Faculty Bibliography

Objective/UNASSIGNED:Scalable nonpharmacologic treatment options are needed for chronic pain conditions. Migraine is an ideal condition to test smartphone-based mind-body interventions (MBIs) because it is a very prevalent, costly, disabling condition. Progressive muscle relaxation (PMR) is a standardized, evidence-based MBI previously adapted for smartphone applications for other conditions. We sought to examine the usability of the RELAXaHEAD application (app), which has a headache diary and PMR capability. Methods/UNASSIGNED:Using the "Think Aloud" approach, we iteratively beta-tested RELAXaHEAD in people with migraine. Individual interviews were conducted, audio-recorded, and transcribed. Using Grounded Theory, we conducted thematic analysis. Participants also were asked Likert scale questions about satisfaction with the app and the PMR. Results/UNASSIGNED:Twelve subjects participated in the study. The mean duration of the interviews (SD, range) was 36 (11, 19-53) minutes. From the interviews, four main themes emerged. People were most interested in app utility/practicality, user interface, app functionality, and the potential utility of the PMR. Participants reported that the daily diary was easy to use (75%), was relevant for tracking headaches (75%), maintained their interest and attention (75%), and was easy to understand (83%). Ninety-two percent of the participants would be happy to use the app again. Participants reported that PMR maintained their interest and attention (75%) and improved their stress and low mood (75%). Conclusions/UNASSIGNED:The RELAXaHEAD app may be acceptable and useful to migraine participants. Future studies will examine the use of the RELAXaHEAD app to deliver PMR to people with migraine in a low-cost, scalable manner.

Spontaneous cervical artery dissection (sCAD) is a major cause of stroke in young adults. Multiple sCAD is a rarer, more poorly understood presentation of sCAD that has been increasingly attributed to cervical trauma such as spinal manipulation or genetic polymorphisms in extracellular matrix components. The authors present the case of a 49-year-old, otherwise healthy woman, who over the course of 2 weeks developed progressive, hemodynamically significant, bilateral internal carotid artery and vertebral artery dissections. Collateral response involved extensive external carotid artery-internal carotid artery anastomoses via the ophthalmic artery, which were instrumental in maintaining perfusion because circle of Willis and leptomeningeal anastomotic responses were hampered by the dissection burden in the corresponding collateral vessels. Endovascular intervention by placement of Pipeline embolization devices and Atlas stents in bilateral internal carotid arteries was successfully performed. No syndromic or systemic etiology was discovered during a thorough workup.

Background/UNASSIGNED:Previous genome-wide association studies (GWAS) have identified 42 loci (P < 5 × 10-8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk. Methods/UNASSIGNED:We conducted a GWAS in European descent CRC cases and control subjects using a discovery-replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5 × 10-8) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided. Results/UNASSIGNED:The discovery GWAS identified 11 variants associated with CRC at P < 5 × 10-8, of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0. Conclusions/UNASSIGNED:This study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screening.

Taurine (TAU) is one of the most abundant amino acids in the brain. It has many important physiological functions. The effects of TAU supplementation on brain function need to be further characterized in humans. The purpose of this study was to investigate whether a single dose of Taurine (TAU) intake would modulate corticospinal excitability and post-exercise facilitation (PEF) of the motor evoked potentials (MEP).

Tuberculosis is the leading infectious cause of death globally and extra-pulmonary disease occurs in 15% of incident cases annually. Tuberculous meningitis (TBM) is arguably the most lethal form of tuberculosis and requires prompt diagnosis and initiation of treatment to prevent death and serious neurological disability. The development of rapid diagnostic tests using polymerase chain reaction (PCR) technology for the detection of Mycobacterium tuberculosis (MTB), including the World Health Organization (WHO) - endorsed Xpert MTB/RIF Ultra assay, has allowed earlier definite diagnosis of TBM than conventional culture methods which usually take two weeks or longer for positive identification of MTB. Detection of MTB in cerebrospinal fluid (CSF) using PCR assays requires special attention to the collection, handling, and processing of CSF. Herein we present best practices guidance to maximize the detection rate of MTB in CSF using Xpert MTB/RIF Ultra.

