17β-Estradiol (E) increases axospinous synapse density in the hippocampal CA1 region of young fem... more 17β-Estradiol (E) increases axospinous synapse density in the hippocampal CA1 region of young female rats, but not in aged rats. This may be linked to age-related alterations in signaling pathways activated by synaptic estrogen receptor α (ER-α) that potentially regulate spine formation, such as LIM-Kinase (LIMK), an actin depolymerizing factor/cofilin kinase. We hypothesized that, as with ER-α, phospho-LIMK (pLIMK) may be less abundant or responsive to E in CA1 synapses of aged female rats. To address this, cellular and subcellular distribution of pLIMK-immunoreactivity (pLIMK-IR) in CA1 was analyzed by light and electron microscopy in young and aged female rats that were ovariectomized and treated with either vehicle or E. pLIMK-IR was found primarily in perikarya within the pyramidal cell layer and dendritic shafts and spines in stratum radiatum (SR). While pLIMK-IR was occasionally present in terminals, post-embedding quantitative analysis of SR showed that pLIMK had a predominant post-synaptic localization and was preferentially localized within the postsynaptic density (PSD). The percentage of pLIMK-labeled synapses increased (30%) with E treatment (p<0.02) in young animals, and decreased (43%) with age (p<0.002) regardless of treatment. The pattern of distribution of pLIMK-IR within dendritic spines and synapses was unaffected by age or E treatment, with the exception of an E-induced increase in the non-synaptic core of spines in young females. These data suggest that age-related synaptic alterations similar to those seen with ER-α occur with signaling molecules such as pLIMK, and support the hypothesis that age-related failure of E treatment to increase synapse number in CA1 may be due to changes in the molecular profile of axospinous synapses with respect to signaling pathways linked to formation of additional spines and synapses in response to E.
American Journal of Geriatric Psychiatry, May 1, 2015
Objective-Executive dysfunction may play a key role in the pathophysiology of late-life depressio... more Objective-Executive dysfunction may play a key role in the pathophysiology of late-life depression. Executive dysfunction can be assessed with cognitive tests and subjective report of difficulties with executive skills. The present study investigated the association between subjective report of executive functioning complaints and time to escitalopram treatment response in older adults with Major Depressive Disorder (MDD). Methods-100 older adults with MDD (58 with executive functioning complaints and 42 without executive functioning complaints) completed a 12-week trial of escitalopram. Treatment response over 12 weeks, as measured by repeated Hamilton Depression Rating Scale scores, was compared for adults with and without executive complaints using mixed-effects modeling. Results-Mixed effects analysis revealed a significant group by time interaction, F (1, 523.34) = 6.00, p = .01. Depressed older adults who reported executive functioning complaints at baseline demonstrated a slower response to escitalopram treatment than those without executive functioning complaints. Conclusion-Self-report of executive functioning difficulties may be a useful prognostic indicator for subsequent speed of response to antidepressant medication.
American Journal of Geriatric Psychiatry, May 1, 2015
Objectives-The aims of this study were to examine: (1) the relationship between apathy and disabi... more Objectives-The aims of this study were to examine: (1) the relationship between apathy and disability in late-life depression, and (2) the functional significance of improvement in apathy following escitalopram treatment in terms of its relationship to disability. Methods-Subjects were 71 non-demented elderly with non-psychotic major depression. After a 2-week single-blind placebo period, subjects who had Hamilton Depression Rating Scale (HDRS) ≥ 18 received escitalopram 10mg daily for 12 weeks. Apathy and disability were assessed with the Apathy Evaluation Scale (AES) and the World Health Organization Disability Assessment Scale II (WHODAS) respectively. These measures and the HDRS were administered at baseline and again following 12 weeks of treatment. Results-At baseline, 38% of depressed subjects had significant apathy (AES ≥ 36.5). Severity of apathy at baseline significantly correlated with severity of disability. In a multivariate regression model, baseline severity of apathy, but not the overall depressive syndrome (HDRS), significantly correlated with baseline disability. Following escitalopram treatment, improvement in apathy significantly correlated with improvement in disability measures, while change in the rest of the depressive syndrome did not. The overall change in apathy and disability in response to escitalopram treatment was significant but small. Conclusions-Apathy is common in late-life depression and is associated with disability above and beyond the influence of other depressive symptoms. Given the strong relationship between apathy and disability, understanding the neurobiology of apathy and developing treatments for apathy may improve the functional outcomes of late-life depression.
