Reseachers from UC San Diego demonstrated a proof of principle for a CAGEX RNA-targeting CRISPR–Cas13d system as a potential allele-sensitive therapeutic approach for HD, a strategy with broad implications for the treatment of other neurodegenerative disorders.

Researchers from UC San Diego and Oregon Health Science Univeristy developed a microelectrode grid for continuous interoperative neuromonitoring. The microelectrode grid includes a flexible substrate with low impedance electrochemical interface materials on conducting metal pads. The metal pads are connectable to stimulation/acquisition electronics through metal lead interconnects forming stimulation and recording channels and eventually to bonding pads. A flap within the substrate is movable away from the remainder of the substrate while at least some of the metal pads on the remainder of the substrate can remain in contact with an organ when the flap is moved away from the remainder of the substrate.

Researchers from UC San Diego's Neuroelectronic Lab (https://neuroelectronics.ucsd.edu/) demonstrate that they can predict neural activity at deeper layers of the brain by only recording potentials from brain surface. This was achieved by performing multimodal experiments with an ultra-high density transparent graphene electrode technology and developing neural network methods to learn nonlinear dynamic between different modalities. They used cross modality inference to predict the activity at deep layers from surface. Prediction of neural activity at depth have the potential to open up new possibilities for developing minimally invasive neural prosthetics or targeted treatments for various neurological disorders.

Researchers from UC San Diego's Neuroelectronics Lab invented an implantable brain electrode technology which allows recording interactions between different cortex regions or interactions of cortex with other subcortical structures. The technology is called Neuro‐FITM. Flexibility and transparency of Neuro‐ FITM allow integration of electrophysiological recordings with any optical imaging (such as high resolution multiphoton imaging) or stimulation technology (such as optogenetics).

Researchers from UC San Diego have developed a patent-pending wearable device for concurrently assessing afferent and efferent visual functions. The invention details novel mobile brain-computer interfacing methods and systems for concurrently assessing afferent and efferent visual functions.

Stress and loneliness are biologically toxic factors with adverse effects on mental and physical health. The 2018 Gallup World Poll found a 25%–40% increase in stress, worry, and anger in the US from 2008 to 2018. Loneliness is associated with considerable distress, and older adults are vulnerable to loneliness due to losses, physical decline, and social isolation. The COVID-19 pandemic led to increased social isolation, though some older adults with higher levels of resilience and wisdom faced the pandemic with greater fortitude than younger adults.Aging is associated with numerous stressors that negatively impact older adults’ well-being. Resilience improves ability to cope with stressors and can be enhanced in older adults. Senior housing communities are promising settings to deliver positive psychiatry interventions due to rising resident populations and potential impact of delivering interventions directly in the community. 

Microelectrodes are the gold standard for measuring the activity of individual neurons at high temporal resolution in any nervous system region and central to defining the role of neural circuits in controlling behavior. Microelectrode technologies such as the Utah or Michigan arrays, have allowed tracking of distributed neural activity with millisecond precision. However, their large footprint and rigidity lead to tissue damage and inflammation that hamper long-term recordings. State of the art Neuropixel and carbon fiber probes have improved on these previous devices by increasing electrode density and reducing probe dimensions and rigidity. Although these probes have advanced the field of recordings, next-generation devices should enable targeted stimulation in addition to colocalized electrical recordings. Optogenetic techniques enable high-speed modulation of cellular activity through targeted expression and activation of light-sensitive opsins. However, given the strong light scattering and high absorption properties of neural tissue optogenetic interfacing with deep neural circuits typically requires the implantation of large-diameter rigid fibers, which can make this approach more invasive than its electrical counterpart.Approaches to integrating optical and electrical modalities have ranged from adding fiber optics to existing Utah arrays to the Optetrode or other integrated electro-optical coaxial structures. These technologies have shown great promise for simultaneous electrical recordings and optical stimulation in vivo. However, the need to reduce the device footprint to minimize immune responses for long-term recordings is still present.

