Reward-related decision making in older adults: relationship to clinical presentation of depression.

OBJECTIVE: Impairment in reward processes has been found in individuals with depression and in the aging population. The purpose of this study was twofold: (1) to use an affective neuroscience probe to identify abnormalities in reward-related decision making in late-life depression; and (2) to examine the relationship of reward-related decision making abnormalities in depressed, older adults to the clinical expression of apathy in depression. We hypothesized that relative to older, healthy subjects, depressed, older patients would exhibit impaired decision making and that apathetic, depressed patients would show greater impairment in decision making than non-apathetic, depressed patients. METHODS: We used the Iowa Gambling Task to examine reward-related decision making in 60 non-demented, older patients with non-psychotic major depression and 36 older, psychiatrically healthy participants. Apathy was quantified using the Apathy Evaluation Scale. Of those with major depression, 18 individuals reported clinically significant apathy, whereas 42 participants did not have apathy. RESULTS: Older adults with depression and healthy comparison participants did not differ in their performance on the Iowa Gambling Task. However, apathetic, depressed older adults adopted an advantageous strategy and selected cards from the conservative decks compared with non-apathetic, depressed older adults. Non-apathetic, depressed patients showed a failure to adopt a conservative strategy and persisted in making risky decisions throughout the task. CONCLUSIONS: This study indicates that apathy in older, depressed adults is associated with a conservative response style on a behavioral probe of the systems involved in reward-related decision making. This conservative response style may be the result of reduced sensitivity to rewards in apathetic individuals.

The salience network in the apathy of late-life depression.

OBJECTIVE: Apathy is prevalent in late-life depression and predicts poor response to antidepressants, chronicity of depression, disability, and greater burden to caregivers. However, little is known about its neurobiology. Salience processing provides motivational context to stimuli. The aim of this study was to examine the salience network (SN) resting-state functional connectivity (rsFC) pattern in elderly depressed subjects with and without apathy. METHODS: Resting-state functional MRI data were collected from 16 non-demented, non-MCI, elderly depressed subjects and 10 normal elderly subjects who were psychotropic-free for at least 2 weeks. The depressed group included 7 elderly, depressed subjects with high comorbid apathy and 9 with low apathy. We analyzed the rsFC patterns of the right anterior insular cortex (rAI), a primary node of the SN. RESULTS: Relative to non-apathetic depressed elderly, depressed elderly subjects with high apathy had decreased rsFC of the rAI to dorsal anterior cingulate and to subcortical/limbic components of the SN. Depressed elderly subjects with high apathy also exhibited increased rsFC of the rAI to right dorsolateral prefrontal cortex and right posterior cingulate cortex when compared to non-apathetic depressed elderly. CONCLUSIONS: Elderly depressed subjects with high apathy display decreased intrinsic rsFC of the SN and an altered pattern of SN rsFC to the right DLPFC node of the central executive network when compared to elderly non-apathetic depressed and normal, elderly subjects. These results suggest a unique biological signature of the apathy of late-life depression and may implicate a role for the rAI and SN in motivated behavior.

MRI signal hyperintensities and failure to remit following antidepressant treatment.

BACKGROUND: MRI signal hyperintensities predict poor remission to antidepressant treatment. Previous studies using volumetrics in outpatient samples have relied on total lesion volume. The purpose of this study was to test whether remission from geriatric depression depends on lesion volume by region of interest (ROI). METHOD: Thirty-eight patients received baseline MRIs as part of a larger 12-week, randomized clinical trial comparing sertraline and nortriptyline in the treatment of late-life depression. MRIcro was used to quantify MRI-hyperintensity volume into total hyperintensity, deep white matter hyperintensity (DWMH), and periventricular hyperintensity (PVH) volumes. High versus low total, DWMH, and PVH volumes were defined based on the highest quartile of their respective distributions. Remission from depression was defined as a 24-item Hamilton Rating Scale for Depression score ≤ 7 for two consecutive weeks. RESULTS: Patients classified as having high DWMH were 7.14 times more likely not to remit following antidepressant treatment compared to patients classified as having low DWMH (p=0.02). Similar odds ratios were obtained for PVH (OR=4.17, p=0.16) and total volumes (OR=5.00, p=0.05). Importantly, adjusting for age did not change the magnitude of these effects. LIMITATIONS: A small and predominantly White sample. CONCLUSIONS: This is the first study to test whether remission from geriatric depression depends on lesion volume by ROI in an outpatient sample. The pattern of remission rates and odds ratios was similar when patients were classified as having high DWMH, PVH or total volume suggesting that lesion location may not be critical.

MRI signal hyperintensities and treatment remission of geriatric depression.

