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1.  The EEG Correlates of the TMS Induced EMG Silent Period in Humans 
NeuroImage  2013;83:120-134.
Application of magnetic or electrical stimulation to the motor cortex can result in a period of electromyography (EMG) silence in a tonically active peripheral muscle. This period of EMG silence is referred to as the silent period (SP). The duration of SP shows intersubject variability and reflects the integrity of cortical and corticospinal pathways. A non-invasive technique for assessing the duration of SP is the combination of Transcranial Magnetic Stimulation (TMS) with EMG. Utilizing TMS-EMG, several studies have reported on the shortening or lengthening of SP in neuropsychiatric disorders such as schizophrenia, bipolar disorder, depression, obsessive compulsive disorder, epilepsy, Parkinson’s disease, and stroke. However, cortical, corticospinal and peripheral components are difficult to disentangle from EMG alone. Here, we use the multimodal neuroimaging technique of TMS-EMG combined with concurrent electroencephalography (EEG) recording to further examine the cortical origin of SP and the cortical oscillatory activity that underlies SP genesis. We demonstrate that the duration of SP is related to the temporal characteristics of the cortical reactivity and the power of delta to alpha oscillations in both local and remote areas ipsilateral and contralateral to the stimulation site, and beta oscillations locally. We illustrate that, compared to EMG, the EEG indices of the SP provide additional information about the brain dynamics and propose that the EEG measures of SP may be used in future clinical and research investigations to more precisely delineate the mechanisms underlying inhibitory impairments.
doi:10.1016/j.neuroimage.2013.06.059
PMCID: PMC4211432  PMID: 23800790
Cortical Inhibition; Motor Cortex; Transcranial Magnetic Stimulation; Electroencephalography; Electromyography; GABA; Cortical Oscillations
2.  PAS-Induced Potentiation of Cortical-Evoked Activity in the Dorsolateral Prefrontal Cortex 
Neuropsychopharmacology  2013;38(12):2545-2552.
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.
doi:10.1038/npp.2013.161
PMCID: PMC3799076  PMID: 23820586
Biological Psychiatry; DLPFC; Learning & Memory; Neurophysiology; Plasticity; TMS; dorsolateral prefrontal cortex; long-term potentiation; neuroplasticity; paired associative stimulation; transcranial magnetic stimulation
3.  Magnetic seizure therapy in an adolescent with refractory bipolar depression: a case report 
Magnetic seizure therapy (MST) has shown efficacy in adult patients with treatment-resistant depression with limited impairment in memory. To date, the use of MST in adolescent depression has not been reported. Here we describe the first successful use of MST in the treatment of an adolescent patient with refractory bipolar depression. This patient received MST in an ongoing open-label study for treatment-resistant major depression. Treatments employed a twin-coil MST apparatus, with the center of each coil placed over the frontal cortex (ie, each coil centered over F3 and F4). MST was applied at 100 Hz and 100% machine output at progressively increasing train durations. Depressive symptoms were assessed using the 24-item Hamilton Depression Rating Scale and cognitive function was assessed with a comprehensive neuropsychological battery. This adolescent patient achieved full remission of clinical symptoms after an acute course of 18 MST treatments and had no apparent cognitive decline, other than some autobiographical memory impairment that may or may not be related to the MST treatment. This case report suggests that MST may be a safe and well tolerated intervention for adolescents with treatment-resistant bipolar depression. Pilot studies to further evaluate the effectiveness and safety of MST in adolescents warrant consideration.
doi:10.2147/NDT.S71056
PMCID: PMC4222618  PMID: 25382978
brain stimulation; treatment-resistant depression; adolescent depression; cognitive effects
4.  A Meta-Analytic Study of Changes in Brain Activation in Depression 
Human brain mapping  2008;29(6):683-695.
Objective
A large number of studies with considerably variable methods have been performed to investigate brain regions involved in the pathophysiology of major depressive disorder. The aim of this study was to use a quantitative meta-analytic technique to synthesise the results of much of this research.
