regions outline the role of the NAc as integral hub for corticolimbic circuitry (Heshmati and Russo, 2015).”
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Agomelatine has shown promising results in treating reward-related symptoms in depression.
“Agomelatine, which acts via the melatonergic system (MT1 and MT2 agonist) and as a antagonist on the 5-HT2C receptor, has shown promising results in a number of studies in this context (Kasper and Hamon, 2009; Di Giannantonio et al., 2011; Martinotti et al., 2012; Gargoloff et al., 2016).”
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A major challenge exists in translating animal results to humans, particularly in females because current animal data is based nearly exclusively on male animals.
“This is particularly true in females because current animal data is based nearly exclusively on male animals. This issue was recently addressed in a review and readers are referred to Heshmati and Russo (Heshmati and Russo, 2015).”
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- Premisecitation
A study using music listening vs scrambled stimuli as a reward paradigm found a negative correlation between anhedonia and functional connectivity of the posterior vmPFC (seed region) with the NAc, VTA/substantia nigra, left OFC, and right insula.
“A study using music listening vs scrambled stimuli as reward paradigm found a negative correlation between anhedonia and functional connectivity of the posterior vmPFC (seed region) and the NAc, VTA/substantia nigra, OFC (left), and insula (right) (Young et al., 2016).”
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- Premisecitation
Striatal activity is disrupted during reward learning, prediction-error encoding, and rewarding outcomes in MDD.
“Several studies showed a disruption of striatal activity during reward learning, prediction-error encoding, and rewarding outcomes (Table 1) (Kumar et al., 2008; Gradin et al., 2011; Robinson et al., 2012).”
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In the same animal model, significant differences in functional connectivity were found between the DRN and the OFC.
“In the same study, significant differences in functional connectivity were found within regions with major relevance to serotonergic transmission such as between the dorsal raphe nucleus (DRN) and the OFC (Gass et al., 2014).”
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- Premisecitation
In large cohort, significant reduction in functional connectivity of medial OFC, BA 13, in MDD vs controls.
“A recent investigation in a large cohort of 421 MDD patients and 488 controls using a “brain-wide” voxel level analysis found a significant reduction in functional connectivity of the medial OFC, BA 13, which is known to be linked to reward processing (Cheng et al., 2016).”
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- Premisecitation
Disturbed function of the caudate in TRD patients was found in a SPECT study comparing cerebral perfusion between TRD patients and healthy individuals, along with fronto-temporal hypoperfusion including the ACC and insula.
“Disturbed function of the caudate in TRD patients was also found in a single-photon emission computed tomography study comparing cerebral perfusion between TRD patients and healthy individuals along with fronto-temporal hypoperfusion, including the ACC and the insula (Richieri et al., 2015).”
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- Interpretationcitation
Overall, TRD is associated with more pronounced hypoconnectivity between cortical regions, mainly frontal areas, and subcortical areas such as the striatum, compared with TSD.
“Overall, studies propose that TRD is associated with more pronounced hypoconnectivity between cortical regions, mainly in frontal areas and subcortical areas such as the striatum, compared with TSD.”
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Decreased striatal activation during prediction-error processing is associated with anhedonia severity in MDD.
“The association between decreased activation of the striatum during prediction-error processing and anhedonia severity was also found in other studies in MDD patients (Gradin et al., 2011).”
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- Premisecitation
When using the caudate as seed region, TRD patients had significantly decreased connectivity to the middle and inferior frontal gyrus.
“When using the caudate as seed region, significantly decreased connectivity to frontal regions, more precisely the middle and inferior frontal gyrus, were found (Ma et al., 2012).”
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- Interpretationnone given
Results are too heterogeneous to make a definite statement about a pattern of MDD-associated alterations of reward processing on neural activation and network level.
“However, results are too heterogenous to make a definite statement about a pattern of MDD-associated alterations of reward processing on both a neural activation and a network level.”
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Unmedicated MDD patients show disruption of inverse correlation between reward expectancy and prediction error-associated reactivity in VS, found in healthy volunteers.
“In line with these results, an fMRI study in a large sample of unmedicated MDD patients showed that depressed patients show a disruption of the inverse correlation between reward expectancy and prediction error-associated reactivity in the VS, which is found in healthy volunteers (Greenberg et al., 2015).”
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- Premisecitation
Reduced activation during consummatory phase of reward in NAc and caudate in MDD vs HCs.
