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There has been recent interest in the administration of transcranial electrical stimulation (tES) by a caregiver, family member, or patient themselves while in their own homes (HB-tES). The need to properly train individuals in the administration of HB-tES is essential, and the lack of a uniform training approach across studies has come to light. The primary aim of this paper is to present the HB-tES training and supervision program, a tele-supervised, instructional, and evaluation program to teach laypersons how to administer HB-tES to a participant and to provide a standardized framework for remote monitoring of participants by teaching staff. The secondary aim is to present early pilot data on the feasibility and effectiveness of the training portion of the program based on its implementation in 379 sessions between two pilot clinical trials.

Deep brain stimulation (DBS) via implanted electrodes is used worldwide to treat patients with severe neurological and psychiatric disorders. However, its invasiveness precludes widespread clinical use and deployment in research. Temporal interference (TI) is a strategy for non-invasive steerable DBS using multiple kHz-range electric fields with a difference frequency within the range of neural activity. Here we report the validation of the non-invasive DBS concept in humans. We used electric field modeling and measurements in a human cadaver to verify that the locus of the transcranial TI stimulation can be steerably focused in the hippocampus with minimal exposure to the overlying cortex. We then used functional magnetic resonance imaging and behavioral experiments to show that TI stimulation can focally modulate hippocampal activity and enhance the accuracy of episodic memories in healthy humans. Our results demonstrate targeted, non-invasive electrical stimulation of deep structures in the human brain.

The COVID-19 pandemic provides a unique opportunity to investigate the psychological impact of a global major adverse situation. Our aim was to examine, in a longitudinal prospective study, the demographic, psychological, and neurobiological factors associated with interindividual differences in resilience to the mental health impact of the pandemic.

The concept of interhemispheric inhibition has been studied for many years, beginning in 1940 with Curtis, who was among the first researchers to stimulate one hemisphere of the brain and [...], Background. Interhemispheric inhibition might be a beneficial cortico-cortical interaction, but also might be maladaptive in people with neurological disorders. One recently revisited technique that has been shown to be effective in improving motor function in people with stroke using interhemispheric modulation is transcranial direct current stimulation (tDCS). Objective. The aim of this study was to investigate the effects of tDCS combined with unilateral motor training with contralateral hand restraint on interhemispheric inhibition between the dominant and nondominant hemispheres of the brain and on motor performance in participants who were healthy. Design, This was a double-blind, prospective, single-center study with participants who were healthy. Methods. Twenty participants who were healthy were randomly assigned to receive either active or sham tDCS of the primary motor cortex (M1) bilaterally combined with unilateral motor training and contralateral hand restraint. A blinded rater assessed motor function and cortical excitability, including assessment of transcallosal inhibition (TCI). Results. There was a larger increase in motor performance in the nondominant hand for the active tDCS group compared with the sham tDCS group. In addition, a decrease in cortical excitability in the dominant hemisphere and a decrease in TCI from the dominant to nondominant hemisphere were observed for the active tDCS group only. The TCI decrease in the active tDCS group was correlated with motor performance improvement for the nondominant hand. Limitations. Limitations of this study included missing the effect of intracortical inhibition due to a floor effect, not using the optimal tDCS montage, and not being able to assess the effects of other variables such as gender due to the small sample size. Conclusions. The results indicate that tDCS enhances the effects of unilateral motor training and contralateral hand restraint on motor function, and this benefit is associated with a different mechanism of action characterized by bihemispheric modulation in which TCI from the dominant to the nondominant hemisphere is decreased. Transcranial direct current stimulation might be a useful tool to enhance the motor effects of constraint-induced movement therapy.

The mechanisms underlying tinnitus are still not completely elucidated, but advances in neuroimaging and brain stimulation have provided us with new insights. Evidence suggests that tinnitus might actually be generated [...]

Transcranial magnetic stimulation (TMS) is a non-invasive technique for focal brain stimulation based on electromagnetic induction where a fluctuating magnetic field induces a small intracranial electric current in the brain. For more than 35 years, TMS has shown promise in the diagnosis and treatment of neurological and psychiatric disorders in adults. In this review, we provide a brief introduction to the TMS technique with a focus on repetitive TMS (rTMS) protocols, particularly theta-burst stimulation (TBS), and relevant rTMS-derived metrics of brain plasticity. We then discuss the TMS-EEG technique, the use of neuronavigation in TMS, the neural substrate of TBS measures of plasticity, the inter- and intraindividual variability of those measures, effects of age and genetic factors on TBS aftereffects, and then summarize alterations of TMS-TBS measures of plasticity in major neurological and psychiatric disorders including autism spectrum disorder, schizophrenia, depression, traumatic brain injury, Alzheimer’s disease, and diabetes. Finally, we discuss the translational studies of TMS-TBS measures of plasticity and their therapeutic implications.

