T1 and T2 quantification using magnetic resonance fingerprinting in mild traumatic brain injury.

OBJECTIVES: To assess whether MR fingerprinting (MRF)-based relaxation properties exhibit cross-sectional and prospective correlations with patient outcome and compare the results with those from DTI. METHODS: Clinical imaging, MRF, and DTI were acquired in patients (24 ± 10 days after injury (timepoint 1) and 90 ± 17 days after injury (timepoint 2)) and once in controls. Patient outcome was assessed with global functioning, symptom profile, and neuropsychological testing. ADC and fractional anisotropy (FA) from DTI and T1 and T2 from MRF were compared in 12 gray and white matter regions with Mann-Whitney tests. Bivariate associations between MR measures and outcome were assessed using the Spearman correlation and logistic regression. RESULTS: Data from 22 patients (38 ± 12 years; 17 women) and 18 controls (32 ± 8 years; 12 women) were analyzed. Fourteen patients (37 ± 12 years; 11 women) returned for timepoint 2, while two patients provided only timepoint 2 clinical outcome data. At timepoint 1, there were no differences between patients and controls in T1, T2, and ADC, while FA was lower in mTBI frontal white matter. T1 at timepoint 1 and the change in T1 exhibited more (n = 18) moderate to strong correlations (|r|= 0.6-0.85) with clinical outcome at timepoint 2 than T2 (n = 3), FA (n = 7), and ADC (n = 2). High T1 at timepoint 1, and serially increasing T1, accounted for five of the six MR measures with the highest utility for identification of non-recovered patients at timepoint 2 (AUC > 0.80). CONCLUSION: T1 derived from MRF was found to have higher utility than T2, FA, and ADC for predicting 3-month outcome after mTBI. KEY POINTS: • In a region-of-interest approach, FA, ADC, and T1 and T2 all showed limited utility in differentiating patients from controls at an average of 24 and 90 days post-mild traumatic brain injury. • T1 at 24 days, and the serial change in T1, revealed more and stronger predictive correlations with clinical outcome at 90 days than did T2, ADC, or FA. • T1 showed better prospective identification of non-recovered patients at 90 days than ADC, T2, and FA.

Kerr-Nonlinearity-Induced Mode-Splitting in Optical Microresonators.

The Kerr effect in optical microresonators plays an important role for integrated photonic devices and enables third harmonic generation, four-wave mixing, and the generation of microresonator-based frequency combs. Here we experimentally demonstrate that the Kerr nonlinearity can split ultra-high-Q microresonator resonances for two continuous-wave lasers. The resonance splitting is induced by self- and cross-phase modulation and counterintuitively enables two lasers at different wavelengths to be simultaneously resonant in the same microresonator mode. We develop a pump-probe spectroscopy scheme that allows us to measure power dependent resonance splittings of up to 35 cavity linewidths (corresponding to 52 MHz) at 10 mW of pump power. The required power to split the resonance by one cavity linewidth is only 286 µW. In addition, we demonstrate threefold resonance splitting when taking into account four-wave mixing and two counterpropagating probe lasers. These Kerr splittings are of interest for applications that require two resonances at optically controlled offsets, e.g., for optomechanical coupling to phonon modes, optical memories, and precisely adjustable spectral filters.

Terahertz wave generation using a soliton microcomb.

The Terahertz or millimeter wave frequency band (300 GHz - 3 THz) is spectrally located between microwaves and infrared light and has attracted significant interest for applications in broadband wireless communications, space-borne radiometers for Earth remote sensing, astrophysics, and imaging. In particular optically generated THz waves are of high interest for low-noise signal generation. Here, we propose and demonstrate stabilized terahertz wave generation using a microresonator-based frequency comb (microcomb). A unitravelling-carrier photodiode (UTC-PD) converts low-noise optical soliton pulses from the microcomb to a terahertz wave at the soliton's repetition rate (331 GHz). With a free-running microcomb, the Allan deviation of the Terahertz signal is 4.5×10-9 at 1 s measurement time with a phase noise of -72 dBc/Hz (-118 dBc/Hz) at 10 kHz (10 MHz) offset frequency. By locking the repetition rate to an in-house hydrogen maser, in-loop fractional frequency stabilities of 9.6×10-15 and 1.9×10-17 are obtained at averaging times of 1 s and 2000 s respectively, indicating that the stability of the generated THz wave is limited by the maser reference signal. Moreover, the terahertz signal is successfully used to perform a proof-of-principle demonstration of terahertz imaging of peanuts. Combining the monolithically integrated UTC-PD with an on-chip microcomb, the demonstrated technique could provide a route towards highly stable continuous terahertz wave generation in chip-scale packages for out-of-the-lab applications. In particular, such systems would be useful as compact tools for high-capacity wireless communication, spectroscopy, imaging, remote sensing, and astrophysical applications.

