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Placebo-controlled trials are the gold standard of evaluating treatment efficacy in clinical research. Neuromodulation is emerging as an important treatment pathway for many neuropsychiatric conditions, and placebo control arms of these trials require careful design with unique considerations (e.g., sham devices that mimic active stimulation, blinding effectiveness). Inherent to placebo-controlled trials are ethical concerns, such as deception, and potential harm of not receiving the active treatment. In this article, we outline important ethical considerations of placebo-controlled trials across neuromodulation approaches and provide recommendations on how ethical principles can be adhered to going forward. We specifically address issues of autonomy and respect for persons, beneficence, and justice. Within the context of this ethical framework, we also discuss factors influencing placebo effects in neuromodulation, the importance of adequate blinding, and alternative trial designs that could be considered.

Understanding the complex mechanisms underlying redox-mediated biological processes is a fundamental pillar of cellular biology. We describe the identification and quantification of disulfide formation and reduction in response to phosphine–borane complexes. We illustrate the specific cysteine reduction effects of the novel phosphine–borane complex bis(3-propionic acid methyl ester) phenylphosphine–borane complex (PB1) on cultured 661W cells. A total of 1073 unique protein fragments from 628 unique proteins were identified and quantified, of which 13 were found to be statistically significant in comparison to control cells. Among the 13 identified proteins were Notch1, HDAC1, UBA1, USP7, and subunits L4 and L7 of the 60S ribosomal subunit, all of which are involved in redox or cell death-associated pathways. Leveraging the ability of tandem mass tagging mass spectrometry to provide quantitative data in an exploratory manner provides insight into the effect PB1 and other phosphine–borane compounds may have on the cysteine redoxome.

Schizophrenia spectrum disorders are more common in autistic individuals than in the general population. A recent meta-analysis found that autistic individuals have a higher prevalence of these disorders (e.g., schizophrenia, schizoaffective, delusional), at 4%, than the general population, at 0.46%. Larger studies of autistic individuals with intellectual disability report higher prevalence of schizophrenia spectrum disorders than those with smaller samples. The overlapping features of autism and schizophrenia may complicate diagnostic assessment. Developmental history and an assessment of speech patterns are helpful in differentiating the disorders. Unlike in schizophrenia, symptoms of autism must be present in early develop mental years and generally have a stable course; however, symptoms may not be recognized until later in life when social communication expectations increase beyond the person's coping abilities. Clinicians can differentiate disorganized speech due to psychosis versus autism by comparing the patterns to an individual's baseline speech and exploring a developmental history. Autistic individuals often have atypical language patterns compared with their neurotypical peers. Treatment guidelines for schizophrenia apply to autistic individuals with co-occurring schizophrenia. Risperidone and aripiprazole should be considered when treating autistic individuals with co-occurring schizophrenia.

There is growing evidence that placebo effects can meaningfully modulate the brain. However, there has been little consideration of whether these changes may overlap with regions/circuits targeted by depression treatments and what the implications of this overlap would be on measuring efficacy in placebo-controlled clinical trials. In this systematic review and meta-analysis, we searched PubMed/Medline and Google Scholar for functional MRI and PET neuroimaging studies of placebo effects. Studies recruiting both healthy subjects and patient populations were included. Neuroimaging coordinates were extracted and included for Activation Likelihood Estimation (ALE) meta-analysis. We then searched for interventional studies of transcranial magnetic stimulation (TMS) and deep brain stimulation (DBS) for depression and extracted target coordinates for comparative spatial analysis with the placebo effects maps. Of 1169 articles identified, 34 neuroimaging studies of placebo effects were included. There were three significant clusters of activation: left dorsolateral prefrontal cortex (DLPFC) (x = −41, y = 16, z = 34), left sub-genual anterior cingulate cortex (sgACC)/ventral striatum (x = −8, y = 18, z = −15) and the right rostral anterior cingulate cortex (rACC) (x = 4, y = 42, z = 10). There were two significant deactivation clusters: right basal ganglia (x = 20, y = 2, z = 7) and right dorsal anterior cingulate cortex (dACC) (x = 1, y = −5, z = 45). TMS and DBS targets for depression treatment overlapped with the left DLPFC cluster and sgACC cluster, respectively. Our findings identify a common set of brain regions implicated in placebo effects across healthy individuals and patient populations, and provide evidence that these regions overlap with depression treatment targets. We model the statistical impacts of this overlap and demonstrate critical implications on measurements of clinical trial efficacy for this field.

Purpose of ReviewMild traumatic brain injury (mTBI) can result in prolonged post-concussive symptoms (e.g., depression, headaches, cognitive impairment) that are debilitating and difficult to treat. This article reviews recent research on neuromodulation for mTBI.Recent FindingsTranscranial magnetic stimulation (TMS) is the most studied neuromodulation approach for mTBI (four studies for depression, four for headache, one for cognitive impairment, and two for global post-concussive symptoms) with promising results for post-concussive depression and headache. Transcranial direct current stimulation (tDCS) has also been evaluated (one study for post-traumatic headache, and three for cognitive impairment), with more mixed results overall.SummaryTMS appears to be a potentially promising neuromodulation treatment strategy for post-concussive symptoms; however, integration into clinical practice will require larger sham-controlled randomized trials with longer and more consistent follow-up periods. Future studies should also explore new stimulation protocols, personalized approaches, and the role of placebo effects.