An experimental examination of neurostimulation and cognitive restructuring as potential components for Misophonia interventions.

Misophonia is a disorder of decreased tolerance to certain aversive, repetitive common sounds, or to stimuli associated with these sounds. Two matched groups of adults (29 participants with misophonia and 30 clinical controls with high emotion dysregulation) received inhibitory neurostimulation (1 Hz) over a personalized medial prefrontal cortex (mPFC) target functionally connected to the left insula; excitatory neurostimulation (10 Hz) over a personalized dorsolateral PFC (dlPFC) target; and sham stimulation over either target. Stimulations were applied while participants were either listening or cognitively downregulating emotions associated with personalized aversive, misophonic, or neutral sounds. Subjective units of distress (SUDS) and psychophysiological measurements (e.g., skin conductance response [SCR] and level [SCL]) were collected. Compared to controls, participants with misophonia reported higher distress (∆SUDS = 1.91-1.93, ps < 0.001) when listening to and when downregulating misophonic distress. Both types of neurostimulation reduced distress significantly more than sham, with excitatory rTMS providing the most benefit (Cohen's dSUDS = 0.53; dSCL = 0.14). Excitatory rTMS also enhanced the regulation of emotions associated with misophonic sounds in both groups when measured by SUDS (dcontrol = 1.28; dMisophonia = 0.94), and in the misophonia group alone when measured with SCL (d = 0.20). Both types of neurostimulation were well tolerated. Engaging in cognitive restructuring enhanced with high-frequency neurostimulation led to the lowest misophonic distress, highlighting the best path forward for misophonia interventions.

Characterization of neural networks involved in transdiagnostic emotion dysregulation from a pilot randomized controlled trial of a neurostimulation-enhanced behavioral intervention.

BACKGROUND: Emotional dysregulation is a serious and impairing mental health problem. We examined functional activity and connectivity of neural networks involved in emotional dysregulation at baseline and following a pilot neurostimulation-enhanced cognitive restructuring intervention in a transdiagnostic clinical adult sample. METHODS: Neuroimaging data were analyzed from adults who scored 89 or higher on the Difficulties with Emotion Regulation (DERS) scale and had at least one DSM-5 diagnosis. These participants were part of a pilot randomized, double-blind, placebo-controlled trial combining a single therapeutic session of cognitive restructuring with active or sham transcranial magnetic stimulation over the dorsolateral prefrontal cortex. During the study, participants engaged in an emotional regulation task using personalized autobiographical stressors while undergoing functional magnetic resonance imaging (fMRI) before and after the pilot intervention. The fMRI task required participants to either experience the emotions associated with the memories or apply cognitive restructuring strategies to reduce their distress. RESULTS: Whole-brain fMRI results during regulation at baseline revealed increased activation in the dorsal frontoparietal network but decreased activation in the supplementary motor area, cingulate cortex, insula, and ventrolateral prefrontal cortex (vlPFC). Emotion dysregulation was associated with greater vmPFC and amygdala activation and functional connectivity between these regions. The strength of functional connectivity between the dlPFC and other frontal regions was also a marker of emotional dysregulation. Preliminary findings from a subset of participants who completed the follow-up fMRI scan showed that active neurostimulation improved behavioral indices of emotion regulation more than sham stimulation. A whole-brain generalized psychophysiological interaction analysis indicated that active neurostimulation selectively increased occipital cortex connectivity with both the insula and the dlPFC. Region-of-interest functional connectivity analyses showed that active neurostimulation selectively increased dlPFC connectivity with the insula and orbitofrontal cortex (OFC). CONCLUSION: Insufficient neural specificity during the emotion regulation process and over-involvement of frontal regions may be a marker of emotional dysregulation across disorders. OFC, vlPFC, insula activity, and connectivity are associated with improved emotion regulation in transdiagnostic adults. In this pilot study, active neurostimulation led to neural changes in the emotion regulation network after a single session; however, the intervention findings are preliminary, given the small sample size. These functional network properties can inform future neuroscience-driven interventions and larger-scale studies.

Neurobiological biomarkers of response to ketamine.

