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Objective. This study aims to develop and validate an end-to-end software platform, PyHFO, that streamlines the application of deep learning (DL) methodologies in detecting neurophysiological biomarkers for epileptogenic zones from EEG recordings.Approach. We introduced PyHFO, which enables time-efficient high-frequency oscillation (HFO) detection algorithms like short-term energy and Montreal Neurological Institute and Hospital detectors. It incorporates DL models for artifact and HFO with spike classification, designed to operate efficiently on standard computer hardware.Main results. The validation of PyHFO was conducted on three separate datasets: the first comprised solely of grid/strip electrodes, the second a combination of grid/strip and depth electrodes, and the third derived from rodent studies, which sampled the neocortex and hippocampus using depth electrodes. PyHFO demonstrated an ability to handle datasets efficiently, with optimization techniques enabling it to achieve speeds up to 50 times faster than traditional HFO detection applications. Users have the flexibility to employ our pre-trained DL model or use their EEG data for custom model training.Significance. PyHFO successfully bridges the computational challenge faced in applying DL techniques to EEG data analysis in epilepsy studies, presenting a feasible solution for both clinical and research settings. By offering a user-friendly and computationally efficient platform, PyHFO paves the way for broader adoption of advanced EEG data analysis tools in clinical practice and fosters potential for large-scale research collaborations.

Postural instability is a detrimental and often treatment-refractory symptom of Parkinsons disease. While many existing studies quantify the biomechanical deficits among various postural domains (static, anticipatory, and reactive) in this population, less is known regarding the neural network dysfunctions underlying these phenomena. This review will summarize current studies on the cortical and subcortical neural activities during postural responses in healthy subjects and those with Parkinsons disease. We will also review the effects of current therapies, including neuromodulation and feedback-based wearable devices, on postural instability symptoms. With recent advances in implantable devices that allow chronic, ambulatory neural data collection from patients with Parkinsons disease, combined with sensors that can quantify biomechanical measurements of postural responses, future work using these devices will enable better understanding of the neural mechanisms of postural control. Bridging this knowledge gap will be the critical first step towards developing novel neuromodulatory interventions to enhance the treatment of postural instability in Parkinsons disease.

Sharing human brain data can yield scientific benefits, but because of various disincentives, only a fraction of these data is currently shared. We profile three successful data-sharing experiences from the NIH BRAIN Initiative Research Opportunities in Humans (ROH) Consortium and demonstrate benefits to data producers and to users.

Overlapping clinical presentations in primary progressive aphasia (PPA) variants present challenges for diagnosis and understanding pathophysiology, particularly in the early stages of the disease when behavioral (speech) symptoms are not clearly evident. Divergent atrophy patterns (temporoparietal degeneration in logopenic variant lvPPA, frontal degeneration in nonfluent variant nfvPPA) can partially account for differential speech production errors in the two groups in the later stages of the disease. While the existing dogma states that neurodegeneration is the root cause of compromised behavior and cortical activity in PPA, the extent to which neurophysiological signatures of speech dysfunction manifest independent of their divergent atrophy patterns remain unknown. We test the hypothesis that nonword deficits in lvPPA and nfvPPA arise from distinct patterns of neural oscillations that are unrelated to atrophy. We use a novel structure-function imaging approach integrating magnetoencephalographic imaging of neural oscillations during a non-word repetition task with voxel-based morphometry-derived measures of gray matter volume to isolate neural oscillation abnormalities independent of atrophy. We find reduced beta band neural activity in left temporal regions associated with the late stages of auditory encoding unique to patients with lvPPA and reduced high-gamma neural activity over left frontal regions associated with the early stages of motor preparation in patients with nfvPPA. Neither of these patterns of reduced cortical oscillations was explained by cortical atrophy in our statistical model. These findings highlight the importance of structure-function imaging in revealing neurophysiological sequelae in early stages of dementia when neither structural atrophy nor behavioral deficits are clinically distinct.

The neurophysiology of cells and tissues are monitored electrophysiologically and optically in diverse experiments and species, ranging from flies to humans. Understanding the brain requires integration of data across this diversity, and thus these data must be findable, accessible, interoperable, and reusable (FAIR). This requires a standard language for data and metadata that can coevolve with neuroscience. We describe design and implementation principles for a language for neurophysiology data. Our open-source software (Neurodata Without Borders, NWB) defines and modularizes the interdependent, yet separable, components of a data language. We demonstrate NWB's impact through unified description of neurophysiology data across diverse modalities and species. NWB exists in an ecosystem, which includes data management, analysis, visualization, and archive tools. Thus, the NWB data language enables reproduction, interchange, and reuse of diverse neurophysiology data. More broadly, the design principles of NWB are generally applicable to enhance discovery across biology through data FAIRness.

