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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.

Electroencephalographic (EEG) microstate analysis is a method of identifying quasi-stable functional brain states (\"microstates\") that are altered in a number of neuropsychiatric disorders, suggesting their potential use as biomarkers of neurophysiological health and disease. However, use of EEG microstates as neurophysiological biomarkers requires assessment of the test-retest reliability of microstate analysis. We analyzed resting-state, eyes-closed, 30-channel EEG from 10 healthy subjects over 3 sessions spaced approximately 48 hours apart. We identified four microstate classes and calculated the average duration, frequency, and coverage fraction of these microstates. Using Cronbach's α and the standard error of measurement (SEM) as indicators of reliability, we examined: (1) the test-retest reliability of microstate features using a variety of different approaches; (2) the consistency between TAAHC and k-means clustering algorithms; and (3) whether microstate analysis can be reliably conducted with 19 and 8 electrodes. The approach of identifying a single set of \"global\" microstate maps showed the highest reliability (mean Cronbach's α > 0.8, SEM ≈ 10% of mean values) compared to microstates derived by each session or each recording. There was notably low reliability in features calculated from maps extracted individually for each recording, suggesting that the analysis is most reliable when maps are held constant. Features were highly consistent across clustering methods (Cronbach's α > 0.9). All features had high test-retest reliability with 19 and 8 electrodes. High test-retest reliability and cross-method consistency of microstate features suggests their potential as biomarkers for assessment of the brain's neurophysiological health.

In a post hoc analysis of prospective cohorts, carbapenems were not superior to in vitro active β-lactam/β-lactam inhibitor combinations (amoxicillin-clavulanic acid or piperacillin-tazobactam) in treatment of bacteremia caused by extended-spectrum ß-lactamase-producing Escherichia coli, mostly from urinary or biliary infections. (See the Editorial Commentary by Perez and Bonomo, on pages 175-7.) Background.  Extended-spectrum ß-lactamase-producing Escherichia coli (ESBL-EC) is an important cause of invasive infections. Alternatives to carbapenems-considered the drugs of choice-are needed because of the emergence of carbapenemase-producing enterobacteria. The efficacy of ß-lactam/ß-lactam inhibitors (BLBLI) in such infections is controversial. Methods.  The authors performed a post hoc analysis of patients with bloodstream infections due to ESBL-EC from 6 published prospective cohorts. Mortality and length of hospital stay in patients treated with an active BLBLI (amoxicillin-clavulanic acid [AMC] and piperacillin-tazobactam [PTZ]) or carbapenem were compared in 2 cohorts: the empirical therapy cohort (ETC) and the definitive therapy cohort (DTC). Confounding was controlled by multivariate analysis; for patients in the ETC, a propensity score for receiving carbapenem was also used. Results.  The ETC included 103 patients (BLBLI, 72; carbapenem, 31), and the DTC included 174 (BLBLI, 54; carbapenem, 120). Mortality rates at day 30 for those treated with BLBLI versus carbapenems were 9.7% versus 19.4% for the ETC and 9.3% versus 16.7% for the DTC, respectively (P > .2, log-rank test). After adjustment for confounders, no association was found between either empirical therapy with BLBLI (adjusted hazard ratio [HR], 1.14; 95% confidence interval [CI], .29-4.40; P = .84) or definitive therapy (adjusted HR, 0.76; 95% CI, .28-2.07; P = .5) and increased mortality. Furthermore, BLBLI therapy, with respect to carbapenem, was not found to influence length of hospital stay. Conclusions.  These results suggest that AMC and PTZ are suitable alternatives to carbapenems for treating patients with bloodstream infections due to ESBL-EC if active in vitro and would be particularly useful as definitive therapy.

Background Alzheimer’s disease (AD) is associated with alterations in cortical perfusion that correlate with cognitive impairment. Recently, neural activity in the gamma band has been identified as a driver of arteriolar vasomotion while, on the other hand, gamma activity induction on preclinical models of AD has been shown to promote protein clearance and cognitive protection. Methods In two open-label studies, we assessed the possibility to modulate cerebral perfusion in 15 mild to moderate AD participants via 40Hz (gamma) transcranial alternating current stimulation (tACS) administered 1 h daily for 2 or 4 weeks, primarily targeting the temporal lobe. Perfusion-sensitive MRI scans were acquired at baseline and right after the intervention, along with electrophysiological recording and cognitive assessments. Results No serious adverse effects were reported by any of the participants. Arterial spin labeling MRI revealed a significant increase in blood perfusion in the bilateral temporal lobes after the tACS treatment. Moreover, perfusion changes displayed a positive correlation with changes in episodic memory and spectral power changes in the gamma band. Conclusions Results suggest 40Hz tACS should be further investigated in larger placebo-controlled trials as a safe, non-invasive countermeasure to increase fast brain oscillatory activity and increase perfusion in critical brain areas in AD patients. Trial registration Studies were registered separately on ClinicalTrials.gov ( NCT03290326 , registered on September 21, 2017; NCT03412604 , registered on January 26, 2018).

