The Interface between Inflammatory Bowel Disease, Neuroinflammation, and Neurological Disorders.

Inflammatory Bowel Disease (IBD) is a complex, chronic inflammatory condition affecting the gastrointestinal tract. IBD has been associated with a variety of neurologic manifestations including peripheral nerve involvement, increased risk of thrombotic, demyelinating and events. Furthermore, an evolving association between IBD and neurodegenerative disorders has been recognized, and early data suggests an increased risk of these disorders in patients diagnosed with IBD. The relationship between intestinal inflammatory disease and neuroinflammation is complex, but the bidirectional interaction between the brain-gut-microbiome axis is likely to play an important role in the pathogenesis of these disorders. Identification of common mechanisms and pathways will be key to developing potential therapies. In this review, we discuss the evolving interface between IBD and neurological conditions, with a focus on clinical, mechanistic, and potentially therapeutic implications.

α-Synuclein Induces Progressive Changes in Brain Microstructure and Sensory-Evoked Brain Function That Precedes Locomotor Decline.

In vivo functional and structural brain imaging of synucleinopathies in humans have provided a rich new understanding of the affected networks across the cortex and subcortex. Despite this progress, the temporal relationship between α-synuclein (α-syn) pathology and the functional and structural changes occurring in the brain is not well understood. Here, we examine the temporal relationship between locomotor ability, brain microstructure, functional brain activity, and α-syn pathology by longitudinally conducting rotarod, diffusion magnetic resonance imaging (MRI), resting-state functional MRI (fMRI), and sensory-evoked fMRI on 20 mice injected with α-syn fibrils and 20 PBS-injected mice at three timepoints (10 males and 10 females per group). Intramuscular injection of α-syn fibrils in the hindlimb of M83+/- mice leads to progressive α-syn pathology along the spinal cord, brainstem, and midbrain by 16 weeks post-injection. Our results suggest that peripheral injection of α-syn has acute systemic effects on the central nervous system such that structural and resting-state functional activity changes occur in the brain by four weeks post-injection, well before α-syn pathology reaches the brain. At 12 weeks post-injection, a separate and distinct pattern of structural and sensory-evoked functional brain activity changes was observed that are co-localized with previously reported regions of α-syn pathology and immune activation. Microstructural changes in the pons at 12 weeks post-injection were found to predict survival time and preceded measurable locomotor deficits. This study provides preliminary evidence for diffusion and fMRI markers linked to the progression of synuclein pathology and has translational importance for understanding synucleinopathies in humans.SIGNIFICANCE STATEMENT α-Synuclein (α-syn) pathology plays a critical role in neurodegenerative diseases such as Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. The longitudinal effects of α-syn pathology on locomotion, brain microstructure, and functional brain activity are not well understood. Using high field imaging, we show preliminary evidence that peripheral injection of α-syn fibrils induces unique patterns of functional and structural changes that occur at different temporal stages of α-syn pathology progression. Our results challenge existing assumptions that α-syn pathology must precede changes in brain structure and function. Additionally, we show preliminary evidence that diffusion and functional magnetic resonance imaging (fMRI) are capable of resolving such changes and thus should be explored further as markers of disease progression.

Ultrahigh-Performance Liquid Chromatography-High-Resolution Mass Spectrometry Metabolomics and Lipidomics Study of Stool from Transgenic Parkinson's Disease Mice Following Immunotherapy.

Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta of the brain, as well as the degeneration of motor and nonmotor circuitries. The cause of neuronal death is currently unknown, although chronic neuroinflammation, aggregated α-synuclein, mitochondrial dysfunction, and oxidative stress have all been implicated. Gliosis has been shown to exacerbate neuroinflammation via secretion of proinflammatory cytokines, and there is a subsequent infiltration of T lymphocytes (T-cells), into the brain of PD patients. Using liquid chromatography-high-resolution mass spectrometry (LC-HRMS), we have observed metabolomic changes in stool samples, thought to be associated with the potential disease-modifying effect of immunotherapy administered to transgenic Parkinsonian (A53T) mice. Significant elevations (p < 0.05) in metabolites associated with immune response (taurine, histamine, and its methylated product, 3-methylhistamine) are identified as being higher in the mice undergoing immunotherapy. Furthermore, a reduction in triacylglycerol (TG) and diacylglycerol (DG) expressions in stool following immunotherapy suggests a regulation of lipid breakdown or biosynthesis with the vaccine. These "omics" markers (among others reported in this article) along with weight gain and increased life expectancy suggest that immunotherapy is positively modifying the disease state.