As an important tool for electrophysiological recordings, neural electrodes implanted on the brain surface have been instrumental in basic neuroscience research to study large-scale neural dynamics in various cognitive processes, such as sensorimotor processing as well as learning and memory. In clinical settings, neural recordings have been adopted as a standard tool to monitor the brain activity in epilepsy patients before surgery for detection and localization of epileptogenic zones initiating seizures and functional cortical mapping. Neural activity recorded from the brain surface exhibits rich information content about the collective neural activities reflecting the cognitive states and brain functions. For the interpretation of surface potentials in terms of their neural correlates, most research has focused on local neural activities.   From basic neuroscience research to clinical treatments and neural engineering, electrocorticography (ECoG) has been widely used to record surface potentials to evaluate brain function and develop neuroprosthetic devices. However, the requirement of invasive surgeries for implanting ECoG arrays significantly limits the coverage of different cortical regions, preventing simultaneous recordings from spatially distributed cortical networks. However, this rich information content of surface potentials encoded for the large-scale cortical activity remains unexploited and little is known on how local surface potentials are correlated with the spontaneous neural activities of distributed large-scale cortical networks. Normal 0 false false false EN-US X-NONE X-NONE /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-parent:""; mso-padding-alt:0in 5.4pt 0in 5.4pt; mso-para-margin-top:0in; mso-para-margin-right:0in; mso-para-margin-bottom:8.0pt; mso-para-margin-left:0in; line-height:107%; mso-pagination:widow-orphan; font-size:11.0pt; font-family:"Calibri",sans-serif; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi;}

Microelectrodes are the gold standard for measuring the activity of individual neurons at high temporal resolution in any nervous system region and central to defining the role of neural circuits in controlling behavior.Microelectrode technologies such as the Utah or Michigan arrays, have allowed tracking of distributed neural activity with millisecond precision. However, their large footprint and rigidity lead to tissue damage and inflammation that hamper long-term recordings. State of the art Neuropixel and carbon fiber probes have improved on these previous devices by increasing electrode density and reducing probe dimensions and rigidity.Although these probes have advanced the field of recordings, next-generation devices should enable targeted stimulation in addition to colocalized electrical recordings. Optogenetic techniques enable high-speed modulation of cellular activity through targeted expression and activation of light-sensitive opsins. However, given the strong light scattering and high absorption properties of neural tissue optogenetic interfacing with deep neural circuits typically requires the implantation of large-diameter rigid fibers, which can make this approach more invasive than its electrical counterpart.Approaches to integrating optical and electrical modalities have ranged from adding fiber optics to existing Utah arrays to the Optetrode or other integrated electro-optical coaxial structures. These technologies have shown great promise for simultaneous electrical recordings and optical stimulation in vivo. However, the need to reduce the device footprint to minimize immune responses for long-term recordings is still present.

Pathological accumulation of phosphorylated Tau (pTau) and accumulation of amyloid-beta (Ab) fragments are the two major biochemical hallmarks of Alzheimer’s disease (AD). Effective strategies to remove Ab in AD-patient brains have been developed, but have not yet shown efficacy to slow cognitive decline in clinical trials. This finding has led to the idea that targeting Tau or combinatorial strategies that target both Tau and Ab are required to treat AD. Genetic, epidemiologic, and biochemical evidence suggests that predisposition to AD may arise from altered cholesterol metabolism, although the molecular pathways that may link cholesterol to AD phenotypes are only partially understood. Stimulation of a brain specific cytochrome that converts cholesterol to 24-hydroxycholesterol, which in turn reduces cholesteryl ester. Reduction of cholesteryl ester has been demonstrated to reduce pathological Tau phosphorylation in human neurons made from induced pluripotent stem cells. Also, low dose Efavirenz/Sustiva reduces neurofibrillary tangles in a mouse model. The pathway may run from cholesteryl ester to Tau via the proteasome.

Anxiety and depression are the two most common psychiatric disorders in the U.S. and affect approximately one-in-five adults at some point in their lifetime. Depression is the leading cause of worldwide disability; anxiety disorders are highly comorbid with depression. Presently, there are several drugs approved by the U.S. Food and Drug Administration for the treatment of both anxiety and depression; however, these drugs have several important limitations. Antidepressant drugs are not effective in all patients, take weeks to produce therapeutic effects, and produce side effects that limit their use. Anxiolytic drugs produce sedating side effects and have significant abuse liability. Therefore, there is an urgent need for better therapeutic agents. Recent studies using both genetic and pharmacological techniques have implicated GLO1 in numerous behaviors, including several that are relevant to depression and anxiety.

