Connectivity-guided intermittent theta burst versus repetitive transcranial magnetic stimulation for treatment-resistant depression: a randomized controlled trial.

Disruption in reciprocal connectivity between the right anterior insula and the left dorsolateral prefrontal cortex is associated with depression and may be a target for neuromodulation. In a five-center, parallel, double-blind, randomized controlled trial we personalized resting-state functional magnetic resonance imaging neuronavigated connectivity-guided intermittent theta burst stimulation (cgiTBS) at a site based on effective connectivity from the right anterior insula to the left dorsolateral prefrontal cortex. We tested its efficacy in reducing the primary outcome depression symptoms measured by the GRID Hamilton Depression Rating Scale 17-item over 8, 16 and 26 weeks, compared with structural magnetic resonance imaging (MRI) neuronavigated repetitive transcranial magnetic stimulation (rTMS) delivered at the standard stimulation site (F3) in patients with 'treatment-resistant depression'. Participants were randomly assigned to 20 sessions over 4-6 weeks of either cgiTBS (n = 128) or rTMS (n = 127) with resting-state functional MRI at baseline and 16 weeks. Persistent decreases in depressive symptoms were seen over 26 weeks, with no differences between arms on the primary outcome GRID Hamilton Depression Rating Scale 17-item score (intention-to-treat adjusted mean, -0.31, 95% confidence interval (CI) -1.87, 1.24, P = 0.689). Two serious adverse events were possibly related to TMS (mania and psychosis). MRI-neuronavigated cgiTBS and rTMS were equally effective in patients with treatment-resistant depression over 26 weeks (trial registration no. ISRCTN19674644).

Clinical effectiveness of active Alpha-Stim AID versus sham Alpha-Stim AID in major depression in primary care in England (Alpha-Stim-D): a multicentre, parallel group, double-blind, randomised controlled trial.

BACKGROUND: Randomised sham-controlled trials of cranial electrostimulation with the Alpha-Stim Anxiety Insomnia and Depression (AID) device have reported improved anxiety and depression symptoms; however, no adequately powered sham-controlled trials in major depression are available. We investigated whether active Alpha-Stim AID is superior to sham Alpha-Stim AID in terms of clinical effectiveness for depression symptoms in major depression. METHODS: The Alpha-Stim-D trial was a multicentre, parallel group, double-blind, randomised controlled trial, recruiting participants from 25 primary care centres in two regions in England, UK. Eligible participants were aged 16 years or older with a current diagnosis of primary major depression, a score of 10-19 on the nine-item Patient Health Questionnaire, and had been offered or prescribed and reported taking antidepressant medication for at least 6 weeks in the previous 3 months. Main exclusion criteria were contraindications to Alpha-Stim AID device use, having persistent suicidal ideation or self-harm, neurological conditions, a substance use disorder or dependence, an eating disorder, bipolar disorder, or non-affective psychosis, or receiving psychological treatment in the past 3 months. Eligible participants were randomly assigned (1:1, minimised by region, anxiety disorder, and antidepressant use) to 1 h daily use of active (100 µA) or sham Alpha-Stim AID treatment for 8 weeks. Randomisation was via an independent web-based system, with participants, outcome assessors, and data analyst masked to treatment assignment. The primary outcome was change from baseline in score on the 17-item Hamilton Depression Rating Scale (HDRS-17, GRID version) at 16 weeks after randomisation, with participants analysed by intention to treat (ITT; all randomly assigned participants). Safety was assessed in all randomly assigned participants. The trial is registered with the ISRCTN registry (ISRCTN11853110); status completed. FINDINGS: Between Sept 8, 2020, and Jan 14, 2022, 236 eligible participants were randomly assigned to active or sham Alpha-Stim AID (n=118 each). 156 (66%) participants were women, 77 (33%) were men, and three (1%) self-reported as other gender; 200 (85%) were White British or Irish; and the mean age was 38·0 years (SD 15·3; range 16-83). 102 (86%) participants in the active Alpha-Stim AID group and 98 (83%) in the sham group were followed up 16 weeks after randomisation. In the ITT population, mean change in GRID-HDRS-17 at 16 weeks was -5·9 (95% CI -7·1 to -4·8) in the active Alpha-Stim AID group and -6·5 (-7·7 to -5·4) in the sham group (mean change difference -0·6 [95% CI -1·0 to 2·2], p=0·46). Among the 236 participants, 17 adverse events were reported in 17 (7%) participants (nine [8%] participants in the active Alpha-Stim AID group; and eight [7%] participants in the sham group). One serious adverse event of suicidal ideation leading to hospitalisation was reported in the sham group, which was judged to be unrelated to the device. INTERPRETATION: Active Alpha-Stim AID was safe and acceptable, but no more clinically effective than sham Alpha-Stim AID in major depression. FUNDING: National Institute for Health Research Applied Research Collaboration East Midlands and Electromedical Products International.

