Faculty Bibliography

The purpose of this study was to determine whether the effects of cumulative head impacts during a season of high school football produce changes in diffusional kurtosis imaging (DKI) metrics in the absence of clinically diagnosed concussion. Subjects were recruited from a high school football team and were outfitted with the Head Impact Telemetry System (HITS) during all practices and games. Biomechanical head impact exposure metrics were calculated, including: total impacts, summed acceleration, and Risk Weighted Cumulative Exposure (RWE). Twenty-four players completed pre- and post-season magnetic resonance imaging, including DKI; players who experienced clinical concussion were excluded. Fourteen subjects completed pre- and post-season Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT). DKI-derived metrics included mean kurtosis (MK), axial kurtosis (K axial), and radial kurtosis (K radial), and white matter modeling (WMM) parameters included axonal water fraction, tortuosity of the extra-axonal space, extra-axonal diffusivity (D_e axial and radial), and intra-axonal diffusivity (D_a). These metrics were used to determine the total number of abnormal voxels, defined as 2 standard deviations above or below the group mean. Linear regression analysis revealed a statistically significant relationship between RWE combined probability (RWE_CP) and MK. Secondary analysis of other DKI-derived and WMM metrics demonstrated statistically significant linear relationships with RWE_CP after covariate adjustment. These results were compared with the results of DTI-derived metrics from the same imaging sessions in this exact same cohort. Several of the DKI-derived scalars (D_a, MK, K axial, and K radial) explained more variance, compared with RWE_CP, suggesting that DKI may be more sensitive to subconcussive head impacts. No significant relationships between DKI-derived metrics and ImPACT measures were found. It is important to note that the pathological implications of these metrics are not well understood. In summary, we demonstrate a single season of high school football can produce DKI measurable changes in the absence of clinically diagnosed concussion.

Sustained exposure to stress or corticosteroids is known to cause changes in brain endocannabinoid (eCB) signaling, such that tissue contents of the eCBs N-arachidonylethanolamine (AEA) are generally reduced while 2-arachidonoylglycerol (2-AG) levels increase. These changes in eCB signaling are important for many of the aspects of chronic stress, such as anxiety, reward sensitivity and stress adaptation, yet the mechanisms mediating these changes are not fully understood. We have recently found that the stress-related neuropeptide corticotropin-releasing hormone (CRH), acting through the CRH type 1 receptor (CRHR1), can reduce AEA content by increasing its hydrolysis by the enzyme fatty acid amide hydrolase (FAAH) as well as increase 2-AG contents. As extra-hypothalamic CRH is upregulated by chronic corticosteroid or stress exposure, we hypothesized that increased CRH signaling through CRHR1 contributes to the effects of chronic corticosteroid exposure on the eCB system within the amygdala and prefrontal cortex. Male rats were exposed to 7 days of systemic corticosterone capsules, with or without concurrent exposure to a CRHR1 antagonist, after which we examined eCB content. Consistent with previous studies in the amygdala, sustained corticosterone exposure increases CRH mRNA in the prefrontal cortex. As was shown previously, FAAH activity was increased and AEA contents were reduced within the amygdala and prefrontal cortex following chronic corticosterone exposure. Chronic corticosterone exposure also elevated 2-AG content in the prefrontal cortex but not the amygdala. These corticosteroid-driven changes were all blocked by systemic CRHR1 antagonism. Consistent with these data indicating sustained increases in CRH signaling can mediate the effects of chronic elevations in corticosteroids, CRH overexpressing mice also exhibited increased FAAH-mediated AEA hydrolysis in the amygdala and prefrontal cortex compared to wild type. CRH overexpression increased 2-AG content in the amygdala, but not the prefrontal cortex. These data indicate that chronic elevations in CRH signaling, as is seen following exposure to chronic elevations in corticosterone or stress, drive persistent changes in eCB function. As reductions in AEA signaling mediate the effects of CRH and chronic stress on anxiety, these data provide a mechanism linking these processes.

