1,721,080 research outputs found
Modulating neural plasticity with non-invasive brain stimulation in schizophrenia
No full textSchizophrenia is a severe mental disorder characterised by a complex phenotype including positive, negative, affective and cognitive symptoms. Various theories have been developed to integrate the clinical phenotype into a strong neurobiological framework. One theory describes schizophrenia as a disorder of impaired neural plasticity. Recently, non-invasive brain stimulation techniques have garnered much attention to their ability to modulate plasticity and treat schizophrenia. The aim of this review is to introduce the basic physiological principles of conventional non-invasive brain stimulation techniques and to review the available evidence for schizophrenia. Despite promising evidence for efficacy in a large number of clinical trials, we continue to have a rudimentary understanding of the underlying neurobiology. Additional investigation is required to improve the response rates to non-invasive brain stimulation, to reduce the interindividual variability and to improve the understanding of non-invasive brain stimulation in schizophrenia
A Randomized Double Blind Sham-controlled Comparison of Bilateral and Unilateral Repetitive Transcranial Magnetic Stimulation for Treatment-resistant Major Depression
Full text linkObjectives: High frequency left-sided (HFL) and low frequency right-sided (LFR) unilateral repetitive transcranial magnetic stimulation (rTMS) are efficacious in treatment-resistant major depression (TRD). Similar benefit has been suggested for sequential bilateral rTMS (LFR then HFL). Therefore, this study evaluated the efficacy of HFL and sequential bilateral rTMS compared to sham in TRD.
Methods: Seventy-four subjects between the ages of 18 and 85 with TRD and a 17-item Hamilton Depression Rating Scale (HDRS) greater than 21 were randomized to receive unilateral, bilateral, or sham rTMS. Remission rates were compared among the three groups.
Results: Remission rates differed significantly among the three groups. The remission rate was significantly higher in the bilateral group (34.6%) than the unilateral (4.5%) and sham (5.0%) groups. The remission rate in the unilateral group did not differ from sham group.
Conclusion: These findings warrant larger controlled studies that compare the efficacy of sequential bilateral rTMS and HFL rTMS in TRD.MAS
Suicidal Ideation and Treatment-Resistant Depression: Clinical Endophenotype Characterization and Exploration of Novel Brain Stimulation Interventions
Full text linkSuicide is a highly stigmatized symptom construct associated with multiple psychiatric conditions. Over 700,000 individuals across the world die by suicide annually. Major depressive disorder (MDD) is the most common co-morbid psychiatric illness in suicide completers. Suicidal ideation (SI) is more prevalent in individuals with treatment-resistant depression (TRD) compared to those with depression who respond to treatment. Given treatment limitations of SI in TRD, novel interventions paired with an improved understanding of the neurobiology of SI are needed.
In this thesis I explore the clinical phenotype of the overlap of TRD and SI through a retrospective analysis of the largest clinical trial in depression, the STAR*D trial. Results from this analysis demonstrate the association between SI and TRD. This analysis also confirms that standard antidepressant treatments do not appear to be effective interventions for individuals with TRD and co-morbid SI, suggesting that novel interventions should be developed for patients struggling with this nexus of conditions. In another published report described in this thesis, our group characterizes the placebo response rates of TRD through a meta-analysis. Placebo response rates tended to be lower in TRD then non-TRD depression, and the implications of this finding are discussed.
In the remaining four publications in this thesis, I explore novel brain stimulation interventions for the treatment of SI and TRD. Bilateral repetitive transcranial magnetic stimulation (rTMS) and magnetic seizure therapy (MST) are assessed for their efficacy through secondary analyses of large clinical trials. Findings suggest a significant effect of bilateral rTMS over sham for inducing remission of SI, and a potentially even stronger effect for MST for the treatment of SI in both unipolar and bipolar depression. The significance of these findings and the potential neurophysiological mechanisms of action are explored.