BACKGROUND: White matter abnormalities may interfere with limbic-cortical balance and contribute to chronic depressive syndromes in the elderly. This study sought to clarify the relationship of SH to treatment response. We hypothesized that patients who failed to remit during a 12-week controlled treatment trial of escitalopram would exhibit greater SH burden than patients who remitted. METHODS: The participants were 42 non-demented individuals with non-psychotic major depression and 25 elderly comparison subjects. After a 2-week single blind placebo period, subjects who still had a Hamilton Depression Rating Scale (HDRS) of 18 or greater received escitalopram 10mg daily for 12 weeks. Remission was defined as a HDRS score of 7 or below for 2 consecutive weeks. FLAIR sequences were acquired on a 1.5 T scanner and total SH were quantified using a semi-automated thresholding method. RESULTS: The patient sample consisted of 22 depressed patients who achieved remission during the study and 20 depressed patients who remained symptomatic. ANCOVA, with age and gender as covariates, revealed that depressed subjects had greater total SH burden relative to non-depressed controls. Furthermore, patients who failed to remit following escitalopram treatment had significantly greater SH burden than both patients who remitted and elderly comparison subjects, whereas SH burden did not differ between depressed patients who remitted and elderly comparison subjects. LIMITATIONS: Patients were treated with a fixed dose of antidepressants and the index of SH is an overall measure that does not permit examination of the relationship of regional SH to treatment remission. DISCUSSION: SH may contribute to a "disconnection state" both conferring vulnerability to and perpetuating late-life depression.

Serotonin transporter polymorphisms, microstructural white matter abnormalities and remission of geriatric depression.

OBJECTIVE: This study compared microstructural abnormalities in depressed elders and controls and studied the association of the serotonin transporter gene status to white matter abnormalities and to remission of depression. METHODS: The subjects were Caucasians with non-psychotic major depression and normal elders. Depressed subjects received escitalopram 10 mg daily for 12 weeks. Remission was defined as a HDRS score of 7 or below for 2 consecutive weeks. Diffusion tensor imaging was performed and voxel-based analysis of fractional anisotropy (FA) was conducted using age and mean diffusivity as covariates. RESULTS: Depressed elders (N=27) had lower FA than controls (N=27) in several frontolimbic areas. Depressed elderly S-allele carriers also had lower FA than L homozygotes in frontolimbic brain areas, including the dorsal and rostral anterior cingulate, posterior cingulate, dorsolateral prefrontal and medial prefrontal regions, thalamus, and in other regions. S-allele carriers had a lower remission rate than L homozygotes. LIMITATIONS: Small number of subjects, lack of random sampling, fixed antidepressant dose, short follow-up. CONCLUSIONS: Lower FA was observed in several frontolimbic and other regions in depressed elders compared to controls. Depressed S-allele carriers had both microstructural white matter abnormalities in frontolimbic networks and a low remission rate. It remains unclear whether the risk for chronicity of geriatric depression in S-allele carriers is mediated by frontolimbic compromise. However, these observations set the stage for studies aiming to identify the relationship of S allele to impairment in specific frontolimbic functions interfering with response of geriatric depression to antidepressants.

Blood pressure and white matter integrity in geriatric depression.

BACKGROUND: Cerebrovascular disease may increase vulnerability to geriatric depression, a syndrome often accompanied by frontal-subcortical lesions. High blood pressure is a risk factor for cerebrovascular disease and white matter changes. This study examined whether and in which brain regions blood pressure is associated with compromised white matter integrity in elderly depressed patients. METHODS: We studied the association between blood pressure and white matter integrity assessed by diffusion tensor imaging (fractional anisotropy, FA) in 41 older patients with major depression. Correlations between FA and blood pressure, after controlling for age, were examined with a voxelwise analysis. RESULTS: Significant associations between FA and blood pressure were detected throughout the anterior cingulate and in multiple frontostriatal and frontotemporal regions. LIMITATIONS: This study did not employ a healthy control group. Moreover, the relatively small sample size precluded a comparison of patients with and without hypertension. CONCLUSIONS: Compromised frontal-striatal white matter integrity may be the anatomical background through which blood pressure confers vulnerability to depression.

Aging of cerebral white matter: a review of MRI findings.

