Factors Influencing Clinical Correlates of Chronic Traumatic Encephalopathy (CTE): a Review.

Chronic traumatic encephalopathy (CTE) is a neuropathologically defined disease reportedly linked to a history of repetitive brain trauma. As such, retired collision sport athletes are likely at heightened risk for developing CTE. Researchers have described distinct pathological features of CTE as well a wide range of clinical symptom presentations, recently termed traumatic encephalopathy syndrome (TES). These clinical symptoms are highly variable, non-specific to individuals described as having CTE pathology in case reports, and are often associated with many other factors. This review describes the cognitive, emotional, and behavioral changes associated with 1) developmental and demographic factors, 2) neurodevelopmental disorders, 3) normal aging, 4) adjusting to retirement, 5) drug and alcohol abuse, 6) surgeries and anesthesia, and 7) sleep difficulties, as well as the relationship between these factors and risk for developing dementia-related neurodegenerative disease. We discuss why some professional athletes may be particularly susceptible to many of these effects and the importance of choosing appropriate controls groups when designing research protocols. We conclude that these factors should be considered as modifiers predominantly of the clinical outcomes associated with repetitive brain trauma within a broader biopsychosocial framework when interpreting and attributing symptom development, though also note potential effects on neuropathological outcomes. Importantly, this could have significant treatment implications for improving quality of life.

Depressive symptom severity is associated with increased cortical thickness in older adults.

OBJECTIVE: Structural neuroimaging studies in older adults have consistently shown volume reductions in both major and subthreshold depression. Cortical thickness, another measure of brain structure, has not been well studied in this population. We examined cortical thickness in older adults across a range of depressive symptom (DS) severity. METHODS: Forty-three community-dwelling older adults (mean age = 68.80 ± 7.00 years) underwent magnetic resonance imaging. Based on a priori hypotheses, we examined cortical thickness in regions of interest in the rostral anterior cingulate, orbitofrontal cortex, middle frontal gyrus, and isthmus cingulate using multiple linear regressions with depression questionnaire scores as the independent variable and age, sex, and mean hemispheric thickness as covariates. We also performed an exploratory vertex-wise analysis. RESULTS: After correction for multiple comparisons, we found an association between increased DSs and greater cortical thickness in the right isthmus cingulate (F(1, 38) = 8.09, false discovery rate corrected p = 0.028; R(2) = 35.78) in the region of interest analysis and in the left precuneus (cluster size = 413, p = 0.00002) in the vertex-wise analysis. CONCLUSIONS: Older adults with higher DSs also have greater cortical thickness in the isthmus cingulate and precuneus, areas important for emotion regulation and self-referential processing. Additional research is needed to elucidate the mechanisms and potential clinical significance underlying this relationship.

Transcranial Direct Current Stimulation Use in the Treatment of Neuropsychiatric Disorders: A Brief Review.

Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique that has grown in popularity over the past two decades as an alternative treatment option for various neuropsychiatric disorders. tDCS modulates cortical excitability through the application of a weak direct current to the scalp via electrodes placed over cortical regions of interest. It has been shown to be a promising and relatively safe treatment tool with few adverse events. In this article, we will briefly review the efficacy of tDCS in depression, bipolar disorder, schizophrenia, and obsessive-compulsive disorder. We will also discuss biomarkers of tDCS efficacy in depression, as it is the most studied neuropsychiatric disorder using tDCS application. We will then offer suggestions for future directions. Although efficacy results show promise, more studies with larger samples and longer treatment periods are needed to better understand the benefits of using tDCS as an alternative treatment option for neuropsychiatric disorders.

The effects of medication use in transcranial direct current stimulation: A brief review.

