How family dementia caregivers perceive benefits of a 4-week Mentalizing Imagery Therapy program: a pilot study.

Background: Family caregivers of dementia patients experience high levels of interpersonal stress that often results in elevated anxiety, and depression, and negative impacts on interpersonal relationships. Changes in behaviors and the structure of relationships with the care recipient (CR) and others in the social milieu challenge the caregivers' ability to mentalize, or understand the links between mental states and behaviors. This study investigates the experiences and perceived benefits of family dementia caregivers who underwent Mentalizing Imagery Therapy (MIT), a treatment aiming to improve balanced self-other mentalizing and reduce psychological symptoms. Methods: Purposeful sampling was used to select 11 family dementia caregivers who underwent a 4-week pilot trial of MIT. Semi-structured interviews were completed post-intervention to identify subjective benefits, putative psychological mediators and perceived active components. Results: Caregivers reported improvements in well-being, mood, anxiety, and sleep, and a majority stated MIT helped with forming and maintaining healthier relationships. Some participants noted benefits extending to how they reacted to their social environment and perceived themselves more objectively from others' perspectives. Specific elements of MIT, including self-compassion, self-care, and the ability to reflect on emotionally arousing challenges, might have mediated these improvements. Conclusion: Family dementia caregivers perceived salutary benefits of MIT on multiple domains of well-being. The self reports suggest MIT holds promise for improving well-being, reducing non-mentalizing patterns of thought, and facilitating improvements in balanced mentalization within the caregivers' relationships.

Mentalizing imagery therapy for depressed family dementia caregivers: Feasibility, clinical outcomes and brain connectivity changes.

BACKGROUND: Family dementia caregivers experience high rates of depression and anxiety that often go untreated due to time demands. We aimed to determine the feasibility of a brief, 4-week Mentalizing Imagery Therapy intervention, which couples mindfulness with guided imagery practices aimed at bolstering mentalizing capacity, to reduce caregiver psychological symptoms and to explore potential impact on dorsolateral prefrontal cortex connectivity. METHODS: Twenty-four family dementia caregivers with moderate depression symptoms (a score of 10 in Patient Health Questionnaire-9) were assigned to either group Mentalizing Imagery Therapy (MIT, n = 12) or a waitlist augmented by optional relaxation exercises (n = 12). Participants completed questionnaires to measure depression and anxiety at baseline and followup, and those eligible also underwent resting state functional magnetic resonance (fMRI) brain imaging at these time points. RESULTS: Eleven of 12 caregivers assigned to MIT completed the intervention and attended weekly groups 98% of the time. MIT home practice logs indicated average practice of 5 ± 2 sessions per week for 23 ± 8 min per session. All participants in waitlist completed the post-assessment. MIT participants exhibited significantly greater improvement than waitlist on self-reported depression and anxiety symptoms (p<.05) after 4 weeks. Neuroimaging results revealed increased dorsolateral prefrontal cortex connectivity with a putative emotion regulation network in the MIT group (p = .05) but not in waitlist (p = 1.0). LIMITATIONS: Sample size limitations necessitate validation of findings in larger, randomized controlled trials. CONCLUSIONS: A 4-week group MIT program was feasible for caregivers, with high levels of participation in weekly group meetings and home practice exercises.

Prospective testing of a neurophysiologic biomarker for treatment decisions in major depressive disorder: The PRISE-MD trial.

Management of Major Depressive Disorder (MDD) might be improved by a biomarker to predict whether a selected medication is likely to lead to remission. We previously reported on a quantitative electroencephalogram-based biomarker, the Antidepressant Treatment Response (ATR) index, that integrated recordings at baseline and after one week of treatment. The present study prospectively tested whether treatment directed by the biomarker increased the likelihood of remission; we hypothesized that continued treatment with a drug predicted to lead to remission (i.e., high ATR values) would be associated with better outcomes than if the drug was predicted not to lead to remission (i.e., low ATR values). We enrolled 180 adult outpatients with unipolar MDD from the community. After one week of escitalopram treatment to determine the biomarker, stratified randomization (high vs. low ATR) was used to assign subjects to either continued escitalopram or a switch to bupropion as a blinded control condition, for seven additional weeks. For the 73 evaluable subjects assigned to continued escitalopram treatment, the remission rate was significantly higher for those in whom ATR had predicted remission versus non-remission (60.4% vs. 30.0%, respectively, p = 0.01). Accuracy was enhanced by combining 1-week depressive symptom change with ATR (68.6% vs 28.9%). This prospective validation study supports further development of the ATR biomarker, alone or together with early symptom change, to improve care by identifying individuals unlikely to remit with their current treatment, and support the decision to change treatment after one week rather than after failing a full, prolonged course of medication.

