Blunted reward responsiveness in remitted depression

Major depressive disorder has been associated with blunted responsiveness to rewards, but inconsistencies exist whether such abnormalities persist after complete remission. To address this issue, across two independent studies, 47 adults with remitted major depressive disorder (rMDD) and 37 healthy controls completed a Probabilistic Reward Task, which used a differential reinforcement schedule of social or monetary feedback to examine reward responsiveness (i.e., ability to modulate behavior as a function of reinforcement history). Relative to controls, adults with rMDD showed blunted reward responsiveness. Importantly, a history of depression predicted reduced reward learning above and beyond residual depressive (including anhedonic) symptoms and perceived stress. Findings indicate that blunted reward responsiveness endures even when adults are in remission and might be a trait-related abnormality in MDD. More research is warranted to investigate if blunted reward responsiveness may predict future depressive episodes and whether targeting reward-related deficits may prevent the re-occurrence of the disorder.     

Reduced hedonic capacity in major depressive disorder: Evidence from a probabilistic reward task

ObjectiveAnhedonia, the lack of reactivity to pleasurable stimuli, is a cardinal feature of depression that has received renewed interest as a potential endophenotype of this debilitating disease. The goal of the present study was to test the hypothesis that individuals with major depression are characterized by blunted reward responsiveness, particularly when anhedonic symptoms are prominent.MethodsA probabilistic reward task rooted within signal-detection theory was utilized to objectively assess hedonic capacity in 23 unmedicated subjects meeting DSM-IV criteria for major depressive disorder (MDD) and 25 matched control subjects recruited from the community. Hedonic capacity was defined as reward responsiveness – i.e., the participants’ propensity to modulate behavior as a function of reward.ResultsCompared to controls, MDD subjects showed significantly reduced reward responsiveness. Trial-by-trial probability analyses revealed that MDD subjects, while responsive to delivery of single rewards, were impaired at integrating reinforcement history over time and expressing a response bias toward a more frequently rewarded cue in the absence of immediate reward. This selective impairment correlated with self-reported anhedonic symptoms, even after considering anxiety symptoms and general distress.ConclusionsThese findings indicate that MDD is characterized by an impaired tendency to modulate behavior as a function of prior reinforcements, and provides initial clues about which aspects of hedonic processing might be dysfunctional in depression.     

Reduced hedonic capacity in major depressive disorder: evidence from a probabilistic reward task

Objective

Anhedonia, the lack of reactivity to pleasurable stimuli, is a cardinal feature of depression that has received renewed interest as a potential endophenotype of this debilitating disease. The goal of the present study was to test the hypothesis that individuals with major depression are characterized by blunted reward responsiveness, particularly when anhedonic symptoms are prominent.

Methods

A probabilistic reward task rooted within signal-detection theory was utilized to objectively assess hedonic capacity in 23 unmedicated subjects meeting DSM-IV criteria for major depressive disorder (MDD) and 25 matched control subjects recruited from the community. Hedonic capacity was defined as reward responsiveness - i.e., the participants’ propensity to modulate behavior as a function of reward.

Results

Compared to controls, MDD subjects showed significantly reduced reward responsiveness. Trial-by-trial probability analyses revealed that MDD subjects, while responsive to delivery of single rewards, were impaired at integrating reinforcement history over time and expressing a response bias toward a more frequently rewarded cue in the absence of immediate reward. This selective impairment correlated with self-reported anhedonic symptoms, even after considering anxiety symptoms and general distress.

Conclusions

These findings indicate that MDD is characterized by an impaired tendency to modulate behavior as a function of prior reinforcements, and provides initial clues about which aspects of hedonic processing might be dysfunctional in depression.     

Decreased cognitive control in response to negative information in patients with remitted depression: an event-related potential study

Background

Major depressive disorder (MDD) is associated with difficulty disengaging attention from emotionally negative information. Few studies have investigated whether euthymic individuals with a history of depression (remitted MDD [rMDD]) show similar deficits, and little is known about concomitant neurophysiological features of such deficits. To fill these gaps, we investigated cognitive control over emotional stimuli in participants with rMDD and controls without history of depression or psychopathology.