AimsDiagnostic tumour samples are mandatory for morphologic and molecular diagnosis of non-small cell lung cancer (NSCLC) to establish the best therapeutic approach. In the presence of small tumour tissue sample, the pathologist needs to make responsible choices to achieve a correct diagnosis and save material for subsequent molecular evaluations. Nevertheless, in some instances, the diagnostic process can lead to tissue depletion. The automated Idylla epidermal growth factor receptor (EGFR) mutation test has been developed to rapidly process formalin-fixed paraffin-embedded (FFPE) pathologic material, without previous DNA extraction. This study aimed to test whether this platform is suitable for the reuse of H&E, immunohistochemistry (IHC) and fluorescence in situ hybridisation (FISH) diagnostic slides.MethodsA training set of 19 FFPE tissues with known EGFRstatus was revaluated on H&E slides. Fourteen of them were also tested using IHC and FISH treated specimens. An additional series of 25 H&E, IHC or FISH slides of NSCLC cases tested for EGFRmutation at an external institution was blindly assessed as a validation cohort.ResultsCombining the two sets, 32 of 32 classical ex19dels and p.L858R were correctly identified. Three uncommon mutations (p.G719X, p.L861Q and ex20ins) were also detected. Four discrepancies were related to rare ex19del/ins not included in the Idylla list of detectable mutations. Two p.T790M variants were missed on one FFPE and two H&E slides but were detected using IHC and FISH sections from the same FFPE blocks.ConclusionsThe Idylla EGFRmutation test is highly reliable using differently treated tumour specimens and should be validated in larger studies.

AimsHeterogeneous implementation of molecular tests in current diagnostic algorithm at a European and international level is emerging as a major issue for efficient lung cancer molecular profiling.MethodsFrom May 2017 until October 2017, N=1612 patients referring to 13 Italian institutions were selected, at advanced stage non-small cell lung cancer (NSCLC), and prospectively evaluated. Principal endpoints were: the percentage of diagnoses performed on cytological and histological material, the proportion of requests for epidermal growth factor receptor (EGFR) mutational status, and resistance mutations detected on tissue and/or liquid biopsy samples after first-generation or second-generation tyrosine kinase inhibitors, the proportion of requests for anaplastic lymphoma kinase (ALK) gene rearrangements, ROS proto-oncogene 1 (ROS1) and Kirsten Rat Sarcoma (KRAS) determinations, the proportion of requests for programmed death-ligand1 (PD-L1) evaluation and, finally, the different assays used for the detection of EGFR mutations, ALK and ROS1 gene rearrangements and PD-L1 expression.ResultsOf 1325 patients finally included, only 50.8% requests were related to driver mutations with target agents already available in first-line at that preplanned time, while 49.2% were associated with PD-L1, ROS1, KRAS and others. Multiplex genomic assays (such as next-generation sequencing) were considered by all participating centres.ConclusionsTo the best of our knowledge, this is the first study in a ‘real-life daily practice’ involving both pathologists and oncologists evaluating routinely workflow and trends towards improvements in molecular requests. Collected data aim to describe the applied algorithms and evolution of molecular screening for stage IV NSCLC in clinical practice.

