A Lifespan Model of Interference Resolution and Inhibitory Control: Risk for Depression and Changes with Illness Progression.

The cognitive processes involved in inhibitory control accuracy (IC) and interference resolution speed (IR) or broadly - inhibition - are discussed in this review, and both are described within the context of a lifespan model of mood disorders. Inhibitory control (IC) is a binary outcome (success or no for response selection and inhibition of unwanted responses) for any given event that is influenced to an extent by IR. IR refers to the process of inhibition, which can be manipulated by task design in earlier and later stages through use of distractors and timing, and manipulation of individual differences in response proclivity. We describe the development of these two processes across the lifespan, noting factors that influence this development (e.g., environment, adversity and stress) as well as inherent difficulties in assessing IC/IR prior to adulthood (e.g., cross-informant reports). We use mood disorders as an illustrative example of how this multidimensional construct can be informative to state, trait, vulnerability and neuroprogression of disease. We present aggregated data across numerous studies and methodologies to examine the lifelong development and degradation of this subconstruct of executive function, particularly in mood disorders. We highlight the challenges in identifying and measuring IC/IR in late life, including specificity to complex, comorbid disease processes. Finally, we discuss some potential avenues for treatment and accommodation of these difficulties across the lifespan, including newer treatments using cognitive remediation training and neuromodulation.

Ventral prefrontal cortex and emotion regulation in aging: A case for utilizing transcranial magnetic stimulation.

OBJECTIVES: The ventrolateral prefrontal cortex (vlPFC) has been speculated to play an important role in complex processes that allow emotional factors to influence human cognition. Accumulating evidence from human neuroimaging studies, in conjunction with studies of patients with lesions and animal models, shed light on the role of the vlPFC in emotion regulation (ER). This review aims to discuss and integrate recent findings related to vlPFC's role in ER in the context of aging, drawing from diverse sources, and suggest future directions for research utilizing transcranial magnetic stimulation (TMS). METHODS/DESIGN: We summarize findings from the existing literature investigating the neural basis of frontal-lobe mediated ER and then highlight major findings from recent studies directly comparing healthy younger and older adult groups. We conclude by pointing to unaddressed questions worth pursuing in future research. RESULTS AND DISCUSSION: We propose future research directions utilizing TMS to answer key unaddressed questions. Moreover, we discuss the potential advantages, challenges, and limitations of using TMS as a complement to the existing neuroimaging methods in ER.

Integrated cross-network connectivity of amygdala, insula, and subgenual cingulate associated with facial emotion perception in healthy controls and remitted major depressive disorder.

Emotion perception deficits could be due to disrupted connectivity of key nodes in the salience and emotion network (SEN), including the amygdala, subgenual anterior cingulate cortex (sgACC), and insula. We examined SEN resting-state (rs-)fMRI connectivity in rMDD in relation to Facial Emotion Perception Test (FEPT) performance. Fifty-two medication-free people ages 18 to 23 years participated. Twenty-seven had major depressive disorder (MDD) in remission (rMDD, 10 males), as MDD is associated with emotion perception deficits and alterations in rsfMRI. Twenty-five healthy controls (10 males) also participated. Participants completed the FEPT during fMRI, in addition to an 8-minute eyes-open resting-state scan. Seed regions of interest were defined in the amygdala, anterior insula and sgACC. Multiple regression analyses co-varied diagnostic group, sex and movement parameters. Emotion perception accuracy was positively associated with connectivity between amygdala seeds and regions primarily in the SEN and cognitive control network (CCN), and also the default mode network (DMN). Accuracy was also positively associated with connectivity between the sgACC seeds and other SEN regions, and the DMN, particularly for the right sgACC. Connectivity negatively associated with emotion perception was mostly with regions outside of these three networks, other than the left insula and part of the DMN. This study is the first to our knowledge to demonstrate relationships between facial emotion processing and resting-state connectivity with SEN nodes and between SEN nodes and regions located within other neural networks.

Differential Resting State Connectivity Patterns and Impaired Semantically Cued List Learning Test Performance in Early Course Remitted Major Depressive Disorder.

