The neurobiological reward system in Prolonged Grief Disorder (PGD): A systematic review.

Prolonged Grief Disorder (PGD) is a debilitating condition affecting between 7% and 10% of bereaved individuals. Past imaging and psychological studies have proposed links between PGD's characteristic symptoms - in particular, profound yearning - and the neural reward system. We conducted a systematic review to investigate this connection. On December 19, 2019, we searched six bibliographic databases for data on the neurobiology of grief and disordered grief. We excluded studies of the hypothalamic-pituitary-adrenal (HPA) axis, animal studies, and reviews. After abstract and full-text screening, twenty-four studies were included in the final review. We found diverse evidence for the activation of several reward-related regions of the brain in PGD. The data reviewed suggest that compared to normative grief, PGD involves a differential pattern of activity in the amygdala and orbitofrontal cortex (OFC); likely differential activity in the posterior cingulate cortex (PCC), rostral or subgenual anterior cingulate cortex (ACC), and basal ganglia overall, including the nucleus accumbens (NAc); and possible differential activity in the insula. It also appears that oxytocin signaling is altered in PGD, though the exact mechanism is unclear. Our findings appear to be consistent with, though not confirmative of, conceptualizing PGD as a disorder of reward, and identify directions for future research.

Decreased axial diffusivity within language connections: a possible biomarker of schizophrenia risk.

Siblings of patients diagnosed with schizophrenia are at elevated risk for developing this disorder. The nature of such risk associated with brain abnormalities, and whether such abnormalities are similar to those observed in schizophrenia, remain unclear. Deficits in language processing are frequently reported in increased risk populations. Interestingly, white matter pathology involving fronto-temporal language pathways, including arcuate fasciculus (AF), uncinate fasciculus (UF), and inferior occipitofrontal fasciculus (IOFF), are frequently reported in schizophrenia. In this study, high spatial and directional resolution diffusion MRI data was obtained on a 3T magnet from 33 subjects with increased familial risk for developing schizophrenia, and 28 control subjects. Diffusion tractography was performed to measure white matter integrity within AF, UF, and IOFF. To understand these abnormalities, Fractional Anisotropy (FA, a measure of tract integrity) and Trace (a measure of overall diffusion), were combined with more specific measures of axial diffusivity (AX, a putative measure of axonal integrity) and radial diffusivity (RD, a putative measure of myelin integrity). Results revealed a significant decrease in Trace within IOFF, and a significant decrease in AX in all tracts. FA and RD anomalies, frequently reported in schizophrenia, were not observed. Moreover, AX group effect was modulated by age, with increased risk subjects demonstrating a deviation from normal maturation trajectory. Findings suggest that familial risk for schizophrenia may be associated with abnormalities in axonal rather than myelin integrity, and possibly associated with disruptions in normal brain maturation. AX should be considered a possible biomarker of risk for developing schizophrenia.

The interplay of stress, gender and cognitive style in depressive onset.

Major depression is more common in women than men, but the reasons for this difference have not been completely understood. We examine recent evidence investigating whether sex differences in exposure or response to stressful life events play an explanatory role in the sex differences found in onset of depression. We also explore the possibility that sexual dimorphism in depressive prevalence and response to events is related to sex differences in cognitive style. We conclude that differences between women and men in response to stressful life events and cognitive style are relevant to understanding sex differences in the onset of depression.

Clopidogrel does not suppress blood markers of coagulation activation in aspirin-treated patients with non-ST-elevation acute coronary syndromes.

