Epileptogenic but MRI-normal perituberal tissue in Tuberous Sclerosis Complex contains tuber-specific abnormalities

Introduction: Recent evidence has implicated perituberal, MRI-normal brain tissue as a possible source of seizures in tuberous sclerosis complex (TSC). Data on aberrant structural features in this area that may predispose to the initiation or progression of seizures are very limited. We used immunohistochemistry and confocal microscopy to compare epileptogenic, perituberal, MRI-normal tissue with cortical tubers. Results: In every sample of epileptogenic, perituberal tissue, we found many abnormal cell types, including giant cells and cytomegalic neurons. The majority of giant cells were surrounded by morphologically abnormal astrocytes with long processes typical of interlaminar astrocytes. Perituberal giant cells and astrocytes together formed characteristic “microtubers”. A parallel analysis of tubers showed that many contained astrocytes with features of both protoplasmic and gliotic cells. Conclusions: Microtubers represent a novel pathognomonic finding in TSC and may represent an elementary unit of cortical tubers. Microtubers and cytomegalic neurons in perituberal parenchyma may serve as the source of seizures in TSC and provide potential targets for therapeutic and surgical interventions in TSC

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

"Epilepsy surgery" versus lesionectomy in patients with seizures secondary to cavernous malformations

Cerebral cavernous malformations (CCMs) are angiographically occult and consist of a honeycomb-like, low-pressure bed of ectatic vasculature with no intervening neural tissue. Although most cases are sporadic, there are several familial forms. A hemosiderin rim frequently exists from repeated microhemorrhage, leading to reactive cortical gliosis. Because there are no neurons within a cavernous malformation, seizures arise from the complex interactions among neurons, astrocytes, and microvasculature at the margin of CCMs. These lesions are highly epileptogenic: seizures are the most common presentation of CCM, occurring in up to 39% of cases.17 When seizures resulting from a CCM are refractory to anti-epileptic medication, resection of the CCM and the surrounding epileptogenic zone is indicated. The most appropriate surgical treatment of epilepsy secondary to cavernous malformation remains controversial. Certain patients benefit from isolated lesionectomy alone, whereas others need more extensive epilepsy evaluation and resection to achieve seizure freedom. As a result, there have been numerous retrospective series attempting to determine the optimal management paradigm for this condition as related to lesion number, location, seizure type, and duration of epilepsy. Despite these efforts, no clear consensus has been reached. We review the literature regarding the role of comprehensive epilepsy surgery versus isolated lesionectomy in patients with seizures secondary to cavernous malformations and present representative cases. Based on our interpretation of the literature and experience managing these lesions, we speculate on the mechanisms involved in the development and maintenance of epilepsy in these patients as well as synthesize a series of management guidelines. These recommendations are founded in proper patient selection and the integration of microsurgical and neuromonitoring techniques. Critical to our guidelines is collaboration by a highly experienced team of neurosurgeons and neurologists working at a tertiary medical center with a high case volume and using a decision-making paradigm designed to minimize treatment risks. MEDICAL INTRACTABILITY As discussed subsequently, seizure intractability with anti-epileptic medication refractoriness is a risk factor for continued epilepsy despite CCM resection. However, what exactly defines “medical intractability” remains imprecise. Conceptually, it is the inability to achieve satisfactory seizure control despite adequate trials with a sufficient number of anti-epileptic medications at doses that are associated with acceptable side effects. Although seemingly straightforward, several questions regarding “medical intractability” remain disputed in the medical literature: 1. What degree of seizure control is “satisfactory”? Are rare simple partial seizures that do not secondarily generalize on medications acceptable? 2. What is an adequate number of anti-epileptic trials? In the landmark study of Kwan and Brodie,14 nearly 90% of seizure freedom was achieved with the first medication tried if the drug was not stopped for side effects. Only 11% of patients who failed to respond to a first anti-epileptic drug at therapeutic dosage achieved seizure freedom on a second drug. In their discussion, the authors suggest that patients who fail two first-line drugs, who have a correctable epileptogenic structural abnormality, should be referred for surgery. Although many neurologists have historically been hesitant to refer patients with epilepsy to neurosurgeons for evaluation, the strong likelihood of seizure freedom after surgery weighs in favor of surgery over continued medication trials. 3. What are acceptable side effects of anti-epileptic medications? Another important issue that must be considered in evaluating both medical intractability and different outcomes of epilepsy surgery for cavernous malformations is the inability of patients to recognize their own seizures reliably. Well recognized in the epilepsy community, poor self-recognition of seizures confounds success rates reported in surgical series. In one study of patients evaluated in the epilepsy monitoring unit with video encephalography, 30% of patients denied all seizures, and only 23% of patients were aware of all of their recorded seizures.5 In addition, patients with the Copyright © 2008 by The Congress of Neurological Surgeons 0148-703/08/5501-01

Microscale multicircuit brain stimulation: Achieving real-time brain state control for novel applications