Current research and practice in the field of therapeutic rTMS is not taking into account 1) inter-individual variability 2) variability between brain areas 3) variability or differences between oscillations in distinct and overlapping frequency bands, 4) existence of high- and low-excitability phase periods in each oscillatory cycle. Clinical treatments with rTMS and experimental research findings show mixed effects, with rTMS protocols inducing variable degrees of brain plasticity over subjects and sessions.

Many diseases of the central nervous system (CNS) arise from the accumulation of proteins such as α-synuclein (aSyn) in Parkinson’s Disease (PD) or Aß in Alzheimer’s disease (AD). The ability to regulate the expression at the gene transcription level would be beneficial for reducing the accumulation of these proteins or regulating expression levels of other genes in the CNS. aSyn also accumulates in other neurodegenerative diseases including dementia with Lewy Body (DLB), multiple system atrophy (MSA) and Gaucher’s disease. This means that regulation of aSyn expression may be crucial to the therapeutic control of numerous neurodegenerative diseases.

Control of gene expression is a general approach to treat diseases where there is too much or too little of a gene product. However, while there are many methods which are available to downregulate the expression of messenger RNA transcripts, very few strategies can upregulate the endogenous gene product. The vast majority of gene regulatory drugs which are commercially available or being developed are designed to knockdown gene expression (i.e. siRNAs, miRNAs, anti-sense, etc.). There exist some methods to enhance gene expression, such as the delivery of messenger RNAs; although, therapeutic delivery of such large and charged RNA molecules is technically challenging, inefficient, and may not be practical. There are also classical gene therapy approaches where a gene product is delivered as viral-encoded products (AAV or lentivirus-packaged). However, these methods suffer from not being able to accurately reproduce the correct alternatively spliced isoforms in the right ratios in cells.  

The neuronal ceroid lipofuscinoses (NCLs), commonly grouped together as Batten disease, are the most common neurodegenerative lysosomal storage diseases of the pediatric population. No cure for NCL has yet been realized. Current treatment regimens offer only symptomatic relief and do not target the underlying cause of the disease. Although the underlying pathophysiology that drives disease progression is unknown, several small molecules have been identified with diverse mechanisms of action that provide promise for the treatment of this devastating disease. On this point, several researchers have reported the use of potential drugs for NCL patient lymphoblasts and fibroblasts, along with neurons derived from animal models of NCL disease. Unfortunately, most of these studies were inconclusive or clinical trials or follow-up results were not available. High concentrations employed and toxicity of the small molecules are clear disadvantages to the use of some of the corresponding derivatives as potential drugs. To circumvent these effects, development of nontoxic alkyl cysteines would be useful for the non-enzymatic and chemo-selective depalmitoylation of S-palmitoyl proteins, which hold good promise as an effective treatment for neuronal ceroid lipofuscinoses.

Measurements based on electroencephalogram (EEG) are made by placing electrodes over a human scalp to apply and receive electrical signals. Various implementations of EEG sensors are available. The electroencephalogram (EEG) has recently gained popularity for use in various non-clinical studies but still lacks any robust, single application outside well-controlled laboratory environments. As the limitations of EEG are mostly due to the low spatial resolution, using multiple bio-sensing modalities proves to be better performing than EEG alone

Stress granule (SG) formation has been suggested as a two-step process, with initial formation of a dense stable SG ‘‘core’’ followed by accumulation of proteins containing intrinsically disordered regions (IDRs) and low-complexity domains (LCDs) into a peripheral ‘‘shell’’ through a process involving liquid-liquid phase separation (LLPS). Recently, SGs have been associated with human neurodegenerative disorders characterized by the presence of toxic insoluble protein aggregates. This link is most compelling in the case of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), where numerous disease-causing mutations are purported to interfere with LLPS-dependent growth and dynamics of SGs.