The experiments strongly suggested that the reason why Purkinje cells die so easily after global ... more The experiments strongly suggested that the reason why Purkinje cells die so easily after global brain ischemia relates to deficiencies in aldolase C and EAAT4 that allow them to survive pathologically intense synaptic input from the inferior olive after the restoration of blood flow. This conclusion is based on: (a) the remarkably tight correspondence between the regional absence of aldolase C and EAAT4 in Purkinje cells and the patterned loss of Purkinje cells after a bout of global brain ischemia; (b) the necessity of the olivocerebellar pathway for the ischemic death of Purkinje cells; and (c) the build-up of pathologically synchronous and high-frequency burst activity within the inferior olive during recovery from ischemia. Indeed, the correspondence between the absence of aldolase C and EAAT4 to sensitivity to ischemia could be demonstrated for zones of Purkinje cells as small as two neurons. A second finding was that Purkinje cells are not uniformly sensitive to transient ischemia, since they die most frequently in zones where aldolase C and EAAT4 are absent. One implication of the experiment is that factors beyond the unique synaptic and membrane properties of Purkinje cells play an important role in determining this neuron's high sensitivity to ischemia. The data strongly imply that two properties of Purkinje cells that make them susceptible to ischemic death are their reduced capability to sequester glutamate and reduced ability to generate energy during anoxia. The patterned death of Purkinje cells is sufficient to induce a form of audiogenic myoclonus, as determined with a neurotoxic dose of ibogaine. Ibogaine-induced myoclonus is recognized behaviorally as a reduced ability to habituate to a startle stimulus and resembles the myoclonic jerk of rats during recovery from a prolonged bout of global brain ischemia. Commonalities of ischemia and ibogaine-induced neurodegeneration are the intricately striped Purkinje cell loss in the posterior lobe and a nearly complete deafferentation of the lateral aspect of the fastigial nucleus from the cerebellar cortex, in particular the dorsolateral protuberance. Thus, the data point strongly to a cerebellar contribution to audiogenic myoclonus. Single-neuron electrophysiology experiments in monkeys have demonstrated that the evoked activity in the deep cerebellar nuclei occurs too late to initiate the startle response (60) and electromyography of the postischemic myoclonus of rats corroborates this view (see Chapter 31) (20). However, the nearly complete loss of GABAergic terminals in the dorsolateral protuberance after Purkinje cell death would be expected to dramatically increase its tonic firing and the background excitation of the brain-stem structures that it innervates. The fastigial nucleus innervates a large number of autonomic and motor structures in the brainstem and diencephalon, including the ventrolateral nucleus of the thalamus and the gigantocellular reticular nucleus in the medulla--structures that have been implicated in human posthypoxic myoclonus (6, 7). We propose that the posthypoxic myoclonic jerk of rats is, at least in part, due to disinhibition of the fastigial nucleus produced by patterned Purkinje cell death in the vermis. The argument is as follows: the loss of GABAergic inhibition in the fastigial nucleus after ischemia leads to diaschisis of the motor thalamus and reticular formation which, in turn, is responsible for enhanced motor excitability and myoclonus. That the audiogenic myoclonus after global brain ischemia in the rat gradually resolves over a period of 2 to 3 weeks is consistent with this view, as restoration of background excitability after CNS damage in rats has been documented to occur within this time-frame (61). Our view brings together the physiologic finding that posthypoxic myoclonus appears to originate in the sensory-motor cortices and/or reticular formation with the consistent anatomical finding of Purkinje cell loss after ischemia, and explains the puzzle of Marsden's unique cases of myoclonus associated with coeliac disease (1). Moreover, our argument is consistent with findings both in rats (62, 63) and humans (64) that damage to the vermis impairs the long-term habituation of the startle reflex. It remains to be determined whether the pathologically enhanced startle responses after vermal damage resemble brain-stem reticular or cortical myoclonus at the electrophysiologic level of analysis. What is the purpose of the regional expression of aldolase C and EAAT4 in Purkinje cells? The close correspondence between the spatial distribution of aldolase C and the parasagittal anatomy of the cerebellum (48) has led to the view that aldolase C may help specify connectivity during development. While the present experiments do not address this issue, they underscore the fact that aldolase plays a fundamental role in metabolism. Because Purkinje cells have a repressed expression of aldolase A (31), whatever role the absence of aldolase C may play during development comes at the price of metabolic frailty later in adulthood. From another point of view, aldolase C and EAAT4 appear to confer upon Purkinje cells the ability to survive their own climbing fiber. Indeed, climbing fibers form a distributed synapse that synchronously releases glutamate (or aspartate) at all levels of the dendritic tree simultaneously (65, 66). Such synchronous activation triggers calcium influx throughout the Purkinje cell dendrites at a magnitude that is unparalleled in the nervous system (12), and, thus, places an extraordinarily high metabolic demand on the Purkinje cell. The apparently reduced level of aldolase in a subpopulation of Purkinje cells provides the condition for energy failure and death during anoxia so long as the climbing fibers are intact or when climbing fiber activation is pharmacologically enhanced under normoxic conditions, such as after ibogaine (53-56). Lastly, the argument that diaschisis produced by patterned cerebellar degeneration leads to thalamo-cortical and reticular hyperexcitability agrees with C. David Marsden and his colleagues' bold demonstration of an inhibitory influence of cerebellar cortex on motor cortex in humans (67). Our anatomic data indicate that the spatially distinct zones of Purkinje cells, which are killed by global brain ischemia, may be the origin of such inhibition.
