A functional serotonin transporter promoter polymorphism, HTTLPR, alters the risk of disease as well as brain morphometry and function. Here, we show that HTTLPR is functionally triallelic. The LG ...allele, which is the L allele with a common G substitution, creates a functional AP2 transcription-factor binding site. Expression assays in 62 lymphoblastoid cell lines representing the six genotypes and in transfected raphe-derived cells showed codominant allele action and low, nearly equivalent expression for the S and LG alleles, accounting for more variation in HTT expression than previously recognized. The gain-of-function LALA genotype was approximately twice as common in 169 whites with obsessive-compulsive disorder (OCD) than in 253 ethnically matched controls. We performed a replication study in 175 trios consisting of probands with OCD and their parents. The LA allele was twofold overtransmitted to the patients with OCD. The HTTLPR LALA genotype exerts a moderate (1.8-fold) effect on risk of OCD, which crystallizes the evidence that the HTT gene has a role in OCD.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Repetitive transcranial magnetic stimulation (rTMS) is an established treatment for major depressive disorder (MDD) and shows promise for posttraumatic stress disorder (PTSD), yet effectiveness ...varies. Electroencephalography (EEG) can identify rTMS-associated brain changes. EEG oscillations are often examined using averaging approaches that mask finer time-scale dynamics. Recent advances show some brain oscillations emerge as transient increases in power, a phenomenon termed "Spectral Events," and that event characteristics correspond with cognitive functions. We applied Spectral Event analyses to identify potential EEG biomarkers of effective rTMS treatment. Resting 8-electrode EEG was collected from 23 patients with MDD and PTSD before and after 5 Hz rTMS targeting the left dorsolateral prefrontal cortex. Using an open-source toolbox ( https://github.com/jonescompneurolab/SpectralEvents ), we quantified event features and tested for treatment associated changes. Spectral Events in delta/theta (1-6 Hz), alpha (7-14 Hz), and beta (15-29 Hz) bands occurred in all patients. rTMS-induced improvement in comorbid MDD PTSD were associated with pre- to post-treatment changes in fronto-central electrode beta event features, including frontal beta event frequency spans and durations, and central beta event maxima power. Furthermore, frontal pre-treatment beta event duration correlated negatively with MDD symptom improvement. Beta events may provide new biomarkers of clinical response and advance the understanding of rTMS.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Background We investigated the use of deep brain stimulation (DBS) of the ventral capsule/ventral striatum (VC/VS) for treatment refractory depression. Methods Fifteen patients with chronic, severe, ...highly refractory depression received open-label DBS at three collaborating clinical sites. Electrodes were implanted bilaterally in the VC/VS region. Stimulation was titrated to therapeutic benefit and the absence of adverse effects. All patients received continuous stimulation and were followed for a minimum of 6 months to longer than 4 years. Outcome measures included the Hamilton Depression Rating Scale—24 item (HDRS), the Montgomery-Asberg Depression Rating Scale (MADRS), and the Global Assessment of Function Scale (GAF). Results Significant improvements in depressive symptoms were observed during DBS treatment. Mean HDRS scores declined from 33.1 at baseline to 17.5 at 6 months and 14.3 at last follow-up. Similar improvements were seen with the MADRS (34.8, 17.9, and 15.7, respectively) and the GAF (43.4, 55.5, and 61.8, respectively). Responder rates with the HDRS were 40% at 6 months and 53.3% at last follow-up (MADRS: 46.7% and 53.3%, respectively). Remission rates were 20% at 6 months and 40% at last follow-up with the HDRS (MADRS: 26.6% and 33.3%, respectively). The DBS was well-tolerated in this group. Conclusions Deep brain stimulation of the VC/VS offers promise for the treatment of refractory major depression.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Objective:Posttraumatic stress disorder (PTSD) is a highly prevalent psychiatric disorder associated with disruption in social and occupational function. Transcranial magnetic stimulation (TMS) ...represents a novel approach to PTSD, and intermittent theta-burst stimulation (iTBS) is a new, more rapid administration protocol with data supporting efficacy in depression. The authors conducted a sham-controlled study of iTBS for PTSD.Methods:Fifty veterans with PTSD received 10 days of sham-controlled iTBS (1,800 pulses/day), followed by 10 unblinded sessions. Primary outcome measures included acceptability (retention rates), changes in PTSD symptoms (clinician- and self-rated), quality of life, social and occupational function, and depression, obtained at the end of 2 weeks; analysis of variance was used to compare active with sham stimulation. Secondary outcomes were evaluated 1 month after treatment, using mixed-model analyses. Resting-state functional MRI was acquired at pretreatment baseline on an eligible subset of participants (N=26) to identify response predictors.Results:Retention was high, side effects were consistent with standard TMS, and blinding was successful. At 2 weeks, active iTBS was significantly associated with improved social and occupational function (Cohen’s d=0.39); depression was improved with iTBS compared with the sham treatment (d=−0.45), but the difference fell short of significance, and moderate nonsignificant effect sizes were observed on self-reported PTSD symptoms (d=−0.34). One-month outcomes, which incorporated data from the unblinded phase of the study, indicated superiority of active iTBS on clinician- and self-rated PTSD symptoms (d=−0.74 and −0.63, respectively), depression (d=−0.47), and social and occupational function (d=0.93) (all significant). Neuroimaging indicated that clinical improvement was significantly predicted by stronger (greater positive) connectivity within the default mode network and by anticorrelated (greater negative) cross-network connectivity.Conclusions:iTBS appears to be a promising new treatment for PTSD. Most clinical improvements from stimulation occurred early, which suggests a need for further investigation of optimal iTBS time course and duration. Consistent with previous neuroimaging studies of TMS, default mode network connectivity played an important role in response prediction.
