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Background There is emerging evidence for abnormal beta oscillations in psychosis. Beta oscillations are likely to play a key role in the coordination of sensorimotor information that is crucial to healthy mental function. Growing evidence suggests that beta oscillations typically manifest as transient beta bursts that increase in probability following a motor response, observable as post-movement beta rebound. Evidence indicates that post-movement beta rebound is attenuated in psychosis, with greater attenuation associated with greater symptom severity and impairment. Delineating the functional role of beta bursts therefore may be key to understanding the mechanisms underlying persistent psychotic illness. Methods We used concurrent electroencephalography and functional magnetic resonance imaging to identify blood oxygen level–dependent correlates of beta bursts during the n-back working memory task and intervening rest periods in healthy participants (n = 30) and patients with psychosis (n = 48). Results During both task blocks and intervening rest periods, beta bursts phasically activated regions implicated in task-relevant content while suppressing currently tonically active regions. Patients showed attenuated post-movement beta rebound that was associated with persisting disorganization symptoms as well as impairments in cognition and role function. Patients also showed greater task-related reductions in overall beta burst rate and showed greater, more extensive, beta burst–related blood oxygen level–dependent activation. Conclusions Our evidence supports a model in which beta bursts reactivate latently maintained sensorimotor information and are dysregulated and inefficient in psychosis. We propose that abnormalities in the mechanisms by which beta bursts coordinate reactivation of contextually appropriate content can manifest as disorganization, working memory deficits, and inaccurate forward models and may underlie a core deficit associated with persisting symptoms and impairment.

BACKGROUND Depression is a substantial health and economic burden. In approximately one-third of patients, depression is resistant to first-line treatment; therefore, it is essential to find alternative treatments. Transcranial magnetic stimulation (TMS) is a neuromodulatory treatment involving the application of magnetic pulses to the brain that is approved in the United Kingdom and the United States in treatment-resistant depression. This trial aims to compare the clinical effectiveness, cost-effectiveness, and mechanism of action of standard treatment repetitive TMS (rTMS) targeted at the F3 electroencephalogram site with a newer treatment—a type of TMS called theta burst stimulation (TBS) targeted based on measures of functional brain connectivity. This protocol outlines brain imaging acquisition and analysis for the Brain Imaging Guided Transcranial Magnetic Stimulation in Depression (BRIGhTMIND) study trial that is used to create personalized TMS targets and answer the proposed mechanistic hypotheses. OBJECTIVE The aims of the imaging arm of the BRIGhTMIND study are to identify functional and neurochemical brain signatures indexing the treatment mechanisms of rTMS and connectivity-guided intermittent theta burst TMS and to identify imaging-based markers predicting response to treatment. METHODS The study is a randomized double-blind controlled trial with 1:1 allocation to either 20 sessions of TBS or standard rTMS. Multimodal magnetic resonance imaging (MRI) is acquired for each participant at baseline (before TMS treatment) with T1-weighted and task-free functional MRI during rest used to estimate TMS targets. For participants enrolled in the mechanistic substudy, additional diffusion-weighted sequences are acquired at baseline and at posttreatment follow-up 16 weeks after treatment randomization. Core data sets of T1-weighted and task-free functional MRI during rest are acquired for all participants and are used to estimate TMS targets. Additional sequences of arterial spin labeling, magnetic resonance spectroscopy, and diffusion-weighted images are acquired depending on the recruitment site for mechanistic evaluation. Standard rTMS treatment is targeted at the F3 electrode site over the left dorsolateral prefrontal cortex, whereas TBS treatment is guided using the coordinate of peak effective connectivity from the right anterior insula to the left dorsolateral prefrontal cortex. Both treatment targets benefit from the level of MRI guidance, but only TBS is provided with precision targeting based on functional brain connectivity. RESULTS Recruitment began in January 2019 and is ongoing. Data collection is expected to continue until January 2023. CONCLUSIONS This trial will determine the impact of precision MRI guidance on rTMS treatment and assess the neural mechanisms underlying this treatment in treatment-resistant depressed patients. CLINICALTRIAL ISRCTN Registry ISRCTN19674644; https://www.isrctn.com/ISRCTN19674644 INTERNATIONAL REGISTERED REPORT DERR1-10.2196/31925