Design and Implementation of a Dual-Probe Microsampling Apparatus for the Direct Analysis of Adherent Mammalian Cells by Ion Mobility-Mass Spectrometry.

Atmospheric pressure sampling mass spectrometric methods are ideal platforms for rapidly analyzing the metabolomes of biological specimens. Several liquid extraction-based techniques have been developed for increasing metabolome coverage in direct sampling workflows. Here, we report the construction of a dual-probe microsampling device (DPM), based on the design of the liquid microjunction surface sampling probe, for analyzing the metabolome of live microglial cells by drift-tube ion mobility spectrometry (IMS) quadrupole time-of-flight mass spectrometry. Utilizing two distinct solvent systems in parallel is demonstrated to extract a wide structural variety of metabolites and lipids, enabling a more comprehensive analysis of intracellular metabolism. Employing the DPM-IM-MS method to adherent cells yielded the detection of 73 unique lipids and 79 small molecule metabolites from each optimized solvent system probe, respectively. Integration of multiplexed ion mobility scans is also shown to increase extracted analyte signal intensities between 2- and 10-fold compared to traditional single-pulse IMS, enabling the detection of 38 low-intensity features not previously detected by single-pulse DPM-IM-MS. To examine the ability of the DPM system to differentiate between sample treatment groups, microglia were stimulated with the endotoxin lipopolysaccharide (LPS). Several metabolic alterations were detected between sample treatment groups by DPM-IM-MS, many of which were not previously detected with conventional single-probe liquid microjunction surface sampling.

Mass Spectrometric Methodologies for Investigating the Metabolic Signatures of Parkinson's Disease: Current Progress and Future Perspectives.

Parkinson's disease (PD) is a neurodegenerative disorder resulting from the loss of dopaminergic neurons of the substantia nigra as well as degeneration of motor and nonmotor basal ganglia circuitries. Typically known for classical motor deficits (tremor, rigidity, bradykinesia), early stages of the disease are associated with a large nonmotor component (depression, anxiety, apathy, etc.). Currently, there are no definitive biomarkers of PD, and the measurement of dopamine metabolites does not allow for detection of prodromal PD nor does it aid in long-term monitoring of disease progression. Given that PD is increasingly recognized as complex and heterogeneous, involving several neurotransmitters and proteins, it is of importance that we advance interdisciplinary studies to further our knowledge of the molecular and cellular pathways that are affected in PD. This approach will possibly yield useful biomarkers for early diagnosis and may assist in the development of disease-modifying therapies. Here, we discuss preanalytical factors associated with metabolomics studies, summarize current mass spectrometric methodologies used to evaluate the metabolic signature of PD, and provide future perspectives of the rapidly developing field of MS in the context of PD.

Monitoring Dopamine ex Vivo during Electrical Stimulation Using Liquid-Microjunction Surface Sampling.

Liquid-microjunction surface sampling (LMJ-SS) is an ambient ionization technique based on the continuous flow of solvent using an in situ microextraction device in which solvent moves through the probe, drawing in the analytes in preparation for ionization using an electrospray ionization source. However, unlike traditional mass spectrometry (MS) techniques, it operates under ambient pressure and requires no sample preparation, thereby making it ideal for rapid sampling of thicker tissue sections for electrophysiological and other neuroscientific research studies. Studies interrogating neural synapses, or a specific neural circuit, typically employ thick, ex vivo tissue sections maintained under near-physiological conditions to preserve tissue viability and maintain the neural networks. Deep brain stimulation (DBS) is a surgical procedure used to treat the neurological symptoms that are associated with certain neurodegenerative and neuropsychiatric diseases. Parkinson's disease (PD) is a neurological disorder which is commonly treated with DBS therapy. PD is characterized by the degeneration of dopaminergic neurons in the substantia nigra pars compacta portion of the brain. Here, we demonstrate that the LMJ-SS methodology can provide a platform for ex vivo analysis of the brain during electrical stimulation, such as DBS. We employ LMJ-SS in the ex vivo analysis of mouse brain tissue for monitoring dopamine during electrical stimulation of the striatum region. The mouse brain tissue was sectioned fresh post sacrifice and maintained in artificial cerebrospinal fluid to create near-physiological conditions before direct sampling using LMJ-SS. A selection of metabolites, including time-sensitive metabolites involved in energy regulation in the brain, were identified using standards, and the mass spectral database mzCloud was used to assess the feasibility of the methodology. Thereafter, the intensity of m/z 154 corresponding to protonated dopamine was monitored before and after electrical stimulation of the striatum region, showing an increase in signal directly following a stimulation event. Dopamine is the key neurotransmitter implicated in PD, and although electrochemical detectors have shown such increases in dopamine post-DBS, this is the first study to do so using MS methodologies.

