Decreased Fronto-Limbic Activation and Disrupted Semantic-Cued List Learning in Major Depressive Disorder.

OBJECTIVES: Individuals with major depressive disorder (MDD) demonstrate poorer learning and memory skills relative to never-depressed comparisons (NDC). Previous studies report decreased volume and disrupted function of frontal lobes and hippocampi in MDD during memory challenge. However, it has been difficult to dissociate contributions of short-term memory and executive functioning to memory difficulties from those that might be attributable to long-term memory deficits. METHODS: Adult males (MDD, n=19; NDC, n=22) and females (MDD, n=23; NDC, n=19) performed the Semantic List Learning Task (SLLT) during functional magnetic resonance imaging. The SLLT Encoding condition consists of 15 lists, each containing 14 words. After each list, a Distractor condition occurs, followed by cued Silent Rehearsal instructions. Post-scan recall and recognition were collected. Groups were compared using block (Encoding-Silent Rehearsal) and event-related (Words Recalled) models. RESULTS: MDD displayed lower recall relative to NDC. NDC displayed greater activation in several temporal, frontal, and parietal regions, for both Encoding-Silent Rehearsal and the Words Recalled analyses. Groups also differed in activation patterns in regions of the Papez circuit in planned analyses. The majority of activation differences were not related to performance, presence of medications, presence of comorbid anxiety disorder, or decreased gray matter volume in MDD. CONCLUSIONS: Adults with MDD exhibit memory difficulties during a task designed to reduce the contribution of individual variability from short-term memory and executive functioning processes, parallel with decreased activation in memory and executive functioning circuits. Ecologically valid long-term memory tasks are imperative for uncovering neural correlates of memory performance deficits in adults with MDD.

Dual-tasking gait variability and cognition in late-life depression.

OBJECTIVES: Studies have demonstrated an association between major depressive disorder (MDD) symptoms and fall risk in older adults, which may be at least partially mediated by executive functioning skills. There have also been observations of increased gait variability associated with fall risk and disease. This preliminary study first sought to understand whether gait variability in the context of dual task cost differs among older adults with MDD, relative to those with no history of psychiatric illness, and second, to identify relationships between gait variability measures and cognitive functioning in the context of MDD. METHODS: We recruited 15 older adults with MDD and 17 non-depressed (ND) community-dwelling older adults. All participants had impaired balance based on unipedal stance time. Assessments included neuropsychological measures and measures of gait variability using an instrumented gait mat (GAITRite© ) in the context of dual task relative to single task performance (i.e., dual task cost). RESULTS: The groups did not differ on any gait variability parameters. The MDD group demonstrated poorer performance in the psychomotor speed domain, relative to the ND group, but cognitive functioning between the groups in other domains was equivalent. In MDD, increased variability in stride time, stride velocity, and swing time during dual-tasking were associated with poorer executive functioning and visual memory. In ND, no significant relationships between gait variables and cognitive performance were observed. CONCLUSIONS: Findings suggest that unique cognitive mechanisms underlie mobility problems associated with fall risk in late-life depression.

Differential prefrontal and subcortical circuitry engagement during encoding of semantically related words in patients with late-life depression.

OBJECTIVE: Verbal memory difficulties are common among individuals with late-life depression (LLD), though there is limited knowledge about disruptions to underlying cerebral circuitry. The purpose of this study is to examine aberrations to cerebral networks implicated in encoding novel verbal semantic material among older adults with LLD. METHODS: Twenty-four older adults with early-onset LLD and 23 non-depressed comparisons participated in the study. Participants completed a word list-learning task while undergoing functional magnetic resonance imaging. RESULTS: In the context of equivalent recall and recognition of words following scanning and similar hippocampal volumes, patients with LLD exhibited less activation in structures known to be relevant for new learning and memory, including hippocampus, parahippocampal gyrus, insula, and cingulate, relative to non-ill comparisons. An important region in which the LLD group displayed greater activation than the non-depressed comparison group was in left inferior frontal gyrus, an area involved in cognitive control and controlled semantic/phonological retrieval and analysis; this region may be critical for LLD patients to consolidate encoded words into memory. CONCLUSIONS: Functional irregularities found in LLD patients may reflect different modes of processing to-be-remembered information and/or early changes predictive of incipient cognitive decline. Future studies might consider mechanisms that could contribute to these functional differences, including hypothalamic-pituitary-adrenal axis functioning and vascular integrity, and utilize longitudinal designs in order to understand whether functional changes are predictive of incipient cognitive decline.