Methods

We collected 128-channel event-related potentials (ERPs) while participants performed a cued emotional conflict task. During the task, a cue instructed the participant to respond to the actual or opposite valence of an upcoming happy or sad face.

Results

We enrolled 15 individuals with rMDD and 18 controls in our study. Event-related potentials showed no group differences in response to the cues, highlighting preserved preparatory processes when anticipating an emotional conflict. However, relative to the control group, the rMDD group responded more slowly and showed reduced N450 amplitudes on trials that required disengaging from negative faces (pressing “happy” in response to a sad face).

Limitations

The sample size was small, and the null finding in the cue-locked N2 analyses may be owing to low power.

Conclusion

Our results suggest a selective deficit in cognitive control over sad stimuli in individuals with rMDD. Additional studies will be required to pinpoint whether the current findings stem from impairments in response conflict, conflict monitoring and/or attentional disengagement in response to sad stimuli. Moreover, future studies are warranted to evaluate whether decreased cognitive control in response to negative information might increase the risk for future depressive episodes.     

Prefrontal cortical response to emotional faces in individuals with major depressive disorder in remission

Abnormalities in the response of the orbitofrontal cortex (OFC) and dorsolateral prefrontal cortex (DLPFC) to negative emotional stimuli have been reported in acutely depressed patients. However, there is a paucity of studies conducted in unmedicated individuals with major depressive disorder in remission (rMDD) to assess whether these are trait abnormalities. To address this issue, 19 medication-free rMDD individuals and 20 healthy comparison (HC) participants were scanned using functional magnetic resonance imaging while performing an implicit emotion processing task in which they labeled the gender of faces depicting negative (fearful), positive (happy) and neutral facial expressions. The rMDD and HC groups were compared using a region-of-interest approach for two contrasts: fear vs. neutral and happy vs. neutral. Relative to HC, rMDD showed reduced activation in left OFC and DLPFC to fearful (vs. neutral) faces. Right DLPFC activation to fearful (vs. neutral) faces in the rMDD group showed a significant positive correlation with duration of euthymia. The findings support deficits in left OFC and DLPFC responses to negative emotional stimuli during euthymic periods of MDD, which may reflect trait markers of the illness or a 'scar' due to previous depression. Recovery may also be associated with compensatory increases in right DLPFC functioning.     

Weak reward source memory in depression reflects blunted activation of VTA/SN and parahippocampus

Reward responses in the medial temporal lobes and dopaminergic midbrain boost episodic memory formation in healthy adults, and weak memory for emotionally positive material in depression suggests this mechanism may be dysfunctional in major depressive disorder (MDD). To test this hypothesis, we performed a study in which unmedicated adults with MDD and healthy controls encoded drawings paired with reward or zero tokens during functional magnetic resonance imaging. In a recognition test, participants judged whether drawings were previously associated with the reward token (‘reward source’) or the zero token (‘zero source’). Unlike controls, depressed participants failed to show better memory for drawings from the reward source vs the zero source. Consistent with predictions, controls also showed a stronger encoding response to reward tokens vs zero tokens in the right parahippocampus and dopaminergic midbrain, whereas the MDD group showed the opposite pattern—stronger responses to zero vs reward tokens—in these regions. Differential activation of the dopaminergic midbrain by reward vs zero tokens was positively correlated with the reward source memory advantage in controls, but not depressed participants. These data suggest that weaker memory for positive material in depression reflects blunted encoding responses in the dopaminergic midbrain and medial temporal lobes.     

Persistent Ventral Anterior Cingulate Cortex and Resolved Amygdala Hyper-responses to Negative Outcomes After Depression Remission: A Combined Cross-sectional and Longitudinal Study