A randomised controlled trial investigating the clinical and cost-effectiveness of Alpha-Stim AID cranial electrotherapy stimulation (CES) in patients seeking treatment for moderate severity depression in primary care (Alpha-Stim-D Trial).

BACKGROUND: Major depression is the second leading cause of years lost to disability worldwide and is a leading contributor to suicide. However, first-line antidepressants are only fully effective for 33%, and only 40% of those offered psychological treatment attend for two sessions or more. Views gained from patients and primary care professionals are that greater treatment uptake might be achieved if people with depression could be offered alternative and more accessible treatment options. Although there is evidence that the Alpha-Stim Anxiety Insomnia and Depression (AID) device is safe and effective for anxiety and depression symptoms in people with anxiety disorders, there is much less evidence of efficacy in major depression without anxiety. This study investigates the effectiveness of the Alpha-Stim AID device, a cranial electrotherapy stimulation (CES) treatment that people can safely use independently at home. The device provides CES which has been shown to increase alpha oscillatory brain activity, associated with relaxation. METHODS: The aim of this study is to investigate the clinical and cost-effectiveness of Alpha-Stim AID in treatment-seeking patients (aged 16 years upwards) with moderate to moderately severe depressive symptoms in primary care. The study is a multi-centre parallel-group, double-blind, non-commercial, randomised controlled superiority trial. The primary objective of the study is to examine the clinical efficacy of active daily use of 8 weeks of Alpha-Stim AID versus sham Alpha-Stim AID on depression symptoms at 16 weeks (8 weeks after the end of treatment) in people with moderate severity depression. The primary outcome is the 17-item Hamilton Depression Rating Scale at 16 weeks. All trial and treatment procedures are carried out remotely using videoconferencing, telephone and postal delivery considering the COVID-19 pandemic restrictions. DISCUSSION: This study is investigating whether participants using the Alpha-Stim AID device display a reduction in depressive symptoms that can be maintained over 8 weeks post-treatment. The findings will help to determine whether Alpha-Stim AID should be recommended, including being made available in the NHS for patients with depressive symptoms. TRIAL REGISTRATION: ISRTCN ISRCTN11853110 . Registered on 14 August 2020.

Connectivity-Guided Theta Burst Transcranial Magnetic Stimulation Versus Repetitive Transcranial Magnetic Stimulation for Treatment-Resistant Moderate to Severe Depression: Magnetic Resonance Imaging Protocol and SARS-CoV-2-Induced Changes for a Randomized Double-blind Controlled Trial.

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. TRIAL REGISTRATION: ISRCTN Registry ISRCTN19674644; https://www.isrctn.com/ISRCTN19674644. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/31925.

Regional Brain Correlates of Beta Bursts in Health and Psychosis: A Concurrent Electroencephalography and Functional Magnetic Resonance Imaging Study.

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 control 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.

Connectivity guided theta burst transcranial magnetic stimulation versus repetitive transcranial magnetic stimulation for treatment-resistant moderate to severe depression: study protocol for a randomised double-blind controlled trial (BRIGhTMIND).