AIMS: The Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) Study demonstrated that clopidogrel plus aspirin was superior to aspirin alone for prevention of recurrent vascular events in patients with acute coronary syndromes. The aim of this study was to compare the effect of these two regimens on biochemical markers of platelet and coagulation activation. METHODS AND RESULTS: We studied 485 patients with non-ST-elevation acute coronary syndrome who were randomized to clopidogrel (300 mg loading dose followed by 75 mg daily) or placebo for a period of 3-12 months. All patients also received aspirin (recommended dose 75-325 mg daily). Blood levels of P-selectin, prothrombin fragment F1.2, D-dimer, and von Willebrand factor were measured at baseline, day 7 (or hospital discharge), and at day 30 after randomization. Patients receiving clopidogrel plus aspirin compared with aspirin alone had similar baseline geometric mean plasma levels of P-selectin (50.2 vs 51.7 ng.ml(-1), P=0.45), prothrombin fragment F1.2 (1.13 vs 1.12 nmol.l(-1), P=0.94), D-dimer (467 vs 460 ng.ml(-1), P=0.85), and von Willebrand factor levels (1.89 vs 1.85 U.ml(-1), P=0.59) and there also were no significant differences at day 7, or day 30. However, compared with baseline, there was a significant rise in prothrombin fragment F1.2 at day 7 (from 1.12 to 1.39 nmol.l(-1), P<0.0001) and day 30 (from 1.12 to 1.44 nmol.l(-1), P<0.0001), and D-dimer at day 7 (from 464 to 539 nmol.l(-1), P<0.0001) and day 30 (from 464 to 576 nmol.l(-1), P<0.0001). The magnitude of this rise appeared to be greatest in patients who experienced the primary outcome, a composite of cardiovascular death, myocardial infarction, stroke, or refractory ischaemia by the end of the study. P-selectin levels were not elevated at any time point but von Willebrand factor values were elevated at baseline and remained elevated at days 7 and 30. CONCLUSION: Our results indicate that the clinical benefits of clopidogrel are not associated with a parallel reduction in markers of coagulation activation. Early suppression of coagulation markers most likely reflects the effects of heparin. The persistence of thrombin generation despite long-term clopidogrel and aspirin therapy suggests that even more intensive antithrombotic therapy may be required in these patients.

Quantitative functional imaging of the brain: towards mapping neuronal activity by BOLD fMRI.

Quantitative magnetic resonance imaging (MRI) and spectroscopy (MRS) measurements of energy metabolism (i.e. cerebral metabolic rate of oxygen consumption, CMR(O2)), blood circulation (i.e. cerebral blood flow, CBF, and volume, CBV), and functional MRI (fMRI) signal over a wide range of neuronal activity and pharmacological treatments are used to interpret the neurophysiologic basis of blood oxygenation level dependent (BOLD) image-contrast at 7 T in glutamatergic neurons of rat cerebral cortex. Multi-modal MRI and MRS measurements of CMR(O2), CBF, CBV and BOLD signal (both gradient-echo and spin-echo) are used to interpret the neuroenergetic basis of BOLD image-contrast. Since each parameter that can influence the BOLD image-contrast is measured quantitatively and separately, multi-modal measurements of changes in CMR(O2), CBF, CBV, BOLD fMRI signal allow calibration and validation of the BOLD image-contrast. Good agreement between changes in CMR(O2) calculated from BOLD theory and measured by (13)C MRS, reveals that BOLD fMRI signal-changes at 7 T are closely linked with alterations in neuronal glucose oxidation, both for activation and deactivation paradigms. To determine the neurochemical basis of BOLD, pharmacological treatment with lamotrigine, which is a neuronal voltage-dependent Na(+) channel blocker and neurotransmitter glutamate release inhibitor, is used in a rat forepaw stimulation model. Attenuation of the functional changes in CBF and BOLD with lamotrigine reveals that the fMRI signal is associated with release of glutamate from neurons, which is consistent with a link between neurotransmitter cycling and energy metabolism. Comparisons of CMR(O2) and CBF over a wide dynamic range of neuronal activity provide insight into the regulation of energy metabolism and oxygen delivery in the cerebral cortex. The current results reveal the energetic and physiologic components of the BOLD fMRI signal and indicate the required steps towards mapping neuronal activity quantitatively by fMRI at steady-state. Consequences of these results from rat brain for similar calibrated BOLD fMRI studies in the human brain are discussed.

Sex differences in [123I]beta-CIT SPECT measures of dopamine and serotonin transporter availability in healthy smokers and nonsmokers.