BackgroundMajor depressive disorder (MDD) is a highly prevalent mood disorder affecting more than 300 million people worldwide. Biased processing of negative information and neural hyper-responses to negative events are hallmarks of depression. This study combined cross-sectional and longitudinal experiments to explore both persistent and resolved neural hyper-responses to negative outcomes from risky decision making in patients with current MDD (cMDD) and remitted MDD (rMDD).MethodsA total of 264 subjects participated in the cross-sectional study, including 117 patients with medication-naïve, first-episode current depression; 45 patients with rMDD with only 1 episode of depression; and 102 healthy control subjects. Participants completed a modified balloon analog risk task during functional magnetic resonance imaging. In the longitudinal arm of the study, 42 patients with cMDD were followed and 26 patients with rMDD were studied again after 8 weeks of antidepressant treatment.ResultsPatients with cMDD showed hyper-responses to loss outcomes in multiple limbic regions including the amygdala and ventral anterior cingulate cortex (vACC). Amygdala but not vACC hyperactivity correlated with depression scores in patients with cMDD. Furthermore, amygdala hyperactivity resolved while vACC hyperactivity persisted in patients with rMDD in both cross-sectional and longitudinal studies.ConclusionsThese findings provide consistent evidence supporting differential patterns of amygdala and vACC hyper-responses to negative outcomes during depression remission. Amygdala hyperactivity may be a symptomatic and state-dependent marker of depressive neural responses, while vACC hyperactivity may reflect a persistent and state-independent effect of depression on brain function. These findings offer new insights into the neural underpinnings of depression remission and prevention of depression recurrence.     

Waiting to win: elevated striatal and orbitofrontal cortical activity during reward anticipation in euthymic bipolar disorder adults

Nusslock R, Almeida JRC, Forbes EE, Versace A, Frank E, LaBarbara EJ, Klein CR, Phillips ML. Waiting to win: elevated striatal and orbitofrontal cortical activity during reward anticipation in euthymic bipolar disorder adults. Bipolar Disord 2012: 14: 249–260. © 2012 The Authors. Journal compilation © 2012 John Wiley & Sons A/S. Objective: Bipolar disorder may be characterized by a hypersensitivity to reward‐relevant stimuli, potentially underlying the emotional lability and dysregulation that characterizes the illness. In parallel, research highlights the predominant role of striatal and orbitofrontal cortical (OFC) regions in reward‐processing and approach‐related affect. We aimed to examine whether bipolar disorder, relative to healthy, participants displayed elevated activity in these regions during reward processing. Methods: Twenty‐one euthymic bipolar I disorder and 20 healthy control participants with no lifetime history of psychiatric disorder underwent functional magnetic resonance imaging (fMRI) scanning during a card‐guessing paradigm designed to examine reward‐related brain function to anticipation and receipt of monetary reward and loss. Data were collected using a 3T Siemens Trio scanner. Results: Region‐of‐interest analyses revealed that bipolar disorder participants displayed greater ventral striatal and right‐sided orbitofrontal [Brodmann area (BA) 11] activity during anticipation, but not outcome, of monetary reward relative to healthy controls (p < 0.05, corrected). Whole‐brain analyses indicated that bipolar disorder, relative to healthy, participants also displayed elevated left‐lateral OFC (BA 47) activity during reward anticipation (p < 0.05, corrected). Conclusions: Elevated ventral striatal and OFC activity during reward anticipation may represent a neural mechanism for predisposition to expansive mood and hypo/mania in response to reward‐relevant cues that characterizes bipolar disorder. Our findings contrast with research reporting blunted activity in the ventral striatum during reward processing in unipolar depressed individuals, relative to healthy controls. Examination of reward‐related neural activity in bipolar disorder is a promising research focus to facilitate identification of biological markers of the illness.     

Neural indicators of emotion regulation via acceptance vs reappraisal in remitted major depressive disorder

Mood disorders are characterized by impaired emotion regulation abilities, reflected in alterations in frontolimbic brain functioning during regulation. However, little is known about differences in brain function when comparing regulatory strategies. Reappraisal and emotional acceptance are effective in downregulating negative affect, and are components of effective depression psychotherapies. Investigating neural mechanisms of reappraisal vs emotional acceptance in remitted major depressive disorder (rMDD) may yield novel mechanistic insights into depression risk and prevention. Thirty-seven individuals (18 rMDD, 19 controls) were assessed during a functional magnetic resonance imaging task requiring reappraisal, emotional acceptance or no explicit regulation while viewing sad images. Lower negative affect was reported following reappraisal than acceptance, and was lower following acceptance than no explicit regulation. In controls, the acceptance > reappraisal contrast revealed greater activation in left insular cortex and right prefrontal gyrus, and less activation in several other prefrontal regions. Compared with controls, the rMDD group had greater paracingulate and right midfrontal gyrus (BA 8) activation during reappraisal relative to acceptance. Compared with reappraisal, acceptance is associated with activation in regions linked to somatic and emotion awareness, although this activation is associated with less reduction in negative affect. Additionally, a history of MDD moderated these effects.     