Background. Nm23 is a gene associated with low tumor metastatic potential and has been proposed to be a metastasis suppressor gene. Nm23 is localized on chromosome 17q21.3-22, whereas the p53 suppressor gene is on 17p13. Allelic deletions of chromosome 17 have been related to the progression of colorectal carcinomas. The purpose of this study was to analyze the allelic deletions of Nm23 and p53 in colorectal carcinomas and to assess their prognostic significance in the evolution of the patients. Methods. Allelic deletions of Nm23 and p53 genes were studied in 56 colorectal carcinomas using different restriction fragment length polymorphisms. DNA ploidy and proliferative activity of the tumors were studied by flow cytometry. Actuarial disease free and overall survival were analyzed by the Kaplan--Meier method, and the curves were compared with the log rank test. Results. Thirty-eight patients were heterozygous for Nm23 gene (68%), and 9 of them (24%) exhibited a loss of heterozygosity in the tumor sample. One of the homozygous patients showed a loss of both Nm23 alleles. Allelic deletions of 17p13 were found in 63% of the 41 informative patients. All patients' tumors that had loss of heterozygosity of the Nm23-H1 locus also had allelic losses on the short arm of chromosome 17 (17p13) and in other loci on 17q. No relationship was found between localization, invasion, lymph node metastasis, or proliferative index of the tumors and the allelic deletions of the Nm23-H1 or 17pl3 locus. Nm23-H1 deletions were relatively more frequent in poorly differentiated adenocarcinomas (P - 0.03). A significant association between 17pl3 deletions and DNA aneuploidy was found (P = 0.016). A similar tendency was observed with Nm23-H1 deletions (P = 0.051). Loss of Nm23-H1, but not of 17p13, was significantly associated with a shorter disease free (P 0.025) and overall (P = 0.04) patient survival. Conclusions. Allelic deletions of Nm23-H1 are significantly associated with a more aggressive behavior of colorectal carcinomas. The loss of this gene seems to be part of extensive deletions of chromosome 17, and it is also associated with DNA aneuploidy. More studies are needed to determine whether Nm23-H1 or a gene linked to this locus is the specific target of the progression of these tumors. Cancer 1994;73:2913-21. Key words: Nm23, p53, DNA ploidy, tumor suppressor genes, colorectal carcinoma.

Tyrosinemia, a hereditary disease, is caused by an enzyme deficiency in the metabolic pathway of tyrosine, an amino acid, and is usually fatal if a liver transplant cannot be performed. Chronic liver failure and kidney problems are the usual features of tyrosinemia, but as many as 40 percent of children may develop neurological problems. In patients suffering from porphyria, a similar onset of neurological problems, which have been attributed to the accumulation of aminolevulinic acid (ALA) in the blood, has been noted; these patients have been successfully treated by reducing ALA production with hematin (heme), an iron-containing compound. The use of hematin in the treatment of a 21-month-old boy, a known tyrosenemic with high ALA levels, is described. The infant showed neurologic weakness that had progressed to quadriplegia (paralysis) two weeks before hematin therapy was started. The patient was alert and regained functional use of his arms and legs by 21 days after beginning hematin therapy. One year after liver transplant, the boy was developing normally. This case suggests that neurological disorders brought on by tyrosinemia may be managed by administering hematin. (Consumer Summary produced by Reliance Medical Information, Inc.)

•Advances in neurobiological understanding about the cause of cognitive disability in AD spark new hopes for therapeutic strategies.•Metrics of neuronal communication and functional integration in large-scale networks are promising biomarkers for AD.•Personally meaningful memories of our past are not fixed, but may be strengthened by later intervention, such as non-invasive brain stimulation.•Transcranial alternating current stimulation studies show that weakened physiological mechanisms may be reversible.

The brain regions responsible for hallucinations remain unclear. We studied 89 brain lesions causing hallucinations using a recently validated technique termed lesion network mapping. We found that hallucinations occurred following lesions to a variety of different brain regions, but these lesion locations fell within a single functionally connected brain network. This network was defined by connectivity to the cerebellar vermis, inferior cerebellum (bilateral lobule X), and the right superior temporal sulcus. Within this single hallucination network, additional connections with the lesion location dictated the sensory modality of the hallucination: lesions causing visual hallucinations were connected to the lateral geniculate nucleus in the thalamus while lesions causing auditory hallucinations were connected to the dentate nucleus in the cerebellum. Our results suggest that lesions causing hallucinations localize to a single common brain network, but additional connections within this network dictate the sensory modality, lending insight into the causal neuroanatomical substrate of hallucinations.