BACKGROUND: Cerebral aging is a complex and heterogeneous process that is associated with a high degree of inter-individual variability. Structural magnetic resonance imaging (MRI) can be used to identify and quantify non-disease-related aging of the cerebral white matter. METHODS: The present article reviews the findings from several MRI techniques, including morphometric approaches, study of white matter hyperintensities, diffusion tensor imaging, and magnetization transfer imaging, that have been used to examine aging of the cerebral white matter. Furthermore, the relationship of MRI indices of white matter integrity to age-related cognitive declines is reported. RESULTS: A general pattern of age-related preservation and decline emerges indicating that the prefrontal white matter is most susceptible to the influence of age. Studies that combine MRI with cognitive measures suggest that such age-related reductions in white matter integrity may produce a disconnection state that underlies some of the age-related performance declines in age-sensitive cognitive domains. CONCLUSIONS: White matter aging may contribute to a disconnection state that is associated with declines in episodic memory, executive functions, and information processing speed.

Executive dysfunction in elderly bipolar manic patients.

OBJECTIVE: This study used neuropsychological measures of executive skills to examine the functioning of frontostriatal networks in elderly bipolar patients. DESIGN: The authors hypothesized that elders with bipolar mania would exhibit poor executive functions relative to both elderly comparison subjects and depressed patients. SETTING: The study was conducted in the geriatric psychiatry services of a university hospital. PARTICIPANTS: Nondemented elders: 14 with bipolar disorder I, manic (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition), 14 with unipolar major depression (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition), and 14 nonpsychiatric comparison (NC) subjects. MEASUREMENTS: Executive functions were assessed with the initiation/perseveration subscale of the Dementia Rating Scale and the manual Go/No-Go tasks from the extended initiation/perseveration scale. RESULTS: Manic elders demonstrated poor performance on tasks of initiation/perseveration and response inhibition, and performed significantly worse than both depressed patients and NC subjects. In this sample, there was no evidence for a relationship between severity of manic symptoms and executive performance. CONCLUSION: These findings extend the observation that elderly bipolar manic patients have deficits in executive functioning compared with NC samples and provide evidence that the executive deficits demonstrated by bipolar manic elders can be more severe than those in unipolar depressed elders. As executive functions require frontostriatal integrity, these observations support investigation of specific frontostriatal network abnormalities in late-life bipolar disorder.

Macromolecular white matter abnormalities in geriatric depression: a magnetization transfer imaging study.

OBJECTIVE: Geriatric depression consists of complex and heterogeneous behaviors unlikely to be caused by a single brain lesion. However, abnormalities in specific brain structures and their interconnections may confer vulnerability to the development of late-life depression. The objective of this study was to identify subtle white matter abnormalities in late-life depression. DESIGN: The authors used magnetization transfer ratio (MTR) imaging, a technique that is thought primarily to reflect myelin integrity, to examine the hypothesis that individuals with late-life depression would exhibit white matter abnormalities in frontostriatal and limbic regions. SETTING: The study was conducted in a university-based, geriatric psychiatry clinic. PARTICIPANTS: Fifty-five older patients with major depression and 24 elderly comparison subjects were assessed. MEASUREMENT: Voxel-based analysis of MTR data were conducted with a general linear model using age as a covariate. RESULTS: Relative to comparison subjects, patients demonstrated lower MTR in multiple left hemisphere frontostriatal and limbic regions, including white matter lateral to the lentiform nuclei, dorsolateral and dorsomedial prefrontal, dorsal anterior cingulate, subcallosal, periamygdalar, insular, and posterior cingulate regions. Depressed patients had lower MTR in additional left hemisphere locales including the thalamus, splenium of the corpus callosum, inferior parietal, precuneus, and middle occipital white matter regions. CONCLUSION: These findings suggest that geriatric depression may be characterized by reduced myelin integrity in specific aspects of frontostriatal and limbic networks, and complement diffusion tensor studies of geriatric depression that indicate decreased organization of white matter fibers in specific frontal and temporal regions.

Microstructural white matter abnormalities and remission of geriatric depression.

OBJECTIVE: White matter abnormalities may interfere with limbic cortical balance and lead to chronic depressive syndromes. The authors used diffusion tensor imaging to test the hypothesis that depressed elders who fail to achieve remission have microstructural white matter abnormalities in cortico-striato-limbic networks implicated in geriatric depression. METHOD: The subjects were nondemented individuals with nonpsychotic major depression. After a 2-week placebo period, those subjects who had a Hamilton Depression Rating Scale (HAM-D) score of 18 or greater received escitalopram, 10 mg daily, for 12 weeks. Remission was defined as a HAM-D score of 7 or below for 2 consecutive weeks. Diffusion tensor imaging was performed at a 1.5 Tesla scanner, and voxel-based analysis of fractional anisotropy was conducted using age as the covariate. RESULTS: Subjects who failed to achieve remission (N=23) had lower fractional anisotropy in multiple frontal limbic brain areas, including the rostral and dorsal anterior cingulate, dorsolateral prefrontal cortex, genu of the corpus callosum, white matter adjacent to the hippocampus, multiple posterior cingulate cortex regions, and insular white matter, relative to those who achieved remission (N=25). In addition, lower fractional anisotropy was detected in the neostriatum and midbrain as well as select temporal and parietal regions. CONCLUSIONS: Lower fractional anisotropy in distributed cerebral networks is associated with poor antidepressant response of geriatric depression and may represent a neuroanatomical substrate that predisposes to this disorder.

