Longitudinal changes in sodium concentration and in clinical outcome in mild traumatic brain injury.

Ionic imbalances and sodium channel dysfunction, well-known sequelae of traumatic brain injury (TBI), promote functional impairment in affected subjects. Therefore, non-invasive measurement of sodium concentrations using 23Na MRI has the potential to detect clinically relevant injury and predict persistent symptoms. Recently, we reported diffusely lower apparent total sodium concentrations (aTSC) in mild TBI patients compared to controls, as well as correlations between lower aTSC and worse clinical outcomes. The main goal of this study was to determine whether these aTSC findings, and their changes over time, predict outcomes at 3- and 12-month from injury. Twenty-seven patients previously studied with 23Na MRI and outcome measures at 22 ± 10 days (average ± standard deviation) after injury (visit-1, v1) were contacted at 3- (visit-2, v2) and 12-month after injury (visit-3, v3) to complete the Rivermead post-concussion symptoms questionnaire (RPQ), the extended Glasgow outcome scale (GOSE), and the brief test of adult cognition by telephone (BTACT). Follow-up 1H and 23Na MRI were additionally scheduled at v2. Linear regression was used to calculate aTSC in global grey and white matters. Six hypotheses were tested in relation to the serial changes in outcome measures and in aTSC, and in relation to the cross-sectional and serial relationships between aTSC and outcome. Twenty patients contributed data at v2 and fifteen at v3. Total RPQ and composite BTACT z-scores differed significantly for v2 and v3 in comparison to v1 (each P < 0.01), reflecting longitudinally reduced symptomatology and improved performance on cognitive testing. No associations between aTSC and outcome were observed at v2. Previously lower grey and white matter aTSC normalized at v2 in comparison to controls, in line with a statistically detectable longitudinal increase in grey matter aTSC between v1 and v2 (P = 0.0004). aTSC values at v1 predicted a subset of future BTACT subtest scores, but not future RPQ scores nor GOSE-defined recovery status. Similarly, aTSC rates of change correlated with BTACT rates of change, but not with those of RPQ. Tissue aTSC, previously shown to be diffusely decreased compared to controls at v1, was no longer reduced by v2, suggesting normalization of the sodium ionic equilibrium. These changes were accompanied by marked improvement in outcome. The results support the notion that early aTSC from 23Na MRI predicts future BTACT, but not RPQ scores, nor future GOSE status.

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.

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.

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.

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.

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.

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.

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.

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.

Invalid symptom reporting and performance: What are we missing?

BACKGROUND: In the evaluation of neurorehabilitation patients involved in compensation or litigation, it is often assumed that poor performance or exaggerated symptoms reflects an intentional attempt to game the system. PURPOSE: The purpose of this article is to review multiple issues that can contribute to invalid symptom reporting and performance. CONCLUSIONS: Multiple factors relevant to normal behavior, including observations from social psychology and behavioral economics, are important in the context of invalid symptom reporting and performance. These factors, which include pre-injury traits and beliefs (e.g., beliefs about prognosis and symptoms after TBI), factors at the time of initial treatment (e.g., expectations of recovery, nocebo effects, stereotype threat), and thoughts and feelings during evaluations (e.g., anger, resentment, injustice), may be important explanations. To best serve our patients, further research is needed to illuminate these relative effects on performance compared to "not trying."

Neuropsychiatry of persistent symptoms after concussion.

A minority of individuals will continue to experience debilitating symptoms for more than several months after sustaining a concussion. These problems may have multiple causes, including persistence of the original concussion symptoms, but they also may be due to factors such as depression and anxiety, physical problems, and psychological issues (including coping with an adverse insurance and legal system). This article reviews the differential diagnosis and treatment strategies for patients with chronic symptoms that persist after a concussion.

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.

Thalamus and cognitive impairment in mild traumatic brain injury: a diffusional kurtosis imaging study.

Conventional imaging is unable to detect damage that accounts for permanent cognitive impairment in patients with mild traumatic brain injury (mTBI). While diffusion tensor imaging (DTI) can help to detect diffuse axonal injury (DAI), it is a limited indicator of tissue complexity. It has also been suggested that the thalamus may play an important role in the development of clinical sequelae in mTBI. The purpose of this study was to determine if diffusional kurtosis imaging (DKI), a novel quantitative magnetic resonance imaging (MRI) technique, can provide early detection of damage in the thalamus and white matter (WM) of mTBI patients, and can help ascertain if thalamic injury is associated with cognitive impairment. Twenty-two mTBI patients and 14 controls underwent MRI and neuropsychological testing. Mean kurtosis (MK), fractional anisotropy (FA), and mean diffusivity (MD) were measured in the thalamus and several WM regions classically identified with DAI. Compared to controls, patients examined within 1 year after injury exhibited variously altered DTI- and DKI-derived measures in the thalamus and the internal capsule, while in addition to these regions, patients examined more than 1 year after injury also showed similar differences in the splenium of the corpus callosum and the centrum semiovale. Cognitive impairment was correlated with MK in the thalamus and the internal capsule. These findings suggest that combined use of DTI and DKI provides a more sensitive tool for identifying brain injury. In addition, MK in the thalamus might be useful for early prediction of permanent brain damage and cognitive outcome.