“Furthermore, reduced activation during the consummatory phase of reward was shown for the NAc and caudate in MDD patients compared with HCs (Pizzagalli et al., 2009; Redlich et al., 2015).”
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In late-life depression, MDD patients showed significantly reduced increase of functional connectivity between the striatum and left operculoinsular cortex, right ventrolateral PFC, temporal gyrus, thalamus, and PCC in response to unpredicted reward vs unpredicted punishment compared with age-matched nondepressed controls.
“In late-life depression, MDD patients showed significantly reduced increase of functional connectivity between the striatum and operculoinsular cortex (left), the ventrolateral PFC (right), temporal gyrus, thalamus, and posterior cingulate cortex (PCC) in response to unpredicted reward vs unpredicted punishment compared with age-matched nondepressed controls (Dombrovski et al., 2015).”
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- Interpretationnone given
Overall, studies report significant reduction in neural activation in caudate, NAc, OFC, and ACC in MDD.
“Overall, studies report a significant reduction in neural activation in the caudate, NAc, OFC, and ACC.”
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A machine-learning approach defined different biotypes based on fMRI resting-state connectivity patterns and clinical data.
“Using a machine-learning approach, different “biotypes” have been defined based on fMRI resting-state connectivity patterns and clinical data (Drysdale et al., 2017).”
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- Premisecitation
TRD vs TSD patients showed more extensive hypoconnectivity of OFC, limbic regions, lateral parietal cortex, lateral temporal cortex, and medial/inferior occipital cortex.
“In a study by He et al., TRD vs TSD patients showed more extensive hypoconnectivity of OFC, limbic regions, lateral parietal cortex, lateral temporal cortex, and medial/inferior occipital cortex (He et al., 2016).”
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In unmedicated MDD, disrupted functional connectivity of NAc with caudate, medial OFC, rostral ACC, superior temporal gyrus, insular lobe, dmPFC, dorsal ACC.
“In a resting-state fMRI study in 75 unmedicated MDD patients and 42 HCs, disrupted functional connectivity was reported for the NAc with the caudate, medial OFC, rostral ACC, superior temporal gyrus (left), insular lobe, dorsomedial PFC (dmPFC), and dorsal ACC (Gong et al., 2017).”
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Disruption of inverse correlation between reward expectancy and prediction error reactivity in VS is associated with anhedonia severity in both HCs and MDD.
“This disruption was associated with anhedonia severity both in HCs and MDD patients.”
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A number of studies have linked the dopaminergic reward circuit and depression.
“Since then, a number of studies have been published linking the dopaminergic reward circuit and depression (Table 1).”
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Less data are available on disruption of reward processing in MDD on a network level compared with fMRI activation studies.
“Compared with fMRI studies investigating neural activation, less data are available on the disruption of reward processing in MDD on a network level (Kraus et al., 2017b; Spies et al., 2017; Kraus et al., 2018).”
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Meta-analysis of 22 fMRI studies found decreased activation in subcortical and limbic areas (caudate, thalamus, ACC, putamen, insula) during reward processing in MDD.
“A meta-analysis of 22 fMRI studies including a total of 341 patients and 367 controls found decreased activation mainly in subcortical and limbic areas (caudate, thalamus and anterior cingulate cortex [ACC], putamen and insula) during reward processing in patients with MDD.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Zhang et al., 2013 source
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- Interpretationreasoning
Results point toward baseline disruption of subcortical connectivity and functional coupling between striatal and frontocortical regions.
“Thus, results point toward baseline disruption of subcortical connectivity and functional coupling between striatal and frontocortical regions.”
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Increased connectivity between the NAc and the VTA in MDD patients vs HCs was described during reward processing in an fMRI task focusing on reward feedback.
“Furthermore, increased connectivity between the NAc and the VTA in MDD patients vs HCs was described during reward processing in an fMRI task focusing on reward feedback (Redlich et al., 2015).”
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In an animal model of TRD (cLH), rats suffering from cLH showed significant differences in relative cerebral blood flow within the LHb compared with non-cLH rats.
“With relevance to reward processing, a translational study in an animal model of TRD (congenital learned helplessness [cLH]) showed significant differences in relative cerebral blood flow within the LHb in rats suffering from cLH compared with non-cLH rats.”
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Increased neural activation in cortical regions (cuneus, middle/superior frontal gyrus, fusiform, lingual) in MDD during reward processing.
