Disrupted topology of the resting state structural connectome in middle-aged APOE ε4 carriers.

The apolipoprotein E (APOE) ε4 allele is the best characterized genetic risk factor for Alzheimer's disease to date. Older APOE ε4 carriers (aged 60 + years) are known to have disrupted structural and functional connectivity, but less is known about APOE-associated network integrity in middle age. The goal of this study was to characterize APOE-related differences in network topology in middle age, as disentangling the early effects of healthy versus pathological aging may aid early detection of Alzheimer's disease and inform treatments. We performed resting state functional magnetic resonance imaging (rs-fMRI) and diffusion tensor imaging (DTI) in healthy, cognitively normal, middle-aged adults (age 40-60; N = 76, 38 APOE ε4 carriers). Graph theoretical analysis was used to calculate local and global efficiency of 1) a whole brain rs-fMRI network; 2) a whole brain DTI network; and 3) the resting state structural connectome (rsSC), an integrated functional-structural network derived using functional-by-structural hierarchical (FSH) mapping. Our results indicated no APOE ε4-associated differences in network topology of the rs-fMRI or DTI networks alone. However, ε4 carriers had significantly lower global and local efficiency of the integrated rsSC compared to non-carriers. Furthermore, ε4 carriers were less resilient to targeted node failure of the rsSC, which mimics the neuropathological process of Alzheimer's disease. Collectively, these findings suggest that integrating multiple neuroimaging modalities and employing graph theoretical analysis may reveal network-level vulnerabilities that may serve as biomarkers of age-related cognitive decline in middle age, decades before the onset of overt cognitive impairment.

Reactivity to unpredictable threat as a treatment target for fear-based anxiety disorders.

BACKGROUND: Heightened reactivity to unpredictable threat (U-threat) is a core individual difference factor underlying fear-based psychopathology. Little is known, however, about whether reactivity to U-threat is a stable marker of fear-based psychopathology or if it is malleable to treatment. The aim of the current study was to address this question by examining differences in reactivity to U-threat within patients before and after 12-weeks of selective serotonin reuptake inhibitors (SSRIs) or cognitive-behavioral therapy (CBT). METHODS: Participants included patients with principal fear (n = 22) and distress/misery disorders (n = 29), and a group of healthy controls (n = 21) assessed 12-weeks apart. A well-validated threat-of-shock task was used to probe reactivity to predictable (P-) and U-threat and startle eyeblink magnitude was recorded as an index of defensive responding. RESULTS: Across both assessments, individuals with fear-based disorders displayed greater startle magnitude to U-threat relative to healthy controls and distress/misery patients (who did not differ). From pre- to post-treatment, startle magnitude during U-threat decreased only within the fear patients who received CBT. Moreover, within fear patients, the magnitude of decline in startle to U-threat correlated with the magnitude of decline in fear symptoms. For the healthy controls, startle to U-threat across the two time points was highly reliable and stable. CONCLUSIONS: Together, these results indicate that startle to U-threat characterizes fear disorder patients and is malleable to treatment with CBT but not SSRIs within fear patients. Startle to U-threat may therefore reflect an objective, psychophysiological indicator of fear disorder status and CBT treatment response.

Decoupling of the amygdala to other salience network regions in adolescent-onset recurrent major depressive disorder.

BACKGROUND: Recent meta-analyses of resting-state networks in major depressive disorder (MDD) implicate network disruptions underlying cognitive and affective features of illness. Heterogeneity of findings to date may stem from the relative lack of data parsing clinical features of MDD such as phase of illness and the burden of multiple episodes. METHOD: Resting-state functional magnetic resonance imaging data were collected from 17 active MDD and 34 remitted MDD patients, and 26 healthy controls (HCs) across two sites. Participants were medication-free and further subdivided into those with single v. multiple episodes to examine disease burden. Seed-based connectivity using the posterior cingulate cortex (PCC) seed to probe the default mode network as well as the amygdala and subgenual anterior cingulate cortex (sgACC) seeds to probe the salience network (SN) were conducted. RESULTS: Young adults with remitted MDD demonstrated hyperconnectivity of the left PCC to the left inferior frontal gyrus and of the left sgACC to the right ventromedial prefrontal cortex (PFC) and left hippocampus compared with HCs. Episode-independent effects were observed between the left PCC and the right dorsolateral PFC, as well as between the left amygdala and right insula and caudate, whereas the burden of multiple episodes was associated with hypoconnectivity of the left PCC to multiple cognitive control regions as well as hypoconnectivity of the amygdala to large portions of the SN. CONCLUSIONS: This is the first study of a homogeneous sample of unmedicated young adults with a history of adolescent-onset MDD illustrating brain-based episodic features of illness.