Neurological and psychiatric disorders typically result from dysfunction across multiple neural circuits. Most of these disorders lack a satisfactory neuromodulation treatment. However, deep brain stimulation (DBS) has been successful in a limited number of disorders; DBS typically targets one or two brain areas with single contacts on relatively large electrodes, allowing for only coarse modulation of circuit function. Because of the dysfunction in distributed neural circuits – each requiring fine, tailored modulation – that characterizes most neuropsychiatric disorders, this approach holds limited promise. To develop the next generation of neuromodulation therapies, we will have to achieve fine-grained, closed-loop control over multiple neural circuits. Recent work has demonstrated spatial and frequency selectivity using microstimulation with many small, closely-spaced contacts, mimicking endogenous neural dynamics. Using custom electrode design and stimulation parameters, it should be possible to achieve bidirectional control over behavioral outcomes, such as increasing or decreasing arousal during central thalamic stimulation. Here, we discuss one possible approach, which we term microscale multicircuit brain stimulation (MMBS). We discuss how machine learning leverages behavioral and neural data to find optimal stimulation parameters across multiple contacts, to drive the brain towards desired states associated with behavioral goals. We expound a mathematical framework for MMBS, where behavioral and neural responses adjust the model in real-time, allowing us to adjust stimulation in real-time. These technologies will be critical to the development of the next generation of neurostimulation therapies, which will allow us to treat problems like disorders of consciousness and cognition

Real-time emotion detection by quantitative facial motion analysis.

BackgroundResearch into mood and emotion has often depended on slow and subjective self-report, highlighting a need for rapid, accurate, and objective assessment tools.MethodsTo address this gap, we developed a method using digital image speckle correlation (DISC), which tracks subtle changes in facial expressions invisible to the naked eye, to assess emotions in real-time. We presented ten participants with visual stimuli triggering neutral, happy, and sad emotions and quantified their associated facial responses via detailed DISC analysis.ResultsWe identified key alterations in facial expression (facial maps) that reliably signal changes in mood state across all individuals based on these data. Furthermore, principal component analysis of these facial maps identified regions associated with happy and sad emotions. Compared with commercial deep learning solutions that use individual images to detect facial expressions and classify emotions, such as Amazon Rekognition, our DISC-based classifiers utilize frame-to-frame changes. Our data show that DISC-based classifiers deliver substantially better predictions, and they are inherently free of racial or gender bias.LimitationsOur sample size was limited, and participants were aware their faces were recorded on video. Despite this, our results remained consistent across individuals.ConclusionsWe demonstrate that DISC-based facial analysis can be used to reliably identify an individual's emotion and may provide a robust and economic modality for real-time, noninvasive clinical monitoring in the future

Cardiac arrest after severe traumatic brain injury can be survivable with good outcomes

Background Resuscitation for traumatic cardiac arrest (TCA) in patients with severe traumatic brain injury (sTBI) has historically been considered futile. There is little information on the characteristics and outcomes of these patients to guide intervention and prognosis. The purpose of the current study is to report the clinical characteristics, survival, and long-term neurological outcomes in patients who experienced TCA after sTBI and analyze the factors contributing to survival.Methods A retrospective review identified 42 patients with TCA from a total of 402 patients with sTBI (Glasgow Coma Scale (GCS) score ≤8) who were admitted to Stony Brook University Hospital, a level I trauma center, from January 2011 to December 2018. Patient demographics, clinical characteristics, survival, and neurological functioning during hospitalization and at follow-up visits were collected.Results Of the 42 patients, the average age was 45 years and 21.4% were female. Eight patients survived the injury (19.0%) to discharge and seven survived with good neurological function. Admission GCS score and bilateral pupil reactivity were found to be significant indicators of survival. The mean GCS score was 5.3 in survivors and 3.2 in non-survivors (p=0.020). Age, Injury Severity Score, or cardiac rhythm was not associated with survival. Frequent neuroimaging findings included subarachnoid hemorrhage, subdural hematoma, and diffuse axonal injury.Discussion TCA after sTBI is survivable and seven out of eight patients in our study recovered with good neurological function. GCS score and pupil reactivity are the best indicators of survival. Our results suggest that due to the possibility of recovery, resuscitation and neurosurgical care should not be withheld from this patient population.Level of evidence Level IV, therapeutic/care management

Brain–Computer Interfaces for Communication in Patients with Disorders of Consciousness:A Gap Analysis and Scientific Roadmap

Background: We developed a gap analysis that examines the role of brain–computer interfaces (BCI) in patients with disorders of consciousness (DoC), focusing on their assessment, establishment of communication, and engagement with their environment. Methods: The Curing Coma Campaign convened a Coma Science work group that included 16 clinicians and neuroscientists with expertise in DoC. The work group met online biweekly and performed a gap analysis of the primary question. Results: We outline a roadmap for assessing BCI readiness in patients with DoC and for advancing the use of BCI devices in patients with DoC. Additionally, we discuss preliminary studies that inform development of BCI solutions for communication and assessment of readiness for use of BCIs in DoC study participants. Special emphasis is placed on the challenges posed by the complex pathophysiologies caused by heterogeneous brain injuries and their impact on neuronal signaling. The differences between one-way and two-way communication are specifically considered. Possible implanted and noninvasive BCI solutions for acute and chronic DoC in adult and pediatric populations are also addressed. Conclusions: We identify clinical and technical gaps hindering the use of BCI in patients with DoC in each of these contexts and provide a roadmap for research aimed at improving communication for adults and children with DoC, spanning the clinical spectrum from intensive care unit to chronic care.</p