Interplay of Polarization and Time-Reversal Symmetry Breaking in Synchronously Pumped Ring Resonators.

Optically induced breaking of symmetries plays an important role in nonlinear photonics, with applications ranging from optical switching in integrated photonic circuits to soliton generation in ring lasers. In this work we study for the first time the interplay of two types of spontaneous symmetry breaking that can occur simultaneously in optical ring resonators. Specifically we investigate a ring resonator that is synchronously pumped with short pulses of light. In this system we numerically study the interplay and transition between regimes of temporal symmetry breaking (in which pulses in the resonator either run ahead or behind the seed pulses) and polarization symmetry breaking (in which the resonator spontaneously generates elliptically polarized light out of linearly polarized seed pulses). We find ranges of pump parameters for which each symmetry breaking can be independently observed, but also a regime in which a dynamical interplay takes place. Besides the fundamentally interesting physics of the interplay of different types of symmetry breaking, our work contributes to a better understanding of the nonlinear dynamics of optical ring cavities which are of interest for future applications including all-optical logic gates, synchronously pumped optical frequency comb generation, and resonator-based sensor technologies.

Replicability of proton MR spectroscopic imaging findings in mild traumatic brain injury: Implications for clinical applications.

PURPOSE: Proton magnetic resonance spectroscopy (1H MRS) offers biomarkers of metabolic damage after mild traumatic brain injury (mTBI), but a lack of replicability studies hampers clinical translation. In a conceptual replication study design, the results reported in four previous publications were used as the hypotheses (H1-H7), specifically: abnormalities in patients are diffuse (H1), confined to white matter (WM) (H2), comprise low N-acetyl-aspartate (NAA) levels and normal choline (Cho), creatine (Cr) and myo-inositol (mI) (H3), and correlate with clinical outcome (H4); additionally, a lack of findings in regional subcortical WM (H5) and deep gray matter (GM) structures (H6), except for higher mI in patients' putamen (H7). METHODS: 26 mTBI patients (20 female, age 36.5 ± 12.5 [mean ± standard deviation] years), within two months from injury and 21 age-, sex-, and education-matched healthy controls were scanned at 3 Tesla with 3D echo-planar spectroscopic imaging. To test H1-H3, global analysis using linear regression was used to obtain metabolite levels of GM and WM in each brain lobe. For H4, patients were stratified into non-recovered and recovered subgroups using the Glasgow Outcome Scale Extended. To test H5-H7, regional analysis using spectral averaging estimated metabolite levels in four GM and six WM structures segmented from T1-weighted MRI. The Mann-Whitney U test and weighted least squares analysis of covariance were used to examine mean group differences in metabolite levels between all patients and all controls (H1-H3, H5-H7), and between recovered and non-recovered patients and their respectively matched controls (H4). Replicability was defined as the support or failure to support the null hypotheses in accordance with the content of H1-H7, and was further evaluated using percent differences, coefficients of variation, and effect size (Cohen's d). RESULTS: Patients' occipital lobe WM Cho and Cr levels were 6.0% and 4.6% higher than controls', respectively (Cho, d = 0.37, p = 0.04; Cr, d = 0.63, p = 0.03). The same findings, i.e., higher patients' occipital lobe WM Cho and Cr (both p = 0.01), but with larger percent differences (Cho, 8.6%; Cr, 6.3%) and effect sizes (Cho, d = 0.52; Cr, d = 0.88) were found in the comparison of non-recovered patients to their matched controls. For the lobar WM Cho and Cr comparisons without statistical significance (frontal, parietal, temporal), unidirectional effect sizes were observed (Cho, d = 0.07 - 0.37; Cr, d = 0.27 - 0.63). No differences were found in any metabolite in any lobe in the comparison between recovered patients and their matched controls. In the regional analyses, no differences in metabolite levels were found in any GM or WM region, but all WM regions (posterior, frontal, corona radiata, and the genu, body, and splenium of the corpus callosum) exhibited unidirectional effect sizes for Cho and Cr (Cho, d = 0.03 - 0.34; Cr, d = 0.16 - 0.51). CONCLUSIONS: We replicated findings of diffuse WM injury, which correlated with clinical outcome (supporting H1-H2, H4). These findings, however, were among the glial markers Cho and Cr, not the neuronal marker NAA (not supporting H3). No differences were found in regional GM and WM metabolite levels (supporting H5-H6), nor in putaminal mI (not supporting H7). Unidirectional effect sizes of higher patients' Cho and Cr within all WM analyses suggest widespread injury, and are in line with the conclusion from the previous publications, i.e., that detection of WM injury may be more dependent upon sensitivity of the 1H MRS technique than on the selection of specific regions. The findings lend further support to the corollary that clinic-ready 1H MRS biomarkers for mTBI may best be achieved by using high signal-to-noise-ratio single-voxels placed anywhere within WM. The biochemical signature of the injury, however, may differ and therefore absolute levels, rather than ratios may be preferred. Future replication efforts should further test the generalizability of these findings.