Anterior cingulate dysfunction in geriatric depression.

BACKGROUND: Although several brain abnormalities have been identified in geriatric depression, their relationship to the pathophysiological mechanisms leading to the development and perpetuation of this syndrome remain unclear. METHODS: This paper reviews findings on the anterior cingulate cortex (ACC) function and on the relationship of ACC abnormalities to the clinical presentation and the course of geriatric depression in order to elucidate the pathophysiological role of ACC in this disorder. RESULTS: The ACC is responsible for conflict detection and emotional evaluation of error and is connected to brain structures that regulate mood, emotional valence of thought and autonomic and visceral responses, which are functions disturbed in depression. Geriatric depression often is accompanied by abnormalities in some executive functions and has a clinical presentation consistent with ACC abnormalities. Indices of ACC dysfunction are associated with adverse outcomes of geriatric depression. CONCLUSIONS: Converging findings suggest that at least some ACC functions are abnormal in depression and these abnormalities are pathophysiologically meaningful. Indices of ACC dysfunction may be used to identify subgroups of depressed elderly patients with distinct illness course and treatment needs and serve as the theoretical background for novel treatment development.

Translational research in late-life mood disorders: implications for future intervention and prevention research.

Clinical and epidemiological studies have consistently observed the heterogeneous symptomatology and course of geriatric depression. Given the importance of genetic and environmental risk factors, aging processes, neurodegenerative and cerebrovascular disease processes, and medical comorbidity, the integration of basic and clinical neuroscience research approaches is critical for the understanding of the variability in illness course, as well as the development of prevention and intervention strategies that are more effective. These considerations were the impetus for a workshop, sponsored by the Geriatrics Research Branch in the Division of Adult Translational Research and Treatment Development of the National Institute of Mental Health that was held on September 7-8, 2005. The primary goal of the workshop was to bring together investigators in geriatric psychiatry research with researchers in specific topic areas outside of geriatric mental health to identify priority areas to advance translational research in geriatric depression. As described in this report, the workshop focused on a discussion of the development and application of integrative approaches combining genetics and neuroimaging methods to understand such complex issues as treatment response variability, the role of medical comorbidity in depression, and the potential overlap between depression and dementia. Future directions for integrative research were identified. Understanding the nature of geriatric depression requires the application of translational research and interdisciplinary research approaches. Geriatric depression could serve as a model for translational research integrating basic and clinical neuroscience approaches that would have implications for the study of other neuropsychiatric disorders.

Event-related potentials in an emotional go/no-go task and remission of geriatric depression.

Anterior cingulate integrity may be required for antidepressant response. To assess anterior cingulate processes related to treatment response, we studied error-related negativity and error positivity produced during an emotional go/no-go challenge, a task activating the rostral anterior cingulate. Twelve elderly patients with major depression, treated with escitalopram 10 mg daily, were studied. Patients who remained symptomatic after 8 weeks of treatment had larger error-related negativity and smaller error positivity amplitude compared with patients who achieved remission. The error-related negativity is elicited during conflict detection and the error positivity reflects the emotional reaction to error. Thus, these findings suggest that two distinct conflict-processing functions of the anterior cingulate are important for antidepressant response of geriatric depression.

White-matter integrity predicts stroop performance in patients with geriatric depression.

BACKGROUND: This study tested the hypothesis that microstructural white matter abnormalities in frontostriatal-limbic tracts are associated with poor response inhibition on the Stroop task in depressed elders. METHOD: Fifty-one elders with major depression participated in a 12-week escitalopram trial. Diffusion tensor imaging was used to determine fractional anisotropy (FA) in white matter regions. Executive function (response inhibition) was assessed with the Stroop task. Voxelwise correlational analysis was used to examine the relationship between Stroop performance and fractional anisotropy. RESULTS: Significant associations between FA and Stroop color word interference were evident in multiple frontostriatal-limbic regions, including white matter lateral to the anterior and posterior cingulate cortex and white matter in prefrontal, insular, and parahippocampal regions. CONCLUSIONS: These findings suggest that microstructural white matter abnormalities of frontostriatal-limbic networks are associated with executive dysfunction of late-life depression. This observation provides the rationale for examination of specific frontostriatal-limbic pathways in the pathophysiology of geriatric depression.