Grief, Mindfulness and Neural Predictors of Improvement in Family Dementia Caregivers.

Background: Family dementia caregivers often suffer from an immense toll of grief while caring for their loved ones. We sought to identify the clinical relationship between grief, depression and mindfulness and identify neural predictors of symptomatology and improvement. Methods: Twenty three family dementia caregivers were assessed at baseline for grief, mindfulness and depression, of which 17 underwent functional magnetic resonance imaging (fMRI). During fMRI, caregivers were shown faces of either their dementia-stricken relative or that of a stranger, paired with grief-related or neutral words. In nine subjects, post fMRI scans were also obtained after 4 weeks of either guided imagery or relaxation. Robust regression was used to predict changes in symptoms with longitudinal brain activation (BA) changes as the dependent variable. Results: Grief and depression symptoms were correlated (r = 0.50, p = 0.01), and both were negatively correlated with mindfulness (r = -0.70, p = 0.0002; r = -0.52, p = 0.01). Relative to viewing strangers, caregivers showed pictures of their loved ones (picture factor) exhibited increased activation in the dorsal anterior cingulate gyrus and precuneus. Improvement in grief but not mindfulness or depression was predicted by increased relative BA in the precuneus and anterior cingulate (different subregions from baseline). Viewing grief-related vs. neutral words elicited activity in the medial prefrontal cortex and precuneus. Conclusions: Caregiver grief, depression and mindfulness are interrelated but have at least partially nonoverlapping neural mechanisms. Picture and word stimuli related to caregiver grief evoked brain activity in regions previously identified with bereavement grief. These activation foci might be useful as biomarkers of treatment response.

Trigeminal Nerve Stimulation for Comorbid Posttraumatic Stress Disorder and Major Depressive Disorder.

OBJECTIVES: External stimulation of the trigeminal nerve (eTNS) is an emerging neuromodulation therapy for epilepsy and depression. Preliminary studies suggest it has an excellent safety profile and is associated with significant improvements in seizures and mood. Neuroanatomical projections of the trigeminal system suggest eTNS may alter activity in structures regulating mood, anxiety, and sleep. In this proof-of-concept trial, the effects of eTNS were evaluated in adults with posttraumatic stress disorder (PTSD) and comorbid unipolar major depressive disorder (MDD) as an adjunct to pharmacotherapy for these commonly co-occurring conditions. MATERIALS AND METHODS: Twelve adults with PTSD and MDD were studied in an eight-week open outpatient trial (age 52.8 [13.7 sd], 8F:4M). Stimulation was applied to the supraorbital and supratrochlear nerves for eight hours each night as an adjunct to pharmacotherapy. Changes in symptoms were monitored using the PTSD Patient Checklist (PCL), Hamilton Depression Rating Scale (HDRS-17), Quick Inventory of Depressive Symptomatology (QIDS-C), and the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q). RESULTS: Over the eight weeks, eTNS treatment was associated with significant decreases in PCL (p = 0.003; median decrease of 15 points; effect size d 1.5), HDRS-17 (p < 0.001; 42% response rate, 25% remission; d 2.1), and QIDS-C scores (p < 0.001; d 1.8), as well as an improvement in quality of life (Q-LES-Q, p < 0.01). eTNS was well tolerated with few treatment emergent adverse events. CONCLUSIONS: Significant improvements in PTSD and depression severity were achieved in the eight weeks of acute eTNS treatment. This novel approach to wearable brain stimulation may have use as an adjunct to pharmacotherapy in these disorders if efficacy and tolerability are confirmed with additional studies.

