Evidence for Altered Basal Ganglia-Brainstem Connections in Cervical Dystonia

Background: There has been increasing interest in the interaction of the basal ganglia with the cerebellum and the brainstem in motor control and movement disorders. In addition, it has been suggested that these subcortical connections with the basal ganglia may help to coordinate a network of regions involved in mediating posture and stabilization. While studies in animal models support a role for this circuitry in the pathophysiology of the movement disorder dystonia, thus far, there is only indirect evidence for this in humans with dystonia. Methodology/Principal Findings: In the current study we investigated probabilistic diffusion tractography in DYT1-negative patients with cervical dystonia and matched healthy control subjects, with the goal of showing that patients exhibit altered microstructure in the connectivity between the pallidum and brainstem. The brainstem regions investigated included nuclei that are known to exhibit strong connections with the cerebellum. We observed large clusters of tractography differences in patients relative to healthy controls, between the pallidum and the brainstem. Tractography was decreased in the left hemisphere and increased in the right hemisphere in patients, suggesting a potential basis for the left/right white matter asymmetry we previously observed in focal dystonia patients. Conclusions/Significance: These findings support the hypothesis that connections between the basal ganglia and brainstem play a role in the pathophysiology of dystonia

Roadmap for optimizing the clinical utility of emotional stress paradigms in human neuroimaging research

The emotional stress response is relevant to a number of psychiatric disorders, including posttraumatic stress disorder (PTSD) in particular. Research using neuroimaging methods such as functional magnetic resonance imaging (fMRI) to probe stress-related neural processing have provided some insights into psychiatric disorders. Treatment providers and individual patients would benefit from clinically useful fMRI paradigms that provide information about patients’ current brain state and responses to stress in order to inform the treatment selection process. However, neuroimaging has not yet made a meaningful impact on real-world clinical practice. This lack of clinical utility may be related to a number of basic psychometric properties that are often overlooked during fMRI task development. The goals of the current review are to discuss important methodological considerations for current human fMRI stress-related paradigms and to provide a roadmap for developing methodologically sound and clinically useful paradigms. This would include establishing various aspects of reliability, including internal consistency, test-retest and multi-site, as well as validity, including face, content, construct, and criterion. In addition, the establishment of standardized normative data from a large sample of participants would support our understanding of how any one individual compares to the general population. Addressing these methodological gaps will likely have a powerful effect on improving the replicability of findings and optimize our chances for improving real-world clinical outcomes. Keywords: fMRI, Validity, Reliability, Treatment, Fear, PTS

Sustained increase in depression and anxiety among psychiatrically healthy adolescents during late stage COVID-19 pandemic

BackgroundAdolescents have experienced increases in anxiety, depression, and stress during the COVID-19 pandemic and may be at particular risk for suffering from long-term mental health consequences because of their unique developmental stage. This study aimed to determine if initial increases in depression and anxiety in a small sample of healthy adolescents after the onset of the COVID-19 pandemic were sustained at follow-up during a later stage of the pandemic.MethodsFifteen healthy adolescents completed self-report measures at three timepoints (pre-pandemic [T1], early pandemic [T2], and later pandemic [T3]). The sustained effect of COVID-19 on depression and anxiety was examined using linear mixed-effect analyses. An exploratory analysis was conducted to investigate the relationship between difficulties in emotion regulation during COVID-19 at T2 and increases in depression and anxiety at T3.ResultsThe severity of depression and anxiety was significantly increased at T2 and sustained at T3 (depression: Hedges’ g [T1 to T2] = 1.04, g [T1 to T3] = 0.95; anxiety: g [T1 to T2] = 0.79, g [T1 to T3] = 0.80). This was accompanied by sustained reductions in positive affect, peer trust, and peer communication. Greater levels of difficulties in emotion regulation at T2 were related to greater symptoms of depression and anxiety at T3 (rho = 0.71 to 0.80).ConclusionIncreased symptoms of depression and anxiety were sustained at the later stage of the pandemic in healthy adolescents. Replication of these findings with a larger sample size would be required to draw firm conclusions