“An increased neural activation was found in cortical regions (cuneus, middle, and superior frontal gyrus, fusiform gyrus, and lingual gyrus).”
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Blockage of either serotonin synthesis or glutamate release resulted in partial impairments in reward experiments.
“Blockage of either serotonin synthesis or glutamate release resulted in partial impairments in reward experiments (Liu et al., 2014).”
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The serotonergic transmitter system has a modulatory impact on the reward network via different receptors such as 5-HT1A, 5-HT2A receptors, and the serotonin transporter (5-HTT).
“It was further reported that the serotonergic transmitter system has a modulatory impact on the reward network via different receptors such as the 5-HT1A, 5-HT2A receptors, and the serotonin transporter (5-HTT) (Lanzenberger et al., 2012; Hahn et al., 2014; Kraus et al., 2014; Spies et al., 2015).”
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Glutamatergic frontal neurons influence dopaminergic neurotransmission in the VS via GABAergic neurons.
“with studies reporting an influence of glutamatergic frontal neurons on dopaminergic neurotransmission in the VS via GABAergic neurons (Carlsson et al. 1999)”
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Some evidence suggests an involvement of serotonin in reward anticipation.
“Although the serotonergic system has been mainly associated with consummatory pleasure, some evidence suggests an involvement of serotonin in reward anticipation (Marutani et al., 2011).”
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The opioid system in the NAc shell and the ventral pallidum mediates consummatory pleasure, with 2 to 3 times increases of hedonic experience to sucrose taste when a microinjection of neuronal opioid was performed in these areas.
“The opioid system in the NAc shell and the ventral pallidum has been shown to mediate consummatory pleasure, with 2 to 3 times increases of hedonic experience to sucrose taste when a microinjection of neuronal opioid was performed in these areas (Berridge and Kringelbach, 2008).”
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Animal data show tonically increased firing of serotonergic neurons in the DRN during reward anticipation.
“Thus, animal data show tonically increased firing of serotonergic neurons in the DRN during reward anticipation (Li et al., 2016).”
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- Interpretationreasoning
The concept of reward prediction-error provides an explanation for how dopamine may drive reward learning and reward choice.
“Importantly, the concept of reward prediction-error has provided an elegant first explanation on how dopamine may drive reward learning and reward choice.”
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MDD is associated with a significant reduction of the 5-HTT in the midbrain and striatum.
“A recent meta-analysis reported that MDD is associated with a significant reduction of the 5-HTT in the midbrain and striatum (Gryglewski et al., 2014).”
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After 6-week treatment with escitalopram, the difference in VS activation during reward anticipation between MDD patients and HCs was no longer measurable.
“After 6-week treatment with escitalopram, this difference was no longer measurable (Stoy et al., 2012).”
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The increase of firing rate of dopaminergic neurons is affected in a size-dependent manner.
“The increase of firing rate is affected in a size-dependent manner (Schultz, 2016).”
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- Interpretationnone given
Interactions with other transmitter systems such as the serotonergic, opioid, and glutamatergic systems have broadened the picture of mediation of reward on a transmitter level.
“More recently, interactions with other transmitter systems such as the serotonergic, opioid, and glutamatergic systems have broadened the picture of mediation of reward on a transmitter level.”
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Anhedonia has a rather low response to SSRI treatment compared with other symptoms.
“These results could reflect the fact that anhedonia has a rather low response to SSRI treatment compared with other symptoms (Opbroek et al., 2002; Price et al., 2009).”
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PET studies showed that reward leads to dopamine release in the striatum and more specifically in the NAc, as indicated by reduction of binding potential of dopamine receptor subtype 2 using [11C] raclopride.
“It was shown in positron emission tomography (PET) studies that reward leads to dopamine release in the striatum and more specifically in the NAc as indicated by reduction of the binding potential of the dopamine receptor subtype 2 using the radioligand [11C] raclopride (Koepp et al., 1998; Zald et al., 2004; Jonasson et al., 2014).”
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The opioid system has a more complex role, including involvement in mediation of incentive motivation and learning via μ- and δ-opioid receptors in the NAc.
“However, in the recent years, a more complex role of the opioid system has been proposed, including its involvement in the mediation of incentive motivation and learning via μ- and δ- opioid receptors in the NAc; for a detailed review, see also Laurent et al. 2015.”
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- Premisecitation
MDD patients exhibit reduced activation of the VS during reward anticipation compared with HCs in an MID task.
