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Major depressive disorder (MDD) is primarily treated with antidepressants, yet many patients fail to respond adequately, and identifying antidepressant response biomarkers is thus of clinical significance. Some hypothesis-driven investigations of epigenetic markers for treatment response have been previously made, but genome-wide approaches remain unexplored. Healthy participants (n = 112) and MDD patients (n = 211) between 18-60 years old were recruited for an 8-week trial of escitalopram treatment. Responders and non-responders were identified using differential Montgomery-Åsberg Depression Rating Scale scores before and after treatment. Genome-wide DNA methylation and gene expression analyses were assessed using the Infinium MethylationEPIC Beadchip and HumanHT-12 v4 Expression Beadchip, respectively, on pre-treatment peripheral blood DNA and RNA samples. Differentially methylated positions (DMPs) located in regions of differentially expressed genes between responders (n = 82) and non-responders (n = 95) were identified, and technically validated using a targeted sequencing approach. Three DMPs located in the genes CHN2 (cg23687322, p = 0.00043 and cg06926818, p = 0.0014) and JAK2 (cg08339825, p = 0.00021) were the most significantly associated with mRNA expression changes and subsequently validated. Replication was then conducted with non-responders (n = 76) and responders (n = 71) in an external cohort that underwent a similar antidepressant trial. One CHN2 site (cg06926818; p = 0.03) was successfully replicated. Our findings indicate that differential methylation at CpG sites upstream of the CHN2 and JAK2 TSS regions are possible peripheral predictors of antidepressant treatment response. Future studies can provide further insight on robustness of our candidate biomarkers, and greater characterization of functional components.

Objective: To report the symptomatic and functional outcomes in patients with major depressive disorder (MDD) during a 2-phase treatment trial and to estimate the value of early improvement after 2 weeks in predicting clinical response to escitalopram and subsequently to adjunctive treatment with aripiprazole., Methods: Participants with MDD (N = 211) identified with the Montgomery-Asberg Depression Rating Scale (MADRS) and confirmed with the Mini-International Neuropsychiatric Interview were recruited from 6 outpatient centers across Canada (August 2013 through December 2016) and treated with open-label escitalopram (10-20 mg) for 8 weeks (Phase 1). Clinical and functional outcomes were evaluated using the MADRS, Quick Inventory of Depressive Symptomatology-Self-Rated (QIDS-SR), Sheehan Disability Scale (SDS), and Lam Employment Absence and Productivity Scale (LEAPS). Participants were evaluated at 8 and 16 weeks for clinical and functional response and remission. Phase 1 responders continued escitalopram while nonresponders received adjunctive aripiprazole (2-10 mg) for a further 8 weeks (Phase 2)., Results: After Phase 1, MADRS response (≥ 50% decrease from baseline) and remission (score ≤ 10) were, respectively, 47% and 31%, and SDS response (score ≤ 12) and remission (score ≤ 6) were, respectively, 53% and 24%. Response to escitalopram was maintained in 91% of participants at week 16, while 61% of the adjunctive aripiprazole group achieved MADRS response during Phase 2. Response and remission rates with the QIDS-SR were lower than with the MADRS. The LEAPS demonstrated significant occupational improvement (P < .05). Early symptomatic improvement predicted outcomes with modest accuracy., Conclusions: This study demonstrates comparable symptomatic and functional outcomes to those of other large practical-design studies. There was a high response rate with the adjunctive use of aripiprazole in escitalopram nonresponders. Given the limited value of early clinical improvement to predict outcome, integration of clinical and biological markers deserves further exploration., Trial Registration: ClinicalTrials.gov identifier: NCT01655706., (© Copyright 2019 Physicians Postgraduate Press, Inc.)

