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Objective To better understand current practices of U.S.-based physicians in the management of Tourette syndrome (TS) and identify gaps that may be addressed by future education. Methods Two survey instruments were developed to gather data on management of TS and perceptions from physicians and caregivers of children with TS. The clinician survey was developed in consultation with a TS physician expert and utilized clinical vignettes to assess and quantify practice patterns. The caregiver survey was adapted from the clinician survey and other published studies and gathered details on diagnosis, treatment, and perceptions regarding management. Results Data included responses from 138 neurologists (including 57 pediatric neurologists), 162 psychiatrists (including 42 pediatric psychiatrists), and 67 caregivers. Most (65%) pediatric neurologists rely solely on clinical findings to make a diagnosis, whereas the majority of other specialists utilize additional testing (eg, neuroimaging, lab testing, and genetics). Most psychiatrists (96%) utilize standardized criteria to make a diagnosis, whereas 22% of neurologists do not. Many physicians (44% of psychiatrists and 20% of neurologists) use pharmacotherapy to treat a patient with “slightly bothersome” tics and no functional impairment, whereas caregivers favored behavioral therapy. Most (76%) caregivers preferred to make the final treatment decision, whereas 80% of physicians preferred equal or physician-directed decision-making. Conclusions This study provides insight into practice patterns and perceptions of U.S.-based neurologists and psychiatrists in managing TS. Results highlight the potential value of physician education, including diagnostic approach, tic management and monitoring, involvement of caregivers in decision-making, and updates on TS management.

To better understand treatment patterns in US patients with multiple sclerosis (MS) initiating generic glatiramer acetate (GA), this study examined adherence, discontinuation and switching patterns from generic follow-on glatiramer acetate (FOGA) therapy in real-world patient cohorts.Retrospective analyses utilized data from two large US databases (administrative claims and linked electronic medical records). Eligible adult MS patients had ≥1 pharmacy claim for FOGA during the identification period; the first FOGA claim was the index date. All analyses were descriptive; proportion of days covered (PDC) was calculated as a measure of adherence to FOGA during the follow-up period.The first cohort consisted of 95 patients, with 93.6% having a branded GA claim for Copaxone during the baseline period. Half these patients (48.4%) had high adherence to FOGA therapy (PDC: 0.8-1.0). Fifty-five patients (57.9%) initially discontinued FOGA with a mean persistence of 112 days. Of those who discontinued, 7.3% had no subsequent disease-modifying therapy (DMT), 30.9% restarted FOGA and 61.8% did not restart FOGA. The second cohort consisted of 1957 patients, with 63.8% having a branded GA claim for Copaxone during the baseline period and 33.5% were treatment naïve. The majority of patients (61.9%) had high adherence to FOGA therapy. A total of 1597 patients (81.6%) initially discontinued FOGA with a mean persistence of 93 days. Of those who discontinued, 55.8% switched to another DMT, 16.7% restarted FOGA and 37.5% had no subsequent DMT.Adherence to FOGA therapy was reasonably high across cohorts; however, most patients discontinued their initial FOGA within four months of the index date and most switches from FOGA were to branded GA products.

Objective Describe the long-term outcomes of early-start (ES) and delayed-start (DS) glatiramer acetate 40 mg/mL treatment three times weekly (GA40) for up to seven years in the Glatiramer Acetate Low-frequency Administration (GALA) study in patients with relapsing multiple sclerosis (RMS). Methods Patients were evaluated every three to six months. The primary efficacy endpoint was annualized relapse rate (ARR); additional endpoints were exploratory or post hoc. For efficacy, data from the entire exposure period were used for the ES and DS cohorts. For safety, exposure only under GA40 was considered. Results Of the patients who continued into the open-label extension (OLE), 580/834 (70%) ES and 261/419 (62%) DS completed the OLE. For the entire placebo-controlled and OLE study period, ARR was 0.26 for ES and 0.31 for DS patients (risk ratio = 0.83; 95% confidence interval [CI]: 0.70–0.99). ES prolonged median time to first relapse versus DS (4.9 versus 4.3 years; hazard ratio = 0.82; 95% CI: 0.6–0.96). OLE-only results showed DS patients experienced similar efficacy for relapse and disability outcomes as ES patients. Adverse events were consistent with the well-established GA safety profile. Conclusions GA40 treatment conferred clinical benefit up to seven years, resulting in sustained efficacy and was generally well tolerated in RMS patients.

Macrophages dominate sites of central nervous system (CNS) injury where they promote both injury and repair. These divergent effects may be caused by distinct macrophage subsets, i.e., “classically-activated” pro-inflammatory (M1) or “alternatively-activated” anti-inflammatory (M2) cells. Here, we show that an M1 macrophage response is rapidly induced then maintained at sites of traumatic spinal cord injury and that this response overwhelms a comparatively smaller and transient M2 macrophage response. The high M1:M2 macrophage ratio has significant implications for CNS repair. Indeed, we present novel data showing that only M1 macrophages are neurotoxic and M2 macrophages promote a regenerative growth response in adult sensory axons, even in the context of inhibitory substrates that dominate sites of CNS injury (e.g., proteoglycans and myelin). Together, these data suggest that polarizing the differentiation of resident microglia and infiltrating blood monocytes toward an M2 or “alternatively” activated macrophage phenotype could promote CNS repair while limiting secondary inflammatory-mediated injury.