“Stoy et al. showed that MDD patients exhibit reduced activation of the VS during reward anticipation compared with HCs in an MID task.”
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- Premisecitation
The interaction between glutamate and striatal activity serves as an important modulator of synaptic plasticity and neural excitability.
“It is believed that the interaction between glutamate and striatal activity serves as an important modulator of synaptic plasticity and neural excitability (Surmeier et al., 2007; Kreitzer et al., 2009; Lovinger et al., 2010; Gleich et al., 2015).”
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There are associations between glutamate concentration and fronto-limbic functional connectivity.
“and associations between glutamate concentration and fronto-limbic functional connectivity (Duncan et al. 2013).”
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For aversive stimuli, dopaminergic neurons show decreased firing rates below baseline.
“This is also true for aversive stimuli, with decreased firing rates of dopaminergic neurons below baseline.”
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- Premisenone given
Reward-related areas, both cortical and subcortical, show extensive innervation by serotonergic neurons, which originate in the raphe nuclei.
“It was shown that reward-related areas, both cortical and subcortical, show extensive innervation by serotonergic neurons, which originate in the raphe nuclei.”
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Four distinct biotypes were found, each associated with a specific symptom profile.
“In addition to this shared pattern of dysfunctional connectivity, 4 distinct biotypes were found, each associated with a specific symptom profile.”
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- Premisecitation
A multimodal study using [11C] raclopride and fMRI during a MID task showed a correlation between dopamine release and hemodynamic response in the substantia nigra/VTA and VS during reward anticipation.
“A multimodal study using the same radioligand and fMRI during a monetary incentive delay (MID) task could show a correlation between dopamine release, again measured using [11C] raclopride, and hemodynamic response in the substantia nigra/VTA and the VS during reward anticipation in fMRI (Schott et al., 2008).”
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PremisecitationReward processing is a multi-step process including stimulus-reward association, interest/desire/anticipation, cost-benefit calculation, action planning, behavioral expenditure, consummatory pleasure, and feedback learning.
“reward processing is a multi-step process starting with the establishment of an association between a given stimulus and a connected reward, which is then followed by the development of interest, desire, and anticipation defined as “state of readiness for a reward””
Quote in the paperSubstantial claim0 of 2 sources checked- cites Kring and Barch, 2014
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PremisecitationHuman studies mainly based on self-report lack comparability with animal behavioral tasks, and interpretation of animal data in human pathophysiology is challenging.
“Studies in humans, which are mainly based on self-report questionnaires, lack adequate comparability with results gained from behavioral tasks in animals. Furthermore, interpretation of animal data in the context of human pathophysiology is often challenging (Der-Avakian et al., 2016).”
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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationAnhedonia might be a trait marker rather than an expression of a disease state, with persistence of reduced hedonic capacity in euthymic remitted patients.
“It was also suggested that anhedonia might be a trait marker rather than an expression of a disease state, with persistence of reduced hedonic capacity in euthymic remitted patients (Di Nicola et al., 2013).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Di Nicola et al., 2013 source
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PremisecitationIn monkeys, smaller than expected reward activates LHb neurons, larger than expected reward inhibits them.
“Thus, using a reward prediction error paradigm in monkeys with a smaller than expected reward led to activation of LHb neurons, whereas a larger than expected reward led to their inhibition (Matsumoto and Hikosaka, 2007).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Matsumoto and Hikosaka, 2007 source
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PremisecitationAnhedonia is an umbrella term including multiple components of reward processing necessary for the ability to feel pleasure.
“Since it was first described in the late 19th century, the knowledge about reward processing has evolved and it has become clear that anhedonia is an umbrella term including a number of different components of reward processing that are necessary for the ability to feel pleasure in response to an event (Berridge and Kringelbach, 2008).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Berridge and Kringelbach, 2008 source
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PremisecitationLHb has an inhibitory influence on dopaminergic neurons via GABAergic interneurons in RMTg, reflected by lesioning of habenula increasing cortical and striatal dopamine.
“It was shown that the LHb has an inhibitory influence on dopaminergic neurons (Matsumoto and Hikosaka, 2007) via GABAergic interneurons in the rostromedial tegmental nucleus (Ji and Shepard, 2007; Jhou et al., 2009), which is reflected by the fact that lesioning of the habenula leads to an increase of cortical and striatal dopamine levels (Nishikawa et al., 1986).”
