Low frequency oscillations reflect neurovascular coupling and disappear after cerebral death.

Spectrum power analysis in the low frequency oscillations (LFO) region of functional near infrared spectroscopy (fNIRS) is a promising method to deliver information about brain activation and therefore might be used for prognostication in patients with disorders of consciousness in the neurocritical care unit alongside with established methods. In this study, we measure the cortical hemodynamic response measured by fNIRS in the LFO region following auditory and somatosensory stimulation in healthy subjects. The significant hemodynamic reaction in the contralateral hemisphere correlation with the physiologic electric response suggests neurovascular coupling. In addition, we investigate power spectrum changes in steady state measurements of cerebral death patients and healthy subjects in the LFO region, the frequency of the heartbeat and respiration. The spectral power within the LFO region was lower in the patients with cerebral death compared to the healthy subjects, whereas there were no differences in spectral power for physiological activities such as heartbeat and respiration rate. This finding indicates the cerebral origin of our low frequency measurements. Therefore, LFO measurements are a potential method to detect brain activation in patients with disorders of consciousness and cerebral death. However, further studies in patients are needed to investigate its potential clinical use.

Increased cranio-caudal spinal cord oscillations are the cardinal pathophysiological change in degenerative cervical myelopathy.

Introduction: Degenerative cervical myelopathy (DCM) is the most common cause of non-traumatic incomplete spinal cord injury, but its pathophysiology is poorly understood. As spinal cord compression observed in standard MRI often fails to explain a patient's status, new diagnostic techniques to assess DCM are one of the research priorities. Minor cardiac-related cranio-caudal oscillations of the cervical spinal cord are observed by phase-contrast MRI (PC-MRI) in healthy controls (HCs), while they become pathologically increased in patients suffering from degenerative cervical myelopathy. Whether transversal oscillations (i.e., anterior-posterior and right-left) also change in DCM patients is not known. Methods: We assessed spinal cord motion simultaneously in all three spatial directions (i.e., cranio-caudal, anterior-posterior, and right-left) using sagittal PC-MRI and compared physiological oscillations in 18 HCs to pathological changes in 72 DCM patients with spinal canal stenosis. The parameter of interest was the amplitude of the velocity signal (i.e., maximum positive to maximum negative peak) during the cardiac cycle. Results: Most patients suffered from mild DCM (mJOA score 16 (14-18) points), and the majority (68.1%) presented with multisegmental stenosis. The spinal canal was considerably constricted in DCM patients in all segments compared to HCs. Under physiological conditions in HCs, the cervical spinal cord oscillates in the cranio-caudal and anterior-posterior directions, while right-left motion was marginal [e.g., segment C5 amplitudes: cranio-caudal: 0.40 (0.27-0.48) cm/s; anterior-posterior: 0.18 (0.16-0.29) cm/s; right-left: 0.10 (0.08-0.13) cm/s]. Compared to HCs, DCM patients presented with considerably increased cranio-caudal oscillations due to the cardinal pathophysiologic change in non-stenotic [e.g., segment C5 amplitudes: 0.79 (0.49-1.32) cm/s] and stenotic segments [.g., segment C5 amplitudes: 0.99 (0.69-1.42) cm/s]). In contrast, right-left [e.g., segment C5 amplitudes: non-stenotic segment: 0.20 (0.13-0.32) cm/s; stenotic segment: 0.11 (0.09-0.18) cm/s] and anterior-posterior oscillations [e.g., segment C5 amplitudes: non-stenotic segment: 0.26 (0.15-0.45) cm/s; stenotic segment: 0.11 (0.09-0.18) cm/s] remained on low magnitudes comparable to HCs. Conclusion: Increased cranio-caudal oscillations of the cervical cord are the cardinal pathophysiologic change and can be quantified using PC-MRI in DCM patients. This study addresses spinal cord oscillations as a relevant biomarker reflecting dynamic mechanical cord stress in DCM patients, potentially contributing to a loss of function.

Stability of the distal radioulnar joint with and without activation of forearm muscles.