Biophysical changes in subcortical nuclei: the impact of diabetes and major depression.

Magnetization transfer (MT) is a neuroimaging technique that is frequently used to characterize the biophysical abnormalities in both gray and white matter regions of the brain. In our study, we used MT to examine the integrity of key nodes in frontal-subcortical circuits in four subject groups: patients diagnosed with type 2 diabetes with and without major depression (MDD), a healthy control group, and a group diagnosed with MDD without diabetes. In the MDD group, MT studies demonstrated lower magnetization transfer ratios (MTR), a marker of abnormalities in the macromolecular protein pool, in the thalami when compared with the control groups. The group with diabetes and MDD showed lower MTR in the globus pallidus when compared with the group with MDD. Biophysical measures, in subcortical nuclei, correlated inversely with measures of glycemic control, cerebrovascular burden and depression scores. These findings have broad implications for the underlying neuronal circuitry and neurobiology of mood disorders.

Disassociation of verbal learning and hippocampal volume in type 2 diabetes and major depression.

OBJECTIVE: The purpose of this study was to examine the relationship between verbal learning and memory performance and hippocampal volume in subjects with co-morbid type 2 diabetes and major depression compared with healthy control subjects and subjects with type 2 diabetes alone. METHODS: Twenty four subjects with type 2 diabetes and 20 subjects with type 2 diabetes and major depression were recruited from endocrinology clinics and were compared with 32 healthy control subjects recruited from the community. Subjects were scanned on a 1.5 T GE scanner, and hippocampal volumes were measured using Freesurfer. The California Verbal Learning Test assessed learning and memory. Significant predictors of verbal learning performance (e.g., age, gender, education, blood pressure, stroke risk, hemoglobin A1c, and hippocampal volume) were determined using a stepwise linear regression. RESULTS: Subjects with diabetes and depression had significantly worse performance on verbal list learning compared with healthy control subjects. Hippocampal volume was a strong predictor of performance in healthy control subjects, and age and hippocampal volume were strong predictors in subjects with type 2 diabetes alone. Age alone was a significant predictor of verbal learning performance in subjects with diabetes and depression. CONCLUSIONS: The relationship between hippocampal volume and performance on the California Verbal Learning Test is decoupled in subjects with type 2 diabetes and major depression and this decoupling may contribute to poor verbal learning and memory performance in this study population.

White-matter tract integrity in late-life depression: associations with severity and cognition.

BACKGROUND: Although significant changes in both gray and white matter have been noted in late-life depression (LLD), the pathophysiology of implicated white-matter tracts has not been fully described. In this study we examined the integrity of specific white-matter tracts in LLD versus healthy controls (HC). METHOD: Participants aged ⩾60 years were recruited from the community. The sample included 23 clinically diagnosed individuals with LLD and 23 HC. White-matter integrity metrics [fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD)] were calculated in the bilateral cingulum and uncinate fasciculus. Depression severity was measured using the Center for Epidemiological Studies Depression Scale (CESD). Composite scores for learning and memory and executive function were created using standardized neuropsychological assessments. RESULTS: White-matter integrity was lower in LLD versus HC in the bilateral cingulum and right uncinate fasciculus (p⩽0.05). In the whole sample, depression severity correlated with integrity in the bilateral cingulum and right uncinate fasciculus (p ⩽0.05). In patients, depression severity correlated with the integrity of the left uncinate fasciculus (p = 0.03); this tract also correlated with executive function (p = 0.02). Among HC, tract integrity did not correlate with depression scores; however, learning and memory correlated with integrity of the bilateral uncinate fasciculus and bilateral cingulum; executive function correlated with the right uncinate and left cingulum (p ⩽0.05). CONCLUSIONS: White-matter tract integrity was lower in LLD than in HC and was associated with depression severity across all participants. Tract integrity was associated with cognition in both groups but more robustly among HC.