Quote in the paperSubstantial claim0 of 3 sources checkedMay combine two claims.
Premisecitation60% of VTA efferent projections are dopaminergic, and VTA also contains glutamatergic and GABAergic neurons.
“A total 60% of efferent projections of the VTA are dopaminergic, although it contains glutamatergic and GABAergic neurons also (Dobi et al., 2010).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Dobi et al., 2010 source
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Classified as probably not a substantial claim.
PremisecitationCurrent standard treatment of MDD, particularly SSRIs, fails to sufficiently treat reward-related symptoms of depression.
“It was proposed that current standard treatment of MDD, particularly selective serotonin reuptake inhibitors (SSRIs), fail to sufficiently treat reward-related symptoms of depression (Dunlop and Nemeroff, 2007; Price et al., 2009; Di Nicola et al., 2013).”
Quote in the paperSubstantial claim0 of 3 sources checkedMay combine two claims.
PremisecitationLHb has dopaminergic projections to SNc and VTA and serotonergic projections to median and dorsal raphe.
“The LHb has dopaminergic projections to the substantia nigra pars compacta and the VTA as well as serotonergic projections to the median and dorsal raphe nuclei (Herkenham and Nauta, 1979).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Herkenham and Nauta, 1979
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Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationEarly increase of positive emotions after start of antidepressant treatment predicts response and remission in MDD patients after 6 weeks.
“Furthermore, early increase of positive emotions after start of antidepressant treatment defined by adjectives such as “satisfied,” “enthusiastic,” and “energetic” in a paper by Geschwind et al. predicted response and remission in MDD patients after 6 weeks (Geschwind et al., 2011).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Geschwind et al., 2011 source
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PremisecitationIn animal models of depression, dopamine depletion in NAc leads to lack of motivation but not reduced liking.
“In animal models of depression, dopamine depletion in the nucleus accumbens (NAc) was shown to lead to a lack of motivation as expressed by reduction of appetitive seeking (Berridge and Robinson, 1998) but not to a reduction of liking (orofacial expression to sucrose and disgust reaction to quinine) (Wise and Raptis, 1986).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Berridge and Robinson, 1998 source
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- cites Wise and Raptis, 1986
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PremisecitationThe importance of OFC in reward processing has been challenged.
“However, the importance of the OFC has been challenged in this and other work (Berridge and Kringelbach, 2008; Stalnaker et al., 2015).”
Quote in the paperNot a substantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationIncreased mPFC excitability leads to reductions in striatal BOLD response to midbrain dopaminergic stimulation and in reward-seeking behavior.
“Furthermore, increased excitability of the mPFC, as shown in depression, led to reductions of BOLD signal in response to stimulation of midbrain dopaminergic neurons in the striatum and of reward-seeking behavior as measured with the sucrose preference test and social interaction test (Ferenczi et al., 2016).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Ferenczi et al., 2016 source
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InterpretationreasoningThe direction of changes in connectivity during reward processing is not consistent, which might be related to differences in used stimuli and investigated reward subdomains.
“However, the direction of these changes are not consistent, which might be related to differences in used stimuli and investigated reward subdomains (Table 1).”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationMFB connects VTA with NAc via mesolimbic dopaminergic connection and VTA with PFC via mesocortical dopaminergic connection.
“This structure connects the VTA with the NAc via the mesolimbic dopaminergic connection and the VTA with the PFC via the mesocortical dopaminergic connection (Döbrössy et al., 2015).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Döbrössy et al., 2015 source
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InterpretationcitationNAc is described as central hub with reduced functional connections to OFC and ACC, and reduced connectivity between insula, ACC, and OFC in MDD.
“From a network perspective, the NAc has been described as a central hub, with reduced functional connections to cortical regions such as the OFC and ACC as well as reduced connectivity between cortical regions such as the insula, ACC, and OFC (Figure 1).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Figure 1
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PremisecitationTRD patients showed disruption of functional connectivity of the OFC and reduced volume of the caudate compared with TSD patients.
“In another study, TRD patients showed disruption of functional connectivity of the OFC and reduced volume of the caudate compared with TSD patients.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Ma et al., 2012
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PremisecitationIn MDD vs HCs, caudate response is reduced for both reward anticipation and consummatory pleasure, with increased activation in middle frontal gyrus and dorsal ACC during reward anticipation.
