Temerty Center for Therapeutic Brain Intervention

Toronto, Canada

Temerty Center for Therapeutic Brain Intervention

Toronto, Canada
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Downar J.,University of Toronto | Geraci J.,University of Toronto | Salomons T.V.,University of Toronto | Dunlop K.,University of Toronto | And 11 more authors.
Biological Psychiatry | Year: 2014

Background Depression is a heterogeneous mental illness. Neurostimulation treatments, by targeting specific nodes within the brain's emotion-regulation network, may be useful both as therapies and as probes for identifying clinically relevant depression subtypes. Methods Here, we applied 20 sessions of magnetic resonance imaging-guided repetitive transcranial magnetic stimulation (rTMS) to the dorsomedial prefrontal cortex in 47 unipolar or bipolar patients with a medication-resistant major depressive episode. Results Treatment response was strongly bimodal, with individual patients showing either minimal or marked improvement. Compared with responders, nonresponders showed markedly higher baseline anhedonia symptomatology (including pessimism, loss of pleasure, and loss of interest in previously enjoyed activities) on item-by-item examination of Beck Depression Inventory-II and Quick Inventory of Depressive Symptomatology ratings. Congruently, on baseline functional magnetic resonance imaging, nonresponders showed significantly lower connectivity through a classical reward pathway comprising ventral tegmental area, striatum, and a region in ventromedial prefrontal cortex. Responders and nonresponders also showed opposite patterns of hemispheric lateralization in the connectivity of dorsomedial and dorsolateral regions to this same ventromedial region. Conclusions The results suggest distinct depression subtypes, one with preserved hedonic function and responsive to dorsomedial rTMS and another with disrupted hedonic function, abnormally lateralized connectivity through ventromedial prefrontal cortex, and unresponsive to dorsomedial rTMS. Future research directly comparing the effects of rTMS at different targets, guided by neuroimaging and clinical presentation, may clarify whether hedonia/reward circuit integrity is a reliable marker for optimizing rTMS target selection. © 2014 Society of Biological Psychiatry.


Atluri S.,Temerty Center for Therapeutic Brain Intervention | Atluri S.,University of Toronto | Frehlich M.,Temerty Center for Therapeutic Brain Intervention | Frehlich M.,University of Toronto | And 8 more authors.
Frontiers in Neural Circuits | Year: 2016

Concurrent recording of electroencephalography (EEG) during transcranial magnetic stimulation (TMS) is an emerging and powerful tool for studying brain health and function. Despite a growing interest in adaptation of TMS-EEG across neuroscience disciplines, its widespread utility is limited by signal processing challenges. These challenges arise due to the nature of TMS and the sensitivity of EEG to artifacts that often mask TMS-evoked potentials (TEP)s. With an increase in the complexity of data processing methods and a growing interest in multi-site data integration, analysis of TMS-EEG data requires the development of a standardized method to recover TEPs from various sources of artifacts. This article introduces TMSEEG, an open-source MATLAB application comprised of multiple algorithms organized to facilitate a step-by-step procedure for TMS-EEG signal processing. Using a modular design and interactive graphical user interface (GUI), this toolbox aims to streamline TMS-EEG signal processing for both novice and experienced users. Specifically, TMSEEG provides: (i) targeted removal of TMS-induced and general EEG artifacts; (ii) a step-by-step modular workflow with flexibility to modify existing algorithms and add customized algorithms; (iii) a comprehensive display and quantification of artifacts; (iv) quality control check points with visual feedback of TEPs throughout the data processing workflow; and (v) capability to label and store a database of artifacts. In addition to these features, the software architecture of TMSEEG ensures minimal user effort in initial setup and configuration of parameters for each processing step. This is partly accomplished through a close integration with EEGLAB, a widely used open-source toolbox for EEG signal processing. In this article, we introduce TMSEEG, validate its features and demonstrate its application in extracting TEPs across several single- and multi-pulse TMS protocols. As the first open-source GUI-based pipeline for TMS-EEG signal processing, this toolbox intends to promote the widespread utility and standardization of an emerging technology in brain research. © 2016 Atluri, Frehlich, Mei, Garcia Dominguez, Rogasch, Wong, Daskalakis and Farzan.


Wheeler A.L.,Research Imaging Center | Wheeler A.L.,University of Toronto | Chakravarty M.M.,Research Imaging Center | Chakravarty M.M.,University of Toronto | And 12 more authors.
Schizophrenia Bulletin | Year: 2014

