Effect of GAD1 genotype status on auditory attention and acute nicotine administration in healthy volunteers.

OBJECTIVE: The effects of GABA modulating drugs and nicotine, the prototypical nicotinic cholinergic agonist, on attention have been investigated using subcomponents of the P300 event-related potentials (ERP), which index involuntary (P3a) and voluntary attention (P3b). However, investigations into how such pharmacologic effects interact with genetic features in the GABA system remain unclear. This study examined the moderating effects of a single nucleotide polymorphism (rs7557793) in the glutamic acid decarboxylase 67 (GAD1) gene, which is implicated in the conversion of glutamate to GABA, on P300-indices of auditory attentional processing; the influence of nicotine administration was also assessed. METHODS: The effects of GAD1 genotype (TT/CC/CT) were examined on the P3a/b in response to an auditory selective attention task in healthy, nonsmoking male volunteers (N = 126; 18-40 years). Participants responded to rare target stimuli (P3b-eliciting) and ignored frequent nontarget stimuli as well as rare distractor stimuli (P3a-eliciting). In a subsample (N = 59), P3a/b profiles to acute nicotine (vs. placebo) administration were examined as a function of GAD1 genotype. As a secondary aim, earlier sensory processes were assessed with N200 ERP subcomponents elicited by novel (N2a) and target (N2b) auditory stimuli. RESULTS: GAD1 allelic variation moderated early sensory processes, enhancing N2a amplitudes in CT versus TT carriers. Further, TT homozygotes exhibited larger P3b amplitudes than CC homozygotes in the placebo versus nicotine condition. Regardless of genotype, nicotine versus placebo moderated the N200 ERP. CONCLUSION: These findings expand our knowledge regarding the attentional effects of GAD1 genetic variants in relation to nicotine.

Transcranial Alternating Current Stimulation Alters Auditory Steady-State Oscillatory Rhythms and Their Cross-Frequency Couplings.

Auditory cortical plasticity deficits in schizophrenia are evidenced with electroencephalographic (EEG)-derived biomarkers, including the 40-Hz auditory steady-state response (ASSR). Aiming to understand the underlying oscillatory mechanisms contributing to the 40-Hz ASSR, we examined its response to transcranial alternating current stimulation (tACS) applied bilaterally to the temporal lobe of 23 healthy participants. Although not responding to gamma tACS, the 40-Hz ASSR was modulated by theta tACS (vs sham tACS), with reductions in gamma power and phase locking being accompanied by increases in theta-gamma phase-amplitude cross-frequency coupling. Results reveal that oscillatory changes induced by frequency-tuned tACS may be one approach for targeting and modulating auditory plasticity in normal and diseased brains.

Influence of GABAA and GABAB receptor activation on auditory sensory gating and its association with anxiety in healthy volunteers.

BACKGROUND: Dysfunctional sensory gating in anxiety disorders, indexed by the failure to inhibit the P50 event-related potential (ERP) to repeated stimuli, has been linked to deficits in the major inhibitory neurotransmitter γ-aminobutyric acid (GABA). AIMS/METHODS: This study, conducted in 30 healthy volunteers, examined the acute effects of GABAA (lorazepam: 1 mg) and GABAB receptor (baclofen: 10 mg) agonists on P50 measures of auditory sensory gating within a paired-stimulus (S1-S2) paradigm and assessed changes in gating in relation to self-ratings of anxiety. RESULTS: Compared to placebo, lorazepam reduced ERP indices of sensory gating by attenuating response to S1. Although not directly impacting P50 inhibition, baclofen-induced changes in gating (relative to placebo) were negatively correlated with trait but not state anxiety. CONCLUSIONS: These preliminary findings support the involvement of GABA in sensory gating and tentatively suggest a role for GABAB receptor signaling in anxiety-associated gating dysregulation.

Synchronized Auditory Gamma Response to Frontal Transcranial Direct Current Stimulation (tDCS) and its Inter-Individual Variation in Healthy Humans.

In schizophrenia, a disorder associated with N-methyl-D-aspartate receptor (NMDAR) hypofunction, auditory cortical plasticity deficits have been indexed by the synchronized electroencephalographic (EEG) auditory steady-state gamma-band (40-Hz) response (ASSR) and the early auditory evoked gamma-band response (aeGBR), both considered to be target engagement biomarkers for NMDAR function, and potentially amenable to treatment by NMDAR modulators. As transcranial direct current stimulation (tDCS) is likely dependent on NMDAR neurotransmission, this preliminary study, conducted in 30 healthy volunteers, assessed the off-line effects of prefrontal anodal tDCS and sham (placebo) treatment on 40-Hz ASSR and aeGBR. Anodal tDCS failed to alter aeGBR but increased both 40-Hz ASSR power, as measured by event-related spectral perturbations (ERSP), and phase locking, as measured by inter-trial phase consistency (ITPC). Inter-individual differences in tDCS-induced increases in ERSP were negatively related to baseline ERSPs. These findings provide tentative support for further study of tDCS as a potential NMDAR neuromodulatory intervention for synchronized auditory gamma response deficits.

Cardiovascular biomarkers of response to accelerated low frequency repetitive transcranial magnetic stimulation in major depression.