Finally, this thesis contains an editorial about the promise of accelerated forms of rTMS treatment combined with a personalized medicine approach. I conclude by exploring how this paradigm of intervention could be applied in suicide prevention trials in the future directions portion of this report.Ph.D
Indexing Cortical Reactivity with TMS in Major Depressive Disorder and Response to Therapeutic Brain Stimulation
No full textThe neuropathophysiology of Major Depressive Disorder (MDD) appears to be linked to aberrant cortical inhibition and excitation. These processes are mediated by -amino butyric acid (GABA) and glutamate, the main inhibitory and excitatory neurotransmitters of the cortex, and modified by therapeutic brain stimulation, such as electroconvulsive therapy (ECT) and repetitive transcranial magnetic stimulation (rTMS). Cortical inhibition and excitation can be indexed via transcranial magnetic stimulation, affording high potential as biomarkers of illness state and response to brain stimulation. When combined with electromyography (TMS-EMG), the motor cortex response is assessed. When combined with electroencephalography (TMS-EEG), TMS indexes cortical inhibition and excitation over other cortical regions, more closely associated with MDD. In study one, cortical inhibition was indexed with TMS-EMG over the motor cortex before and after a course of ECT. A TMS-EMG measure of GABAB receptor-mediated cortical inhibition, the cortical silent period, was shorter at baseline in patients who responded to ECT, when compared to the non-responder group. Contrary to evidence, neither cortical silent period nor short interval cortical inhibition (both TMS-EMG measures of cortical inhibition) were altered by a course of ECT. In study two, TMS-EEG indexed cortical inhibition and excitation over the dorsolateral prefrontal cortex (DLPFC) in healthy subjects and patients with MDD. MDD patients had larger TMS-EEG amplitudes of markers of cortical inhibition (N45 and N100) and excitation (P60 and GMFA Area Under the Curve). In fact, the N45 predicted illness state with high accuracy, and N100 was associated with illness severity. In study three, DLPFC response to rTMS was indexed via TMS-EEG in patients recruited for a trial comparing active rTMS to sham rTMS. Sham rTMS did not alter TMS-EEG markers. Active rTMS resulted in differences in the markers of cortical inhibition. The N100 amplitude, a marker associated with GABAB receptor mediated inhibition, decreased in amplitude after rTMS in association with improvement in depressive symptoms. Moreover, a local dampening of cortical activity over the DLPFC, where rTMS was applied, was noted only with active rTMS. TMS markers of cortical inhibition and excitation therefore demonstrate high potential as biomarkers of MDD and response to therapeutic brain stimulation.Ph.D
Inhibition of Gamma Oscillations as a Neurophysiological Endophenotype of Schizophrenia
Full text linkAbstract
Background
The pathophysiology of schizophrenia (SCZ) has not been fully elucidated. Studies have demonstrated that SCZ patients have impairments in the dorsolateral prefrontal cortex (DLPFC). Two findings have been shown in the DLPFC: deficits in GABAergic inhibitiory neurotransmission and abnormal inhibition of cortical oscillations. Thus, we aimed to assess frontal inhibition as a potential endophenotype of SCZ.
Objectives
The first objective was to quantitatively assess transcranial magnetic stimulation (TMS) motor cortex measures of inhibition and excitation in obsessive-compulsive disorder (OCD), major depressive disorder (MDD) and SCZ, as a meta-analysis. The second objective was to evaluate the inhibition of overall and gamma oscillations in the DLPFC and motor cortex using TMS and EEG in SCZ and OCD. The final objective was to evaluate the inhibition of overall and gamma oscillations in SCZ patients, OCD patients, and their unaffected first-degree relatives with TMS and EEG.
Hypotheses
First, we hypothesized that motor cortex inhibitory deficits would be a ubiquitous finding across OCD, MDD and SCZ patients. Second, we hypothesized that patients with SCZ would show deficits in overall and gamma inhibition in the DLPFC compared to healthy subjects and patients with OCD. Lastly, it was hypothesized that frontal inhibition in first-degree relatives of SCZ would be intermediate of healthy subjects and their related probands.
Results
The first study showed that motor inhibitory deficits were a ubiquitous finding across OCD, MDD, and SCZ. The second paper found that SCZ patients demonstrated inhibitory deficits in the DLPFC (overall and gamma inhibition), not observed in OCD patients. This was found to be independent of illness severity and medication. The final study demonstrated deficits in frontal inhibition in SCZ patients, which were significantly less than their unaffected first-degree relatives. No differences were found between first-degree relatives of SCZ and healthy controls. First-degree relatives were intermediate of their related probands and healthy controls. We did not show inhibition deficits in OCD patients and their first-degree relatives.