Effort, exaggeration and malingering after concussion.

Although most individuals who suffer a mild traumatic brain injury have complete recovery, a number experience persistent symptoms that appear inconsistent with the severity of the injury. Symptoms may be ascribed to malingering, exaggeration or poor effort on cognitive testing. The purpose of this paper is to propose that previously unconsidered factors, informed by social psychology and behavioural economics, can appear as 'symptom magnification' or 'poor effort', which are incorrectly interpreted as the result of a conscious process. These are complex and multi-determined behaviours with a unique differential diagnosis which have important implications for research, evaluation and treatment.

Global decrease in brain sodium concentration after mild traumatic brain injury.

The pathological cascade of tissue damage in mild traumatic brain injury is set forth by a perturbation in ionic homeostasis. However, whether this class of injury can be detected in vivo and serve as a surrogate marker of clinical outcome is unknown. We employ sodium MRI to test the hypotheses that regional and global total sodium concentrations: (i) are higher in patients than in controls and (ii) correlate with clinical presentation and neuropsychological function. Given the novelty of sodium imaging in traumatic brain injury, effect sizes from (i), and correlation types and strength from (ii), were compared to those obtained using standard diffusion imaging metrics. Twenty-seven patients (20 female, age 35.9 ± 12.2 years) within 2 months after injury and 19 controls were scanned with proton and sodium MRI at 3 Tesla. Total sodium concentration, fractional anisotropy and apparent diffusion coefficient were obtained with voxel averaging across 12 grey and white matter regions. Linear regression was used to obtain global grey and white matter total sodium concentrations. Patient outcome was assessed with global functioning, symptom profiles and neuropsychological function assessments. In the regional analysis, there were no statistically significant differences between patients and controls in apparent diffusion coefficient, while differences in sodium concentration and fractional anisotropy were found only in single regions. However, for each of the 12 regions, sodium concentration effect sizes were uni-directional, due to lower mean sodium concentration in patients compared to controls. Consequently, linear regression analysis found statistically significant lower global grey and white matter sodium concentrations in patients compared to controls. The strongest correlation with outcome was between global grey matter sodium concentration and the composite z-score from the neuropsychological testing. In conclusion, both sodium concentration and diffusion showed poor utility in differentiating patients from controls, and weak correlations with clinical presentation, when using a region-based approach. In contrast, sodium linear regression, capitalizing on partial volume correction and high sensitivity to global changes, revealed high effect sizes and associations with patient outcome. This suggests that well-recognized sodium imbalances in traumatic brain injury are (i) detectable non-invasively; (ii) non-focal; (iii) occur even when the antecedent injury is clinically mild. Finally, in contrast to our principle hypothesis, patients' sodium concentrations were lower than controls, indicating that the biological effect of traumatic brain injury on the sodium homeostasis may differ from that in other neurological disorders. Note: This figure has been annotated.

Spectral extension and synchronization of microcombs in a single microresonator.

Broadband optical frequency combs are extremely versatile tools for precision spectroscopy, ultrafast ranging, as channel generators for telecom networks, and for many other metrology applications. Here, we demonstrate that the optical spectrum of a soliton microcomb generated in a microresonator can be extended by bichromatic pumping: one laser with a wavelength in the anomalous dispersion regime of the microresonator generates a bright soliton microcomb while another laser in the normal dispersion regime both compensates the thermal effect of the microresonator and generates a repetition-rate-synchronized second frequency comb. Numerical simulations agree well with experimental results and reveal that a bright optical pulse from the second pump is passively formed in the normal dispersion regime and trapped by the primary soliton. In addition, we demonstrate that a dispersive wave can be generated and influenced by cross-phase-modulation-mediated repetition-rate synchronization of the two combs. The demonstrated technique provides an alternative way to generate broadband microcombs and enables the selective enhancement of optical power in specific parts of a comb spectrum.

