publications

2025

1. In progress: Subgenual cingulate TMS-EEG response from dorsolateral prefrontal transcranial magnetic stimulation relates to the functional connectivity between the two regions in patients with treatment resistant depression

   Yinming Sun, Mohsen Poorganji, Emma Boyd, and 9 more authors

   Jan 2025

   Abs

   Introduction: Treatment resistant depression (TRD) is associated with an overactivation of the subgenual cingulate (SGC). Transcranial magnetic stimulation (TMS) delivered to the left dorsolateral prefrontal cortex (DLFPC) may achieve its antidepressant effect via transsynaptic activation of the SGC. While higher activation of the SGC by single pulse TMS -EEG assessed from the DLPFC is associated with worse depression, a more negative fMRI resting state functional connectivity (RSFC) between the DLPFC and SGC is associated with better TMS treatment outcomes. To reconcile previous findings, we wanted to determine how those two measures are related based on multimodal data from the same TRD patients. Methods: Baseline RSFC and TMS-EEG measures from 42 MDD patients enrolled in a course of individualized accelerated intermittent theta-burst stimulation (iTBS) treatment were analyzed. The RSFC was calculated between the individual treatment target and the SGC, while the cortical evoked activity (CEA) from 20 to 500 ms and the negative peak at 100 ms (N100) were calculated from the SGC source localized TMS evoked potential. Results: More negative RSFC between the DLPFC target and SGC was associated with a smaller N100 (i.e., less negative) (Spearman’s Rho = -0.37, Pval = 0.02) and a smaller CEA (Spearman’s Rho = 0.29, Pval = 0.07) at the SGC. Conclusion: A higher anticorrelation between the DLPFC and SGC may indicate a stronger inhibitory connection between the two that enables a TMS pulse delivered at the anticorrelated DLPFC region to better suppress excitatory and inhibitory activity at the SGC.

2. Relationship between TMS-EEG source activity in the subgenual cingulate following left dorsolateral prefrontal cortex stimulation and the resting state functional connectivity between the two regions

   Yinming Sun, Mohsen Poorganji, Emma Boyd, and 5 more authors

   Jan 2025

   Abs DOI

   Major depressive disorder (MDD) is a debilitating illness that affects nearly 20% of the US population. MDD has been associated with an overactivation of the subgenual cingulate (SGC), while effective treatments have been associated with a suppression of SGC activity. While treatments involving transcranial magnetic stimulation (TMS) of the left dorsolateral prefrontal cortex (LDLPFC) cannot directly activate the SGC, it has been postulated that part of the therapeutic effect is achieved via transsynaptic activation of the deeper SGC region. Support for this theory comes from both studies with fMRI-based resting-state functional connectivity (RSFC) and concurrent TMS and EEG (TMS-EEG) source activation. Indeed, it has been shown that stimulating the region of the LDLPFC that is most anticorrelated with the SGC based on individual pretreatment RSFC can lead to better treatment outcomes. At the same time, larger EEG based current density from the SGC following single TMS pulses before treatment has been shown to be correlated with better treatment outcomes. To reconcile the two supporting theories, baseline RSFC and TMS-EEG data from 50 MDD patients undergoing a course of accelerated intermittent theta burst (iTBS) treatment are analyzed. Single pulse TMS-EEG is assessed by stimulating the RSFC based treatment target, while the exact value of the RSFC between the SGC and LDLPFC are determined based on cortical regions activated above a certain electric field threshold. It is hypothesized that a stronger negative RSFC (i.e., anticorrelation) between the stimulation target and the SGC will result in a larger evoked current density in the region by single pulse TMS. If our hypothesis is correct, it would mean that the targeted region and the SGC are coupled through transsynaptic connections that rely on inhibitory synapses that suppress each other at rest while strengthening the transient neuronal synchronization resulting from an external stimulus (i.e., TMS pulse).

3. Accelerated Intermittent Theta-Burst Stimulation for Treatment-Resistant Bipolar Depression: A Randomized Clinical Trial

   Lawrence G. Appelbaum, Hadley Daniels, Liam Lochhead, and 6 more authors

   JAMA Network Open, Feb 2025

   DOI

2024

1. Stochastic Approximator of Motor Threshold for Transcranial Magnetic Stimulation (SAMT): Performance in Clinical Trials

   Boshuo Wang, Vedarsh Shah, Lari Koponen, and 15 more authors

   Neuromodec Journal, Oct 2024

   DOI

2023

1. Pre-Stimulus Power but Not Phase Predicts Prefrontal Cortical Excitability in TMS-EEG

   Mohsen Poorganji, Reza Zomorrodi, Christoph Zrenner, and 10 more authors

   Biosensors, Feb 2023

   Number: 2 Publisher: Multidisciplinary Digital Publishing Institute

   Abs DOI

   The cortical response to transcranial magnetic stimulation (TMS) has notable inter-trial variability. One source of this variability can be the influence of the phase and power of pre-stimulus neuronal oscillations on single-trial TMS responses. Here, we investigate the effect of brain oscillatory activity on TMS response in 49 distinct healthy participants (64 datasets) who had received single-pulse TMS over the left dorsolateral prefrontal cortex. Across all frequency bands of theta (4–7 Hz), alpha (8–13 Hz), and beta (14–30 Hz), there was no significant effect of pre-TMS phase on single-trial cortical evoked activity. After high-powered oscillations, whether followed by a TMS pulse or not, the subsequent activity was larger than after low-powered oscillations. We further defined a measure, corrected_effect, to enable us to investigate brain responses to the TMS pulse disentangled from the power of ongoing (spontaneous) oscillations. The corrected_effect was significantly different from zero (meaningful added effect of TMS) only in theta and beta bands. Our results suggest that brain state prior to stimulation might play some role in shaping the subsequent TMS-EEG response. Specifically, our findings indicate that the power of ongoing oscillatory activity, but not phase, can influence brain responses to TMS. Aligning the TMS pulse with specific power thresholds of an EEG signal might therefore reduce variability in neurophysiological measurements and also has the potential to facilitate more robust therapeutic effects of stimulation.