Gravity affects every aspect of cardiac performance. When gravitational gradients are at their greatest on Earth (i.e., during upright posture), orthostatic intolerance may ensue and is a common ...clinical problem that appears to be exacerbated by the adaptation to spaceflight. We sought to elucidate the alterations in cardiac performance during preload reduction with progressive upright tilt that are relevant both for space exploration and the upright posture, particularly the preload dependence of various parameters of cardiovascular performance.
This was a prospective observational study with tilt-induced hydrostatic stress. Echocardiographic images were recorded at four different tilt angles in 13 astronauts, to mimic varying degrees of gravitational stress: 0° (supine, simulating microgravity of space), 22° head-up tilt (0.38 G, simulating Martian gravity), 41° (0.66 G, simulating approximate G load of a planetary lander), and 80° (1 G, effectively full Earth gravity). These images were then analyzed offline to assess the effects of preload reduction on anatomical and functional parameters.
Although three-dimensional end-diastolic, end-systolic, and stroke volumes were significantly reduced during tilting, ejection fractions showed no significant change. Mitral annular e' and a' velocities were reduced with increasing gravitational load (P < .001 and P = .001), although s' was not altered. Global longitudinal strain (GLS; from -19.8% ± 2.2% to -14.7% ± 1.5%) and global circumferential strain (GCS; from -29.2% ± 2.5% to -26.0% ± 1.8%) were reduced significantly with increasing gravitational stress (both P < .001), while the change in strain rates were less certain: GLSR (P = .049); GCSR (P = .55). End-systolic elastance was not consistently changed (P = .53), while markers of cardiac afterload rose significantly (effective arterial elastance, P < .001; systemic vascular resistance, P < .001).
Preload modification with gravitational loading alters most hemodynamic and echocardiographic parameters including e' velocity, GLS, and GCS. However, end-systolic elastance and strain rate appear to be more load-independent measures to examine alterations in the cardiovascular function during postural and preload changes, including microgravity.
The basal ganglia have been a target for neuromodulation surgery since Russell Meyers’ pioneering works in the late 1930s. Contemporary movement disorder surgery on the brain has evolved from empiric ...observations on movement behavior after neurological lesions. So too has the development of psychiatric surgical procedures followed the observation of lesions in the brain on cognitive and affective behavior. Just as deep brain stimulation (DBS) has revolutionized the practice of movement disorder surgery, its application to psychiatric illness has become the cutting edge of functional and restorative neurosurgery.
The fundamental concept of the cortico-striatal-pallido-thalamocortical loop will be explored in the context of psychiatric disorders. DBS targeting this circuitry appears from initial evidence in obsessive–compulsive disorder (OCD) to be a promising option for patients with neuropsychiatric illness resistant to conventional therapies. Further exploring the anatomic interconnectivity of the physiologically relevant cortical and subcortical areas will inevitably lead to better applications of DBS for the treatment of OCD, major depression (MD) and potentially for other psychiatric disorders. Implementing such therapies optimally will require the creation of treatment centers with specialized expertize in the psychiatric, neurosurgical, and ethical issues that arise with these populations.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Caffeine is a widely used psychostimulant. In the brain, caffeine acts as a competitive, non-selective adenosine receptor antagonist of A1 and A2A, both known to modulate long-term potentiation ...(LTP), the cellular basis of learning and memory. Repetitive transcranial magnetic stimulation (rTMS) is theorized to work through LTP induction and can modulate cortical excitability as measured by motor evoked potentials (MEPs). The acute effects of single caffeine doses diminish rTMS-induced corticomotor plasticity. However, plasticity in chronic daily caffeine users has not been examined.
We conducted a
secondary covariate analysis from two previously published plasticity-inducing pharmaco-rTMS studies combining 10 Hz rTMS and D-cycloserine (DCS) in twenty healthy subjects.
In this hypothesis-generating pilot study, we observed enhanced MEP facilitation in non-caffeine users compared to caffeine users and placebo.