Background: Patients with familial dysautonomia (FD) have asthmalike exacerbations with coughing, wheezing, and hypoxia. While many are treated empirically with bronchodilators, it is still unknown whether airway obstruction in these patients is pharmacologically reversible by modifying autonomic tone.
Method(s): We conducted a two-center, randomized, placebo-controlled, double blind, crossover study to assess the safety and efficacy of albuterol (a direct acting sympathomimetic) vs. ipratropium bromide (a parasympatholytic muscarinic blocker). Albuterol (0.083 %, 2.5 mg/3 ml), ipratroprium bromide (0.02 %, 500 mcg/2.5 ml) and placebo (0.9 % sodium chloride 3 ml) were administered by nebulization in random order over 15 min in the seated position. Airway responses were assessed with spirometry and impulse oscillometry pre- and 30 min post-dose. Continuous blood pressure, RR-intervals and cardiac impedance were measured non-invasively (TaskForce Monitor, CNSystems, Graz, Austria). Raw data tracings were analyzed blindly.
Result(s): Fifteen patients were enrolled. All had a documented history of aspiration into the airway and acute episodes of coughing and wheezing. Beta-adrenergic activation with albuterol significantly increased forced vital capacity (p = 0.041) and forced expiratory volume within 1 s (p = 0.002). In line with this, impulse oscillometry at 5 Hz was significantly lower post-albuterol (p = 0.006), suggesting a reduction in total airway resistance. Blockade of muscarinic acetylcholine receptors with ipratroprium had less bronchodilatory effects. Both treatments were well tolerated and had no effects on blood pressure, heart rate or derived cardiac output.
Conclusion(s): In patients with FD, beta-adrenergic stimulation more effectively reversed airway obstruction than muscarinic blockade. Both treatments were well tolerated and had no measureable systemic effects

Droxidopa, a synthetic norepinephrine precursor, was recently approved to treat symptomatic neurogenic orthostatic hypotension (nOH). The pressor response is variable with some patients responding to doses of 100 mg while others requiring up to 600 mg three times/day. It is not known which factors predict the magnitude of the pressor response to droxidopa. We prospectively evaluated the BP response to increasing doses of droxidopa in patients with nOH in an outpatient setting. BP supine and after 3-min standing was measured before and 1-h after oral administration of 100 mg of droxidopa. Droxidopa was progressively increased until (i) complete relief of symptoms, (ii) supine systolic BP >180 mmHg, (iii) occurrence of side effects, or (iv) the maximum dose of 600 mg was reached. Sixteen subjects with nOH (6 with Parkinson disease, 5 with pure autonomic failure, 3 with autoimmune autonomic ganglionopathy, and 2 with multiple system atrophy) were evaluated. Mean BP was 126 +/- 28/72 +/- 11 mmHg supine, and 89 +/- 19/ 53 +/- 15 mmHg after 3-min standing (fall of 37/18 mmHg). Mean plasma norepinephrine while supine was 192 +/- 216 pg/ml. Maximum droxidopa dose during the titration was 212 +/- 102 mg (range 100-400 mg). Droxidopa increased BP to an average of 148 +/- 53/ 90 +/- 13 mmHg supine and 135 +/- 38/66 +/- 16 mmHg after 3-min standing (p<0.001). Plasma norepinephrine levels were inversely correlated with higher systolic BP after 3-min standing following droxidopa treatment (R2 = 0.42; p = 0.023). Four patients (3 with AAG and 1 with PAF) with very low plasma norepinephrine levels (<90 pg/ml) experienced transient nausea, vomiting, and abdominal pain during titration with dosages of 200 mg. In these patients, treatment with 100 mg/day was effective and well tolerated. Diagnostic categories did not predict response to droxidopa. In patients with nOH, lower plasma norepinephrine levels are associated with a greater pressor response to droxidopa. This response is probably related to the degree of denervation supersensitivity. Supine norepinephrine levels may be useful to predict appropriate dosing of droxidopa in a clinical setting

Background: Infusion of vasoactive agents in the assessment of orthostatic intolerance in the autonomic laboratory is controversial. The technique of lower body negative pressure (LBNP) was described two decades ago. LBNP exaggerates orthostatic stress by closely mimicking a physiologic stimulus, and has the advantage of being quickly reversible. However, it is not routinely used in clinical practice.
Objective(s): To describe our experience using LBNP in the clinical autonomic laboratory in patients with orthostatic intolerance of unclear origin.
Method(s): We used a customized airtight cover, sealed to a tilttable and to the subject at the level of the iliac crest. After 30 min of asymptomatic passive head-up tilt, LBNP was applied while the patient was still upright. Suction was briefly initiated at -20 mmHg for 1-min and then increased to -40 mmHg for the following 10-min. Blood pressure, heart rate and plasma catecholamines when supine, after 10-min of head up tilt, and during syncope or other paroxysmal event, were measured. Time from LBNP onset to episode was recorded.
Result(s): Fifteen subjects (8 men; aged 40 +/- 20 years, range: 12-75 years) were enrolled. During LBNP, 7 subjects developed typical vasovagal syncope (after 3.8 +/- 1.3 min of LBNP) with hypotension and bradycardia and marked increases in plasma levels of epinephrine and vasopressin. Six tolerated the procedure uneventfully. One patient became unresponsive and his head stooped forward but BP and HR remained stable without changes in plasma catecholamines. The remaining patient had flailing bilateral movements with no changes in consciousness, BP or HR, but a significant increase in plasma epinephrine levels. All patients recovered without sequelae.
Conclusion(s): LBNP is a useful technique in the differential diagnosis of patients with orthostatic intolerance of unclear origin and can be easily implemented in the clinical setting. In addition to its wellknown value to induce vasovagal syncope, this technique can also be useful to induce psychogenic episodes