Cognitive, behavioral, and autonomic correlates of mind wandering and perseverative cognition in major depression.

Autonomic dysregulation has been hypothesized to play a role in the relationships between psychopathology and cardiovascular risk. An important transdiagnostic factor that has been associated with autonomic dysfunction is perseverative cognition (PC), mainly present in Major Depressive Disorder (MDD) in the form of rumination. As the ability to adaptively let our mind wander without ruminating is critical to mental health, this study aimed to examine the autonomic concomitants of functional vs. dysfunctional intrusive thoughts in MDD. Ambulatory heart rate (HR) and variability (HRV) of 18 MDD subjects and 18 healthy controls were recorded for 24 h. Approximately every 30 min during waking hours subjects reported their ongoing thoughts and moods using electronic diaries. Random regression models were performed. Compared to controls, MDD subjects were more often caught during episodes of PC. In both groups, PC required more effort to be inhibited and interfered more with ongoing activities compared to mind wandering (MW) (ps < 0.0001). This cognitive rigidity was mirrored by autonomic inflexibility, as PC was characterized by lower HRV (p < 0.0001) compared to MW. A worse mood was reported by MDD patients compared to controls, independently of their ongoing cognitive process. Controls, however, showed the highest mood worsening during PC compared to being on task and MW. HRV during rumination correlated with self-reported somatic symptoms on the same day and several dispositional traits. MDD subjects showed lower HRV during sleep, which correlated with hopelessness rumination. Results show that PC is associated with autonomic dysfunctions in both healthy and MDD subjects. Understanding when spontaneous thought is adaptive and when it is not may clarify its role in the etiology of mood disorders, shedding light on the still unexplained association between psychopathology, chronic stress, and risk for health.

Neurophysiologic effects of repeated exposure to antidepressant medication: are brain functional changes during antidepressant administration influenced by learning processes?

Major Depressive Disorder (MDD) is a lifelong and recurrent illness, such that many individuals require multiple courses of antidepressant medication treatment. While some patients respond completely to each course of treatment, many do not, and with each unsuccessful antidepressant trial the likelihood that a patient will respond decreases. This raises the possibility that neurophysiologic response in subsequent antidepressant treatment may be influenced by learning processes including sensitization, habituation, and/or classical conditioning. Classical conditioning would entail the association of cues such as pill-taking (conditioned stimuli; CS) with the effects of active medication (unconditioned stimulus; US), such that later presentation of the CS alone would come to elicit a conditioned response (CR). Such effects could be revealed by blinded administration of placebo following a period of treatment with active medication. Habituation effects (tolerance), or sensitization effects (increased response), which require only repeated exposure to a stimulus, might be evidenced after repeated courses of antidepressant treatment. Knowledge of how learning processes impact neurophysiologic response to successive courses of antidepressant treatment would have relevance for clinical populations. Specific hypotheses, however, may be tested in healthy non-clinical samples to avoid potential confounding factors related to severity or chronicity of illness. Learning theories would suggest two hypotheses: (1) neurophysiologic response to placebo will differ between subjects who were previously treated with antidepressant treatment as compared to placebo (classical conditioning hypothesis); and (2) neurophysiologic response to an initial course of antidepressant treatment will differ from response to a repeated course of antidepressant treatment. Pilot data addressed these hypotheses in healthy never-depressed women who had previously received four weeks of venlafaxine IR, 150 mg (antidepressant-experienced subjects; n=2) or matching placebo (antidepressant-naive subjects; n=4) under double-blind conditions. Six-and-a-half years later, we treated these six women with placebo for one week, followed by four weeks of double-blind treatment with venlafaxine IR, 150 mg. Brain functional changes over the course of treatment were assessed using quantitative electroencephalography (qEEG) to compare prefrontal neurophysiologic responses between subjects who had, versus had not, previously been exposed to venlafaxine. Antidepressant-experienced versus antidepressant-naive subjects showed greater decreases in prefrontal cordance (PFC) during venlafaxine administration (sensitization hypothesis) but did not show significantly different PFC changes during treatment with placebo in this small pilot sample (classical conditioning hypothesis). Data suggest that brief treatment with antidepressant medication may have an enduring impact on neurophysiologic responses to a subsequent course of antidepressant treatment. Hypotheses should be tested in larger samples.