2. Magnetic seizure therapy and electroconvulsive therapy increase frontal aperiodic activity

   Sydney E. Smith, Eena L. Kosik, Quirine van Engen, and 6 more authors

   Jan 2023

   * Equal contribution

   Abs DOI

   Major depressive disorder (MDD) is a leading cause of disability worldwide. One of the most efficacious treatments for treatment-resistant MDD is electroconvulsive therapy (ECT). Recently, magnetic seizure therapy (MST) was developed as an alternative to ECT due to its more favorable side effect profile. While these approaches have been very successful clinically, the neural mechanisms underlying their therapeutic effects are unknown. For example, clinical “slowing” of the electroencephalogram has been observed in both treatment modalities. A recent longitudinal study of a small cohort of ECT patients revealed that observed clinical slowing was better explained by increases in frontal aperiodic activity, an emerging EEG signal linked to neural inhibition. Here we investigate the role of aperiodic activity in a cohort of patients who received ECT and a cohort of patients who received MST treatment. We find that across treatments, frontal aperiodic activity better explains increases in delta band power associated with clinical slowing, compared to delta oscillations. Increased aperiodic activity is also linked to therapeutic efficacy, which is suggestive of a potential shared neural mechanism of action across ECT and MST: an increase in frontal inhibitory activity.

3. Magnetic seizure therapy and electroconvulsive therapy increase aperiodic activity

   Sydney E. Smith, Eena L. Kosik, Quirine Engen, and 7 more authors

   Translational Psychiatry, Nov 2023

   * Equal contribution

   Abs DOI

   Major depressive disorder (MDD) is a leading cause of disability worldwide. One of the most efficacious treatments for treatment-resistant MDD is electroconvulsive therapy (ECT). Recently, magnetic seizure therapy (MST) was developed as an alternative to ECT due to its more favorable side effect profile. While these approaches have been very successful clinically, the neural mechanisms underlying their therapeutic effects are unknown. For example, clinical “slowing” of the electroencephalogram beginning in the postictal state and extending days to weeks post-treatment has been observed in both treatment modalities. However, a recent longitudinal study of a small cohort of ECT patients revealed that, rather than delta oscillations, clinical slowing was better explained by increases in aperiodic activity, an emerging EEG signal linked to neural inhibition. Here we investigate the role of aperiodic activity in a cohort of patients who received ECT and a cohort of patients who received MST treatment. We find that aperiodic neural activity increases significantly in patients receiving either ECT or MST. Although not directly related to clinical efficacy in this dataset, increased aperiodic activity is linked to greater amounts of neural inhibition, which is suggestive of a potential shared neural mechanism of action across ECT and MST.

4. EEG microstates in early-to-middle childhood show associations with age, biological sex, and alpha power

   Aron T. Hill, Neil W. Bailey, Reza Zomorrodi, and 5 more authors

   Human Brain Mapping, Nov 2023

   Number: 18 _eprint: https://onlinelibrary.wiley.com/doi/pdf/10.1002/hbm.26525

   Abs DOI

   Electroencephalographic (EEG) microstates can provide a unique window into the temporal dynamics of large-scale brain networks across brief (millisecond) timescales. Here, we analysed fundamental temporal features of microstates extracted from the broadband EEG signal in a large (N = 139) cohort of children spanning early-to-middle childhood (4–12 years of age). Linear regression models were used to examine if participants’ age and biological sex could predict the temporal parameters GEV, duration, coverage, and occurrence, for five microstate classes (A–E) across both eyes-closed and eyes-open resting-state recordings. We further explored associations between these microstate parameters and posterior alpha power after removal of the 1/f-like aperiodic signal. The microstates obtained from our neurodevelopmental EEG recordings broadly replicated the four canonical microstate classes (A to D) frequently reported in adults, with the addition of the more recently established microstate class E. Biological sex served as a significant predictor in the regression models for four of the five microstate classes (A, C, D, and E). In addition, duration and occurrence for microstate E were both found to be positively associated with age for the eyes-open recordings, while the temporal parameters of microstates C and E both exhibited associations with alpha band spectral power. Together, these findings highlight the influence of age and sex on large-scale functional brain networks during early-to-middle childhood, extending understanding of neural dynamics across this important period for brain development.