Physicians who specialize in autonomic disorders think in terms of orthostasis, synapses, catecholamines, ganglionopathies, and baroreflexes. Patients, on the other hand, inhabit a world of streaming, downloads, hashtags, tweets, and blogs. In an increasingly digital era, if we are to communicate effectively with patients, we must understand their language, including that of social media. The cultural revolution of social media opens new opportunities for autonomic medicine. First, social media can direct patients to specialists who have the expertise to evaluate and treat their disorders when such expertise is not available locally. Listing contact information on reputable dysautonomia websites is an effective way to facilitate these connections, as is creating practice websites to showcase unique expertise and resources. Secondly, online platforms can empower the patient population through education. In clinical practice, we see how frequently patients turn to the Internet for medical information. However, search engines alone are inadequate because of the sheer volume of available information, much of which is unmonitored. Patients can quickly be led down a path of misinformation about their particular condition. Dr. Google is frequently wrong. Moreover, it takes on average 2.5 clicks to get from a headache to a brain tumor. As experts in the field, we have an obligation to participate online in the translation and dissemination of accurate medical information. It is important to consider the demographics of the target audience and how best to reach them, be it Facebook, Twitter, Instagram or Snap Chat. By doing this we can assist patients in understanding their autonomic disorders and managing their symptoms. Thirdly, social media can be an important tool for research. Social media platforms can be used to recruit research subjects with rare disorders and as a tool to promote the need for research funding from the public. Social media is undoubtedly an effective way to spread news and can be used to disseminate new knowledge arising from research, which allows patients to keep abreast of current breakthroughs. Lastly, social media can be leveraged to raise public awareness about autonomic disorders and their treatment, build community, share experiences, and engage patient groups in partnership

Background: Stress-induced adrenergic hypertensive crises are a cardinal feature of familial dysautonomia (FD). Classically, this is treated with clonidine and benzodiazepines, which cause excessive sedation and can lead to respiratory arrest. Dexmedetomidine is a recently introduced compound, 8 times more specific for central alpha-2 adrenergic receptors than clonidine, resulting in less sedation. Advantages over clonidine are also that dexmedetomidine can be administered intravenously (IV), and its half-life is shorter (12 vs. 2 h), which allows an easy titration.
Method(s): Retrospective chart review of IV dexmedetomidine use to treat refractory hypertensive crisis in patients with FD.
Result(s): IV dexmedetomidine was used 15 times in 9 patients (mean age: 26 years; 44 % men) with acute adrenergic crisis. Crisis triggers included respiratory infection (n = 8), emotional stress (n = 3), surgery (n = 1), bacteremia (n = 1), gastroenteritis (n = 1) and bleeding gastric ulcer (n = 1). Before treatment, all patients had signs of adrenergic activation including skin flushing, nausea/retching, vomiting, diaphoresis, and agitation. Blood pressure (BP) was 1616/1026 mmHg and heart rate (HR) was 1134 bpm. IV dexmedetomidine was administered at an average rate of 0.510.13 mcg/kg/h. One hour post-infusion, BP decreased to 1165/586 mmHg (p<0.0001) and HR to 975 bpm (p = 0.002). Drowsiness occurred in one patient, although he was easily arousable. There were no episodes of rebound hypertension or respiratory depression. In one case, rapid titration at a high dose resulted in paradoxical hypertension, which subsided immediately upon dexmedetomidine discontinuation.
Conclusion(s): IV dexmedetomidine is an effective, well-tolerated approach for managing adrenergic crises in patients with FD. In contrast to other commonly used medications, dexmedetomidine does not induce excessive sedation or respiratory depression. In a small percentage of patients, rapid IV dosing may result in paradoxical hypertension due to its direct action on peripheral postsynaptic alpha2-adrenergic receptors