IMPORTANCE: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of the motor nervous system. Clinical studies have demonstrated cortical and spinal motor neuron hyperexcitability using transcranial magnetic stimulation and threshold tracking nerve conduction studies, respectively, although metrics of excitability have not been used as pharmacodynamic biomarkers in multi-site clinical trials. OBJECTIVE: To ascertain whether ezogabine decreases cortical and spinal motor neuron excitability in ALS. DESIGN, SETTING, AND PARTICIPANTS: This double-blind, placebo-controlled phase 2 randomized clinical trial sought consent from eligible participants from November 3, 2015, to November 9, 2017, and was conducted at 12 US sites within the Northeast ALS Consortium. Participants were randomized in equal numbers to a higher or lower dose of ezogabine or to an identical matched placebo, and they completed in-person visits at screening, baseline, week 6, and week 8 for clinical assessment and neurophysiological measurements. INTERVENTIONS: Participants were randomized to receive 600 mg/d or 900 mg/d of ezogabine or a matched placebo for 10 weeks. MAIN OUTCOMES AND MEASURES: The primary outcome was change in short-interval intracortical inhibition (SICI; SICI−1 was used in analysis to reflect stronger inhibition from an increase in amplitude) from pretreatment mean at screening and baseline to the full-dose treatment mean at weeks 6 and 8. The secondary outcomes included levels of cortical motor neuron excitability (including resting motor threshold) measured by transcranial magnetic stimulation and spinal motor neuron excitability (including strength-duration time constant) measured by threshold tracking nerve conduction studies. RESULTS: A total of 65 participants were randomized to placebo (23), 600 mg/d of ezogabine (23), and 900 mg/d of ezogabine (19 participants); 45 were men (69.2%) and the mean (SD) age was 58.3 (8.8) years. The SICI−1 increased by 53% (mean ratio, 1.53; 95% CI, 1.12-2.09; P = .009) in the 900-mg/d ezogabine group vs placebo group. The SICI−1 did not change in the 600-mg/d ezogabine group vs placebo group (mean ratio, 1.15; 95% CI, 0.87-1.52; P = .31). The resting motor threshold increased in the 600-mg/d ezogabine group vs placebo group (mean ratio, 4.61; 95% CI, 0.21-9.01; P = .04) but not in the 900-mg/d ezogabine group vs placebo group (mean ratio, 1.95; 95% CI, −2.64 to 6.54; P = .40). Ezogabine caused a dose-dependent decrease in excitability by several other metrics, including strength-duration time constant in the 900-mg/d ezogabine group vs placebo group (mean ratio, 0.73; 95% CI, 0.60 to 0.87; P < .001). CONCLUSIONS AND RELEVANCE: Ezogabine decreased cortical and spinal motor neuron excitability in participants with ALS, suggesting that such neurophysiological metrics may be used as pharmacodynamic biomarkers in multisite clinical trials. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02450552

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.

IMPORTANCE: Small studies suggest that head trauma in men may be associated with low testosterone levels and sexual dysfunction through mechanisms that likely include hypopituitarism secondary to ischemic injury and pituitary axonal tract damage. Athletes in contact sports may be at risk for pituitary insufficiencies or erectile dysfunction (ED) because of the high number of head traumas experienced during their careers. Whether multiple symptomatic concussive events are associated with later indicators of low testosterone levels and ED is unknown. OBJECTIVE: To explore the associations between concussion symptom history and participant-reported indicators of low testosterone levels and ED. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study of former professional US-style football players was conducted in Boston, Massachusetts, from January 2015 to March 2017. Surveys on past football exposures, demographic factors, and current health conditions were sent via electronic and postal mail to participants within and outside of the United States. Analyses were conducted in Boston, Massachusetts; the data analysis began in March 2018 and additional analyses were performed through June 2019. Of the 13 720 male former players eligible to enroll who were contacted, 3506 (25.6%) responded. EXPOSURES: Concussion symptom score was calculated by summing the frequency with which participants reported 10 symptoms, such as loss of consciousness, disorientation, nausea, memory problems, and dizziness, at the time of football-related head injury. MAIN OUTCOMES AND MEASURES: Self-reported recommendations or prescriptions for low testosterone or ED medication served as indicators for testosterone insufficiency and ED. RESULTS: In 3409 former players (mean [SD] age, 52.5 [14.1] years), the prevalence of indicators of low testosterone levels and ED was 18.3% and 22.7%, respectively. The odds of reporting low testosterone levels or ED indicators were elevated for previously established risk factors (eg, diabetes, sleep apnea, and mood disorders). Models adjusted for demographic characteristics, football exposures, and current health factors showed a significant monotonically increasing association of concussion symptom score with the odds of reporting the low testosterone indicator (highest vs lowest quartile, odds ratio, 2.39; 95% CI, 1.79-3.19; P < .001). The ED indicator showed a similar association (highest quartile vs lowest, odds ratio, 1.72; 95% CI, 1.30-2.27; P < .001). CONCLUSIONS AND RELEVANCE: Concussion symptoms at the time of injury among former football players were associated with current participant-reported low testosterone levels and ED indicators. These findings suggest that men with a history of head injury may benefit from discussions with their health care clinicians regarding testosterone deficiency and sexual dysfunction.