Structural neuroimaging research methods in geriatric depression.

Geriatric depression consists of complex and heterogeneous behaviors unlikely to be caused by a single brain lesion. However, there is evidence that abnormalities in specific brain structures and their interconnections confer vulnerability to the development of late-life depression. Structural magnetic resonance imaging methods can be used to identify and quantify brain abnormalities predisposing to geriatric depression and in prediction of treatment response. This article reviews several techniques, including morphometric approaches, study of white matter hyperintensities, diffusion tensor imaging, magnetization transfer imaging, t2 relaxography, and spectroscopy, that have been used to examine these brain abnormalities with a focus on the type of information obtained by each method as well as each method's limitations. The authors argue that the available methods provide complementary information and that, when combined judiciously, can increase the knowledge gained from neuroimaging findings and conceptually advance the field of geriatric depression.

Neuroanatomical correlates of selected executive functions in middle-aged and older adults: a prospective MRI study.

Neuroanatomical substrates of age-related differences in working memory and perseverative behavior were examined in a sample of healthy adults (50-81 years old). The participants, who were screened for history of neurological, psychiatric, and medical conditions known to be linked to poor cognitive performance, underwent magnetic resonance imaging (MRI) and were administered tests of working memory and perseveration. Regional brain volumes and the volume of white matter hyperintensities (WMH) were measured on magnetic resonance images. The analyses indicate that the volume of the prefrontal cortex (PFC) and the volume of white matter hyperintensities in the prefrontal region are independently associated with age-related increases in perseverative errors on the Wisconsin Card Sorting Test (WCST). When participants taking antihypertensive medication were excluded from the analysis, both the volume of the prefrontal cortex and the frontal white matter hyperintensities (FWMH) still predicted increases in perseveration. Neither reduced volume of the prefrontal cortex nor the FWMH volume was linked to age-associated declines in working memory. The volumes of the fusiform gyrus (FG) and the temporal white matter hyperintensities (TWMH) were unrelated to cognitive performance.

Age-related differences in brain activation during emotional face processing.

Advancing age is associated with significant declines on neurobehavioral tasks that demand substantial mental effort. Functional imaging studies of mental abilities indicate that older adults faced with cognitive challenges tend to activate more regions, particularly frontal, than their younger counterparts, and that this recruitment of additional regions may reflect an attempt to compensate for inefficiency in cortical networks. The neural basis of emotion processing in aging has received little attention, and the goal of the present study was to use functional magnetic resonance imaging (fMRI) to examine the influence of age on facial emotion processing and activation in cortical and limbic regions. Participants (eight old and eight young adults) viewed facial displays of happiness, sadness, anger, fear, disgust, and neutrality in alternating blocks of emotion and age discrimination. We predicted that in response to an emotion discrimination task, older adults would demonstrate increased use of frontal regions relative to younger adults, perhaps combined with diminished use of regions recruited by younger adults, such as temporo-limbic regions. During the emotion discrimination task, young participants activated, visual, frontal and limbic regions, whereas older participants activated parietal, temporal and frontal regions. A direct comparison between emotion and age discrimination revealed that while younger adults activated the amygdala and surrounding temporo-limbic regions, older adults activated left frontal regions. The results of this study suggest that older adults may rely on different cortical networks to perceive emotional facial expressions than do their younger counterparts.

Brain region and sex differences in age association with brain volume: a quantitative MRI study of healthy young adults.

There is evidence that some brain regions show age-associated volume decline and that men undergo more accelerated cerebral aging than women. However, limited information is available on age-associated changes during young adulthood. The authors performed quantitative magnetic resonance imaging in 116 healthy young adults (57 men, 59 women; age range: 18-49 years) to evaluate the relationship of age and sex with volumes of frontal and temporal regions, including selected limbic structures and the basal ganglia. Regardless of sex, increasing age was moderately associated with decrease in total gray matter (GM) and mildly with increase in sulcal cerebrospinal fluid (CSF). Associations of age with reduced GM volume were observed in all frontal and temporal cortical regions and some basal ganglia structures, but were generally less prominent in subcortical regions. The associations were stronger for men than women in the dorsolateral prefrontal cortex. Thus, in young, healthy adults, age-associated changes are selective as well as sex-specific, with men experiencing greater volume decrement across age-groups than women, particularly in the dorsolateral prefrontal regions. Reduced GM and increased CSF in this age range suggests that the aging process is a continuum, with changes evident before senescence. Thus, the biological changes commonly attributed to "aging" do, in fact, begin much earlier in the life-cycle.