Methods
Three separate quantitative meta-analytical studies were conducted using the Activation Likelihood Estimation technique. Analysis was performed on three types of studies: (1) those conducted at rest comparing brain activation in patients with depression and controls; (2) those involving brain changes following antidepressant treatment; and (3) those comparing brain activation patterns induced by the induction of positive or negative emotion in patients with depression compared with controls.
Results
There appears to be a complex series of areas of the brain implicated in the pathophysiology of depression although limited overlap was found across imaging paradigms. This included a network of regions including frontal and temporal cortex as well as the insula and cerebellum that are hypoactive in depressed subjects and in which there is increase in activity with treatment. There was a corresponding set of subcortical and limbic regions in which opposite changes were found.
Conclusions
There is limited overlap between the brain regions identified using differing imaging methods. The most consistently identified regions include areas of the anterior cingulate, dorsolateral, medial and inferior prefrontal cortex, insula, superior temporal gyrus, basal ganglia and cerebellum. Further research is required to identify if different imaging methods are identifying complementary networks that are equally involved in the disorder.
doi:10.1002/hbm.20426
PMCID: PMC2873772  PMID: 17598168
fMRI; depression; meta-analysis
5.  Evidence for Cortical Inhibitory and Excitatory Dysfunction in Obsessive Compulsive Disorder 
Neuropsychopharmacology  2011;37(5):1144-1151.
Several lines of evidence suggest that obsessive-compulsive disorder (OCD) is associated with an inability to inhibit unwanted intrusive thoughts. The neurophysiological mechanisms mediating such inhibitory deficits include abnormalities in cortical γ-aminobutyric acid (GABA) inhibitory as well as N-methyl--aspartate (NMDA) receptor-mediated mechanisms. Molecular evidence suggests that both these neurotransmitter systems are involved in OCD. Transcranial magnetic stimulation (TMS) represents a noninvasive technique to ascertain neurophysiological indices of inhibitory GABA and facilitatory NMDA receptor-mediated mechanisms. In this study, both mechanisms were indexed in 34 patients with OCD (23 unmedicated and 11 medicated) and compared with 34 healthy subjects. Cortical inhibitory and facilitatory neurotransmission was measured using TMS paradigms known as short-interval cortical inhibition (SICI), cortical silent period (CSP), and intracortical facilitation (ICF). Patients with OCD demonstrated significantly shortened CSP (p<0.001, Cohen's d=0.91) and increased ICF (p<0.009, Cohen's d=0.71) compared with healthy subjects. By contrast, there were no significant deficits in SICI. After excluding patients with OCD and comorbid major depressive disorder (MDD) from the analysis, these differences remained significant. Our findings suggest that OCD is associated with dysregulation in cortical inhibitory and facilitatory neurotransmission. Specifically, these findings suggest impairments in GABAB receptor-mediated and NMDA receptor-mediated neurotransmission. These findings are consistent with previously published genetic studies implicating GABAB, and NMDA transporter and receptor genes in OCD. It is posited that dysregulation of such mechanisms may lead to the generation and persistence of intrusive thoughts that form the basis for this disorder.
doi:10.1038/npp.2011.300
PMCID: PMC3306876  PMID: 22169948
GABA; OCD; TMS; physiology; inhibition; cortical; neurophysiology; GABA; mood/anxiety/stress disorders; Glutamate; Cortical; TMS; Inhibition
6.  Interpersonal motor resonance in autism spectrum disorder: evidence against a global “mirror system” deficit 
The mirror neuron hypothesis of autism is highly controversial, in part because there are conflicting reports as to whether putative indices of mirror system activity are actually deficient in autism spectrum disorder (ASD). Recent evidence suggests that a typical putative mirror system response may be seen in people with an ASD when there is a degree of social relevance to the visual stimuli used to elicit that response. Individuals with ASD (n = 32) and matched neurotypical controls (n = 32) completed a transcranial magnetic stimulation (TMS) experiment in which the left primary motor cortex (M1) was stimulated during the observation of static hands, individual (i.e., one person) hand actions, and interactive (i.e., two person) hand actions. Motor-evoked potentials (MEP) were recorded from the contralateral first dorsal interosseous, and used to generate an index of interpersonal motor resonance (IMR; a putative measure of mirror system activity) during action observation. There was no difference between ASD and NT groups in the level of IMR during the observation of these actions. These findings provide evidence against a global mirror system deficit in ASD, and this evidence appears to extend beyond stimuli that have social relevance. Attentional and visual processing influences may be important for understanding the apparent role of IMR in the pathophysiology of ASD.