Conclusions
Frontal inhibition (measured via TMS and EEG) may be an essential neurophysiological process that is impaired in SCZ. Multi-site trials are needed to investigate inhibition as a potential endophenotype for SCZ.Ph.D
Pharmacological Mechanisms of Interhemispheric Signal Propagation and its Disruption in Schizophrenia and Depression
No full textAltered interhemispheric connectivity, linked to deficits of gamma-aminobutyric-acid (GABA) neurotransmission and transcallosal microstructure, is implicated in the pathophysiology of schizophrenia (SCZ) and major depressive disorder (MDD). Objectives: First, we investigated the neurochemical mechanisms of interhemispheric signal propagation (ISP) using combined transcranial magnetic stimulation and electroencephalography (TMS-EEG) with pharmacological modulation in healthy participants. Next, we assessed differences of TMS-evoked ISP between SCZ, MDD, and healthy participants. Hypothesis: It was predicted that ISP would be selectively modulated by the GABAB receptor agonist baclofen and altered in SCZ patients only. Results: Baclofen was the only pharmacological agent that altered and reduced ISP. Additionally, ISP was elevated in both SCZ and MDD patients compared to healthy participants. Conclusions: ISP is modulated by GABAergic neurotransmission and altered in SCZ and MDD. This provides a fundamental step to characterize the mechanisms of TMS-evoked ISP and identify treatments for disorders in which transcallosal signal transmission is dysfunctional.M.Sc
Indexing Cortical Reactivity with TMS in Major Depressive Disorder and Response to Therapeutic Brain Stimulation
Full text linkThe neuropathophysiology of Major Depressive Disorder (MDD) appears to be linked to aberrant cortical inhibition and excitation. These processes are mediated by -amino butyric acid (GABA) and glutamate, the main inhibitory and excitatory neurotransmitters of the cortex, and modified by therapeutic brain stimulation, such as electroconvulsive therapy (ECT) and repetitive transcranial magnetic stimulation (rTMS). Cortical inhibition and excitation can be indexed via transcranial magnetic stimulation, affording high potential as biomarkers of illness state and response to brain stimulation. When combined with electromyography (TMS-EMG), the motor cortex response is assessed. When combined with electroencephalography (TMS-EEG), TMS indexes cortical inhibition and excitation over other cortical regions, more closely associated with MDD. In study one, cortical inhibition was indexed with TMS-EMG over the motor cortex before and after a course of ECT. A TMS-EMG measure of GABAB receptor-mediated cortical inhibition, the cortical silent period, was shorter at baseline in patients who responded to ECT, when compared to the non-responder group. Contrary to evidence, neither cortical silent period nor short interval cortical inhibition (both TMS-EMG measures of cortical inhibition) were altered by a course of ECT. In study two, TMS-EEG indexed cortical inhibition and excitation over the dorsolateral prefrontal cortex (DLPFC) in healthy subjects and patients with MDD. MDD patients had larger TMS-EEG amplitudes of markers of cortical inhibition (N45 and N100) and excitation (P60 and GMFA Area Under the Curve). In fact, the N45 predicted illness state with high accuracy, and N100 was associated with illness severity. In study three, DLPFC response to rTMS was indexed via TMS-EEG in patients recruited for a trial comparing active rTMS to sham rTMS. Sham rTMS did not alter TMS-EEG markers. Active rTMS resulted in differences in the markers of cortical inhibition. The N100 amplitude, a marker associated with GABAB receptor mediated inhibition, decreased in amplitude after rTMS in association with improvement in depressive symptoms. Moreover, a local dampening of cortical activity over the DLPFC, where rTMS was applied, was noted only with active rTMS. TMS markers of cortical inhibition and excitation therefore demonstrate high potential as biomarkers of MDD and response to therapeutic brain stimulation.Ph.D
Using Paired Associative Stimulation and Cortical Silent Period to Examine Neural Plasticity in Healthy and Depressed Youth
Full text linkBackground: Major depressive disorder (MDD) is a disorder that typically arises in youth. MDD may results from impaired neural plasticity that can be probed and treated with transcranial magnetic stimulation (TMS). Methods: We evaluated the feasibility of using two common TMS measures, paired associated stimulation (PAS) and cortical silent period (CSP), in youth. PAS and CSP are thought to index NMDA- and GABA-B dependent plasticity, respectively. Results: In our first experiment, we examined 34 healthy adolescents aged 13-19. We found that PAS induced motor cortical plasticity at 15- and 30-min post-PAS. PAS also lengthened CSP in males but not females. In our second experiment, we applied PAS and CSP to a case series of 6 depressed adolescents aged 16-24 and found that both measures were feasible, safe, and tolerable in this population. Conclusions: PAS and CSP are feasible, safe, and tolerable TMS indices of neural plasticity in youth.M.Sc