Midline and right frontal brain function as a physiologic biomarker of remission in major depression.

Prior investigations have reported that changes in the prefrontal electroencephalogram (EEG) precede symptom improvement from antidepressant medications, and could serve as a biomarker of treatment outcome in major depressive disorder (MDD). A new physiologically defined region of interest (ROI), overlying the midline and right frontal (MRF) cortical area, was examined here for a relationship between early decreases in theta-band cordance and remission. Subjects were 72 adults with unipolar MDD who had completed placebo-controlled antidepressant treatment trials, with 37 randomized to medication and 35 to placebo. We assessed changes in cordance and absolute and relative power in the MRF region at 48 h, 1 week, and 2 weeks after start of drug, as potential predictors of remission (final score on the 17-item Hamilton Depression Rating Scale of 5 or below. Out of 37 medication-treated subjects, 11 (30%) remitted versus 6 of 35 placebo subjects (17%). Change in MRF cordance 1 and 2 weeks after the beginning of treatment was significantly associated with remission in medication-treated subjects at 1 week, with receiver operating characteristic (ROC) analysis yielding 0.76 area under the curve. Decreases in MRF cordance at 1 week predicted remission with medication with 69% overall accuracy (90% sensitivity; 60% specificity). MRF cordance changes were not associated with remission with placebo. Absolute and relative power did not differentiate groups. These results suggest that remission may be predictable from physiologic measurements after 1 week of treatment, and that this region merits further investigation in the neurobiology of treatment response.

Brain functional changes and duloxetine treatment response in fibromyalgia: a pilot study.

OBJECTIVES: Serotonin-norepinephrine reuptake inhibitor (SNRI) antidepressant medications may have efficacy in relieving pain associated with fibromyalgia syndrome (FMS), even in the absence of major depressive disorder (MDD). Current practice is to use a trial-and-error treatment strategy, often requiring 8-12 weeks to determine the effectiveness of a given pharmacological intervention. The ability to predict response to antidepressant medications would facilitate clinical management of FMS. Prior work in MDD has shown that the quantitative electroencephalographic (QEEG) cordance biomarker of brain functional changes early in the course of antidepressant treatment is related to later clinical response. We hypothesized that cordance might also predict response to antidepressant medications for symptoms of FMS. DESIGN: Twelve adults (9 females) meeting American College of Rheumatology criteria for FMS participated in a double-blind placebo-controlled treatment trial utilizing duloxetine 60 mg. QEEG cordance changes were examined over the first week of treatment. Primary clinical outcomes included change in average pain severity on the Brief Pain Inventory (BPI) and global improvement in pain on the Patient's Global Impressions of Improvement (PGI-I) scale at 12 weeks. RESULTS: Changes in left frontal QEEG cordance after the first week of duloxetine treatment significantly predicted BPI pain improvement (regression coefficient = 2.9, R(2) = 0.93, P = 0.008) and PGI-I global improvement (regression coefficient = 0.94, R(2) = 0.81, P = 0.04). CONCLUSIONS: This pilot study suggests that QEEG biomarkers may prove useful for predicting improvement in painful symptoms during SNRI treatment in FMS. Larger studies are needed to confirm this finding.

Changes in brain function during administration of venlafaxine or placebo to normal subjects.

Previous research has demonstrated neurophysiologic effects of antidepressants in depressed subjects. We evaluated neurophysiologic effects of venlafaxine in normal subjects. Healthy adults (n=32) received a 1-week placebo lead-in followed by 4 weeks randomized double-blind treatment with venlafaxine IR 150 mg. (n = 17) or placebo (n = 15). Brain function was examined using quantitative electroencephalographic (QEEG) power and theta cordance. Normal subjects receiving venlafaxine showed a decrease in theta-band cordance in the midline-and-right-frontal (MRF) region at 48 hours and at 1 week after randomization. Decreases in relative power also were seen in the MRF region; there were no significant changes in absolute power. These changes were significantly different from those in subjects receiving placebo. Changes in MRF cordance accurately identified treatment condition at 48 hours in 81.3% of subjects, and relative power from this region identified 60.7% of subjects. In conclusion, cordance may detect the pharmacological effects of antidepressant medication in normal subjects. Future studies should examine other classes of medication, as well as antidepressants with other mechanisms of action, to determine if cordance detects antidepressant medication effects in general in normal subjects.