Therapeutic seizures may work for treatment-resistant depression (TRD) by producing neuroplasticity. We evaluated whether magnetic seizure therapy (MST) produces changes in suicidal ideation and neuroplasticity as indexed through transcranial magnetic stimulation and electroencephalography (TMS-EEG) of the dorsolateral prefrontal cortex (DLPFC). Twenty-three patients with TRD were treated with MST. Changes in suicidal ideation was assessed through the Scale for Suicidal Ideation (SSI). Before and after the treatment course, neuroplasticity in excitatory and inhibitory circuits was assessed with TMS-EEG measures of cortical-evoked activity (CEA) and long-interval cortical inhibition (LICI) from the left DLPFC, and the left motor cortex as a control condition. As in our previous report, the relationship between TMS-EEG measures and suicidal ideation was examined with the SSI. Results show that 44.4% of patients experienced resolution of suicidal ideation. Based on DLPFC assessment, MST produced significant CEA increase over the frontal central electrodes (cluster p < 0.05), but did not change LICI on a group level. MST also reduced the SSI scores (p < 0.005) and the amount of reduction correlated with the decrease in LICI over the right frontal central electrodes (cluster p < 0.05; rho = 0.73 for Cz). LICI change identified patients who were resolved of suicidal ideation with 90% sensitivity and 88% specificity (AUC = 0.9, p = 0.004). There was no significant finding with motor cortex assessment. Overall, MST produced significant rates of resolution of suicidal ideation. MST also produced neuroplasticity in the frontal cortex, likely through long-term potentiation (LTP)-like mechanisms. The largest reduction in suicidal ideation was demonstrated in patients showing concomitant decreases in cortical inhibition-a mechanism linked to enhanced LTP-like plasticity. These findings provide insights into the mechanisms through which patients experience resolution of suicidal ideation following seizure treatments in depression.

Background: This study aims to compare the effectiveness of EEG frequency band activity including interhemispheric asymmetry and prefrontal theta cordance in predicting response to escitalopram therapy at 8-weeks post-treatment, in a multi-site initiative., Methods: Resting state 64-channel EEG data were recorded from 44 patients with a diagnosis of major depressive disorder (MDD) as part of a larger, multisite discovery study of biomarkers in antidepressant treatment response, conducted by the Canadian Biomarker Integration Network in Depression (CAN-BIND). Clinical response was measured at 8-weeks post-treatment as change from baseline Montgomery-Asberg Depression Rating Scale (MADRS) score of 50% or more. EEG measures were analyzed at (1) pre-treatment baseline (2) 2 weeks post-treatment and (3) as an ''early change" variable defined as change in EEG from baseline to 2 weeks post-treatment., Results: At baseline, treatment responders showed elevated absolute alpha power in the left hemisphere while non-responders showed the opposite. Responders further exhibited a cortical asymmetry in the parietal region. Groups also differed in pre-treatment relative delta power with responders showing greater power in the right hemisphere over the left while non-responders showed the opposite. At 2 weeks post-treatment, responders exhibited greater absolute beta power in the left hemisphere relative to the right and the opposite was noted for non-responders. A reverse pattern was noted for absolute and relative delta power at 2 weeks post-treatment. Responders exhibited early reductions in relative alpha power and early increments in relative theta power. Non-responders showed a significant early increase in prefrontal theta cordance., Conclusions: Hemispheric asymmetries in the alpha and delta bands at baseline and at 2 weeks post-treatment have moderately strong predictive utility in predicting response to antidepressant treatment., (Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.)

Background: Cholinergic dysfunction is increasingly assumed to be involved in the pathophysiology of schizophrenia. Short-latency afferent inhibition (SAI) is a transcranial magnetic stimulation (TMS) paradigm that has been shown to assay central cholinergic activity from the motor cortex (M1). Recently, we established a method to index SAI from the dorsolateral prefrontal cortex (DLPFC), an area implicated in the pathophysiology of schizophrenia. We investigated SAI in M1 and DLPFC in schizophrenia. We hypothesized that modulation of N100 on TMS-evoked potentials (TEPs) from the DLPFC would be attenuated in patients with schizophrenia compared to healthy controls., Methods: SAI was examined in 12 patients, whose age was matched to controls, using TMS combined with electroencephalography (EEG). SAI was recorded with TMS applied to left M1 (M1-SAI) and DLPFC (DLPFC-SAI). For group comparison, we used the SAI data of healthy participants in our previous study., Results: In patients, N100 TEP was significantly attenuated with DLPFC-SAI, whereas P180 TEP was significantly increased with M1-SAI. Between patients and controls, there were significant differences in modulation of P180 TEP by M1-SAI (t22 = -2.748, P = .012; patients > controls) and N100 TEP by DLPFC-SAI (t22 = 5.456, P < .0001; patients < controls). Further, modulation of N100 TEP by DLPFC-SAI significantly correlated with executive function (r = -.740, P = .006, N = 12)., Conclusion: Our findings suggest that DLPFC-SAI but not M1-SAI were reduced in patients with schizophrenia and this was linked to deficits in cognition. This may reflect prefrontal cholinergic deficits and represent a biomarker for cholinergic and executive dysfunction in patients with schizophrenia., (© The Author(s) 2017. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The neurobiological correlates of human fluid intelligence (Gf) remain elusive. Here, we demonstrate that spatiotemporal dynamics of EEG activity correlate with baseline measures of Gf and with its modulation by cognitive training. EEG dynamics were assessed in 74 healthy participants by examination of fast-changing, recurring, topographically-defined electric patterns termed "microstates", which characterize the electrophysiological activity of distributed cortical networks. We find that the frequency of appearance of specific brain topographies, spatially associated with visual (microstate B) and executive control (microstate C) networks, respectively, is inversely related to Gf scores. Moreover, changes in Gf scores with cognitive training are inversely correlated with changes in microstate properties, indicating that the changes in brain network dynamics are behaviorally relevant. Finally, we find that cognitive training that increases Gf scores results in a posterior shift in the topography of microstate C. These results highlight the role of fast-changing brain electrical states in individual variability in Gf and in the response to cognitive training.