Background: Pure autonomic failure is a neurodegenerative synucleinopathy largely restricted to the peripheral nervous system. Later in the clinical course of the disease some patients may develop parkinsonism, cerebellar ataxia or cognitive impairment. The purpose of this study is to define the clinical features and biomarkers that predict which patients will retain a pure autonomic failure phenotype, and which will develop clinical deficits indicating spread of the synucleinopathy to the central nervous system.
Method(s): One hundred patients with pure autonomic failure were recruited at 5 medical centers in the US. Participants were followed at 12-months intervals, for 4 years to determine whether they had developed motor/cognitive abnormalities and met the diagnostic criteria of Parkinson disease (PD)/dementia with Lewy bodies (DLB) or multiple system atrophy (MSA). Smell discrimination, occurrence of REM sleep behavior disorder (RBD) and sympathetic and parasympathetic cardiovascular autonomic functions were assessed.
Finding(s): Mean age of onset of autonomic failure was 61 (+/-12) years. Patients had a 10 % per year cumulative risk for developing a CNS synucleinopathy with locomotor dysfunction or dementia. All patients who developed a CNS synucleinopathy had subtle motor impairment and RBD at the time of enrolment. Factors that predicted a future diagnosis of MSA included younger age at onset of autonomic failure, severe bladder/bowel abnormalities, normal olfaction and a >10 bpm cardiac chronotrophic response to tilt. Factors that predicted future diagnosis of PD/DLB were abnormal olfaction, a lesser chronotrophic response to tilt and longer disease duration. Patients that retained a PAF phenotype had very low circulating norepinephrine levels, slow resting heart rate, no RBD or subtle motor deficits and preserved smell discrimination.
Interpretation(s): Pure autonomic failure can be a premotor stage of a central nervous system synucleinopathy or may remain as a restricted peripheral disorder. Patients who developed PD/DLB or MSA have distinct premotor features. Patients who retain a pure autonomic failure phenotype had more severe peripheral sympathetic involvement

Background: Normally, during sleep, when cortical influences are minimized, blood pressure (BP) and heart rate (HR) fall (i.e., nocturnal dipping). In patients with afferent baroreflex failure, in whom BP and HR are highly dependent on cortical influences, this nocturnal dipping is usually preserved. There are, however, a number of patients with afferent baroreflex failure in whom BP does not dip at night. The reasons for this are unknown.
Method(s): We examined the 24-hour ambulatory BP profiles in 50 patients with afferent baroreflex failure of acquired (n = 6) or genetic origin (familial dysautonomia n = 44). BP and HR were captured at 30-minute intervals over a 24-h period. Nighttime sleep periods were identified from the patient's diary. Dipping was defined as a 10 % or greater fall in systolic and diastolic blood pressure at night.
Result(s): Normal BP nocturnal dipping was present in only 50 % of the patients; 33 % of patients had reversal of the circadian rhythm with higher blood pressures at night. In the remaining 17 %, nocturnal BP was similar to daytime BP. Patients with preserved nocturnal dipping had a significantly higher glomerular filtration rate (8430 mL/ min) than those that did not dip at night (6130 mL/min, p = 0.043).
Conclusion(s): Lack of nocturnal BP dipping in patients with afferent baroreflex failure was associated with impaired renal function. These findings suggest that in patients with FD, a non-dipping profile may involve abnormalities in extracellular volume and/or impaired regulation of vascular resistance (i.e., abnormal endothelial function)

Congenital insensitivity to pain with anhidrosis (CIPA, also known as hereditary sensory and autonomic neuropathy type IV) is a rare autosomal recessive disorder caused by mutations in the gene encoding for neurotrophic tyrosine kinase receptor type 1, a receptor for nerve growth factor (NTRK1-NGF). We recently described that patients with CIPA have very low or undetectable circulating norepinephrine levels. Since these mutations severely deplete the development of noradrenergic neurons in the periphery, they presumably also affect those in the central nervous system. Patients with CIPA have low IQ and behavioral problems including hyperactivity and reckless impulsivity, likely the result of a central deficiency in norepinephrine. We explored whether treatment with droxidopa, a synthetic norepinephrine precursor, which crosses the blood brain barrier, could improve behavioral features in a patient with CIPA. Our patient was a 29-year-old woman with a classic phenotype and molecular confirmation of a mutation in the NTRK1 gene (c360- 2A >C pathogenic variant). She had symptoms of attention deficit and hyperactivity and scored highly on the adult ADHD self-report scales (Scores Part A: 4/6 and Part B: 9/12). She had high scores in the attentional (17 and 4), motor (21 and 10), and planning (21 and 17) domains of Barratt impulsiveness scale. NICHQ Vanderbilt assessment scale also indicated attention deficits and hyperactivity. After two months treatment with droxidopa (at 400 mg/day), attention and hyperactivity scales scores decreased to the normal range (Scores Part A: 3/6 and Part B: 4/12). Impulsiveness scores assessed by Barratt impulsiveness scales also improved (attentional scores 15 and 11, motor scores 19 and 9 and planning scores 20 and 9). This case report suggests that behavioral deficits might be reversed in patients with CIPA by norepinephrine replenishment therapy. Clinical studies to evaluate the usefulness of droxidopa to treat behavioral problems in CIPA patients are warranted