The purpose of this study was to quantify the effect of the flexor carpi ulnaris and the extensor carpi ulnaris muscles on distal radioulnar joint stability. The anteroposterior ulnar head translation in relation to the radius was measured sonographically when the forearm was in a neutral resting position and when the hand was actively pressed on to a surface, with and without intentional flexor carpi ulnaris and extensor carpi ulnaris activation, while also being monitored by an electromyogram. Data on 40 healthy participants indicated a mean anteroposterior translation in the distal radioulnar joint of 4.1 mm (SD 1.08) without and 1.2 mm (SD 0.54) with muscle activation. Our results indicate that intentional ulnar forearm muscle activation results in 70% less anteroposterior ulnar head translation and greater distal radioulnar joint stability. Therefore, the flexor carpi ulnaris and extensor carpi ulnaris muscles serve as dynamic stabilizers of the distal radioulnar joint. This finding may be clinically significant since ulnar forearm muscles strengthening may increase distal radioulnar joint stability.

bTUNED: transcutaneous tibial nerve stimulation for neurogenic lower urinary tract dysfunction.

OBJECTIVE: To present the protocol for a randomized controlled trial (RCT) evaluating the efficacy and safety of transcutaneous tibial nerve stimulation (TTNS) for refractory neurogenic lower urinary tract dysfunction (NLUTD). STUDY DESIGN AND RESULTS: bTUNED (bladder and TranscUtaneous tibial Nerve stimulation for nEurogenic lower urinary tract Dysfunction) is an international multicentre, sham-controlled, double-blind RCT investigating the efficacy and safety of TTNS. The primary outcome is success of TTNS, defined as improvements in key bladder diary variables at study end compared to baseline values. The focus of the treatment is defined by the Self-Assessment Goal Achievement (SAGA) questionnaire. Secondary outcomes are the effect of TTNS on urodynamic, neurophysiological, and bowel function outcome measures, as well as the safety of TTNS. CONCLUSIONS: A total of 240 patients with refractory NLUTD will be included and randomized 1:1 into the verum or sham TTNS group from March 2020 until August 2026. TTNS will be performed twice a week for 30 min during 6 weeks. The patients will attend baseline assessments, 12 treatment visits and follow-up assessments at the study end.

Cerebrospinal Fluid Pressure Dynamics as a Bedside Test in Traumatic Spinal Cord Injury to Assess Surgical Spinal Cord Decompression: Safety, Feasibility, and Proof-of-Concept.

BACKGROUND: Sufficient and timely spinal cord decompression is a critical surgical objective for neurological recovery in spinal cord injury (SCI). Residual cord compression may be associated with disturbed cerebrospinal fluid pressure (CSFP) dynamics. OBJECTIVES: This study aims to assess whether intrathecal CSFP dynamics in SCI following surgical decompression are feasible and safe, and to explore the diagnostic utility. METHODS: Prospective cohort study. Bedside lumbar CSFP dynamics and cervical MRI were obtained following surgical decompression in N = 9 with mostly cervical acute-subacute SCI and N = 2 patients with non-traumatic SCI. CSFP measurements included mean CSFP, cardiac-driven CSFP peak-to-valley amplitudes (CSFPp), Valsalva maneuver, and Queckenstedt's test (firm pressure on jugular veins, QT). From QT, proxies for cerebrospinal fluid pulsatility curve were calculated (ie, relative pulse pressure coefficient; RPPC-Q). CSFP metrics were compared to spine-healthy patients. computer tomography (CT)-myelography was done in 3/8 simultaneous to CSFP measurements. RESULTS: Mean age was 45 ± 9 years (range 17-67; 3F), SCI was complete (AIS A, N = 5) or incomplete (AIS B-D, N = 6). No adverse events related to CSFP assessments. CSFP rise during QT was induced in all patients [range 9.6-26.6 mmHg]. However, CSFPp was reduced in 3/11 (0.1-0.3 mmHg), and in 3/11 RPPC-Q was abnormal (0.01-0.05). Valsalva response was reduced in 8/11 (2.6-23.4 mmHg). CSFP dynamics corresponded to CT-myelography. CONCLUSIONS: Comprehensive bedside lumbar CSFP dynamics in SCI following decompression are safe, feasible, and can reveal distinct patterns of residual spinal cord compression. Longitudinal studies are required to define critical thresholds of impaired CSFP dynamics that may impact neurological recovery and requiring surgical revisions.

Functional NIRS to detect covert consciousness in neurocritical patients.