There is growing recognition that psychological stress influences pain. Hormones that comprise the physiological response to stress (e.g., corticosterone; CORT) may interact with effectors of neuropathic pain. To test this hypothesis, mice received a spared nerve injury (SNI) after exposure to 60 min restraint stress. In stressed mice, allodynia was consistently increased. The mechanism(s) underlying the exacerbated pain response involves CORT acting via glucocorticoid receptors (GRs); RU486, a GR antagonist, prevented the stress-induced increase in allodynia whereas exogenous administration of CORT to non-stressed mice reproduced the allodynic response caused by stress. Since nerve injury-induced microglial activation has been implicated in the onset and propagation of neuropathic pain, we evaluated cellular and molecular indices of microglial activation in the context of stress. Activation of dorsal horn microglia was accelerated by stress; however, this effect was transient and was not associated with the onset or maintenance of a pro-inflammatory phenotype. Stress-enhanced allodynia was associated with increased dorsal horn extracellular signal-regulated kinase phosphorylation (pERK). ERK activation could indicate a stress-mediated increase in glutamatergic signaling, therefore mice were treated prior to SNI and stress with memantine, an N-methyl-D-aspartate receptor (NMDAR) antagonist. Memantine prevented stress-induced enhancement of allodynia after SNI. These data suggest that the hormonal responses elicited by stress exacerbate neuropathic pain through enhanced central sensitization. Moreover, drugs that inhibit glucocorticoids (GCs) and/or NMDAR signaling could ameliorate pain syndromes caused by stress.

Both positive and negative social interactions can modulate the hypothalamic-pituitary-adrenal (HPA) axis and influence recovery from injuries and illnesses, such as wounds, stroke, and cardiac arrest. Stress exacerbates neuronal death following stroke and cardiac arrest, and delays cutaneous wound healing, via a common mechanism involving stress-induced increases in corticosterone, acting on glucocorticoid receptors. In contrast, hamsters and mice that form social bonds are buffered against stress and heal cutaneous wounds more quickly than socially isolated animals, presumably because the physical contact experienced by the pairs releases oxytocin, which in turn suppresses the HPA axis and facilitates wound healing. Social housing also decreases stroke-induced neuronal death and improves functional recovery, but the mechanism appears to involve suppressing the inflammatory response that accompanies stroke, rather than alterations in HPA axis activity. An interaction between the HPA axis and immune system determines stroke outcome in neonatally manipulated mice that exhibit life-long dampening of the HPA axis. Taken together, these studies provide support for the detrimental effects of stress and identify potential mechanisms underlying the well-documented clinical observation that social support positively influences human health.

A large and rapidly increasing body of evidence indicates that microglia-to-neuron signaling is essential for chronic pain hypersensitivity. Using multiple approaches, we found that microglia are not required for mechanical pain hypersensitivity in female mice; female mice achieved similar levels of pain hypersensitivity using adaptive immune cells, likely T lymphocytes. This sexual dimorphism suggests that male mice cannot be used as proxies for females in pain research.

Macrophage migration inhibitory factor (MIF) is a multipotent cytokine that is associated with clinical worsening and relapses in multiple sclerosis (MS) patients. The mechanism through which MIF promotes MS progression remains undefined. In this study, we identify a critical role for MIF in regulating CNS effector mechanisms necessary for the development of inflammatory pathology in a mouse model of MS, experimental autoimmune encephalomyelitis (EAE). Despite the ability to generate pathogenic myelin-specific immune responses peripherally, MIF-deficient mice have reduced EAE severity and exhibit less CNS inflammatory pathology, with a greater percentage of resting microglia and fewer infiltrating inflammatory macrophages. We demonstrate that MIF is essential for promoting microglial activation and production of the innate soluble mediators IL-1β, IL-6, TNF-α, and inducible NO synthase. We propose a novel role for MIF in inducing microglial C/EBP-β, a transcription factor shown to regulate myeloid cell function and play an important role in neuroinflammation. Intraspinal stereotaxic microinjection of MIF resulted in upregulation of inflammatory mediators in microglia, which was sufficient to restore EAE-mediated inflammatory pathology in MIF-deficient mice. To further implicate a role for MIF, we show that MIF is highly expressed in human active MS lesions. Thus, these results illustrate the ability of MIF to influence the CNS cellular and molecular inflammatory milieu during EAE and point to the therapeutic potential of targeting MIF in MS.