An overly negative self-schema is a proposed cognitive mechanism of major depressive disorder (MDD). Self-schema - one's core conception of self, including how strongly one believes one possesses various characteristics - is part of semantic memory (SM), our knowledge about concepts and their relationships. We used the N400 event-related potential (ERP) - elicited by meaningful stimuli, and reduced by greater association of the stimulus with preceding context - to measure association strength between self-concept and positive, negative, and neutral characteristics in SM. ERPs were recorded from MDD patients (n=16) and controls (n=16) who viewed trials comprising a self-referential phrase followed by a positive, negative, or neutral adjective. Participants' task was to indicate via button-press whether or not they felt each adjective described themselves. Controls endorsed more positive adjectives than did MDD patients, but the opposite was true for negative adjectives. Patients had smaller N400s than controls specifically for negative adjectives, suggesting that MDD is associated with stronger than normal functional neural links between self-concept and negative characteristics in SM., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Gamma-aminobutyric acid (GABA)ergic and glutamatergic neurotransmissions in the prefrontal cortex decreases with age. Further, cognitive function mediated through the dorsolateral prefrontal cortex (DLPFC) also declines with age. Although neuroimaging studies have demonstrated decreased levels of these substances, direct neurophysiological data investigating the effect of aging in the DLPFC in human subjects is lacking. The advent of transcranial magnetic stimulation (TMS) combined with electroencephalography (EEG) has allowed for the assessment of functional neurotransmission in vivo. In the present study, we examined short interval intracortical inhibition (SICI) and intracortical facilitation (ICF) in a group of older adults (> 60 yrs) to evaluate the strength of GABA A and glutamate-mediated neurotransmission in the DLPFC, compared to younger adults (18-59 yrs). Older adults showed an increase of amplitude of N100 by the SICI paradigm, while N45 amplitude was increased and N100 amplitude was decreased by ICF. Moreover, these modulations significantly correlated with age. Our findings provide evidence for age-related alterations of excitatory and inhibitory functions in the prefrontal cortex in healthy adults. Future studies may aim to explore these neurophysiological relationships in the DLPFC in pathological forms of aging that affect cortical functioning such as mild cognitive impairment and Alzheimer's disease.

Short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF) are noninvasive transcranial magnetic stimulation (TMS) measures of GABA A receptor-mediated inhibition and glutamatergic excitatory transmission, respectively. Conventionally these measures have been restricted to the motor cortex. We investigated whether SICI and ICF could be recorded from the dorsolateral prefrontal cortex (DLPFC) using combined TMS and electroencephalography (TMS-EEG). We first characterized the neural signature of SICI and ICF in M1 in terms of TMS-evoked potentials (TEPs) and spectral power modulation. Subsequently, these paradigms were applied in the DLPFC to determine whether similar neural signatures were evident. With TMS at M1, SICI and ICF led to bidirectional modulation (inhibition and facilitation, respectively) of P30 and P60 TEP amplitude, which correlated with MEP amplitude changes. With DLPFC stimulation, P60 was bidirectionally modulated by SICI and ICF in the same manner as for M1 stimulation, whereas P30 was absent. The sole modulation of early TEP components is in contradistinction to other measures such as long-interval intracortical inhibition and may reflect modulation of short latency excitatory and inhibitory postsynaptic potentials (EPSPs and IPSPs). Overall, the data suggest that SICI and ICF can be recorded using TMS-EEG in DLPFC providing noninvasive measures of glutamatergic and GABA A receptor-mediated neurotransmission. This may facilitate future research attempting to ascertain the role of these neurotransmitters in the pathophysiology and treatment of neurological and psychiatric disorders.

