Ketogenic diet for human diseases: the underlying mechanisms and potential for clinical implementations

The ketogenic diet (KD) is a high-fat, adequate-protein, and very-low-carbohydrate diet regimen that mimics the metabolism of the fasting state to induce the production of ketone bodies. The KD has long been established as a remarkably successful dietary approach for the treatment of intractable epilepsy and has increasingly garnered research attention rapidly in the past decade, subject to emerging evidence of the promising therapeutic potential of the KD for various diseases, besides epilepsy, from obesity to malignancies. In this review, we summarize the experimental and/or clinical evidence of the efficacy and safety of the KD in different diseases, and discuss the possible mechanisms of action based on recent advances in understanding the influence of the KD at the cellular and molecular levels. We emphasize that the KD may function through multiple mechanisms, which remain to be further elucidated. The challenges and future directions for the clinical implementation of the KD in the treatment of a spectrum of diseases have been discussed. We suggest that, with encouraging evidence of therapeutic effects and increasing insights into the mechanisms of action, randomized controlled trials should be conducted to elucidate a foundation for the clinical use of the KD.

Autoimmune Epilepsy - Novel Multidisciplinary Analysis, Discoveries and Insights

Epilepsy affects ~50 million people. In ~30% of patients the etiology is unknown, and ~30% are unresponsive to anti-epileptic drugs. Intractable epilepsy often leads to multiple seizures daily or weekly, lasting for years, and accompanied by cognitive, behavioral, and psychiatric problems. This multidisciplinary scientific (not clinical) ‘Perspective’ article discusses Autoimmune Epilepsy from immunological, neurological and basic-science angles. The article includes summaries and novel discoveries, ideas, insights and recommendations. We summarize the characteristic features of the respective antigens, and the pathological activity in vitro and in animal models of autoimmune antibodies to: Glutamate/AMPA-GluR3, Glutamate/NMDA-NR1, Glutamate/NMDA-NR2, GAD-65, GABA-R, GLY-R, VGKC, LGI1, CASPR2, and β2 GP1, found in subpopulations of epilepsy patients. Glutamate receptor antibodies: AMPA-GluR3B peptide antibodies, seem so far as the most exclusive and pathogenic autoimmune antibodies in Autoimmune Epilepsy. They kill neural cells by three mechanisms: excitotoxicity, Reactive-Oxygen-Species, and complement-fixation, and induce and/or facilitate brain damage, seizures, and behavioral impairments. In this article we raise and discuss many more topics and new insights related to Autoimmune Epilepsy. 1. Few autoimmune antibodies tilt the balance between excitatory Glutamate and inhibitory GABA, thereby promoting neuropathology and epilepsy; 2. Many autoantigens are synaptic, and have extracellular domains. These features increase the likelihood of autoimmunity against them, and the ease with which autoimmune antibodies can reach and harm these self-proteins. 3. Several autoantigens have ‘frenetic character’- undergoing dynamic changes that can increase their antigenicity; 4. The mRNAs of the autoantigens are widely expressed in multiple organs outside the brain. If translated by default to proteins, broad spectrum detrimental autoimmunity is expected; 5. The autoimmunity can precede seizures, cause them, and be detrimental whether primary or epiphenomenon; 6. Some autoimmune antibodies induce, and associate with, cognitive, behavioral and psychiatric impairments; 7. There are evidences for epitope spreading in Autoimmune Epilepsy; 8. T cells have different ‘faces’ in the brain, and in Autoimmune Epilepsy: Normal T cells are needed for the healthy brain. Normal T cells are damaged by autoimmune antibodies to Glutamate/AMPA GluR3, which they express, and maybe by additional autoantibodies to: Dopamine-R, GABA-R, Ach-R, Serotonin-R, and Adrenergic-R, present in various neurological diseases (summarized herein), since T cells express all these Neurotransmitter receptors. However, autoimmune and/or cytotoxic T cells damage the brain; 9. The HLA molecules are important for normal brain function. The HLA haplotype can confer susceptibility or protection from Autoimmune Epilepsy; 10. There are several therapeutic strategies for Autoimmune Epilepsy.