BACKGROUND: There has been increased interest in the potential use of transcranial direct current stimulation (tDCS) as treatment for multiple conditions including depression, pain, and cognitive impairment. However, few studies account for the possible influence of comorbid medications when conducting tDCS research. OBJECTIVE/HYPOTHESIS: This literature review was conducted to examine what is currently known about the impact of medications on tDCS, provide recommendations for future research practices, and highlight areas where more research is needed. METHODS: Key terms were searched in PubMed and Web of Science to identify studies that examine the impact of medication on tDCS effects in adults. Relevant papers' reference lists were also reviewed for thoroughness. Studies examined the effects of medication on 1 mA tDCS delivered to M1 (motor) and orbit/supraorbital (SO) area. All studies measured the effects of tDCS via MEP TMS paradigm. RESULTS: Results of the literature review suggest multiple classes of medications, including sodium and calcium channel blockers, and medications that influence various neurotransmitter systems (GABA, dopamine, serotonin, etc.) may all impact tDCS effects on tissue excitability. CONCLUSIONS: Research to date suggests multiple classes of medications may impact tDCS effects. These results highlight the importance of documenting medication use in research subjects and carefully considering what types of medications should be allowed into tDCS trials. Many questions still remain regarding the exact mechanisms of action for tDCS and how various parameters (medication dosages, tDCS stimulation intensity, etc.) may further impact the effects of medications on tDCS.

Non-invasive Brain Stimulation: Probing Intracortical Circuits and Improving Cognition in the Aging Brain.

The impact of cognitive aging on brain function and structure is complex, and the relationship between aging-related structural changes and cognitive function are not fully understood. Physiological and pathological changes to the aging brain are highly variable, making it difficult to estimate a cognitive trajectory with which to monitor the conversion to cognitive decline. Beyond the information on the structural and functional consequences of cognitive aging gained from brain imaging and neuropsychological studies, non-invasive brain stimulation techniques such as transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) can enable stimulation of the human brain in vivo, offering useful insights into the functional integrity of intracortical circuits using electrophysiology and neuromodulation. TMS measurements can be used to identify and monitor changes in cortical reactivity, the integrity of inhibitory and excitatory intracortical circuits, the mechanisms of long-term potentiation (LTP)/depression-like plasticity and central cholinergic function. Repetitive TMS and tDCS can be used to modulate neuronal excitability and enhance cortical function, and thus offer a potential means to slow or reverse cognitive decline. This review will summarize and critically appraise relevant literature regarding the use of TMS and tDCS to probe cortical areas affected by the aging brain, and as potential therapeutic tools to improve cognitive function in the aging population. Challenges arising from intra-individual differences, limited reproducibility, and methodological differences will be discussed.

Vertex-wise examination of depressive symptom dimensions and brain volumes in older adults.

Differences in brain volumes have commonly been reported in older adults with both subthreshold and major depression. Few studies have examined the association between specific symptom dimensions of depression and brain volumes. This study used vertex-wise analyses to examine the association between specific symptom dimensions of depression and brain volumes in older adults with subthreshold levels of depressive symptoms. Forty-three community-dwelling adults between the ages of 55 and 81 years underwent a structural Magnetic Resonance Imaging scan and completed the Center for Epidemiologic Studies Depression Scale (CES-D). Vertex-wise analyses were conducted using Freesurfer Imaging Suite to examine the relationship between CES-D subscale scores and gray matter volumes while controlling for sex, age, and education. We found distinct associations between depressed mood, somatic symptoms, and lack of positive affect subscales with regional volumes, including primarily positive relationships in temporal regions and a negative association with the lingual gyrus. The relationship between higher depressed mood subscale scores and larger volumes in the left inferior temporal lobe withstood Monte-Carlo correction for multiple comparisons. Results from this preliminary study highlight the importance of examining depression on a symptom dimension level and identify brain regions that may be important in larger studies of depression.

Depressive symptoms modify age effects on hippocampal subfields in older adults.

AIM: Major depression is associated with hippocampal volume changes, especially in late-life depression. These changes usually consist of volume reductions, but depression-related increases in hippocampal volume have also been reported. Subfield analysis has identified structural changes primarily in the cornu ammonis (CA) 1, CA2-3 and subiculum of the hippocampus in individuals with major depression; however, it is unclear whether lower levels of depressive symptoms are also associated volume reduction, or if depressive symptoms interact with age to impact hippocampal subfields. The current study addressed these questions. METHODS: A total of 43 community-dwelling older adults completed the Center for Epidemiologic Studies Depression Scale and underwent magnetic resonance imaging. Hippocampal subfield segmentation was carried out using an automated procedure, and left and right volumes from CA1, CA2-3, and the subiculum served as outcome measures. Multiple hierarchical regressions were carried out with age, Center for Epidemiologic Studies Depression Scale scores and their interaction as the independent variables, and sex and total intracranial volume as covariates. RESULTS: Higher Center for Epidemiologic Studies Depression Scale scores were associated with less age-related volumetric decreases in the right subiculum and right CA1. CONCLUSIONS: Age-related atrophy in the hippocampus might be counteracted by depressive symptom-related enlargement of CA1 and the subiculum. More research is required to better understand the functional significance of this relationship. Geriatr Gerontol Int 2017; 17: 1494-1500.