Precast Gelatin-Based Molds for Tissue Embedding Compatible with Mass Spectrometry Imaging.

Preparation of tissue for matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI) generally involves embedding the tissue followed by freezing and cryosectioning, usually between 5 and 25 µm thick, depending on the tissue type and the analyte(s) of interest. The brain is approximately 60% fat; it therefore lacks rigidity and poses structural preservation challenges during sample preparation. Histological sample preparation procedures are generally transferable to MALDI-MSI; however, there are various limitations. Optimal cutting temperature compound (OCT) is commonly used to embed and mount fixed tissue onto the chuck inside the cryostat during cryosectioning. However, OCT contains potential interferences that are detrimental to MALDI-MSI, while fixation is undesirable for the analysis of some analytes either due to extraction or chemical modification (i.e., polar metabolites). Therefore, a method for both fixed and fresh tissue compatible with MALDI-MSI and histology is desirable to increase the breadth of analyte(s), maintain the topographies of the brain, and provide rigidity to the fragile tissue while eliminating background interference. The method we introduce uses precast gelatin-based molds in which a whole mouse brain is embedded, flash frozen, and cryosectioned in preparation for mass spectrometry imaging (MSI).

Tissue Response to Deep Brain Stimulation and Microlesion: A Comparative Study.

OBJECTIVES: Deep brain stimulation (DBS) is used for a variety of movement disorders, including Parkinson's disease. There are several theories regarding the biology and mechanisms of action of DBS. Previously, we observed an up-regulation of neural progenitor cell proliferation in post-mortem tissue suggesting that DBS can influence cellular plasticity in regions beyond the site of stimulation. We wanted to support these observations and investigate the relationship if any, between DBS, neural progenitor cells, and microglia. METHODS: We used naïve rats in this study for DBS electrode implantation, stimulation, and microlesions. We used immunohistochemistry techniques for labeling microglial and progenitor cells, and fluorescence microscopy for viewing and quantification of labeled cells. RESULTS: We present data that demonstrates a reciprocal relationship of microglia and neural precursor cells in the presence of acute high frequency stimulation. In our hands, stimulated animals demonstrate significantly lower numbers of activated microglia (p = 0.026) when compared to microlesion and sham animals. The subthalamic region surrounding the DBS stimulating electrode reveals a significant increase in the number of neural precursor cells expressing cell cycle markers, plasticity and precursor cell markers (Ki67; p = 0.0013, MCM2; p = 0.0002). INTERPRETATION: We conclude that in this animal model, acute DBS results in modest local progenitor cell proliferation and influenced the total number of activated microglia. This could be of clinical significance in patients with PD, as it is thought to progress via neuroinflammatory processes involving microglia, cytokines, and the complement system. Further studies are required to comprehend the behavior of microglia in different activation states and their ability to regulate adult neurogenesis under physiologic and pathologic conditions.

Analyzing the effect of the COVID-19 vaccine on Parkinson's disease symptoms.

Background: Parkinson's Disease (PD) is one of the most common neurodegenerative diseases. PD has recently received more attention by researchers in the midst of the COVID-19 pandemic. Objective: Yet to be researched is the effect of the COVID-19 vaccines on PD patients. Several PD patients are still hesitant to the vaccine due to this unaddressed fear. The purpose of this study is to address this gap. Methods: Surveys were administered to PD patients 50 years and older at UF Fixel Institute who received at least one dose of the COVID-19 vaccine. Survey questions included patients' severity of PD symptoms before and after the vaccine and extent of worsening PD symptoms post-vaccination. After three weeks of collecting responses, the data was analyzed. Results: 34 respondents were eligible for data consideration because they fell within the age range being studied. A total of 14 respondents out of 34 (41%, p=0. 0001) reported that their PD symptoms worsened after the COVID-19 vaccine to some extent. Conclusion: There was strong evidence of worsening of PD symptoms post COVID-19 vaccination, however it was mostly mild and limited to a couple of days. The worsening had statistically significant moderate positive correlation with vaccine hesitancy and post-vaccine general side effects. A possible causative mechanism of PD symptom worsening using existing scientific knowledge would be stress and anxiety associated with vaccine hesitancy and the extent of post-vaccine general side effects (fever, chills, pain), likely via simulating a mild systemic infection/inflammation the latter already established causes of PD symptom worsening.