Functional activity in the human brain is intrinsically organized into independently active, connected brain regions. These networks include sensorimotor systems, as well as higher-order cognitive networks such as the default mode network (DMN), which dominates activity when the brain is at rest, and the frontoparietal (FPN) and salience (SN) networks, which are often engaged during demanding tasks. Evidence from functional magnetic resonance imaging (fMRI) suggests that although sensory systems are mature by the end of childhood, the integrity of the FPN and SN develops throughout adolescence. There has been little work to corroborate these findings with electrophysiology. Using magnetoencephalography (MEG) recordings of 48 participants (aged 9–25 yr) at rest, we find that beta-band functional connectivity within the FPN, SN, and DMN continues to increase through adolescence, whereas connectivity in the visual system is mature by late childhood. In contrast to fMRI results, but replicating the MEG findings of Schäfer et al. (Schäfer CB, Morgan BR, Ye AX, Taylor MJ, Doesburg SM. Hum Brain Mapp 35: 5249–5261, 2014), we also see that connectivity between networks increases rather than decreases with age. This suggests that the development of coordinated beta-band oscillations within and between higher-order cognitive networks through adolescence might contribute to the developing abilities of adolescents to focus their attention and coordinate diverse aspects of mental activity. NEW & NOTEWORTHY Using magnetoencephalography to assess beta frequency oscillations, we show that functional connectivity within higher-order cognitive networks increases from childhood, reaching adult values by age 20 yr. In contrast, connectivity within a primary sensory (visual) network reaches adult values by age 14 yr. In contrast to functional MRI findings, connectivity between cognitive networks matures at a rate similar to within-network connectivity, suggesting that coordination of beta oscillations both within and between networks is associated with maturation of cognitive skills.

AimsTo identify the BOLD (blood oxygenation level dependent) correlates of bursts of beta frequency band electrophysiological activity, and to compare BOLD responses between healthy controls and patients with psychotic illness.The post movement beta rebound (PMBR) is a transient increase in power in the beta frequency band (13-30 Hz), recorded with methods such as electroencephalography (EEG), following the completion of a movement. PMBR size is reduced in patients with schizophrenia and inversely correlated with severity of illness. PMBR size is inversely correlated with measures of schizotypy in non-clinical groups. Therefore, beta-band activity may reflect a fundamental neural process whose disruption plays an important role in the pathophysiology of schizophrenia. Recent work has found that changes in beta power reflect changes in the probability-of-occurrence of transient bursts of beta-frequency activity. Understanding the generators of beta bursts could help unravel the pathophysiology of psychotic illness and thus identify novel treatment targets.MethodEEG data were recorded simultaneously with BOLD data measured with 3T functional magnetic resonance imaging (fMRI), whilst participants performed an n-back working memory task. We included seventy-eight participants – 32 patients with schizophrenia, 16 with bipolar disorder and 30 healthy controls. Beta bursts were identified in the EEG data using a thresholding method and burst timings were used as markers in an event-related fMRI design convolved with a conventional haemodynamic response function. A region of interest analysis compared beta-event-related BOLD activity between patients and controls.ResultBeta bursts phasically activated brain regions implicated in coding task-relevant content (specifically, regions involved in the phonological representation of letter stimuli, as well as areas representing motor responses). Further, bursts were associated with suppression of tonically-active regions. In the EEG, PMBR was greater in controls than patients, and, in patients, PMBR size was positively correlated with Global Assessment of Functioning scores, and negatively correlated with persisting symptoms of disorganisation and performance on a digit symbol substition test. Despite this, patients showed greater, more extensive, burst-related BOLD activation than controls.ConclusionOur findings are consistent with a recent model in which beta bursts serve to reactivate latently-maintained, task-relevant, sensorimotor information. The increased BOLD response associated with bursts in patients, despite reduced PMBR, could reflect inefficiency of burst-mediated cortical synchrony, or it may suggest that the sensorimotor information reactivated by beta bursts is less precisely specified in psychosis. We propose that dysfunction of the mechanisms by which beta bursts reactivate task-relevant content can manifest as disorganisation and working memory deficits, and may contribute to persisting symptoms and impairment in psychosis.