Complementing the phenotypical spectrum of TUBA1A tubulinopathy and its role in early-onset epilepsies

TUBA1A tubulinopathy is a rare neurodevelopmental disorder associated with brain malformations as well as early-onset and intractable epilepsy. As pathomechanisms and genotype-phenotype correlations are not completely understood, we aimed to provide further insights into the phenotypic and genetic spectrum. We here present a multicenter case series of ten unrelated individuals from four European countries using systematic MRI re-evaluation, protein structure analysis, and prediction score modeling. In two cases, pregnancy was terminated due to brain malformations. Amongst the eight living individuals, the phenotypic range showed various severity. Global developmental delay and severe motor impairment with tetraparesis was present in 63% and 50% of the subjects, respectively. Epilepsy was observed in 75% of the cases, which showed infantile onset in 83% and a refractory course in 50%. One individual presented a novel TUBA1A-associated electroclinical phenotype with evolvement from early myoclonic encephalopathy to continuous spike-and-wave during sleep. Neuroradiological features comprised a heterogeneous spectrum of cortical and extracortical malformations including rare findings such as cobblestone lissencephaly and subcortical band heterotopia. Two individuals developed hydrocephalus with subsequent posterior infarction. We report four novel and five previously published TUBA1A missense variants whose resulting amino acid substitutions likely affect longitudinal, lateral, and motor protein interactions as well as GTP binding. Assessment of pathogenic and benign variant distributions in synopsis with prediction scores revealed sections of variant enrichment and intolerance to missense variation. We here extend the clinical, neuroradiological, and genetic spectrum of TUBA1A tubulinopathy and provide insights into residue-specific pathomechanisms and genotype-phenotype correlations.

BrainQuake: An Open-Source Python Toolbox for the Stereoelectroencephalography Spatiotemporal Analysis

Intracranial stereoelectroencephalography (SEEG) is broadly used in the presurgical evaluation of intractable epilepsy, due to its high temporal resolution in neural activity recording and high spatial resolution within suspected epileptogenic zones. Neurosurgeons or technicians face the challenge of conducting a workflow of post-processing operations with the multimodal data (e.g., MRI, CT, and EEG) after the implantation surgery, such as brain surface reconstruction, electrode contact localization, and SEEG data analysis. Several software or toolboxes have been developed to take one or more steps in the workflow but without an end-to-end solution. In this study, we introduced BrainQuake, an open-source Python software for the SEEG spatiotemporal analysis, integrating modules and pipelines in surface reconstruction, electrode localization, seizure onset zone (SOZ) prediction based on ictal and interictal SEEG analysis, and final visualizations, each of which is highly automated with a user-friendly graphical user interface (GUI). BrainQuake also supports remote communications with a public server, which is facilitated with automated and standardized preprocessing pipelines, high-performance computing power, and data curation management to provide a time-saving and compatible platform for neurosurgeons and researchers.

Modeling Somatic Mutations Associated With Neurodevelopmental Disorders in Human Brain Organoids

Neurodevelopmental disorders (NDDs) are a collection of diseases with early life onset that often present with developmental delay, cognitive deficits, and behavioral conditions. In some cases, severe outcomes such as brain malformations and intractable epilepsy can occur. The mutations underlying NDDs may be inherited or de novo, can be gain- or loss-of-function, and can affect one or more genes. Recent evidence indicates that brain somatic mutations contribute to several NDDs, in particular malformations of cortical development. While advances in sequencing technologies have enabled the detection of these somatic mutations, the mechanisms by which they alter brain development and function are not well understood due to limited model systems that recapitulate these events. Human brain organoids have emerged as powerful models to study the early developmental events of the human brain. Brain organoids capture the developmental progression of the human brain and contain human-enriched progenitor cell types. Advances in human stem cell and genome engineering provide an opportunity to model NDD-associated somatic mutations in brain organoids. These organoids can be tracked throughout development to understand the impact of somatic mutations on early human brain development and function. In this review, we discuss recent evidence that somatic mutations occur in the developing human brain, that they can lead to NDDs, and discuss how they could be modeled using human brain organoids.