Therapies for Parkinson's disease and the gut microbiome: evidence for bidirectional connection.

The gut brain axis (GBA), a bidirectional communication pathway has often been linked to health and disease, and gut microbiota (GM), a key component of this pathway shown to be altered in Parkinson's disease (PD), are suggested to contribute to the pathogenesis of PD. There are few studies that report the impact of oral medication therapy on GM, however, there are even fewer studies that discuss the impact of other treatments such as device assisted therapies (DAT) including deep brain stimulation (DBS), levodopa-carbidopa intestinal gel infusion (LCIG) and photobiomodulation (PBM) and how these might impact GM. Here, we review the literature and summarize findings of the potential contributions of GM to the heterogenous clinical response to pharmaceutical therapies among individuals with PD. We also discuss the potential interactions between the GM and DATs such as DBS and LCIG and present evidence for alterations in GM in response to DATs. Given the complexity and highly individual nature of the GM of patients with PD and the potential influence that other external factors such as diet, lifestyle, medications, stage of the disease and other comorbidities, further investigations into the response of GM to therapies are worthy of future study in prospective, controlled trials as well as medication naïve individuals. Such detailed studies will help us further comprehend the relationship between GM in PD patients, and will help investigate the potential of targeting GM associated changes as a treatment avenue for PD.

Evaluation of an Adoptive Cellular Therapy-Based Vaccine in a Transgenic Mouse Model of α-synucleinopathy.

Aggregated α-synuclein, a major constituent of Lewy bodies plays a crucial role in the pathogenesis of α-synucleinopathies (SPs) such as Parkinson's disease (PD). PD is affected by the innate and adaptive arms of the immune system, and recently both active and passive immunotherapies targeted against α-synuclein are being trialed as potential novel treatment strategies. Specifically, dendritic cell-based vaccines have shown to be an effective treatment for SPs in animal models. Here, we report on the development of adoptive cellular therapy (ACT) for SP and demonstrate that adoptive transfer of pre-activated T-cells generated from immunized mice can improve survival and behavior, reduce brain microstructural impairment via magnetic resonance imaging (MRI), and decrease α-synuclein pathology burden in a peripherally induced preclinical SP model (M83) when administered prior to disease onset. This study provides preclinical evidence for ACT as a potential immunotherapy for LBD, PD and other related SPs, and future work will provide necessary understanding of the mechanisms of its action.

Postmortem observation of collagenous lead tip region fibrosis as a rare complication of DBS.

BACKGROUND: Despite the widespread effective use of deep brain stimulation (DBS) for various movement and psychiatric disorders, little is known about its safety and tissue responses. METHODS: The University of Florida Deep Brain Stimulation Brain Tissue Network (DBS-BTN) conducted postmortem brain examinations on 26 cases to identify and characterize (using histological techniques) pathologic tissue changes associated with the placement of DBS devices. RESULTS: We report the unusual finding of prominent collagenous fibrosis around the lead tip in a 74-year-old man with idiopathic Parkinson's disease who had bilateral STN-DBS. Histological study confirmed the diagnosis of idiopathic Parkinson's disease, and there was striking, dense collagenous fibrosis at the distal end of the right DBS lead associated with focal hemosiderin deposition, chronic inflammation, and mild gliosis. We have in our brain bank 25 other DBS cases that on examination showed only mild to moderate gliosis and no dramatic tissue response to DBS lead placement. CONCLUSIONS: We are not aware of any prior reports of such a dramatic reaction to DBS placement to date.

Biovalue in Human Brain Banking: Applications and Challenges for Research in Neurodegenerative Diseases.

Brain banking occupies a central role for the advancement of the study of human neurodegenerative and neuropsychiatric diseases. The smooth functioning and effectiveness of a brain bank is largely a multidisciplinary effort and requires the cooperation and participation of several players including neurologists, neuropathologists, and research coordinators to guarantee that donated tissue is properly processed and archived. If properly run, brain banks can ultimately lay the foundation for new brain research and pioneer the discovery of new therapies for a variety of neurological diseases.