Background-Apathy is common in late-life depression and is associated with disability and poor an... more Background-Apathy is common in late-life depression and is associated with disability and poor antidepressant response. This study examined whether resting functional connectivity (FC) of the nucleus accumbens (NAcc) and the dorsal anterior cingulate (dACC) with other structures can distinguish apathetic depressed older patients from nonapathetic depressed patients and normal subjects.
International Journal of Geriatric Psychiatry, Jul 3, 2014
Objective-Apathy is prevalent in late-life depression and predicts poor response to antidepressan... more 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 two 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.
The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry, Jan 27, 2013
Executive dysfunction may play a key role in the pathophysiology of late-life depression. Executi... more Executive dysfunction may play a key role in the pathophysiology of late-life depression. Executive dysfunction can be assessed with cognitive tests and subjective report of difficulties with executive skills. The present study investigated the association between subjective report of executive functioning complaints and time to escitalopram treatment response in older adults with major depressive disorder (MDD). 100 older adults with MDD (58 with executive functioning complaints and 42 without executive functioning complaints) completed a 12-week trial of escitalopram. Treatment response over 12 weeks, as measured by repeated Hamilton Depression Rating Scale scores, was compared for adults with and without executive complaints using mixed-effects modeling. Mixed effects analysis revealed a significant group × time interaction, F(1, 523.34) = 6.00, p = 0.01. Depressed older adults who reported executive functioning complaints at baseline demonstrated a slower response to escitalopra...
International Journal of Geriatric Psychiatry, 2014
Objective-Impairment in reward processes has been found in individuals with depression and in the... more 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. 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 elderly, healthy subjects, depressed, elderly 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, elderly patients with non-psychotic major depression and 36 elderly, 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 IGT. However, apathetic, depressed older adults adopted an advantageous strategy and selected cards from the conservative decks compared to 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 American Journal of Geriatric Psychiatry, 2015
Objectives-The aims of this study were to examine: (1) the relationship between apathy and disabi... more Objectives-The aims of this study were to examine: (1) the relationship between apathy and disability in late-life depression, and (2) the functional significance of improvement in apathy following escitalopram treatment in terms of its relationship to disability. Methods-Subjects were 71 non-demented elderly with non-psychotic major depression. After a 2-week single-blind placebo period, subjects who had Hamilton Depression Rating Scale (HDRS) ≥ 18 received escitalopram 10mg daily for 12 weeks. Apathy and disability were assessed with the Apathy Evaluation Scale (AES) and the World Health Organization Disability Assessment Scale II (WHODAS) respectively. These measures and the HDRS were administered at baseline and again following 12 weeks of treatment. Results-At baseline, 38% of depressed subjects had significant apathy (AES ≥ 36.5). Severity of apathy at baseline significantly correlated with severity of disability. In a multivariate regression model, baseline severity of apathy, but not the overall depressive syndrome (HDRS), significantly correlated with baseline disability. Following escitalopram treatment, improvement in apathy significantly correlated with improvement in disability measures, while change in the rest of the depressive syndrome did not. The overall change in apathy and disability in response to escitalopram treatment was significant but small. Conclusions-Apathy is common in late-life depression and is associated with disability above and beyond the influence of other depressive symptoms. Given the strong relationship between apathy and disability, understanding the neurobiology of apathy and developing treatments for apathy may improve the functional outcomes of late-life depression.
