Inflammation in obsessive-compulsive disorder: A literature review and hypothesis-based potential of transcranial photobiomodulation.

Obsessive-compulsive disorder (OCD) is a disabling neuropsychiatric disorder that affects about 2%-3% of the global population. Despite the availability of several treatments, many patients with OCD do not respond adequately, highlighting the need for new therapeutic approaches. Recent studies have associated various inflammatory processes with the pathogenesis of OCD, including alterations in peripheral immune cells, alterations in cytokine levels, and neuroinflammation. These findings suggest that inflammation could be a promising target for intervention. Transcranial photobiomodulation (t-PBM) with near-infrared light is a noninvasive neuromodulation technique that has shown potential for several neuropsychiatric disorders. However, its efficacy in OCD remains to be fully explored. This study aimed to review the literature on inflammation in OCD, detailing associations with T-cell populations, monocytes, NLRP3 inflammasome components, microglial activation, and elevated proinflammatory cytokines such as TNF-α, CRP, IL-1ß, and IL-6. We also examined the hypothesis-based potential of t-PBM in targeting these inflammatory pathways of OCD, focusing on mechanisms such as modulation of oxidative stress, regulation of immune cell function, reduction of proinflammatory cytokine levels, deactivation of neurotoxic microglia, and upregulation of BDNF gene expression. Our review suggests that t-PBM could be a promising, noninvasive intervention for OCD, with the potential to modulate underlying inflammatory processes. Future research should focus on randomized clinical trials to assess t-PBM's efficacy and optimal treatment parameters in OCD. Biomarker analyses and neuroimaging studies will be important in understanding the relationship between inflammatory modulation and OCD symptom improvement following t-PBM sessions.

Case Report of Dual-Site Neurostimulation and Chronic Recording of Cortico-Striatal Circuitry in a Patient With Treatment Refractory Obsessive Compulsive Disorder.

Psychiatric disorders are increasingly understood as dysfunctions of hyper- or hypoconnectivity in distributed brain circuits. A prototypical example is obsessive compulsive disorder (OCD), which has been repeatedly linked to hyper-connectivity of cortico-striatal-thalamo-cortical (CSTC) loops. Deep brain stimulation (DBS) and lesions of CSTC structures have shown promise for treating both OCD and related disorders involving over-expression of automatic/habitual behaviors. Physiologically, we propose that this CSTC hyper-connectivity may be reflected in high synchrony of neural firing between loop structures, which could be measured as coherent oscillations in the local field potential (LFP). Here we report the results from the pilot patient in an Early Feasibility study (https://clinicaltrials.gov/ct2/show/NCT03184454) in which we use the Medtronic Activa PC+ S device to simultaneously record and stimulate in the supplementary motor area (SMA) and ventral capsule/ventral striatum (VC/VS). We hypothesized that frequency-mismatched stimulation should disrupt coherence and reduce compulsive symptoms. The patient reported subjective improvement in OCD symptoms and showed evidence of improved cognitive control with the addition of cortical stimulation, but these changes were not reflected in primary rating scales specific to OCD and depression, or during blinded cortical stimulation. This subjective improvement was correlated with increased SMA and VC/VS coherence in the alpha, beta, and gamma bands, signals which persisted after correcting for stimulation artifacts. We discuss the implications of this research, and propose future directions for research in network modulation in OCD and more broadly across psychiatric disorders.

Homeostatic enhancement of sensory transduction.

Our sense of hearing boasts exquisite sensitivity, precise frequency discrimination, and a broad dynamic range. Experiments and modeling imply, however, that the auditory system achieves this performance for only a narrow range of parameter values. Small changes in these values could compromise hair cells' ability to detect stimuli. We propose that, rather than exerting tight control over parameters, the auditory system uses a homeostatic mechanism that increases the robustness of its operation to variation in parameter values. To slowly adjust the response to sinusoidal stimulation, the homeostatic mechanism feeds back a rectified version of the hair bundle's displacement to its adaptation process. When homeostasis is enforced, the range of parameter values for which the sensitivity, tuning sharpness, and dynamic range exceed specified thresholds can increase by more than an order of magnitude. Signatures in the hair cell's behavior provide a means to determine through experiment whether such a mechanism operates in the auditory system. Robustness of function through homeostasis may be ensured in any system through mechanisms similar to those that we describe here.

Elastic force restricts growth of the murine utricle.