Coherent suppression of backscattering in optical microresonators.

As light propagates along a waveguide, a fraction of the field can be reflected by Rayleigh scatterers. In high-quality-factor whispering-gallery-mode microresonators, this intrinsic backscattering is primarily caused by either surface or bulk material imperfections. For several types of microresonator-based experiments and applications, minimal backscattering in the cavity is of critical importance, and thus, the ability to suppress backscattering is essential. We demonstrate that the introduction of an additional scatterer into the near field of a high-quality-factor microresonator can coherently suppress the amount of backscattering in the microresonator by more than 30 dB. The method relies on controlling the scatterer position such that the intrinsic and scatterer-induced backpropagating fields destructively interfere. This technique is useful in microresonator applications where backscattering is currently limiting the performance of devices, such as ring-laser gyroscopes and dual frequency combs, which both suffer from injection locking. Moreover, these findings are of interest for integrated photonic circuits in which back reflections could negatively impact the stability of laser sources or other components.

Long-term effects of rivastigmine capsules in patients with traumatic brain injury.

OBJECTIVE: To investigate the safety, tolerability and efficacy of rivastigmine capsules (3-12 mg/day) in a 26-week, multi-centre, open-label extension of a double-blind study. METHODS: Patients with traumatic brain injury (TBI) and persistent cognitive impairment who had received rivastigmine (3-6 mg/day) or placebo for 12 weeks could enter the extension study and receive rivastigmine (< or =12 mg/day). Patients were assessed using a range of cognitive tests including the Hopkins Verbal Learning Test (HVLT) and the Cambridge Neuropsychological Test Automated Battery Rapid Visual Information Processing (CANTAB RVIP) A' sub-test. Safety measures included monitoring of adverse events. RESULTS: In the extension study (n = 127), the mean duration of rivastigmine treatment was 23.8 weeks and the mean final dosage was 7.9 mg/day. Approximately 40% of patients were responders (> or =1.0 SD improvement from baseline) on CANTAB RVIP A' or HVLT total score at week 38 or endpoint. Statistically significant changes from week 12 at week 38 were observed for CANTAB-RVIP A' and HVLT-total word recall for the sub-group of ex-placebo patients with greater severity of initial impairment. The safety profile of rivastigmine capsules was consistent with the label. CONCLUSIONS: Treatment with rivastigmine for up to 38 weeks was safe in patients with TBI and cognitive impairment.

Symmetry Breaking of Counter-Propagating Light in a Nonlinear Resonator.

Spontaneous symmetry breaking is a concept of fundamental importance in many areas of physics, underpinning such diverse phenomena as ferromagnetism, superconductivity, superfluidity and the Higgs mechanism. Here we demonstrate nonreciprocity and spontaneous symmetry breaking between counter-propagating light in dielectric microresonators. The symmetry breaking corresponds to a resonance frequency splitting that allows only one of two counter-propagating (but otherwise identical) states of light to circulate in the resonator. Equivalently, this effect can be seen as the collapse of standing waves and transition to travelling waves within the resonator. We present theoretical calculations to show that the symmetry breaking is induced by Kerr-nonlinearity-mediated interaction between the counter-propagating light. Our findings pave the way for a variety of applications including optically controllable circulators and isolators, all-optical switching, nonlinear-enhanced rotation sensing, optical flip-flops for photonic memories as well as exceptionally sensitive power and refractive index sensors.

Diagnosis and management of pathological laughter and crying.

Patients with various neurologic disorders exhibit exaggerated or inappropriate episodes of laughter, crying, or both without an apparent motivating stimulus or in response to stimuli that would not have elicited such an emotional response before the onset of the underlying disease. During these episodes, patients have difficulty controlling their emotional expression according to the contextual information. In contrast, patients with mood disorders have a pervasive and sustained change in their emotional experience and thus exhibit spells of laughter or crying because of an underlying mania or depression. This article focuses on the clinical presentation, diagnosis, prevalence, and proposed pathophysiological mechanisms of and available treatment options for this clinical phenomenon.

Guidelines for the pharmacologic treatment of neurobehavioral sequelae of traumatic brain injury.