Background-Apathy is a prominent feature of geriatric depression that predicts poor clinical outc... more Background-Apathy is a prominent feature of geriatric depression that predicts poor clinical outcomes and hinders depression treatment. Yet little is known about the neurobiology and treatment of apathy in late-life depression. This study examined apathy prevalence in a clinical sample of depressed elderly, response of apathy to selective serotonin reuptake inhibitor (SSRI) treatment, and neuroanatomical correlates that distinguished responders from nonresponders and healthy controls. Methods-Participants included 45 non-demented, elderly with major depression and 43 elderly comparison individuals. After a 2-week single-blind placebo period, depressed participants received escitalopram 10mg daily for 12 weeks. The Apathy Evaluation Scale (AES) and 24-item Hamilton Depression Rating Scale (HDRS) were administered at baseline and 12 weeks. MRI scans were acquired at baseline for concurrent structural and diffusion tensor imaging of anterior cingulate grey matter and associated white matter tracts. Results-35.5% of depressed patients suffered from apathy. This declined to 15.6% (p<0.1) following treatment, but 43% of initial sufferers continued to report significant apathy. Improvement of apathy with SSRI was independent of change in depression but correlated with larger left posterior subgenual cingulate volumes and greater fractional anisotropy of left uncinate fasciculi. Limitations-modest sample size, no placebo control, post-hoc secondary analysis, use of 1.5T MRI scanner Conclusions-While prevalent in geriatric depression, apathy is separable from depression with regards to medication response. Structural abnormalities of the posterior subgenual cingulate and uncinate fasciculus may perpetuate apathetic states by interfering with prefrontal cortical recruitment of limbic activity essential to motivated behavior.
Background-Apathy is common in late-life depression and is associated with disability and poor an... more Background-Apathy is common in late-life depression and is associated with disability and poor antidepressant response. This study examined whether resting functional connectivity (FC) of the nucleus accumbens (NAcc) and the dorsal anterior cingulate (dACC) with other structures can distinguish apathetic depressed older patients from nonapathetic depressed patients and normal subjects.
Electrical synapses are formed by gap junctions and permit electrical coupling, which shapes the ... more Electrical synapses are formed by gap junctions and permit electrical coupling, which shapes the synchrony of neuronal ensembles. Here, we provide a direct demonstration of receptor-mediated strengthening of electrical coupling in mammalian brain. Electrical coupling in the inferior olive of rats was strengthened by activation of NMDA-type glutamate receptors (NMDARs), which were found at synaptic loci and at extrasynaptic loci 20-100 nm proximal to gap junctions. Electrical coupling was strengthened by pharmacological and synaptic activation of NMDARs, whereas costimulation of ionotropic non-NMDAR glutamate receptors transiently antagonized the effect of NMDAR activation. NMDAR-dependent strengthening (1) occurred despite increased input conductance, (2) induced Ca 2+-influx microdomains near dendritic spines, (3) required activation of the Ca 2+ /calmodulin-dependent protein-kinase II, (4) was restricted to neurons that were weakly coupled, and (5) thus strengthened coupling, mainly between nonadjacent neurons. This provided a mechanism to expand the synchronization of rhythmic membrane potential oscillations by chemical neurotransmitter input.
In this sample of depressed, non-demented elderly subjects, severity of apathy at baseline signif... more In this sample of depressed, non-demented elderly subjects, severity of apathy at baseline significantly correlated with degree of functional disability.
International Journal of Geriatric Psychiatry, 2014
Objective: Apathy is prevalent in late-life depression and predicts poor response to antidepressa... more 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.
The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry, Jan 27, 2013
Executive dysfunction may play a key role in the pathophysiology of late-life depression. Executi... more Executive dysfunction may play a key role in the pathophysiology of late-life depression. Executive dysfunction can be assessed with cognitive tests and subjective report of difficulties with executive skills. The present study investigated the association between subjective report of executive functioning complaints and time to escitalopram treatment response in older adults with major depressive disorder (MDD). 100 older adults with MDD (58 with executive functioning complaints and 42 without executive functioning complaints) completed a 12-week trial of escitalopram. Treatment response over 12 weeks, as measured by repeated Hamilton Depression Rating Scale scores, was compared for adults with and without executive complaints using mixed-effects modeling. Mixed effects analysis revealed a significant group × time interaction, F(1, 523.34) = 6.00, p = 0.01. Depressed older adults who reported executive functioning complaints at baseline demonstrated a slower response to escitalopra...
International Journal of Geriatric Psychiatry, 2014
Impairment in reward processes has been found in individuals with depression and in the aging pop... more 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. 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. 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. 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.