Dysfunctions of hearing and balance are often irreversible in mammals owing to the inability of cells in the inner ear to proliferate and replace lost sensory receptors. To determine the molecular basis of this deficiency we have investigated the dynamics of growth and cellular proliferation in a murine vestibular organ, the utricle. Based on this analysis, we have created a theoretical model that captures the key features of the organ's morphogenesis. Our experimental data and model demonstrate that an elastic force opposes growth of the utricular sensory epithelium during development, confines cellular proliferation to the organ's periphery, and eventually arrests its growth. We find that an increase in cellular density and the subsequent degradation of the transcriptional cofactor Yap underlie this process. A reduction in mechanical constraints results in accumulation and nuclear translocation of Yap, which triggers proliferation and restores the utricle's growth; interfering with Yap's activity reverses this effect.

Physiological Preparation of Hair Cells from the Sacculus of the American Bullfrog (Rana catesbeiana).

The study of hearing and balance rests upon insights drawn from biophysical studies of model systems. One such model, the sacculus of the American bullfrog, has become a mainstay of auditory and vestibular research. Studies of this organ have revealed how sensory cells hair can actively detect signals from the environment. Because of these studies, we now better understand the mechanical gating and localization of a hair cell's transduction channels, calcium's role in mechanical adaptation, and the identity of hair cell currents. This highly accessible organ continues to provide insight into the workings of hair cells. Here we describe the preparation of the bullfrog's sacculus for biophysical studies on its hair cells. We include the complete dissection procedure and provide specific protocols for the preparation of the sacculus in specific contexts. We additionally include representative results using this preparation, including the calculation of a hair bundle's instantaneous force-displacement relation and measurement of a bundle's spontaneous oscillation.

Identification of Bifurcations from Observations of Noisy Biological Oscillators.

Hair bundles are biological oscillators that actively transduce mechanical stimuli into electrical signals in the auditory, vestibular, and lateral-line systems of vertebrates. A bundle's function can be explained in part by its operation near a particular type of bifurcation, a qualitative change in behavior. By operating near different varieties of bifurcation, the bundle responds best to disparate classes of stimuli. We show how to determine the identity of and proximity to distinct bifurcations despite the presence of substantial environmental noise. Using an improved mechanical-load clamp to coerce a hair bundle to traverse different bifurcations, we find that a bundle operates within at least two functional regimes. When coupled to a high-stiffness load, a bundle functions near a supercritical Hopf bifurcation, in which case it responds best to sinusoidal stimuli such as those detected by an auditory organ. When the load stiffness is low, a bundle instead resides close to a subcritical Hopf bifurcation and achieves a graded frequency response-a continuous change in the rate, but not the amplitude, of spiking in response to changes in the offset force-a behavior that is useful in a vestibular organ. The mechanical load in vivo might therefore control a hair bundle's responsiveness for effective operation in a particular receptor organ. Our results provide direct experimental evidence for the existence of distinct bifurcations associated with a noisy biological oscillator, and demonstrate a general strategy for bifurcation analysis based on observations of any noisy system.

Control of a hair bundle's mechanosensory function by its mechanical load.

Hair cells, the sensory receptors of the internal ear, subserve different functions in various receptor organs: they detect oscillatory stimuli in the auditory system, but transduce constant and step stimuli in the vestibular and lateral-line systems. We show that a hair cell's function can be controlled experimentally by adjusting its mechanical load. By making bundles from a single organ operate as any of four distinct types of signal detector, we demonstrate that altering only a few key parameters can fundamentally change a sensory cell's role. The motions of a single hair bundle can resemble those of a bundle from the amphibian vestibular system, the reptilian auditory system, or the mammalian auditory system, demonstrating an essential similarity of bundles across species and receptor organs.

Incorporating the principles of the patient-centered medical home into a student-run free clinic.

As the health care delivery landscape changes, medical schools must develop creative strategies for preparing future physicians to provide quality care in this new environment. Despite the growing prominence of the patient-centered medical home (PCMH) as an effective model for health care delivery, few medical schools have integrated formal education on the PCMH into their curricula. Incorporating the PCMH model into medical school curricula is important to ensure that students have a comprehensive understanding of the different models of health care delivery and can operate effectively as physicians. The authors provide a detailed description of the process by which the Weill Cornell Community Clinic (WCCC), a student-run free clinic, has integrated PCMH principles into a service-learning initiative. The authors assessed patient demographics, diagnoses, and satisfaction along with student satisfaction. During the year after a PCMH model was adopted, 112 students and 19 licensed physicians volunteered their time. A review of the 174 patients seen from July 2011 to June 2012 found that the most common medical reasons for visits included management of hypertension, hyperlipidemia, diabetes, gastrointestinal conditions, arthritis, anxiety, and depression. During the year after the adoption of the PCMH model, 87% were very or extremely satisfied with their care, and 96% of the patients would recommend the WCCC to others. Students who participate in the WCCC gain hands-on experience in coordinating care, providing continuity of care, addressing issues of accessibility, and developing quality and safety metrics. The WCCC experience provides an integrative model that links service-learning with education on health care delivery in a primary care setting. The authors propose that adoption of this approach by other student-run clinics provides a substantial opportunity to improve medical education nationwide and better prepare future physicians to practice within this new model of health care delivery.