5. Isolating sensory artifacts in the suprathreshold TMS-EEG signal over DLPFC

   Mohsen Poorganji, Reza Zomorrodi, Colin Hawco, and 8 more authors

   Scientific Reports, Apr 2023

   Abs DOI

   Combined transcranial magnetic stimulation and electroencephalography (TMS-EEG) is an effective way to evaluate neurophysiological processes at the level of the cortex. To further characterize the TMS-evoked potential (TEP) generated with TMS-EEG, beyond the motor cortex, we aimed to distinguish between cortical reactivity to TMS versus non-specific somatosensory and auditory co-activations using both single-pulse and paired-pulse protocols at suprathreshold stimulation intensities over the left dorsolateral prefrontal cortex (DLPFC). Fifteen right-handed healthy participants received six blocks of stimulation including single and paired TMS delivered as active-masked (i.e., TMS-EEG with auditory masking and foam spacing), active-unmasked (TMS-EEG without auditory masking and foam spacing) and sham (sham TMS coil). We evaluated cortical excitability following single-pulse TMS, and cortical inhibition following a paired-pulse paradigm (long-interval cortical inhibition (LICI)). Repeated measure ANOVAs revealed significant differences in mean cortical evoked activity (CEA) of active-masked, active-unmasked, and sham conditions for both the single-pulse (F(1.76, 24.63) = 21.88, p \textless 0.001, η2 = 0.61) and LICI (F(1.68, 23.49) = 10.09, p \textless 0.001, η2 = 0.42) protocols. Furthermore, global mean field amplitude (GMFA) differed significantly across the three conditions for both single-pulse (F(1.85, 25.89) = 24.68, p \textless 0.001, η2 = 0.64) and LICI (F(1.8, 25.16) = 14.29, p \textless 0.001, η2 = 0.5). Finally, only active LICI protocols but not sham stimulation ([active-masked (0.78 ± 0.16, P \textless 0.0001)], [active-unmasked (0.83 ± 0.25, P \textless 0.01)]) resulted in significant signal inhibition. While previous findings of a significant somatosensory and auditory contribution to the evoked EEG signal are replicated by our study, an artifact attenuated cortical reactivity can reliably be measured in the TMS-EEG signal with suprathreshold stimulation of DLPFC. Artifact attenuation can be accomplished using standard procedures, and even when masked, the level of cortical reactivity is still far above what is produced by sham stimulation. Our study illustrates that TMS-EEG of DLPFC remains a valid investigational tool.

6. Masking sensory artifacts in single and paired-pulse suprathreshold TMS-EEG of DLPFC

   Mohsen Poorganji, Reza Zomorrodi, Colin Hawco, and 7 more authors

   Brain Stimulation: Basic, Translational, and Clinical Research in Neuromodulation, Apr 2023

2022

1. Dose-response of intermittent theta burst stimulation of the prefrontal cortex: A TMS-EEG study

   Manon Desforges, Itay Hadas, Brian Mihov, and 8 more authors

   Clinical Neurophysiology, Jan 2022

   Abs DOI

   Objective Using concurrent transcranial magnetic stimulation (TMS) and electroencephalography (TMS-EEG), this study aims to compare the effect of three intermittent theta-burst stimulation (iTBS) doses on cortical activity in the left dorsolateral prefrontal (DLPFC) cortex. Methods Fourteen neurotypical participants took part in the following three experimental conditions: 600, 1200 and 1800 pulses. TMS-EEG recordings were conducted on the left DLPFC pre/post iTBS, including single-pulse TMS and short- and long-interval intracortical inhibition (SICI, LICI). TMS-evoked potentials (TEP) and event-related spectral perturbation (ERSP) were quantified. Linear mixed models were used to assess the effect of iTBS on brain activity. Results The effects of iTBS on DLPFC activity did not significantly differ between the three doses. Specifically, regardless of dose, iTBS modulated the amplitude of most TEP components (P30, N45, P60, P200), reduced SICI and LICI ratios of P30 and P200, and decreased ERSP power of theta oscillations. Conclusions In neurotypical individuals, doubling or tripling the number of iTBS pulses does not result in stronger potentiation of prefrontal activity. However, all iTBS conditions induced significant modulations of DLPFC activity. Significance Replicating the study in clinical populations could help define optimal parameters for clinical applications.

2021

1. Variability in TMS-EEG response can partially be described by the phase of ongoing brain oscillation

   Mohsen Poorganji, Reza Zomorrodi, Colin Hawco, and 7 more authors

   Nov 2021

   0 citations (Crossref) [2021-11-24]

   DOI
2. Confirmatory Efficacy and Safety Trial of Magnetic Seizure Therapy for Depression (CREST-MST): protocol for identification of novel biomarkers via neurophysiology

   Zafiris J. Daskalakis, Shawn M. McClintock, Itay Hadas, and 8 more authors

   Trials, Dec 2021

   0 citations (Crossref) [2021-12-12] Number: 1 Publisher: BioMed Central

   Abs DOI

   Electroconvulsive therapy (ECT) is the most effective treatment for treatment-resistant depression (TRD), especially for acute suicidal ideation, but the associated cognitive adverse effects and negative stigma limit its use. Another seizure therapy under development is magnetic seizure therapy (MST), which could potentially overcome the restrictions associated with ECT with similar efficacy. The neurophysiological targets and mechanisms of seizure therapy, however, remain poorly understood. This neurophysiological study protocol is published as a companion to the overall Confirmatory Efficacy and Safety Trial of Magnetic Seizure Therapy for Depression (CREST-MST) protocol that describes our two-site, double-blind, randomized, non-inferiority clinical trial to develop MST as an effective and safe treatment for TRD. Our aim for the neurophysiological component of the study is to evaluate two biomarkers, one to predict remission of suicidal ideation (primary outcome) and the other to predict cognitive impairment (secondary outcome). Suicidal ideation will be assessed through cortical inhibition, which according to our preliminary studies, correlates with remission of suicidal ideation. Cortical inhibition will be measured with simultaneous transcranial magnetic stimulation (TMS) and electroencephalography (EEG), TMS-EEG, which measures TMS-evoked EEG activity. Cognitive adverse effects associated with seizure therapy, on the contrary, will be evaluated via multiscale entropy analysis reflecting the complexity of ongoing resting-state EEG activity. ECT and MST are known to influence cortical inhibition associated with depression, suicidal ideation severity, and clinical outcome. Therefore, evaluating cortical inhibition and brain temporal dynamics will help understand the pathophysiology of depression and suicidal ideation and define new biological targets that could aid clinicians in diagnosing and selecting treatments. Resting-state EEG complexity was previously associated with the degree of cognitive side effects after a seizure therapy. This neurophysiological metric may help clinicians assess the risk for adverse effects caused by these useful and effective treatments. ClinicalTrials.gov NCT03191058 . Registered on June 19, 2017.