doi:10.3389/fnhum.2013.00218
PMCID: PMC3661943  PMID: 23734121
mirror neurons; interaction; transcranial magnetic stimulation; primary motor cortex; electromyography
7.  A transcranial magnetic stimulation study of the effect of visual orientation on the putative human mirror neuron system 
Mirror neurons are a class of motor neuron that are active during both the performance and observation of behavior, and have been implicated in interpersonal understanding. There is evidence to suggest that the mirror response is modulated by the perspective from which an action is presented (e.g., egocentric or allocentric). Most human research, however, has only examined this when presenting intransitive actions. Twenty-three healthy adult participants completed a transcranial magnetic stimulation experiment that assessed corticospinal excitability whilst viewing transitive hand gestures from both egocentric (i.e., self) and allocentric (i.e., other) viewpoints. Although action observation was associated with increases in corticospinal excitability (reflecting putative human mirror neuron activity), there was no effect of visual perspective. These findings are discussed in the context of contemporary theories of mirror neuron ontogeny, including models concerning associative learning and evolutionary adaptation.
doi:10.3389/fnhum.2013.00679
PMCID: PMC3797389  PMID: 24137125
mirror neurons; transcranial magnetic stimulation; electromyography; associative learning; action observation; visual perspective
8.  Treatment and outcomes of an Australian cohort of outpatients with bipolar I or schizoaffective disorder over twenty-four months: implications for clinical practice 
BMC Psychiatry  2012;12:228.
Background
The Bipolar Comprehensive Outcomes Study (BCOS) is a 2-year, prospective, non-interventional, observational study designed to explore the clinical and functional outcomes associated with ‘real-world’ treatment of participants with bipolar I or schizoaffective disorder. All participants received treatment as usual. There was no study medication.
Methods
Participants prescribed either conventional mood stabilizers (CMS; n = 155) alone, or olanzapine with, or without, CMS (olanzapine ± CMS; n = 84) were assessed every 3 months using several measures, including the Young Mania Rating Scale, 21-item Hamilton Depression Rating Scale, Clinical Global Impressions Scale – Bipolar Version, and the EuroQol Instrument. This paper reports 24-month longitudinal clinical, pharmacological, functional, and socioeconomic data.
Results
On average, participants were 42 (range 18 to 79) years of age, 58%; were female, and 73%; had a diagnosis of bipolar I. Polypharmacy was the usual approach to pharmacological treatment; participants took a median of 5 different psychotropic medications over the course of the study, and spent a median proportion of time of 100%; of the study on mood stabilizers, 90%; on antipsychotics, 9%; on antidepressants, and 5%; on benzodiazepines/hypnotics. By 24 months, the majority of participants had achieved both symptomatic and syndromal remission of both mania and depression. Symptomatic relapse rates were similar for both the CMS alone (65%;) and the olanzapine ± CMS (61%;) cohorts.
Conclusions
Participants with bipolar I or schizoaffective disorder in this study were receiving complex medication treatments that were often discordant with recommendations made in contemporary major treatment guidelines. The majority of study participants demonstrated some clinical and functional improvements, but not all achieved remission of symptoms or syndrome.