The cortical silent period (CSP), assessed with transcranial magnetic stimulation (TMS), provides insights into motor cortex excitability. Alterations in the CSP have been observed in multiple sclerosis (MS), although a comparison of the sometimes contradictory results is difficult due to methodological differences. The aim of this study is to provide a more profound neurophysiological understanding of fatigue's pathophysiology and its relationship to the CSP. Twenty-three patients with MS, along with a matched control group, underwent comprehensive CSP measurements at four intensities (125, 150, 175, and 200% resting motor threshold), while their fatigue levels were assessed using the Fatigue Scale for Motor and Cognitive Functions (FSMC) and its motor and cognitive subscore. MS patients exhibited a significantly increased CSP duration compared to controls (p = 0.02), but CSP duration was not associated with the total FSMC, or the motor or cognitive subscore. Our data suggest a systematic difference in MS patients compared to healthy controls in the CSP but no association with fatigue when measured with the FSMC. Based on these results, and considering the heterogeneous literature in the field, our study highlights the need for a more standardized approach to neurophysiological data collection and validation. This standardization is crucial for exploring the link between TMS and clinical impairments in diseases like MS. [ABSTRACT FROM AUTHOR]

IntroductionNeurophysiological manifestations selectively associated with amyloid beta and tau depositions in Alzheimer's disease (AD) are useful network biomarkers to identify peptide specific pathological processes. The objective of this study was to validate the associations between reduced neuronal synchrony within alpha oscillations and neurofibrillary tangle (NFT) density in autopsy examination, in patients with AD.MethodsIn a well-characterized clinicopathological cohort of AD patients (n = 13), we quantified neuronal synchrony within alpha (8-12 Hz) and delta-theta (2-8 Hz) oscillations, using magnetoencephalography during the disease course, within six selected neocortical and hippocampal regions, including angular gyrus, superior temporal gurus, middle frontal gyrus, primary motor cortex, CA1, and subiculum, and correlated these with regional NFT density quantified at histopathological examination.ResultsAbnormal synchrony in alpha, but not in delta-theta, significantly predicted the NFT density at post mortem neuropathological examination.DiscussionReduced alpha synchrony is a sensitive neurophysiological index associated with pathological tau, and a potential network biomarker for clinical trials, to gauge the extent of network dysfunction and the degree of rescue in treatments targeting tau pathways in AD.

BackgroundElectroconvulsive therapy (ECT) is the most effective treatment for treatment-resistant depression (TRD), especially for acute suicidal ideation, but the associated cognitive adverse effects and negative stigma limit its use. Another seizure therapy under development is magnetic seizure therapy (MST), which could potentially overcome the restrictions associated with ECT with similar efficacy. The neurophysiological targets and mechanisms of seizure therapy, however, remain poorly understood.Methods/designThis neurophysiological study protocol is published as a companion to the overall Confirmatory Efficacy and Safety Trial of Magnetic Seizure Therapy for Depression (CREST-MST) protocol that describes our two-site, double-blind, randomized, non-inferiority clinical trial to develop MST as an effective and safe treatment for TRD. Our aim for the neurophysiological component of the study is to evaluate two biomarkers, one to predict remission of suicidal ideation (primary outcome) and the other to predict cognitive impairment (secondary outcome). Suicidal ideation will be assessed through cortical inhibition, which according to our preliminary studies, correlates with remission of suicidal ideation. Cortical inhibition will be measured with simultaneous transcranial magnetic stimulation (TMS) and electroencephalography (EEG), TMS-EEG, which measures TMS-evoked EEG activity. Cognitive adverse effects associated with seizure therapy, on the contrary, will be evaluated via multiscale entropy analysis reflecting the complexity of ongoing resting-state EEG activity.DiscussionECT and MST are known to influence cortical inhibition associated with depression, suicidal ideation severity, and clinical outcome. Therefore, evaluating cortical inhibition and brain temporal dynamics will help understand the pathophysiology of depression and suicidal ideation and define new biological targets that could aid clinicians in diagnosing and selecting treatments. Resting-state EEG complexity was previously associated with the degree of cognitive side effects after a seizure therapy. This neurophysiological metric may help clinicians assess the risk for adverse effects caused by these useful and effective treatments.Trial registrationClinicalTrials.gov NCT03191058 . Registered on June 19, 2017.

Adults can learn to identify nonnative speech sounds with training, albeit with substantial variability in learning behavior. Increases in behavioral accuracy are associated with increased separability for sound representations in cortical speech areas. However, it remains unclear whether individual auditory neural populations all show the same types of changes with learning, or whether there are heterogeneous encoding patterns. Here, we used high-resolution direct neural recordings to examine local population response patterns, while native English listeners learned to recognize unfamiliar vocal pitch patterns in Mandarin Chinese tones. We found a distributed set of neural populations in bilateral superior temporal gyrus and ventrolateral frontal cortex, where the encoding of Mandarin tones changed throughout training as a function of trial-by-trial accuracy ("learning effect"), including both increases and decreases in the separability of tones. These populations were distinct from populations that showed changes as a function of exposure to the stimuli regardless of trial-by-trial accuracy. These learning effects were driven in part by more variable neural responses to repeated presentations of acoustically identical stimuli. Finally, learning effects could be predicted from speech-evoked activity even before training, suggesting that intrinsic properties of these populations make them amenable to behavior-related changes. Together, these results demonstrate that nonnative speech sound learning involves a wide array of changes in neural representations across a distributed set of brain regions.