BACKGROUND AND OBJECTIVE: Repetitive transcranial magnetic stimulation (rTMS) is an effective and safe treatment for major depressive disorder (MDD). rTMS is in need of a reliable biomarker of treatment response. High frequency (HF) dorsolateral prefrontal cortex (DLPFC) rTMS has been reported to induce significant changes in the cardiac activity of MDD patients. Low frequency DLPFC rTMS has many advantages over HF-DLPFC rTMS and thus this study aims to further investigate the effect of low frequency 1 Hz right hemisphere (R)-DLPFC rTMS on the cardiac activity of MDD patients, as well as the potential of using electrocardiogram (ECG) parameters as biomarkers of treatment outcome. METHODS: Baseline ECG sessions were performed for 19 MDD patients. All patients then underwent 40 sessions of accelerated 1 Hz R-DLPFC rTMS one week after the baseline session. RESULTS: Heart rate (HR) significantly decreased from the resting period to the first and third minute of the 1 Hz R-DLPFC rTMS period. Resting HR was found to have a significant negative association with treatment outcome. Prior to Bonferroni correction, HR during stimulation and the degree of rTMS-induced HR reduction were significantly negatively associated with treatment outcome. No significant changes were observed for the heart rate variability (HRV) parameters. LIMITATIONS: Sample size (n = 19); the use of electroencephalography equipment for ECG; lack of respiration monitoring; relatively short recording duration for HRV parameters. CONCLUSION: This novel study provides further preliminary evidence that ECG may be utilized as a biomarker of rTMS treatment response in MDD. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04376697.

Optimized repetitive transcranial magnetic stimulation techniques for the treatment of major depression: A proof of concept study.

Although effective in major depressive disorder (MDD), repetitive transcranial magnetic stimulation (rTMS) is costly and complex, limiting accessibility. To address this, we tested the feasibility of novel rTMS techniques with cost-saving opportunities, such as an open-room setting, large non-focal parabolic coils, and custom-built coil arms. We employed a low-frequency (LF) 1 Hz stimulation protocol (360 pulses per session), delivered on the most affordable FDA-approved device. MDD participants received an initial accelerated rTMS course (arTMS) of 6 sessions/day over 5 days (30 total), followed by a tapering course of daily sessions (up to 25) to decrease the odds of relapse. The self-reported Beck Depression Inventory II (BDI-II) was used to measure severity of depression. Forty-eight (48) patients completed the arTMS course. No serious adverse events occurred, and all patients reported manageable pain levels. Response and remission rates were 35.4% and 27.1% on the BDI-II, respectively, at the end of the tapering course. Repeated measures ANOVA showed significant changes of BDI-II scores over time. Even though our protocol will require further improvements, some of the concepts we introduced here could help guide the design of future trials aiming at increasing accessibility to rTMS.

Cholinergic modulation of auditory P3 event-related potentials as indexed by CHRNA4 and CHRNA7 genotype variation in healthy volunteers.

Schizophrenia (SZ) is a psychiatric disorder characterized by cognitive dysfunction within the realm of attentional processing. Reduced P3a and P3b event-related potentials (ERPs), indexing involuntary and voluntary attentional processing respectively, have been consistently observed in SZ patients who also express prominent cholinergic deficiencies. The involvement of the brain's cholinergic system in attention has been examined for several decades; however, further inquiry is required to further comprehend how abnormalities in this system affect neighbouring neurotransmitter systems and contribute to neurocognitive deficits. The objective of this pilot study was to examine the moderating role of the CHRNA4 (rs1044396), CHRNA7 (rs3087454), and SLC5A7 (rs1013940) genes on ERP indices of attentional processing in healthy volunteers (N=99; Caucasians and non-Caucasians) stratified by genotype and assessed using the auditory P300 "oddball" paradigm. Results indicated significantly greater P3a and P3b-indexed attentional processing for CT (vs. CC) CHRNA4 carriers and greater P3b for AA (vs. CC) CHRNA7 carriers. SLC5A7 allelic variants did not show significant differences in P3a and P3b processing. These findings expand our knowledge on the moderating effect of cholinergic genes on attention and could help inform targeted drug developments aimed at restoring attention deficits in SZ patients.

Schistosoma mansoni morbidity among school-aged children: a SCORE project in Kenya.

Schistosomiasis control programs aim to reduce morbidity but are evaluated by infection prevalence and intensity reduction. We present baseline cross-sectional data from a nested cohort study comparing indicators of morbidity for measuring program impact. Eight hundred twenty-two schoolchildren 7-8 years of age from Nyanza Province, Kenya, contributed stool for diagnosis of Schistosoma mansoni and soil-transmitted helminths (STH) and blood smears for malaria, and were evaluated for anemia, quality of life, exercise tolerance, anthropometry, and ultrasound abnormalities. Schistosoma mansoni, STH, and malaria infection prevalence were 69%, 25%, and 8%, respectively. Only anemia and S. mansoni infection (adjusted odds ratio [aOR] = 1.70; confidence interval [CI] = 1.03-2.80), and hepatomegaly and heavy S. mansoni infection (aOR = 2.21; CI = 1.19-4.11) were associated. Though anemia and hepatomegaly appeared most useful at baseline, additional morbidity indicators may be sensitive longitudinal measures to evaluate schistosomiasis program health impact.

Regulation of telomere elongation by the cyclin-dependent kinase CDK1.

Telomere elongation is cell-cycle regulated and requires the coordinated activity of proteins involved in the DNA damage response. We used an assay that detects de novo telomere addition to examine the role of the cyclin-dependent kinase Cdk1 (Cdc28) in cell-cycle-specific telomere elongation. Inhibition of an ATP analog-sensitive allele of Cdk1 completely blocked the addition of telomere repeats. Mutations in Rif2 and DNA polymerase alpha that cause increased telomere elongation were unable to compensate for the loss of Cdk1 activity, suggesting Cdk1 activity is required for an early step in telomere addition. Mutations in DNA repair proteins that act with Cdk1 at double-strand breaks also prevented telomere elongation. Cdk1 activity was required for the generation of 3' single-strand overhangs at both native and de novo telomeres. We propose Cdk1 activity controls the timing of telomere elongation by regulating the single-strand overhang at chromosome ends.