Effects of body mass index and education on verbal and nonverbal memory.

We previously reported that higher education protects against executive dysfunction related to higher body mass index (BMI) in younger, but not older, adults. We now extend the previous analyses to verbal and nonverbal memory. Fifty-nine healthy, dementia-free community-dwelling adults ranging in age from 18 to 81 years completed the Hopkins Verbal Learning Test - Revised (HVLT-R) and the Brief Visuospatial Memory Test - Revised (BVMT-R). Self-reported years of education served as a proxy for cognitive reserve. We found that more highly educated individuals maintained their BVMT-R immediate recall performance across the range of BMI, but in less educated individuals, higher BMI was associated with worse performance. Our findings suggest that education may play a protective role against BMI-related nonverbal learning deficits, similar to previous reports for verbal memory and executive functioning. Results highlight the importance of considering educational background when determining the risk for BMI-related cognitive impairment in clinical settings.

Precuneus abnormalities in middle-aged to older adults with depressive symptoms: An analysis of BDI-II symptom dimensions.

We recently reported age-related increases in left precuneus cortical thickness (CT) in older adults with elevated total depressive symptoms. However, it is unclear whether abnormalities in precuneus surface area (SA) are also evident and whether specific symptom dimensions of depression moderated age effects on these measurements. Seventy-three adults completed the Beck Depression Inventory - 2nd edition (BDI-II) and underwent structural neuroimaging. Measures of CT and SA were extracted from the right and left precuneus via FreeSurfer. Regression models included regions of interest as dependent variables, with age, BDI-II subscale scores (e.g., affective, cognitive, and somatic symptoms), and their interactions as independent variables, controlling for mean hemispheric thickness (for CT) or total intracranial volume (for SA). A significant age × somatic symptom interaction was found for left precuneus CT, such that elevated levels of somatic symptoms were significantly associated with age-related cortical thinning. No depressive symptom dimensions moderated the relationship between age and SA, suggesting that CT may be a more sensitive measure of brain abnormalities in middle-aged to older adults with depressive symptoms.

Anxiety Modifies the Association between Fatigue and Verbal Fluency in Cognitively Normal Adults.

OBJECTIVE: In the present study, we examined the association between self-reported fatigue and verbal fluency in a sample of healthy adults. Given the co-occurrence of anxiety and depressive symptoms with fatigue, we examined whether these affective dimensions would modify this association. METHOD: Fifty-nine cognitively normal adults took part in the study. Fatigue symptoms were assessed using the Fatigue Severity Scale (FSS), depressive symptomatology with the Center for Epidemiologic Studies Depression Scale (CES-D), and situational anxiety using the state subscale of the State-Trait Anxiety Inventory (STAI-S).We used a composite measure of verbal fluency comprising letter fluency and semantic fluency as the outcome measure. RESULTS: Multiple regression analyses revealed higher fatigue was associated with better verbal fluency when STAI-S scores were high. We did not find a significant interaction between the FSS and CES-D. CONCLUSION: Greater situational anxiety levels may buffer against the negative influence of fatigue on verbal fluency in non-clinical populations, consistent with previous research showing that moderate levels of anxiety can benefit cognitive function. Whether subthreshold depressive symptoms modify the association between fatigue and verbal fluency is still unclear. Measures that assess different symptom dimensions specific to depression would help to clarify this issue.

Impact of Education on Memory Deficits in Subclinical Depression.