Background: This study investigated the efficacy of electrical nerve stimulation for neuromuscular and functional performance recovery after acute traumatic spinal cord injury (TSCI). Methods: Twenty-nine participants with TSCI (20 males and 9 females) were randomly assigned to study group (SG) and control group (CG). Treatment started within 24 h of injury at 3 days/week for 24 weeks. Both groups were treated with a functional re-education approach while SG had electrical nerve stimulation in addition. The American Spinal Cord Injury Association (ASIA) scale was used to assess the severity of TSCI, the Spinal Cord Independence Measure evaluated functional performance, Neuromuscular Recovery Scale measured neuromuscular recovery, Walking Index assessed walking function, and a tape rule was used to measure participants' girth. Measurements were taken at baseline and every 6 weeks thereafter. Data were analyzed using the Friedman Analysis of Variance, the Wilcoxon–rank test, and Independent t-test. Results: Participants were aged 15–58 years (mean = 36.75 ± 11.75 and median = 37 years), with 19 (65.5%) within 19–40 years' range. Eighteen (62.1%) had cervical, three (10.2%) thoracic, and eight (27.5%) had lumbar TSCI. Nine (31.0%) each presented with ASIA-A and ASIA-C, seven (24.1%) ASIA-B, and four (13.9%) ASIA-D. Consistent significant (P < 0.05) improvement in neuromuscular and functional performance recovery within SG as compared with CG was recorded, with improvements across the five points of measurement. Walking function improved clinically in SG and no muscle atrophy was recorded throughout 24 weeks. The level of statistical significance was set at P < 0.05. Conclusion: Electrical nerve stimulation combined with early functional re-training effectively improves neuromuscular and functional performance recovery in acute TSCI. [ABSTRACT FROM AUTHOR]

[Figure: see text].

The broad concept of emergence is instrumental in various of the most challenging open scientific questions-yet, few quantitative theories of what constitutes emergent phenomena have been proposed. This article introduces a formal theory of causal emergence in multivariate systems, which studies the relationship between the dynamics of parts of a system and macroscopic features of interest. Our theory provides a quantitative definition of downward causation, and introduces a complementary modality of emergent behaviour-which we refer to as causal decoupling. Moreover, the theory allows practical criteria that can be efficiently calculated in large systems, making our framework applicable in a range of scenarios of practical interest. We illustrate our findings in a number of case studies, including Conway's Game of Life, Reynolds' flocking model, and neural activity as measured by electrocorticography.

BackgroundThere is a need for reliable and robust Parkinson's disease biomarkers that reflect severity and are sensitive to disease modifying investigational therapeutics.ObjectiveTo demonstrate the utility of EEG as a reliable, quantitative biomarker with potential as a pharmacodynamic endpoint for use in clinical assessments of neuroprotective therapeutics for Parkison's disease.MethodsA multi modal study was performed including aquisition of resting state EEG data and dopamine transporter PET imaging from Parkinson's disease patients off medication and compared against age-matched controls.ResultsQualitative and test/retest analysis of the EEG data demonstrated the reliability of the methods. Source localization using low resolution brain electromagnetic tomography identified significant differences in Parkinson's patients versus control subjects in the anterior cingulate and temporal lobe, areas with established association to Parkinson's disease pathology. Changes in cortico-cortical and cortico-thalamic coupling were observed as excessive EEG beta coherence in Parkinson's disease patients, and correlated with UPDRS scores and dopamine transporter activity, supporting the potential for cortical EEG coherence to serve as a reliable measure of disease severity. Using machine learning approaches, an EEG discriminant function analysis classifier was identified that parallels the loss of dopamine synapses as measured by dopamine transporter PET.ConclusionOur results support the utility of EEG in characterizing alterations in neurophysiological oscillatory activity associated with Parkinson's disease and highlight potential as a reliable method for monitoring disease progression and as a pharmacodynamic endpoint for Parkinson's disease modification therapy.

Psychobiological techniques to assess emotional responding have revolutionized the field of emotional development in recent decades by equipping researchers with the tools to quantify children's emotional reactivity and regulation more directly than behavioral approaches allow. Knowledge gained from the incorporation of methods spanning levels of analysis has been substantial, yet many open questions remain. In this prospective review, we (a) describe the major conceptual and empirical advances that have resulted from this methodological innovation, and (b) lay out a case for what we view as the most pressing challenge for the next decades of research into the psychobiology of emotional development: focusing empirical efforts toward understanding the implications of the broader sociocultural contexts in which children develop that shape the psychobiology of emotion. Thus, this review integrates previous knowledge about the psychobiology of emotion with a forward-looking set of recommendations for incorporating sociocultural processes into future investigations.