BackgroundChildhood abuse is a risk factor for poorer illness course in bipolar disorder, but the reasons why are unclear. Trait-like features such as affective instability and impulsivity could be part of the explanation. We aimed to examine whether childhood abuse was associated with clinical features of bipolar disorder, and whether associations were mediated by affective instability or impulsivity.MethodsWe analysed data from 923 people with bipolar I disorder recruited by the Bipolar Disorder Research Network. Adjusted associations between childhood abuse, affective instability and impulsivity and eight clinical variables were analysed. A path analysis examined the direct and indirect links between childhood abuse and clinical features with affective instability and impulsivity as mediators.ResultsAffective instability significantly mediated the association between childhood abuse and earlier age of onset [effect estimate (θ)/standard error (SE): 2.49], number of depressive (θ/SE: 2.08) and manic episodes/illness year (θ/SE: 1.32), anxiety disorders (θ/SE: 1.98) and rapid cycling (θ/SE: 2.25). Impulsivity significantly mediated the association between childhood abuse and manic episodes/illness year (θ/SE: 1.79), anxiety disorders (θ/SE: 1.59), rapid cycling (θ/SE: 1.809), suicidal behaviour (θ/SE: 2.12) and substance misuse (θ/SE: 3.09). Measures of path analysis fit indicated an excellent fit to the data.ConclusionsAffective instability and impulsivity are likely part of the mechanism of why childhood abuse increases risk of poorer clinical course in bipolar disorder, with each showing some selectivity in pathways. They are potential novel targets for intervention to improve outcome in bipolar disorder.

ObjectivesTo investigate the effects of adding high-grade quantitative evidence of outcomes of treatments into relevant Wikipedia pages on further information-seeking behaviour by the use of routinely collected data.SettingWikipedia, Cochrane summary pages and the Cochrane Library.DesignRandomised trial.ParticipantsWikipedia pages which were highly relevant to up-to-date Cochrane Schizophrenia systematic reviews that contained a Summary of Findings table.InterventionsEligible Wikipedia pages in the intervention group were seeded with tables of best evidence of the effects of care and hyperlinks to the source Cochrane review. Eligible Wikipedia pages in the control group were left unchanged.Main outcome measuresRoutinely collected data on access to the full text and summary web page (after 12 months).ResultsWe randomised 70 Wikipedia pages (100% follow-up). Six of the 35 Wikipedia pages in the intervention group had the tabular format deleted during the study but all pages continued to report the same data within the text. There was no evidence of effect on either of the coprimary outcomes: full-text access adjusted ratio of geometric means 1.30, 95% CI: 0.71 to 2.38; page views 1.14, 95% CI: 0.6 to 2.13. Results were similar for all other outcomes, with exception of Altmetric score for which there was some evidence of clear effect (1.36, 95% CI: 1.05 to 1.78).ConclusionsThe pursuit of fair balance within Wikipedia healthcare pages is impressive and its reach unsurpassed. For every person who sought and clicked the reference on the ‘intervention’ Wikipedia page to seek more information (the primary outcome), many more are likely to have been informed by the page alone. Enriching Wikipedia content is, potentially, a powerful way to improve health literacy and it is possible to test the effects of seeding pages with evidence. This trial should be replicated, expanded and developed.Trial registration numberIRCT2017070330407N2.