Advancing Our Understanding of Brain Disorders: Research Using Postmortem Brain Tissue.

It is thought that proliferative potential of neural progenitor cells, from postmortem tissue obtained from idiopathic PD patients, present in the substantia nigra (SN) as well as other brain regions can be maintained in vitro. While they might be lacking in factors required for differentiation into mature neurons, their regenerative potential is undeniable and suggestive that progenitor cells are found endogenously in the diseased brain. Adult stem/progenitor cells exist in several regions within the PD brain and are likely a valuable source of progenitor cells for understanding disease course, as well as useful tools for generating potential cellular and pharmacologic therapies. One successful therapy for some PD patients is deep brain stimulation (DBS) and has been used for more than a decade to treat PD; however its mechanism of action remains unknown. Given the close proximity of the electrode trajectory to areas of the brain known as the "germinal niches" and the Parkinsonian brain's regenerative potential, it is possible that DBS influences neural stem cell proliferation locally, as well as distally. A study of banked brain tissue from idiopathic PD patients treated with DBS, compared to 12 control brains without CNS disease, identified a significant increase in the number of proliferating precursor cells in the subventricular zone (SVZ) of the lateral ventricles, the third ventricle, and the tissue surrounding the DBS lead. Our studies with banked human tissues from the aforementioned regions demonstrate the importance of studying brain-banked tissue from germinal niches and DBS perielectrode tissue. We reveal in these studies the presence of proliferative potential in diseased brains as well as an increase in cellular plasticity in the brain as a consequence of DBS.

A pilot study of human brain tissue post-magnetic resonance imaging: information from the National Deep Brain Stimulation Brain Tissue Network (DBS-BTN).

INTRODUCTION: The safety of magnetic resonance imaging (MRI) for deep brain stimulation (DBS) patients is of great importance to both movement disorders clinicians and to radiologists. The present study utilized the Deep Brain Stimulation Brain Tissue Network's (DBS-BTN's) clinical and neuropathological database to search for evidence of adverse effects of MRI performed on implanted DBS patients. HYPOTHESIS: Performing a 1.5 T MRI with a head receive coil on patients with implanted DBS devices should not result in evidence of adverse clinical or pathological effects in the DBS-BTN cohort. Further, exposing post-mortem DBS-BTN brains with DBS leads to extended 3T MRI imaging should not result in pathological adverse effects. METHODS: An electronic literature search was performed to establish clinical and neuropathological criteria for evidence of MRI-related adverse reactions in DBS patients. A retrospective chart review of the DBS-BTN patients was then performed to uncover potential adverse events resulting from MRI scanning. DBS patient characteristics and MRI parameters were recorded for each patient. In addition, 3T MRI scans were performed on 4 post-mortem brains with DBS leads but without batteries attached. Detailed neuropathological studies were undertaken to search for evidence of MRI-induced adverse tissue changes. RESULTS: No clinical signs or symptoms or MRI-induced adverse effects were discovered in the DBS-BTN database, and on detailed review of neuroimaging studies. Neuropathological examination did not reveal changes consistent with MRI-induced heating damage. The novel study of four brains with prolonged 3T post-mortem magnetic field exposure (DBS leads left in place) also did not reveal pathological changes consistent with heat related damage. DISCUSSION: The current study adds important information to the data on the safety of MRI in DBS patients. Novel post-mortem MRI studies provide additional information regarding the safety of 3T MRI in DBS patients, and could justify additional studies especially post-mortem scans with battery sources in place. CONCLUSION: The lack of pathological findings in the DBS-BTN database and the lack of tissue related changes following prolonged exposure to 3T MRI in the post-mortem brains suggest that MRI scanning in DBS patients may be relatively safe, especially under current guidelines requiring a head receive coil. Subsequent studies exploring the safety of 1.5 T versus 3T MRI in DBS patients should utilize more in depth post-mortem imaging to better simulate the human condition.

Harnessing the immune system for the treatment of Parkinson's disease.