OBJECTIVES: There is a well-known association between memory impairment and major depressive disorder (MDD). Additionally, recent studies are also showing resting-state functional magnetic resonance imaging (rsMRI) abnormalities in active and remitted MDD. However, no studies to date have examined both rs connectivity and memory performance in early course remitted MDD, nor the relationship between connectivity and semantically cued episodic memory. METHODS: The rsMRI data from two 3.0 Tesla GE scanners were collected from 34 unmedicated young adults with remitted MDD (rMDD) and 23 healthy controls (HCs) between 18 and 23 years of age using bilateral seeds in the hippocampus. Participants also completed a semantically cued list-learning test, and their performance was correlated with hippocampal seed-based rsMRI. Regression models were also used to predict connectivity patterns from memory performance. RESULTS: After correcting for sex, rMDD subjects performed worse than HCs on the total number of words recalled and recognized. rMDD demonstrated significant in-network hypoactivation between the hippocampus and multiple fronto-temporal regions, and multiple extra-network hyperconnectivities between the hippocampus and fronto-parietal regions when compared to HCs. Memory performance negatively predicted connectivity in HCs and positively predicted connectivity in rMDD. Conclusions Even when individuals with a history of MDD are no longer displaying active depressive symptoms, they continue to demonstrate worse memory performance, disruptions in hippocampal connectivity, and a differential relationship between episodic memory and hippocampal connectivity.

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.

Shared dimensions of performance and activation dysfunction in cognitive control in females with mood disorders.

Major depressive disorder and bipolar disorder share symptoms that may reflect core mood disorder features. This has led to the pursuit of intermediate phenotypes and a dimensional approach to understand neurobiological disruptions in mood disorders. Executive dysfunction, including cognitive control, may represent a promising intermediate phenotype across major depressive disorder and bipolar disorder. This study examined dimensions of cognitive control in women with major depressive disorder or bipolar disorder in comparison to healthy control subjects using two separate, consecutive experiments. For Experiment 1, participants completed a behavioural cognitive control task (healthy controls = 150, major depressive disorder = 260, bipolar disorder = 202; age range 17-84 years). A sample of those participants (healthy controls = 17, major depressive disorder = 19, and bipolar disorder = 16) completed a similar cognitive control task in an event-related design functional magnetic resonance imaging protocol for Experiment 2. Results for Experiment 1 showed greater impairments on the cognitive control task in patients with mood disorders relative to healthy controls (P < 0.001), with more of those in the mood disorder group falling into the 'impaired' range when using clinical cut-offs (<5th percentile). Experiment 2 revealed only a few areas of shared activation differences in mood disorder greater than healthy controls. Activation analyses using performance as a regressor, irrespective of diagnosis, revealed within and extra-network areas that were more active in poor performers. In summary, performance and activation during cognitive control tasks may represent an intermediate phenotype for mood disorders. However, cognitive control dysfunction is not uniform across women with mood disorders, and activation is linked to performance more so than disease. These findings support subtype and dimensional approaches to understanding risk and expression of mood disorders and are a promising area of inquiry, in line with the Research Domain Criteria initiative of NIMH.

Age and gender modulate the neural circuitry supporting facial emotion processing in adults with major depressive disorder.

OBJECTIVES: Emotion processing, supported by frontolimbic circuitry known to be sensitive to the effects of aging, is a relatively understudied cognitive-emotional domain in geriatric depression. Some evidence suggests that the neurophysiological disruption observed in emotion processing among adults with major depressive disorder (MDD) may be modulated by both gender and age. Therefore, the present study investigated the effects of gender and age on the neural circuitry supporting emotion processing in MDD. DESIGN: Cross-sectional comparison of fMRI signal during performance of an emotion processing task. SETTING: Outpatient university setting. PARTICIPANTS: One hundred adults recruited by MDD status, gender, and age. MEASUREMENTS: Participants underwent fMRI while completing the Facial Emotion Perception Test. They viewed photographs of faces and categorized the emotion perceived. Contrast for fMRI was of face perception minus animal identification blocks. RESULTS: Effects of depression were observed in precuneus and effects of age in a number of frontolimbic regions. Three-way interactions were present between MDD status, gender, and age in regions pertinent to emotion processing, including frontal, limbic, and basal ganglia. Young women with MDD and older men with MDD exhibited hyperactivation in these regions compared with their respective same-gender healthy comparison (HC) counterparts. In contrast, older women and younger men with MDD exhibited hypoactivation compared to their respective same-gender HC counterparts. CONCLUSIONS: This the first study to report gender- and age-specific differences in emotion processing circuitry in MDD. Gender-differential mechanisms may underlie cognitive-emotional disruption in older adults with MDD. The present findings have implications for improved probes into the heterogeneity of the MDD syndrome.

Stress Response to the Functional Magnetic Resonance Imaging Environment in Healthy Adults Relates to the Degree of Limbic Reactivity during Emotion Processing.

BACKGROUND: Imaging techniques are increasingly being used to examine the neural correlates of stress and emotion processing; however, relations between the primary stress hormone cortisol, the functional magnetic resonance imaging (fMRI) environment, and individual differences in response to emotional challenges are not yet well studied. The present study investigated whether cortisol activity prior to, and during, an fMRI scan may be related to neural processing of emotional information. METHODS: Twenty-six healthy individuals (10 female) completed a facial emotion perception test during 3-tesla fMRI. RESULTS: Prescan cortisol was significantly correlated with enhanced amygdala, hippocampal, and subgenual cingulate reactivity for facial recognition. Cortisol change from pre- to postscanning predicted a greater activation in the precuneus for both fearful and angry faces. A negative relationship between overall face accuracy and activation in limbic regions was observed. CONCLUSION: Individual differences in response to the fMRI environment might lead to a greater heterogeneity of brain activation in control samples, decreasing the power to detect differences between clinical and comparison groups. © 2015 S. Karger AG, Basel.