Yoga as a complementary treatment of depression: effects of traits and moods on treatment outcome.

Preliminary findings support the potential of yoga as a complementary treatment of depressed patients who are taking anti-depressant medications but who are only in partial remission. The purpose of this article is to present further data on the intervention, focusing on individual differences in psychological, emotional and biological processes affecting treatment outcome. Twenty-seven women and 10 men were enrolled in the study, of whom 17 completed the intervention and pre- and post-intervention assessment data. The intervention consisted of 20 classes led by senior Iyengar yoga teachers, in three courses of 20 yoga classes each. All participants were diagnosed with unipolar major depression in partial remission. Psychological and biological characteristics were assessed pre- and post-intervention, and participants rated their mood states before and after each class. Significant reductions were shown for depression, anger, anxiety, neurotic symptoms and low frequency heart rate variability in the 17 completers. Eleven out of these completers achieved remission levels post-intervention. Participants who remitted differed from the non-remitters at intake on several traits and on physiological measures indicative of a greater capacity for emotional regulation. Moods improved from before to after the yoga classes. Yoga appears to be a promising intervention for depression; it is cost-effective and easy to implement. It produces many beneficial emotional, psychological and biological effects, as supported by observations in this study. The physiological methods are especially useful as they provide objective markers of the processes and effectiveness of treatment. These observations may help guide further clinical application of yoga in depression and other mental health disorders, and future research on the processes and mechanisms.

Does the clinical course of depression determine improvement in symptoms and quality of life?

Clinical course factors characterizing individuals' history with depression may be helpful in predicting treatment-related change in quality of life (QOL). Such factors have been studied in relation to symptomatic change with mixed results. This 9-week single-blind treatment trial using reboxetine (1 week placebo lead-in) evaluated the impact of age of onset, history of antidepressant treatment, duration of index episode, number of past episodes, and the presence of precipitating stress on depressed individuals' treatment response. We found that QOL did not normalize along with clinical remission in all areas. Using multivariate analysis, we found that age of onset, history with antidepressants, and the presence of identifiable precipitating stress were all significant predictors of QOL change (controlling for symptomatic change); some factors also predicted symptomatic improvement. Our results support the trend of distinguishing between treatment-related change in QOL and symptomatic change and suggest clinical course factors as promising predictors of QOL.

Evaluation of reboxetine, a noradrenergic antidepressant, for the treatment of fibromyalgia and chronic low back pain.

Clinical experience supports the use of antidepressant medications to treat chronic pain syndromes, such as low back pain and fibromyalgia. Although this use of antidepressants is common in clinical practice, the literature supporting this off-label use has some limitations. In this report, the authors review the body of clinical data on the use of antidepressants in treating pain and present a case series of depressed patients with these syndromes who experienced relief of pain symptoms while being treated with the noradrenergic antidepressant reboxetine. These subjects experienced significant relief of pain before any significant improvement in actual mood symptoms. Our experience with reboxetine suggests that this noradrenergic antidepressant may have efficacy in the treatment of chronic pain in patients with depression.

Changes in prefrontal activity characterize clinical response in SSRI nonresponders: a pilot study.

Previous studies in unipolar depression have shown that early decreases in prefrontal values of the QEEG cordance measure identified responders to pharmacotherapy. These studies have all examined individuals who were drug-free prior to the first physiologic assessment, yet in the clinical management of treatment resistant depression (TRD), many patients undergo changes in treatment without a drug-free interval between treatments. Here, we investigated whether cordance decreases were associated with response in Stage I TRD subjects without wash-out between treatment trials. Awake EEGs were recorded from 12 adults with unipolar depression. Subjects were receiving naturalistic treatment, had failed SSRI monotherapy, and were starting a new treatment prescribed by their treating psychiatrists. EEG data were recorded before starting the new treatment and after approximately 1 week. Six of the 12 subjects responded to treatment after 8--10 weeks. Five of the six responders showed an early cordance decreases, compared with two of the six nonresponders (accurate characterization in 75% of the cases). Consistent with previous treatment trials, decreases in prefrontal cordance differentiated responders from nonresponders in this setting as well. These findings suggest that cordance biomarkers may be a useful tool in effectiveness trials that parallel clinical practices in SSRI nonresponders, and may not require a wash-out period between treatments.