17β-Estradiol (E) increases axospinous synapse density in the hippocampal CA1 region of young fem... more 17β-Estradiol (E) increases axospinous synapse density in the hippocampal CA1 region of young female rats, but not in aged rats. This may be linked to age-related alterations in signaling pathways activated by synaptic estrogen receptor α (ER-α) that potentially regulate spine formation, such as LIM-Kinase (LIMK), an actin depolymerizing factor/cofilin kinase. We hypothesized that, as with ER-α, phospho-LIMK (pLIMK) may be less abundant or responsive to E in CA1 synapses of aged female rats. To address this, cellular and subcellular distribution of pLIMK-immunoreactivity (pLIMK-IR) in CA1 was analyzed by light and electron microscopy in young and aged female rats that were ovariectomized and treated with either vehicle or E. pLIMK-IR was found primarily in perikarya within the pyramidal cell layer and dendritic shafts and spines in stratum radiatum (SR). While pLIMK-IR was occasionally present in terminals, post-embedding quantitative analysis of SR showed that pLIMK had a predominant post-synaptic localization and was preferentially localized within the postsynaptic density (PSD). The percentage of pLIMK-labeled synapses increased (30%) with E treatment (p<0.02) in young animals, and decreased (43%) with age (p<0.002) regardless of treatment. The pattern of distribution of pLIMK-IR within dendritic spines and synapses was unaffected by age or E treatment, with the exception of an E-induced increase in the non-synaptic core of spines in young females. These data suggest that age-related synaptic alterations similar to those seen with ER-α occur with signaling molecules such as pLIMK, and support the hypothesis that age-related failure of E treatment to increase synapse number in CA1 may be due to changes in the molecular profile of axospinous synapses with respect to signaling pathways linked to formation of additional spines and synapses in response to E.
American Journal of Geriatric Psychiatry, May 1, 2015
Objective-Executive dysfunction may play a key role in the pathophysiology of late-life depressio... more Objective-Executive dysfunction may play a key role in the pathophysiology of late-life depression. Executive dysfunction can be assessed with cognitive tests and subjective report of difficulties with executive skills. The present study investigated the association between subjective report of executive functioning complaints and time to escitalopram treatment response in older adults with Major Depressive Disorder (MDD). Methods-100 older adults with MDD (58 with executive functioning complaints and 42 without executive functioning complaints) completed a 12-week trial of escitalopram. Treatment response over 12 weeks, as measured by repeated Hamilton Depression Rating Scale scores, was compared for adults with and without executive complaints using mixed-effects modeling. Results-Mixed effects analysis revealed a significant group by time interaction, F (1, 523.34) = 6.00, p = .01. Depressed older adults who reported executive functioning complaints at baseline demonstrated a slower response to escitalopram treatment than those without executive functioning complaints. Conclusion-Self-report of executive functioning difficulties may be a useful prognostic indicator for subsequent speed of response to antidepressant medication.
American Journal of Geriatric Psychiatry, May 1, 2015
Objectives-The aims of this study were to examine: (1) the relationship between apathy and disabi... more Objectives-The aims of this study were to examine: (1) the relationship between apathy and disability in late-life depression, and (2) the functional significance of improvement in apathy following escitalopram treatment in terms of its relationship to disability. Methods-Subjects were 71 non-demented elderly with non-psychotic major depression. After a 2-week single-blind placebo period, subjects who had Hamilton Depression Rating Scale (HDRS) ≥ 18 received escitalopram 10mg daily for 12 weeks. Apathy and disability were assessed with the Apathy Evaluation Scale (AES) and the World Health Organization Disability Assessment Scale II (WHODAS) respectively. These measures and the HDRS were administered at baseline and again following 12 weeks of treatment. Results-At baseline, 38% of depressed subjects had significant apathy (AES ≥ 36.5). Severity of apathy at baseline significantly correlated with severity of disability. In a multivariate regression model, baseline severity of apathy, but not the overall depressive syndrome (HDRS), significantly correlated with baseline disability. Following escitalopram treatment, improvement in apathy significantly correlated with improvement in disability measures, while change in the rest of the depressive syndrome did not. The overall change in apathy and disability in response to escitalopram treatment was significant but small. Conclusions-Apathy is common in late-life depression and is associated with disability above and beyond the influence of other depressive symptoms. Given the strong relationship between apathy and disability, understanding the neurobiology of apathy and developing treatments for apathy may improve the functional outcomes of late-life depression.