doi:10.1186/1471-244X-12-228
PMCID: PMC3570370  PMID: 23244301
9.  A Randomized Double-Blind Sham-Controlled Study of Transcranial Direct Current Stimulation for Treatment-Resistant Major Depression 
Objectives: Transcranial direct current stimulation (tDCS) has demonstrated some efficacy in treatment-resistant major depression (TRD). The majority of previous controlled studies have used anodal stimulation to the left dorsolateral prefrontal cortex (DLPFC) and a control location such as the supraorbital region for the cathode. Several open-label studies have suggested effectiveness from anodal stimulation to the left DLPFC combined with cathodal stimulation to the right DLPFC. Thus, this study evaluated the efficacy of tDCS using anodal stimulation to the left DLPFC and cathodal stimulation to the right DLPFC compared to sham tDCS. Methods: Subjects between the ages of 18 and 65 were recruited from a tertiary care university hospital. Twenty-four subjects with TRD and a 17-item Hamilton Rating Scale for Depression greater than 21 were randomized to receive tDCS or sham tDCS. The rates of remission were compared between the two treatment groups. Results: The remission rates did not differ significantly between the two groups using an intention to treat analysis. More subjects in the active tDCS group had failed a course of electroconvulsive therapy in the current depressive episode. Side effects did not differ between the two groups and in general the treatment was very well tolerated. Conclusion: Anodal stimulation to the left DLPFC and cathodal stimulation to the right DLPFC was not efficacious in TRD. However, a number of methodological limitations warrant caution in generalizing from this study. Ongoing, controlled studies should provide further clarification on the efficacy of this stimulation configuration in TRD. ClinicalTrials.gov Identifier: NCT01078948.
doi:10.3389/fpsyt.2012.00074
PMCID: PMC3421236  PMID: 22912618
depression; transcranial direct current stimulation; treatment-resistance; clinical trial
10.  A consensus statement for safety monitoring guidelines of treatments for major depressive disorder 
Objective
This paper aims to present an overview of screening and safety considerations for the treatment of clinical depressive disorders and make recommendations for safety monitoring.
Method
Data were sourced by a literature search using MEDLINE and a manual search of scientific journals to identify relevant articles. Draft guidelines were prepared and serially revised in an iterative manner until all co-authors gave final approval of content.
Results
Screening and monitoring can detect medical causes of depression. Specific adverse effects associated with antidepressant treatments may be reduced or identified earlier by baseline screening and agent-specific monitoring after commencing treatment.
Conclusion
The adoption of safety monitoring guidelines when treating clinical depression is likely to improve overall physical health status and treatment outcome. It is important to implement these guidelines in the routine management of clinical depression.
doi:10.3109/00048674.2011.595686
PMCID: PMC3190838  PMID: 21888608
11.  The Effect of Repetitive Transcranial Magnetic Stimulation on Gamma Oscillatory Activity in Schizophrenia 
PLoS ONE  2011;6(7):e22627.
Background
Gamma (γ) oscillations (30–50 Hz) have been shown to be excessive in patients with schizophrenia (SCZ) during working memory (WM). WM is a cognitive process that involves the online maintenance and manipulation of information that is mediated largely by the dorsolateral prefrontal cortex (DLPFC). Repetitive transcranial magnetic stimulation (rTMS) represents a non-invasive method to stimulate the cortex that has been shown to enhance cognition and γ oscillatory activity during WM.
Methodology and Principal Findings
We examined the effect of 20 Hz rTMS over the DLPFC on γ oscillatory activity elicited during the N-back task in 24 patients with SCZ compared to 22 healthy subjects. Prior to rTMS, patients with SCZ elicited excessive γ oscillatory activity compared to healthy subjects across WM load. Active rTMS resulted in the reduction of frontal γ oscillatory activity in patients with SCZ, while potentiating activity in healthy subjects in the 3-back, the most difficult condition. Further, these effects on γ oscillatory activity were found to be specific to the frontal brain region and were absent in the parieto-occipital brain region.
Conclusions and Significance
We suggest that this opposing effect of rTMS on γ oscillatory activity in patients with SCZ versus healthy subjects may be related to homeostatic plasticity leading to differential effects of rTMS on γ oscillatory activity depending on baseline differences. These findings provide important insights into the neurophysiological mechanisms underlying WM deficits in SCZ and demonstrated that rTMS can modulate γ oscillatory activity that may be a possible avenue for cognitive potentiation in this disorder.