Electrocorticography (ECoG) is becoming more prevalent due to improvements in fabrication and recording technology as well as its ease of implantation compared to intracortical electrophysiology, larger cortical coverage, and potential advantages for use in long term chronic implantation. Given the flexibility in the design of ECoG grids, which is only increasing, it remains an open question what geometry of the electrodes is optimal for an application. Conductive polymer, PEDOT:PSS, coated microelectrodes have an advantage that they can be made very small without losing low impedance. This makes them suitable for evaluating the required granularity of ECoG recording in humans and experimental animals. We used two-dimensional (2D) micro-ECoG grids to record intra-operatively in humans and during acute implantations in mouse with separation distance between neighboring electrodes (i.e., pitch) of 0.4 mm and 0.2/0.25 mm respectively. To assess the spatial properties of the signals, we used the average correlation between electrodes as a function of the pitch. In agreement with prior studies, we find a strong frequency dependence in the spatial scale of correlation. By applying independent component analysis (ICA), we find that the spatial pattern of correlation is largely due to contributions from multiple spatially extended, time-locked sources present at any given time. Our analysis indicates the presence of spatially structured activity down to the sub-millimeter spatial scale in ECoG despite the effects of volume conduction, justifying the use of dense micro-ECoG grids.

A striking observation among veterans returning from the recent conflicts in Iraq and Afghanistan has been the co-occurrence of blast-related mild traumatic brain injury (mTBI) and post-traumatic stress disorder (PTSD). PTSD and mTBI might coexist due to additive effects of independent psychological and physical traumas experienced in a war zone. Alternatively blast injury might induce PTSD-related traits or damage brain structures that mediate responses to psychological stressors, increasing the likelihood that PTSD will develop following a subsequent psychological stressor. Rats exposed to repetitive low-level blasts consisting of three 74.5 kilopascal exposures delivered once daily for three consecutive days develop a variety of anxiety and PTSD-related behavioral traits that are present for at least 9 months after blast exposure. A single predator scent challenge delivered 8 months after the last blast exposure induces additional anxiety-related changes that are still present 45 days later. Because the blast injuries occur under general anesthesia, it appears that blast exposure in the absence of a psychological stressor can induce chronic PTSD-related traits. The reaction to a predator scent challenge delivered many months after blast exposure suggests that blast exposure in addition sensitizes the brain to react abnormally to subsequent psychological stressors. The development of PTSD-behavioral related traits in the absence of a psychological stressor suggests the existence of blast-induced "PTSD". Findings that PTSD-related behavioral traits can be reversed by BCI-838, a group II metabotropic glutamate receptor antagonist offers insight into pathogenesis and possible treatment options for blast-related brain injury.