Influence of age, gender, health status, and depression on quantitative EEG.

Quantitative electroencephalography (QEEG) has shown increasing utility in assessing brain function in clinical research studies of depression. QEEG findings may be influenced by a variety of factors other than the presence of depression, including age, gender, depression severity, and physical health status. Many of these factors have not been systematically evaluated. We therefore examined QEEG measures in 104 subjects with depression and normal controls to determine the influence of these factors. We examined QEEG power as well as cordance, a QEEG measure that has a stronger association with cerebral perfusion than conventional QEEG measures. Prefrontal cordance in the theta band has been associated with the pathophysiology of depression and response to treatment. We found that prefrontal cordance and relative power in the theta band were unaffected by age, gender, severity of depression, and health status, while prefrontal absolute power was higher in women than men. All of these measures were different from global measures of absolute and relative power, which were influenced by age, gender, and health status. These findings suggest that prefrontal cordance in depressed patients is not significantly affected by factors of age, gender, severity of depression, or physical illness. Global measures of power, and to a lesser extent prefrontal absolute power, must be interpreted with regard to confounding factors of age, gender, physical illness, and severity of depression.

Neurophysiologic correlates of side effects in normal subjects randomized to venlafaxine or placebo.

Adverse events reported in the context of medication administration may be due to pharmacodynamic and/or nonpharmacodynamic effects (eg, nocebo phenomena). Neurophysiological substrates of side effects may be examined in placebo-controlled antidepressant treatment trials. We explored the relationship between side effects and regional neurophysiologic changes in normal subjects receiving a 1-week placebo lead-in followed by 4 weeks randomized treatment with placebo (n = 15) or venlafaxine IR (n = 17). Quantitative electroencephalographic (QEEG) cordance measures were obtained before and during treatment, and side effects were assessed weekly using semistructured interviews. Side effect burden, characterized as the mean number of side effects per postrandomization visit, correlated significantly with neurophysiologic changes in the antidepressant group but not the placebo group. Medication group side effects were negatively correlated with changes in prefrontal cordance at end of placebo lead-in (r = -0.67, p < 0.003), at 2 weeks (r = -0.77, p < 0.002), and at 4 weeks (r = -0.77, p < 0.004) post randomization. After controlling for the prefrontal change at the end of placebo lead-in, postrandomization brain changes did not further explain side effect burden. Changes in prefrontal brain function associated with later antidepressant side effects were observed during placebo lead-in-prior to the administration of medication. Prefrontal brain function during brief placebo administration may help explain susceptibility to the development of antidepressant side effects. Results of these exploratory hypothesis-generating analyses should be considered tentative until replicated.

Subject expectations of treatment effectiveness and outcome of treatment with an experimental antidepressant.

OBJECTIVE: To evaluate the association between treatment expectations and response in a 9-week, single-blind experimental antidepressant treatment study. METHOD: Twenty-five adult subjects meeting DSM-IV criteria for major depressive disorder with Hamilton Rating Scale for Depression (HAM-D) scores of >/= 17 completed a treatment trial using the experimental antidepressant reboxetine. Following a 1-week placebo lead-in, subjects received single-blind treatment for 8 weeks with reboxetine 8 to 10 mg/day. During the screening visit, subjects were asked to self-rate their expectations of the effectiveness of the study medication. Forced-choice responses were "not at all effective," "somewhat effective," or "very effective." Response to treatment was defined as a final HAM-D score of

Pretreatment neurophysiological and clinical characteristics of placebo responders in treatment trials for major depression.