The American Society of Neurophysiological Monitoring (ASNM) was founded in 1989 as the American Society of Evoked Potential Monitoring. From the beginning, the Society has been made up of physicians, doctoral degree holders, Technologists, and all those interested in furthering the profession. The Society changed its name to the ASNM and held its first Annual Meeting in 1990. It remains the largest worldwide organization dedicated solely to the scientifically-based advancement of intraoperative neurophysiology. The primary goal of the ASNM is to assure the quality of patient care during procedures monitoring the nervous system. This goal is accomplished primarily through programs in education, advocacy of basic and clinical research, and publication of guidelines, among other endeavors. The ASNM is committed to the development of medically sound and clinically relevant guidelines for the performance of intraoperative neurophysiology. Guidelines are formulated based on exhaustive literature review, recruitment of expert opinion, and broad consensus among ASNM membership. Input is likewise sought from sister societies and related constituencies. Adherence to a literature-based, formalized process characterizes the construction of all ASNM guidelines. The guidelines covering the Professional Practice of intraoperative neurophysiological monitoring were initially published January 24th, 2013, and subsequently that document has undergone review and revision to accommodate broad inter- and intra-societal feedback. This current version of the ASNM Professional Practice Guideline was fully approved for publication according to ASNM bylaws on February 22nd, 2018, and thus overwrites and supersedes the initial guideline.

To combat retinal degeneration, healthy fetal retinal sheets have been successfully transplanted into both rodent models and humans, with synaptic connectivity between transplant and degenerated host retina having been confirmed. In rodent studies, transplants have been shown to restore responses to flashes of light in a region of the superior colliculus corresponding to the location of the transplant in the host retina. To determine the quality and detail of visual information provided by the transplant, visual responsivity was studied here at the level of visual cortex where higher visual perception is processed. For our model, we used the transgenic Rho-S334ter line-3 rat (both sexes), which loses photoreceptors at an early age and is effectively blind at postnatal day 30. These rats received fetal retinal sheet transplants in one eye between 24 and 40 d of age. Three to 10 months following surgery, visually responsive neurons were found in regions of primary visual cortex matching the transplanted region of the retina that were as highly selective as normal rat to stimulus orientation, size, contrast, and spatial and temporal frequencies. Conversely, we found that selective response properties were largely absent in nontransplanted line-3 rats. Our data show that fetal retinal sheet transplants can result in remarkably normal visual function in visual cortex of rats with a degenerated host retina and represents a critical step toward developing an effective remedy for the visually impaired human population.SIGNIFICANCE STATEMENT Age-related macular degeneration and retinitis pigmentosa lead to profound vision loss in millions of people worldwide. Many patients lose both retinal pigment epithelium and photoreceptors. Hence, there is a great demand for the development of efficient techniques that allow for long-term vision restoration. In this study, we transplanted dissected fetal retinal sheets, which can differentiate into photoreceptors and integrate with the host retina of rats with severe retinal degeneration. Remarkably, we show that transplants generated visual responses in cortex similar in quality to normal rats. Furthermore, transplants preserved connectivity within visual cortex and the retinal relay from the lateral geniculate nucleus to visual cortex, supporting their potential application in curing vision loss associated with retinal degeneration.

An intrinsic difficulty in studying cognitive processes is that they are unobservable states that exist in between observable responses to the sensory environment. Cognitive states must be inferred from indirect behavioral measures. Neuroscience potentially provides the tools necessary to measure cognitive processes directly, but it is challenged on two fronts. First, neuroscientific measures often lack the spatiotemporal resolution to identify the neural computations that underlie a cognitive process. Second, the activity of a single neuron, which is the fundamental building block of neural computation, is too noisy to provide accurate measurements of a cognitive process. In this paper, I examine recent developments in neurophysiological recording and analysis methods that provide a potential solution to these problems.

Purpose of reviewNeurophysiology is a complex network of cellular, electrical, and vascular systems which function to maximize neuronal functioning and brain performance. The brain exists in a closed system made up of parenchyma, cerebrospinal fluid, and blood with any increase in volume leading to a corresponding decrease in one of the components. Once these compensatory mechanisms are exhausted, there is a precipitous increase in the intracranial pressure leading to decreases in cerebral perfusion and resulting ischemia. The cerebral vasculature has significant control over the total volume of blood and regional flow throughout the brain via autoregulation. Through this process, blood flow is tightly regulated to prevent fluctuations and is coupled precisely with metabolic demand. Moreover, oxygen delivery and aerobic respiration are essential for proper brain functioning and can become deranged in various disease states leading to cellular injury and death.Recent findingsOngoing trials have provided evidence that in addition to targeted therapy for intracranial pressure monitoring, optimizing brain tissue oxygenation and cerebral autoregulation may lead to improved clinical outcomes. An understanding of neurophysiology is not only essential for treating patients suffering from intracranial injury but also for the development of novel monitoring and therapeutic techniques.