Current treatment options for Parkinson's disease (PD) typically aim to replace dopamine, and hence only provide symptomatic relief. However, in the long run, this approach alone loses its efficacy as it is associated with debilitating side effects. Hence there is an unmet clinical need for addressing levodopa resistant symptoms, and an urgency to develop therapies that can halt or prevent the course of PD. The premise that α-syn can transmit from cell-to-cell in a prion like manner has opened up the possibility for the use of immunotherapy in PD. There is evidence for inflammation in PD as is evidenced by microglial activation, as well as the involvement of the peripheral immune system in PD, and peripheral inflammation can exacerbate dopaminergic degeneration as seen in animal models of the disease. However, mechanisms that link the immune system with PD are not clear, and the sequence of immune responses with respect to PD are still unknown. Nevertheless, our present knowledge offers avenues for the development of immune-based therapies for PD. In order to successfully employ such strategies, we must comprehend the state of the peripheral immune system during the course of PD. This review describes the developments in the field of both active and passive immunotherapies in the treatment of PD, and highlights the crucial need for future research for clarifying the role of inflammation and immunity in this debilitating disease.

The Gut-Brain Axis and Its Relation to Parkinson's Disease: A Review.

Parkinson's disease is a chronic neurodegenerative disease characterized by the accumulation of misfolded alpha-synuclein protein (Lewy bodies) in dopaminergic neurons of the substantia nigra and other related circuitry, which contribute to the development of both motor (bradykinesia, tremors, stiffness, abnormal gait) and non-motor symptoms (gastrointestinal issues, urinogenital complications, olfaction dysfunction, cognitive impairment). Despite tremendous progress in the field, the exact pathways and mechanisms responsible for the initiation and progression of this disease remain unclear. However, recent research suggests a potential relationship between the commensal gut bacteria and the brain capable of influencing neurodevelopment, brain function and health. This bidirectional communication is often referred to as the microbiome-gut-brain axis. Accumulating evidence suggests that the onset of non-motor symptoms, such as gastrointestinal manifestations, often precede the onset of motor symptoms and disease diagnosis, lending support to the potential role that the microbiome-gut-brain axis might play in the underlying pathological mechanisms of Parkinson's disease. This review will provide an overview of and critically discuss the current knowledge of the relationship between the gut microbiota and Parkinson's disease. We will discuss the role of α-synuclein in non-motor disease pathology, proposed pathways constituting the connection between the gut microbiome and the brain, existing evidence related to pre- and probiotic interventions. Finally, we will highlight the potential opportunity for the development of novel preventative measures and therapeutic options that could target the microbiome-gut-brain axis in the context of Parkinson's disease.

Corrigendum: Proceedings of the Eighth Annual Deep Brain Stimulation Think Tank: Advances in Optogenetics, Ethical Issues Affecting DBS Research, Neuromodulatory Approaches for Depression, Adaptive Neurostimulation, and Emerging DBS Technologies.

[This corrects the article DOI: 10.3389/fnhum.2021.644593.].

Proceedings of the Eighth Annual Deep Brain Stimulation Think Tank: Advances in Optogenetics, Ethical Issues Affecting DBS Research, Neuromodulatory Approaches for Depression, Adaptive Neurostimulation, and Emerging DBS Technologies.

We estimate that 208,000 deep brain stimulation (DBS) devices have been implanted to address neurological and neuropsychiatric disorders worldwide. DBS Think Tank presenters pooled data and determined that DBS expanded in its scope and has been applied to multiple brain disorders in an effort to modulate neural circuitry. The DBS Think Tank was founded in 2012 providing a space where clinicians, engineers, researchers from industry and academia discuss current and emerging DBS technologies and logistical and ethical issues facing the field. The emphasis is on cutting edge research and collaboration aimed to advance the DBS field. The Eighth Annual DBS Think Tank was held virtually on September 1 and 2, 2020 (Zoom Video Communications) due to restrictions related to the COVID-19 pandemic. The meeting focused on advances in: (1) optogenetics as a tool for comprehending neurobiology of diseases and on optogenetically-inspired DBS, (2) cutting edge of emerging DBS technologies, (3) ethical issues affecting DBS research and access to care, (4) neuromodulatory approaches for depression, (5) advancing novel hardware, software and imaging methodologies, (6) use of neurophysiological signals in adaptive neurostimulation, and (7) use of more advanced technologies to improve DBS clinical outcomes. There were 178 attendees who participated in a DBS Think Tank survey, which revealed the expansion of DBS into several indications such as obesity, post-traumatic stress disorder, addiction and Alzheimer's disease. This proceedings summarizes the advances discussed at the Eighth Annual DBS Think Tank.