These preliminary data highlight a need to directly test the effects of caffeine in prospective well-powered studies, because in theory, they suggest that chronic caffeine use could limit learning or plasticity, including rTMS effectiveness.
IMPORTANCE: Posttraumatic stress disorder (PTSD) is a common psychiatric disorder that is particularly difficult to treat in military veterans. Noninvasive brain stimulation has significant potential ...as a novel treatment to reduce PTSD symptoms. OBJECTIVE: To test whether active transcranial direct current stimulation (tDCS) plus virtual reality (VR) is superior to sham tDCS plus VR for warzone-related PTSD. DESIGN, SETTING, AND PARTICIPANTS: This double-blind randomized clinical trial was conducted among US military veterans enrolled from April 2018 to May 2023 at a secondary care Department of Veterans Affairs hospital and included 1- and 3-month follow-up visits. Participants included US military veterans with chronic PTSD and warzone-related exposure, recruited via referral and advertisement. Patients in psychiatric treatment had to be on a stable regimen for at least 6 weeks to be eligible for enrollment. Data were analyzed from May to September 2023. INTERVENTION: Participants were randomly assigned to receive 2-mA anodal tDCS or sham tDCS targeted to the ventromedial prefrontal cortex, during six 25-minute sessions of standardized warzone VR exposure, delivered over 2 to 3 weeks. MAIN OUTCOMES AND MEASURES: The co–primary outcomes were self-reported PTSD symptoms, measured via the PTSD checklist for DSM-5 (PCL-5), alongside quality of life. Other outcomes included psychophysiological arousal, clinician-assessed PTSD, depression, and social/occupational function. RESULTS: A total of 54 participants (mean SD age, 45.7 10.5 years; 51 94% males) were assessed, including 26 in the active tDCS group and 28 in the sham tDCS group. Participants in the active tDCS group reported a superior reduction in self-reported PTSD symptom severity at 1 month (t = −2.27, P = .02; Cohen d = −0.82). There were no significant differences in quality of life between active and sham tDCS groups. Active tDCS significantly accelerated psychophysiological habituation to VR events between sessions compared with sham tDCS (F5,7689.8 = 4.65; P < .001). Adverse effects were consistent with the known safety profile of the corresponding interventions. CONCLUSIONS AND RELEVANCE: These findings suggest that combined tDCS plus VR may be a promising strategy for PTSD reduction and underscore the innovative potential of these combined technologies. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03372460
Expression quantitative trait locus (eQTL) studies illuminate genomic variants that regulate specific genes and contribute to fine-mapped loci discovered via genome-wide association studies (GWAS). ...Efforts to maximize their accuracy are ongoing. Using 240 glomerular (GLOM) and 311 tubulointerstitial (TUBE) micro-dissected samples from human kidney biopsies, we discovered 5371 GLOM and 9787 TUBE genes with at least one variant significantly associated with expression (eGene) by incorporating kidney single-nucleus open chromatin data and transcription start site distance as an "integrative prior" for Bayesian statistical fine-mapping. The use of an integrative prior resulted in higher resolution eQTLs illustrated by (1) smaller numbers of variants in credible sets with greater confidence, (2) increased enrichment of partitioned heritability for GWAS of two kidney traits, (3) an increased number of variants colocalized with the GWAS loci, and (4) enrichment of computationally predicted functional regulatory variants. A subset of variants and genes were validated experimentally in vitro and using a Drosophila nephrocyte model. More broadly, this study demonstrates that tissue-specific eQTL maps informed by single-nucleus open chromatin data have enhanced utility for diverse downstream analyses.
Abstract Background Repetitive transcranial magnetic stimulation (TMS) has been shown to be safe and effective for treatment-resistant depression (TRD) in the general adult population. Efficacy among ...older (≥60 years) patients, who have a greater burden of cognitive, physical, and functional impairment compared to their younger counterparts, remains unclear. The current study aimed to characterize antidepressant response to an acute course of TMS therapy among patients aged ≥60 years compared to those <60 years in naturalistic clinical practice settings. Methods Data were retrospectively collected and pooled for adults with TRD (N = 231; n = 75 aged ≥60 years and n = 156 <60 years) who underwent an acute course of outpatient TMS therapy at two outpatient clinics. Self-report depression scales were administered at baseline and end of acute treatment. Change on continuous measures and categorical outcomes were compared across older vs. younger patients. Results Both age groups showed significant improvements in depression symptoms. Response and remission rates did not differ between groups. Age group was not a significant predictor of change in depression severity, nor of clinical response or remission, in a model controlling for other predictors (all p >.05). Limitations Limitations include reliance on self-report clinical measures and variability in comorbidity and concurrent pharmacotherapy due to the naturalistic nature of the study. Conclusions Results suggest that effectiveness of TMS for TRD is not differentially modified by age. Based on these naturalistic data, age alone should not be considered a contraindication or poor prognostic indicator of the antidepressant efficacy of TMS.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
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