Patient-specific connectomic models correlate with, but do not reliably predict, outcomes in deep brain stimulation for obsessive-compulsive disorder.

Deep brain stimulation (DBS) of the ventral internal capsule/ventral striatum (VCVS) is an emerging treatment for obsessive-compulsive disorder (OCD). Recently, multiple studies using normative connectomes have correlated DBS outcomes to stimulation of specific white matter tracts. Those studies did not test whether these correlations are clinically predictive, and did not apply cross-validation approaches that are necessary for biomarker development. Further, they did not account for the possibility of systematic differences between DBS patients and the non-diagnosed controls used in normative connectomes. To address these gaps, we performed patient-specific diffusion imaging in 8 patients who underwent VCVS DBS for OCD. We delineated tracts connecting thalamus and subthalamic nucleus (STN) to prefrontal cortex via VCVS. We then calculated which tracts were likely activated by individual patients' DBS settings. We fit multiple statistical models to predict both OCD and depression outcomes from tract activation. We further attempted to predict hypomania, a VCVS DBS complication. We assessed all models' performance on held-out test sets. With this best-practices approach, no model predicted OCD response, depression response, or hypomania above chance. Coefficient inspection partly supported prior reports, in that capture of tracts projecting to cingulate cortex was associated with both YBOCS and MADRS response. In contrast to prior reports, however, tracts connected to STN were not reliably correlated with response. Thus, patient-specific imaging and a guideline-adherent analysis were unable to identify a tractographic target with sufficient effect size to drive clinical decision-making or predict individual outcomes. These findings suggest caution in interpreting the results of normative connectome studies.

The use of hydrogel-delivered extracellular vesicles in recovery of motor function in stroke: a testable experimental hypothesis for clinical translation including behavioral and neuroimaging assessment approaches.

Neural tissue engineering, nanotechnology and neuroregeneration are diverse biomedical disciplines that have been working together in recent decades to solve the complex problems linked to central nervous system (CNS) repair. It is known that the CNS demonstrates a very limited regenerative capacity because of a microenvironment that impedes effective regenerative processes, making development of CNS therapeutics challenging. Given the high prevalence of CNS conditions such as stroke that damage the brain and place a severe burden on afflicted individuals and on society, it is of utmost significance to explore the optimum methodologies for finding treatments that could be applied to humans for restoration of function to pre-injury levels. Extracellular vesicles (EVs), also known as exosomes, when derived from mesenchymal stem cells, are one of the most promising approaches that have been attempted thus far, as EVs deliver factors that stimulate recovery by acting at the nanoscale level on intercellular communication while avoiding the risks linked to stem cell transplantation. At the same time, advances in tissue engineering and regenerative medicine have offered the potential of using hydrogels as bio-scaffolds in order to provide the stroma required for neural repair to occur, as well as the release of biomolecules facilitating or inducing the reparative processes. This review introduces a novel experimental hypothesis regarding the benefits that could be offered if EVs were to be combined with biocompatible injectable hydrogels. The rationale behind this hypothesis is presented, analyzing how a hydrogel might prolong the retention of EVs and maximize the localized benefit to the brain. This sustained delivery of EVs would be coupled with essential guidance cues and structural support from the hydrogel until neural tissue remodeling and regeneration occur. Finally, the importance of including non-human primate models in the clinical translation pipeline, as well as the added benefit of multi-modal neuroimaging analysis to establish non-invasive, in vivo, quantifiable imaging-based biomarkers for CNS repair are discussed, aiming for more effective and safe clinical translation of such regenerative therapies to humans.

Individual variations of the human corticospinal tract and its hand-related motor fibers using diffusion MRI tractography.

The corticospinal tract (CST) is one of the most well studied tracts in human neuroanatomy. Its clinical significance can be demonstrated in many notable traumatic conditions and diseases such as stroke, spinal cord injury (SCI) or amyotrophic lateral sclerosis (ALS). With the advent of diffusion MRI and tractography the computational representation of the human CST in a 3D model became available. However, the representation of the entire CST and, specifically, the hand motor area has remained elusive. In this paper we propose a novel method, using manually drawn ROIs based on robustly identifiable neuroanatomic structures to delineate the entire CST and isolate its hand motor representation as well as to estimate their variability and generate a database of their volume, length and biophysical parameters. Using 37 healthy human subjects we performed a qualitative and quantitative analysis of the CST and the hand-related motor fiber tracts (HMFTs). Finally, we have created variability heat maps from 37 subjects for both the aforementioned tracts, which could be utilized as a reference for future studies with clinical focus to explore neuropathology in both trauma and disease states.

Taking central nervous system regenerative therapies to the clinic: curing rodents versus nonhuman primates versus humans.