Rett syndrome (RTT) is a devastating disease that affects 1 in every 10,000 children born in the United States, primarily females. RTT patients undergo apparently normal development until 6-18 months of age, followed by impaired motor function, stagnation and then regression of developmental skills, hypotonia, seizures and a spectrum of autistic behaviors. Rett syndrome is a rare disease that shares certain pathways with major developmental disorders such as autism and schizophrenia, increasing the potential impact. There is no cure for Rett syndrome and the animal model does not entirely recapitulate the human disease. Thus, having the possibility to screen drugs directly in human neurons is a major milestone.

Most people who suffer traumatic spinal cord injuries have incomplete lesions of neural circuits whose function can be partially restored from the reconfiguration of the spared circuits with rehabilitative training. Methods for improving nerve regeneration after spinal cord injury or nerve transplantation are needed for improved patient outcome. Also, neurodegenerative diseases such as amyotrophic lateral sclerosis, Alzheimer’s Disease and Parkinson’s Disease negatively impact quality of life. 

1-D electrophysiological probes of the needle and micropipette configuration were the first tools to measure action potentials in neurons.   Since its development in the 1970s, this patch-clamp technique remains the standard in high fidelity detection of small potential subthreshold activity.  However, the use of tapered submicron micropipette tips to patch into cell membranes and measure sub-threshold potentials and ionic currents are not scalable to large neuronal densities and to long recording times. Automated patch-clamp are scalable but cannot perform recordings from networks of neurons that resemble cell arrangements in organs from brain, to heart, to muscle, to liver, etc.  Microelectrode arrays (MEAs) on the other hand are scalable but their planar geometry preclude intimate interaction and sufficient charge coupling between the neuron and the electrode site.  The weakly coupled sub-threshold activity in MEAs is usually below the noise level and is therefore lost and not observed in MEA measurements. None of prior technologies, can sense activity in 3D networks of neurons. Nanowire geometries are ideal for minimally invasive intracellular nanoscale probes but prior works have been limited to single nanowire device demonstrations or to devices encompassing ensembles of several nanowires and without sensitivity to subthreshold neuron activity or demonstration of interfacing with human neurons. 

Nerve injury in the Peripheral Nervous System is caused by trauma, vehicular accidents, repetitive stress, and wartime injuries and affects up to 1% of the U.S. population by age 70. Severed nerves lead to severe pain or the lack of sensation and mobility.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized clinically by progressive paralysis leading to death from respiratory failure, typically within two to three years of symptom onset. ALS is the third most common neurodegenerative disease in the Western world, and there are currently no effective therapies. Approximately 10% of cases are familial in nature, whereas the bulk of the cases occur randomly throughout the population. Recently a mutation in the C9ORF72 gene has been linked to ALS, frontotemporal degeneration (FTD) and ALS-FTD. It is postulated that the ALS-FTD causing mutation is a large hexanucleotide (GGGGCC) repeat expansion in the first intron of the C9ORF72 gene. There are currently no effective therapies to treat such neurodegenerative diseases. Therefore, it is an object to provide methods for the treatment of such neurodegenerative diseases.

Although the CD33 null mouse was originally developed as a means of understanding the basic biology of human CD33 (hCD33 or Siglec-3), recent studies have identified the CD33 gene is a primary risk factor for Alzheimer’s disease and allelic variants of CD33 may play a primary role in the clearance of amyloid beta by microglial cell in the brain.

Traumatic brain injury (TBI) is a leading cause of sustained impairment in military andcivilian populations. However, mild (and some moderate) TBI can be difficult to diagnose, with only a ~10% positive-finding rate when using conventional neuroimaging methods of CT and MRI. The diffusion tensor imaging (DTI), which is still under development, has a positive-finding rate of ~20-30% in mild TBI patients. Furthermore pre-surgical functional brain mapping of the brain regions mediating sensation, movement, and language can facilitate surgical planning and reduce function loss.

Cell-based therapeutics and research and development in the area of neural injury and neurological disorders could benefit from a renewable source of neural stem cells. Human embryonic stem cells provide indefinitely self-renewing cells with differentiation potential, but are inferior to lineage-restricted cells as they are prone to causing teratomas and fail to repopulate host tissues in vivo. Significant challenges in isolation and long-term cultivation of tissue-specific stem cells has restricted broad use of neural stem cells. Accordingly, there is a need for a method for obtaining a renewable source of neural stem cells.