Modulation of Gamma Oscillatory Activity Through Repetitive Transcranial Magnetic Stimulation in Healthy Subjects and Patients with Schizophrenia
Full text linkBackground: Gamma oscillations (30-80 Hz) in the dorsolateral prefrontal cortex (DLPFC) are associated with working memory; a process involving the maintenance and manipulation of information on line (Baddeley, 1986). Gamma oscillations are supported by gamma-aminobutyric acid (GABA) inhibitory interneurons in the DLPFC. Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive method in which to stimulate the cortex that has been shown to modify oscillations, cognition and GABAergic mechanisms. Patients with schizophrenia have severe deficits in working memory that may be related to impairments in GABAergic inhibitory neurotransmission underlying gamma oscillations in the DLPFC. Objective: First, to evaluate gamma oscillatory activity in patients with schizophrenia during working memory compared to healthy subjects. Second, to examine the effect of rTMS applied over the DLPFC on gamma oscillations generated during working memory in healthy subjects. Third, to examine the effect of rTMS applied to the DLPFC on gamma oscillations in patients with schizophrenia compared to healthy subjects. Hypotheses: First, it was hypothesized that patients with schizophrenia would exhibit an alteration in gamma oscillatory activity. Second, it was hypothesized that rTMS would be effective in enhancing gamma oscillations in healthy subjects. Third, it was hypothesized that rTMS would be effective in inhibiting gamma oscillations in patients with schizophrenia. Results: The first study found that patients with schizophrenia generate excessive gamma oscillations during working memory compared to healthy subjects. The second experiment found that rTMS over the DLPFC resulted in the potentiation of gamma oscillations in healthy subjects during working memory. The third experiment demonstrated that rTMS inhibited excessive gamma oscillations in patients with schizophrenia while an opposite effect was found in healthy subjects. Conclusions: rTMS applied over the DLPFC modulates frontal gamma oscillatory in healthy subjects and in patients with schizophrenia depending on baseline levels of activity, a finding that may ultimately translate into a better understanding of the mechanisms leading to cognitive improvement in this disorder.Ph
Modulation of Gamma Oscillatory Activity Through Repetitive Transcranial Magnetic Stimulation in Healthy Subjects and Patients with Schizophrenia
No full textBackground: Gamma oscillations (30-80 Hz) in the dorsolateral prefrontal cortex (DLPFC) are associated with working memory; a process involving the maintenance and manipulation of information on line (Baddeley, 1986). Gamma oscillations are supported by gamma-aminobutyric acid (GABA) inhibitory interneurons in the DLPFC. Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive method in which to stimulate the cortex that has been shown to modify oscillations, cognition and GABAergic mechanisms. Patients with schizophrenia have severe deficits in working memory that may be related to impairments in GABAergic inhibitory neurotransmission underlying gamma oscillations in the DLPFC. Objective: First, to evaluate gamma oscillatory activity in patients with schizophrenia during working memory compared to healthy subjects. Second, to examine the effect of rTMS applied over the DLPFC on gamma oscillations generated during working memory in healthy subjects. Third, to examine the effect of rTMS applied to the DLPFC on gamma oscillations in patients with schizophrenia compared to healthy subjects. Hypotheses: First, it was hypothesized that patients with schizophrenia would exhibit an alteration in gamma oscillatory activity. Second, it was hypothesized that rTMS would be effective in enhancing gamma oscillations in healthy subjects. Third, it was hypothesized that rTMS would be effective in inhibiting gamma oscillations in patients with schizophrenia. Results: The first study found that patients with schizophrenia generate excessive gamma oscillations during working memory compared to healthy subjects. The second experiment found that rTMS over the DLPFC resulted in the potentiation of gamma oscillations in healthy subjects during working memory. The third experiment demonstrated that rTMS inhibited excessive gamma oscillations in patients with schizophrenia while an opposite effect was found in healthy subjects. Conclusions: rTMS applied over the DLPFC modulates frontal gamma oscillatory in healthy subjects and in patients with schizophrenia depending on baseline levels of activity, a finding that may ultimately translate into a better understanding of the mechanisms leading to cognitive improvement in this disorder.Ph
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