3. Altered interhemispheric signal propagation in schizophrenia and depression

   Jeanette Hui, Reza Zomorrodi, Pantelis Lioumis, and 7 more authors

   Clinical Neurophysiology, Apr 2021

   Abs DOI

   Objective Altered interhemispheric connectivity is implicated in the pathophysiology of schizophrenia (SCZ) and major depressive disorder (MDD) and may account for deficits in lateralized cognitive processes. We measured transcranial magnetic stimulation evoked interhemispheric signal propagation (ISP), a non-invasive measure of transcallosal connectivity, and hypothesized that the SCZ and MDD groups will have increased ISP compared to healthy controls. Methods We evaluated ISP over the dorsolateral prefrontal cortex in 34 patients with SCZ and 34 patients with MDD compared to 32 age and sex-matched healthy controls. Results ISP was significantly increased in patients with SCZ and patients with MDD compared to healthy controls but did not differ between patient groups. There were no effects of antidepressant, antipsychotic, and benzodiazepine medications on ISP and our results remained unchanged after re-analysis with a region of interest method. Conclusion Altered ISP was found in both SCZ and MDD patient groups. This indicates that disruptions of interhemispheric signaling processes can be indexed with ISP across psychiatric populations. Significance These findings enhance our knowledge of the physiological mechanisms of interhemispheric imbalances in SCZ and MDD, which may serve as potential treatment targets in future patients.

4. Characterizing Cortical Oscillatory Responses in Major Depressive Disorder Before and After Convulsive Therapy: A TMS-EEG Study

   Aron T. Hill, Itay Hadas, Reza Zomorrodi, and 4 more authors

   Journal of Affective Disorders, May 2021

   Abs DOI

   Background Combined transcranial magnetic stimulation and electroencephalography (TMS-EEG) is emerging as a powerful technique for interrogating neural circuit dysfunction in psychiatric disorders. Here, we utilized time-frequency analyses to characterize differences in neural oscillatory dynamics between subjects with major depressive disorder (MDD) and healthy controls (HC). We further examined changes in TMS-related oscillatory power following convulsive therapy. Methods Oscillatory power was examined following TMS over the dorsolateral prefrontal and motor cortices (DLPFC and M1) in 38 MDD subjects, and 22 HCs. We further investigated how these responses changed in the MDD group following an acute course of convulsive therapy (either magnetic seizure therapy [MST, n = 24] or electroconvulsive therapy [ECT, n = 14]). Results Prior to treatment, MDD subjects exhibited increased oscillatory power within delta, theta, and alpha frequency bands with TMS-EEG over the DLPFC, but showed no differences to HCs with stimulation over M1. Following MST, DLPFC stimulation revealed attenuated baseline-normalized power in the delta and theta bands, with reductions in the delta, theta, and alpha power following ECT. TMS over M1 revealed reduced delta and theta power following ECT, with no changes observed following MST. An association was also observed between the treatment- induced change in alpha power and depression severity score. Limitations Limitations include the modest sample size, open-label MST and ECT treatment designs, and lack of a placebo condition. Conclusions These results provide evidence of alterations in TMS-related oscillatory activity in MDD, and further suggest modulation of oscillatory power following ECT and MST.

5. Differentiating transcranial magnetic stimulation cortical and auditory responses via single pulse and paired pulse protocols: A TMS-EEG study

   Mohsen Poorganji, Reza Zomorrodi, Colin Hawco, and 8 more authors

   Clinical Neurophysiology, Aug 2021

   Number: 8 0 citations (Crossref) [2021-06-20]

   Abs DOI

   Objective We measured the neurophysiological responses of both active and sham transcranial magnetic stimulation (TMS) for both single pulse (SP) and paired pulse (PP; long interval cortical inhibition (LICI)) paradigms using TMS-EEG (electroencephalography). Methods Nineteen healthy subjects received active and sham (coil 90° tilted and touching the scalp) SP and PP TMS over the left dorsolateral prefrontal cortex (DLPFC). We measured excitability through SP TMS and inhibition (i.e., cortical inhibition (CI)) through PP TMS. Results Cortical excitability indexed by area under the curve (AUC(25-275ms)) was significantly higher in the active compared to sham stimulation (F(1,18) = 43.737, p \textless 0.001, η2 = 0.708). Moreover, the amplitude of N100-P200 complex was significantly larger (F(1,18) = 9.118, p \textless 0.01, η2 = 0.336) with active stimulation (10.38 ± 9.576 µV) compared to sham (4.295 ± 2.323 µV). Significant interaction effects were also observed between active and sham stimulation for both the SP and PP (i.e., LICI) cortical responses. Finally, only active stimulation (CI = 0.64 ± 0.23, p \textless 0.001) resulted in significant cortical inhibition. Conclusion The significant differences between active and sham stimulation in both excitatory and inhibitory neurophysiological responses showed that active stimulation elicits responses from the cortex that are different from the non-specific effects of sham stimulation. Significance Our study reaffirms that TMS-EEG represents an effective tool to evaluate cortical neurophysiology with high fidelity.