OBJECTIVE: This pilot study assesses the feasibility to detect covert consciousness in clinically unresponsive patients by means of functional near infrared spectroscopy (fNIRS) in a real intensive care unit setting. We aimed to verify if the hemodynamic response to familiar music measured with fNIRS varies according to the level consciousness of the patients. METHODS: 22 neurocritical patients and 6 healthy controls were included. The experiment consisted in 3 subsequent blocks including a first resting state recording, a period of music playback and a second resting state recording. fNIRS measurement were performed on each subject with two optodes on the forehead. Main oscillatory frequencies of oxyhemoglobin signal were analyzed. Spectral changes of low frequency oscillations (LFO) between subsequent experimental blocks were used as a marker of cortical response. Cortical response was compared to the level of consciousness of the patients and their functional outcome, through validated clinical scores. RESULTS: Cortical hemodynamic response to music on the left prefrontal brain was associated with the level of consciousness of the patients and with their clinical outcome after three months. CONCLUSIONS: Variations in LFO spectral power measured with fNIRS may be a new marker of cortical responsiveness to detect covert consciousness in neurocritical patients. Left prefrontal cortex may play an important role in the perception of familiar music. SIGNIFICANCE: We showed the feasibility of a simple fNIRS approach to detect cortical response in the real setting of an intensive care unit.

Comparison of axial and sagittal spinal cord motion measurements in degenerative cervical myelopathy.

BACKGROUND AND PURPOSE: The timing of decision-making for a surgical intervention in patients with mild degenerative cervical myelopathy (DCM) is challenging. Spinal cord motion phase contrast MRI (PC-MRI) measurements can reveal the extent of dynamic mechanical strain on the spinal cord to potentially identify high-risk patients. This study aims to determine the comparability of axial and sagittal PC-MRI measurements of spinal cord motion with the prospect of improving the clinical workup. METHODS: Sixty-four DCM patients underwent a PC-MRI scan assessing spinal cord motion. The agreement of axial and sagittal measurements was determined by means of intraclass correlation coefficients (ICCs) and Bland-Altman analyses. RESULTS: The comparability of axial and sagittal PC-MRI measurements was good to excellent at all cervical levels (ICCs motion amplitude: .810-.940; p < .001). Significant differences between axial and sagittal amplitude values could be found at segments C3 and C4, while its magnitude was low (C3: 0.07 ± 0.19 cm/second; C4: -0.12 ± 0.30 cm/second). Bland-Altman analysis showed a good agreement between axial and sagittal PC-MRI scans (coefficients of repeatability: minimum -0.23 cm/second at C2; maximum -0.58 cm/second at C4). Subgroup analysis regarding anatomic conditions (stenotic vs. nonstenotic segments) and different velocity encoding (2 vs. 3 cm/second) showed comparable results. CONCLUSIONS: This study demonstrates good comparability between axial and sagittal spinal cord motion measurements in DCM patients. To this end, axial and sagittal PC-MRI are both accurate and sensitive in detecting pathologic cord motion. Therefore, such measures could identify high-risk patients and improve clinical decision-making (ie, timing of decompression).

Increase in Low-Frequency Oscillations in fNIRS as Cerebral Response to Auditory Stimulation with Familiar Music.

Recognition of typical patterns of brain response to external stimuli using near-infrared spectroscopy (fNIRS) may become a gateway to detecting covert consciousness in clinically unresponsive patients. This is the first fNIRS study on the cortical hemodynamic response to favorite music using a frequency domain approach. The aim of this study was to identify a possible marker of cognitive response in healthy subjects by investigating variations in the oscillatory signal of fNIRS in the spectral regions of low-frequency (LFO) and very-low-frequency oscillations (VLFO). The experiment consisted of two periods of exposure to preferred music, preceded and followed by a resting phase. Spectral power in the LFO region increased in all the subjects after the first exposure to music and decreased again in the subsequent resting phase. After the second music exposure, the increase in LFO spectral power was less distinct. Changes in LFO spectral power were more after first music exposure and the repetition-related habituation effect strongly suggest a cerebral origin of the fNIRS signal. Recognition of typical patterns of brain response to specific environmental stimulation is a required step for the concrete validation of a fNIRS-based diagnostic tool.