Background: Prominent regional cortical thickness reductions have been shown in schizophrenia. In contrast, little is known regarding alterations of structural coupling between regions in schizophrenia and how these alterations may be related to cognitive impairments in this disorder. Methods: T1-weighted magnetic resonance images were acquired in 54 patients with schizophrenia and 68 healthy control subjects aged 18-55 years. Cortical thickness was compared between groups using a vertex-wise approach. To assess structural coupling, seeds were selected within regions of reduced thickness, and brain-wide cortical thickness correlations were compared between groups. The relationships between identified patterns of circuit structure disruption and cognitive task performance were then explored. Results: Prominent cortical thickness reductions were found in patients compared with controls at a 5% false discovery rate in a predominantly frontal and temporal pattern. Correlations of the left dorsolateral prefrontal cortex (DLPFC) with right prefrontal regions were significantly different in patients and controls. The difference remained significant in a subset of 20 first-episode patients. Participants with stronger frontal interhemispheric thickness correlations had poorer working memory performance. Conclusions: We identified structural impairment in a left-right DLPFC circuit in patients with schizophrenia independent of illness stage or medication exposure. The relationship between left-right DLPFC thickness correlations and working memory performance implicates prefrontal interhemispheric circuit impairment as a vulnerability pathway for poor working memory performance. Our findings could guide the development of novel therapeutic interventions aimed at improving working memory performance in patients with schizophrenia. © 2014 The Author.


Voineskos D.,University of Toronto | Rogasch N.C.,Monash University | Rajji T.K.,University of Toronto | Fitzgerald P.B.,Monash University | And 2 more authors.
Canadian Journal of Psychiatry | Year: 2013

The adaptations resulting from neural plasticity lead to changes in cognition and behaviour, which are strengthened through repeated exposure to the novel environment or stimulus. Learning and memory have been hypothesized to occur through modifications of the strength of neural circuits, particularly in the hippocampus and cortex. Cognitive deficits, specifically in executive functioning and negative symptoms, may be a corollary to deficits in neural plasticity. Moreover, the main excitatory and inhibitory neurotransmitters associated with neural plasticity have also been extensively investigated for their role in the cognitive deficits associated with schizophrenia. Transcranial magnetic stimulation (TMS) represents some of the most promising approaches to directly explore the physiological manifestations of neural plasticity in the human brain. Three TMS paradigms (use-dependent plasticity, paired associative stimulation, and repetitive TMS) have been used to evaluate neurophysiological measures of neural plasticity in the healthy brain and in patients with schizophrenia, and to examine the brain's responses to such stimulation. In schizophrenia, deficits in neural plasticity have been consistently shown which parallel the molecular evidence appearing to be entwined with this debilitating disorder. Such pathophysiology may underlie the learning and memory deficits that are key symptoms of this disorder and may even be a key mechanism involved in treatment with antipsychotics.


Rajji T.K.,University of Toronto | Rajji T.K.,Temerty Center for Therapeutic Brain Intervention | Sun Y.,University of Toronto | Sun Y.,Temerty Center for Therapeutic Brain Intervention | And 9 more authors.
Neuropsychopharmacology | Year: 2013

Neuroplasticity and long-term potentiation (LTP) in the dorsolateral prefrontal cortex (DLPFC) are considered important mechanisms in learning and memory, and their disruption may be related to the pathophysiology of several neuropsychiatric disorders. Paired associative stimulation (PAS) is a brain stimulation paradigm that produces enhanced activity in the human motor cortex that may be related to LTP. In a group of 15 healthy participants, we report on the potentiation of cortical-evoked activity in the human DLPFC using the combination of PAS and electroencephalography. In contrast, a PAS control condition did not result in potentiation in another group of nine healthy participants. We also demonstrate that PAS-induced potentiation of cortical-evoked activity is characterized by anatomical specificity that is largely confined to the site of stimulation. Finally, we show that PAS results in potentiation of θ-and γ-activity and θ-phase-γ- amplitude coupling. These neurophysiological indices may be related to working memory, an important function of the DLPFC. To our knowledge, this is the first report of potentiation of cortical-evoked activity in the DLPFC. As this potentiation may be related to LTP, our findings provide a model through which neuroplasticity in health and disease states in the frontal cortex can be studied. © 2013 American College of Neuropsychopharmacology.


Khanna A.,Beth Israel Deaconess Medical Center | Pascual-Leone A.,Beth Israel Deaconess Medical Center | Farzan F.,Beth Israel Deaconess Medical Center | Farzan F.,Temerty Center for Therapeutic Brain Intervention
PLoS ONE | Year: 2014

Background: Electroencephalographic (EEG) microstate analysis is a method of identifying quasi-stable functional brain states ("microstates") that are altered in a number of neuropsychiatric disorders, suggesting their potential use as biomarkers of neurophysiological health and disease. However, use of EEG microstates as neurophysiological biomarkers requires assessment of the test-retest reliability of microstate analysis. Methods: We analyzed resting-state, eyes-closed, 30-channel EEG from 10 healthy subjects over 3 sessions spaced approximately 48 hours apart. We identified four microstate classes and calculated the average duration, frequency, and coverage fraction of these microstates. Using Cronbach's α and the standard error of measurement (SEM) as indicators of reliability, we examined: (1) the test-retest reliability of microstate features using a variety of different approaches; (2) the consistency between TAAHC and k-means clustering algorithms; and (3) whether microstate analysis can be reliably conducted with 19 and 8 electrodes. Results: The approach of identifying a single set of "global" microstate maps showed the highest reliability (mean Cronbach's α>0.8, SEM ≈10% of mean values) compared to microstates derived by each session or each recording. There was notably low reliability in features calculated from maps extracted individually for each recording, suggesting that the analysis is most reliable when maps are held constant. Features were highly consistent across clustering methods (Cronbach's α>0.9). All features had high test-retest reliability with 19 and 8 electrodes. Conclusions: High test-retest reliability and cross-method consistency of microstate features suggests their potential as biomarkers for assessment of the brain's neurophysiological health. © 2014 Khanna et al.


