Neurobiology and Target Validation of Novel Therapeutic Agents in Mood Disorders

National Institute Of Mental Health

Investigators

Linked publications, trials & patents

Abstract

This Report involves work collected under protocols 01-M-0254 (NCT00024635); 08-M-0196 (NCT00759395); 08-M-0150 (NCT00697268); 14-M-0085 (NCT02122562); 07-M-0021 (NCT00397111); 14-M-0041 (NCT02049385); 07-M-0152 (NCT00472576), 09-M-N230; 15-M-0151 (NCT 02484456), 15-M-0188 (NCT02543983), 17-M-0181 (NCT03304665); 19-M-0107 (NCT03973268), 000101-M (NCT04821271), 001602-M (NCT06511908), 001874-M (NCT06462196), and 000375-M (NCT04877977). Results this past year: Study 1: Potential association between suicide risk, aggression, impulsivity, and the somatosensory system Aggression and impulsivity are linked to suicidal behaviors, but their relationship to the suicidal crisis, or time when someone is seriously considering suicide, remains unclear. This magnetoencephalography (MEG) study investigated the link between aggression, impulsivity, and resting-state MEG power and connectivity. Four risk groups were enrolled: high-risk (HR; n = 14), who had experienced a recent suicidal crisis; lower-risk (LR; n = 41), who had a history of suicide attempts but no suicide attempt or ideation in the past year; clinical control (CC; n = 38), who had anxiety/mood disorders but no suicidal history; and minimal risk (MR; n = 28), who had no psychiatric/suicidal history. No difference in resting-state MEG power was observed between the groups. Individuals in the HR group with high self-reported aggression and impulsivity scores had reduced MEG power in regions responsible for sensory/emotion regulation versus those in the HR group with low scores. The HR group also showed downregulated bidirectional glutamatergic feedback between the precuneus (PRE) and insula (INS) compared to the LR, CC, and MR groups. High self-reported impulsivity was linked to reduced PRE to INS feedback, whereas high risk-taking impulsivity was linked to upregulated INS to postcentral gyrus (PCG) and PCG to INS feedback. The preliminary findings suggest that aggression and impulsivity may contribute to reduced activity and effective connectivity within brain regions associated with sensory/emotional regulation brain regions in individuals who recently experienced a suicidal crisis. Future studies should examine whether glutamatergic-mediated sensory and emotion-regulation processes may function as potential suicide risk markers. Study 2: Clinical indicators of the suicide crisis and response to ketamine This analysis sought to identify potential clinical targets for the suicide crisis, which is the time just before someone decides to act on their suicidal thoughts. Characteristics of a useful clinical target include elevation at the time of suicide crisis and responsiveness to rapid-acting interventions. We hypothesized that suicidal ideation (SI), depression, and hopelessness would meet these criteria. Participants were 118 adults across the continuum of suicide risk, including 14 high-risk (HR) individuals who had attempted or seriously considered suicide within the last two weeks. Clinical characteristics were evaluated by: 1) comparing individuals with a recent crisis state to those whose suicide crises had resolved; 2) quantifying responses to a semi-structured interview about the time just before a suicide crisis; and 3) comparing symptomatology before and after an open-label ketamine infusion (0.5 mg/kg) in a subset of the HR group (n = 10). As hypothesized, SI, depression, and hopelessness were elevated just after a suicide crisis and responded to ketamine, although findings were mixed depending on the assessment used. Psychological pain and traumatic stress symptoms were also associated with the suicide crisis and responded to ketamine. Participants reported high levels of SI, depression, and anxiety just before their suicide attempt. These results underscore the importance of SI, depression, hopelessness, psychological pain, and traumatic stress in this population, all of which were elevated during the suicide crisis and responded to ketamine. A multifactorial and longitudinal approach is indicated to assess and treat suicide risk. Study 3: Understanding the temporal dynamics of emotion processing in the human brain Understanding how the brain distinguishes emotional from neutral scenes is crucial for advancing brain-computer interfaces, enabling real-time emotion detection for faster, more effective responses, and improving treatments for emotional disorders like depression and anxiety. However, inconsistent research findings have arisen from differences in study settings, such as variations in the time windows, brain regions, and emotion categories examined across studies. This review from our laboratory sought to compile the existing literature on the timing at which the adult brain differentiates basic affective from neutral scenes in less than one second, especially because previous studies have consistently shown that the brain can begin recognizing emotions within just a few milliseconds. The review included studies that used electroencephalography (EEG) or magnetoencephalography (MEG) in healthy adults to examine brain responses to emotional versus neutral images within one second. Articles of interest were limited to the English language but not to any publication year. Excluded studies involved only patients (of any diagnosis), participants under age 18 (since emotional processing can differ between adults and younger individuals), non-passive tasks, low temporal resolution techniques, time intervals over one second, and animals. Of the 3,045 screened articles, 19 met these criteria. Despite the variations between studies, we found that the earliest onset for heightened brain responses to basic affective scenes compared to neutral ones was most commonly observed within the 250-300 ms time window. To the best of our knowledge, this review is the first to synthesize data on the timing of brain differentiation between emotional and neutral scenes in healthy adults. Study 4: Waking gamma and sleep delta power in healthy volunteers and individuals with treatment-resistant depression Sleep disruptions are a core feature of both major depressive disorder and treatment-resistant depression (TRD), which is defined by persistent symptoms despite multiple treatment efforts. In addition, disruptions in wakeful gamma power and sleep-related delta power have been observed in individuals with TRD. This study explored the association between gamma oscillations (30-100 Hz) occurring during wakefulness and delta power (0.5-4 Hz) in non-rapid eye movement (NREM) sleep—both of which have separately been implicated in plasticity—in healthy volunteers (HVs) and individuals with TRD. Specifically, the study explored whether a relationship exists between daytime wake gamma power and sleep NREM delta power in HVs and those with TRD. Brain activity was measured via electroencephalography (night-time) and magnetoencephalography (daytime resting state) in 23 HVs and 40 medication-free TRD participants. We found that, in HVs, NREM episode (NREM1) sleep delta power correlated with daytime wake gamma power, a correlation that was absent in TRD participants. Taken together, the findings identify a possible link between daytime wake gamma power and NREM1 sleep delta power in HVs, supporting an association between gamma and delta power in sleep homeostasis. The lack of such a relationship in medication-free individuals with TRD suggests disrupted synaptic homeostasis that may contribute to impaired synaptic plasticity in TRD.