Increased self-reported reward responsiveness predicts better response to cognitive behavioral therapy for youth with anxiety

Few consistent predictors of differential cognitive behavioral therapy (CBT) outcome for anxious youth have been identified, although emerging literature points to youth reward responsiveness as a potential predictor. In a sample of youth ages 7–17 with a primary anxiety disorder (N = 136; M_age = 12.18 years, SD_age = 3.12; 70 females; Caucasian n = 108, Black n = 12, Asian n = 4, Hispanic n = 5, other n = 7), the current study examined whether youth reward responsiveness assessed via the Behavioral Inhibition and Behavioral Activation System Scales for children, reward responsiveness subscale, predicted post-treatment (a) anxiety symptom severity, (b) depressive symptom severity, (c) functioning, (d) responder status and (e) number of homework/exposure tasks completed following 16-weeks of CBT, controlling for pre-treatment age, sex, anxiety/depressive symptom severity, and functioning. Moderation analyses examined whether relationships differed by age. Increased reward responsiveness was associated with lower anxiety and depressive symptom severity, higher functioning, and increased likelihood of being a responder, but not homework or exposure completion. Moderation analyses showed that younger, but not older, youth who were more reward responsive completed more exposures. Findings indicate that increased reward responsiveness is a predictor of better CBT outcomes for anxious youth, particularly functional outcomes, and that reward responsiveness may play a different role in exposure completion across development.     

Elevated inflammatory markers in women with remitted major depressive disorder and the role of early life maltreatment

Major depressive disorder (MDD) has been linked to elevated inflammation markers. It remains unclear whether the elevation of C-reactive protein (CRP) and interleukin-6 (IL-6) levels are not only observable in acute MDD but also in patients after remission. MDD is a common sequela of early life maltreatment (ELM), which has also been associated with elevated inflammation markers. While the majority of studies investigated (acute) MDD and ELM as isolated predictors of inflammation, a few studies found inflammation levels to be more pronounced in patients with MDD that were exposed to ELM. This investigation included both ELM and MDD in one study and aimed at distinguishing between the effects of MDD in remission (rMDD) and ELM and investigating potential accumulative effects on the inflammatory markers CRP and IL-6 in a population of N = 126 women (n = 122 for CRP and n = 66 for IL-6). We further investigated how disorder characteristics (course and severity) and specific types of ELM affect levels of CRP and IL-6. We found that rMDD predicted levels of CRP and IL-6 and physical abuse predicted levels of CRP when considering both predictors simultaneously, while other types of ELM did not. A later onset of MDD and a shorter time interval since the last episode were associated with higher levels of IL-6. Our findings contribute to the existing literature on the association between MDD and inflammation, suggesting that elevated levels of inflammation markers may persist even after remission of MDD. Our findings on physical abuse as a specific predictor of CRP in the presence of rMDD suggest that different types of ELM could result in distinct inflammation profiles.     

CACNA1C risk variant affects reward responsiveness in healthy individuals

The variant at rs1006737 in the L-type voltage-gated calcium channel (alpha 1c subunit) CACNA1C gene is reliably associated with both bipolar disorder and schizophrenia. We investigated whether this risk variant affects reward responsiveness because reward processing is one of the central cognitive-motivational domains implicated in both disorders. In a sample of 164 young, healthy individuals, we show a dose-dependent response, where the rs1006737 risk genotype was associated with blunted reward responsiveness, whereas discriminability did not significantly differ between genotype groups. This finding suggests that the CACNA1C risk locus may have a role in neural pathways that facilitate value representation for rewarding stimuli. Impaired reward processing may be a transdiagnostic phenotype of variation in CACNA1C that could contribute to anhedonia and other clinical features common to both affective and psychotic disorders.     