6. Right prefrontal activation predicts ADHD and its severity: A TMS-EEG study in young adults

   Itay Hadas, Aviad Hadar, Avi Lazarovits, and 2 more authors

   Progress in Neuro-Psychopharmacology and Biological Psychiatry, Dec 2021

   Abs DOI

   Objective Here we bring a neurophysiological diagnostic tool, based on pathophysiologically-relevant brain region, that is critical for reducing the variability between clinicians, and necessary for quantitative measures of ADHD severity. Methods 54 healthy and 57 ADHD adults participated in the study. Electroencephalography (EEG) was recorded when combined with transcranial magnetic stimulation (TMS) over the right prefrontal cortex and also recorded during the Stop Signal task. Results TMS evoked potentials (TEPs) and the event related potential (ERP) components in the Stop Signal task were found to be significantly reduced in ADHD relative to the matched healthy controls. Stop signal reaction time (SSRT) and stopping accuracy was found to correlate with the ERP signal, and ADHD severity correlated with the TEP signal. Cortical activity (early TEP and Stop Signal ERP) diagnostic model yielded accuracy of 72%. Conclusion TEPs and ERPs reveal that right PFC excitability was associated with ADHD severity, and with behavioral impulsivity – as a hallmark of ADHD pathology. This electrophysiological biomarker supports the potential of objective diagnosis for ADHD. Significance Such tools would allow better assessment of treatment efficacy and prognosis, may advance understanding of the pathophysiology of the disease and better the public’s attitudes and stigma towards ADHD. Trial Registration: Trial to Evaluate the Efficacy of the HLPFC Coil Deep Transcranial Magnetic Stimulation System in Treating Attention Deficit and Hyperactivity Disorder (ADHD) in Adults, https://clinicaltrials.gov/ct2/show/NCT01737476, ClinicalTrials.gov number NCT01737476

7. Predictors of change in suicidal ideation across treatment phases of major depressive disorder: analysis of the STAR*D data

   Cory R. Weissman, Itay Hadas, Dengdeng Yu, and 5 more authors

   Neuropsychopharmacology, Jan 2021

   Publisher: Nature Publishing Group

   Abs DOI

   The effects of common antidepressants on suicidal ideation (SI) is unclear. In the landmark STAR*D trial antidepressants were effective for Major Depressive Disorder (MDD) in early treatment phases, but less effective in later phases. The effects of antidepressants on SI across the entire sample of the STAR*D trial has never been investigated. We performed a secondary analysis of the STAR*D data with the primary outcome of change in score on the suicide item (item three) of the Hamilton Rating Scale for Depression (HRSD17) across all four study levels. We used descriptive statistics and logistic regression analyses. Pearson correlation was used for change in SI versus change in depression (HRSD16). Reduction in mean (SD) SI was greater in levels one: 0.29 (±0.78) (p \textless 0.001) and two: 0.26 (±0.88) (p \textless 0.001) than in levels three: 0.16 (±0.92) (p = 0.005) and four: 0.18 (±0.93) (p = 0.094). A history of past suicide attempts (OR 1.72, p = 0.007), comorbid medical illness (OR 2.23, p = 0.005), and a family history of drug abuse (OR 1.69, p = 0.008) were correlated with worsening of SI across level one. Treatment with bupropion (OR 0.24, p \textless 0.001) or buspirone (OR 0.24, p = 0.001) were correlated with lowering of SI across level two. Improvement in SI was correlated with improvement in overall depression (HRSD16) at level one: r(3756) = 0.48; level two: r(1027) = 0.38; level three: r(249) = 0.31; and level four: r(75) = 0.42 (p \textless 0.001 for all levels). Improvement in SI is limited with pharmacotherapy in patients with treatment-resistant depression. Treatments with known anti-suicidal effects in MDD, such as ECT, should be considered in these patients.

2020

1. Subgenual cingulate connectivity and hippocampal activation are related to MST therapeutic and adverse effects

   Itay Hadas, Reza Zomorrodi, Aron T. Hill, and 4 more authors

   Translational Psychiatry, Nov 2020

   Number: 1 Publisher: Nature Publishing Group

   Abs DOI

   Aberrant connectivity between the dorsolateral prefrontal cortex (DLPFC) and the subgenual cingulate cortex (SGC) has been linked to the pathophysiology of depression. Indirect evidence also links hippocampal activation to the cognitive side effects of seizure treatments. Magnetic seizure therapy (MST) is a novel treatment for patients with treatment resistant depression (TRD). Here we combine transcranial magnetic stimulation with electroencephalography (TMS-EEG) to evaluate the effects of MST on connectivity and activation between the DLPFC, the SGC and hippocampus (Hipp) in patients with TRD. The TMS-EEG was collected from 31 TRD patients prior to and after an MST treatment trial. Through TMS-EEG methodology we evaluated significant current scattering (SCS) as an index of effective connectivity between the SGC and left DLPFC. Significant current density (SCD) was used to assess activity at the level of the Hipp. The SCS between the SGC and DLPFC was reduced after the course of MST (p \textless 0.036). The DLPFC-SGC effective connectivity reduction correlated with the changes in Hamilton depression score pre-to-post treatment (R = 0.46; p \textless 0.031). The SCD localized to the Hipp was reduced after the course of MST (p \textless 0.015), and the SCD change was correlated with montreal cognitive assessment (MOCA) scores pre-post the course of MST (R = −0.59; p \textless 0.026). Our findings suggest that MST treatment is associated with SGC-DLPFC connectivity reduction and that changes to cognition are associated with Hipp activation reduction. These findings demonstrate two distinct processes which drive efficacy and side effects separately, and might eventually aid in delineating physiological TRD targets in clinical settings.