Nicotine and other constituents of tobacco smoke elevate dopamine (DA) and serotonin (5-HT) levels in brain and may cause homeostatic adaptations in DA and 5-HT transporters. Since sex steroids alter DA and 5-HT transporter expression, the effects of smoking on DA and 5-HT transporter availability may differ between sexes. In the present study, DA and 5-HT transporter availabilities were quantitated using single photon emission computed tomography (SPECT) imaging approximately 22 h after bolus administration of [123I]beta-CIT, an analog of cocaine which labels DA and 5-HT transporters. Forty-two subjects including 21 pairs of age-, race-, and gender-matched healthy smokers and nonsmokers (12 female and 9 male pairs) were imaged. Regional uptake was assessed by the outcome measures, V3", which is the ratio of specific (i.e., ROI-cerebellar activity) to nondisplaceable (cerebellar) activity, and V3, the ratio of specific to free plasma parent. Overall, striatal and diencephalic [123I]beta-CIT uptake was not altered by smoking, whereas brainstem [123I]beta-CIT uptake was modestly higher (10%) in smokers vs. nonsmokers. When subgrouped by sex, regardless of smoking status, [123I]beta-CIT uptake was higher in the striatum (10%), diencephalon (15%), and brainstem (15%) in females vs. males. The sex*smoking interaction was not significant in the striatum, diencephalon, or brainstem, despite the observation of 20% higher brainstem [123I]beta-CIT uptake in male smokers vs. nonsmokers and less than a 5% difference between female smokers and nonsmokers. The results demonstrate higher DA and 5-HT transporter availability in females vs. males and no overall effect of smoking with the exception of a modest elevation in brainstem 5-HT transporters in male smokers. Although these findings are preliminary and need validation with a more selective 5-HT transporter radiotracer, the results suggest that brainstem 5-HT transporters may be regulated by smoking in a sex-specific manner.

Sex differences in event-related risk for major depression.

BACKGROUND: This study sought to determine if women are more likely than men to experience an episode of major depression in response to stressful life events. METHOD: Sex differences in event-related risk for depression were examined by means of secondary analyses employing data from the Americans' Changing Lives study. The occurrence and time of occurrence of depression onset and instances of stressful life events within a 12-month period preceding a structured interview were documented in a community-based sample of 1024 men and 1800 women. Survival analytical techniques were used to examine sex differences in risk for depression associated with generic and specific stressful life events. RESULTS: Women were approximately three times more likely than men to experience major depression in response to any stressful life event. Women and men did not differ in risk for depression associated with the death of a spouse or child, events affecting their relationship to a spouse/partner (divorce and marital/love problems) or events corresponding to acute financial or legal difficulties. Women were at elevated risk for depression associated with more distant interpersonal losses (death of a close friend or relative) and other types of events (change of residence, physical attack, or life-threatening illness/injury). CONCLUSION: Stressful life events overall, with some exceptions among specific event types, pose a greater risk for depression among women compared to men.

Goals for the care of frail older adults: do caregivers and clinicians agree?

PURPOSE: Establishing shared treatment goals for patients may improve the quality of care by facilitating achievement of appropriate and desired outcomes. The purpose of this study was to describe types of family caregiver and physician treatment goals for frail elderly patients who had a high prevalence of cognitive impairment, and to ascertain the level of agreement between family caregivers and physicians on principal treatment goals. SUBJECTS AND METHODS: We surveyed family caregivers and physicians for 200 consecutive older adults who were initially evaluated at the outpatient geriatric assessment center of a major teaching hospital. Treatment goals for patients were measured after a comprehensive geriatric assessment. RESULTS: Goals commonly chosen as most important by family caregivers and physicians pertained to day-to-day functioning (61 [31%] family caregivers, 81 [41%] physicians), behavior and emotional health (56 [28%] family caregivers, 50 [25%] physicians), and safety (40 [20%] family caregivers, 29 [15%] physicians). Although a substantial proportion of family caregiver and physician pairs shared at least one goal (157 [79%] of 200), agreement on presence or absence of individual categories of goals was poor (kappas from -0.19 to 0.28), and agreement on the most important goal was also poor (kappa 0.20). CONCLUSIONS: Agreement on treatment goals between family caregivers and physicians for patients at the study site was low. These results suggest that encounters between family caregiver and physician may need improvement. Further research is needed to assess whether lack of agreement is found in other settings, persists over time, and affects achievement of goals and optimal health outcomes.