Background: Fas ligand (FasL) is a transmembrane protein that induces apoptosis (programmed cell death) in susceptible cells by interacting with its receptor, Fas. Transmembrane FasL is cleaved by a metalloproteinase enzyme into a soluble form that is released into the extracellular medium. Tumors of the Ewing's sarcoma family express functional transmembrane FasL and release soluble FasL. This cleavage is inhibited by a matrix metalloproteinase inhibitor (MMPI). We therefore hypothesized that MMPIs can lead to apoptosis of tumor cells by inducing accumulation of transmembrane FasL. Methods: Ewing's sarcoma and neuroblastoma cell lines were treated with two synthetic MMPIs (BB-3103 and A-151011) and examined for apoptosis and expression of FasL and Fas. Results: Although MMPIs increase levels of FasL and Fas proteins on the surface of all tumor cells studied, they induced apoptosis in Fas-sensitive but not in Fas-resistant cell lines; the induction of apoptosis was inhibited by a Fasneutralizing antibody. The increase in protein expression was not associated with enhanced transcription. Treatment with an MMPI sensitized the Ewing's sarcoma cells to Fas-activating antibody and to doxorubicin-induced apoptosis. Conclusions: MMPIs cause accumulation of transmembrane FasL by inhibiting its cleavage, accumulation of Fas (probably secondarily to FasL cleavage inhibition), and decreased levels of soluble FasL. These effects lead to apoptosis in Fas-sensitive cell lines. The observed cooperative action of MMPIs and doxorubicin suggests a possible role of MMPIs in combination treatments with standard apoptosis-inducing chemotherapeutic agents. [J Natl Cancer Inst 1999;91:1678-84]

AimThe rapid and fully automated Idylla EGFRMutation Assay has been specifically designed to process formalin-fixed, paraffin-embedded sections without requiring preliminary DNA extraction. This study evaluates whether this approach can also process archival smears from patients with non–small cell lung cancer (NSCLC) by scraping the stained cellular material directly into the cartridge.MethodsThe study was divided into two parts. In the first part, we carried out Idylla EGFRMutation Assay on archival stained smears from 39 patients with NSCLC. Among these, 14 cases harboured a mutation in either exon 19 (n=11) or exon 21 (n=3), previously detected on DNA extracts by fragment length and TaqMan assays. In the second part, we evaluated whether de-staining of the smears could reduce background fluorescence.ResultsThe Idylla EGFRMutation Assay confirmed the presence of EGFRmutation in 11 instances (78.6%). However, concordance was higher for exon 19 deletions (10/11) than for exon 21 p.L858R assessments. Raw data showed a high background fluorescence in channel 2, where the EGFRexon 21 p.L858R mutation was detected. This interference, due to dye residues from the original staining, was partially reduced by de-staining the cytological material.ConclusionsOur data, although preliminary, show that the Idylla EGFRMutation Assay can reliably process most archival smears without requiring preliminary DNA extraction. Results may be further improved by de-staining the cellular material before insertion into the cartridge.

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•MCI who progressed to AD overestimated memory performance at baseline.•MCI who remained stable underestimated memory performance at baseline.•Progressor MCI group showed more concern about memory at baseline than Stable MCI.•Only Progressor MCI appeared to show less concern about memory over time.

We are on the cusp of transforming Alzheimer's care, but we aren't positioned to take this win. [ABSTRACT FROM AUTHOR]

Biomarkers have transformed modern medicine but remain largely elusive in psychiatry, partly because there is a weak correspondence between diagnostic labels and their neurobiological substrates. Like other neuropsychiatric disorders, depression is not a unitary disease, but rather a heterogeneous syndrome that encompasses varied, co-occurring symptoms and divergent responses to treatment. By using functional magnetic resonance imaging (fMRI) in a large multisite sample (n = 1,188), we show here that patients with depression can be subdivided into four neurophysiological subtypes ('biotypes') defined by distinct patterns of dysfunctional connectivity in limbic and frontostriatal networks. Clustering patients on this basis enabled the development of diagnostic classifiers (biomarkers) with high (82–93%) sensitivity and specificity for depression subtypes in multisite validation (n = 711) and out-of-sample replication (n = 477) data sets. These biotypes cannot be differentiated solely on the basis of clinical features, but they are associated with differing clinical-symptom profiles. They also predict responsiveness to transcranial magnetic stimulation therapy (n = 154). Our results define novel subtypes of depression that transcend current diagnostic boundaries and may be useful for identifying the individuals who are most likely to benefit from targeted neurostimulation therapies.

