The utility of an RDoC motor domain to understand psychomotor symptoms in depression.

Despite the clinical impact of motor symptoms such as agitation or retardation on the course of depression, these symptoms are poorly understood. Novel developments in the field of instrumentation and mobile devices allow for dimensional and continuous recording of motor behavior in various settings, particularly outside the laboratory. Likewise, the use of novel assessments enables to combine multimodal neuroimaging with behavioral measures in order to investigate the neural correlates of motor dysfunction in depression. The research domain criteria (RDoC) framework will soon include a motor domain that will provide a framework for studying motor dysfunction in mood disorders. In addition, new studies within this framework will allow investigators to study motor symptoms across different stages of depression as well as other psychiatric diagnoses. Finally, the introduction of the RDoC motor domain will help test how motor symptoms integrate with the original five RDoC domains (negative valence, positive valence, cognitive, social processes, and arousal/regulation).

Considering sex differences clarifies the effects of depression on facial emotion processing during fMRI.

BACKGROUND: Sex differences in emotion processing may play a role in women's increased risk for Major Depressive Disorder (MDD). However, studies of sex differences in brain mechanisms involved in emotion processing in MDD (or interactions of sex and diagnosis) are sparse. METHODS: We conducted an event-related fMRI study examining the interactive and distinct effects of sex and MDD on neural activity during a facial emotion perception task. To minimize effects of current affective state and cumulative disease burden, we studied participants with remitted MDD (rMDD) who were early in the course of the illness. In total, 88 individuals aged 18-23 participated, including 48 with rMDD (32 female) and 40 healthy controls (HC; 25 female). RESULTS: fMRI revealed an interaction between sex and diagnosis for sad and neutral facial expressions in the superior frontal gyrus and left middle temporal gyrus. Results also revealed an interaction of sex with diagnosis in the amygdala. LIMITATIONS: Data was from two sites, which might increase variability, but it also increases power to examine sex by diagnosis interactions. CONCLUSIONS: This study demonstrates the importance of taking sex differences into account when examining potential trait (or scar) mechanisms that could be useful in identifying individuals at-risk for MDD as well as for evaluating potential therapeutic innovations.

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.

Reactivity to uncertain threat as a familial vulnerability factor for alcohol use disorder.

BACKGROUND: When sober, problematic drinkers display exaggerated reactivity to threats that are uncertain (U-threat). Since this aversive affective state can be alleviated via acute alcohol intoxication, it has been posited that individuals who exhibit heightened reactivity to U-threat at baseline are motivated to use alcohol as a means of avoidance-based coping, setting the stage for excessive drinking. To date, however, no study has attempted to characterize the dispositional nature of exaggerated reactivity to U-threat and test whether it is a vulnerability factor or exclusively a disease marker of problematic alcohol use. METHOD: The current investigation utilized a family study design to address these gaps by examining whether (1) reactivity to U-threat is associated with risk for problematic alcohol use, defined by family history of alcohol use disorder (AUD) and (2) reactivity to U-threat is correlated amongst adult biological siblings. A total of 157 families, and 458 individuals, participated in the study and two biological siblings completed a threat-of-shock task designed to probe reactivity to U-threat and predictable threat (P-threat). Startle potentiation was collected as an index of aversive responding. RESULTS: Within biological siblings, startle potentiation to U-threat [intraclass correlation (ICC) = 0.35] and P-threat (ICC = 0.63) was significantly correlated. In addition, independent of an individuals' own AUD status, startle potentiation to U-threat, but not P-threat, was positively associated with risk for AUD (i.e. AUD family history). CONCLUSION: This suggests that heightened reactivity to U-threat may be a familial vulnerability factor for problematic drinking and a novel prevention target for AUD.

Disorder specificity despite comorbidity: resting EEG alpha asymmetry in major depressive disorder and post-traumatic stress disorder.