Combat trauma: trauma with highest risk of delayed onset and unresolved posttraumatic stress disorder symptoms, unemployment, and abuse among men.

Little is known about the risk and course of posttraumatic stress disorder (PTSD), and other forms of dysfunction, associated with combat trauma relative to other traumas. Modified versions of the DSM-III-R PTSD module from the Diagnostic Interview Schedule and Composite International Diagnostic Interview were administered to a representative national sample of 5,877 persons 15-54 years old in the part 2 subsample of the National Comorbidity Survey. Of the weighted subsample, 1,703 men reported a traumatic event. The risk of PTSD and other forms of dysfunction were compared for men who nominated combat as their worst trauma versus men nominating other traumas as worst, controlling for confounding influences. Men reporting combat as their worst trauma were more likely to have lifetime PTSD, delayed PTSD symptom onset, and unresolved PTSD symptoms, and to be unemployed, fired, divorced, and physically abusive to their spouses than men reporting other traumas as their worst experience.

Detection of diazepam in horse hair samples by mass spectrometric methods.

A method for the detection of diazepam in horse hair samples by low resolution gas chromatography-mass spectrometry (GC-MS) was developed. Two other techniques, gas chromatography-high-resolution mass spectrometry (GC-HRMS) and high-performance liquid chromatography-atmospheric pressure chemical-ionisation mass spectrometry (HPLC-APCI-MS-MS) were applied on some selected samples. Sample preparation was performed according to a technique previously described for human hair, involving incubation with Sorensen buffer and solvent extraction. Hair samples from different sites such as coat on the neck, coat on the back, mane and tail were collected from two thoroughbreds which had received several dosages of diazepam corresponding to a total dose of 750 mg and 200 mg of diazepam respectively. In the first experiment, by low resolution GC-MS using single ion monitoring, diazepam was detected in the mane for at least 85 d after the last administration. In the second one, using the same method, diazepam was detected in the coat on the neck up to 25 d following the last administration. Low resolution GC-MS data were confirmed by the two other techniques. Furthermore, GC-HRMS even made possible the detection of diazepam up to 38 d after the administration of 200 mg of diazepam.

Quality of life impairments associated with diagnostic criteria for traumatic grief.

BACKGROUND: This study examined the association between a diagnosis of traumatic grief and quality of life outcomes. METHOD. Sixty-seven widowed persons were interviewed at a median of 4 months after their loss. The multiple regression procedure was used to estimate the effects of a traumatic grief diagnosis on eight quality of life domains, controlling for age, sex, time from loss and diagnoses of major depressive episode and post-traumatic stress disorder. RESULTS: A positive traumatic grief diagnosis was significantly associated with lower social functioning scores, worse mental health scores, and lower energy levels than a negative traumatic grief diagnosis. In each of these domains, traumatic grief was found to be a better predictor of lower scores than either major depressive episode or post-traumatic stress disorder. CONCLUSIONS: The results suggest that a traumatic grief diagnosis is significantly associated with quality of life impairments. These findings provide evidence supporting the criterion validity of the proposed consensus criteria and the newly developed diagnostic interview for traumatic grief the Traumatic Grief Evaluation of Response to Loss (TRGR2L).

Adverse life events and cognitive-personality characteristics in the prediction of major depression and antidepressant response.