Effect of brain structure and function on reward anticipation in children and adults with attention deficit hyperactivity disorder combined subtype

Attention deficit hyperactivity disorder (ADHD) is associated with decreased ventral-striatal responsiveness during reward anticipation. However, previous research mostly focused on adults with heterogeneous ADHD subtype and divers drug treatment status while studies in children with ADHD are sparse. Moreover, it remains unclear to what degree ADHD is characterized by a delay of normal brain structure or function maturation. We therefore attempt to determine whether results from structural and functional magnetic resonance imaging (fMRI) are associated with childhood and adult ADHD combined subtype (ADHD-CT). This study used fMRI to compare VS structure and function of 30 participants with ADHD-CT (16 adults, 14 children) and 30 controls (20 adults, 10 children), using a monetary incentive delay task. Joint analyses of structural and functional imaging data were conducted with Biological Parametric Mapping. Reward anticipation elicited decreased ventral-striatal responsiveness in adults but not in children with ADHD-CT. Children and adults with ADHD showed reduced ventral-striatal volume. Taking these gray matter differences into account, the results remained the same. These results suggest that decreased ventral-striatal responsiveness during reward anticipation is present in adults but not in children with ADHD-CT, irrespective of structural characteristics. The question arises whether ventral-striatal hypoactivity is an ADHD correlate that develops during the course of illness.     

Differential effects of 5-HTTLPR genotypes on the behavioral and neural responses to tryptophan depletion in patients with major depression and controls

CONTEXT: Tryptophan depletion (TD) is a model used to study the contribution of reduced serotonin transmission to the pathogenesis of major depressive disorder (MDD). Recent studies have not sufficiently addressed the relative contribution of a functional-length triallelic polymorphism in the promoter of the serotonin transporter, 5-HTTLPR, to the behavioral and neural responses to TD in individuals with remitted MDD (rMDD) and controls. OBJECTIVE: To determine the role of 5-HTTLPR on the behavioral and neural responses to TD in medication-free patients with rMDD and individually matched controls. DESIGN: Participants were stratified according to diagnosis and 5-HTTLPR genotypes and underwent TD on one test day and sham depletion on the other test day in a prospective, double-blind, randomized order. SETTING: Outpatient clinic. PARTICIPANTS: Twenty-seven medication-free patients with rMDD (18 women and 9 men) and 26 controls (17 women and 9 men). INTERVENTIONS: Tryptophan depletion was induced by administration of capsules containing an amino acid mixture without tryptophan. Sham depletion used identical capsules containing lactose. Fludeoxyglucose F 18 positron emission tomography was performed 6 hours after TD. Magnetic resonance images were obtained for each participant. MAIN OUTCOME MEASURES: Quantitative positron emission tomography of regional cerebral metabolic rates for glucose and measures of depression using the Hamilton Depression Rating Scale. RESULTS: Behavioral responses to TD are affected by 5-HTTLPR in patients with rMDD and controls. A direct effect of 5-HTTLPR on the regulation of regional cerebral metabolic rates for glucose was identified in patients with rMDD for the amygdala, hippocampus, and subgenual anterior cingulate cortex. CONCLUSIONS: Variations in 5-HTTLPR modulate the sensitivity of patients with rMDD and controls to the behavioral effects of TD. In patients with rMDD, variations in triallelic 5-HTTLPR have a direct effect on regulation of regional cerebral metabolic rates for glucose in a corticolimbic circuit that has been implicated in rMDD.     

Congruence between diagnosis of recurrent major depressive disorder and psychotropic treatment in the general population

Objective: We explored in a sample representative of the French general population the congruence between lifetime use of psychotropic drugs and diagnosis of recurrent major depressive disorder (rMDD). Method: A total of 2111 (5.6%) subjects with rMDD were identified in the sample of 36 785 subjects assessed in the Mental Health survey in the General Population. A treatment congruent with a diagnosis of rMDD was defined as lifetime use of antidepressants or mood stabilizers. Results: Only one‐third of subjects with rMDD reported having ever used a congruent treatment. Female gender, higher income and presence of anxiety disorder were associated with a higher probability of having used a congruent treatment. Conclusion: Although these findings indicate that a large proportion of subjects with rMMD do not benefit from adequate treatment, community surveys not primarily designed to assess utilization and adequacy of psychotropic treatment in the community may overestimate the frequency of unmet need for care.     

