Improving late life depression and cognitive control through the use of therapeutic video game technology: A proof-of-concept randomized trial.
ABSTRACT: BACKGROUND:Existing treatments for depression are known to have only modest effects, are insufficiently targeted, and are inconsistently utilized, particularly in older adults. Indeed, older adults with impaired cognitive control networks tend to demonstrate poor response to a majority of existing depression interventions. Cognitive control interventions delivered using entertainment software have the potential to not only target the underlying cerebral dysfunction associated with depression, but to do so in a manner that is engaging and engenders adherence to treatment protocol. METHODS:In this proof-of-concept trial (Clinicaltrials.gov #: NCT02229188), individuals with late life depression (LLD) (22; 60+ years old) were randomized to either problem solving therapy (PST, n = 10) or a neurobiologically inspired digital platform designed to enhance cognitive control faculties (Project: EVO™, n = 12). Given the overlapping functional neuroanatomy of mood disturbances and executive dysfunction, we explored the impact of an intervention targeting cognitive control abilities, functional disability, and mood in older adults suffering from LLD, and how those outcomes compare to a therapeutic gold standard. RESULTS:EVO participants demonstrated similar improvements in mood and self-reported function after 4 weeks of treatment to PST participants. The EVO participants also showed generalization to untrained measures of working memory and attention, as well as negativity bias, a finding not evident in the PST condition. Individuals assigned to EVO demonstrated 100% adherence. CONCLUSIONS:This study provides preliminary findings that this therapeutic video game targeting cognitive control deficits may be an efficacious LLD intervention. Future research is needed to confirm these findings.
Project description:Late-life depression (LLD) is a debilitating condition that is associated with poor response to antidepressant medications and deficits in cognitive performance. Nicotinic cholinergic stimulation has emerged as a potentially effective candidate to improve cognitive performance in patients with cognitive impairment. Previous studies of nicotinic stimulation in animal models and human populations with cognitive impairment led to examining potential cognitive and mood effects of nicotinic stimulation in older adults with LLD. We report results from a pilot study of transdermal nicotine in LLD testing whether nicotine treatment would enhance cognitive performance and mood. The study used electroencephalography (EEG) recordings as a tool to test for potential mechanisms underlying the effect of nicotine. Eight non-smoking participants with LLD completed EEG recordings at baseline and after 12 weeks of transdermal nicotine treatment (NCT02816138). Nicotine augmentation treatment was associated with improved performance on an auditory oddball task. Analysis of event-related oscillations showed that nicotine treatment was associated with reduced beta desynchronization at week 12 for both standard and target trials. The change in beta power on standard trials was also correlated with improvement in mood symptoms. This pilot study provides preliminary evidence for the impact of nicotine in modulating cortical activity and improving mood in depressed older adults and shows the utility of using EEG as a marker of functional engagement in nicotinic interventions in clinical geriatric patients.
Project description:<h4>Background</h4>Late-life depression (LLD) is considered as a prodrome to dementia and plays a major role in the development of long-term cognitive disabilities. We aimed to estimate the prevalence and correlates of LLD and cognitive impairment and to explore their associations among older adults in India.<h4>Methods</h4>Data for this study was derived from the Longitudinal Ageing Study in India (LASI) Wave 1 (2017-18). The total sample included 31,464 (15,098 male and 16,366 female) older individuals aged 60 years and above. Cognitive impairment measured from various domains derived from the cognitive module of the Health and Retirement Study (HRS), and major depression measured by the CIDI-SF (Composite International Diagnostic Interview- Short Form) were the outcome variables. Descriptive, bivariate, and multivariable analyses were performed to fulfill the objectives of the study.<h4>Results</h4>The overall prevalence of LLD and cognitive impairment for the current sample was 8.7% and 13.7 % respectively. Among older individuals who have rated their health status as poor were 2.59 times more likely to suffer from LLD [OR: 2.59, CI: 2.24-2.99] as compared to their counterparts. The older adults who had difficulty in activities of daily living (ADL) and instrumental activities of daily living (IADL) were 74% and 69 % more likely to suffer from LLD. Similarly, older adults who were depressed had higher odds of cognitive impairment [OR: 1.22, CI: 1.01-1.48] compared to their counterparts. Also, older adults who were depressed and belonged to rural areas were 2.58 times [AOR: 2.58, CI: 1.95-3.41] more likely to be cognitively impaired than those who were not depressed and resided in urban areas.<h4>Conclusions</h4>Depression is linked to an increased risk of cognitive decline and dementia; therefore, failing to diagnose and treat LLD in later life may have significant health implications. Moreover, treatment under the care of a cognitive neurologist or geriatric psychiatrist is recommended for people with LLD and cognitive disability due to both the disorders' complex existence.