“When distinguishing between different aspects of reward processing, namely reward anticipation and consummatory pleasure, reduction of caudate response was reported for both conditions along with an increased activation in the middle frontal gyrus and dorsal ACC during reward anticipation in patients vs healthy controls (HCs) (Zhang et al., 2013).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Zhang et al., 2013 source
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Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing).
PremisecitationDepression is associated with deficits in reward motivation to a greater extent than consummatory aspects of reward.
“It was suggested that depression is associated with deficits in reward motivation to a greater extent than consummatory aspects of reward (Chentsova-Dutton and Hanley, 2010; Lally et al., 2014).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Chentsova-Dutton and Hanley, 2010
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- cites Lally et al., 2014 source
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PremisecitationDuring reward processing, in loss vs reward conditions, higher coupling between the VS and prefrontal areas including the ACC, and connectivity of the VS with the left caudate and mid-cingulate, was observed, mainly driven by higher connectivity during loss/disappointment vs relief/win.
“During reward processing, more specifically loss vs reward conditions, higher coupling between the VS and prefrontal areas, including the ACC, as well as connectivity of the VS and the left caudate and mid-cingulate was shown, which was mainly driven by higher connectivity during loss/disappointment vs relief/win (Quevedo et al., 2017).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Quevedo et al., 2017 source
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Study design and conductreasoningAnalysis of functional connectivity allows only indirect measurements of connections between areas because it represents statistical analysis of synchronous fluctuations in neural activity of two brain regions, without statement about anatomical tracts and fibers, and with uncertainty if connectivity might be based on shared modulation by a third region or if other regions are interposed.
“Furthermore, the analysis of functional connectivity allows for only the indirect measurements of connections between areas because it represents the statistical analysis of synchronous fluctuations in neural activity of two brain regions, without statement about anatomical tracts and fibers as well as uncertainty if this connectivity might be based on the shared modulation by a third region or if”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
PremisecitationA neuroanatomical core pathology was proposed including reward-related areas such as the insula, OFC, vmPFC, and VS among other subcortical areas.
“First, a “neuroanatomical core pathology” was proposed including reward-related areas such as the insula, OFC, vmPFC, and VS among other subcortical areas.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Drysdale et al., 2017 source
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PremisecitationOther studies show significantly reduced response to rewarding monetary outcomes in NAc and caudate and equally disrupted anticipatory and consummatory pleasure in daily activities in depressed patients, not supporting greater motivation deficits.
“However, this fact is not supported by other studies that showed significantly reduced response to rewarding monetary outcomes in the NAc and the caudate (Pizzagalli et al., 2009) and equally disrupted anticipatory and consummatory pleasure in daily activities in depressed patients (Wu et al., 2017).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Pizzagalli et al., 2009 source
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- cites Wu et al., 2017
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PremisecitationThree core symptoms were present in >90% of included patients, one of which was anhedonia (96.7%).
“It was further described that 3 “core” symptoms were present in >90% of included patients, one of which was anhedonia (96.7%).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Drysdale et al., 2017 source
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Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).
Interpretationnone givenDifferences in reward tasks used, analysis approaches, and presentation in published material hamper comparability of results and their summarized presentation.
“However, differences in reward tasks used, analysis approaches, and presentation in published material hamper the comparability of results and their summarized presentation (Figure 1).”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationDifference in VS is reduced by SSRI treatment and correlates with extent of symptom reduction.
“Importantly, this difference in the VS was reduced by SSRI treatment and correlated with the extent of symptom reduction (Takamura et al., 2017).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Takamura et al., 2017 source
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PremisecitationStudies examining serotonergic drugs on reward processing in HCs revealed significant effects of both acute and prolonged treatment with drugs enhancing serotonergic transmission such as SSRIs and SNRIs and suppression of serotonergic transmission using acute tryptophan depletion.
“These studies revealed significant effects both of acute and prolonged treatment with drugs enhancing serotonergic transmission such as SSRIs and SNRIs and suppression of serotonergic transmission using acute tryptophan depletion in HCs (for a review, see (Macoveanu, 2014).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Macoveanu, 2014 source
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PremisecitationDopaminergic neurons increase firing rate for unpredicted reward outcomes only, whereas expected rewards provoke no change in dopamine firing rate.
“It was thus shown that dopaminergic neurons increase the firing rate for unpredicted reward outcomes only, whereas expected rewards provoke no change in dopamine firing rate.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Schultz, 2016 source
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PremisecitationOptogenetic stimulation of DRN neurons led to exploration of stimulation-coupled spatial regions, shift in sucrose preference, optical self-stimulation, and guidance of sensory discrimination learning on a behavioral level.