Brenda Milner: Pioneer of the Study of the Human Frontal Lobes

Although the behavioral effects of damage to the frontal lobes date back to at least the late 19th century even midway through the 20th century very little was known about human frontal lobe function and there was a general consensus that the frontal lobe did not play a key role in cognition. This all changed when Brenda Milner published a chapter in a 1964 volume entitled: The Frontal Granular Cortex and Behavior. Milner’s chapter, “Some effects of frontal lobectomy in man,” was the first systematic study of the effect of frontal lobe excisions on cognition in human patients. Milner had access to a unique population of frontal excision patients at the Montreal Neurological Institute that were being treated by Wilder Penfield and his associates for a wide range of neurological disorders, including intractable epilepsy. Milner and her colleagues engaged in a more than 50-year study that has had a formidable impact on our understanding of frontal lobe function. Paralleling studies of frontal lobe function in non-humans they influence on understanding the evolution and function of the prefrontal cortex of mammals. Thus, although Brenda Milner is best known for her studies of human memory, she has had an equally important contribution to our understanding of the frontal lobes.

Automatic Detection of High-Frequency Oscillations Based on an End-to-End Bi-Branch Neural Network and Clinical Cross-Validation

Accurate identification of high-frequency oscillation (HFO) is an important prerequisite for precise localization of epileptic foci and good prognosis of drug-refractory epilepsy. Exploring a high-performance automatic detection method for HFOs can effectively help clinicians reduce the error rate and reduce manpower. Due to the limited analysis perspective and simple model design, it is difficult to meet the requirements of clinical application by the existing methods. Therefore, an end-to-end bi-branch fusion model is proposed to automatically detect HFOs. With the filtered band-pass signal (signal branch) and time-frequency image (TFpic branch) as the input of the model, two backbone networks for deep feature extraction are established, respectively. Specifically, a hybrid model based on ResNet1d and long short-term memory (LSTM) is designed for signal branch, which can focus on both the features in time and space dimension, while a ResNet2d with a Convolutional Block Attention Module (CBAM) is constructed for TFpic branch, by which more attention is paid to useful information of TF images. Then the outputs of two branches are fused to realize end-to-end automatic identification of HFOs. Our method is verified on 5 patients with intractable epilepsy. In intravalidation, the proposed method obtained high sensitivity of 94.62%, specificity of 92.7%, and F1-score of 93.33%, and in cross-validation, our method achieved high sensitivity of 92.00%, specificity of 88.26%, and F1-score of 89.11% on average. The results show that the proposed method outperforms the existing detection paradigms of either single signal or single time-frequency diagram strategy. In addition, the average kappa coefficient of visual analysis and automatic detection results is 0.795. The method shows strong generalization ability and high degree of consistency with the gold standard meanwhile. Therefore, it has great potential to be a clinical assistant tool.

The Use of Medical Cannabis on Cancer in Thailand

The objective of this paper is to indicate the beneficial utility of medical marijuana. Marijuana throughout history is known for its property to alternate consciousness. However, the medical utilization of marijuana or cannabis was dated as far back as 2900 BC, when it was used by Emperor Ru Hsi of Ancient Chinese. During the 19th century, marijuana was introduced to Western Medicine as a therapeutic drug, mostly known for its pain control properties. Marijuana by itself consists of more than 100 active components. In consideration of the amount of THC, tetrahydrocannabinol, a psychological chemical released by the glands of marijuana plants, CBD or cannabidiol, amongst the most prevalent ingredients in cannabis, is the least controversial extract extracted from the marijuana plants to be used. As of the year 2019, Thailand Narcotics Act legalized cannabis for medical use in Thailand. A study survey conducted by N.Z. shows that in just over a year, 20% of the patients report the use of cannabis for medical purposes regarding its benefits of neuropathic pain, chemotherapy-induced nausea and vomiting, Aids-related cachexia, intractable epilepsy, and palliative care conditions. Further clinical trials are conducted to further perceive the potential cannabis has on treating cancer. One of the two successful clinical trials that have been published proposes that cannabis may make it possible to treat brain cancer with few side effects. Keywords: Cancer, Marijuana, Tetrahydrocannabinol (THC), Cannabidiol (CBD), Medical Usage, Cannabis in Thailand.