Project description:<h4>Objectives</h4>Telomeres are structures at the extremity of chromosomes that prevents genomic instability, and its shortening seems to be a hallmark of cellular aging. Past studies have shown contradictory results of telomere length (TL) in major depression, and are a few studies in late-life depression (LLD). This explores the association between TL as a molecular marker of aging and diagnosis of LLD, the severity of depressive symptoms, and cognitive performance in older adults.<h4>Methods/design</h4>We included 78 older adults (45 with LLD and 33 nondepressed controls, according to DSM-V criteria), aged 60-90 years. TL was measured in leukocytes by a quantitative polymerase chain reaction, determining the relative ratio (T/S) between the telomere region copy number (T) and a single copy gene (S), using a relative standard curve.<h4>Results</h4>TL was significantly shorter in the LLD compared with control participants (p = .039). Comparing groups through the severity of depressive symptoms, we found a negative correlation with the severity of depressive symptoms (Hamilton Depression Rating Scale-21, r = -0.325, p = .004) and medical burden (r = -0.271, p = .038). There was no significant correlation between TL and cognitive performance (Mattis Dementia Rating Scale, r = 0.152, p = .21).<h4>Conclusions</h4>We found that older adults with LLD have shorter telomere than healthy controls, especially those with a more severe depressive episode. Our findings suggest that shorter TL can be a marker of the severity of depressive episodes in older adults and indicate that these individuals may be at higher risk of age-associated adverse outcomes linked to depression.
Project description:OBJECTIVE:Late-life depression (LLD) is characterized by poor antidepressant response and cognitive dysfunction. This study examined whether transdermal nicotine benefits mood symptoms and cognitive performance in LLD. METHODS:In a 12-week open-label outpatient study conducted between November 2016 and August 2017, transdermal nicotine was given to 15 nonsmoking older adults (? 60 years of age). Eligible participants met DSM-IV-TR criteria for major depressive disorder with ? 15 on the Montgomery-Asberg Depression Rating scale (MADRS) and endorsed subjective cognitive impairment. Transdermal nicotine patches were applied daily and titrated in a rigid dose escalation strategy to a maximum dose of 21.0 mg/d, allowing dose reductions for tolerability. The primary mood outcome was MADRS change measured every 3 weeks, with response defined as ? 50% improvement from baseline and remission as MADRS score ? 8. The primary cognitive outcome was the Conners Continuous Performance Test (CPT), a test of attention. RESULTS:Robust rates of response (86.7%; 13/15 subjects) and remission (53.3%; 8/15 subjects) were observed. There was a significant decrease in MADRS scores over the study (? = -1.51, P < .001), with improvement seen as early as 3 weeks (Bonferroni-adjusted P value = .004). We also observed improvement in apathy and rumination. We did not observe improvement on the CPT but did observe improvement in subjective cognitive performance and signals of potential drug effects on secondary cognitive measures of working memory, episodic memory, and self-referential emotional processing. Overall, transdermal nicotine was well tolerated, although 6 participants could not reach the maximum targeted dose. CONCLUSIONS:Nicotine may be a promising therapy for depressed mood and cognitive performance in LLD. A definitive placebo-controlled trial and establishment of longer-term safety are necessary before clinical usage. TRIAL REGISTRATION:ClinicalTrials.gov identifier: NCT02816138?.