Although growing awareness about the potential long-term deleterious effects of sport-related concussion has led to increased attention to the risks of collision sports, calls to ban these sports, such as American football, might be premature. Collision sports have a relatively high incidence of concussions, but participation in these sports also confers a host of benefits. In addition, the associated risks of participation, including concussion, have not been definitively shown to outweigh the benefits they provide, and the risk–benefit ratio might vary among individuals. The risks of concussion and repetitive concussions associated with collision sports are unknown in the general population and not well characterized even in elite athlete populations. In this article, we discuss current knowledge on sports-related concussion, its neurological consequences, and implications for regulation of the practice of collision sports.

We thank Dr. Pase for his comments regarding our systematic review.1We share Dr. Pase's concern that a very large number of different cognitive tasks have been used in past studies on the effects of exercise, which poses substantial challenges to systematic reviews. Furthermore, as pointedly stated by Colcombe and Kramer2in a review of exercise and cognitive function, considerable overlap in cognitive constructs exists. We appreciate Dr. Pase's suggestion of considering the framework offered by cognitive maps and agree with their promise and value. Having the ability to prescribe the correct exercise dose for a specific cognitive domain would provide a wonderful tool for clinicians that would push the field beyond theoretical status into an established, evidence-based treatment.

Recent case reports have described athletes previously exposed to repetitive head trauma while participating in contact sports who later in life developed mood disorders, headaches, cognitive difficulties, suicidal ideation, difficulties with speech, and aggressive behavior. Postmortem discoveries show that some of these athletes have pathologic findings that are collectively termed chronic traumatic encephalopathy (CTE). Current hypotheses suggest that concussions or perhaps blows to the head that do not cause the signs and symptoms necessary for making the diagnosis of concussion, so-called subconcussive blows, cause both the clinical and pathologic findings. There are, however, some athletes who participate in contact sports who do not develop the findings ascribed to CTE. Furthermore, there are people who have headaches, mood disorders, cognitive difficulties, suicidal ideation, and other clinical problems who have neither been exposed to repeated head trauma nor possessed the pathologic postmortem findings of those currently diagnosed with CTE. The current lack of prospective data and properly designed case-control studies limits the current understanding of CTE, leading to debate about the causes of the neuropathologic findings and the clinical observations. Given the potential for referral and recall bias in available studies, it remains unclear whether or not the pathologic findings made postmortem cause the presumed neurobehavioral sequela and whether the presumed risk factors, such as sports activity, cerebral concussions, and subconcussive blows, are solely causative of the clinical signs and symptoms. This article discusses the current evidence and the associated limitations.

•tES allows to safely modulate brain activity by the means of transcranial electric fields.•tES provides greater anatomical specificity respect to other cognitive enhancer like drugs.•tES shows state and trait-dependency effects.•Regulation about tES application outside laboratory environment are needed.

Prior studies have suggested that oscillatory activity in cortical networks can modulate stimulus-evoked responses through time-varying fluctuations in neural excitation-inhibition dynamics. Studies combining transcranial magnetic stimulation (TMS) with electromyography (EMG) and electroencephalography (EEG) can provide direct measurements to examine how instantaneous fluctuations in cortical oscillations contribute to variability in TMS-induced corticospinal responses. However, the results of these studies have been conflicting, as some reports showed consistent phase effects of sensorimotor mu-rhythms with increased excitability at the negative mu peaks, while others failed to replicate these findings or reported unspecific mu-phase effects across subjects. Given the lack of consistent results, we systematically examined the modulatory effects of instantaneous and pre-stimulus sensorimotor mu-rhythms on corticospinal responses with offline EEG-based motor evoked potential (MEP) classification analyses across five identical visits. Instantaneous sensorimotor mu-phase or pre-stimulus mu-power alone did not significantly modulate MEP responses. Instantaneous mu-power analyses showed weak effects with larger MEPs during high-power trials at the overall group level analyses, but this trend was not reproducible across visits. However, TMS delivered at the negative peak of high magnitude mu-oscillations generated the largest MEPs across all visits, with significant differences compared to other peak-phase combinations. High power effects on MEPs were only observed at the trough phase of ongoing mu oscillations originating from the stimulated region, indicating site and phase specificity, respectively. More importantly, such phase-dependent power effects on corticospinal excitability were reproducible across multiple visits. We provide further evidence that fluctuations in corticospinal excitability indexed by MEP amplitudes are partially driven by dynamic interactions between the magnitude and the phase of ongoing sensorimotor mu oscillations at the time of TMS, and suggest promising insights for (re)designing neuromodulatory TMS protocols targeted to specific cortical oscillatory states.