RATIONALE: High placebo response rates are a confound in treatment trials for major depressive disorder (MDD). A method for prospective identification of placebo responders could enhance the efficiency of clinical trials. OBJECTIVE: The objective was to identify the neurophysiological, symptomatic, and cognitive characteristics of subjects who were likely to respond to placebo in clinical trials for MDD. METHODS: Fifty-one subjects with MDD were treated in clinical trials with either fluoxetine ( n=24) or venlafaxine ( n=27) versus placebo. All subjects underwent pretreatment assessment with quantitative electroencephalographic (QEEG) power and cordance, as well as symptom ratings and neuropsychological testing. After a 1-week single-blind placebo lead-in, subjects were randomized to double-blind placebo controlled treatment with a medication or placebo. At the end of 8 weeks, the blind was broken and treatment response assessed. Response was defined by a final Hamilton Depression Rating Scale score of

Longitudinal progression of subclinical structural brain disease in normal aging.

OBJECTIVE: The authors describe four types of brain structural change in "normal aging:" cortical atrophy, central atrophy, deep white-matter hyperintensities (DWMH), and periventricular hyperintensities (PVH). Cross-sectional investigations have reported that greater volumes of these forms of "subclinical structural brain disease" (SSBD) were found with increasing age. Greater volumes were also associated with poorer cognition, even though subjects performed within the normal range. The natural history of these forms of SSBD and their functional impact are not well established. METHODS: Twenty-nine normal subjects, ages 60-89, were examined longitudinally by volumetric magnetic resonance imagery, with two assessments performed at least 2 years apart; 26 also completed neuropsychological testing to evaluate processing speed, executive functions, language, and other cognitive functions. Associations between structure and function were evaluated with regression models. RESULTS: For most subjects, the volumes for signs of all types of SSBD were found to have increased; for many subjects, increases were small, and a few showed no change or small decreases. PVH and DWMH increases were predicted by baseline cerebrovascular risk factors. Cognitive test performance changed little over time for these normal subjects. CONCLUSIONS: SSBD volumes increased for most subjects over time, with small average increases for most types. Pretreatment cerebrovascular risk factors were associated with greater increases of PVH and DWMH, suggesting that progression of these types of SSBD may be amenable to intervention.

Cognitive and physiologic correlates of subclinical structural brain disease in elderly healthy control subjects.

CONTEXT: Healthy elderly persons commonly show 4 types of change in brain structure-cortical atrophy, central atrophy, deep white-matter hyperintensities, and periventricular hyperintensities-as forms of subclinical structural brain disease (SSBD). OBJECTIVES: To characterize the volumes of SSBD present with aging and to determine the associations of SSBD, physiology, and cognitive function. DESIGN: Cross-sectional study. SETTING: University of California, Los Angeles, Neuropsychiatric Institute. SUBJECTS: Forty-three community-dwelling healthy control subjects, aged 60 through 93 years. MAIN OUTCOME MEASURES: Volumetric magnetic resonance imaging, neuropsychological testing, and quantitative electroencephalographic coherence (functional connectivity) between brain regions. RESULTS: Regression models demonstrated significant relationships between SSBD volumes, age, cognitive performance, and connectivity. Cortical and central atrophy and periventricular hyperintensities had significant associations with age while deep white-matter hyperintensities did not. Posterior atrophy showed stronger associations with age than did anterior atrophy. Only a subset of subjects at older ages showed large SSBD volumes; older subjects primarily showed increasing variance of SSBD. Although all subjects scored within the normal range on cognitive testing, SSBD volume was inversely related to performance, most notably on the Trail-Making Test part B and the Shipley-Hartford Abstract Reasoning test. Coherence had significant associations with SSBD. Path analysis supported mediation of the effects of deep white-matter hyperintensities and periventricular hyperintensities on cognition by altered connectivity. For several measures, cognitive performance was best explained by coherence, and only secondarily by SSBD. CONCLUSIONS: Modest volumes of SSBD were associated with decrements in cognitive performance within the normal range in healthy subjects. Lower coherence was associated with greater volumes of SSBD and increasing age. Path analysis models suggest that brain functional connectivity mediates some effects of SSBD on cognition.