Neurofeedback-Augmented Mindfulness Training Elicits Distinct Responses in the Subregions of the Insular Cortex in Healthy Adolescents

Mindfulness training (MT) reduces self-referential processing and promotes interoception, the perception of sensations from inside the body, by increasing one’s awareness of and regulating responses to them. The posterior cingulate cortex (PCC) and the insular cortex (INS) are considered hubs for self-referential processing and interoception, respectively. Although MT has been consistently found to decrease PCC, little is known about how MT relates to INS activity. Understanding links between mindfulness and interoception may be particularly important for informing mental health in adolescence, when neuroplasticity and emergence of psychopathology are heightened. We examined INS activity during real-time functional magnetic resonance imaging neurofeedback-augmented mindfulness training (NAMT) targeting the PCC. Healthy adolescents (N = 37; 16 female) completed the NAMT task, including Focus-on-Breath (MT), Describe (self-referential processing), and Rest conditions, across three neurofeedback runs and two non-neurofeedback runs (Observe, Transfer). Regression coefficients estimated from the generalized linear model were extracted from three INS subregions: anterior (aINS), mid (mINS), and posterior (pINS). Mixed model analyses revealed the main effect of run for Focus-on-Breath vs. Describe contrast in aINS [R2 = 0.39] and pINS [R2 = 0.33], but not mINS [R2 = 0.34]. Post hoc analyses revealed greater aINS activity and reduced pINS activity during neurofeedback runs, and such activities were related to lower self-reported life satisfaction and less pain behavior, respectively. These findings revealed the specific involvement of insula subregions in rtfMRI-nf MT

Neural responses to maternal praise and criticism: Relationship to depression and anxiety symptoms in high-risk adolescent girls

AbstractBackgroundThe parent-child relationship may be an important factor in the development of adolescent depressive and anxious symptoms. In adults, depressive symptoms relate to increased amygdala and attenuated prefrontal activation to maternal criticism. The current pilot study examined how depressive and anxiety symptoms in a high-risk adolescent population relate to neural responses to maternal feedback. Given previous research relating oxytocin to maternal behavior, we conducted exploratory analyses using oxytocin receptor (OXTR) genotype.MethodsEighteen females (ages 12–16) listened to maternal praise, neutral, and critical statements during functional magnetic resonance imaging. Participants completed the Mood and Feelings Questionnaire and the Screen for Child Anxiety Related Emotional Disorders. The OXTR single nucleotide polymorphism, rs53576, was genotyped. Linear mixed models were used to identify symptom or allele (GG, AA/AG) by condition (critical, neutral, praise) interaction effects on brain activation.ResultsGreater symptoms related to greater right amygdala activation for criticism and reduced activation to praise. For left amygdala, greater symptoms related to reduced activation to both conditions. Anxiety symptoms related to differences in superior medial PFC activation patterns. Parental OXTR AA/AG allele related to reduced activation to criticism and greater activation to praise within the right amygdala.ConclusionsResults support a relationship between anxiety and depressive symptoms and prefrontal-amygdala responses to maternal feedback. The lateralization of amygdala findings suggests separate neural targets for interventions reducing reactivity to negative feedback or increasing salience of positive feedback. Exploratory analyses suggest that parents' OXTR genetic profile influences parent-child interactions and related adolescent brain responses

Behavioral activation therapy for depression is associated with a reduction in the concentration of circulating quinolinic acid