TASCI-transcutaneous tibial nerve stimulation in patients with acute spinal cord injury to prevent neurogenic detrusor overactivity: protocol for a nationwide, randomised, sham-controlled, double-blind clinical trial.

INTRODUCTION: Neurogenic lower urinary tract dysfunction (NLUTD), including neurogenic detrusor overactivity (NDO) and detrusor sphincter dyssynergia, is one of the most frequent and devastating sequelae of spinal cord injury (SCI), as it can lead to urinary incontinence and secondary damage such as renal failure. Transcutaneous tibial nerve stimulation (TTNS) is a promising, non-invasive neuromodulatory intervention that may prevent the emergence of the C-fibre evoked bladder reflexes that are thought to cause NDO. This paper presents the protocol for TTNS in acute SCI (TASCI), which will evaluate the efficacy of TTNS in preventing NDO. Furthermore, TASCI will provide insight into the mechanisms underlying TTNS, and the course of NLUTD development after SCI. METHODS AND ANALYSIS: TASCI is a nationwide, randomised, sham-controlled, double-blind clinical trial, conducted at all four SCI centres in Switzerland. The longitudinal design includes a baseline assessment period 5-39 days after acute SCI and follow-up assessments occurring 3, 6 and 12 months after SCI. A planned 114 participants will be randomised into verum or sham TTNS groups (1:1 ratio), stratified on study centre and lower extremity motor score. TTNS is performed for 30 min/day, 5 days/week, for 6-9 weeks starting within 40 days after SCI. The primary outcome is the occurrence of NDO jeopardising the upper urinary tract at 1 year after SCI, assessed by urodynamic investigation. Secondary outcome measures assess bladder and bowel function and symptoms, sexual function, neurological structure and function, functional independence, quality of life, as well as changes in biomarkers in the urine, blood, stool and bladder tissue. Safety of TTNS is the tertiary outcome. ETHICS AND DISSEMINATION: TASCI is approved by the Swiss Ethics Committee for Northwest/Central Switzerland, the Swiss Ethics Committee Vaud and the Swiss Ethics Committee Zürich (#2019-00074). Findings will be disseminated through peer-reviewed publications. TRIAL REGISTRATION NUMBER: NCT03965299.

The Damaged Spinal Cord Is a Suitable Target for Stem Cell Transplantation.

Background. Given individuals with spinal cord injury (SCI) approaching 2 million, viable options for regenerative repair are desperately needed. Human central nervous system stem cells (HuCNS-SC) are self-renewing, multipotent adult stem cells that engraft, migrate, and differentiate in appropriate regions in multiple animal models of injured brain and spinal cord. Preclinical improved SCI locomotor function provided rationale for the first-in-human SCI clinical trial of HuCNS-SC cells. Evidence of feasibility and long-term safety of cell transplantation into damaged human cord is needed to foster translational progression of cellular therapies. Methods. A first-ever, multisite phase I/IIa trial involving surgical transplantation of 20 million HuCNS-SC cells into the thoracic cord in 12 AIS A or B subjects (traumatic, T2-T11 motor-complete, sensory-incomplete), aged 19 to 53 years, demonstrated safety and preliminary efficacy. Six-year follow-up data were collected (sensory thresholds and neuroimaging augmenting clinical assessments). Findings. The study revealed short- and long-term surgical and medical safety (well-tolerated immunosuppression in population susceptible to infections). Preliminary efficacy measures identified 5/12 with reliable sensory improvements. Unfortunately, without thoracic muscles available for manual muscle examination, thoracic motor changes could not be measured. Lower limb motor scores did not change during the study. Cervical cord imaging revealed, no tumor formation or malformation of the lesion area, and secondary supralesional structural changes similar to SCI control subjects. Interpretation. Short- and long-term safety and feasibility support the consideration of cell transplantation for patients with complete and incomplete SCI. This report is an important step to prepare, foster, and maintain the therapeutic development of cell transplantation for human SCI.

In cervical spondylotic myelopathy spinal cord motion is focally increased at the level of stenosis: a controlled cross-sectional study.