While prior noninvasive (e.g., electroencephalographic) studies suggest that the human primary motor cortex (M1) is active during gait processes, the limitations of noninvasive recordings make it impossible to determine whether M1 is involved in high-level motor control (e.g., obstacle avoidance, walking speed), low-level motor control (e.g., coordinated muscle activation), or only nonmotor processes (e.g., integrating/relaying sensory information). This study represents the first invasive electroneurophysiological characterization of the human leg M1 during walking. Two subjects with an electrocorticographic grid over the interhemispheric M1 area were recruited. Both exhibited generalized γ-band (40-200 Hz) synchronization across M1 during treadmill walking, as well as periodic γ-band changes within each stride (across multiple walking speeds). Additionally, these changes appeared to be of motor, rather than sensory, origin. However, M1 activity during walking shared few features with M1 activity during individual leg muscle movements, and was not highly correlated with lower limb trajectories on a single channel basis. These findings suggest that M1 primarily encodes high-level gait motor control (i.e., walking duration and speed) instead of the low-level patterns of leg muscle activation or movement trajectories. Therefore, M1 likely interacts with subcortical/spinal networks, which are responsible for low-level motor control, to produce normal human walking.

Current therapies for neurogenic bladder do not allow spinal cord injury patients to regain conscious control of urine storage or voiding. Novel neural technologies may provide means to improve or restore the connection between the brain and the bladder; however, the specific brain areas and their underlying neural activities responsible for micturition must be better understood in order to design such technologies. In this retrospective study, we analyzed electrocorticographic (ECoG) data obtained from epilepsy patients who underwent ECoG grid implantation for epilepsy surgery evaluation, in the hopes of determining specific electrophysiological activity associated with micturition. Our results indicate modulation of the delta (δ, 0.1-4 Hz) and low-gamma (\gamma, 25-50 Hz) activity in the peri-Sylvian area and the inferior temporal lobe. These findings suggest involvement of the insular cortex and the uncinate fasciculus in micturition, important structures related to sensation and decision making. To date, this is the first known study utilizing ECoG data to elucidate the electrophysiological activity of the brain associated with bladder control and sensation.

OBJECTIVE: Although patients with schizophrenia exhibit impaired suppression of the P50 event-related brain potential in response to the second of two identical auditory stimuli during a paired-stimulus paradigm, uncertainty remains over whether this deficit in inhibitory gating of auditory sensory processes has relevance for patients clinical symptoms or cognitive performance. The authors examined associations between P50 suppression deficits and several core features of schizophrenia to address this gap. METHOD: P50 was recorded from 52 patients with schizophrenia and 41 healthy comparison subjects during a standard auditory paired-stimulus task. Clinical symptoms were assessed with the Scale for the Assessment of Positive Symptoms and the Scale for the Assessment of Negative Symptoms. The MATRICS Consensus Cognitive Battery was utilized to measure cognitive performance in a subsample of 39 patients. Correlation and regression analyses were conducted to examine P50 suppression in relation to clinical symptom and cognitive performance measures. RESULTS: Schizophrenia patients demonstrated a deficit in P50 suppression when compared with healthy subjects, replicating prior research. Within the patient sample, impaired P50 suppression covaried reliably with greater difficulties in attention, poorer working memory, and reduced processing speed. CONCLUSIONS: Impaired suppression of auditory stimuli was associated with core pathological features of schizophrenia, increasing confidence that P50 inhibitory processing can inform the development of interventions that target cognitive impairments in this chronic and debilitating mental illness.

Electroencephalography and magnetoencephalography are noninvasive neuroimaging techniques that have been used extensively to study various resting-state and cognitive processes in the brain. The purpose of this review is to highlight a number of recent studies that have investigated the alpha band (8-12 Hz) oscillatory activity present in magnetoencephalography and electroencephalography, to provide new insights into the maladaptive network activity underlying attentional impairments in attention-deficit/hyperactivity disorder (ADHD). Studies reviewed demonstrate that event-related decrease in alpha is attenuated during visual selective attention, primarily in ADHD inattentive type, and is often significantly associated with accuracy and reaction time during task performance. Furthermore, aberrant modulation of alpha activity has been reported across development and may have abnormal or atypical lateralization patterns in ADHD. Modulations in the alpha band thus represent a robust, relatively unexplored putative biomarker of attentional impairment and a strong prospect for future studies aimed at examining underlying neural mechanisms and treatment response among individuals with ADHD. Potential limitations of its use as a diagnostic biomarker and directions for future research are discussed.