The central nervous system is known to have limited regenerative capacity. Not only does this halt the human body's reparative processes after central nervous system lesions, but it also impedes the establishment of effective and safe therapeutic options for such patients. Despite the high prevalence of stroke and spinal cord injury in the general population, these conditions remain incurable and place a heavy burden on patients' families and on society more broadly. Neuroregeneration and neural engineering are diverse biomedical fields that attempt reparative treatments, utilizing stem cells-based strategies, biologically active molecules, nanotechnology, exosomes and highly tunable biodegradable systems (e.g., certain hydrogels). Although there are studies demonstrating promising preclinical results, safe clinical translation has not yet been accomplished. A key gap in clinical translation is the absence of an ideal animal or ex vivo model that can perfectly simulate the human microenvironment, and also correspond to all the complex pathophysiological and neuroanatomical factors that affect functional outcomes in humans after central nervous system injury. Such an ideal model does not currently exist, but it seems that the nonhuman primate model is uniquely qualified for this role, given its close resemblance to humans. This review considers some regenerative therapies for central nervous system repair that hold promise for future clinical translation. In addition, it attempts to uncover some of the main reasons why clinical translation might fail without the implementation of nonhuman primate models in the research pipeline.

Translational Regenerative Therapies for Chronic Spinal Cord Injury.

Spinal cord injury is a chronic and debilitating neurological condition that is currently being managed symptomatically with no real therapeutic strategies available. Even though there is no consensus on the best time to start interventions, the chronic phase is definitely the most stable target in order to determine whether a therapy can effectively restore neurological function. The advancements of nanoscience and stem cell technology, combined with the powerful, novel neuroimaging modalities that have arisen can now accelerate the path of promising novel therapeutic strategies from bench to bedside. Several types of stem cells have reached up to clinical trials phase II, including adult neural stem cells, human spinal cord stem cells, olfactory ensheathing cells, autologous Schwann cells, umbilical cord blood-derived mononuclear cells, adult mesenchymal cells, and autologous bone-marrow-derived stem cells. There also have been combinations of different molecular therapies; these have been either alone or combined with supportive scaffolds with nanostructures to facilitate favorable cell⁻material interactions. The results already show promise but it will take some coordinated actions in order to develop a proper step-by-step approach to solve impactful problems with neural repair.

Injectable Hydrogel versus Plastically Compressed Collagen Scaffold for Central Nervous System Applications.

Central Nervous System (CNS) repair has been a challenge, due to limited CNS tissue regenerative capacity. The emerging tools that neural engineering has to offer have opened new pathways towards the discovery of novel therapeutic approaches for CNS disorders. Collagen has been a preferable material for neural tissue engineering due to its similarity to the extracellular matrix, its biocompatibility, and antigenicity. The aim was to compare properties of a plastically compressed collagen hydrogel with the ones of a promising collagen-genipin injectable hydrogel and a collagen-only hydrogel for clinical CNS therapy applications. The focus was demonstrating the effects of genipin cross-linking versus plastic compression methodology on a collagen hydrogel and the impact of each method on clinical translatability. The results showed that injectable collagen-genipin hydrogel is better clinical translation material. Full collagen compression seemed to form extremely stiff hydrogels (up to about 2300 kPa) so, according to our findings, a compression level of up to 75% should be considered for CNS applications, being in line with CNS stiffness. Taking that into consideration, partially compressed collagen 3D hydrogel systems may be a good tunable way to mimic the natural hierarchical model of the human body, potentially facilitating neural repair application.

Stem cells for spinal cord injuries bearing translational potential.

Spinal cord injury (SCI) is a highly debilitating neurological disease, which still lacks effective treatment strategies, causing significant financial burden and distress to the affected families. Nevertheless, nanotechnology and regenerative medicine strategies holding promise for the development of novel therapies that would reach from bench to bedside to serve the SCI patients. There has already been significant progress in the field of cell-based therapies, with the clinical application for SCI, currently in phase II of the clinical trial. Stem cells (e.g., induced pluripotent stem cells, fetal stem cells, human embryonic stem cells, and olfactory ensheathing cells) are certainly not to be considered the panacea for neural repair but, especially when combined with rehabilitation or other combinatorial approaches using the help of nanotechnology, they seem to be the source of some of the most promising and clinical translatable cell-based therapies that could help solving impactful problems on neural repair.

Advances in peripheral nervous system regenerative therapeutic strategies: A biomaterials approach.