The impact of depression on dual tasking among patients with high fall risk.

Depression predicts fall risk among older adults, and this relationship may be partially explained by depression-associated executive dysfunction, relevant to navigating demanding environments. This pilot study examined timed stepping accuracy under simple and complex dual-task conditions, using an instrumented walkway based on the Trail Making Test. Participants were balance-impaired older adults, either with (n = 8; major depressive disorder [MDD]) or without (n = 8; nondepressed [ND]) MDD. After accounting for comfortable gait speed and age, the MDD group was significantly slower than the ND group on the walkway with the highest cognitive demand and demonstrated greater dual-task cost, both of which were correlated with performance on traditional measures of executive functioning. No group differences were observed on the walkway with the least cognitive demand. Balance-impaired older adults with MDD demonstrate increased stepping accuracy time under cognitively demanding conditions, reflecting executive dysfunction and an additional contribution to increased fall risk.

Examining HPA-axis functioning as a mediator of the relationship between depression and cognition across the adult lifespan.

Altered HPA-axis functioning is a hypothesized mechanism for worsened cognition in depression. The current study examines the indirect effects of depression on processing speed, executive functioning, and memory as a function of the HPA-axis. 38 individuals with a depression diagnosis and 50 healthy controls (HCs) aged 18-86 underwent neuropsychological testing and at-home diurnal salivary cortisol collection. Depression was assessed via structured clinical interviews and rating scales. Cognitive composite scores were derived from factor analysis. Daytime cortisol exposure was estimated using area under the curve (AUC). Depression was associated with higher cortisol levels and slower processing speed . A significant suppression effect of AUC was present on the relationship between depression and processing speed. Limitations include the cross-sectional design and limited sample heterogeneity. Though poorly modulated HPA-axis is one proposed mechanism of cognitive alterations in depression, our results did not support this conclusion for processing speed. Alternative mechanisms should be considered to inform interventions to target cognitive alterations in depression.

Striatal dopamine D2/3 receptor-mediated neurotransmission in major depression: Implications for anhedonia, anxiety and treatment response.

Dopamine (DA) neurotransmission within the brain's reward circuit has been implicated in the pathophysiology of depression and in both, cognitive and pharmacological mechanisms of treatment response. Still, a direct relationship between measures of DA neurotransmission and reward-related deficits in patients with depression has not been demonstrated. To gain insight into the symptom-specific alterations in the DA system in patients with depression, we used positron emission tomography (PET) and the D2/3 receptor-selective radiotracer [11C]raclopride in twenty-three non-smoking un-medicated Major Depressive Disorder (MDD) patients and sixteen healthy controls (HC). We investigated the relationship between D2/3 receptor availability and baseline measures of depression severity, anxiety, anhedonia, and cognitive and pharmacological mechanisms of treatment response. We found that, compared to controls, patients with depression showed greater D2/3 receptor availability in several striatal regions, including the bilateral ventral pallidum/nucleus accumbens (vPAL/NAc), and the right ventral caudate and putamen. In the depressed sample, D2/3 receptor availability in the caudal portion of the ventral striatum (NAc/vPAL) correlated with higher anxiety symptoms, whereas D2/3 receptor availability in the rostral area of the ventral striatum correlated negatively with the severity of motivational anhedonia. Finally, MDD non-remitters showed greater baseline anxiety, greater D2/3 availability in the NAc/vPAL, and greater placebo-induced DA release in the bilateral NAc. Our results demonstrate abnormally high D2/3 receptor availability in the ventral striatum of patients with MDD, which seem to be associated with comorbid anxiety symptoms and lack of response to antidepressants.