The experiments strongly suggested that the reason why Purkinje cells die so easily after global ... more The experiments strongly suggested that the reason why Purkinje cells die so easily after global brain ischemia relates to deficiencies in aldolase C and EAAT4 that allow them to survive pathologically intense synaptic input from the inferior olive after the restoration of blood flow. This conclusion is based on: (a) the remarkably tight correspondence between the regional absence of aldolase C and EAAT4 in Purkinje cells and the patterned loss of Purkinje cells after a bout of global brain ischemia; (b) the necessity of the olivocerebellar pathway for the ischemic death of Purkinje cells; and (c) the build-up of pathologically synchronous and high-frequency burst activity within the inferior olive during recovery from ischemia. Indeed, the correspondence between the absence of aldolase C and EAAT4 to sensitivity to ischemia could be demonstrated for zones of Purkinje cells as small as two neurons. A second finding was that Purkinje cells are not uniformly sensitive to transient ischemia, since they die most frequently in zones where aldolase C and EAAT4 are absent. One implication of the experiment is that factors beyond the unique synaptic and membrane properties of Purkinje cells play an important role in determining this neuron's high sensitivity to ischemia. The data strongly imply that two properties of Purkinje cells that make them susceptible to ischemic death are their reduced capability to sequester glutamate and reduced ability to generate energy during anoxia. The patterned death of Purkinje cells is sufficient to induce a form of audiogenic myoclonus, as determined with a neurotoxic dose of ibogaine. Ibogaine-induced myoclonus is recognized behaviorally as a reduced ability to habituate to a startle stimulus and resembles the myoclonic jerk of rats during recovery from a prolonged bout of global brain ischemia. Commonalities of ischemia and ibogaine-induced neurodegeneration are the intricately striped Purkinje cell loss in the posterior lobe and a nearly complete deafferentation of the lateral aspect of the fastigial nucleus from the cerebellar cortex, in particular the dorsolateral protuberance. Thus, the data point strongly to a cerebellar contribution to audiogenic myoclonus. Single-neuron electrophysiology experiments in monkeys have demonstrated that the evoked activity in the deep cerebellar nuclei occurs too late to initiate the startle response (60) and electromyography of the postischemic myoclonus of rats corroborates this view (see Chapter 31) (20). However, the nearly complete loss of GABAergic terminals in the dorsolateral protuberance after Purkinje cell death would be expected to dramatically increase its tonic firing and the background excitation of the brain-stem structures that it innervates. The fastigial nucleus innervates a large number of autonomic and motor structures in the brainstem and diencephalon, including the ventrolateral nucleus of the thalamus and the gigantocellular reticular nucleus in the medulla--structures that have been implicated in human posthypoxic myoclonus (6, 7). We propose that the posthypoxic myoclonic jerk of rats is, at least in part, due to disinhibition of the fastigial nucleus produced by patterned Purkinje cell death in the vermis. The argument is as follows: the loss of GABAergic inhibition in the fastigial nucleus after ischemia leads to diaschisis of the motor thalamus and reticular formation which, in turn, is responsible for enhanced motor excitability and myoclonus. That the audiogenic myoclonus after global brain ischemia in the rat gradually resolves over a period of 2 to 3 weeks is consistent with this view, as restoration of background excitability after CNS damage in rats has been documented to occur within this time-frame (61). Our view brings together the physiologic finding that posthypoxic myoclonus appears to originate in the sensory-motor cortices and/or reticular formation with the consistent anatomical finding of Purkinje cell loss after ischemia, and explains the puzzle of Marsden's unique cases of myoclonus associated with coeliac disease (1). Moreover, our argument is consistent with findings both in rats (62, 63) and humans (64) that damage to the vermis impairs the long-term habituation of the startle reflex. It remains to be determined whether the pathologically enhanced startle responses after vermal damage resemble brain-stem reticular or cortical myoclonus at the electrophysiologic level of analysis. What is the purpose of the regional expression of aldolase C and EAAT4 in Purkinje cells? The close correspondence between the spatial distribution of aldolase C and the parasagittal anatomy of the cerebellum (48) has led to the view that aldolase C may help specify connectivity during development. While the present experiments do not address this issue, they underscore the fact that aldolase plays a fundamental role in metabolism. Because Purkinje cells have a repressed expression of aldolase A (31), whatever role the absence of aldolase C may play during development comes at the price of metabolic frailty later in adulthood. From another point of view, aldolase C and EAAT4 appear to confer upon Purkinje cells the ability to survive their own climbing fiber. Indeed, climbing fibers form a distributed synapse that synchronously releases glutamate (or aspartate) at all levels of the dendritic tree simultaneously (65, 66). Such synchronous activation triggers calcium influx throughout the Purkinje cell dendrites at a magnitude that is unparalleled in the nervous system (12), and, thus, places an extraordinarily high metabolic demand on the Purkinje cell. The apparently reduced level of aldolase in a subpopulation of Purkinje cells provides the condition for energy failure and death during anoxia so long as the climbing fibers are intact or when climbing fiber activation is pharmacologically enhanced under normoxic conditions, such as after ibogaine (53-56). Lastly, the argument that diaschisis produced by patterned cerebellar degeneration leads to thalamo-cortical and reticular hyperexcitability agrees with C. David Marsden and his colleagues' bold demonstration of an inhibitory influence of cerebellar cortex on motor cortex in humans (67). Our anatomic data indicate that the spatially distinct zones of Purkinje cells, which are killed by global brain ischemia, may be the origin of such inhibition.