Subcortical biophysical abnormalities in patients with mood disorders.

Cortical-subcortical circuits have been implicated in the pathophysiology of mood disorders. Structural and biochemical abnormalities have been identified in patients diagnosed with mood disorders using magnetic resonance imaging-related approaches. In this study, we used magnetization transfer (MT), an innovative magnetic resonance approach, to study biophysical changes in both gray and white matter regions in cortical-subcortical circuits implicated in emotional regulation and behavior. Our study samples comprised 28 patients clinically diagnosed with major depressive disorder (MDD) and 31 non-depressed subjects of comparable age and gender. MT ratio (MTR), representing the biophysical integrity of macromolecular proteins within key components of cortical-subcortical circuits-the caudate, thalamic, striatal, orbitofrontal, anterior cingulate and dorsolateral regions-was the primary outcome measure. In our study, the MTR in the head of the right caudate nucleus was significantly lower in the MDD group when compared with the comparison group. MTR values showed an inverse relationship with age in both groups, with more widespread relationships observed in the MDD group. These data indicate that focal biophysical abnormalities in the caudate nucleus may be central to the pathophysiology of depression and critical to the cortical-subcortical abnormalities that underlie mood disorders. Depression may also accentuate age-related changes in the biophysical properties of cortical and subcortical regions. These observations have broad implications for the neuronal circuitry underlying mood disorders across the lifespan.

MEASURING INTER-HEMISPHERIC INTEGRATION IN BIPOLAR AFFECTIVE DISORDER USING BRAIN NETWORK ANALYSES AND HARDI.

Bipolar disorder is characterized by extreme mood swings, including both manic and depressive episodes commonly accompanied by psychosis. Many imaging studies have investigated white matter changes in bipolar illness, and the results have suggested abnormal intra- and inter-hemispheric white matter structures, particularly in the fronto-limbic and callosal systems. However, some inconsistency remains in the literature, and no study to-date has utilized brain network analysis using graph theory. Here, we acquired 64-direction diffusion weighted imaging (DWI) on 25 euthymic bipolar I subjects and 25 gender/age matched healthy subjects. White matter integrity measures were computed and compared in 50 white matter ROIs. The results indicated impaired integrity in the corpus callosum. Guided by this, we constructed whole brain structural connectivity networks using graph theory. We devised brain network metrics (inter-hemispheric path length and efficiency) to further probe inter-hemispheric integration, and demonstrated relatively preserved intra-hemispheric but significantly impaired inter-hemispheric integration in our bipolar subjects.

Sparing of neuronal function postseizure with gene therapy.

Numerous studies have demonstrated that gene therapy interventions can protect neurons from death after neurological insults. In nearly all such studies, however, "protection" consists of reduced neurotoxicity, with no demonstrated preservation of neuronal function. We used a herpes simplex virus-1 system to overexpress either the Glut-1 glucose transporter (GT) (to buffer energetics), or the apoptosis inhibitor Bcl-2. Both decreased hippocampal neuron loss to similar extents during excitotoxic insults in vitro and in vivo. However, the mediating mechanisms and consequences of the two interventions differed. GT overexpression attenuated early, energy-dependent facets of cell death, blocking oxygen radical accumulation. Bcl-2 expression, in contrast, blocked components of death downstream from the energetic and oxidative facets. Most importantly, GT- but not Bcl-2-mediated protection preserved hippocampal function as assessed spatial maze performance. Thus, gene therapeutic sparing of neurons from insult-induced death does not necessarily translate into sparing of function.

Glucocorticoids exacerbate insult-induced declines in metabolism in selectively vulnerable hippocampal cell fields.