2. Modulation of functional network properties in major depressive disorder following electroconvulsive therapy (ECT): a resting-state EEG analysis

   Aron T. Hill, Itay Hadas, Reza Zomorrodi, and 5 more authors

   Scientific Reports, Oct 2020

   Abs DOI

   Electroconvulsive therapy (ECT) is a highly effective neuromodulatory intervention for treatment-resistant major depressive disorder (MDD). Presently, however, understanding of its neurophysiological effects remains incomplete. In the present study, we utilised resting-state electroencephalography (RS-EEG) to explore changes in functional connectivity, network topology, and spectral power elicited by an acute open-label course of ECT in a cohort of 23 patients with treatment-resistant MDD. RS-EEG was recorded prior to commencement of ECT and again within 48 h following each patient’s final treatment session. Our results show that ECT was able to enhance connectivity within lower (delta and theta) frequency bands across subnetworks largely confined to fronto-central channels, while, conversely, more widespread subnetworks of reduced connectivity emerged within faster (alpha and beta) bands following treatment. Graph-based topological analyses revealed changes in measures of functional segregation (clustering coefficient), integration (characteristic path length), and small-world architecture following ECT. Finally, post-treatment enhancement of delta and theta spectral power was observed, which showed a positive association with the number of ECT sessions received. Overall, our findings indicate that RS-EEG can provide a sensitive measure of dynamic neural activity following ECT and highlight network-based analyses as a promising avenue for furthering mechanistic understanding of the effects of convulsive therapies.

3. Resting-state electroencephalographic functional network alterations in major depressive disorder following magnetic seizure therapy

   Aron T. Hill, Reza Zomorrodi, Itay Hadas, and 6 more authors

   Progress in Neuro-Psychopharmacology and Biological Psychiatry, Aug 2020

   Abs DOI

   Magnetic seizure therapy (MST) is emerging as a safe and well-tolerated experimental intervention for major depressive disorder (MDD), with very minimal cognitive side-effects. However, the underlying mechanism of action of MST remains uncertain. Here, we used resting-state electroencephalography (RS-EEG) to characterise the physiological effects of MST for treatment resistant MDD. We recorded RS-EEG in 21 patients before and after an open label trial of MST applied over the prefrontal cortex using a bilateral twin coil. RS-EEG was analysed for changes in functional connectivity, network topology, and spectral power. We also ran further baseline comparisons between the MDD patients and a cohort of healthy controls (n = 22). Network-based connectivity analysis revealed a functional subnetwork of significantly increased theta connectivity spanning frontal and parieto-occipital channels following MST. The change in theta connectivity was further found to predict clinical response to treatment. An additional widespread subnetwork of reduced beta connectivity was also elucidated. Graph-based topological analyses showed an increase in functional network segregation and reduction in integration in the theta band, with a decline in segregation in the beta band. Finally, delta and theta power were significantly elevated following treatment, while gamma power declined. No baseline differences between MDD patients and healthy subjects were observed. These results highlight widespread changes in resting-state brain dynamics following a course of MST in MDD patients, with changes in theta connectivity providing a potential physiological marker of treatment response. Future prospective studies are required to confirm these initial findings.

2019

1. Association of Repetitive Transcranial Magnetic Stimulation Treatment With Subgenual Cingulate Hyperactivity in Patients With Major Depressive Disorder: A Secondary Analysis of a Randomized Clinical Trial

   Itay Hadas, Yinming Sun, Pantelis Lioumis, and 7 more authors

   JAMA Network Open, Jun 2019

   Number: 6 15 citations (Crossref) [2021-06-13]

   Abs DOI

   Importance: Hyperactivity in the subgenual cingulate cortex (SGC) is associated with major depressive disorder (MDD) and anticorrelated with activity in the dorsolateral prefrontal cortex (DLPFC). This association was found to be predictive of responsiveness to repetitive transcranial magnetic stimulation (rTMS) treatment. Such findings suggest that DLPFC-SGC connectivity is important for understanding both the therapeutic mechanism of rTMS in patients with MDD and the underlying pathophysiology of MDD. Objective: To evaluate SGC hyperactivity in patients with MDD before and after rTMS treatment. Design, Setting, and Participants In this diagnostic study, among participants recruited from the adult and geriatric mood and anxiety services at the Centre for Addiction and Mental Health, Toronto, Ontario, Canada, who had participated in a randomized clinical trial, baseline SGC activity of patients with MDD was compared with healthy controls. In patients with MDD, SGC activity was compared before and after active or sham high-frequency rTMS treatment. Data collection started in July 2008 and concluded in March 2012. Neurophysiological data analysis started in January 2017 and ended in May 2018. Main Outcomes and Measures Hyperactivity in the SGC before and after rTMS treatment was measured. Subgenual cingulate cortex hyperactivity activity was quantified using significant current density (SCD), and effective connectivity between the left DLPFC and SGC was computed using significant current scattering (SCS). Both measures were computed around TMS evoked potentials standard peak latencies prior to rTMS and after rTMS treatment, comparing patients with MMD treated with active and sham rTMS. Patients with MDD were assessed with the 17-item Hamilton Rating Scale for Depression. Results: Of 121 patients with MDD in the initial trial, 30 (15 [50.0%] women) were compared with 30 healthy controls (15 [50.0%] women) at rTMS treatment baseline. The mean (SD) age of the cohort with MDD was 39.1 (10.9) years, and the mean (SD) age of healthy controls was 37.0 (11.0) years. Following rTMS treatment, 26 patients with MDD who had active rTMS treatment (21.5%) were compared with 17 patients with MDD who had sham treatment (14.0%). At baseline, the SGC mean (SD) SCD and mean (SD) SCS at 200 milliseconds after TMS pulse were higher in participants with MDD compared with healthy controls (SCD: 1.04 × 10−6 [1.41 × 10−6] μA/mm2 vs 3.8 × 10−7 [7.8 × 10−7] μA/mm2; z = –2.95; P = .004; SCS: 0.87 [0.86] mm vs 0.54 [0.87] mm; z = –2.27; P = .02). Baseline source current density was able to classify MDD with 77% accuracy. Scores on the 17-item Hamilton Rating Scale for Depression were correlated with current density at the SGC (ρ = 0.41; P = .03). After rTMS treatment, SGC mean (SD) SCD and mean (SD) SCS at 200 milliseconds after rTMS pulse were attenuated to approximately the standard TMS-evoked potential latencies in the active rTMS group compared with the sham rTMS group (SCD: 1.57 × 10−7 [3.67 × 10−7] μA/mm2 vs 7.00 × 10−7 [7.51 × 10−7] μA/mm2; z = −2.91; P = .004; SCS: 0.20 [0.44] mm vs 0.74 [0.73] mm; z = −2.78; P = .006). Additionally, the SGC SCS change was correlated with symptom improvement on the 17-item Hamilton Rating Scale for Depression in the active rTMS group (ρ = 0.58; P = .047). Conclusions and Relevance: The findings of this study further implicate left DLPFC-SGC effective connectivity and SGC excitability in the pathophysiology of MDD and treatment with rTMS. These findings suggest that DLPFC-SGC connectivity may be a marker of rTMS treatment responsiveness. Trial Registration: ClinicalTrials.gov identifier: NCT01515215