BackgroundNeonatal neurocritical care is a growing and rapidly evolving medical subspecialty, with increasing numbers of dedicated multidisciplinary clinical, educational, and research programs established at academic institutions. The growth of these programs has provided trainees in neurology, neonatology, and pediatrics with increased exposure to the field, sparking interest in dedicated fellowship training in fetal-neonatal neurology.ObjectivesTo meet this rising demand, increasing numbers of training programs are being established to provide trainees with the requisite knowledge and skills to independently deliver care for infants with neurological injury or impairment from the fetal care center and neonatal intensive care unit to the outpatient clinic. This article provides an initial framework for standardization of training across these programs.ResultsRecommendations include goals and objectives for training in the field; core areas where clinical competency must be demonstrated; training activities and neuroimaging and neurodiagnostic modalities which require proficiency; and programmatic requirements necessary to support a comprehensive and well-rounded training program.ConclusionsWith consistent implementation, the proposed model has the potential to establish recognized standards of professional excellence for training in the field, provide a pathway toward Accreditation Council for Graduate Medical Education certification for program graduates, and lead to continued improvements in medical and neurological care provided to patients in the neonatal intensive care unit.

A narrative starting with the author's entering the Optometry program at the Sydney Technical College in 1940, taking him through his days as an optometry and science student, an optometrist in private practice, and participant in organized optometry in Sydney. It described his steps to become an optometric scientist and his service as faculty member in three optometry schools in the United States. Finally, it follows him into a long career in vision science and neurophysiology at Berkeley.

A long-standing question in systems neuroscience is how the activity of single neurons gives rise to our perceptions and actions. Critical insights into this question occurred in the last part of the 20th century when scientists began linking modulations of neuronal activity directly to perceptual behavior. A significant conceptual advance was the application of signal detection theory to both neuronal activity and behavior, providing a quantitative assessment of the relationship between brain and behavior. One metric that emerged from these efforts was choice probability (CP), which provides information about how well an ideal observer can predict the choice an animal makes from a neuron's discharge rate distribution. In this review, we describe where CP has been studied, locational trends in the values found, and why CP values are typically so low. We discuss its dependence on correlated activity among neurons of a population, assess whether it arises from feedforward or feedback mechanisms, and investigate what CP tells us about how many neurons are required for a decision and how they are pooled to do so.

Attention control is the ability to selectively attend to some sensory signals while ignoring others. This ability is thought to involve two processes: enhancement of sensory signals that are to be attended and the attenuation of sensory signals that are to be ignored. The overall strength of attentional modulation is often measured by comparing the amplitude of a sensory neural response to an external input when attended versus when ignored. This method is robust for detecting attentional modulation, but precludes the ability to assess the separate dynamics of attending and ignoring processes. Here, we describe methodology to measure independently the neurophysiological signals of attending and ignoring using the intermodal attention task (IMAT). This task, when combined with electroencephalography, isolates neurophysiological sensory responses in auditory and visual modalities, when either attending or ignoring, with respect to a passive control. As a result, independent dynamics of attending and of a ignoring can be assessed in either modality. Our results using this task indicate that the timing and cortical sources of attending and ignoring effects differ, as do their contributions to the attention modulation effect, pointing to unique neural trajectories and demonstrating sample utility of measuring them separately.

Cumulating evidence from epidemiologic studies implicates cardiovascular health and cerebrovascular function in several brain diseases in late life. We examined vascular risk factors with respect to a cerebrovascular measure of brain functioning in subjects in mid-life, which could represent a marker of brain changes in later life. Breath-hold functional MRI (fMRI) was performed in 541 women and men (mean age 50.4 years) from the Coronary Artery Risk Development in Young Adults (CARDIA) Brain MRI sub-study. Cerebrovascular reactivity (CVR) was quantified as percentage change in blood-oxygen level dependent (BOLD) signal in activated voxels, which was mapped to a common brain template and log-transformed. Mean CVR was calculated for anatomic regions underlying the default-mode network (DMN) - a network implicated in AD and other brain disorders - in addition to areas considered to be relatively spared in the disease (e.g. occipital lobe), which were utilized as reference regions. Mean CVR was significantly reduced in the posterior cingulate/precuneus (β=-0.063, 95% CI: -0.106, -0.020), anterior cingulate (β=-0.055, 95% CI: -0.101, -0.010), and medial frontal lobe (β=-0.050, 95% CI: -0.092, -0.008) relative to mean CVR in the occipital lobe, after adjustment for age, sex, race, education, and smoking status, in subjects with pre-hypertension/hypertension compared to normotensive subjects. By contrast, mean CVR was lower, but not significantly, in the inferior parietal lobe (β=-0.024, 95% CI: -0.062, 0.014) and the hippocampus (β=-0.006, 95% CI: -0.062, 0.050) relative to mean CVR in the occipital lobe. Similar results were observed in subjects with diabetes and dyslipidemia compared to those without these conditions, though the differences were non-significant. Reduced CVR may represent diminished vascular functionality for the DMN for individuals with prehypertension/hypertension in mid-life, and may serve as a preclinical marker for brain dysfunction in later life.