BackgroundAn inflammation-induced imbalance in the kynurenine pathway (KP) has been reported in major depressive disorder but the utility of these metabolites as predictive or therapeutic biomarkers of behavioral activation (BA) therapy is unknown.MethodsSerum samples were provided by 56 depressed individuals before BA therapy and 29 of these individuals also provided samples after 10 weeks of therapy to measure cytokines and KP metabolites. The PROMIS Depression Scale (PROMIS-D) and the Sheehan Disability Scale were administered weekly and the Beck depression inventory was administered pre- and post-therapy. Data were analyzed with linear mixed-effect, general linear, and logistic regression models. The primary outcome for the biomarker analyses was the ratio of kynurenic acid to quinolinic acid (KynA/QA).ResultsBA decreased depression and disability scores (p's < 0.001, Cohen's d's > 0.5). KynA/QA significantly increased at post-therapy relative to baseline (p < 0.001, d = 2.2), an effect driven by a decrease in QA post-therapy (p < 0.001, uncorrected, d = 3.39). A trend towards a decrease in the ratio of kynurenine to tryptophan (KYN/TRP) was also observed (p = 0.054, uncorrected, d = 0.78). Neither the change in KynA/QA, nor baseline KynA/QA were associated with response to BA therapy.ConclusionThe current findings together with previous research show that electronconvulsive therapy, escitalopram, and ketamine decrease concentrations of the neurotoxin, QA, raise the possibility that a common therapeutic mechanism underlies diverse forms of anti-depressant treatment but future controlled studies are needed to test this hypothesis

A randomized clinical trial of behavioral activation and exposure-based therapy for adults with generalized anxiety disorder.

OBJECTIVE: Exposure-based therapy (EXP) and behavioral activation (BA) are empirically-supported behavioral intervention techniques that target avoidance and approach behavior to alleviate symptoms. Although EXP is an established treatment for generalized anxiety disorder (GAD), the effectiveness of BA for GAD has not been directly tested or compared with that of EXP. This study examined the efficacy of EXP and BA for adults with GAD. METHOD: In a randomized clinical trial (clinicaltrials.gov: NCT02807480) with partial blinding in Tulsa, OK, 102 adults with GAD were allocated to manualized, 10-session EXP or BA between April 2016-April 2021. Primary analyses were intention-to-treat and included the 94 (46 EXP, 48 BA) participants who started treatment. The GAD-7 self-report scale was the primary outcome measure. RESULTS: Similar GAD-7 declines were observed at post-treatment for EXP (d=-0.97 [95% CI -1.40 to -0.53]) and BA (d=-1.14 [95% CI -1.57 to -0.70]), and were maintained through 6-month follow-up (EXP: d=-2.13, BA: d=-1.98). Compared to EXP, BA yielded more rapid declines in anxiety and depression scores during therapy (d=0.75-0.77), as well as lower anxiety and depression scores (d=0.13-0.14) and greater participant-rated improvement (d=0.64) at post-treatment. Bayesian analyses indicated 74-99% probability of greater change in BA than EXP at post-treatment. CONCLUSIONS: BA and EXP are both effective in treating GAD, and BA may confer greater benefit during treatment. Future research is warranted to inform personalized treatment approaches

Group differences for voxel-wise probabilistic diffusion tractography contrast (12 cervical dystonia patients versus 12 matched controls).

*<p>Met significance criteria (p<0.00011 [p<0.05 corrected, or t = 4.70] for t values, and 291 voxels for cluster threshold).</p><p>Negative t values indicate that tractography measures were reduced in cervical dystonia patients relative to control subjects. Positive t values indicate that tractography measures were elevated in cervical dystonia patients relative to control subjects. Note that all regions included in the cluster are reported; however, only one peak within the cluster was required to reach statistical significance (t>4.12). t values are reported for all regions exhibiting peaks of 3.5 or greater. L = left hemisphere; R = right hemisphere; wm = white matter.</p

Group differences for voxel-wise FA contrast (12 cervical dystonia patients versus 12 matched controls).

*<p>Met significance criteria (p<0.00022, [p<0.05, corrected, or t = 4.42] for t values, and 72 voxels for cluster threshold).</p>†<p>p value was within an order of magnitude of the corrected threshold (a trend).</p><p>Positive t values indicate FA values were elevated in cervical dystonia patients relative to control subjects; negative t values indicate FA values were reduced in cervical dystonia patients relative to control subjects. L = left hemisphere; R = right hemisphere; wm = white matter.</p

Clinical characteristics of cervical dystonia patients.

*<p>subjects included in 2006 study using different analyses.</p><p>BFM: Burke Fahn Marsden dystonia rating scale.</p><p>Tsui: Tsui rating scale for cervical dystonia.</p><p>TW: Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) for cervical dyston.</p