Recent meta-analyses of structural and functional neuroimaging studies are converging on a collective core of brain regions affected across most psychiatric disorders, centered on the dorsal anterior ...cingulate cortex (dACC) and anterior insula. These nodes correspond well to an anterior cingulo-insular (aCIN) or ‘salience’ network, and stand at a crossroads within the functional architecture of the brain, acting as a switch to deploy other major functional networks according to motivational demands and environmental constraints. Therefore, disruption of these ‘linchpin’ areas may be disproportionately disabling, even when other networks remain intact. These regions may represent promising targets for a new generation of anatomically directed brain stimulation treatments. Here, we review the potential of the psychiatric core areas as targets for therapeutic brain stimulation in psychiatric disease.
Transcranial direct current stimulation (tDCS) is a non-pharmacological intervention for depression. It has mixed results, possibly caused by study heterogeneity.
To assess tDCS efficacy and to ...explore individual response predictors.
Systematic review and individual patient data meta-analysis.
Data were gathered from six randomised sham-controlled trials, enrolling 289 patients. Active tDCS was significantly superior to sham for response (34% v. 19% respectively, odds ratio (OR) = 2.44, 95% CI 1.38-4.32, number needed to treat (NNT) = 7), remission (23.1% v. 12.7% respectively, OR = 2.38, 95% CI 1.22-4.64, NNT = 9) and depression improvement (B coefficient 0.35, 95% CI 0.12-0.57). Mixed-effects models showed that, after adjustment for other predictors and confounders, treatment-resistant depression and higher tDCS 'doses' were, respectively, negatively and positively associated with tDCS efficacy.
The effect size of tDCS treatment was comparable with those reported for repetitive transcranial magnetic stimulation and antidepressant drug treatment in primary care. The most important parameters for optimisation in future trials are depression refractoriness and tDCS dose.
Biomarkers are essential for understanding the underlying pathologies in brain disorders and for developing effective treatments. Combined transcranial magnetic stimulation and electroencephalography ...(TMS-EEG) is an emerging neurophysiological tool that can be used for biomarker development. This method can identify biomarkers associated with the function and dynamics of the inhibitory and excitatory neurotransmitter systems and effective connectivity between brain areas. In this review, we outline the current state of the TMS-EEG biomarker field by summarizing the existing protocols and the possibilities and challenges associated with this methodology.
•TMS-EEG is an emerging neurophysiological method for searching biomarkers.•TMS-EEG can measure neurotransmitter functionality and effective connectivity.•The main challenges are various artifacts that may influence the biomarkers.
The search for biological targets in psychiatric disorders is essential to better understand illness mechanisms and also to monitor and predict response to currently available therapeutic ...interventions. To this end, the combination of transcranial magnetic stimulation with electroencephalography (TMS‐EEG) has emerged as a powerful clinical research tool. TMS‐EEG allows cortical properties, such as excitability, inhibition, oscillatory activity, and connectivity, to be directly probed within a specific region of the cortex. This review will summarize the state of the current literature on TMS‐EEG and its potential to uncover biological targets in psychiatric illnesses, with a focus on major depressive disorder, bipolar disorder, and schizophrenia. Collectively, the reviewed studies suggest that alterations in gamma‐aminobutyric acid‐mediated inhibition and gamma oscillations in the dorsolateral prefrontal cortex and neighboring frontal regions are potential shared biomarkers in psychiatry, highlighting the potential of TMS‐EEG to help identify translational biomarkers.
Treatment-resistant depression (TRD) is a subset of Major Depressive Disorder which does not respond to traditional and first-line therapeutic options. There are several definitions and staging ...models of TRD and a consensus for each has not yet been established. However, in common for each model is the inadequate response to at least 2 trials of antidepressant pharmacotherapy. In this review, a comprehensive analysis of existing literature regarding the challenges and management of TRD has been compiled. A PubMed search was performed to assemble meta-analyses, trials and reviews on the topic of TRD. First, we address the confounds in the definitions and staging models of TRD, and subsequently the difficulties inherent in assessing the illness. Pharmacological augmentation strategies including lithium, triiodothyronine and second-generation antipsychotics are reviewed, as is switching of antidepressant class. Somatic therapies, including several modalities of brain stimulation (electroconvulsive therapy, repetitive transcranial magnetic stimulation, magnetic seizure therapy and deep brain stimulation) are detailed, psychotherapeutic strategies and subsequently novel therapeutics including ketamine, psilocybin, anti-inflammatories and new directions are reviewed in this manuscript. Our review of the evidence suggests that further large-scale work is necessary to understand the appropriate treatment pathways for TRD and to prescribe effective therapeutic options for patients suffering from TRD.