As a field, psychiatry is undergoing an exciting paradigm shift toward early identification and intervention that will likely minimize both the burden associated with severe mental illnesses as well as their duration. In this context, the rapid-acting antidepressant ketamine has revolutionized our understanding of antidepressant response and greatly expanded the pharmacologic armamentarium for treatment-resistant depression. Efforts to characterize biomarkers of ketamine response support a growing emphasis on early identification, which would allow clinicians to identify biologically enriched subgroups with treatment-resistant depression who are more likely to benefit from ketamine therapy. This chapter presents a broad overview of a range of translational biomarkers, including those drawn from imaging and electrophysiological studies, sleep and circadian rhythms, and HPA axis/endocrine function as well as metabolic, immune, (epi)genetic, and neurotrophic biomarkers related to ketamine response. Ketamine's unique, rapid-acting properties may serve as a model to explore a whole new class of novel rapid-acting treatments with the potential to revolutionize drug development and discovery. However, it should be noted that although several of the biomarkers reviewed here provide promising insights into ketamine's mechanism of action, most studies have focused on acute rather than longer-term antidepressant effects and, at present, none of the biomarkers are ready for clinical use.

Sleep and suicide: A systematic review and meta-analysis of longitudinal studies.

The current review provides a quantitative synthesis of the empirical literature on sleep disturbance as a risk factor for suicidal thoughts and behaviors (STBs). A systematic search of PsycINFO, MEDLINE, and the references of prior reviews resulted in 41 eligible studies included in this meta-analysis. Sleep disturbance, including insomnia, prospectively predicted STBs, yielding small-to-medium to medium effect sizes for these associations. Complicating interpretation of these findings however, is that few studies of suicidal ideation and suicide attempts, as well as none of suicide deaths, assessed short-term risk (i.e., employed follow-up assessments of under a month). Such studies are needed to evaluate current conceptualizations of sleep dysregulation as being involved in acute risk for suicidal behavior. This want of short-term risk studies also suggests that current clinical recommendations to monitor sleep as a potential warning sign of suicide risk has a relatively modest empirical basis, being largely driven by cross-sectional or retrospective research. The current review ends with recommendations for generating future research on short-term risk and greater differentiation between acute and chronic aspects of sleep disturbance, and by providing a model of how sleep disturbance may confer risk for STBs through neuroinflammatory and stress processes and associated impairments in executive control.

Neurobiological research with suicidal participants: A framework for investigators.

OBJECTIVE: Suicide is a public health threat. Nevertheless, the research literature on actively suicidal participants is relatively sparse, in part because they are often excluded from medical, psychiatric, and psychological research for a host of logistical, ethical, and safety concerns. These obstacles to research participation and enrollment may contribute to our lack of understanding regarding the neurobiology of the suicidal crisis as well as to the dearth of evidence concerning both risk prediction and treatment. METHOD: In order to directly investigate neurobiological markers of acute suicide risk, the National Institute of Mental Health Intramural Research Program (NIMH-IRP) implemented the Neurobiology of Suicide protocol. In this protocol, actively suicidal individuals consent to research for both neurobiological assessment and potential rapid-acting interventions. RESULTS AND CONCLUSIONS: This article reviews lessons learned from implementing this protocol in the hopes of assisting future research on the neurobiology of suicide. Areas of specific discussion include the Failure Modes and Effects Analysis (FMEA), recruitment and informed consent, participant monitoring, and the safety of the physical environment.

A behavioral and cognitive neuroscience perspective on impulsivity, suicide, and non-suicidal self-injury: Meta-analysis and recommendations for future research.

We conducted a meta-analysis of neurobehavioral and neurocognitive indices of impulsivity in relation to suicidal thoughts and behaviors, as well as non-suicidal self-injury (NSSI). In our systematic review, 34 studies were identified and submitted to a random-effects meta-analysis. A small pooled effect size was observed for the association between behavioral impulsivity and NSSI (OR=1.34, p<0.05). A small-to-medium pooled effect size (OR=2.23, p<0.001) was found for the association between behavioral impulsivity and suicide attempts, and a medium-to-large pooled effect size was observed for this outcome in relation to cognitive impulsivity (OR=3.14, p<0.01). Length of time between suicide attempt and impulsivity assessment moderated the strength of the relation between impulsivity and attempts, with a large pooled effect size (OR=5.54, p<0.001) evident when the suicide attempt occurred within a month of behavioral impulsivity assessment. Studies of clinically significant NSSI temporally proximal to impulsivity assessment are needed. Longitudinal research is required to clarify the prognostic value of behavioral and cognitive impulsivity for short-term risk for self-harm.