Objective: Transcranial magnetic stimulation (TMS) is a non-invasive tool used for studying cortical excitability and plasticity in the human brain. This review aims to quantitatively synthesize the literature on age-related differences in cortical excitability and plasticity, examined by TMS., Methods: A literature search was conducted using MEDLINE, Embase, and PsycINFO from 1980 to December 2015. We extracted studies with healthy old (50-89years) versus young (16-49years) individuals that utilized the following TMS measures: resting motor threshold (RMT), short-interval cortical inhibition (SICI), short-latency afferent inhibition (SAI), cortical silent period (CSP), intracortical facilitation (ICF), and paired associative stimulation (PAS)., Results: We found a significant increase in RMT (g=0.414, 95% confidence interval (CI) [0.284, 0.544], p<0.001), a significant decrease in SAI (g=0.778, 95% CI [0.478, 1.078], p<0.001), and a trending decrease in LTP-like plasticity (g=-0.528, 95% CI [-1.157, 0.100] p<0.1) with age., Conclusions: Our findings suggest an age-dependent reduction in cortical excitability and sensorimotor integration within the human motor cortex., Significance: Alterations in the ability to regulate cortical excitability, sensorimotor integration and plasticity may underlie several age-related motor deficits., (Copyright © 2016 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

Bistable perception occurs when a stimulus is ambiguous and has two distinct interpretations that spontaneously alternate in observers' consciousness. Studies using functional magnetic resonance imaging, electroencephalography (EEG), and transcranial magnetic stimulation (TMS) in healthy subjects and patient studies point towards a right fronto-parietal network regulating the balance between percept stabilization and the arising of alternative interpretations. However, the causal role of the interaction between parietal and prefrontal areas is not clearly understood. Using intermittent presentations of bistable images, we confirmed that maintaining or switching percepts had neural correlates identifiable on EEG. Single-pulse TMS applied over the right anterior intraparietal sulcus (IPS) 70 msec before image presentation interfered with evoked potentials and destabilized the percept. However, with paired-pulse TMS applied over right IPS and dorsolateral prefrontal cortex (DLPFC) 70 and 60 msec before image presentation, both perceptual and neurophysiological effects were canceled. Thus, TMS over IPS and DLPFC interacted with each other and influenced upcoming percepts. We suggest that when the visual world is ambiguous, IPS plays a stabilizing role, whereas DLPFC is important for triggering perceptual switches or for modulating parietal activity. The balance between maintaining and switching visual conscious percepts relies on the dynamic interaction between IPS and DLPFC., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Brain oscillations are increasingly used for understanding complex psychiatric disorders. Gamma (30-50Hz) oscillations have warranted special attention due to their omnipresence in cognitive tasks. For patients with schizophrenia (SCZ), a disease associated with poor cognition, abnormal gamma oscillations have been reported in many experimental paradigms. The goal of this paper is to review the literature on gamma oscillations in SCZ. The review is structured into four sections. First, the functional role, neurobiology, and analysis of brain oscillations, especially gamma oscillations will be outlined. Second, the neurobiological abnormalities of SCZ in relation to gamma oscillations will be reviewed. Third, selected paradigms for investigating irregular gamma oscillations in SCZ will be discussed in detail. Finally, a discussion on the limitations of current findings and potential future research directions will be provided. The reviewed evidence suggests that gamma oscillations are disrupted in SCZ and could account for cognitive disturbances in this disorder. With additional analysis and experimentation, these indices may ultimately serve as endophenotypes that facilitate the development of etiologically based diagnostic methods, foster early identification and treatment, and advance our understanding of the complex genetic mechanisms involved in this disorder., (Copyright © 2011 Elsevier B.V. All rights reserved.)