BackgroundThe COGS is a multi-site NIMH-sponsored investigation of the genetic basis of 12 primary and multiple secondary quantitative endophenotypes in schizophrenia.MethodsSince 2003, COGS has completed studies using a family-based ascertainment strategy (COGS-1), and a case-control ascertainment strategy (COGS-2) (cumulative "n">4000).ResultsCOGS-1 family study confirmed robust deficits in, and heritability of, these endophenotypes in schizophrenia, and provided evidence for a coherent genetic architecture underlying the risk for neurocognitive and neurophysiological deficits in this disorder. COGS-2 case-control findings, many reported herein, establish a foundation for fine genomic mapping and other analyses of these endophenotypes and risk genes for SZ. Several reports in this Special Issue compare findings of endophenotype deficits generated by fundamentally different COGS-1 vs. COGS-2 ascertainment strategies. Despite the expectation that family-based and case-control designs would establish demographically and potentially biologically distinct patient cohorts, findings generally revealed comparable patterns of endophenotype deficits across studies. The COGS-2 case-control design facilitated the accrual of a larger "n", permitting detailed analyses of factors moderating endophenotype performance. Some COGS-2 endophenotypes not assessed in COGS-1 are also reported, as is a new factor analytic strategy for identifying shared vs. unique factors among the COGS endophenotypes which can be used to develop composite variables with distinct genetic signatures.DiscussionThe path to date of COGS-1 endophenotype and genetic findings, followed by replication and extension in COGS-2, establishes benchmarks for endophenotype deficits in SZ and their moderation by specific factors, and clear expectations for informative findings from upcoming COGS-2 genetic analyses.

BackgroundAlthough many endophenotypes for schizophrenia have been studied individually, few studies have examined the extent to which common neurocognitive and neurophysiological measures reflect shared versus unique endophenotypic factors. It may be possible to distill individual endophenotypes into composite measures that reflect dissociable, genetically informative elements.MethodsThe first phase of the Consortium on the Genetics of Schizophrenia (COGS-1) is a multisite family study that collected neurocognitive and neurophysiological data between 2003 and 2008. For these analyses, participants included schizophrenia probands (n=83), their nonpsychotic siblings (n=151), and community comparison subjects (n=209) with complete data on a battery of 12 neurocognitive tests (assessing domains of working memory, declarative memory, vigilance, spatial ability, abstract reasoning, facial emotion processing, and motor speed) and 3 neurophysiological tasks reflecting inhibitory processing (P50 gating, prepulse inhibition and antisaccade tasks). Factor analyses were conducted on the measures for each subject group and across the entire sample. Heritability analyses of factors were performed using SOLAR.ResultsAnalyses yielded 5 distinct factors: 1) Episodic Memory, 2) Working Memory, 3) Perceptual Vigilance, 4) Visual Abstraction, and 5) Inhibitory Processing. Neurophysiological measures had low associations with these factors. The factor structure of endophenotypes was largely comparable across probands, siblings and controls. Significant heritability estimates for the factors ranged from 22% (Episodic Memory) to 39% (Visual Abstraction).ConclusionsNeurocognitive measures reflect a meaningful amount of shared variance whereas the neurophysiological measures reflect largely unique contributions as endophenotypes for schizophrenia. Composite endophenotype measures may inform our neurobiological and genetic understanding of schizophrenia.

Brain oscillatory activity from the midline prefrontal region has been shown to reflect brain dysfunction in subjects with Major Depressive Disorder (MDD). It is not known, however, whether electrodes from this area provide unique information about brain function in MDD. We examined a set of midline sites and two other prefrontal locations for detecting cerebral activity differences between subjects with MDD and healthy controls. Resting awake quantitative EEG (qEEG) data were recorded from 168 subjects: 47 never-depressed adults and 121 with a current major depressive episode. Individual midline electrodes (Fpz, Fz, Cz, Pz, and Oz) and prefrontal electrodes outside the hairline (Fp1, Fp2) were examined with absolute and relative power and cordance in the theta band. We found that MDD subjects exhibited higher values of cordance (p = 0.0066) at Fpz than controls; no significant differences were found at other locations, and power measures showed trend-level differences. Depressed adults showed higher midline cordance than did never-depressed subjects at the most-anterior midline channel. Salient abnormalities in MDD may be detectable by focusing on the prefrontal midline region, and EEG metrics from focused electrode arrays may offer clinical practicality for clinical monitoring.