2. Hyperactivation of the Subgenual Cingulate in Depressed Patients that is normalized with rTMS treatment

   I. Hadas, D. Blumberger, and Z. Daskalakis

   Brain Stimulation: Basic, Translational, and Clinical Research in Neuromodulation, Mar 2019

   Number: 2

   Abs DOI

   Background:Hyperactivity in the subgenual cingulate (SGC) has been demonstrated in major depressive disorder (MDD). These findings suggest that the DLPFC-SGC connectivity is important for understanding the rTMS therapeutic mechanism in MDD, and MDD pathophysiology in general.

2018

1. Combined Transcranial Magnetic Stimulation and Electroencephalography of the Dorsolateral Prefrontal Cortex

   Pantelis Lioumis, Reza Zomorrodi, Itay Hadas, and 2 more authors

   JoVE (Journal of Visualized Experiments), Aug 2018

   Number: 138

   Abs DOI

   Transcranial magnetic stimulation (TMS) is a non-invasive method that produces neural excitation in the cortex by means of brief, time-varying magnetic field pulses. The initiation of cortical activation or its modulation depends on the background activation of the neurons of the cortical region activated, the characteristics of the coil, its position and its orientation with respect to the head. TMS combined with simultaneous electrocephalography (EEG) and neuronavigation (nTMS-EEG) allows for the assessment of cortico-cortical excitability and connectivity in almost all cortical areas in a reproducible manner. This advance makes nTMS-EEG a powerful tool that can accurately assess brain dynamics and neurophysiology in test-retest paradigms that are required for clinical trials. Limitations of this method include artifacts that cover the initial brain reactivity to stimulation. Thus, the process of removing artifacts may also extract valuable information. Moreover, the optimal parameters for dorsolateral prefrontal (DLPFC) stimulation are not fully known and current protocols utilize variations from the motor cortex (M1) stimulation paradigms. However, evolving nTMS-EEG designs hope to address these issues. The protocol presented here introduces some standard practices for assessing neurophysiological functioning from stimulation to the DLPFC that can be applied in patients with treatment resistant psychiatric disorders that receive treatment such as transcranial direct current stimulation (tDCS), repetitive transcranial magnetic stimulation (rTMS), magnetic seizure therapy (MST) or electroconvulsive therapy (ECT).

2017

1. Answering the missed call: Initial exploration of cognitive and electrophysiological changes associated with smartphone use and abuse

   Aviad Hadar, Itay Hadas, Avi Lazarovits, and 3 more authors

   PLOS ONE, Jul 2017

   Number: 7

   Abs DOI

   Background Smartphone usage is now integral to human behavior. Recent studies associate extensive usage with a range of debilitating effects. We sought to determine whether excessive usage is accompanied by measurable neural, cognitive and behavioral changes. Method Subjects lacking previous experience with smartphones (n = 35) were compared to a matched group of heavy smartphone users (n = 16) on numerous behavioral and electrophysiological measures recorded using electroencephalogram (EEG) combined with transcranial magnetic stimulation (TMS) over the right prefrontal cortex (rPFC). In a second longitudinal intervention, a randomly selected sample of the original non-users received smartphones for 3 months while the others served as controls. All measurements were repeated following this intervention. Results Heavy users showed increased impulsivity, hyperactivity and negative social concern. We also found reduced early TMS evoked potentials in the rPFC of this group, which correlated with severity of self-reported inattention problems. Heavy users also obtained lower accuracy rates than nonusers in a numerical processing. Critically, the second part of the experiment revealed that both the numerical processing and social cognition domains are causally linked to smartphone usage. Conclusion Heavy usage was found to be associated with impaired attention, reduced numerical processing capacity, changes in social cognition, and reduced right prefrontal cortex (rPFC) excitability. Memory impairments were not detected. Novel usage over short period induced a significant reduction in numerical processing capacity and changes in social cognition.