“Optogenetic stimulation of DRN neurons led to exploration of stimulation-coupled spatial regions, shift in sucrose preference, optical self-stimulation, and guidance of sensory discrimination learning on a behavioral level.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Liu et al., 2014 source
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PremisecitationAnother study using citalopram found a reduction of activation within the VS as well as the vmPFC/OFC to positive stimuli and of the OFC in response to aversive stimuli.
“However, another study using citalopram found a reduction of the activation within the VS as well as the vmPFC/OFC to positive stimuli and of the OFC in response to aversive stimuli (McCabe et al., 2010).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites McCabe et al., 2010 source
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May combine two claims.
PremisecitationDifferent transmitter systems might mediate different domains of reward, with consummatory pleasure linked to the opioid and serotonergic system and anticipatory pleasure mainly to dopaminergic mechanisms.
“It has been suggested that different transmitter systems might mediate different domains of reward, with consummatory pleasure being linked to the opioid and serotonergic system and anticipatory pleasure mainly to dopaminergic mechanisms (Barbano and Cador, 2007; Der-Avakian et al., 2016).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Barbano and Cador, 2007
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- cites Der-Avakian et al., 2016 source
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PremisecitationThese biotypes showed different response rates for rTMS treatment of the dmPFC, and the combination of biotype classification and connectivity features had a high predictive accuracy of 89.6%.
“These biotypes showed different response rates for repeated transcranial magnetic stimulation (rTMS) treatment of the dmPFC and the combination of biotype classification and connectivity features had a high predictive accuracy of 89.6% (Drysdale et al., 2017).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Drysdale et al., 2017 source
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PremisecitationAn animal study showed that the DRN increases firing rates during reward-associated tasks and that effects are mediated via the serotonergic and glutamatergic system on a postsynaptic level.
“Importantly, an animal study showed that the DRN increases firing rates during reward-associated tasks and that effects are mediated via the serotonergic and glutamatergic system on a postsynaptic level.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Liu et al., 2014 source
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PremisecitationA number of brain regions, such as the frontal cortex and the hippocampus, provide glutamatergic input to the VTA and NAc.
“It has been described that a number of brain regions, such as the frontal cortex and the hippocampus, provide glutamatergic input to the VTA and NAc (Nestler, 2015).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Nestler, 2015 source
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PremisecitationTwo biotypes showed hyperconnectivity in thalamic and frontostriatal networks and were related to increased anhedonia and psychomotor retardation.
“Particularly, 2 biotypes should be highlighted that showed hyperconnectivity in thalamic and frontostriatal networks and were related to increased anhedonia and psychomotor retardation.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Drysdale et al., 2017 source
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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisenone givenThe dopaminergic system is traditionally associated with reward processing, which has been confirmed in preclinical and clinical studies.
“The dopaminergic system is traditionally associated with reward processing, which has been confirmed in a number of preclinical and clinical studies.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationThe VTA contains dopaminergic neurons (about 60% of all VTA neurons), GABAergic (25%), and glutamatergic (15%) neurons.
“In fact, the VTA contains not only dopaminergic neurons, which constitute about 60% of all VTA neurons, but also GABAergic (25%) and glutamatergic (15%) neurons (Volman et al., 2013).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Volman et al., 2013 source
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The paper relies on this without support.
Intact hedonic capacity requires an undisturbed interplay between a number of different brain regions and transmitter systems.
“Intact hedonic capacity requires an undisturbed interplay between a number of different brain regions and transmitter systems.”
The paper relies on this without support.
The clinical phenotype of anhedonia reflects dysfunctional processing of reward on a neurobiological level.
“The clinical phenotype of anhedonia is thought to reflect a dysfunctional processing of reward on a neurobiological level.”
The paper relies on this without support.
Depression is a complex network disorder rather than a dysfunction of a few specific brain regions.
“Scientific progress with refinement and evolution of the technical possibilities to investigate brain function have led to the perception that depression is a complex network disorder rather than a dysfunction of a few specific brain regions.”
The paper relies on this without support.
Current subtypes of depression based on clinical stratification have only limited relevance for prognosis and treatment choice.
“Current subtypes of depression are based on clinical stratification without inclusion of neurobiological information and have only limited relevance for prognosis and treatment choice.”