Alterations in glutamatergic neurotransmission are implicated in the pathophysiology of depression, and the glutamatergic system represents a treatment target for depression. To summarize the nature ...of glutamatergic alterations in patients with depression, we conducted a meta-analysis of proton magnetic resonance (
H-MRS) spectroscopy studies examining levels of glutamate. We used the search terms: depress* AND (MRS OR "magnetic resonance spectroscopy"). The search was performed with MEDLINE, Embase, and PsycINFO. The inclusion criteria were
H-MRS studies comparing levels of glutamate + glutamine (Glx), glutamate, or glutamine between patients with depression and healthy controls. Standardized mean differences (SMD) were calculated to assess group differences in the levels of glutamatergic neurometabolites. Forty-nine studies met the eligibility criteria, which included 1180 patients and 1066 healthy controls. There were significant decreases in Glx within the medial frontal cortex (SMD = -0.38; 95% CI, -0.69 to -0.07) in patients with depression compared with controls. Subanalyses revealed that there was a significant decrease in Glx in the medial frontal cortex in medicated patients with depression (SMD = -0.50; 95% CI, -0.80 to -0.20), but not in unmedicated patients (SMD = -0.27; 95% CI, -0.76 to 0.21) compared with controls. Overall, decreased levels of glutamatergic metabolites in the medial frontal cortex are linked with the pathophysiology of depression. These findings are in line with the hypothesis that depression may be associated with abnormal glutamatergic neurotransmission.
Recently, a growing body of data has revealed that beyond a dysfunction of connectivity among different brain areas in schizophrenia patients (SCZ), there is also an abnormal asymmetry of functional ...connectivity compared with healthy subjects. The loss of the cerebral torque and the abnormalities of gyrification, with an increased or more complex cortical folding in the right hemisphere may provide an anatomical basis for such aberrant connectivity in SCZ. Furthermore, diffusion tensor imaging studies have shown a significant reduction of leftward asymmetry in some key white-matter tracts in SCZ. In this paper, we review the studies that investigated both structural brain asymmetry and asymmetry of functional connectivity in healthy subjects and SCZ. From an analysis of the existing literature on this topic, we can hypothesize an overall generally attenuated asymmetry of functional connectivity in SCZ compared to healthy controls. Such attenuated asymmetry increases with the duration of the disease and correlates with psychotic symptoms. Finally, we hypothesize that structural deficits across the corpus callosum may contribute to the abnormal asymmetry of intra-hemispheric connectivity in schizophrenia.
•An overview of TMS-EEG methodology and neurophysiological derivations.•A comprehensive review of TMS-EEG as a clinical tool to study healthy and disease brain states.•A discussion of current ...challenges in the field of TMS-EEG and recommendations for future studies.
Concurrent transcranial magnetic stimulation and electroencephalography (TMS–EEG) has emerged as a powerful tool to non-invasively probe brain circuits in humans, allowing for the assessment of several cortical properties such as excitability and connectivity. Over the past decade, this technique has been applied to various clinical populations, enabling the characterization and development of potential TMS–EEG predictors and markers of treatments and of the pathophysiology of brain disorders. The objective of this article is to present a comprehensive review of studies that have used TMS–EEG in clinical populations and to discuss potential clinical applications. To provide a technical and theoretical framework, we first give an overview of TMS–EEG methodology and discuss the current state of knowledge regarding the use of TMS–EEG to assess excitability, inhibition, plasticity and connectivity following neuromodulatory techniques in the healthy brain. We then review the insights afforded by TMS–EEG into the pathophysiology and predictors of treatment response in psychiatric and neurological conditions, before presenting recommendations for how to address some of the salient challenges faced in clinical TMS–EEG research. Finally, we conclude by presenting future directions in line with the tremendous potential of TMS–EEG as a clinical tool.
Background
Considerable research has demonstrated the efficacy of repetitive transcranial magnetic stimulation (rTMS) treatment in patients with depression. However, limited research has described ...the pattern of response to rTMS treatment or explored possible predictors of the likelihood of treatment response.
Methods
Data from 11 clinical trials (n = 1,132) was pooled and we described the pattern of response to rTMS, rate of response, and remission as well as potential clinical and demographic predictors of response.
Results
There was a bimodal pattern of response to rTMS with the response‐associated peak at 57% reduction in depression rating scale scores. About 46% of patients achieved response criteria, with 31% completing rTMS treatment in remission. A greater likelihood of response was seen for patients who had less severe depression at baseline, a shorter duration of the current episode, and recurrent rather than single episode of depression. Greater response was also seen in patients treated at higher stimulation intensity.
Conclusions
A meaningful percentage (>40%) of patients respond to a course of rTMS treatment. Response does vary with a number of clinical and demographic variables but none of these variables exert a sufficiently strong influence on response rates to warrant using these criteria to exclude patients from treatment.
Cognitive deficits are a core feature of schizophrenia. Among these deficits, working memory impairment is considered a central cognitive impairment in schizophrenia. The prefrontal cortex, a region ...critical for working memory performance, has been demonstrated as a critical liability region in schizophrenia. As yet, there are no standardized treatment options for working memory deficits in schizophrenia. In this review, we summarize the neuronal basis for working memory impairment in schizophrenia, including dysfunction in prefrontal signaling pathways (e.g., γ-aminobutyric acid transmission) and neural network synchrony (e.g., gamma/theta oscillations). We discuss therapeutic strategies for working memory dysfunction such as pharmacological agents, cognitive remediation therapy, and repetitive transcranial magnetic stimulation. Despite the drawbacks of current approaches, the advances in neurobiological and translational treatment strategies suggest that clinical application of these methods will occur in the near future.
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