Project description:<h4>Background</h4>Depression and cognitive impairment often coexist in older adults. The relation between depression and cognitive impairment is complex. The objective of this article is to review recent literature on cognitive impairment in older adults with depression and provide clinicians an update.<h4>Methods</h4>We searched PubMed, Google Scholar, Science Direct, and Psych Info for the articles published in the English language related to late-life depression (LLD)/geriatric depression and cognitive impairment. We considered original research articles, relevant systematic reviews, chapters, and important conceptual articles published in the last 9 years (2011-2019). We selected relevant articles for this narrative review.<h4>Conclusion</h4>The concept pseudodementia, indicating depression with cognitive impairment mimicking dementia, is now seen only as a historical concept. The current literature strongly agrees with fact that cognitive deficits often exist in LLD. The cognitive deficits in depression were initially seen as trait marker; however, some recent studies suggest that cognitive deficits persist even in the remission phase. There is heterogeneity among the studies in terms of the nature of the cognitive deficits, but higher number of studies reported impairment in attention and executive function. LLD with cognitive deficits is at a higher risk of progression to dementia. In older adults, depression with cognitive impairments requires a comprehensive evaluation. Electroencephalography, event-related potentials, fluorodeoxyglucose-positron emission tomography, amyloid positron emission tomography, and CSF amyloid will supplement clinical evaluation in differentiating functional depressive disorder with cognitive impairment from depression with an underlying degenerative condition.
Project description:<h4>Objectives</h4>Late-life depression (LLD) is associated with reduced neurotrophic support and abnormalities in neurodegenerative cascades. The aim of the present study is to determine the concentrations of brain-derived neurotrophic factor (BDNF), amyloid-?42, total Tau, and phosphorylated Tau in the cerebrospinal fluid (CSF) of patients with LLD and cognitive impairment compared to healthy older adults.<h4>Method</h4>We included 25 antidepressant-free patients with LLD (10 with mild cognitive impairment [LLD + MCI] and 15 with no cognitive decline [LLD + NCD]) and 25 healthy older adults as a comparison group. Depressive symptoms were assessed by the 21-item Hamilton Depression Rating Scale (HDRS-21) and cognitive performance by a comprehensive cognitive battery.<h4>Results</h4>Patients with LLD + MCI showed significantly lower CSF BDNF levels compared to LLD + NCD and healthy controls (p = .003). There were no significant differences in Alzheimer's disease-related CSF biomarkers between groups. CSF BDNF concentrations were positively correlated with Cambridge Cognitive Test (CAMCOG) scores (r = .36, p = .02).<h4>Discussion</h4>The present study adds to the growing body of evidence that abnormalities in the BDNF system are involved in the pathophysiology of LLD. The reduction of the availability of BDNF in the central nervous system may indicate increased vulnerability to the development of several age-related neuropsychiatric disorders as well as to adverse cognitive outcomes.
Project description:Cognitive impairment is highly prevalent among individuals with late-life depression (LLD) and tends to persist even after successful treatment. The biological mechanisms underlying cognitive impairment in LLD are complex and likely involve abnormalities in multiple pathways, or 'cascades,' reflected in specific biomarkers. Our aim was to evaluate peripheral (blood-based) evidence for biological pathways associated with cognitive impairment in older adults with LLD. To this end, we used a data-driven comprehensive proteomic analysis (multiplex immunoassay including 242 proteins), along with measures of structural brain abnormalities (gray matter atrophy and white matter hyperintensity volume via magnetic resonance imaging), and brain amyloid-? (A?) deposition (PiB-positron emission tomography). We analyzed data from 80 older adults with remitted major depression (36 with mild cognitive impairment (LLD+MCI) and 44 with normal cognitive (LLD+NC)) function. LLD+MCI was associated with differential expression of 24 proteins (P<0.05 and q-value <0.30) related mainly to the regulation of immune-inflammatory activity, intracellular signaling, cell survival and protein and lipid homeostasis. Individuals with LLD+MCI also showed greater white matter hyperintensity burden compared with LLD+NC (P=0.015). We observed no differences in gray matter volume or brain A? deposition between groups. Machine learning analysis showed that a group of three proteins (Apo AI, IL-12 and stem cell factor) yielded accuracy of 81.3%, sensitivity of 75% and specificity of 86.4% in discriminating participants with MCI from those with NC function (with an averaged cross-validation accuracy of 76.3%, sensitivity of 69.4% and specificity of 81.8% with nested cross-validation considering the model selection bias). Cognitive impairment in LLD seems to be related to greater cerebrovascular disease along with abnormalities in immune-inflammatory control, cell survival, intracellular signaling, protein and lipid homeostasis, and clotting processes. These results suggest that individuals with LLD and cognitive impairment may be more vulnerable to accelerated brain aging and shed light on possible mediators of their elevated risk for progression to dementia.