Key Points Sensory deprivation is associated with striking crossmodal neuroplastic changes in the brain. Following sensory deprivation (for example, blindness or deafness), there is functional recruitment of brain areas that are normally associated with the processing of the lost sense by those sensory modalities that are spared. These changes seem to underlie adaptive and compensatory behaviours in both blind and deaf individuals. In the case of blindness, occipital cortical areas are recruited to process non-visual forms of sensory information such as touch, hearing and verbal memory. In the case of deafness, auditory and language-related areas are recruited to process tactile as well as linguistic and non-linguistic visual information. Experiments in animal models have helped to uncover potential mechanisms underlying these neuroplastic changes, such as the existence of direct cortico-cortical connections between relevant sensory processing areas. Not all neuroplastic changes are beneficial. There is the possibility of maladaptive consequences, particularly in the context of rehabilitation and the restoration of lost sensory function. The remarkable functional and structural changes that take place in the brains of blind and deaf individuals following sensory loss enable them to operate effectively in their environment. Here the authors discuss the current understanding of the mechanisms that underlie this crossmodal neuroplasticity and its implications for rehabilitation. There is growing evidence that sensory deprivation is associated with crossmodal neuroplastic changes in the brain. After visual or auditory deprivation, brain areas that are normally associated with the lost sense are recruited by spared sensory modalities. These changes underlie adaptive and compensatory behaviours in blind and deaf individuals. Although there are differences between these populations owing to the nature of the deprived sensory modality, there seem to be common principles regarding how the brain copes with sensory loss and the factors that influence neuroplastic changes. Here, we discuss crossmodal neuroplasticity with regards to behavioural adaptation after sensory deprivation and highlight the possibility of maladaptive consequences within the context of rehabilitation.

Therapies for motor recovery after stroke or traumatic brain injury are still not satisfactory. To date the best approach seems to be the intensive physical therapy. However the results are limited and functional gains are often minimal. The goal of motor training is to minimize functional disability and optimize functional motor recovery. This is thought to be achieved by modulation of plastic changes in the brain. Therefore, adjunct interventions that can augment the response of the motor system to the behavioural training might be useful to enhance the therapy-induced recovery in neurological populations. In this context, noninvasive brain stimulation appears to be an interesting option as an add-on intervention to standard physical therapies. Two non-invasive methods of inducing electrical currents into the brain have proved to be promising for inducing long-lasting plastic changes in motor systems: transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS). These techniques represent powerful methods for priming cortical excitability for a subsequent motor task, demand, or stimulation. Thus, their mutual use can optimize the plastic changes induced by motor practice, leading to more remarkable and outlasting clinical gains in rehabilitation. In this review we discuss how these techniques can enhance the effects of a behavioural intervention and the clinical evidence to date.

The emergence of multidrug resistant (MDR) pathogenic bacteria is jeopardizing the value of antimicrobials, which had previously changed the course of medical science. In this study, we identified endolysins ElyA1 and ElyA2 (GH108-PG3 family), present in the genome of bacteriophages Ab1051Φ and Ab1052Φ, respectively. The muralytic activity of these endolysins against MDR clinical isolates ( Acinetobacter baumannii , Pseudomonas aeruginosa and Klebsiella pneumoniae ) was tested using the turbidity reduction assay. Minimal inhibitory concentrations (MICs) of endolysin, colistin and a combination of endolysin and colistin were determined, and the antimicrobial activity of each treatment was confirmed by time kill curves. Endolysin ElyA1 displayed activity against all 25 strains of A. baumannii and P. aeruginosa tested and against 13 out of 17 strains of K. pneumoniae . Endolysin ElyA2 did not display any such activity. The combined antimicrobial activity of colistin and ElyA1 yielded a reduction in the colistin MIC for all strains studied, except K. pneumoniae . These results were confirmed in vivo in G. mellonella survival assays and in murine skin and lung infection models. In conclusion, combining colistin (1/4 MIC) with the new endolysin ElyA1 (350 µg) enhanced the bactericidal activity of colistin in both in vitro and in vivo studies. This will potentially enable reduction of the dose of colistin used in clinical practice.

Cerebellar ataxias are a heterogenous group of degenerative disorders for which we currently lack effective and disease-modifying interventions. The field of non-invasive brain stimulation has made much progress in the development of specific stimulation protocols to modulate cerebellar excitability and try to restore the physiological activity of the cerebellum in patients with ataxia. In light of limited evidence-based pharmacologic and non-pharmacologic treatment options for patients with ataxia, several different non-invasive brain stimulation protocols have emerged, particularly employing repetitive transcranial magnetic stimulation (rTMS) or transcranial direct current stimulation (tDCS) techniques. In this review, we summarize the most relevant rTMS and tDCS therapeutic trials and discuss their implications in the care of patients with degenerative ataxias.

Transcranial magnetic stimulation (TMS), a tool that allows noninvasive modulation of cortical neural activity, has become an important tool in cognitive neuroscience and is being increasingly explored in neurotherapeutics. Amongst the factors that are likely to influence its efficacy, the importance of the baseline cortical activation state on the impact of TMS has not received much attention. However, this state-dependency is important as the neural impact of any external stimulus represents an interaction with the ongoing brain activity at the time of stimulation. The effects of any external stimulus are therefore not only determined by the properties of that stimulus but also by the activation state of the brain. Here we review the existing evidence on the state-dependency of TMS and propose how its systematic study can provide unique insights into brain function and significantly enhance the effectiveness of TMS in investigations on the neural basis of perception and cognition. We also describe novel approaches based on this state-dependency which can be used to investigate the properties of distinct neural subpopulations within the stimulated region. Furthermore, we discuss how state-dependency can explain the functional mechanisms through which TMS impairs perception and behavior.