Background-Apathy is common in late-life depression and is associated with disability and poor an... more Background-Apathy is common in late-life depression and is associated with disability and poor antidepressant response. This study examined whether resting functional connectivity (FC) of the nucleus accumbens (NAcc) and the dorsal anterior cingulate (dACC) with other structures can distinguish apathetic depressed older patients from nonapathetic depressed patients and normal subjects.
International Journal of Geriatric Psychiatry, Jul 3, 2014
Objective-Apathy is prevalent in late-life depression and predicts poor response to antidepressan... more 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 two 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.
The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry, Jan 27, 2013
Executive dysfunction may play a key role in the pathophysiology of late-life depression. Executi... more Executive dysfunction may play a key role in the pathophysiology of late-life depression. Executive dysfunction can be assessed with cognitive tests and subjective report of difficulties with executive skills. The present study investigated the association between subjective report of executive functioning complaints and time to escitalopram treatment response in older adults with major depressive disorder (MDD). 100 older adults with MDD (58 with executive functioning complaints and 42 without executive functioning complaints) completed a 12-week trial of escitalopram. Treatment response over 12 weeks, as measured by repeated Hamilton Depression Rating Scale scores, was compared for adults with and without executive complaints using mixed-effects modeling. Mixed effects analysis revealed a significant group × time interaction, F(1, 523.34) = 6.00, p = 0.01. Depressed older adults who reported executive functioning complaints at baseline demonstrated a slower response to escitalopra...
International Journal of Geriatric Psychiatry, 2014
Objective-Impairment in reward processes has been found in individuals with depression and in the... more 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. 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 elderly, healthy subjects, depressed, elderly 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, elderly patients with non-psychotic major depression and 36 elderly, 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 IGT. However, apathetic, depressed older adults adopted an advantageous strategy and selected cards from the conservative decks compared to 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 American Journal of Geriatric Psychiatry, 2015
Objectives-The aims of this study were to examine: (1) the relationship between apathy and disabi... more Objectives-The aims of this study were to examine: (1) the relationship between apathy and disability in late-life depression, and (2) the functional significance of improvement in apathy following escitalopram treatment in terms of its relationship to disability. Methods-Subjects were 71 non-demented elderly with non-psychotic major depression. After a 2-week single-blind placebo period, subjects who had Hamilton Depression Rating Scale (HDRS) ≥ 18 received escitalopram 10mg daily for 12 weeks. Apathy and disability were assessed with the Apathy Evaluation Scale (AES) and the World Health Organization Disability Assessment Scale II (WHODAS) respectively. These measures and the HDRS were administered at baseline and again following 12 weeks of treatment. Results-At baseline, 38% of depressed subjects had significant apathy (AES ≥ 36.5). Severity of apathy at baseline significantly correlated with severity of disability. In a multivariate regression model, baseline severity of apathy, but not the overall depressive syndrome (HDRS), significantly correlated with baseline disability. Following escitalopram treatment, improvement in apathy significantly correlated with improvement in disability measures, while change in the rest of the depressive syndrome did not. The overall change in apathy and disability in response to escitalopram treatment was significant but small. Conclusions-Apathy is common in late-life depression and is associated with disability above and beyond the influence of other depressive symptoms. Given the strong relationship between apathy and disability, understanding the neurobiology of apathy and developing treatments for apathy may improve the functional outcomes of late-life depression.