doi:10.1371/journal.pone.0022627
PMCID: PMC3144924  PMID: 21818354
12.  Investigating the Role of Current Strength in tDCS Modulation of Working Memory Performance in Healthy Controls 
Transcranial direct current stimulation (tDCS) is a brain stimulation technique that has the potential to improve working memory (WM) deficits in many clinical disorders. The aim of this study was to investigate the role of current strength on the ability of anodal tDCS to improve WM, and secondly to investigate the time course of effects. Twelve healthy participants underwent three stimulation sessions consisting of 20 min of either 1 mA anodal tDCS, 2 mA anodal tDCS, or sham tDCS to the left dorsolateral prefrontal cortex (DLPFC) localized via F3, all whilst completing a WM task. Intra-stimulation and post-stimulation WM performances were measured using the n-back and Sternberg tasks respectively. Results revealed no significant improvements in participants’ accuracy, but a significant interaction was found with respect to current strength and time for accurate reaction time. The finding provides partial support for the hypothesis, in that it appears current strength may affect aspects of WM performance. However, more research is needed, and a higher difficulty level of WM tasks is one of the suggestions discussed for future research.
doi:10.3389/fpsyt.2011.00045
PMCID: PMC3141358  PMID: 21811474
transcranial direct current stimulation; working memory; dorsolateral prefrontal cortex
13.  Symptom Correlates of Static and Dynamic Facial Affect Processing in Schizophrenia: Evidence of a Double Dissociation? 
Schizophrenia Bulletin  2008;36(4):680-687.
Schizophrenia patients have been shown to be compromised in their ability to recognize facial emotion. This deficit has been shown to be related to negative symptoms severity. However, to date, most studies have used static rather than dynamic depictions of faces. Nineteen patients with schizophrenia were compared with seventeen controls on 2 tasks; the first involving the discrimination of facial identity, emotion, and butterfly wings; the second testing emotion recognition using both static and dynamic stimuli. In the first task, the patients performed more poorly than controls for emotion discrimination only, confirming a specific deficit in facial emotion recognition. In the second task, patients performed more poorly in both static and dynamic facial emotion processing. An interesting pattern of associations suggestive of a possible double dissociation emerged in relation to correlations with symptom ratings: high negative symptom ratings were associated with poorer recognition of static displays of emotion, whereas high positive symptom ratings were associated with poorer recognition of dynamic displays of emotion. However, while the strength of associations between negative symptom ratings and accuracy during static and dynamic facial emotion processing was significantly different, those between positive symptom ratings and task performance were not. The results confirm a facial emotion-processing deficit in schizophrenia using more ecologically valid dynamic expressions of emotion. The pattern of findings may reflect differential patterns of cortical dysfunction associated with negative and positive symptoms of schizophrenia in the context of differential neural mechanisms for the processing of static and dynamic displays of facial emotion.
doi:10.1093/schbul/sbn136
PMCID: PMC2894589  PMID: 18953071
schizophrenia; schizoaffective disorder; social cognition; facial affect; positive symptoms; negative symptoms
14.  Personality Goes a Long a Way: An Interhemispheric Connectivity Study 
Throughout the development of psychology the delineation of personality has played a central role. Together with the NEO-PI-R, a questionnaire derived from the Five Factor Model of Personality, and recent advances in research technology it is now possible to investigate the relationship between personality features and neurophysiological brain processes. The NEO-FFI, the short version of the NEO-PI-R, reliably measures five main personality traits: Neuroticism, Extraversion, Openness to experience, Agreeableness, and Conscientiousness. As behavior and some psychiatric disorders have been related to interhemispheric connectivity, the present study used the combination of transcranial magnetic stimulation (TMS) and electroencephalography (EEG) to measure frontal interhemispheric connectivity and its association with personality as indexed by the NEO-FFI. Results demonstrated that prefrontal interhemispheric connectivity between the left and right dorsolateral prefrontal cortex correlates with Agreeableness in healthy subjects. This is the first study to relate personality features to interhemispheric connectivity through TMS–EEG and suggests that Agreeableness relates to the effectiveness of prefrontal communication between hemispheres.
doi:10.3389/fpsyt.2010.00140
PMCID: PMC3059614  PMID: 21423449
transcranial magnetic stimulation; electroencephalography; interhemispheric connectivity; NEO-PI-R; agreeableness

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