AimsTo assess patient and clinician acceptability of handheld 6-lead ECG, for obtaining information about cardiac rhythm and electrical intervals, in acute general adult mental health ward inpatients who refuse traditional 12-lead ECG.BackgroundIn a previous audit of patients admitted to four acute general adult mental health wards, we found that 1 in 4 patients refused 12-lead ECG for at least two weeks, with 1 in 6 refusing throughout their entire stay. ECG refusers were significantly more likely to have a psychotic illness than non-refusers and were thus more likely to benefit from medications that carry a risk of prolonging the QT interval. Less invasive, handheld, 6-lead ECG, which includes measurement of lead II (the lead used to define traditional QT-interval cut-off values) is available on the NHS supply chain. Whilst not providing the full range of information that 12-lead ECG is able to provide, handheld 6-lead ECG might be an acceptable alternative in patients who would otherwise never have any form of ECG performed.MethodWe developed a Standard Operating Procedure for use of handheld 6-lead ECG and provided training for junior doctors on the four wards that were the subject of our original audit. These doctors were then able to offer the device to patients on their wards who refused 12-lead ECG. Doctors completed a short feedback form each time a handheld ECG was offered.ResultSo far, handheld 6-lead ECGs have been offered to 17 patients who refused 12-lead ECGs. Mean age (± SD) was 36.1 (± 12.6) years, and 4 of these patients were female. 13 patients (76%) accepted a handheld ECG. One of these attempts failed due to patient agitation. Attempts took a mean of 7 (± 5.4) minutes. 54% of recordings were described as “very easy” by clinicians, whereas 15%, 23% and 8% were described as “somewhat easy”, “intermediate”, and “somewhat difficult”, respectively. Clinician difficulties focussed on patient movement with impact on electrode contact and trace quality. Where answered (N = 10), 90% of patients stated they would recommend a handheld ECG to others. Patients liked the speed of the process, that it felt “less scary”, and that it was less invasive and did not involve removing clothing.ConclusionOur initial findings from this pilot suggest that handheld 6-lead ECG may be acceptable, both to clinicians and patients, as a means of obtaining information on cardiac rhythm and electrical intervals for patients who refuse 12-lead ECGs.

Network connectivity is an integral feature of human brain function, and characterising its maturational trajectory is a critical step towards understanding healthy and atypical neurodevelopment. Here, we used magnetoencephalography (MEG) to investigate both stationary (i.e. time averaged) and rapidly modulating (dynamic) electrophysiological connectivity, in participants aged from mid-childhood to early adulthood (youngest participant 9 years old; oldest participant 25 years old). Stationary functional connectivity (measured via inter-regional coordination of neural oscillations) increased with age in the alpha and beta frequency bands, particularly in bilateral parietal and temporo-parietal connections. Our dynamic analysis (also applied to alpha/beta oscillations) revealed the spatiotemporal signatures of 8 dynamic networks; these modulate on a ∼100 ms time scale, and temporal stability in attentional networks was found to increase with age. Significant overlap was found between age-modulated dynamic networks and inter-regional oscillatory coordination, implying that altered network dynamics underlie age related changes in functional connectivity. Our results provide novel insights into brain network electrophysiology, and lay a foundation for future work in childhood disorders.

The neural response to a sensory stimulus tends to be more strongly reduced when the stimulus is preceded by the same, rather than a different, stimulus. This stimulus-specific adaptation (SSA) is ubiquitous across the senses. In hearing, SSA has been suggested to play a role in change detection as indexed by the mismatch negativity. This study sought to test whether SSA, measured in human auditory cortex, is caused by neural fatigue (reduction in neural responsiveness) or by sharpening of neural tuning to the adapting stimulus. For that, we measured event-related cortical potentials to pairs of pure tones with varying frequency separation and stimulus onset asynchrony (SOA). This enabled us to examine the relationship between the degree of specificity of adaptation as a function of frequency separation and the rate of decay of adaptation with increasing SOA. Using simulations of tonotopic neuron populations, we demonstrate that the fatigue model predicts independence of adaptation specificity and decay rate, whereas the sharpening model predicts interdependence. The data showed independence and thus supported the fatigue model. In a second experiment, we measured adaptation specificity after multiple presentations of the adapting stimulus. The multiple adapters produced more adaptation overall, but the effect was more specific to the adapting frequency. Within the context of the fatigue model, the observed increase in adaptation specificity could be explained by assuming a 2.5-fold increase in neural frequency selectivity. We discuss possible bottom-up and top-down mechanisms of this effect.