Brain oscillatory activity from the midline prefrontal region has been shown to reflect brain dysfunction in subjects with Major Depressive Disorder (MDD). It is not known, however, whether electrodes from this area provide unique information about brain function in MDD. We examined a set of midline sites and two other prefrontal locations for detecting cerebral activity differences between subjects with MDD and healthy controls. Resting awake quantitative EEG (qEEG) data were recorded from 168 subjects: 47 never-depressed adults and 121 with a current major depressive episode. Individual midline electrodes (Fpz, Fz, Cz, Pz, and Oz) and prefrontal electrodes outside the hairline (Fp1, Fp2) were examined with absolute and relative power and cordance in the theta band. We found that MDD subjects exhibited higher values of cordance (p = 0.0066) at Fpz than controls; no significant differences were found at other locations, and power measures showed trend-level differences. Depressed adults showed higher midline cordance than did never-depressed subjects at the most-anterior midline channel. Salient abnormalities in MDD may be detectable by focusing on the prefrontal midline region, and EEG metrics from focused electrode arrays may offer clinical practicality for clinical monitoring.

This paper investigates how commonly prescribed pharmacologic treatments for Alzheimer's disease (AD) affect Event-Related Potential (ERP) biomarkers as tools for predicting AD conversion in individuals with Mild Cognitive Impairment (MCI). We gathered baseline ERP data from two MCI groups (those taking AD medications and those not) and later determined which subjects developed AD (Convert->AD) and which subjects remained cognitively stable (Stable). We utilized a previously developed and validated multivariate system of ERP components to measure medication effects among these four subgroups. Discriminant analysis produced classification scores for each individual as a measure of similarity to each clinical group (Convert->AD, Stable), and we found a large significant main Group effect but no main AD Medications effect and no Group by Medications interaction. This suggested AD medications have negligible influence on this set of ERP components as weighted markers of disease progression. These results provide practical information to those using ERP measures as a biomarker to identify and track AD in individuals in a clinical or research setting.

Symptoms of Major Depressive Disorder (MDD) are hypothesized to arise from dysfunction in brain networks linking the limbic system and cortical regions. Alterations in brain functional cortical connectivity in resting-state networks have been detected with functional imaging techniques, but neurophysiologic connectivity measures have not been systematically examined. We used weighted network analysis to examine resting state functional connectivity as measured by quantitative electroencephalographic (qEEG) coherence in 121 unmedicated subjects with MDD and 37 healthy controls. Subjects with MDD had significantly higher overall coherence as compared to controls in the delta (0.5-4 Hz), theta (4-8 Hz), alpha (8-12 Hz), and beta (12-20 Hz) frequency bands. The frontopolar region contained the greatest number of "hub nodes" (surface recording locations) with high connectivity. MDD subjects expressed higher theta and alpha coherence primarily in longer distance connections between frontopolar and temporal or parietooccipital regions, and higher beta coherence primarily in connections within and between electrodes overlying the dorsolateral prefrontal cortical (DLPFC) or temporal regions. Nearest centroid analysis indicated that MDD subjects were best characterized by six alpha band connections primarily involving the prefrontal region. The present findings indicate a loss of selectivity in resting functional connectivity in MDD. The overall greater coherence observed in depressed subjects establishes a new context for the interpretation of previous studies showing differences in frontal alpha power and synchrony between subjects with MDD and normal controls. These results can inform the development of qEEG state and trait biomarkers for MDD.

Aims: Assessing the reliability of electrical pain threshold (PT) and evaluating the impact of stimulation frequency at different locations in the healthy lower urinary tract (LUT). Methods: Ninety subjects (age: 18.3‐35.8 years, 40 females, 50 males) were randomly allocated to one stimulation site (bladder dome [BD], trigone, proximal, membranous (only males), or distal urethra). Using 0.5 Hz/1.1 Hz/1.6 Hz electrical stimulation (square wave, pulse width:1 ms), current perception thresholds (CPTs), PTs and tolerance thresholds were assessed at two visits. Analyses were performed using linear mixed models, intraclass correlation coefficients (ICC) and Bland‐Altman method. Results: PTs vary in relation to stimulation frequency, location and between genders. PT decreased with higher stimulation frequency. The highest PTs were measured at the BD and membranous urethra with males reporting higher PTs than females. Reliability of PT assessments according to ICC was good to excellent across all frequencies, locations, and genders (ICC = 0.61‐0.97), except for BD and distal urethra in females showing poor to fair reliability (BD: all frequencies, distal urethra: 0.5 Hz). Conclusions: PTs can be safely and reliably assessed from bladder and urethral locations. Semi‐objective PT assessment may provide additional information on functionality and sensitivity of the LUT slow fiber afferents and complement findings from urodynamic investigations and CPT assessments. In conclusion, the developed methodology may open new opportunities for using electrical stimulation paradigms for LUT PT assessments and diagnostics. All this allows a more precise, location‐specific characterization of pain origin and pain reaction towards therapy. [ABSTRACT FROM AUTHOR]