STUDY DESIGN: Level-, age-, and gender-matched controlled cross-sectional cohort study. OBJECTIVES: To investigate alterations of spinal cord (SC) motion within cervical spondylotic myelopathy (CSM) across the cervical spinal segments and its relation to cerebrospinal fluid (CSF)-flow, anatomic conditions, and clinical parameters. SETTING: University Hospital Balgrist, Zurich, Switzerland. METHODS: Overall, 12 patients suffering from CSM at level C5 and 12 controls underwent cardiac-gated 2D phase-contrast-MRI at level C2 and C5 and standard MRI sequences. Parameters of interest: Velocity measurements of SC and CSF (area under the curve = total displacement (normalization for duration of the heart cycle), total displacement ratio (C5/C2; intraindividual normalization for confounders)), spinal canal diameters, clinical motor- and sensory scores, and performance measures. RESULTS: Interrater reliability was excellent for SC motion at both levels and for CSF flow at C2, but not reliable for CSF flow at C5. Within controls, SC motion at C2 positively correlated with SC motion at C5 (p = 0.000); this correlation diminished in patients (p = 0.860). SC total displacement ratio was significantly increased in patients (p = 0.029) and correlated with clinical impairment (p = 0.017). Morphometric measures of the extent of stenosis were not related to SC motion or clinical symptoms. CONCLUSION: The findings revealed physiological interactions of CSF flow and SC motion across the cervical spine in healthy controls while being diminished in CSM patients. Findings of focally increased SC motion at the level of stenosis were related to clinical impairment and might be promising as a diagnostic and prognostic marker in CSM. SPONSORSHIP: CRPP Neurorehab of the University of Zurich, Switzerland.

Voxel-based analysis of grey and white matter degeneration in cervical spondylotic myelopathy.

In this prospective study, we made an unbiased voxel-based analysis to investigate above-stenosis spinal degeneration and its relation to impairment in patients with cervical spondylotic myelopathy (CSM). Twenty patients and 18 controls were assessed with high-resolution MRI protocols above the level of stenosis. Cross-sectional areas of grey matter (GM), white matter (WM), and posterior columns (PC) were measured to determine atrophy. Diffusion indices assessed tract-specific integrity of PC and lateral corticospinal tracts (CST). Regression analysis was used to reveal relationships between MRI measures and clinical impairment. Patients showed mainly sensory impairment. Atrophy was prominent within the cervical WM (13.9%, p = 0.004), GM (7.2%, p = 0.043), and PC (16.1%, p = 0.005). Fractional anisotropy (FA) was reduced in the PC (-11.98%, p = 0.006) and lateral CST (-12.96%, p = 0.014). In addition, radial (+28.47%, p = 0.014), axial (+14.72%, p = 0.005), and mean (+16.50%, p = 0.001) diffusivities were increased in the PC. Light-touch score was associated with atrophy (R(2) = 0.3559, p = 0.020) and FA (z score 3.74, p = 0.003) in the PC, as was functional independence and FA in the lateral CST (z score 3.68, p = 0.020). This study demonstrates voxel-based degeneration far above the stenosis at a level not directly affected by the compression and provides unbiased readouts of tract-specific changes that relate to impairment.

Antimicrobial activities of single aroma compounds.

Commercially available aroma samples were evaluated for their olfactory quality by professional perfumers and tested for their antimicrobial activity. Agar diffusion and agar-dilution were used as test methods and a set of two Gram-positive (Staphylococcus aureus and Enterococcus faecalis) and four Gram-negative bacterial strains (Escherichia coli, Pseudomonas aeruginosa, Proteus vulgaris G, Klebsiella pneumoniae and Salmonella abony) and a yeast, Candida albicans, were the test microorganisms. All the investigated compounds were active against Gram-positive bacteria, especially beta-caryophyllene against Enterococcus faecalis (MIC 6 ppm), but only few substances showed activity towards Gram-negative bacteria, except for cinnamic acid, which was active against all (MIC 60 ppm) and Candida albicans, against which cinnamic acid and caryophyllene oxide showed high activity (MIC < 60 ppm).

Comparison of liquid-liquid partition, HS-SPME and static HS GC/MS analysis for the quantification of (-)-linalool in human whole blood samples.