Studies on humans and other mammals have provided evidence for a two-channel or three-channel representation of horizontal space in the auditory system, with one channel maximally responsive to each of the left hemispace, the right hemispace and, possibly, the midline. Mammalian studies have suggested that the contralateral channel is larger in both cortices, but human studies have found this contralateral preference in only one of the cortices. However, human studies are in conflict as to whether the contralateral preference is in the left or the right auditory cortex, and there are a number of methodological differences that this conflict could be attributed to. A key difference between studies is the duration of the silent interval preceding each stimulus and any perception of sound-source movement that the absence of a silent interval creates. We presented auditory noises that alternated between -90° (left) and +90° (right) and recorded neural responses (event-related potentials) using electroencephalography. We randomly varied the duration of the silent interval preceding each stimulus to create a condition with an immediate (local) stimulus context similar to that used in a study reporting contralateral preference in the left auditory cortex, a condition with a local context similar to that in a study reporting contralateral preference in the right auditory cortex, and an intermediate condition. Surprisingly, we found that both auditory cortices exhibited a similarly strong contralateral preference under all conditions, with responses 27% greater, on average, to the contralateral than the ipsilateral space. This suggests that both the cortices can exhibit a contralateral preference, but whether these preferences manifest depends on the global, rather than the local, stimulus context. Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.

Some areas in auditory cortex respond preferentially to sounds that elicit pitch, such as musical sounds or voiced speech. This study used human electroencephalography (EEG) with an adaptation paradigm to investigate how pitch is represented within these areas and, in particular, whether the representation reflects the physical or perceptual dimensions of pitch. Physically, pitch corresponds to a single monotonic dimension: the repetition rate of the stimulus waveform. Perceptually, however, pitch has to be described with 2 dimensions, a monotonic, “pitch height,” and a cyclical, “pitch chroma,” dimension, to account for the similarity of the cycle of notes (c, d, e, etc.) across different octaves. The EEG adaptation effect mirrored the cyclicality of the pitch chroma dimension, suggesting that auditory cortex contains a representation of pitch chroma. Source analysis indicated that the centroid of this pitch chroma representation lies somewhat anterior and lateral to primary auditory cortex.

Background\ud \ud Affective instability (AI), childhood trauma, and mental illness are linked, but evidence in affective disorders is limited, despite both AI and childhood trauma being associated with poorer outcomes. Aims were to compare AI levels in bipolar disorder I (BPI) and II (BPII), and major depressive disorder recurrent (MDDR), and to examine the association of AI and childhood trauma within each diagnostic group.\ud \ud Methods\ud \ud AI, measured using the Affective Lability Scale (ALS), was compared between people with DSM-IV BPI (n=923), BPII (n=363) and MDDR (n=207) accounting for confounders and current mood. Regression modelling was used to examine the association between AI and childhood traumas in each diagnostic group.\ud \ud Results\ud \ud ALS scores in descending order were BPII, BPI, MDDR, and differences between groups were significant (p

One of the principal auditory disabilities associated with older age is difficulty in locating and tracking sources of sound. This study investigated whether these difficulties are associated with deterioration in the representation of space in the auditory cortex. In psychophysical tests, half of a group of older (>60 years) adults displayed spatial acuity similar to that of young adults throughout the frontal horizontal plane. The remaining half had considerably poorer spatial acuity at the more peripheral regions of frontal space. Computational modeling of electroencephalographic responses to abrupt location shifts demonstrated marked differences in the spatial tuning of populations of cortical neurons between the older adults with poor spatial acuity on the one hand, and those with good spatial acuity, as well as young adults, on the other hand. In those with poor spatial acuity, cortical responses contained little information with which to distinguish peripheral locations. We demonstrate a clear link between neural responses and spatial acuity measured behaviorally, and provide evidence for age-related changes in the coding of horizontal space.