Frequency-selective exocytosis by ribbon synapses of hair cells in the bullfrog's amphibian papilla.

The activity of auditory afferent fibers depends strongly on the frequency of stimulation. Although the bullfrog's amphibian papilla lacks the flexible basilar membrane that effects tuning in mammals, its afferents display comparable frequency selectivity. Seeking additional mechanisms of tuning in this organ, we monitored the synaptic output of hair cells by measuring changes in their membrane capacitance during sinusoidal electrical stimulation at various frequencies. Using perforated-patch recordings, we found that individual hair cells displayed frequency selectivity in synaptic exocytosis within the frequency range sensed by the amphibian papilla. Moreover, each cell's tuning varied in accordance with its tonotopic position. Using confocal imaging, we observed a tonotopic gradient in the concentration of proteinaceous Ca(2+) buffers. A model for synaptic release suggests that this gradient maintains the sharpness of tuning. We conclude that hair cells of the amphibian papilla use synaptic tuning as an additional mechanism for sharpening their frequency selectivity.

Optimizing the osteogenic potential of adult stem cells for skeletal regeneration.

Adult stem cells, including mesenchymal stem cells, display plasticity in that they can differentiate toward various lineages including bone cells, cartilage cells, fat cells, and other types of connective tissue cells. However, it is not clear what factors direct adult stem cell lineage commitment and terminal differentiation. Emerging evidence suggests that extracellular physical cues have the potential to control stem cell lineage specification. In this perspective article, we review recent findings on biomaterial surface and mechanical signal regulation of stem cell differentiation. Specifically, we focus on stem cell response to substrate nanoscale topography and fluid flow induced shear stress and how these physical factors may regulate stem cell osteoblastic differentiation in vitro.

Increased mechanosensitivity of cells cultured on nanotopographies.

Enhancing cellular mechanosensitivity is recognized as a novel tool for successful musculoskeletal tissue engineering. We examined the hypothesis that mechanosensitivity of human mesenchymal stem cells (hMSCs) is enhanced on nanotopographic substrates relative to flat surfaces. hMSCs were cultured on polymer-demixed, randomly distributed nanoisland surfaces with varying island heights and changes in intracellular calcium concentration, [Ca(2+)](i), in response to fluid flow induced shear stress were quantifide. Stem cells cultured on specific scale nanotopographies displayed greater intracellular calcium responses to fluid flow. hMSCs cultured on 10-20nm high nanoislands displayed a greater percentage of cells responding in calcium relative to cells cultured on flat control, and showed greater average [Ca(2+)](i) increase relative to cells cultured on other nanoislands (45-80nm high nanoislands). As [Ca(2+)](i) is an important regulator of downstream signaling, as well as proliferation and differentiation of hMSCs, this observation suggests that specific scale nanotopographies provide an optimal milieu for promoting stem cell mechanotransduction activity. That mechanical signals and substrate nanotopography may synergistically regulate cell behavior is of significant interest in the development of regenerative medicine protocols.

Finite element analyses of fluid flow conditions in cell culture.

Numerous studies in tissue engineering and biomechanics use fluid flow stimulation, both unidirectional and oscillatory, to analyze the effects of shear stresses on cell behavior. However, it has typically been assumed that these shear stresses are uniform and that cell and substrate properties do not adversely affect these assumptions. With the increasing utilization of fluid flow in cell biology, it would be beneficial to determine the validity of various experimental protocols. Because it is difficult to determine the velocity profiles and shear stresses empirically, we used the finite element method (FEM). Using FEM, we determined the effects of cell confluence on fluid flow, the effects of cell height on the uniformity of shear stresses, apparent shear stresses exhibited by cells cultured on various substrates, and the effects of oscillatory fluid flow relative to the unidirectional flow. FEM analyses could successfully analyze flow patterns over cells for various cell confluence and shape and substrate characteristics. Our data suggest the benefits of the utilization of oscillatory fluid flow and the use of substrates that stimulate cell spreading in the distribution of more uniform shear stresses across the surface of cells. Also we demonstrated that the cells cultured on nanotopographies were exposed to greater apparent shear stresses than cells on flat controls when using the same fluid flow conditions. FEM thus provides an excellent tool for the development of experimental protocols and the design of bioreactor systems.