Glucocorticoids (GCs), the adrenal steroids released during stress, can compromise the ability of hippocampal neurons to survive necrotic neurological insults. This GC-induced endangerment has energetic facets, in that it can be attenuated with energy supplementation. In the present report, we studied the effects of GCs on the metabolic response of specific hippocampal cell fields to necrotic insults. We used silicon microphysiometry, which allows indirect measurement of metabolism in real time in tissue explants. Aglycemia caused a significant decline in metabolism in dentate gyrus explants, but not in CA1 or CA3 explants. When coupled with our prior report of cyanide disrupting metabolism only in CA1 explants, and the glutamatergic excitotoxin kainic acid disrupting metabolism only in CA3 explants, this demonstrates that microphysiometry can detect the selective regional vulnerability that characterizes the hippocampal response to these necrotic insults. We then examined the effects of GCs on the response to these insults, monitoring explants taken from rats that were adrenalectomized, intact, or treated with corticosterone (the GC of rats) that produced circulating levels equivalent to those of major stressors. Increased exposure to GCs worsened the decline in metabolism in dentate gyrus explants induced by hypoglycemia, and in CA1 explants induced by cyanide (after eliminating the effects of glial release of lactate for the support of neuronal metabolism). Thus, GCs worsen the metabolic consequences of necrotic insults in hippocampal explants.

Glucocorticoids exacerbate the deleterious effects of gp120 in hippocampal and cortical explants.

Glucocorticoids (GCs), the adrenal steroids secreted during stress, can compromise the ability of hippocampal neurons to survive numerous necrotic insults. We have previously observed that GCs worsen the deleterious effects of gp120, the glycoprotein of the acquired immune deficiency syndrome virus, which can indirectly damage neurons and which is thought to play a role in the neuropathological features of human immunodeficiency virus infection. Specifically, GCs augment gp120-induced calcium mobilization, ATP depletion, decline in mitochondrial potential, and neurotoxicity in fetal monolayer cultures from a number of brain regions. In the present report, we demonstrate a similar gp120/GC synergy in adult hippocampal and cortical explants. We generated explants from rats that were either adrenalectomized, adrenally intact, or intact and treated with corticosterone to produce levels seen in response to major stressors. Metabolic rates in explants were then indirectly assessed with silicon microphysiometry, and cytosolic calcium concentrations were assessed with fura-2 fluorescent microscopy. We observed that basal levels of GCs tonically augment the disruptive effects of gp120 on metabolism in the CA1 cell field of the hippocampus and in the cortex. Moreover, raising GC concentrations into the stress range exacerbated the ability of gp120 to mobilize cytosolic calcium in a number of hippocampal cell fields. Finally, we observed that the synthetic GC prednisone had similarly exacerbating effects on gp120. Thus, GCs can worsen the deleterious effects of gp120 in a system that is more physiologically relevant than the fetal monolayer culture and in a region-specific manner.

In vivo characterization of 11beta-hydroxysteroid dehydrogenase in rat hippocampus using glucocorticoid neuroendangerment as an endpoint.

11beta-Hydroxysteroid dehydrogenase (11beta-HSD) is the enzyme responsible for the interconversion of corticosterone (CORT) to 11-dehydrocorticosterone (11-DHC). CORT is an adrenal hormone secreted during the stress response and it has widespread effects in many different target tissues. In addition, CORT can exacerbate damage caused by neurological insults, such as kainic acid-induced seizures. In addition to its protective role in the kidney, 11beta-HSD is also thought to play a role in steroid regulation in the brain. However, it is not known whether the enzyme is acting in vivo as a reductase or a dehydrogenase. If the enzyme is working as a reductase, converting 11-DHC to CORT, it has the potential to exacerbate neurotoxicity due to other agents. On the other hand, 11beta-HSD could be neuroprotective if the enzyme is acting as a dehydrogenase, deactivating CORT by converting it into 11-DHC. To characterize the enzyme in vivo, we have utilized glucocorticoid neuroendangerment in the hippocampus as an indirect assay of 11beta-HSD function. We have shown that 11-DHC can exacerbate kainic acid toxicity in adrenalectomized (ADX) rats and this exacerbation is blocked by the 11beta-HSD antagonist, carbenoxolone; these findings suggest that 11beta-HSD is working as a reductase in ADX rats. The presumptive reductase activity found in ADX rats was derived from both hippocampal and peripheral forms of the enzyme. In the presence of physiological levels of glucocorticoids, reductase activity was decreased and no dehydrogenase activity was detected. The present study demonstrates that 11beta-HSD reductase activity, both in vivo and in vitro, occurs only in the presence of low levels of circulating glucocorticoids.