BACKGROUND:There are no clear guidelines on how to treat posttraumatic headache (PTH) or post-concussive symptoms (PCS). However, behavioral interventions such as cognitive behavioral therapy, biofeedback, and relaxation are Level-A evidence-based treatments for headache prevention. To understand how to develop and study further mind-body interventions (MBIs) and behavioral therapies for PTH and PCS, we developed the following question using the PICO framework: Are behavioral therapies and MBIs effective for treating PTH and PCS? METHODS:We conducted a systematic search of 3 databases (Medline, PsycINFO, and EMBASE) for behavioral interventions and MBIs with the subject headings and keywords for PTH, concussion, and traumatic brain injury (TBI). Inclusion criteria were (1) randomized controlled trials, (2) the majority of the intervention had to be behavioral or mind-body therapy focused, (3) the majority of the participants (>50%) had to have had a mild TBI (not a moderate or severe TBI), (4) published in a peer-reviewed publication, and (5) meeting pre-specified primary and/or secondary outcomes. Primary outcome(s): whether there was a significant change in concussion symptom severity (yes/no) based on the symptom severity checklist/scale used, whether there was a 50% reduction in headache days and/or disability; secondary outcome(s): sleep variables, cognitive complaints, depression, and anxiety. The search identified 917 individual studies. Two independent reviewers screened citations and full-text articles independently. Nineteen articles were pulled for full article review. Seven articles met the final inclusion criteria. The systematic review was registered in Prospero (CRD42017070072). RESULTS:Overall, there was vast heterogeneity across the studies, making it difficult to fully assess efficacy. The heterogeneity ranged from differences in patient populations, the timing of when the interventions were initiated, the types of intervention implemented, and the measures used to assess outcomes. Seven studies were identified as meeting final inclusion criteria, resulting in a total of 1108 adult participants ranging from 18 to 80. Sixty-nine percent were male. Of the 7 studies, 3 were focused on military staff (retired and active). Time post-injury for inclusion into the studies varied from 48 hours post-injury to more than 2 years post-injury. One of the 7 studies did not include time post-TBI in the inclusion criteria. Two studies recruited patients who had visited their emergency departments, 4 of the studies recruited subjects through outpatient referrals, and 1 study recruited patients who had been in a prior traffic accident with resulting chronic PTH directly from a headache center. Group cognitive behavioral therapy (CBT) sessions and telephonic counseling or communication were common intervention methods used in the studies, with group CBT being used in 2 of the studies and telephonic counseling being used in 3. Other intervention methods used included individual CBT, cognitive training, psychoeducation, and computer-based and/or therapist-directed cognitive rehabilitation. CONCLUSIONS:Many of the interventions offered vastly different methods of delivery of intervention and doses of intervention. Many of the negative studies were done after an extended duration post-injury (>1-year posttraumatic brain injury [TBI]). In addition, the participants were lumped together regardless of their pre-concussion comorbidities, their mechanism of injury, their symptoms, and the duration from injury to the start of the intervention. The mass heterogeneity found between the studies led to inconclusive findings. Thus, there are various considerations for the design of the intervention for future behavioral/MBI studies for PTH and concussion that must be addressed before the leading question of this review may be effectively answered.

OBJECTIVE:Behavior is encoded across multiple spatiotemporal scales of brain activity. Modern technology can simultaneously record various scales, from spiking of individual neurons to large neural populations measured with field activity. This capability necessitates developing multiscale modeling and decoding algorithms for spike-field activity, which is challenging because of the fundamental differences in statistical characteristics and time-scales of these signals. Spikes are binary-valued with a millisecond time-scale while fields are continuous-valued with slower time-scales. APPROACH/METHODS:We develop a multiscale encoding model, adaptive learning algorithm, and decoder that explicitly incorporate the different statistical profiles and time-scales of spikes and fields. The multiscale model consists of combined point process and Gaussian process likelihood functions. The multiscale filter (MSF) for decoding runs at the millisecond time-scale of spikes while adding information from fields at their slower time-scales. The adaptive algorithm learns all spike-field multiscale model parameters simultaneously, in real time, and at their different time-scales. MAIN RESULTS/RESULTS:We validated the multiscale framework within motor tasks using both closed-loop brain-machine interface (BMI) simulations and non-human primate (NHP) spike and local field potential (LFP) motor cortical activity during a naturalistic 3D reach task. Our closed-loop simulations show that the MSF can add information across scales and that the adaptive MSF can accurately learn all parameters in real time. We also decoded the seven joint angular trajectories of the NHP arm using spike-LFP activity. These data showed that the MSF outperformed single-scale decoding, this improvement was due to the addition of information across scales rather than the dominance of one scale and was largest in the low-information regime, and the improvement was similar regardless of the degree of overlap between spike and LFP channels. SIGNIFICANCE/CONCLUSIONS:This multiscale framework provides a tool to study encoding across scales and may help enhance future neurotechnologies such as motor BMIs.