Downar J.,University of Toronto | Geraci J.,University of Toronto | Salomons T.V.,University of Toronto | Dunlop K.,University of Toronto | And 11 more authors.
Biological Psychiatry | Year: 2014

Background Depression is a heterogeneous mental illness. Neurostimulation treatments, by targeting specific nodes within the brain's emotion-regulation network, may be useful both as therapies and as probes for identifying clinically relevant depression subtypes. Methods Here, we applied 20 sessions of magnetic resonance imaging-guided repetitive transcranial magnetic stimulation (rTMS) to the dorsomedial prefrontal cortex in 47 unipolar or bipolar patients with a medication-resistant major depressive episode. Results Treatment response was strongly bimodal, with individual patients showing either minimal or marked improvement. Compared with responders, nonresponders showed markedly higher baseline anhedonia symptomatology (including pessimism, loss of pleasure, and loss of interest in previously enjoyed activities) on item-by-item examination of Beck Depression Inventory-II and Quick Inventory of Depressive Symptomatology ratings. Congruently, on baseline functional magnetic resonance imaging, nonresponders showed significantly lower connectivity through a classical reward pathway comprising ventral tegmental area, striatum, and a region in ventromedial prefrontal cortex. Responders and nonresponders also showed opposite patterns of hemispheric lateralization in the connectivity of dorsomedial and dorsolateral regions to this same ventromedial region. Conclusions The results suggest distinct depression subtypes, one with preserved hedonic function and responsive to dorsomedial rTMS and another with disrupted hedonic function, abnormally lateralized connectivity through ventromedial prefrontal cortex, and unresponsive to dorsomedial rTMS. Future research directly comparing the effects of rTMS at different targets, guided by neuroimaging and clinical presentation, may clarify whether hedonia/reward circuit integrity is a reliable marker for optimizing rTMS target selection. © 2014 Society of Biological Psychiatry.


Buchy L.,University of Calgary | Hawco C.,Temerty Center for Therapeutic Brain Intervention | Joober R.,University Institute of Mental Health | Malla A.,University Institute of Mental Health | And 3 more authors.
Schizophrenia Research | Year: 2015

In people with psychoses, Self-Reflectiveness may rely on the right ventrolateral prefrontal cortex (VLPFC). We used functional magnetic resonance imaging (fMRI) and a novel virtual reality paradigm to evaluate the role of the VLPFC for Self-Reflectiveness in 25 first-episode of schizophrenia (FES) participants and 24 controls. Participants first viewed 20 characters each paired with a unique object/location, and later completed source memory judgements during fMRI scanning. Self-Reflectiveness, measured with the Beck Cognitive Insight Scale, was significantly and positively correlated to activation in bilateral VLPFC in FES, but not in controls, providing further evidence that the VLPFC supports Self-Reflectiveness in FES. © 2015 Elsevier B.V.


Blumberger D.M.,University of Toronto | Blumberger D.M.,Temerty Center for Therapeutic Brain Intervention | Mulsant B.H.,University of Toronto | Daskalakis Z.J.,University of Toronto | Daskalakis Z.J.,Temerty Center for Therapeutic Brain Intervention
Current Psychiatry Reports | Year: 2013

Brain stimulation therapies have demonstrated efficacy in the treatment of depression and treatment-resistant depression (TRD). Non-invasive brain stimulation in the treatment of depression has grown substantially due to their favorable adverse effect profiles. The role of transcranial direct current stimulation in TRD is unclear, but emerging data suggests that it may be an effective add-on treatment. Repetitive transcranial magnetic stimulation has demonstrated efficacy in TRD that is supported by several multicenter randomized controlled trials. Though, vagus nerve stimulation has been found to be effective in some studies, sham controlled studies were equivocal. Electroconvulsive therapy (ECT) is a well-established brain stimulation treatment for severe depression and TRD, yet stigma and cognitive adverse effects limit its wider use. Magnetic seizure therapy has a more favorable cognitive adverse effect profile; however, equivalent efficacy to ECT needs to be established. Deep brain stimulation may play a role in severe TRD and controlled trials are now underway. © 2013 Springer Science+Business Media New York.


Zomorrodi R.,Temerty Center for Therapeutic Brain Intervention
Neuropsychopharmacology | Year: 2016

Short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF) are noninvasive transcranial magnetic stimulation (TMS) measures of GABAA 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 GABAA 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.Neuropsychopharmacology advance online publication, 17 August 2016; doi:10.1038/npp.2016.133. © 2016 American College of Neuropsychopharmacology

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