Elevated depressive symptoms are associated with cognitive deficits, while higher education protects against cognitive decline. This study was conducted to test if education level moderates the relationship between depressive symptoms and cognitive function. Seventy-three healthy, dementia-free adults aged 18-81 completed neuropsychological tests, as well as depression and anxiety questionnaires. Controlling for age, sex, and state anxiety, we found a significant interaction of depressive symptoms and education for immediate and delayed verbal memory, such that those with a higher education level performed well regardless of depressive symptomatology, whereas those with lower education and high depressive symptoms had worse performance. No effects were found for executive functioning or processing speed. Results suggest that education protects against verbal memory deficits in individuals with elevated depressive symptoms. Further research on cognitive reserve in depression-related cognitive deficits and decline is needed to understand the mechanisms behind this phenomenon.

Age Differences in Prefrontal Surface Area and Thickness in Middle Aged to Older Adults.

Age is associated with reductions in surface area and cortical thickness, particularly in prefrontal regions. There is also evidence of greater thickness in some regions at older ages. Non-linear age effects in some studies suggest that age may continue to impact brain structure in later decades of life, but relatively few studies have examined the impact of age on brain structure within middle-aged to older adults. We investigated age differences in prefrontal surface area and cortical thickness in healthy adults between the ages of 51 and 81 years. Participants received a structural 3-Tesla magnetic resonance imaging scan. Based on a priori hypotheses, primary analyses focused on surface area and cortical thickness in the dorsolateral prefrontal cortex, anterior cingulate cortex, and orbitofrontal cortex. We also performed exploratory vertex-wise analyses of surface area and cortical thickness across the entire cortex. We found that older age was associated with smaller surface area in the dorsolateral prefrontal and orbitofrontal cortices but greater cortical thickness in the dorsolateral prefrontal and anterior cingulate cortices. Vertex-wise analyses revealed smaller surface area in primarily frontal regions at older ages, but no age effects were found for cortical thickness. Results suggest age is associated with reduced surface area but greater cortical thickness in prefrontal regions during later decades of life, and highlight the differential effects age has on regional surface area and cortical thickness.

Unique and interactive effect of anxiety and depressive symptoms on cognitive and brain function in young and older adults.

OBJECTIVE: Depression and anxiety and are associated with cognitive deficits and brain changes, especially in older adults. Despite the frequent co-occurrence of these conditions, cognitive neuroscience studies examining comorbid depression and anxiety are limited. The goal of the present study was to examine the unique and combined effect of depressive and anxiety symptoms on cognitive and brain functioning in young and older adults. METHODS: Seventy-one healthy, community-dwelling adults between the ages of 18 and 81 were administered a neuropsychological battery and completed the Center for Epidemiologic Studies Depression Scale (CES-D) and the trait form of the State-Trait Anxiety Inventory (STAI-T). A subset of 25 participants also underwent functional magnetic resonance imaging (fMRI) scanning while completing the n-back working memory task. RESULTS: Total depressive symptoms, depressed mood symptoms, and somatic symptoms were associated with deficits in speed, working memory and executive functions, especially in older adults. Symptoms of lack of well-being were not associated with any neuropsychological test. Anxiety was associated with better attention and working memory. Moreover, anxiety modified the relationship between depressive symptoms and executive functioning in older adults, as elevated depressive symptoms were associated with worse performance at low levels of anxiety, but not at higher anxiety levels. Similarly, analysis of fMRI data showed that total depressive symptoms and depressed mood symptoms were associated with decreased activity in the superior frontal gyrus at low anxiety levels, but not at high anxiety levels. CONCLUSION: Results confirm previous reports that subthreshold depression and anxiety impact cognitive and brain functioning and suggest that the interaction of depression and anxiety results in distinct cognitive and brain changes. Findings highlight the importance of assessing and controlling for symptoms of depression and anxiety in research studies of either condition.

Impact of aerobic exercise on neurobehavioral outcomes.

Numerous studies have examined the relationship between physical activity and cognitive function, demonstrating that greater physical activity is associated with lower incidence of cognitive impairment in later life. Due to an increasingly large number of older adults at risk for cognitive impairment, the relationship between physical activity and cognition has garnered increasing public health relevance and multiple randomized trials have demonstrated that exercise interventions among sedentary adults improve cognitive performance in multiple domains of function. This article will examine the relationship between physical activity and cognitive function by reviewing several different areas of literature, including the prevalence of cognitive impairment, assessment methods, observational studies examining physical activity and cognition, and intervention studies. The present review is intended to provide a historical tutorial of existing literature linking physical activity, exercise, and cognitive function among both healthy and clinical populations.