OBJECTIVE: Stressful life events are known to precipitate major depression. However, it remains unclear why some individuals who experience adverse events develop depression whereas others do not, and how the occurrence of life events affects treatment outcome. Emerging models posit that the effect of adverse life events varies by cognitive-personality style. This study examines the direct and interactive effects of stressful life events and cognitive-personality style in predicting 1) episode onset in patients with DSM-IV unipolar depression versus community comparison subjects and 2) depressive symptom severity at the completion of a 6-week standard antidepressant regimen. METHOD: Multivariate models were used to test the effects of adverse life events, cognitive-personality style, and the congruence of event type (interpersonal versus achievement) with cognitive-personality style on depressive onset and treatment outcome in 43 patients with major depression and 43 healthy comparison subjects. Cognitive-personality characteristics were assessed by using Beck's measures of sociotropy (interpersonal dependency) and autonomy (need for independence and control). RESULTS: Adverse life events, sociotropy, and an autonomy factor need for control were each significantly related to depressive onset and predicted group status for 88% of the subjects. Event types affected outcome differently, and specific life event types interacted with cognitive-personality styles in predicting response to treatment. A multivariate model accounted for 65% of the variance in predicting outcome. CONCLUSIONS: Adverse life events are a potent factor in predicting depression. However, cognitive-personality characteristics also confer susceptibility to depression. Better outcome is associated with occurrence of adverse interpersonal events (e.g., death of a loved one) rather than adverse achievement events (e.g., loss of job) and occurs when the event type is congruent with cognitive-personality style.

Preliminary explorations of the harmful interactive effects of widowhood and marital harmony on health, health service use, and health care costs.

This study examined effects of widowhood and marital harmony on health, health service use, and health care costs. The Americans Changing Lives data set contains 694 subjects who remained married and 61 subjects who became widowed between 1986 and 1989. Estimated annual mean 1989 health costs, adjusting for 1986 costs, age, sex, socioeconomic status, mental/physical health, 1989 health insurance, and selection biases are: $2,384 for widowed, $1,498 for married subjects. Adjusted annual 1989 estimates are: $2,766 for those widowed after harmonious marriages; $2,100 for those widowed after discordant marriages; $1,790 for spouses in discordant marriages; $1,228 for spouses in harmonious marriages. Harmonious marriages appear protective until widowhood, after which higher health costs result.

Susceptibility to neuromediated syncope after acute myocardial infarction.

BACKGROUND: Syncope after acute myocardial infarction (AMI) is a common clinical problem. It may be hypothesised that remodelling and neurohormonal changes following AMI may predispose to neuromediated syncope. DESIGN: To address this issue we prospectively evaluated the incidence of positive results of head-up tilt-table testing in 40 patients following AMI and 40 age and sex matched controls without a history of syncope. The mechanisms of tilt-induced changes in autonomic tone were assessed using spectral analysis of heart rate variability. The patients were followed-up for one year. RESULTS: Positive results of tilt-test occurred in 4 (10%) controls and 13 (33%) AMI patients (P = 0.01). No significant differences in sympathovagal interaction (assessed by a low frequency/high frequency ratio) were detected between the groups before tilting (2. 9 +/- 1.9 vs. 3.1 +/- 2.2; NS). However, dynamic changes of this parameter differed significantly during the first 5 symptomless minutes of the active phase of tilt-test. The ratio increased in the majority of controls (87%) and decreased in the majority of patients (62%) (P < 0.0001). During one year follow-up, syncope or presyncope occurred in 10 (25%) AMI patients but did not occur in any control subject (P < 0.001). The sensitivity, specificity and predictive accuracy of an early tilt-test after AMI for the prediction of syncope or presyncope was 70%, 80% and 78%, respectively. CONCLUSION: Patients after AMI are prone to neuromediated reactions. Sympathetic withdrawal seems to be the most likely mechanism of syncope. The role of tilt testing for identification of patients susceptible to syncope or presyncope after AMI needs further investigation.

Self-efficacy as a mediator between stressful life events and depressive symptoms. Differences based on history of prior depression.

BACKGROUND: Self-efficacy, a characteristic that is protective against depressive symptoms, may be undermined by stressful life events. AIMS: To estimate the effects of stressful life events on self-efficacy, and to examine self-efficacy as a mediator of the effect of stressful life events on symptoms of depression. METHOD: Using a sample of 2858 respondents from the longitudinal Americans' Changing Lives study, path analyses were used to evaluate interrelationships between self-efficacy, life events and symptoms of depression controlling for a variety of potentially confounding variables. Separate models were estimated for those with and without prior depression. RESULTS: For those with prior depression, dependent life events had a significant, negative impact on self-efficacy. For those without prior depression, life events had no effect on self-efficacy. CONCLUSIONS: For those with prior depression, self-efficacy mediates approximately 40% of the effect of dependent stressful life events on symptoms of depression.