Toward an objective characterization of an anhedonic phenotype: a signal-detection approach.

BACKGROUND: Difficulties in defining and characterizing phenotypes has hindered progress in psychiatric genetics and clinical neuroscience. Decreased approach-related behavior and anhedonia (lack of responsiveness to pleasure) are considered cardinal features of depression, but few studies have used laboratory-based measures to objectively characterize these constructs. METHODS: To assess hedonic capacity in relation to depressive, particularly anhedonic, symptoms, 62 participants completed a signal-detection task based on a differential reinforcement schedule. Anhedonia was operationalized as decreased reward responsiveness. RESULTS: Unequal frequency of reward between two correct responses produced a response bias (i.e., a systematic preference to identify the stimulus paired with the more frequent reward). Subjects with elevated depressive symptoms (Beck Depression Inventory scores >/= 16) failed to show a response bias. Impaired reward responsiveness predicted higher anhedonic symptoms 1 month later, after controlling for general negative affectivity. CONCLUSIONS: Impaired tendency to modulate behavior as a function of prior reinforcement might underline diminished hedonic capacity in depression. When applied to a clinical population, objective assessments of participants' propensity to modulate behavior as a function of reward might provide a powerful tool for improving the phenotypic definition of depression and thus offer a reliable behavioral screening approach for neuroscience studies of depression.     

Attenuated intrinsic connectivity within cognitive control network among individuals with remitted depression: Temporal stability and association with negative cognitive styles

Many individuals with major depressive disorder (MDD) experience cognitive dysfunction including impaired cognitive control and negative cognitive styles. Functional connectivity magnetic resonance imaging studies of individuals with current MDD have documented altered resting‐state connectivity within the default‐mode network and across networks. However, no studies to date have evaluated the extent to which impaired connectivity within the cognitive control network (CCN) may be present in remitted MDD (rMDD), nor have studies examined the temporal stability of such attenuation over time. This represents a major gap in understanding stable, trait‐like depression risk phenotypes. In this study, resting‐state functional connectivity data were collected from 52 unmedicated young adults with rMDD and 47 demographically matched healthy controls, using three bilateral seeds in the CCN (dorsolateral prefrontal cortex, inferior parietal lobule, and dorsal anterior cingulate cortex). Mean connectivity within the entire CCN was attenuated among individuals with rMDD, was stable and reliable over time, and was most pronounced with the right dorsolateral prefrontal cortex and right inferior parietal lobule, results that were corroborated by supplemental independent component analysis. Attenuated connectivity in rMDD appeared to be specific to the CCN as opposed to representing attenuated within‐network coherence in other networks (e.g., default‐mode, salience). In addition, attenuated connectivity within the CCN mediated relationships between rMDD status and cognitive risk factors for depression, including ruminative brooding, pessimistic attributional style, and negative automatic thoughts. Given that these cognitive markers are known predictors of relapse, these results suggest that attenuated connectivity within the CCN could represent a biomarker for trait phenotypes of depression risk. Hum Brain Mapp 38:2939–2954, 2017. © 2017 Wiley Periodicals, Inc.     

Lipopolysaccharide,Immune Biomarkers and Cerebral Amyloid-Beta Deposition in Older Adults With Mild Cognitive Impairment & Major Depressive Disorder

ObjectiveInflammatory activation and increased immune response to lipopolysaccharide occur in both depression and cognitive decline and may link these two conditions. We investigated whether lipopolysaccharide (LPS), LPS binding protein (LBP) and peripheral biomarkers of immune response were associated with increased cerebral deposition of amyloid-beta (Abeta) in older adults with mild cognitive impairment (MCI) and remitted major depressive disorder (rMDD).DesignCross-sectional analysis.SettingFive academic health centers in Toronto.ParticipantsOlder adults with MCI with/without rMDD.MeasurementsWe investigated the associations among serum LPS, LBP, biomarkers of inflammatory activation – Interleukin-6 (IL-6), C-reactive protein (CRP), monocyte chemoattractant protein-1 (MCP-1), and cerebral Abeta deposition quantified by positron emission tomography.ResultsAmong 133 study participants (82 with MCI and 51 with MCI+rMDD) there was no association between LPS (beta – 0.17, p = 0.8) or LBP (beta - 0.11, p = 0.12) and global deposition of Abeta following adjustment for age, gender, and APOE genotype in multivariable regression analyses. LBP was positively correlated with CRP (r = 0.5, p <0.001) and IL-6 (r = 0.2, p = 0.02) but no inflammatory biomarker was associated with Abeta deposition; rMDD was not associated with deposition of Abeta (beta -0.09, p = 0.22).ConclusionIn this cross-sectional analysis, we did not find an association among LPS/LBP, immune biomarkers or rMDD and global deposition of Abeta. Future analyses should assess the longitudinal relationships between peripheral and central biomarkers of immune activation, depression and cerebral Abeta deposition.     