Background-Apathy is a prominent feature of geriatric depression that predicts poor clinical outc... more Background-Apathy is a prominent feature of geriatric depression that predicts poor clinical outcomes and hinders depression treatment. Yet little is known about the neurobiology and treatment of apathy in late-life depression. This study examined apathy prevalence in a clinical sample of depressed elderly, response of apathy to selective serotonin reuptake inhibitor (SSRI) treatment, and neuroanatomical correlates that distinguished responders from nonresponders and healthy controls. Methods-Participants included 45 non-demented, elderly with major depression and 43 elderly comparison individuals. After a 2-week single-blind placebo period, depressed participants received escitalopram 10mg daily for 12 weeks. The Apathy Evaluation Scale (AES) and 24-item Hamilton Depression Rating Scale (HDRS) were administered at baseline and 12 weeks. MRI scans were acquired at baseline for concurrent structural and diffusion tensor imaging of anterior cingulate grey matter and associated white matter tracts. Results-35.5% of depressed patients suffered from apathy. This declined to 15.6% (p<0.1) following treatment, but 43% of initial sufferers continued to report significant apathy. Improvement of apathy with SSRI was independent of change in depression but correlated with larger left posterior subgenual cingulate volumes and greater fractional anisotropy of left uncinate fasciculi. Limitations-modest sample size, no placebo control, post-hoc secondary analysis, use of 1.5T MRI scanner Conclusions-While prevalent in geriatric depression, apathy is separable from depression with regards to medication response. Structural abnormalities of the posterior subgenual cingulate and uncinate fasciculus may perpetuate apathetic states by interfering with prefrontal cortical recruitment of limbic activity essential to motivated behavior.
Background-Apathy is common in late-life depression and is associated with disability and poor an... more Background-Apathy is common in late-life depression and is associated with disability and poor antidepressant response. This study examined whether resting functional connectivity (FC) of the nucleus accumbens (NAcc) and the dorsal anterior cingulate (dACC) with other structures can distinguish apathetic depressed older patients from nonapathetic depressed patients and normal subjects.
Electrical synapses are formed by gap junctions and permit electrical coupling, which shapes the ... more Electrical synapses are formed by gap junctions and permit electrical coupling, which shapes the synchrony of neuronal ensembles. Here, we provide a direct demonstration of receptor-mediated strengthening of electrical coupling in mammalian brain. Electrical coupling in the inferior olive of rats was strengthened by activation of NMDA-type glutamate receptors (NMDARs), which were found at synaptic loci and at extrasynaptic loci 20-100 nm proximal to gap junctions. Electrical coupling was strengthened by pharmacological and synaptic activation of NMDARs, whereas costimulation of ionotropic non-NMDAR glutamate receptors transiently antagonized the effect of NMDAR activation. NMDAR-dependent strengthening (1) occurred despite increased input conductance, (2) induced Ca 2+-influx microdomains near dendritic spines, (3) required activation of the Ca 2+ /calmodulin-dependent protein-kinase II, (4) was restricted to neurons that were weakly coupled, and (5) thus strengthened coupling, mainly between nonadjacent neurons. This provided a mechanism to expand the synchronization of rhythmic membrane potential oscillations by chemical neurotransmitter input.
In this sample of depressed, non-demented elderly subjects, severity of apathy at baseline signif... more In this sample of depressed, non-demented elderly subjects, severity of apathy at baseline significantly correlated with degree of functional disability.
International Journal of Geriatric Psychiatry, 2014
Objective: Apathy is prevalent in late-life depression and predicts poor response to antidepressa... more 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.
The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry, Jan 27, 2013
Executive dysfunction may play a key role in the pathophysiology of late-life depression. Executi... more Executive dysfunction may play a key role in the pathophysiology of late-life depression. Executive dysfunction can be assessed with cognitive tests and subjective report of difficulties with executive skills. The present study investigated the association between subjective report of executive functioning complaints and time to escitalopram treatment response in older adults with major depressive disorder (MDD). 100 older adults with MDD (58 with executive functioning complaints and 42 without executive functioning complaints) completed a 12-week trial of escitalopram. Treatment response over 12 weeks, as measured by repeated Hamilton Depression Rating Scale scores, was compared for adults with and without executive complaints using mixed-effects modeling. Mixed effects analysis revealed a significant group × time interaction, F(1, 523.34) = 6.00, p = 0.01. Depressed older adults who reported executive functioning complaints at baseline demonstrated a slower response to escitalopra...
International Journal of Geriatric Psychiatry, 2014
Impairment in reward processes has been found in individuals with depression and in the aging pop... more 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. 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. 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. 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.
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Papers by Genevieve Yuen