The approach-withdrawal and valence-arousal models highlight that specific brain laterality profiles may distinguish depression and anxiety. However, studies remain to be conducted in multiple clinical populations that directly test the diagnostic specificity of these hypotheses. The current study compared electroencephalographic data under resting state, eyes closed conditions in patients with major depressive disorder (MDD) (N=15) and post-traumatic stress disorder (PTSD) (N=14) relative to healthy controls (N=15) to examine the specificity of brain laterality in these disorders. Key findings included (1) reduced left-frontal activity in MDD, (2) a positive correlation between PTSD severity and right-frontal lateralisation, (3) greater activity in PTSD patients relative to MDD within the right-parietotemporal region, and (4) globally increased alpha power in MDD. Findings partially support the diagnostic applicability of the theoretical frameworks. Future studies may benefit from examining task-driven differences between groups.

Family study of subthreshold psychopathology in a community sample.

BACKGROUND: There has been increasing interest in the validity and familial transmission of subthreshold psychiatric conditions and the relationship between subthreshold conditions and full syndrome (FS) disorders. However, most of these studies examined a single subthreshold condition and thus fail to take into account the high co-morbidity among subthreshold conditions and between subthreshold conditions and FS disorders. METHOD: A family study of subthreshold psychiatric conditions was conducted with 739 community-drawn young adults and their 1744 relatives. We examined (1) whether relatives of probands with subthreshold major depression, bipolar disorder, anxiety disorders, alcohol use, substance use, and/or conduct disorder exhibited an increased rate of the corresponding (homotypic) FS disorder; (2) whether subthreshold disorders were associated with increased familial rates of other (heterotypic) FS disorders; (3) whether subthreshold and FS conditions are associated with similar familial liabilities; and (4) whether these homotypic and heterotypic associations persisted after controlling for co-morbidity. RESULTS: Significant homotypic associations were observed for subthreshold anxiety, alcohol, conduct, and a trend was observed for major depression. Only the homotypic association for alcohol and conduct remained after controlling for co-morbid subthreshold and FS conditions. Many heterotypic associations were observed and most remained after controlling for co-morbidity. CONCLUSIONS: It is important to broaden the study of subthreshold psychopathology to multiple disorders. In particular cases, controlling for co-morbidity with other subthreshold and FS conditions altered the patterns of familial aggregation. Etiological processes that are common to particular disorders and subthreshold conditions are discussed.

Family study of co-morbidity between major depressive disorder and anxiety disorders.

BACKGROUND: Numerous studies have documented high rates of co-morbidity between major depressive disorder (MDD) and the anxiety disorders (ANX). However, the reason for this is unclear. Family studies provide one potentially useful approach for addressing this issue. METHOD: We explored six explanations of the co-morbidity between MDD and ANX using a family study of a large community sample of young adults and their first-degree relatives. Participants included 112 probands with a lifetime history of both MDD and one or more ANX, 290 probands with a history of MDD but no ANX, 43 probands with a history of one or more ANX but no MDD. 352 probands with no lifetime history of either MDD or ANX, and the probands' 2608 first-degree relatives. Probands were assessed using semi-structured diagnostic interviews on two occasions in adolescence and a third time at age 24. Diagnostic data on relatives were collected using both direct and family history interviews. RESULTS: Compared with controls, MDD aggregated in the families of probands with MDD, whether or not they had co-morbid ANX; ANX aggregated in the families of probands with ANX, regardless of whether they had co-morbid MDD; and co-morbid MDD/ANX aggregated only in the families of probands with both MDD and ANX. The relatives of probands with ANX alone had a significantly higher rate of ANX than the relatives of probands with MDD alone, although none of the other comparisons between the depressed and anxious groups were significant. CONCLUSIONS: This pattern of findings is largely, although not completely, consistent with the view that MDD and ANX are transmitted independently within families, and suggests that the comorbidity between MDD and ANX is caused by non-familial aetiological factors.