Peripheral nerve injury is a very common medical condition with varying clinical severity but always great impact on the patients' productivity and the quality of life. Even the current 1st-choice surgical therapeutic approach or the "gold standard" as frequently called in clinical practice, is not addressing the problem efficiently and cost-effectively, increasing the mortality through the need of a second surgical intervention, while it does not take into account the several different types of nerves involved in peripheral nerve injuries. Neural tissue engineering approaches could potentially offer a very promising and attractive tool for the efficient peripheral nerve injury management, not only by mechanically building the gap, but also by inducing neuroregenerative mechanisms in a well-regulated microenvironment which would mimic the natural environment of the specific nerve type involved in the injury to obtain an optimum clinical outcome. There is still room for a lot of optimizations in regard to the conduits which have been developed with the help of neural engineering since many parameters affect the clinical outcome and the underlying mechanisms are still not well understood. Especially the intraluminal cues controlling the microenvironment of the conduits are in an infantile stage but there is profound potential in the application of the scaffolds. The aim of our review is to provide a quick reference to the recent advances in the field, focusing on the parameters that can significantly affect the clinical potentials of each approach, with suggestions for future improvements that could take the current work from bench to bedside. Thus, further research could shed light to those questions and it might hold the key to discover new more efficient and cost-effective therapies.

Advancing research in regeneration and repair of the motor circuitry: non-human primate models and imaging scales as the missing links for successfully translating injectable therapeutics to the clinic.

Regeneration and repair is the ultimate goal of therapeutics in trauma of the central nervous system (CNS). Stroke and spinal cord injury (SCI) are two highly prevalent CNS disorders that remain incurable, despite numerous research studies and the clinical need for effective treatments. Neural engineering is a diverse biomedical field, that addresses these diseases using new approaches. Research in the field involves principally rodent models and biologically active, biodegradable hydrogels. Promising results have been reported in preclinical studies of CNS repair, demonstrating the great potential for the development of new treatments for the brain, spinal cord and peripheral nerve injury. Several obstacles stand in the way of clinical translation of neuroregeneration research. There seems to be a key gap in the translation of research from rodent models to human applications, namely non-human primate models, which constitute a critical bridging step. Applying injectable therapeutics and multimodal neuroimaging in stroke lesions using experimental rhesus monkey models is an avenue that a few research groups have begun to embark on. Understanding and assessing the changes that the injured brain or spinal cord undergoes after an intervention with biodegradable hydrogels in non-human primates seem to represent critical preclinical research steps. Existing innovative models in non-human primates allow us to evaluate the potential of neural engineering and injectable hydrogels. The results of these preliminary studies will pave the way for translating this research into much needed clinical therapeutic approaches. Cutting edge imaging technology using Connectome scanners represents a tremendous advancement, enabling the in vivo, detailed, high-resolution evaluation of these therapeutic interventions in experimental animals. Most importantly, they also allow quantifiable and clinically meaningful correlations with humans, increasing the translatability of these innovations to the bedside.

Advances in regenerative therapies for spinal cord injury: a biomaterials approach.

Spinal cord injury results in the permanent loss of function, causing enormous personal, social and economic problems. Even though neural regeneration has been proven to be a natural mechanism, central nervous system repair mechanisms are ineffective due to the imbalance of the inhibitory and excitatory factors implicated in neuroregeneration. Therefore, there is growing research interest on discovering a novel therapeutic strategy for effective spinal cord injury repair. To this direction, cell-based delivery strategies, biomolecule delivery strategies as well as scaffold-based therapeutic strategies have been developed with a tendency to seek for the answer to a combinatorial approach of all the above. Here we review the recent advances on regenerative/neural engineering therapies for spinal cord injury, aiming at providing an insight to the most promising repair strategies, in order to facilitate future research conduction.

AQP4 tag single nucleotide polymorphisms in patients with traumatic brain injury.

Accumulating evidence suggests that the extent of brain injury and the clinical outcome after traumatic brain injury (TBI) are modulated, to some degree, by genetic variants. Aquaporin-4 (AQP4) is the predominant water channel in the central nervous system and plays a critical role in controlling the water content of brain cells and the development of brain edema after TBI. We sought to investigate the influence of the AQP4 gene region on patient outcome after TBI by genotyping tag single nucleotide polymorphisms (SNPs) along AQP4 gene. A total of 363 patients with TBI (19.6% female) were prospectively evaluated. Data including the Glasgow Coma Scale (GCS) scores at admission, the presence of intracranial hemorrhage, and the 6-month Glasgow Outcome Scale (GOS) scores were collected. Seven tag SNPs across the AQP4 gene were identified based on the HapMap data. Using logistic regression analyses, SNPs and haplotypes were tested for associations with 6-month GOS after adjusting for age, GCS score, and sex. Significant associations with TBI outcome were detected for rs3763043 (OR [95% confidence interval (CI)]: 5.15 [1.60-16.5], p=0.006, for recessive model), rs3875089 (OR [95% CI]: 0.18 [0.07-0.50] p=0.0009, for allele difference model), and a common haplotype of AQP4 tag SNPs (OR [95% CI]: 2.94, [1.34-6.36], p=0.0065). AQP4 tag SNPs were not found to influence the initial severity of TBI or the presence of intracranial hemorrhages. In conclusion, the present study provides evidence for possible involvement of genetic variations in AQP4 gene in the functional outcome of patients with TBI.