Stress and glucocorticoids exacerbate pain via undefined mechanisms. Macrophage migration inhibitory factor (MIF) is a constitutively expressed protein that is secreted to maintain immune function when glucocorticoids are elevated by trauma or stress. Here we show that MIF is essential for the development of neuropathic and inflammatory pain, and for stress-induced enhancement of neuropathic pain. Mif null mutant mice fail to develop pain-like behaviors in response to inflammatory stimuli or nerve injury. Pharmacological inhibition of MIF attenuates pain-like behaviors caused by nerve injury and prevents sensitization of these behaviors by stress. Conversely, injection of recombinant MIF into naive mice produces dose-dependent mechanical sensitivity that is exacerbated by stress. MIF elicits pro-inflammatory signaling in microglia and activates sensory neurons, mechanisms that underlie pain. These data implicate MIF as a key regulator of pain and provide a mechanism whereby stressors exacerbate pain. MIF inhibitors warrant clinical investigation for the treatment of chronic pain.

There is a need to develop therapies that promote growth or remyelination of mammalian CNS axons. Although the feasibility of pre-clinical treatment strategies should be tested in animal models, in vitro assays are usually faster and less expensive. As a result, in vitro models are ideal for screening large numbers of potential therapeutics prior to use in more complex in vivo systems. In 1953, Sholl introduced a technique that is a reliable and sensitive method for quantifying indices of neurite outgrowth. However, application of the technique is limited because it is labor-intensive. Several methods have been developed to reduce the analysis time for the Sholl technique; but these methods require extensive pre-processing of digital images, they introduce user bias or they have not been compared to manual analysis to ensure accuracy. Here we describe a new, semi-automated Sholl technique for quantifying neuronal and glial process morphology. Using MetaMorph, we developed an unbiased analysis protocol that can be performed approximately 3x faster than manual quantification with a comparable level of accuracy regardless of cell morphology. The laborious image processing typical of most computer-aided analysis is avoided by embedding image correction functions into the automated portion of the analysis. The sensitivity and validity of the technique was confirmed by quantifying neuron growth treated with growth factors or oligodendroglial maturation in the presence or absence of thyroid hormone. Thus, this technique provides a rapid and sensitive method for quantifying changes in cell morphology and screening for treatment effects in multiple cell types in vitro.

Traumatic spinal cord injury triggers a complex local inflammatory reaction capable of enhancing repair and exacerbating pathology. The composition and effector potential of the post-injury cellular and molecular immune cascade changes as a function of time and distance from the lesion. Production along this time-space continuum of cytokines, proteases, and growth factors establishes dynamic environments that lead to the death, damage, repair or growth of affected neurons and glia. Microenvironmental cues, therefore, generated by the cells therein, may determine these distinct fates of repair versus pathology. To harness repair, it is necessary to manipulate the assembly and phenotype of cells that comprise the neuroinflammatory response to injury. Here, the potential of the neuroinflammatory response to cause outcomes such as pain, regeneration, and functional recovery is reviewed.

Traumatic spinal cord injury triggers a complex local inflammatory reaction capable of enhancing repair and exacerbating pathology. The composition and effector potential of the post-injury cellular and molecular immune cascade changes as a function of time and distance from the lesion. Production along this time-space continuum of cytokines, proteases, and growth factors establishes dynamic environments that lead to the death, damage, repair or growth of affected neurons and glia. Microenvironmental cues, therefore, generated by the cells therein, may determine these distinct fates of repair versus pathology. To harness repair, it is necessary to manipulate the assembly and phenotype of cells that comprise the neuroinflammatory response to injury. Here, the potential of the neuroinflammatory response to cause outcomes such as pain, regeneration, and functional recovery is reviewed.

Spinal cord injury is a long-lasting, debilitating condition that affects ∼250,000 people in the United States. Spontaneous functional recovery after human spinal cord injury is limited because of severe axonal damage and poor axonal regeneration. Hence, a major area of focus has been to preserve

Stress is known to activate the noradrenergic system which may have a modulatory influence on cognitive flexibility. We investigated whether an auditory stressor would thus affect performance on cognitive flexibility. A task utilizing cognitive flexibility and two memory tasks were presented in both stressful and non-stressful condition. In the stressful condition performance was impaired for the cognitive flexibility task but not for the memory tasks, arguing against the stressor serving as a general distracter. These findings suggest that stress caused by an auditory stressor may negatively impact performance on more complex tasks requiring a rapid search of the semantic and lexical associative networks.

Both positive and negative social interactions can modulate the hypothalamic-pituitary-adrenal (HPA) axis and influence recovery from injuries and illnesses, such as wounds, stroke, and cardiac arrest. Stress exacerbates neuronal death following stroke and cardiac arrest, and delays cutaneous wound healing, via a common mechanism involving stress-induced increases in corticosterone, acting on glucocorticoid receptors. In contrast, hamsters and mice that form social bonds are buffered against stress and heal cutaneous wounds more quickly than socially isolated animals, presumably because the physical contact experienced by the pairs releases oxytocin, which in turn suppresses the HPA axis and facilitates wound healing. Social housing also decreases stroke-induced neuronal death and improves functional recovery, but the mechanism appears to involve suppressing the inflammatory response that accompanies stroke, rather than alterations in HPA axis activity. An interaction between the HPA axis and immune system determines stroke outcome in neonatally manipulated mice that exhibit life-long dampening of the HPA axis. Taken together, these studies provide support for the detrimental effects of stress and identify potential mechanisms underlying the well-documented clinical observation that social support positively influences human health.