Normal prefrontal gamma-aminobutyric acid levels in remitted depressed subjects determined by proton magnetic resonance spectroscopy.

BACKGROUND: There is growing evidence that the brain gamma-aminobutyric acid (GABA) system is involved in depression. Lowered plasma GABA levels were identified as a traitlike abnormality found in patients with remitted unipolar depression and in healthy first-degree relatives of patients with unipolar depression. Major depressive disorder has been associated with neuroimaging and neuropathological abnormalities in the prefrontal cortex by various types of evidence. As a result, the current study investigates whether GABA levels in the prefrontal cortex differ between unmedicated subjects with remitted major depressive disorder (rMDD) and healthy control subjects. METHODS: Sixteen rMDD subjects and 15 healthy control subjects underwent magnetic resonance spectroscopy. We used a 3 Tesla GE whole body scanner with a homogeneous resonator coil providing a homogenous radiofrequency field and capability of obtaining measurement from the prefrontal cortex. Gamma-aminobutyric acid levels were measured in the ventromedial prefrontal cortex and dorsolateral/anterior medial prefrontal cortex. RESULTS: There was no difference in GABA concentrations between rMDD subjects and healthy control subjects in the ventromedial prefrontal cortex and dorsolateral/anterior medial prefrontal cortex. Secondary analyses provided preliminary evidence for a negative relationship between the glutamate/glutamine (Glx)/GABA ratio and age of onset of major depression in the ventromedial prefrontal cortex. CONCLUSIONS: This result suggests that GABA levels in the prefrontal cortex, if found to be reduced in symptomatic depression, do not represent a persistent characteristic of major depression. Further research is needed to determine brain GABA levels in different brain regions, in different stages of depressive illness, and in different depressive subtypes.     

Assessment of reward responsiveness in the response bias probabilistic reward task in rats: implications for cross-species translational research

Mood disorders, such as major depressive disorder, are characterized by abnormal reward responsiveness. The Response Bias Probabilistic Reward Task (hereafter referred to as probabilistic reward task (PRT)) quantifies reward responsiveness in human subjects, and an equivalent animal assessment is needed to facilitate preclinical translational research. Thus, the goals of the present studies were to develop, validate and characterize a rat analog of the PRT. Adult male Wistar and Long–Evans rats were trained in operant testing chambers to discriminate between two tone stimuli that varied in duration (0.5 and 2 s). During a subsequent test session consisting of 100 trials, the two tones were made ambiguous (0.9 and 1.6 s) and correct identification of one tone was reinforced with a food pellet three times more frequently than the other tone. In subsequent experiments, Wistar rats were administered either a low dose of the dopamine D₂/D₃ receptor agonist pramipexole (0.1 mg kg⁻¹, subcutaneous) or the psychostimulant amphetamine (0.5 mg kg⁻¹, intraperitoneal) before the test session. Similar to human subjects, both rat strains developed a response bias toward the more frequently reinforced stimulus, reflecting robust reward responsiveness. Mirroring prior findings in humans, a low dose of pramipexole blunted response bias. Moreover, in rats, amphetamine potentiated response bias. These results indicate that in rats, reward responsiveness can be quantified and bidirectionally modulated by pharmacological manipulations that alter striatal dopamine transmission. Thus, this new procedure in rats, which is conceptually and procedurally analogous to the one used in humans, provides a reverse translational platform to investigate abnormal reward responsiveness across species.