Bistable perception occurs when a stimulus is ambiguous and has two distinct interpretations that spontaneously alternate in observers' consciousness. Studies using functional magnetic resonance imaging, electroencephalography (EEG), and transcranial magnetic stimulation (TMS) in healthy subjects and patient studies point towards a right fronto-parietal network regulating the balance between percept stabilization and the arising of alternative interpretations. However, the causal role of the interaction between parietal and prefrontal areas is not clearly understood. Using intermittent presentations of bistable images, we confirmed that maintaining or switching percepts had neural correlates identifiable on EEG. Single-pulse TMS applied over the right anterior intraparietal sulcus (IPS) 70 msec before image presentation interfered with evoked potentials and destabilized the percept. However, with paired-pulse TMS applied over right IPS and dorsolateral prefrontal cortex (DLPFC) 70 and 60 msec before image presentation, both perceptual and neurophysiological effects were canceled. Thus, TMS over IPS and DLPFC interacted with each other and influenced upcoming percepts. We suggest that when the visual world is ambiguous, IPS plays a stabilizing role, whereas DLPFC is important for triggering perceptual switches or for modulating parietal activity. The balance between maintaining and switching visual conscious percepts relies on the dynamic interaction between IPS and DLPFC.

Transcranial magnetic stimulation (TMS) holds great potential in the treatment of a host of neurological conditions due to its ability to focally modulate—suppress or enhance—activity in targeted cortical brain regions and modify activity across specific brain networks. Results from early trials in a number of neurological indications are presented, including stroke rehabilitation, Parkinson’s disease, tinnitus, chronic pain, migraine, and epilepsy. We emphasize both the challenges, such as the limited efficacy to date in tinnitus, as well as the opportunities, such as the use of TMS in epilepsy caused by focal/cortical lesions. However, to establish TMS as a clinically valuable neurological therapeutic intervention, a number of hurdles must be overcome, including accurate targeting of the treatment, characterization of its therapeutic benefit for specific patients/symptoms, proof of efficacy in multicenter trials that are adequately blinded and powered, proof of the durability of the effects, and assessment of potential adverse effects of cumulative dose and repeated application.[[Psychiatr Ann.2014; 44(6):299–304.]

Transcranial magnetic stimulation (TMS) is a neurophysiologic technique to noninvasively induce a controlled current pulse in a prespecified cortical target. This can be used to transiently disrupt the function of the targeted cortical region and explore causal relations to behavior, assess cortical reactivity, and map out functionally relevant brain regions, for example during presurgical assessments. Particularly when applied repetitively, TMS can modify cortical excitability and the effects can propagate trans-synaptically to interconnected cortical, subcortical, and spinal cord regions. As such, TMS can be used to assess the functional integrity of neural circuits and to modulate brain activity with potential therapeutic intent.

Non-small-cell lung cancer (NSCLC) subtyping has recently been a key factor in determining patient management with novel drugs. In addition, the identification of distinct oncogenic driver mutations frequently associated with NSCLC histotype and coupled to the clinical responses to targeted therapies have revolutionized the impact of histologic type and molecular biomarkers in lung cancer. Several molecular alterations involving different genes (EGFR, KRAS, ALK, BRAF, and HER2) seem to have a remarkable predilection for adenocarcinoma and specific inhibitors of EGFR and ALK are now available for patients with adenocarcinoma harboring the relevant gene alterations. The efficacy of histology-based and molecular-targeted therapies had a deep impact in (1) re-defining classification of lung cancer (particularly adenocarcinomas) and (2) routine clinical practice of pathologists involved in optimization of handling of tissue samples in order to guarantee NSCLC subtyping with the help of immunohistochemistry and adequately preserve tumor cells for molecular analysis. In agreement with the modern multidisciplinary approach to lung cancer, we reviewed here the diagnostic and predictive value of molecular biomarkers according to the clinical, pathologic, and molecular biologist viewpoints.