Executive Functioning at Baseline Prospectively Predicts Depression Treatment Response.

OBJECTIVE: Existing cognitive and clinical predictors of treatment response to date are not of sufficient strength to meaningfully impact treatment decision making and are not readily employed in clinical settings. This study investigated whether clinical and cognitive markers used in a tertiary care clinic could predict response to usual treatment over a period of 4 to 6 months in a sample of 75 depressed adults. METHODS: Patients (N = 384) were sequentially tested in 2 half-day clinics as part of a quality improvement project at an outpatient tertiary care center between August 2003 and September 2007; additional subjects evaluated in the clinic between 2007 and 2009 were also included. Diagnosis was according to DSM-IV-TR criteria and completed by residents and attending faculty. Test scores obtained at intake visits on a computerized neuropsychological screening battery were the Parametric Go/No-Go task and Facial Emotion Perception Task. Treatment outcome was assessed using 9-item Patient Health Questionnaire (PHQ-9) self-ratings at follow-up (n = 75). Usual treatment included psychotropic medication and psychotherapy. Decline in PHQ-9 scores was predicted on the basis of baseline PHQ-9 score and education, with neuropsychological variables entered in the second step. RESULTS: PHQ-9 scores declined by 46% at follow-up (56% responders). Using 2-step multiple regression, baseline PHQ-9 score (P ≤ .05) and education (P ≤ .01) were significant step 1 predictors of percent change in PHQ-9 follow-up scores. In step 2 of the model, faster processing speed with interference resolution (go reaction time) independently explained a significant amount of variance over and above variables in step 1 (12% of variance, P < .01), while other cognitive and affective skills did not. This 2-step model accounted for 28% of the variance in treatment change in PHQ-9 scores. Processing speed with interference resolution also accounted for 12% variance in treatment and follow-up attrition. CONCLUSIONS: Use of executive functioning assessments in clinics may help identify individuals with cognitive weaknesses at risk for not responding to standard treatments.

Salience Network Functional Connectivity Predicts Placebo Effects in Major Depression.

BACKGROUND: Recent neuroimaging studies have demonstrated resting-state functional connectivity (rsFC) abnormalities among intrinsic brain networks in Major Depressive Disorder (MDD); however, their role as predictors of treatment response has not yet been explored. Here, we investigate whether network-based rsFC predicts antidepressant and placebo effects in MDD. METHODS: We performed a randomized controlled trial of two weeklong, identical placebos (described as having either "active" fast-acting, antidepressant effects or as "inactive") followed by a ten-week open-label antidepressant medication treatment. Twenty-nine participants underwent a rsFC fMRI scan at the completion of each placebo condition. Networks were isolated from resting-state blood-oxygen-level-dependent signal fluctuations using independent component analysis. Baseline and placebo-induced changes in rsFC within the default-mode, salience, and executive networks were examined for associations with placebo and antidepressant treatment response. RESULTS: Increased baseline rsFC in the rostral anterior cingulate (rACC) within the salience network, a region classically implicated in the formation of placebo analgesia and the prediction of treatment response in MDD, was associated with greater response to one week of active placebo and ten weeks of antidepressant treatment. Machine learning further demonstrated that increased salience network rsFC, mainly within the rACC, significantly predicts individual responses to placebo administration. CONCLUSIONS: These data demonstrate that baseline rsFC within the salience network is linked to clinical placebo responses. This information could be employed to identify patients who would benefit from lower doses of antidepressant medication or non-pharmacological approaches, or to develop biomarkers of placebo effects in clinical trials.