Influence of traumatic grief on suicidal ideation among young adults.

OBJECTIVE: The purpose of this study was to examine the influence of traumatic grief on suicidal ideation. METHOD: The Beck-Kovacs Scale for Suicidal Ideation was administered to 76 young adult friends of suicide victims. RESULTS: Traumatic grief was associated with a 5.08 times greater likelihood of suicidal ideation, after control for depression. Comorbid traumatic grief and depression were not associated with a greater likelihood of suicidal ideation. CONCLUSIONS: Syndromal traumatic grief heightens vulnerability to suicidal ideation.

The effects of marital dissolution and marital quality on health and health service use among women.

BACKGROUND: Little is known about the impact of marital dissolution and/or marital harmony on health service use. OBJECTIVES: To examine the ways in which marital dissolution and/or marital quality influence health and health service use. RESEARCH DESIGN: The Americans' Changing Lives (ACL) survey was designed to provide a longitudinal study of successful aging. The ACL contains a nationally representative sample of people over age 24, with an oversampling of individuals age 60 and above. SUBJECTS: Nine hundred and twenty seven female subjects who were married at baseline (1986); 101 (10.9%) of those were no longer married at follow up (1989). MEASURES: Health status and health service use at follow up. RESULTS: Marital dissolution, alone and together with marital quality, was associated with worsened mental and physical health and increased mental health service use. Marital harmony was associated with better sleep and fewer depressive symptoms and physician visits. Widowhood was associated with worsened health, but not with greater health service use. Separated women and women divorced from a discordant marriage were not more depressed but used more mental health services. Women separated from a marriage they had rated as harmonious increased their alcohol consumption. CONCLUSIONS: Marital dissolution increases the risk for mental and physical health problems, some of which emerge only among women who had harmonious marriages. Marital harmony appears protective against physician visits. Widows should be encouraged to seek help for their health difficulties. Separated women should be counseled that they are at heightened risk for increased alcohol consumption. Divorced and separated women appear to seek help for emotional problems, over and above depressive symptoms.

Consensus criteria for traumatic grief. A preliminary empirical test.

BACKGROUND: Studies suggest that symptoms of traumatic grief constitute a distinct syndrome worthy of diagnosis. AIMS: A consensus conference aimed to develop and test a criteria set for traumatic grief. METHOD: The expert panel proposed consensus criteria for traumatic grief. Receiver operator characteristic (ROC) analyses tested the performance of the proposed criteria on 306 widowed respondents at seven months post loss. RESULTS: ROC analyses indicated that three of four separation distress symptoms (e.g. yearning, searching, loneliness) had to be endorsed as at least 'sometimes true' and four of the final eight traumatic distress symptoms (e.g. numbness, disbelief, distrust, anger, sense of futility about the future) had to be endorsed as at least 'mostly true' to yield a sensitivity of 0.93 and a specificity of 0.93 for a diagnosis of traumatic grief. CONCLUSIONS: Preliminary analyses suggest the consensus criteria for traumatic grief have satisfactory operating characteristics, and point to directions for further refinement of the criteria set.

Anxiety among widowed elders: is it distinct from depression and grief?

The purpose of this study was to test the validity and utility of distinguishing symptoms of anxiety from those of depression and grief in recently spousally bereaved elders. We also examined pathways from baseline (six months or less post-spousal death) to follow-up (12 and 18 months post-death) levels of anxiety, depression and grief-related symptoms. Baseline and follow-up data were available from 56 recently widowed elderly subjects recruited for an investigation of physiological changes in bereavement. Confirmatory factor analyses indicated that a model in which anxiety was specified as a third factor, apart from depression and grief factors, fit the data well and significantly better than either the one or two factor models. Path analyses revealed that both baseline severity of grief and anxiety had significant lagged effects and predicted follow-up severity of depression. Symptoms of anxiety appeared distinct from those of depression and grief, and the anxiety, depression and grief factors differentially predicted subsequent symptomatology. These findings suggest a need for more specific identification and treatment of anxiety, depression and grief symptoms within the context of late-life spousal bereavement.