The aim of this investigation was to develop a fast and convenient method for the determination of (-)-linalool in human whole blood to facilitate pharmacokinetic studies. Analytical protocols were elaborated for three different GC/MS sampling techniques, i.e., static headspace (s-HS), headspace solid phase micro extraction (HS-SPME), and liquid-liquid partition. In principle, all tested methods were feasible, but s-HS had the greatest benefit because of the easy handling of the blood samples and its short analysis time. For s-HS two different incubation temperatures were tested (40 degrees C and 60 degrees C). The limit of detection was slightly lower when samples were incubated at 60 degrees C, but the same quantitative results were achieved using alpha-terpineol as internal standard. An accurate and sensitive method for the quantification of (-)-linalool in blood samples after either inhalation or percutaneous application, as well as pharmacokinetic data are presented.

Structure-activity relationships of sandalwood odorants: total synthesis and fragrance properties of cyclopropano-beta-santalol.

The synthesis and odor properties of cyclopropano-beta-santalol, a new santalol analogue, are described. The exocyclic double bond of the original molecule, beta-santalol, is replaced by a cyclopropane ring. Despite the analogies in the binding properties between the double bond and cyclopropane this change in the bulky hydrophobic part of the molecule leads to the complete loss of the characteristic sandalwood odor: in an olfactory evaluation the (Z)-product appears spicy and sweet, the (E)-isomer woody, but neither of them exhibits the typical sandalwood character.

Dynamic reconstruction of eye closure by muscle transposition or functional muscle transplantation in facial palsy.

For patients with facial palsy, lagophthalmus is often a more serious problem than the inability to smile. Dynamic reconstruction of eye closure by muscle transposition or by free functional muscle transplantation offers a good solution for regaining near-normal eye protection without the need for implants. This is the first quantitative study of three-dimensional preoperative and postoperative lid movements in patients treated for facial paralysis. Between February of 1998 and April of 2002, 44 patients were treated for facial palsy, including reconstruction of eye closure. Temporalis muscle transposition to the eye was used in 34 cases, and a regionally differentiated part of a free gracilis muscle transplant after double cross-face nerve grafting was used in 10 cases. Patients' facial movements were documented by a three-dimensional video analysis system preoperatively and 6, 12, 18, and 24 months postoperatively. For this comparative study, only the data of patients with preoperative and 12-month postoperative measurements were included. In the 27 patients with a final result after temporalis muscle transposition for eye closure, the distance between the upper and lower eyelid points during eye closing (as for sleep) was reduced from 10.33 +/- 2.43 mm (mean +/- SD) preoperatively to 5.84 +/- 4.34 mm postoperatively on the paralyzed side, compared with 0.0 +/- 0.0 mm preoperatively and postoperatively on the contralateral healthy side. In the resting position, preoperative values for the paralyzed side changed from 15.11 +/- 1.92 mm preoperatively to 13.46 +/- 1.94 mm postoperatively, compared with 12.17 +/- 2.02 mm preoperatively and 12.05 +/- 1.95 mm postoperatively on the healthy side. In the nine patients with a final result after surgery using a part of the free gracilis muscle transplant reinnervated by a zygomatic branch of the contralateral healthy side through a cross-face nerve graft, eyelid closure changed from 10.21 +/- 2.72 mm to 1.68 +/- 1.35 mm, compared with 13.70 +/- 1.56 mm to 6.63 +/- 1.51 mm preoperatively. The average closure for the healthy side was from 11.20 +/- 3.11 mm to 0.0 +/- 0.0 mm preoperatively and from 12.70 +/- 1.95 mm to 0.0 +/- 0.0 mm postoperatively. In three cases, the resting tonus of the part of the gracilis muscle transplant around the eye had increased to an extent that muscle weakening became necessary. Temporalis muscle transposition and free functional muscle transplantation for reanimation of the eye and mouth at the same time are reliable methods for reconstructing eye closure, with clinically adequate results. Detailed analysis of the resulting facial movements led to an important improvement of the authors' operative techniques within the last few years. Thus, the number of secondary operative corrections could be significantly reduced. These qualitative and quantitative studies of the reconstructed lid movements by three-dimensional video analysis support the authors' clinical concept of temporalis muscle transposition being the first-choice method in adult patients with facial palsy. In children, free muscle transplantation is preferred for eye closure, so as not to interfere with the growth of the face by transposition of a masticatory muscle. In addition, a higher degree of central plasticity in children might be expected.