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.

Current understanding of the neurobiology and longitudinal course of geriatric depression.

Late life depression is a complex disease associated with a number of contributing neurobiological factors, including cerebrovascular disease, neurodegeneration, and inflammation, which also contribute to its longitudinal prognosis and course. These factors create a context in which the brain is more vulnerable to the impact of stress, and thus, to depression. At the same time, some individuals are protected from late life depression and its consequences, even in the face of neurobiological vulnerability, through benefitting from one or more attributes associated with resilience, including social support, engagement in physical and cognitive activities, and brain reserve. Enhanced understanding of how neurobiological and environmental factors interact in predicting vulnerability and resilience is needed to predict onset and course of depression in late life and develop more effective interventions.

The double burden of age and disease on cognition and quality of life in bipolar disorder.

OBJECTIVE: Bipolar disorder (BPD) and normal aging are known to impact cognitive skills and health-related quality of life (HRQOL). This study investigated how aging and disease interact in predicting cognitive and psychosocial outcomes. METHODS: Eight cognitive and ten subjective HRQOL domain ratings were measured. Subjects included 80 young (18-29 years) and late middle-aged (50-65 years) BPD patients in the euthymic phase and 70 age-equivalent healthy comparison participants. RESULTS: An age X disease interaction was detected in three domains of cognitive functioning that reflect emotion processing, processing speed, and executive functioning skills, with BPD patients in the older group performing most poorly. There was a double burden of aging and disease on reported ability to perform physical tasks. However, regardless of age, disease status was associated with lower ratings of HRQOL in the psychosocial/affective sphere and the majority of cognitive domains. Post hoc analyses revealed that number of years ill was positively associated with select HRQOL ratings in older, but not younger BPD adults. CONCLUSIONS: These findings may stimulate future longitudinal study of cognition and quality of life in BPD patients across the life span, focusing on additive and interactive effects of aging and disease burden, which could culminate in developing more effective treatment and rehabilitation strategies for this traditionally challenging to treat population.

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.

Treatment resistant late-life depression: A narrative review of psychosocial risk factors, non-pharmacological interventions, and the role of clinical phenotyping.

BACKGROUND: Treatment resistant depression (TRD) is a subset of major depressive disorder (MDD) in which symptoms do not respond to front line therapies. In older adults, the assessment and treatment of TRD is complicated by psychosocial risk factors unique to this population, as well as a relative paucity of research. METHODS: Narrative review aimed at (1) defining TRLLD for clinical practice and research; (2) describing psychosocial risk factors; (3) reviewing psychological and non-pharmacological treatments; (4) discussing the role of clinical phenotyping for personalized treatment; and (5) outlining research priorities. RESULTS: Our definition of TRLLD centers on response to medication and neuromodulation in primary depressive disorders. Psychosocial risk factors include trauma and early life adversity, chronic physical illness, social isolation, personality, and barriers to care. Promising non-pharmacological treatments include cognitive training, psychotherapy, and lifestyle interventions. The utility of clinical phenotyping is highlighted by studies examining the impact of comorbidities, symptom dimensions (e.g., apathy), and structural/functional brain changes. LIMITATIONS: There is a relative paucity of TRLLD research. This limits the scope of empirical data from which to derive reliable patterns and complicates efforts to evaluate the literature quantitatively. CONCLUSIONS: TRLLD is a complex disorder that demands further investigation given our aging population. While this review highlights the promising breadth of TRLLD research to date, more research is needed to help elucidate, for example, the optimal timing for implementing risk mitigation strategies, the value of collaborative care approaches, specific treatment components associated with more robust response, and phenotyping to help inform treatment decisions.

Depression and cognitive impairment in older adults.

Late life depression (LLD) is a heterogeneous illness with high rates of treatment resistance. Cognitive impairment is common in the context of LLD, and LLD may be a prodromal symptom and/or potentially a risk factor for dementia. This manuscript reviews the most recent research into the cognitive deficits associated with LLD and risk of conversion to dementia in the context of LLD. We discuss potential moderators and mediators of cognitive deficits in LLD, including demographic and clinical variables, in addition to brain structure and function. Potential interventions for cognitive symptoms of LLD are reviewed. We conclude with a discussion of the broader implications of what is now known about LLD, and how this might be applied toward improved prognosis and models for effective treatment.