Research with barn owls suggested that sound source location is represented topographically in the brain by an array of neurons each tuned to a narrow range of locations. However, research with small-headed mammals has offered an alternative view in which location is represented by the balance of activity in two opponent channels broadly tuned to the left and right auditory space. Both channels may be present in each auditory cortex, although the channel representing contralateral space may be dominant. Recent studies have suggested that opponent channel coding of space may also apply in humans, although these studies have used a restricted set of spatial cues or probed a restricted set of spatial locations, and there have been contradictory reports as to the relative dominance of the ipsilateral and contralateral channels in each cortex. The current study used electroencephalography (EEG) in conjunction with sound field stimulus presentation to address these issues and to inform the development of an explicit computational model of human sound source localization. Neural responses were compatible with the opponent channel account of sound source localization and with contralateral channel dominance in the left, but not the right, auditory cortex. A computational opponent channel model reproduced every important aspect of the EEG data and allowed inferences about the width of tuning in the spatial channels. Moreover, the model predicted the oft-reported decrease in spatial acuity measured psychophysically with increasing reference azimuth. Predictions of spatial acuity closely matched those measured psychophysically by previous authors.

When the same sound is presented repeatedly, the electrical brain response recorded over the scalp decreases in amplitude, an effect known as adaptation. Adaptation is dependent on both the similarity of the sounds and the time between them. It has been particularly well studied for a deflection of the electrical response known as the N100, which peaks about 100 ms after sound onset and receives major contributions from auditory cortical sources. Adaptation may reflect decreased sensitivity to repetitive stimuli, but could also indicate more efficient processing of familiar events. Research on adaptation has often employed an alternating tone paradigm (A‐B‐A‐B), examining the effects of changing inter‐stimulus interval (ISI) or the frequency separation between A and B tones. Decreasing the frequency separation leads to an increase in N100 adaptation, and it has been suggested that the frequency specificity of this adaptation sharpens with decreasing ISI. In contrast, some studies have used A‐B pairs with long inter‐pair gaps and have found an enhancement of the N100 response to the B tone at short ISIs. In order to gain a better understanding of the processes contributing to adaptation and enhancement, this study investigates the temporal dynamics and the frequency selectivity of these effects.

Studies with humans and other mammals have provided support for a two-channel representation of horizontal (“azimuthal”) space in the auditory system. In this representation, location-sensitive neurons contribute activity to one of two broadly tuned channels whose responses are compared to derive an estimate of sound-source location. One channel is maximally responsive to sounds towards the left and the other to sounds towards the right. However, recent psychophysical studies of humans, and physiological studies of other mammals, point to the presence of an additional channel, maximally responsive to the midline. In this study, we used electroencephalography to seek physiological evidence for such a midline channel in humans. We measured neural responses to probe stimuli presented from straight ahead (0 °) or towards the right (+30 ° or +90 °). Probes were preceded by adapter stimuli to temporarily suppress channel activity. Adapters came from 0 ° or alternated between left and right (−30 ° and +30 ° or −90 ° and +90 °). For the +90 ° probe, to which the right-tuned channel would respond most strongly, both accounts predict greatest adaptation when the adapters are at ±90 °. For the 0 ° probe, the two-channel account predicts greatest adaptation from the ±90 ° adapters, while the three-channel account predicts greatest adaptation when the adapters are at 0 ° because these adapters stimulate the midline-tuned channel which responds most strongly to the 0 ° probe. The results were consistent with the three-channel account. In addition, a computational implementation of the three-channel account fitted the probe response sizes well, explaining 93 % of the variance about the mean, whereas a two-channel implementation produced a poor fit and explained only 61 % of the variance.