The paper relies on this without support.
Treatment does not influence all aspects of reward processing to the same extent.
“it was suggested that treatment does not influence all aspects of reward processing to the same extent, with some studies showing stronger effects on reward anticipation than consummatory aspects of reward.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Increased functional connectomes and activities of the DMN and LIM areas are related to suicide, including the orbitofrontal cortex, medial prefrontal cortex, cingulate cortex, and striatum.
“Studies have shown that the increased functional connectomes and activities of the DMN and LIM areas are related to suicide, including the orbitofrontal cortex, medial prefrontal cortex, cingulate cortex, and striatum [56-59].”
From Mapping neurophysiological subtypes of major depressive disorder using normative models of the functional connectome (2023) · cites this paper as [57]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Greenberg study lists no controls despite a reported control-group result
MinorTable 1 records zero healthy controls for Greenberg et al. (2015), but the text attributes an association to both healthy controls and MDD patients in its discussion of that study.
“| Greenberg | 2015 | 148 | 148 MDD | 0 | Monetary reward | VS |”
“This disruption was associated with anhedonia severity both in HCs and MDD patients.”
Gong study sample sizes differ between table and text
MinorTable 1 lists 80 patients and 43 healthy controls for Gong et al. (2017), whereas the text describes the study as having 75 patients and 42 controls.
“| Gong | 2017 | 123 | 80 MDD | 43 | None | NAc |”
“In a resting-state fMRI study in 75 unmedicated MDD patients and 42 HCs, disrupted functional connectivity was reported for the NAc with the caudate, medial OFC, rostral ACC, superior temporal gyrus (left), insular lobe, dorsomedial PFC (dmPFC), and dorsal ACC (Gong et al., 2017).”
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“Compared with fMRI studies investigating neural activation, less data are available on the disruption of reward processing in MDD on a network level (Kraus et al., 2017b; Spies et al., 2017; Kraus et al., 2018).”
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“%) compared with an overall rate of 46% (Goodwin et al., 2017).”
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Understanding the effects of chronic benzodiazepine use in depression: a focus on neuropharmacology
Lim, B., Sproule, B. A., Zahra, Z., Sunderji, N., Kennedy, S. H., & Rizvi, S. J. (2020) · International Clinical Psychopharmacology · doi:10.1097/yic.0000000000000316 · Cited by 50 · see citing works
Altered hippocampal subfield volumes in major depressive disorder with and without anhedonia
Wu, C., Jia, L., Mu, Q., Fang, Z., Hamoudi, H. J. A. S., Huang, M., Hu, S., Zhang, P., Xu, Y., & Lu, S. (2023) · BMC Psychiatry · doi:10.1186/s12888-023-05001-6 · Cited by 29 · see citing works
Advances in the research of comorbid insomnia and depression: mechanisms, impacts, and interventions
Gao, T., Xiang, H., Wu, Q. N., Zhu, L. S., Pei, W. J., Fu, W. J., & Chou, T. S. (2025) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2025.1468212 · Cited by 17 · see citing works
- Authors
- Höflich, A., Michenthaler, P., Kasper, S., & Lanzenberger, R.
- Affiliations
- Medical University of Vienna (AT)
- Corresponding author
- Lanzenberger, Rupert
- Venue
- International Journal of Neuropsychopharmacology
- Publisher
- Oxford University Press (OUP)
- Published
- 2018-09-15
- Volume
- 22
- Issue
- 2
- Pages
- 105-118
- ISSN
- 1461-1457 (ISSN-L)
- 1469-5111
- PMC
- PMC6368373
- OpenAlex
- W2892070805
- Semantic Scholar
- e4525c9fb953683a5d52d731adac182033a00f1c
- Cited by
- 253
- References
- 125
- Citations by year
- 2026: 32 · 2025: 47 · 2024: 45 · 2023: 49 · 2022: 27 · 2021: 30 · 2020: 15 · 2019: 8
- FWCI
- 1.71
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- The International Journal of Neuropsychopharmacology (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural and Behavioral Psychology Studies
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Keywords
- anhedonia, depression, reward processing, reward systems, neurotransmitter systems, deep brain stimulation, optogenetics, functional connectivity, motivation, psychiatric treatment, personalized treatment
- MeSH terms
- Major Depressive Disorder, Humans, Nerve Net, Reward, Anhedonia, Connectome
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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