Application of silicon microphysiometry to tissue slices: detection of metabolic correlates of selective vulnerability.

The silicon microphysiometer is a recently developed instrument which measures rates of proton efflux in real time from small numbers of cultured cells. Since the main products of cellular metabolism are lactic acid and carbon dioxide, this instrument affords an indirect but sensitive measure of cellular metabolism. We previously described the use of the instrument with primary neuronal cultures (Raley-Susman, K.M., Miller, K.R., Owicki, J.C. and Sapolsky, R.M., Effects of excitotoxin exposure on metabolic rate of primary hippocampal cultures: application of silicon microphysiometer to neurobiology, J. Neurosci., 12 (1992) 773-780). In the present report, we adapt the instrument for the indirect measurement of metabolism in tissue slices. In initial studies, we demonstrate stable measures of metabolism with low background noise in hippocampal slices. In addition, measures were relatively insensitive to slice thickness, preparation time or the possible contribution of contaminating bacteria. We then demonstrate the ability to detect metabolic correlates of selective vulnerability in individual hippocampal cell fields. Specifically, we observe a metabolic response to kainic acid that was selective for CA3-derived tissue, and a response to cyanide that was selective for CA1-derived tissue. This corresponds to the well-known vulnerability of CA3 and CA1 to excitotoxic and ischemic insults, respectively. Finally, we show that glucocorticoids, stress-sensitive steroid hormones which are known to exacerbate the toxicity in kainic acid in CA3 neurons, exacerbate the metabolic effects of this excitotoxin as well; in this case, the steroid manipulation was carried out in rats prior to killing. Thus, this instrument represents a complement to more traditional approaches for assessing metabolism in specific brain regions and it can potentially be used for a broad variety of studies with animals of differing ages and pre-mortem manipulations.

Endocrine modulators of necrotic neuron death.

In recent years, there has been extraordinary progress in understanding the cellular and molecular cascades that mediate neuron death following necrotic insults. With this knowledge has come the recognition of ways in which these cascades can be modulated by extrinsic factors, altering the likelihood of subsequent neuron death. In this review, we consider the ability of a variety of hormones to modulate necrotic death cascades. Specifically, we will examine the ability of the stress hormones glucocorticoids and corticotropin-releasing factor, of thyroid hormone, and of pre-ischemic exposure to catecholamines to augment necrotic neuron death. In contrast, estrogen, insulin and postischemic exposure to catecholamines appear to decrease necrotic neuron death. We review the heterogeneous mechanisms that are likely to mediate these hormone effects, some possible clinical implications and the therapeutic potentials of these findings.

Nightcap: laboratory and home-based evaluation of a portable sleep monitor.

In this paper, we describe the first field tests of a home-based sleep monitoring system, the Nightcap, which uses eyelid and body movement sensors to discriminate wake, NREM, and REM sleep automatically. Ten normal young adults were studied in the sleep laboratory and at home to allow comparison of Nightcap-derived measures with those obtained by traditional polysomnography. The agreement between the two techniques was 87% based on 1-min epochs--93% for NREM, 80% for REM, and 72% for wake. When the values for sleep latency, REM latency, wake time, NREM time, and REM time calculated from polysomnograph records were compared with the values calculated from Nightcap data, no significant differences were seen. In cases of extremely poor sleep, objective sleep efficiency estimates correlated well with subjective reports, suggesting that the Nightcap is sensitive to clinically relevant changes in the quality of sleep. This new device should prove useful to researchers wishing to study the psychophysiology and pathophysiology of sleep in more naturalistic and cost-effective paradigms than possible in the traditional sleep laboratory.