Project description:BACKGROUND:Mobile apps for mental health have the potential to overcome access barriers to mental health care, but there is little information on whether patients use the interventions as intended and the impact they have on mental health outcomes. OBJECTIVE:The objective of our study was to document and compare use patterns and clinical outcomes across the United States between 3 different self-guided mobile apps for depression. METHODS:Participants were recruited through Web-based advertisements and social media and were randomly assigned to 1 of 3 mood apps. Treatment and assessment were conducted remotely on each participant's smartphone or tablet with minimal contact with study staff. We enrolled 626 English-speaking adults (?18 years old) with mild to moderate depression as determined by a 9-item Patient Health Questionnaire (PHQ-9) score ?5, or if their score on item 10 was ?2. The apps were (1) Project: EVO, a cognitive training app theorized to mitigate depressive symptoms by improving cognitive control, (2) iPST, an app based on an evidence-based psychotherapy for depression, and (3) Health Tips, a treatment control. Outcomes were scores on the PHQ-9 and the Sheehan Disability Scale. Adherence to treatment was measured as number of times participants opened and used the apps as instructed. RESULTS:We randomly assigned 211 participants to iPST, 209 to Project: EVO, and 206 to Health Tips. Among the participants, 77.0% (482/626) had a PHQ-9 score >10 (moderately depressed). Among the participants using the 2 active apps, 57.9% (243/420) did not download their assigned intervention app but did not differ demographically from those who did. Differential treatment effects were present in participants with baseline PHQ-9 score >10, with the cognitive training and problem-solving apps resulting in greater effects on mood than the information control app (?22=6.46, P=.04). CONCLUSIONS:Mobile apps for depression appear to have their greatest impact on people with more moderate levels of depression. In particular, an app that is designed to engage cognitive correlates of depression had the strongest effect on depressed mood in this sample. This study suggests that mobile apps reach many people and are useful for more moderate levels of depression. CLINICALTRIAL:Clinicaltrials.gov NCT00540865; https://www.clinicaltrials.gov/ct2/show/NCT00540865 (Archived by WebCite at http://www.webcitation.org/6mj8IPqQr).
Project description: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.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.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.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.
Project description:The amygdala, a crucial hub of the emotional processing neural system, has been implicated in late-life depression (LLD) pathophysiology. However, the overlapping and diverging amygdala network function abnormalities underlying two clinical LLD phenotypes (i.e., LLD alone and LLD with mild cognitive impairment [LLD-MCI]) are unknown. The aim of this study is to investigate the amygdala functional connectivity (FC) differences between LLD alone, LLD-MCI and healthy controls, and to examine the relationships between amygdala network dysfunction and symptom dimensions. A resting-state functional connectivity magnetic resonance imaging study was conducted to probe amygdala FC in a total of 63 elderly participants (LLD [n = 22], LLD-MCI [n = 15], and age- and gender-equated healthy older adults [n = 26]) using a seed-based voxelwise R-fcMRI approach. LLD-only adults showed increased FC in the posterior default mode and vermis, and diminished connections in the fronto-parietal, salience and temporal areas, relative to controls. The LLD-MCI participants showed diminished FC in the default mode, cognitive control, salience and visual regions, whereas increased FC was limited to lateral parietal cortex compared with healthy controls. The LLD-MCI group also showed diminished FC in the occipital and posterior default mode areas, relative to the LLD-only group. Distinct amygdala FC abnormalities that explain depressive and anxiety symptom severity, and executive functioning were identified. The amygdala FC impairments may distinguish LLD phenotypes. These functional network abnormalities may also explain the heterogeneity seen in the LLD clinical presentations.