Association Between Placebo-Activated Neural Systems and Antidepressant Responses: Neurochemistry of Placebo Effects in Major Depression.

IMPORTANCE: High placebo responses have been observed across a wide range of pathologies, severely impacting drug development. OBJECTIVE: To examine neurochemical mechanisms underlying the formation of placebo effects in patients with major depressive disorder (MDD). DESIGN, SETTING, AND PARTICIPANTS: In this study involving 2 placebo lead-in phases followed by an open antidepressant administration, we performed a single-blinded 2-week crossover randomized clinical trial of 2 identical oral placebos (described as having either active or inactive fast-acting antidepressant-like effects) followed by a 10-week open-label treatment with a selective serotonin reuptake inhibitor or, in some cases, another agent as clinically indicated. The volunteers (35 medication-free patients with MDD at a university health system) were studied with positron emission tomography and the µ-opioid receptor-selective radiotracer [11C]carfentanil after each 1-week inactive and active oral placebo treatment. In addition, 1 mL of isotonic saline was administered intravenously within sight of the volunteer during positron emission tomographic scanning every 4 minutes over 20 minutes only after the 1-week active placebo treatment, with instructions that the compound may be associated with the activation of brain systems involved in mood improvement. This challenge stimulus was used to test the individual capacity to acutely activate endogenous opioid neurotransmision under expectations of antidepressant effect. MAIN OUTCOMES AND MEASURES: Changes in depressive symptoms in response to active placebo and antidepressant. Baseline and activation measures of µ-opioid receptor binding. RESULTS: Higher baseline µ-opioid receptor binding in the nucleus accumbens was associated with better response to antidepressant treatment (r = 0.48; P = .02). Reductions in depressive symptoms after 1 week of active placebo treatment, compared with the inactive, were associated with increased placebo-induced µ-opioid neurotransmission in a network of regions implicated in emotion, stress regulation, and the pathophysiology of MDD, namely, the subgenual anterior cingulate cortex, nucleus accumbens, midline thalamus, and amygdala (nucleus accumbens: r = 0.6; P < .001). Placebo-induced endogenous opioid release in these regions was associated with better antidepressant treatment response, predicting 43% of the variance in symptom improvement at the end of the antidepressant trial. CONCLUSIONS AND RELEVANCE: These data demonstrate that placebo-induced activation of the µ-opioid system is implicated in the formation of placebo antidepressant effects in patients with MDD and also participate in antidepressant responses, conferring illness resiliency, during open administration. TRIAL REGISTRATION: clinicaltrials.gov Identifier:NCT02178696.

The double burden of age and major depressive disorder on the cognitive control network.

Poor cognitive control (CC) is common among older individuals with major depressive disorder (OMDD). At the same time, studies of CC in OMDD with fMRI are relatively limited and often have small samples. The present study was conducted to further examine poor CC in OMDD with early onset depression, as well as to investigate the interactive effects of MDD and aging on cognitive control. Twenty OMDD, 17 older never-depressed comparisons (ONDC), 16 younger adults with MDD (YMDD), and 18 younger never-depressed comparisons (YNDC) participated. All participants completed the Go level of the Parametric Go/No-Go Test, which requires sustained attention and inhibitory control while undergoing functional MRI (fMRI). YNDC were faster in reaction times (RTs) to go targets relative to the other 3 groups, and the YMDD group was faster than the OMDD group. fMRI effects of both age and diagnosis were present, with greater activation in MDD, and in aging. Additionally, the interaction of age and MDD was also significant, such that OMDD exhibited greater recruitment of fronto-subcortical regions relative to older comparisons. These results are consistent with prior research reporting that OMDD recruit more fronto-striatal regions in order to perform at the same level as their never-depressed peers, here on a task of sustained attention and inhibitory control. There may be an interaction of cognitive aging and depression to create a double burden on the CC network in OMDD, including possible fronto-striatal compensation during CC that is unique to OMDD, as younger MDD individuals do not show this pattern.