The use of noninvasive cortical electrical stimulation with weak currents has significantly increased in basic and clinical human studies. Initial, preliminary studies with this technique have shown encouraging results; however, the safety and tolerability of this method of brain stimulation have not been sufficiently explored yet. The purpose of our study was to assess the effects of direct current (DC) and alternating current (AC) stimulation at different intensities in order to measure their effects on cognition, mood, and electroencephalogram.

Functional MRI (fMRI) studies could provide crucial information on the neural mechanisms of motor recovery in patients with stroke. Resting-state fMRI is applicable to patients with stroke who are not capable of proper performance of the motor task. In this study, we explored neural correlates of motor recovery in patients with stroke by investigating longitudinal changes in resting-state functional connectivity of the ipsilesional primary motor cortex (M1).

Procedural skills consist of several components that can be simultaneously acquired. During a motor-learning task we can distinguish between how a “movement” is performed (intrinsic component) and the spatial-related (extrinsic) component of this movement. The intrinsic movement component is thought to be supported by motor loops, including primary motor cortex (M1) as assessed with neuroimaging studies. Here we want to test further whether M1 makes a critical contribution to the movement rather than spatial-related component of skill-learning.

Background and Purpose—Residual motor deficits frequently linger after stroke. Search for newer effective strategies to promote functional recovery is ongoing. Brain stimulation, as a means of directing adaptive plasticity, is appealing. Animal studies and Phase I and II trials in humans have indicated safety, feasibility, and efficacy of combining rehabilitation and concurrent invasive cortical stimulation. However, a recent Phase III trial showed no advantage of the combination. We critically review results of various trials and discuss the factors that contributed to the distinctive result.

Individuals using a visual-to-auditory sensory substitution device (SSD) called ‘The vOICe’ can identify objects in their environment through images encoded by sound. We have shown that identifying objects with this SSD is associated with activation of occipital visual areas. Here, we show that repetitive transcranial magnetic stimulation (rTMS) delivered to a specific area of occipital cortex (identified by functional MRI) profoundly impairs a blind user's ability to identify objects. rTMS delivered to the same site had no effect on a visual imagery task. The task and site-specific disruptive effect of rTMS in this individual suggests that the cross-modal recruitment of occipital visual areas is functional in nature and critical to the patient's ability to process and decode the image sounds using this SSD.

Electromagnetic brain stimulation might have value to reduce motor deficits after stroke. Safety and behavioral effects of higher frequencies of repetitive transcranial magnetic stimulation (rTMS) require detailed assessment.

Previous studies have shown that patients with major depression have an interhemispheric imbalance between right and left prefrontal and motor cortex. We aimed to investigate the interhemispheric interactions in patients with major depression using repetitive transcranial magnetic stimulation (rTMS). Thirteen patients with major depression and 14 age-matched healthy subjects participated in this study. Corticospinal excitability before and after 1 Hz rTMS (applied to the left primary motor cortex) was assessed in the left and right motor cortex and these results were compared with those in healthy subjects. There was a significant difference in the interhemispheric effects between patients with depression and healthy subjects. In healthy subjects, 1 Hz rTMS significantly decreased corticospinal excitability in the stimulated, left hemisphere and increased it in the contralateral, right hemisphere. In depressed subjects, 1 Hz rTMS also decreased corticospinal excitability in the left hemisphere; however, it induced no significant changes in corticospinal excitability in the contralateral, right hemisphere. In addition, there was a significant correlation between the degree of interhemispheric modulation and the severity of the depression as indexed by the Beck Depression Inventory scores. Our findings showing a decreased interhemispheric modulation in patients with major depression are consistent with the notion that mood disorders are associated with slow interhemispheric switching mechanisms.

Pain in chronic pancreatitis is frequently refractory to medical and even surgical treatment. This refractoriness leads us to believe that a pancreas-independent, brain-mediated mechanism must be responsible. If so, several scenarios are worth considering. First, chronic pain could be the consequence of undesirable neuroplastic changes, by which pathology becomes established and causes disability. Alternatively, pain may be linked to the salutogenic (from salutogenesis, the Latin word for health and well-being) central nervous system response (we defined 'salutogenic response' as the specific modulation of the immune system induced by brain activity changes) to promote healing of the injured viscera. If so, chronic pain could index the ongoing nervous system attempt to promote healing. In this review, we discuss (1) the mechanisms of pain in chronic pancreatitis; (2) potential brain-related salutogenic mechanisms, and (3) the potential relationship of these two factors to the disease status. Furthermore, we consider these aspects in light of a new approach to treat visceral pain: transcranial magnetic stimulation, a noninvasive method of brain stimulation.