2016

1. Exposure to salient, dynamic sensory stimuli during development increases distractibility in adulthood

   Itay Hadas, Ram Gal, Lihi Bokovza, and 3 more authors

   Scientific Reports, Feb 2016

   Abs DOI

   It has been suggested that excessive exposure of children to the dynamic and highly salient audio-visual stimuli conveyed by electronic media may induce attention-related deficits in adulthood.

2. Long-lasting attentional impairments induced by sensory loading

   Itay Hadas

   Feb 2016

   Abs

   Executive functions are considered to be mostly heritable psychological traits (Engelhardt et al., 2015; Friedman et al., 2008). Throughout the lifespan, executive functions can be acutely affected by distracting environmental settings, but evidence that correlates non-aversive, chronic, and exogenic stimuli to long-term effects on these functions is scarce. Such observations are of great importance because the modern environment surrounds us with pervasive and salient stimuli in the form of electronic media (e.g., television, smartphones, etc.), which can continuously grab or distract our attention. As such, this phenomenon requires new experimental approaches that will enable researchers to determine a causal link between electronic media exposure and impairments of executive functions. The aim of this thesis is to actualize that by establishing a novel animal model and to manipulate human volunteers in the attempt to draw a causal link between attentional modifications and chronic exposure to attention-grabbing stimuli. Animal arm: Most of the scientific work involving animal models for attentional impairments explores the neurophysiological mechanisms underlying attention. Those studies usually employ an invasive physiological, genetic, or pharmacological manipulation, which are means that do not accurately model the etiology of human attentional impairments. As such, a novel animal model that adequately models human attention-related deficits and disorders is needed. To that end, I developed an animal model where long-lasting attentional impairments were induced by applying excessive olfactory stimulation (“sensory loading”) to young rats. The stimuli used were non-aversive, dynamic, salient, and ecologically relevant, especially in the context of the digital media in the modern environment (taking into account that rats rely mostly on olfaction, like humans rely on vision). The model was developed based on studies in which children exposed to “fast- paced” electronic media at young ages demonstrated attentional deficits later in life. By using this novel animal model in a tightly controlled set-up, I found that rats exposed to developmental, dynamic, and salient stimulation (DDSS) demonstrated altered behavior in a 5-choice serial reaction time task (5-CSRTT) apparatus. Initially, I found that the DDSS group demonstrated higher approaching behavior toward the reward chamber. Thereafter, during training, the performances of the DDSS group was better than that of the control group; but this effect was reversed during the distractibility tests, in which the DDSS group demonstrated reduced and more variable performance. At the anatomical-molecular level, I found that brain-derived neurotrophic factor (BDNF) levels in the dorsal striatum of the DDSS rats were significantly higher than that of the control rats. BDNF is a necessary signaling protein in many cognitive functions and is considered to be a reliable proxy for many forms of neuronal plasticity. The animal data provide empirical evidence that a continuous exposure to dynamic, salient stimuli has a long-term influence over attentional functions in adulthood and that this effect may be mediated by neurochemical alterations in the dorsal striatum. Taken together, the animal findings suggest an altered attribution of incentive saliency, a cognitive mechanism that is believed to be tightly related to ADHD symptomology. In continuation of my animal work, I looked further for how chronic, dynamic, and salient exogenous stimuli can affect human cognitive functions similarly to what has been found in rats. Human arm: Using a translational approach, I explored the effect of a highly stimulating environment on human attentional behavior. In that regard, converging evidence suggests the immense attention-grabbing capacity of smartphone devices, one that is equivalent to that of the highly stimulating odor environment in rats. Users always have their smartphones with them throughout the day, which serves as an example of the pervasiveness of electronic media in contemporary human lives. In the first correlative phase of the study, 16 “heavy” smartphone users were recruited out of 2711 who responded to an online questionnaire. Following enrollment into the study, these heavy users were compared to a group of 35 non-users (i.e., individuals who owned a regular phone and had never owned a smartphone) in a battery of tests that were used for the assessment of ADHD symptomology and pathophysiology. These tests included the gold standard questionnaire for assessment of ADHD (the CAARS), an EEG recording during a stop-signal task that assessed inhibitory control (one of the ADHD hallmarks), and an information processing capacity task, which is known to be aberrant in ADHD patients. In the second manipulative phase, the non-users were divided into two groups: one group continued to use their own phones (n=7), but the other group received smartphones (n=8). Following a six month period of exposure, the two groups were re-examined using the same battery of tests. As such, the first phase of the study was correlational in nature and was designed to assess the possible impact of heavy smartphone use; the second phase was manipulative in nature and was designed to allow a better deduction of causality between behavioral impairments and smartphone use. In the first phase of the study, I found differences between heavy-users and non-users in terms of inattentiveness, impulsiveness, and ADHD-like symptoms, as measured by CAARS. In addition, heavy users demonstrated reduced arithmetic processing abilities compared to non-users. In the manipulative phase of the study, I found that, compared to controls, exposure to smartphones led to a development of inattentiveness, to higher intra-individual reaction-time variability in the stop-signal task, and to modified brain activity that resembled ADHD psychopathology. These findings demonstrate a causal relationship between smartphone use, affected executive functioning, and ADHD-like symptomology. Faulty response inhibition as measured in the stop-signal task is considered to be an endophenotype of ADHD and also believed to stem from maladaptive “over” approaching tendencies to environmental stimuli. Thus, these findings may imply that the manipulated group changed their approaching behavior tendencies (i.e., changed the way in which they attribute incentive saliency). Taken together, the animal and the human studies demonstrated a causal link between chronic exposure to dynamic and attention-grabbing stimuli and changes in executive functioning. As such, these findings support the notion that heightened exposure to electronic media in contemporary human society is related to the increasing occurrence of attention-related disorders.