INTRODUCTION: The BRIGhTMIND study aims to determine the clinical effectiveness, cost-effectiveness and mechanism of action of connectivity guided intermittent theta burst stimulation (cgiTBS) versus standard repetitive transcranial magnetic stimulation (rTMS) in adults with moderate to severe treatment resistant depression. METHODS AND ANALYSIS: The study is a randomised double-blind controlled trial with 1:1 allocation to either 20 sessions of (1) cgiTBS or (2) neuronavigated rTMS not using connectivity guidance. A total of 368 eligible participants with a diagnosis of current unipolar major depressive disorder that is both treatment resistant (defined as scoring 2 or more on the Massachusetts General Hospital Staging Score) and moderate to severe (scoring >16 on the 17-item Hamilton Depression Rating Scale (HDRS-17)), will be recruited from primary and secondary care settings at four treatment centres in the UK. The primary outcome is depression response at 16 weeks (50% or greater reduction in HDRS-17 score from baseline). Secondary outcomes include assessments of self-rated depression, anxiety, psychosocial functioning, cognition and quality of life at 8, 16 and 26 weeks postrandomisation. Cost-effectiveness, patient acceptability, safety, mechanism of action and predictors of response will also be examined. ETHICS AND DISSEMINATION: Ethical approval was granted by East Midlands Leicester Central Research Ethics Committee (ref: 18/EM/0232) on 30 August 2018. The results of the study will be published in relevant peer-reviewed journals, and then through professional and public conferences and media. Further publications will explore patient experience, moderators and mediators of outcome and mechanism of action. TRIAL REGISTRATION NUMBER: ISRCTN19674644.

Adding evidence of the effects of treatments into relevant Wikipedia pages: a randomised trial.

OBJECTIVES: To 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. SETTING: Wikipedia, Cochrane summary pages and the Cochrane Library. DESIGN: Randomised trial. PARTICIPANTS: Wikipedia pages which were highly relevant to up-to-date Cochrane Schizophrenia systematic reviews that contained a Summary of Findings table. INTERVENTIONS: Eligible 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 MEASURES: Routinely collected data on access to the full text and summary web page (after 12 months). RESULTS: We 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). CONCLUSIONS: The 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 NUMBER: IRCT2017070330407N2.

Explaining why childhood abuse is a risk factor for poorer clinical course in bipolar disorder: a path analysis of 923 people with bipolar I disorder.

BACKGROUND: Childhood 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. METHODS: We 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. RESULTS: Affective 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. CONCLUSIONS: Affective 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.

Development of human electrophysiological brain networks.

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.

Altered temporal stability in dynamic neural networks underlies connectivity changes in neurodevelopment.

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.

Physiological Evidence for a Midline Spatial Channel in Human Auditory Cortex.

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.

Asymmetries in the representation of space in the human auditory cortex depend on the global stimulus context.

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.

Age-related deterioration of the representation of space in human auditory cortex.

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.

The specificity of stimulus-specific adaptation in human auditory cortex increases with repeated exposure to the adapting stimulus.

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.

Mechanisms of adaptation in human auditory cortex.

This study investigates the temporal properties of adaptation in the late auditory-evoked potentials in humans. The results are used to make inferences about the mechanisms of adaptation in human auditory cortex. The first experiment measured adaptation by single adapters as a combined function of the adapter duration and the stimulus onset asynchrony (SOA) and interstimulus interval (ISI) between the adapter and the adapted sound ("probe"). The results showed recovery from adaptation with increasing ISI, as would be expected, but buildup of adaptation with increasing adapter duration and thus SOA. This suggests that adaptation in auditory cortex is caused by the ongoing, rather than the onset, response to the adapter. Quantitative modeling indicated that the rate of buildup of adaptation is almost an order of magnitude faster than the recovery rate of adaptation. The recovery rate suggests that cortical adaptation is caused by synaptic depression and slow afterhyperpolarization. The P2 was more strongly affected by adaptation than the N1, suggesting that the two deflections originate from different cortical generators. In the second experiment, the single adapters were replaced by trains of two or four identical adapters. The results indicated that adaptation decays faster after repeated presentation of the adapter. This increase in the recovery rate of adaptation might contribute to the elicitation of the auditory mismatch negativity response. It may be caused by top-down feedback or by local processes such as the buildup of residual Ca(2+) within presynaptic neurons.

Evidence for pitch chroma mapping in human auditory cortex.

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.

Evidence for opponent process analysis of sound source location in humans.

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.