There is currently a lack of evidence-based guidelines to guide the pharmacological treatment of neurobehavioral problems that commonly occur after traumatic brain injury (TBI). It was our objective to review the current literature on the pharmacological treatment of neurobehavioral problems after traumatic brain injury in three key areas: aggression, cognitive disorders, and affective disorders/anxiety/ psychosis. Three panels of leading researchers in the field of brain injury were formed to review the current literature on pharmacological treatment for TBI sequelae in the topic areas of affective/anxiety/ psychotic disorders, cognitive disorders, and aggression. A comprehensive Medline literature search was performed by each group to establish the groups of pertinent articles. Additional articles were obtained from bibliography searches of the primary articles. Group members then independently reviewed the articles and established a consensus rating. Despite reviewing a significant number of studies on drug treatment of neurobehavioral sequelae after TBI, the quality of evidence did not support any treatment standards and few guidelines due to a number of recurrent methodological problems. Guidelines were established for the use of methylphenidate in the treatment of deficits in attention and speed of information processing, as well as for the use of beta-blockers for the treatment of aggression following TBI. Options were recommended in the treatment of depression, bipolar disorder/mania, psychosis, aggression, general cognitive functions, and deficits in attention, speed of processing, and memory after TBI. The evidence-based guidelines and options established by this working group may help to guide the pharmacological treatment of the person experiencing neurobehavioral sequelae following TBI. There is a clear need for well-designed randomized controlled trials in the treatment of these common problems after TBI in order to establish definitive treatment standards for this patient population.

Pharmacotherapy of posttraumatic cognitive impairments.

Pharmacotherapy may contribute to the rehabilitation of persons with posttraumatic cognitive impairments. This article reviews first the neurobiological consequences of traumatic brain injury with a particular emphasis on acute and long-term posttraumatic neurochemical disturbances. Studies of pharmacotherapies for posttraumatic cognitive impairments are reviewed next, and are organized according to medication class and the neurotransmitter system they affect most. Based on the evidence provided by that review, augmentation of posttraumatic cerebral catecholaminergic and cholinergic function are suggested as potentially useful neurochemical targets for pharmacologic intervention in this population. More specifically, it is suggested that persons with posttraumatic impairments in arousal, speed of processing, and possibly attention may benefit most from treatment with an agent that augments cerebral catecholaminergic function, and that persons whose predominant posttraumatic impairment is in the domain of memory may benefit most from treatment with cholinesterase inhibitors. Practical considerations regarding the use of pharmacotherapies for posttraumatic cognitive impairments are offered, and the need for additional research in this area is highlighted.

Chronic Post-Concussion Neurocognitive Deficits. II. Relationship with Persistent Symptoms.

Individuals who sustain a concussion may continue to experience problems long after their injury. However, it has been postulated in the literature that the relationship between a concussive injury and persistent complaints attributed to it is mediated largely by the development of symptoms associated with posttraumatic stress disorder (PTSD) and depression. We sought to characterize cognitive deficits of adult patients who had persistent symptoms after a concussion and determine whether the original injury retains associations with these deficits after accounting for the developed symptoms that overlap with PTSD and depression. We compared the results of neurocognitive testing from 33 patients of both genders aged 18-55 at 3 months to 5 years post-injury with those from 140 control subjects. Statistical comparisons revealed that patients generally produced accurate responses on reaction time-based tests, but with reduced efficiency. On visual tracking, patients increased gaze position error variability following an attention demanding task, an effect that may reflect greater fatigability. When neurocognitive performance was examined in the context of demographic- and symptom-related variables, the original injury retained associations with reduced performance at a statistically significant level. For some patients, reduced cognitive efficiency and fatigability may represent key elements of interference when interacting with the environment, leading to varied paths of recovery after a concussion. Poor recovery may be better understood when these deficits are taken into consideration.

The differential diagnosis of pseudobulbar affect (PBA). Distinguishing PBA among disorders of mood and affect. Proceedings of a roundtable meeting.

This monograph summarizes the proceedings of a roundtable meeting convened to discuss pseudobulbar affect (PBA). Two didactic lectures were presented followed by a moderated discussion among 11 participants. Post-meeting manuscript development synthesized didactic- and discussion-based content ad incorporated additional material from the neuroscience literature. A conceptual framework with which to distinguish between disorders of mood and affect is presented first, and disorders of affect regulation are then reviewed briefly. A detailed description of the most common of these disorders, PBA, is the focus of the remainder of the monograph. The prevalence, putative neuranatomic and neurochemical bases of PBA are reviewed, and current and emerging methods of evaluation and treatment of persons with PBA are discussed. The material presented in this monograph will help clinicians better recognize, diagnose, and treat PBA, and will form a foundation for understanding and interpreting future studies of this condition.